Volume 116, Issue 1; July 3, 2007,PP. 1-124
Issue Highlights
Issue Highlights
Circulation 2007 116: 1, doi:10.1161/CIRCULATIONAHA.107.183534
Editors' Note
Gary J. Balady and Ravin Davidoff
Circulation 2007 116: 2, doi:10.1161/CIRCULATIONAHA.107.184813
Editorials
Cardiovascular Biomarkers: Added Value With an Integrated Approach?
Wolfgang Koenig
Circulation 2007 116: 3 - 5, doi:10.1161/CIRCULATIONAHA.107.707984
The ST-Segment–Elevation Myocardial Infarction Chain of Survival
Joseph P. Ornato
Circulation 2007 116: 6 - 9, doi:10.1161/CIRCULATIONAHA.107.710970
Original Articles
Arrhythmia/Electrophysiology
Common NOS1AP Variants Are Associated With a Prolonged QTc Interval in the
Rotterdam Study
Albert-Jan L.H.J. Aarnoudse, Christopher Newton-Cheh, Paul I.W. de Bakker,
Sabine M.J.M. Straus, Jan A. Kors, Albert Hofman, André G. Uitterlinden,
Jacqueline C.M. Witteman, and Bruno H.C. Stricker
Circulation 2007 116: 10 - 16; published online before print June 18 2007,
doi:10.1161/CIRCULATIONAHA.106.676783
Nonsense Mutations in hERG Cause a Decrease in Mutant mRNA Transcripts by
Nonsense-Mediated mRNA Decay in Human Long-QT Syndrome
Qiuming Gong, Li Zhang, G. Michael Vincent, Benjamin D. Horne, and
Zhengfeng Zhou
Circulation 2007 116: 17 - 24; published online before print June 18 2007,
doi:10.1161/CIRCULATIONAHA.107.708818
Coronary Heart Disease
Coronary Artery Calcification Progression Is Heritable
Andrea E. Cassidy-Bushrow, Lawrence F. Bielak, Patrick F. Sheedy, II, Stephen
T. Turner, Iftikhar J. Kullo, Xihong Lin, and Patricia A. Peyser
Circulation 2007 116: 25 - 31; published online before print June 11 2007,
doi:10.1161/CIRCULATIONAHA.106.658583
Epidemiology
Association of Carotid Artery Intima-Media Thickness, Plaques, and C-Reactive
Protein With Future Cardiovascular Disease and All-Cause Mortality: The
Cardiovascular Health Study
Jie J. Cao, Alice M. Arnold, Teri A. Manolio, Joseph F. Polak, Bruce M. Psaty,
Calvin H. Hirsch, Lewis H. Kuller, and Mary Cushman
Circulation 2007 116: 32 - 38; published online before print June 18 2007,
doi:10.1161/CIRCULATIONAHA.106.645606
Abdominal Visceral and Subcutaneous Adipose Tissue Compartments: Association
With Metabolic Risk Factors in the Framingham Heart Study
Caroline S. Fox, Joseph M. Massaro, Udo Hoffmann, Karla M. Pou, Pal
Maurovich-Horvat, Chun-Yu Liu, Ramachandran S. Vasan, Joanne M. Murabito,
James B. Meigs, L. Adrienne Cupples, Ralph B. D’Agostino, Sr, and Christopher
J. O’Donnell
Circulation 2007 116: 39 - 48; published online before print June 18 2007,
doi:10.1161/CIRCULATIONAHA.106.675355
Heart Failure
Metoprolol Reverses Left Ventricular Remodeling in Patients With Asymptomatic
Systolic Dysfunction: The REversal of VEntricular Remodeling with Toprol-XL
(REVERT) Trial
Wilson S. Colucci, Theodore J. Kolias, Kirkwood F. Adams, William F.
Armstrong, Jalal K. Ghali, Stephen S. Gottlieb, Barry Greenberg, Michael I.
Klibaner, Marrick L. Kukin, Jennifer E. Sugg on behalf of the REVERT Study
Group
Circulation 2007 116: 49 - 56; published online before print June 18 2007,
doi:10.1161/CIRCULATIONAHA.106.666016
Negative Inotropy of the Gastric Proton Pump Inhibitor Pantoprazole in
Myocardium From Humans and Rabbits: Evaluation of Mechanisms
Wolfgang Schillinger, Nils Teucher, Samuel Sossalla, Sarah Kettlewell, Carola
Werner, Dirk Raddatz, Andreas Elgner, Gero Tenderich, Burkert Pieske, Giuliano
Ramadori, Friedrich A. Schöndube, Harald Kögler, Jens Kockskämper, Lars S.
Maier, Harald Schwörer, Godfrey L. Smith, and Gerd Hasenfuss
Circulation 2007 116: 57 - 66; published online before print June 18 2007,
doi:10.1161/CIRCULATIONAHA.106.666008
Interventional Cardiology
Emergency Department Physician Activation of the Catheterization Laboratory and
Immediate Transfer to an Immediately Available Catheterization Laboratory
Reduce Door-to-Balloon Time in ST-Elevation Myocardial Infarction
Umesh N. Khot, Michele L. Johnson, Curtis Ramsey, Monica B. Khot, Randall
Todd, Saeed R. Shaikh, and William J. Berg
Circulation 2007 116: 67 - 76; published online before print June 11 2007,
doi:10.1161/CIRCULATIONAHA.106.677401
Contemporary Reviews in Cardiovascular Medicine
The Brain–Heart Connection
Martin A. Samuels
Circulation 2007 116: 77 - 84, doi:10.1161/CIRCULATIONAHA.106.678995
Cardiovascular Involvement in General Medical
Conditions
Chronic Kidney Disease: Effects on the Cardiovascular System
Ernesto L. Schiffrin, Mark L. Lipman, and Johannes F.E. Mann
Circulation 2007 116: 85 - 97, doi:10.1161/CIRCULATIONAHA.106.678342
ACCF/AHA/SCAI Clinical Competence Statement
ACCF/AHA/SCAI 2007 Update of the Clinical Competence Statement on Cardiac
Interventional Procedures: A Report of the American College of Cardiology
Foundation/American Heart Association/American College of Physicians Task
Force on Clinical Competence and Training (Writing Committee to Update the 1998
Clinical Competence Statement on Recommendations for the Assessment and
Maintenance of Proficiency in Coronary Interventional Procedures)
Circulation 2007 116: 98 - 124; published online before print June 25 2007,
doi:10.1161/CIRCULATIONAHA.107.185159
Images in Cardiovascular Medicine
An Unusual Site for a Common Disease
Maysaa Alzetani, Joseph J. Boyle, David Lefroy, and Petros Nihoyannopoulos
Circulation 2007 116: e1, doi:10.1161/CIRCULATIONAHA.106.677120
Sine-Wave Pattern Arrhythmia and Sudden Paralysis That Result From Severe
Hyperkalemia
Maurice J.H.M. Pluijmen and Ferry M.R.J. Hersbach
Circulation 2007 116: e2 - e4, doi:10.1161/CIRCULATIONAHA.106.687202
Lipomatous Metaplasia in Ischemic Cardiomyopathy: A Common but
Unappreciated Entity
Matthias Schmitt, Nilesh Samani, and Gerry McCann
Circulation 2007 116: e5 - e6, doi:10.1161/CIRCULATIONAHA.107.690800
Correspondence
Letter by Brewster and van Montfrans Regarding Article, "Risks Associated With
Statin Therapy: A Systematic Overview of Randomized Clinical Trials"
Lizzy M. Brewster and Gert A. van Montfrans
Circulation 2007 116: e7, doi:10.1161/CIRCULATIONAHA.107.689497
Letter by Rosenberg and Uretsky Regarding Article, "Risks Associated With Statin
Therapy: A Systematic Overview of Randomized Clinical Trials"
Lauren Rosenberg and Seth Uretsky
Circulation 2007 116: e8, doi:10.1161/CIRCULATIONAHA.107.690867
Response to Letters Regarding Article, "Risks Associated With Statin Therapy: A
Systematic Overview of Randomized Clinical Trials"
Amir Kashani, JoAnne M. Foody, Yongfei Wang, Harlan M. Krumholz,
Christopher O. Phillips, Sandeep Mangalmurti, and Dennis T. Ko
Circulation 2007 116: e9, doi:10.1161/CIRCULATIONAHA.107.697227
Acknowledgment of Reviewers
Acknowledgment of Reviewers
Circulation 2007 116: e10 - e21, doi:10.1161/CIRCULATIONAHA.107.184814
News From the American Heart Association
News From the American Heart Association
Circulation 2007 116: 1B - 2B, doi:10.1161/CIRCULATIONAHA.107.184673
Meetings Calendar
Meetings Calendar
Circulation 2007 116: 3B - 4B, doi:10.1161/CIRCULATIONAHA.107.184672
American Heart Association Newly Elected Fellows,
Spring 2007
American Heart Association Newly Elected Fellows, Spring 2007
Circulation 2007 116: 5B - 6B, doi:10.1161/CIRCULATIONAHA.107.184674
European Perspectives
European Perspectives
Circulation 2007 116: 1F - 6F, doi:10.1161/CIRCULATIONAHA.107.185417
Issue Highlights
Vol 116, No 1, July 3, 2007
ASSOCIATION OF CAROTID ARTERY INTIMA-MEDIA
THICKNESS, PLAQUES, AND C-REACTIVE PROTEIN
WITH FUTURE CARDIOVASCULAR DISEASE AND
ALL-CAUSE MORTALITY: THE CARDIOVASCULAR
HEALTH STUDY, by Cao et al.
There is increasing interest in methods to risk-stratify individuals’ risk for
cardiovascular disease. Cao et al examined the ability of C-reactive protein
concentrations with or without carotid intima-media thickness and carotid
plaques to predict incident cardiovascular events and death in about 5000
elderly participants in the Cardiovascular Health Study. The investigators
report that C-reactive protein was not prognostically useful without
evidence of carotid atherosclerosis. However, they observed an interaction
between C-reactive protein and carotid disease; increasing C-reactive
protein concentrations were associated with a 72% and 52% increased risk
of cardiovascular death and all-cause mortality, respectively, in the setting
of carotid atheroslerosis. Similar to other studies, as assessed by the c
statistic, both C-reactive protein and carotid atherosclerosis added only
modest incremental information to standard cardiovascular disease risk
factors. The study underscores the need for further statistical and clinical
tools to enhance clinical risk prediction. See p 32 (editorial p 3).
METOPROLOL REVERSES LEFT VENTRICULAR
REMODELING IN PATIENTS WITH ASYMPTOMATIC
SYSTOLIC DYSFUNCTION: THE REVERSAL OF
VENTRICULAR REMODELING WITH TOPROL-XL
(REVERT) TRIAL, by Colucci et al.
Until now, there has been no randomized, controlled trial data to
support the benefit of ␤-blockers in patients with asymptomatic left
ventricular systolic dysfunction. Colucci and colleagues investigate
this question with the REversal of VEntricular Remodeling with
Toprol-XL (REVERT) trial by randomly assigning patients, with a
left ventricular ejection fraction ⬍40%, mild left ventricular dilation, and no symptoms of heart failure (New York Heart Association class I), to 3 treatment groups: extended-release metoprolol
succinate 200 mg or 50 mg and placebo. Echocardiographic
assessment of left ventricular end-systolic volume, end-diastolic
volume, mass, and ejection fraction were performed at baseline.
After 12 months, in the 200-mg group, there was a decrease in
end-systolic volume index and an increase in left ventricular
ejection fraction. In the 50-mg group, similar effects of a lesser
magnitude were observed. These results demonstrate that the
antiremodeling benefits of ␤-blocker therapy with metoprolol
succinate extend to patients with asymptomatic left ventricular
dysfunction. See p 49.
EMERGENCY DEPARTMENT PHYSICIAN ACTIVATION
OF THE CATHETERIZATION LABORATORY AND
IMMEDIATE TRANSFER TO AN IMMEDIATELY
AVAILABLE CATHETERIZATION LABORATORY
REDUCE DOOR-TO-BALLOON TIME IN ST-ELEVATION
MYOCARDIAL INFARCTION, by Khot et al.
Guidelines recommend that hospitals strive to achieve a door-to-balloon
time within 90 minutes based upon considerable observational data.
Currently, most hospitals are not achieving this goal. National efforts are
now under way to improve the door-to-balloon times, but the impact of
these efforts has not been prospectively evaluated. In this prospective
observational study, the impact of a protocol mandating that the
emergency department physician activate the cardiac catheterization
laboratory and transfer the patient immediately to the laboratory was
evaluated and compared with the door-to-balloon times achieved prior
to the institution of the protocol. This study by Khot et al showed that
door-to-balloon times decreased significantly from 113.5 minutes to
75.5 minutes after adoption of the protocol. Treatment within 90
minutes rose from 28% to 71%. As a result, mean infarct size
decreased, as did hospital length of stay and total hospital costs per
admission. The findings suggest that emergency department physician
activation of the catheterization laboratory with immediate transfer to
the laboratory is highly effective in reducing door-to-balloon times and
also appears to improve outcomes and reduce cost. See p 67 (editorial
p 6).
Visit http://circ.ahajournals.org:
Images in Cardiovascular Medicine
An Unusual Site for a Common Disease. See p e1.
Sine-Wave Pattern Arrhythmia and Sudden Paralysis That
Result From Severe Hyperkalemia. See p e2.
Lipomatous Metaplasia in Ischemic Cardiomyopathy: A Common but Unappreciated Entity. See p e5.
Correspondence
See p e7.
Editors’ Note
Medical students often learn about the cardiovascular system as an isolated entity; in many cases
a focused approach to anatomy, physiology, and pathophysiology is presented without consideration of other biological systems. While this may be a reasonable way to learn the fundamentals
of cardiovascular science, it becomes quite clear to these students during their clinical training that
the cardiovascular system functions in a remarkably complex milieu in concert with other organ
systems. The development of perturbations in one system often leads to responses in other systems
in an attempt to maintain functional homeostasis. Accordingly, the cardiovascular system is
subject to the complex interplay among organ systems and a multitude of other factors, including
those from the environment and the individual’s lifestyle. When problems with other organ
systems develop, the initial clinical manifestations may be cardiovascular in nature (eg,
abnormalities in heart rate, rhythm, and blood pressure). Understanding that today’s busy
practitioner is regularly faced with patients who have many complex medical problems, the
Editors of Circulation have commissioned this special series that focuses on the cardiovascular
consequences of other medical disorders.
Articles in this series, Cardiovascular Involvement in General Medical Conditions, will be
published monthly over the next 7 months. Each article, which is written by highly respected
experts in the field, will provide a comprehensive and insightful overview of the pathophysiology,
clinical manifestations, and treatment options for a specific condition. Topics will cover thyroid
diseases, rheumatological disorders, sepsis, pulmonary diseases, cancer and chemotherapy, and
alcohol use and abuse. We anticipate that this series will provide a valuable resource for the
clinician, who can readily bring this information to the bedside. We also hope that the gaps in the
knowledge base that are highlighted in each article of this series will inspire the researcher to
move the field forward.
Gary J. Balady, MD
Ravin Davidoff, MD
Series Editors, Cardiovascular Involvement in General Medical Conditions,
Circulation
(Circulation. 2007;116:2.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.184813
2
Editorial
Cardiovascular Biomarkers
Added Value With an Integrated Approach?
Wolfgang Koenig, MD, FRCP, FESC
I
ment procedure is well standardized and automated, and highsensitive assays with sufficient precision are available. On the
basis of substantial evidence of a contribution of inflammation to
atherothrombogenesis, a recent American Heart Association/
Centers for Disease Control and Prevention consensus report has
recommended the measurement of CRP in asymptomatic subjects at intermediate risk for future coronary events (10-year risk,
10% to 20%).9 However, there are other emerging biomarkers
like lipoprotein-associated phospholipase A2 (Lp-PLA2), an
enzyme that is produced by monocytes/macrophages, T-cells,
and mast cells and has been found to generate proinflammatory
and proatherogenic molecules.10 Because Lp-PLA2, in contrast
to CRP, does not correlate with most other risk factors, there is
an additive effect of CRP and Lp-PLA2 in risk prediction.11,12
This may also apply to combinations of other biomarkers,
though evidence so far is limited. In the future, we might see a
biomarker profile that covers various aspects of the complex
pathophysiology of the atherothrombotic process, and potentially, we would be able to focus on biological patterns or
systems rather than on single biomarkers. To date, however,
there is no sound evidence to suggest such a procedure for
clinical practice, and there is even an ongoing discussion of
whether any of the emerging blood biomarkers alone contributes
incremental information over and above the information gained
from available “global risk” scores.13,14
n primary prevention, traditional risk factors are a useful
first step in the determination of who could be at risk for
cardiovascular events. In the era of “global risk assessment”
scores such as the Framingham score, the Prospective Cardiovascular Münster (PROCAM) score, or the European Society of
Cardiology Systematic Coronary Risk Evaluation (SCORE),
which are derived from multivariable statistical models, should
be used.1 However, it has been noted that a considerable number
of at-risk patients cannot be identified on the basis of traditional
risk factors alone.2 This has prompted the search for novel
markers of cardiovascular risk to help improve risk prediction.3
Such markers could either represent various blood biomarkers
relevant to the pathophysiology of atherothrombosis (eg, markers of the inflammatory response, coagulation markers, markers
of platelet aggregation, lipoproteins, or lipid-related variables),
genetic markers, or markers of subclinical disease, which may
also aid in improved risk prediction. Determination of global risk
on the basis of traditional risk factors allows categorization into
high (10-year risk, ⬎20%), low (10-year risk, ⬍10%), or
intermediate risk (10-year risk, 10% to 20%). Subjects at high
risk should be recommended lifestyle changes or prescribed a
statin. Subjects at low risk would be reevaluated 3 to 5 years
later. Those at intermediate risk, however, who comprise up to
40% of the population at risk,4 would be candidates for additional testing to increase or decrease their actual risk. A large
panel of blood biomarkers are available for this purpose, but
most of them are not yet applicable in clinical practice for
various reasons5,6
Markers of Subclinical Atherosclerotic Disease
There is mounting evidence that markers of subclinical
disease (eg, intima-media thickness as assessed by highresolution carotid ultrasound;15 coronary calcium determined
with multislice computed tomography;16 or ankle-brachial
index, a strong marker of atherosclerotic burden17) may also
contribute to improved risk prediction. However, the clinical
utility of multislice computed tomography needs to be further
tested, and measurement of carotid intima-media thickness
may be burdened by considerable interobserver variability
when it is used in routine clinical practice. Thus, similar to
blood biomarkers, the potential incremental value of such
surrogate markers of clinical atherosclerotic complications is
not unequivocally evident. Still, from a theoretical viewpoint
the combination of blood biomarkers and markers of subclinical disease seems an attractive approach because this may
integrate information on structural or functional vascular wall
pathology and systemic “activity” of the disease (Figure).
However, for markers of subclinical disease as well as for
blood biomarkers, controversy exists with regard to which
parameter represents the most useful one and for which time
period of the atherosclerotic process, and which combination of
markers may be most appropriate for decision making. Finally,
analytical and cost considerations deserve further study.
Article p 32
Emerging Blood Biomarkers
Atherosclerosis is characterized by a nonspecific local inflammatory process7 that is accompanied by a systemic response.
Thus a number of prospective studies in initially healthy subjects
have convincingly demonstrated an independent association
between even slightly elevated concentrations of various systemic markers of inflammation and important cardiovascular
end points. At this time, the largest database exists for C-reactive
protein (CRP), the classic acute-phase protein.8 The measureThe opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Department of Internal Medicine II, Cardiology, University
of Ulm Medical Center, Ulm, Germany.
Correspondence to Wolfgang Koenig, MD, Department of Internal
Medicine II, Cardiology, University of Ulm Medical Center, Robert-Koch
Str 8, D-89081 Ulm, Germany. E-mail wolfgang.koenig@uniklinik-ulm.de
(Circulation. 2007;116:3-5.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.707984
3
4
Circulation
July 3, 2007
Screening for subjects at risk for cardiovascular complications: blood biomarkers/risk factors and/or markers of subclinical disease. Apo indicates apolipoprotein; BP, blood pressure; CT, computed tomography; HDL, high-density lipoprotein; IMT, intima-media thickness; LDL, lowdensity lipoprotein; Lp(a), lipoprotein a; Lp-PLA2, lipoprotein-associated phospholipase A2; MRI, magnetic resonance imaging; and Syn,
syndrome. Reprinted from Naghavi M et al. Am J Cardiol. 2006;98(suppl):2H–15H, with permission from Elsevier. Copyright 2006.
Statistical Methodology: Limitations
in Assessment of Incremental
Diagnostic Information
A great deal of such uncertainty is based on the limited
availability of adequate statistical tools to demonstrate the
incremental value of an emerging biomarker in addition to
global risk scoring. We have realized that evidence of just some
moderately strong association in epidemiological studies is
insufficient to assess the true clinical utility of a new candidate
marker. Most frequently, c statistics and area under the receiveroperating characteristic curve have been used. Risk estimates
that would be needed here to show a clinically important
increase in the area under the curve are usually not seen in
cardiovascular medicine.18 Thus, disappointingly, only a few
studies have shown a statistically significant improvement in the
area under the curve, which, however, in most cases was too
small to be considered clinically relevant. The aggregate experience from a number of such studies demonstrates that once
there is a single strong predictor of risk in the model, which may
be even age alone, it is extremely difficult to show a relevant
contribution of any additional variable to model prediction. This
has recently been discussed in detail by Cook,18 and alternative
statistical approaches have been suggested, such as clinical risk
reclassification.19 This procedure attempts to improve risk prediction by development and validation of algorithms that more
precisely allocate an individual to a risk category by use of a
model that has incorporated a new risk variable in addition to
conventional risk factors, compared with a basic model that
contains conventional risk factors alone. Such approach focuses
particularly on those subjects at intermediate risk to either
reclassify an individual into the low- or high-risk category.
Integration of Biochemical and Bioimaging
Markers: The Solution?
In the presence of such complex background, Cao and
colleagues20 present important data from the Cardiovascular
Health Study in this issue of Circulation. The investigators
simultaneously measured carotid intima-media thickness,
plaque characteristics, and CRP, and related all 3 variables to
the 12-year incidence of cardiovascular disease (CVD) events
and all-cause mortality in 5888 elderly subjects. Main results
showed that all parameters were correlated with one another,
Koenig
yet each parameter independently predicted risk of CVD
events and mortality in multivariable models, which included
all 3 measures and traditional risk factors. Being in the top
tertile of the carotid intima-media thickness distribution was
more predictive for various events than having CRP ⬎3 mg/L
or than being in the high-risk group on the basis of carotid
plaque characteristics. Elevated CRP was a particularly useful
predictor in the presence of subclinical atherosclerosis with a
72% increase in risk for CVD and 52% increase in total
mortality. Cumulative event rates suggested a possible additive interaction for composite CVD and all-cause mortality
with an excess risk attributable to the interaction of CRP and
subclinical atherosclerosis of 54% for CVD death and 79%
for all-cause mortality. By contrast, CRP did not add predictive power in the absence of carotid atherosclerosis. Finally,
both CRP and subclinical atherosclerosis added only modest
incremental information to risk prediction when adjusted for
the effect of conventional risk factors with either c statistics
or area under the curve derived from receiver-operating
characteristic analysis.
Conclusions
First, global risk assessment, with traditional risk factors, still
represents the rational basis for cardiovascular risk stratification.
Second, although theoretically attractive, currently available
biomarkers, even the combination of a robust systemic marker of
“disease activity” with a marker that provides information on
structural changes of the arterial vasculature, which must be seen
as a surrogate/precursor of clinical disease, does not appreciably
improve risk prediction. However, the Cardiovascular Health
Study cohort was an elderly population and results may not be
generalizable to younger individuals with low risk, in whom
CRP may work in the absence of significant atherosclerotic
burden. Also, the statistical tools used, as mentioned earlier, may
be debatable. Third, in the future, despite such somewhat
disappointing information regarding single markers, the clinical
application of multimarker panels, for which the possibilities of
model improvement are greater, may still prove to be a promising approach, provided that such variables show low correlations with conventional risk factors and with each other but
provide strong associations with clinical events. Such emerging
markers will have to be rigorously evaluated in large cohorts for
their clinical efficacy and effectiveness with innovative statistical analytical tools. The world of proteomics and metabolomics,
together with advanced imaging modalities such as functional
molecular imaging, may offer such promising candidates.
Disclosures
None.
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17. Heald CL, Fowkes FG, Murray GD, Price JF; Ankle Brachial Index Collaboration. Risk of mortality and cardiovascular disease associated with the
ankle-brachial index: systematic review. Atherosclerosis. 2006;189:61– 69.
18. Cook NR. Use and misuse of the receiver-operating characteristic curve
in risk prediction. Circulation. 2007;115:928 –935.
19. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of
improved algorithms for the assessment of global cardiovascular risk in
women: the Reynolds Risk Score. JAMA. 2007;297:611– 619.
20. Cao JJ, Arnold AM, Manolio TA, Polak JF, Psaty BM, Hirsch CH, Kuller
LH, Cushman M. Association of carotid artery intima-media thickness,
plaques, and C-reactive protein with future cardiovascular disease and
all-cause mortality: the Cardiovascular Heath Study. Circulation. 2007;
116:32–38.
KEY WORDS: Editorials 䡲 atherosclerosis
inflammation 䡲 risk factors
䡲
epidemiology
䡲
imaging
䡲
Editorial
The ST-Segment–Elevation Myocardial Infarction Chain
of Survival
Joseph P. Ornato, MD
T
he benefit of expertly performed, timely, primary
percutaneous coronary intervention (PCI) over fibrinolysis is clear for patients with ST-segment– elevation myocardial infarction (STEMI). Primary PCI is superior
to fibrinolysis for reduction of overall short-term mortality,
nonfatal reinfarction, stroke, and the combined end point of
death, nonfatal reinfarction, and stroke.1 These results remain
valid during long-term follow-up and are independent of both
the type of fibrinolytic used and whether the patient is
transferred for primary PCI.
the ACC’s Guidelines Applied in Practice Door-to-Balloon
(GAP-D2B) campaign goal of a door-to-balloon time interval
of ⱕ90 minutes in 75% of PCI-treated STEMI patients at
participating hospitals nationwide.6
On the ACC President’s Page, Nissen et al6 described the
new GAP-D2B campaign and stated:
In successful hospitals, the arrival of a STEMI
patient initiates a chain of well-orchestrated events,
including activation of the catheterization laboratory
directly by an emergency department physician with a
single phone call to the interventional cardiologist on
call. The catheterization laboratory team is expected to
arrive within 20 to 30 minutes. Programs with the best
outcomes employ a multidisciplinary team-based approach that includes committed administrators, physician champions, and nurse champions, along with
mechanisms for rapid data feedback. This collaboration can extend to the local and regional emergency
medical systems (EMS). In some successful hospitals,
the catheterization laboratory is activated based on a
prehospital electrocardiography.
Article p 67
Although the relationship between time delay from hospital emergency department arrival to fibrinolytic treatment and
increasing mortality has been firmly established,2 a similar
relationship for primary PCI treatment has been proven only
recently. De Luca et al3 assessed the relationship between
ischemic time and 1-year mortality in 1791 primary PCItreated STEMI patients. After adjustment for age, gender,
diabetes, and previous revascularization, these investigators
showed that every 30 minutes of primary PCI treatment delay
is associated with a 7.5% (95% CI, 1.008 to 1.15; P⫽0.041)
relative increase in 1-year mortality. With use of hierarchical
models adjusted for patient characteristics to evaluate the
effect of door-to-balloon time on in-hospital mortality on
29 222 PCI-treated STEMI patients treated in ⱕ6 hours of
presentation at 395 hospitals that participated in the National
Registry of Myocardial Infarction–3 and – 4 from 1999 to
2002, McNamara et al4 found that a longer door-to-balloon
time interval is associated with increased in-hospital mortality. Adjusted for patient characteristics, patients with a
door-to-balloon time interval ⬎90 minutes were more likely
to die (odds ratio, 1.42; 95% CI, 1.24 to 1.62) compared with
patients who had a door-to-balloon time interval ⱕ90 minutes. These findings provide evidence-based support for the
goal of a door-to-balloon time interval “within 90 minutes”
cited in the 2004 American College of Cardiology/American
Heart Association (ACC/AHA) guidelines for the management of patients with STEMI5 and serve as a foundation for
In this issue of Circulation, Khot et al7 report on their
experience before and after implementation of STEMI GAPD2B–like strategies in a 591-bed, tertiary care, Indianapolisarea, community hospital that consists of 2 separate campuses
7 miles apart (a 13-minute drive). Although they began their
program long before the recently announced ACC initiative,
Khot et al7 instituted most of the GAP-D2B recommendations
on the basis of characteristics of best-performing National
Registry of Myocardial Infarction hospitals.8 –10 Critical elements of their new system included empowerment of emergency physicians to activate the catheterization laboratory
and team without cardiology consultation as well as implementation of an in-house transfer team. Their new strategy
reduced the median door-to-balloon time interval significantly during normal and off-duty work hours, even for
patients who had to be transferred physically from 1 facility
to another, which thus increased the percentage of patients
treated within the ⱕ90-minute door-to-balloon goal from
28% to 71%. And, as predicted by the relationship between
time to treatment and outcome, there were significant improvements in mean infarct size, hospital length of stay, and
total hospital cost per admission.
The ACC’s GAP-D2B initiative stands on even more solid
ground as a result of the Indiana Heart Physicians/St. Francis
Heart Center experience reported by Khot et al.7 The common
element shared by both is choreographed multidisciplinary
teamwork with effective communication among different
disciplines of healthcare providers, rather than the traditional
linear progression of care most patients experience as they
pass through a series of hospital units that operate as
individual silos. Both initiatives are focused on the portion of
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Department of Emergency Medicine, Virginia Commonwealth University, Richmond.
Correspondence to Joseph P. Ornato, MD, Virginia Commonwealth
University, Department of Emergency Medicine, 1201 East Marshall St,
AD Williams 2nd Floor, Richmond, VA 23298᎑0401. E-mail
ornato@aol.com
(Circulation. 2007;116:6-9.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.710970
6
Ornato
STEMI patient treatment delay that is potentially most
changeable by hospital-based healthcare providers—that
which occurs after a patient presents to the hospital. This is
clearly the right place to start, but it represents only part of a
broader community-based opportunity to improve STEMI
patient care.
In 1991, the AHA adopted a metaphor—the “Chain of
Survival”—to describe the sequence of events that must
occur for the best likelihood of successful resuscitation from
hospital cardiopulmonary arrest.11 This educational construct,
which consists of early access, early cardiopulmonary resuscitation, early defibrillation, and early advanced cardiac life
support, now serves as the structural foundation for improvements in the community approach to sudden cardiac death
worldwide. It may now be appropriate for the AHA to
consider adoption of a similar metaphor—the “STEMI Chain
of Survival” (Figure)—that can be used to target global
improvements in STEMI patient care. This approach is very
similar to that which has been followed for ⬎25 years by the
American College of Surgeons Committee on Trauma, as it
has led our nation to develop one of the finest and most
effective trauma care systems in the world. The new STEMI
chain begins with an emphasis on the role of the patient in the
recognition of early or prodromal heart attack symptoms and
immediate request for help, preferably by calling 911 and
accessing the EMS system12,13; the chain works its way
through the critical elements of prehospital, emergency department, and reperfusion care.
There is presently no uniform national STEMI triage and
treatment system equivalent to the system that directs major
trauma victims to verified trauma centers in the United States.
Because the majority of US hospitals do not have primary
PCI capability, many communities struggle to decide whether
they should direct EMS-transported, prehospital, 12-lead
ECG–identified STEMI patients to only primary PCI facilities to bypass nonprimary PCI hospitals. Unfortunately, the
majority of STEMI patients do not use the 911 ambulance
system for transport to the hospital, the national paramedic
training curriculum considers 12-lead ECG training as an
enhanced rather than core skill, and not all EMS ambulances
currently have 12-lead ECG capability.14 Many US hospitals
continue to use fibrinolysis as their primary reperfusion
strategy with transfer to an interventional facility for rescue
when needed. Other hospitals transfer patients more regularly
for primary PCI, but even the most recently published
National Registry of Myocardial Infarction data on 4278
patients transferred to 419 hospitals for primary PCI show a
median initial hospital door-to-balloon time of 180 minutes,
with only 4.2% of patients treated with reperfusion in ⬍90
minutes, the benchmark recommended by national quality
STEMI Chain of Survival
7
guidelines.15 Khot et al7 have shown us that this challenging
time interval also can be decreased dramatically by an
organized transfer and PCI treatment team that can be
activated by emergency physicians.
Our national challenge to provide optimal STEMI care
needs to be solved at 2 levels: the community and the
hospital. We must continue to educate the public on the signs
and symptoms of a myocardial infarction and reinforce the
National Heart Attack Alert Program and AHA message to
“Call 911, Call Fast.”16 The community needs to be organized
into a system of care that directs STEMI patients quickly and
efficiently to primary PCI centers whenever possible, and all
hospitals, whether primary PCI-capable or not, need to have
a system in place to avoid unnecessary delays, just like that
which has been implemented by Khot et al.7
The AHA’s Acute Myocardial Infarction Advisory Working Group recently released recommendations on how to
increase the number of STEMI patients who have timely
access to primary PCI.17 The group commissioned PricewaterhouseCoopers to conduct national market research, and the
Working Group interviewed a wide variety of key stakeholders (such as patients, physicians, nurses, EMS representatives, community hospitals, primary PCI facilities, payers,
and evaluation/outcomes organizations such as the Agency
for Healthcare Research and Quality, the Food and Drug
Administration, and the Joint Commission on Accreditation
of Healthcare Organizations) to determine the desirability,
feasibility, and potential effectiveness of establishment of
regional systems and/or centers of care for STEMI patients
with a focus on whether and how this might improve patient
access to quality care and outcomes. The researchers found
that key stakeholders would support a national primary PCI
certification program with the understanding that some nonprimary PCI hospitals would experience a modest decline in
revenue. On the basis of these findings, the AHA hosted a
national stakeholder meeting in 2006 to continue development of a more detailed plan for a national system of STEMI
patient care. As has been suggested, this is an idea whose time
may have come.18
Many communities are currently developing organized
STEMI care plans. Three sites—a major city, a large region
of a state, and an entire state—already have model community STEMI systems in place based on the trauma care system
model. In 2003, Boston, Mass., implemented a comprehensive system of care in which STEMI patients identified by
paramedics with the use of prehospital 12-lead ECGs were
transported only to designated PCI centers.19 Participating
PCI centers agreed to collect and submit performance measures data to a Central Data Coordinating Center on all EMSand non-EMS–transported STEMI patients. System oversight
Figure 1. The STEMI chain of survival.
8
Circulation
July 3, 2007
was provided by a Steering Committee with representatives
from 9 area hospitals and the Boston EMS, which developed
their performance indicators and minimum standards on the
basis of nationally accepted guidelines. A central Data
Coordinating Center at Tufts–New England Medical Center
received and tabulated data from EMS and area hospitals to
provide aggregated data reports with receiving hospitals
designated only A, B, C, D, etc, rather than by name. The
reports were reviewed by an independent Data and Safety
Monitoring Board composed of highly respected cardiologists and a statistician. After discussion between the hospital
and Data and Safety Monitoring Board and review by the
Steering Committee, any hospital that did not meet preestablished quality treatment, door-to-balloon, and outcome goals
for 2 successive 6-month periods could be excluded from
receiving EMS-transported STEMI patients for the next
6-month period.
From March 2003 to May 2005, 448 STEMI patients were
transferred from 31 community hospitals by paramedicstaffed ambulance (n⫽149) or paramedic/critical care nurse–
staffed helicopter (n⫽299) to the Minneapolis Heart Institute
in Minneapolis, Minn., for primary PCI. A standardized
protocol with accompanying checklists was developed on the
basis of national guidelines. Community hospitals were
required to transfer all patients with STEMI or new left
bundle– branch block within 12 hours of symptom onset to
the regional interventional center. A level 1 myocardial
infarction protocol was developed and used to specify the
sequence of events, diagnostic tests, and treatments. Patients
are preregistered by admitting personnel prior to arrival by
use of a demographic form faxed from the referring hospital.
On arrival at the primary PCI center, patients are admitted
directly to the cardiac catheterization laboratory and thus
bypass the emergency department except in rare circumstances, such as when 2 STEMI patients arrive simultaneously. Prompt verbal and written feedback (which includes
1-month and 1-year follow-up phone calls) is provided to the
referring hospital physician and nursing staff, and the time
intervals, clinical and angiographic data, and clinical outcomes are entered into a database. Time and outcome
summary reports meeting Joint Commission on Accreditation
of Healthcare Organizations requirements are sent to each
community hospital on a quarterly basis.
Patient treatment times and outcomes have been superb
with this regional STEMI care system. No STEMI patients
were excluded from transfer, even those with cardiogenic
shock (13.7%), cardiac arrest (9.9%), and the elderly (17%,
⬎80 years of age). No patient died during transport. The
median total door-to-balloon time was reduced from ⬎3
hours before implementation of the regional system to 97
minutes for 11 participating hospitals located ⱕ70 miles
(zone 1) after implementation.18,20 The median total door-toballoon time was 117 minutes with use of a facilitated PCI
protocol in 17 participating hospitals located ⱕ210 miles
(zone 2) from the interventional center. The improvements in
time to treatment were accompanied by low 30-day mortality
rates of 4.3% in zone 1 and 3.4% in zone 2.
The common denominator of these 2 models is that they
are based on a community system of care rather than centered
only on 1 hospital. A third model is the Reperfusion of Acute
Myocardial Infarction in Carolina Emergency Departments
(RACE) project, which is a collaborative effort to increase the
rate and speed of coronary reperfusion through systematic
changes in emergency care. The project is based on the
collaborative efforts of EMS personnel, physicians, nurses,
administrators, and payers from 5 regions and 68 hospitals
throughout North Carolina. The recommendations of this
project are based on established national guidelines, published data, and the knowledge and experience of numerous
individuals who specialize in STEMI patient care. Detailed
information about the program, such as transfer criteria,
protocols, training materials, and educational posters, are
available on the North Carolina ACC Chapter Web site
(http://www.nccacc.org/race.html).
In summary, cardiologists (and interventionalists), emergency physicians, nurses, and EMS providers must work
together to establish effective regional community systems of
STEMI patient care similar to the well-developed and highly
successful systems that direct major trauma victims to verified trauma centers in the United States. All hospitals,
whether primary PCI– capable or not, should develop a
STEMI protocol that includes procedures to expedite time to
reperfusion treatment modeled after concepts inherent in the
GAP-D2B program and the Indiana Heart Physicians/St.
Francis Heart Center experience. A multidisciplinary committee should oversee the process and provide performance
improvement suggestions based on continuous data collection
and analysis.
Disclosures
Dr Ornato has served on the science advisory board for the National
Registry of Myocardial Infarction, which is funded by Genentech.
References
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Gore JM, Weaver WD, Rogers WJ, Tiefenbrunn AJ. Relationship of
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3. De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to
treatment and mortality in primary angioplasty for acute myocardial
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4. McNamara RL, Wang Y, Herrin J, Curtis JP, Bradley EH, Magid DJ,
Peterson ED, Blaney M, Frederick PD, Krumholz HM. Effect of doorto-balloon time on mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2006;47:2180 –2186.
5. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M,
Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ,
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Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka
LF, Hunt SA, Jacobs AK. ACC/AHA guidelines for the management of
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Management of Patients with Acute Myocardial Infarction). Circulation.
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6. Nissen SE, Brush JE Jr, Krumholz HM. President’s page: GAP-D2B: an
alliance for quality. J Am Coll Cardiol. 2006;48:1911–1912.
7. Khot UN, Johnson ML, Ramsey C, Khot MB, Todd R, Shaikh SR, Berg
WJ. Emergency department physician activation of the catheterization
laboratory and immediate transfer to an immediately available catheter-
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Bradley EH, Curry LA, Webster TR, Mattera JA, Roumanis SA, Radford
MJ, McNamara RL, Barton BA, Berg DN, Krumholz HM. Achieving
rapid door-to-balloon times: how top hospitals improve complex clinical
systems. Circulation. 2006;113:1079 –1085.
Bradley EH, Herrin J, Wang Y, McNamara RL, Radford MJ, Magid DJ,
Canto JG, Blaney M, Krumholz HM. Door-to-drug and door-to-balloon
times: where can we improve? Time to reperfusion therapy in patients
with ST-segment elevation myocardial infarction (STEMI). Am Heart J.
2006;151:1281–1287.
Bradley EH, Roumanis SA, Radford MJ, Webster TR, McNamara RL,
Mattera JA, Barton BA, Berg DN, Portnay EL, Moscovitz H, Parkosewich J, Holmboe ES, Blaney M, Krumholz HM. Achieving door-toballoon times that meet quality guidelines: how do successful hospitals do
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Cummins RO, Ornato JP, Thies WH, Pepe PE. Improving survival from
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Bahr RD. Access to early cardiac care: chest pain as a risk factor for heart
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Garvey JL, MacLeod BA, Sopko G, Hand MM. Pre-hospital 12-lead
electrocardiography programs: a call for implementation by emergency
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STEMI Chain of Survival
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Moyer P, Ornato J, Peterson ED, Sadwin L, Smith SC. Recommendation
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18. Henry TD, Atkins JM, Cunningham MS, Francis GS, Groh WJ, Hong
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Brown D, Cardoza J, Grossman S, Jacobs A, Kerman B, Kimmelstiel C,
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2005;112:II᎑620.
KEY WORDS: Editorials
䡲
infarction
䡲
myocardium
Common NOS1AP Variants Are Associated With a
Prolonged QTc Interval in the Rotterdam Study
Albert-Jan L.H.J. Aarnoudse, MD*; Christopher Newton-Cheh, MD, MPH*; Paul I.W. de Bakker, PhD;
Sabine M.J.M. Straus, MD, PhD; Jan A. Kors, PhD; Albert Hofman, MD, PhD;
André G. Uitterlinden, PhD; Jacqueline C.M. Witteman, PhD; Bruno H.C. Stricker, PhD
Background—QT prolongation is an important risk factor for sudden cardiac death. About 35% of QT-interval variation
is heritable. In a recent genome-wide association study, a common variant (rs10494366) in the nitric oxide synthase 1
adaptor protein (NOS1AP) gene was found to be associated with QT-interval variation. We tested for association of 2
NOS1AP variants with QT duration and sudden cardiac death.
Methods and Results—The Rotterdam Study is a population-based, prospective cohort study of individuals ⱖ55 years of
age. The NOS1AP variants rs10494366 T⬎G and rs10918594 C⬎G were genotyped in 6571 individuals. Heart
rate– corrected QT interval (QTc) was determined with ECG analysis software on up to 3 digital ECGs per individual
(total, 11 108 ECGs from 5374 individuals). The association with QTc duration was estimated with repeated-measures
analyses, and the association with sudden cardiac death was estimated by Cox proportional-hazards analyses. The
rs10494366 G allele (36% frequency) was associated with a 3.8-ms (95% confidence interval, 3.0 to 4.6; P⫽7.8⫻10⫺20)
increase in QTc interval duration for each additional allele copy, and the rs10918594 G allele (31% frequency) was
associated with a 3.6-ms (95% confidence interval, 2.7 to 4.4; P⫽6.9⫻10⫺17) increase per additional allele copy. None
of the inferred NOS1AP haplotypes showed a stronger effect than the individual single-nucleotide polymorphisms. There
were 233 sudden cardiac deaths over 11.9 median years of follow-up. No significant association was observed with
sudden cardiac death risk.
Conclusions—Common variants in NOS1AP are strongly associated with QT-interval duration in an elderly population.
Larger sample sizes are needed to confirm or exclude an effect on sudden cardiac death risk. (Circulation. 2007;116:
10-16.)
Key Words: arrhythmia 䡲 death, sudden 䡲 electrocardiography 䡲 genetics 䡲 long-QT syndrome
S
udden cardiac death (SCD) claims 300 000 lives annually
in the United States.1 Although certain high-risk groups
have been identified,2 most SCD occurs in individuals unrecognized to be at risk.3
Clinical Perspective p 16
Familial aggregation of SCD suggests a substantial contribution of genetic variation to SCD risk,4 –7 but mendelian
mutations identified to date individually explain little of the
population burden of SCD.8,9 Until recently, the search for
sequence variants contributing to SCD risk has been restricted to candidate genes known for their role in arrhythmogenesis.10 The recent development of large single-nucleotide polymorphism (SNP) databases,11 genotyping arrays of
great accuracy and genome-wide coverage of common variation,12 together with analytical methods,13 has enabled unbiased surveys of most of the common variation in the human
genome. Still, the relatively small size of existing SCD
collections and etiologic heterogeneity limit the statistical
power to detect causal variants; therefore, initial attention has
focused on quantitative SCD risk factors in large cohorts.
The electrocardiographic QT interval is a noninvasive
measure of ventricular repolarization. About 35% of the
variation in QT-interval duration in unselected communitybased samples is heritable.14,15 Mendelian congenital longand short-QT syndromes are both characterized by SCD from
ventricular arrhythmias. Moreover, nonsyndromal long QT
interval16 –19 and short QT interval20 impart increased risk of
Received November 16, 2006; accepted May 1, 2007.
From the Departments of Epidemiology and Biostatistics (A.L.H.J.A., S.M.J.M.S, A.H., A.G.U., J.C.M.W., B.H.C.S.), Internal Medicine (A.G.U.,
B.H.C.S.), and Medical Informatics (J.A.K.), Erasmus Medical Center, Rotterdam, the Netherlands; Cardiology Division (C.N.-C.), Department of
Molecular Biology (P.I.W.d.B.), and Center for Human Genetics Research (P.I.W.d.B.), Massachusetts General Hospital, Boston; Program in Medical
and Population Genetics (C.N.-C., P.I.W.d.B.), Broad Institute of Harvard and MIT, Cambridge, Mass; National Heart, Lung, and Blood Institute’s
Framingham Heart Study (C.N.-C.), Framingham, Mass; Department of Genetics, Harvard Medical School (P.I.W.d.B.), Boston, Mass; Inspectorate for
Health Care (A.L.H.J.A., B.H.C.S.), the Hague, the Netherlands; and Dutch Medicines Evaluation Board (S.M.J.M.S), the Hague, the Netherlands.
*The first 2 authors contributed equally to this work.
Correspondence to Bruno H.C. Stricker, PhD, Department of Epidemiology and Biostatistics, Erasmus Medical Center, PO Box 2040, 3000 CA,
Rotterdam, The Netherlands. E-mail b.stricker@erasmusmc.nl
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.676783
Aarnoudse et al
160,200kb
160,300kb
NOS1AP Variants Are Associated With QTc Duration
160,400kb
OLFML2B
rs10918594
160,500kb
160,600kb
11
Chr. 1q23
NOS1AP
rs10494366
NOS1AP and location of rs10494366 and rs10918594. The ruler indicates the physical position on chromosome 1. Thick horizontal
lines indicate genes in the region; thick vertical lines, NOS1AP exons; and arrows, the direction of transcription. Thick vertical lines on
the ruler indicate the positions of rs10918594 and rs10494366, which are ⬇55 kb apart. The 2 SNPs were in linkage disequilibrium,
with an r2 of 0.63 and D⬘ of 0.89.
SCD in unselected populations. In addition, medicationinduced prolonged QT interval and ventricular arrhythmias
have led to the withdrawal of many noncardiac medications,21
making the QT interval an important phenotype to study.
Previously, we identified a locus on chromosome 3 with
suggestive evidence of linkage to QT-interval duration, but
the genomic interval was large, and the finding has yet to be
confirmed.15 More recently, Arking et al22 reported the
finding from a genome-wide association study that a common
variant (rs10494366; minor allele frequency, 38%) in the
NOS1AP gene was reproducibly associated with QT-interval
variation in several large population samples. The NOS1AP
gene, encoding the nitric oxide synthase 1 adaptor protein,
has been found to regulate neuronal nitric oxide synthase
activation23 and to enhance Dexras1 activation by neuronal
nitric oxide synthase through a ternary complex.24 Neuronal
nitric oxide synthase– knockout mice have been found to have
altered cardiac contractility, which suggests a role for
NOS1AP in cardiac depolarization.25–27 Furthermore,
NOS1AP is capable of interaction with ion channels through
its PDZ domain.28 –30 Nevertheless, the involvement of
NOS1AP in myocardial repolarization was not known until
the initial report of the association.
The impact of NOS1AP variants on QT-interval duration in
older populations, in whom nongenetic factors might play a
stronger role than heritable factors, is unknown.
The goal of the present study was to test for association of
the NOS1AP variant with QT duration and to test for its
association with SCD in the Rotterdam Study.
Methods
Study Population
The Rotterdam Study is a prospective population-based cohort study
of chronic diseases in the elderly. All inhabitants of Ommoord, a
Rotterdam suburb, ⱖ55 years of age (n⫽10 278), were ascertained
from the municipal register and invited to participate. Of them, 78%
(n⫽7983; 58% female, 98% white) took part in the baseline
examination from March 1990 through July 1993. Second and third
examinations were conducted from September 1993 to August 1996
and from April 1997 to December 1999, respectively. Objectives and
methods of the Rotterdam Study have been described in detail.31 The
medical ethics committee of Erasmus Medical Center (Rotterdam,
the Netherlands) approved the study, and all participants provided
signed informed consent for participation, including retrieval of
medical records, use of blood and DNA for scientific purposes, and
publication of data. DNA for genotyping is available for 6571
participants (82%) from the baseline visit.
Clinical characteristics, including smoking, body mass index,
hypertension, diabetes mellitus, heart failure, and myocardial infarction, were ascertained as previously described.19,32–36 Active surveillance for incident diabetes mellitus, heart failure, and myocardial
infarction is conducted continuously between exams. In addition,
exposure of study participants to medications has been gathered
continuously from January 1, 1991, to the present through computerized pharmacy records of the pharmacies in the study area.
Genotyping
All participants were genotyped for the NOS1AP SNP rs10494366
T⬎G, previously shown to be associated with QT interval in 3
independent samples.22 The correlated SNP rs10918594 C⬎G,
which had evidence of association with QT interval in one of the
original samples,22 also was genotyped (see the Figure). Both were
genotyped with Taqman assays C_1777074_10 and C_1777009_10
(Applied Biosystems, Foster City, Calif) in 1 ng genomic DNA
extracted from leukocytes, as previously reported.37
Assessment of QTc Interval and Other
Electrocardiographic Measurements
The electrocardiography (ECG) phenotype studied was the heart
rate– corrected QT interval (QTc) in milliseconds using Bazett’s
formula (QTc⫽QT/公RR).38 As in previous studies of QTc in the
Rotterdam Study19 we used a 10-second resting 12-lead ECG
(average of 8 to 10 beats), which was recorded on an ACTA ECG
(ESAOTE, Florence, Italy) at a sampling frequency of 500 Hz and
stored digitally. All ECGs were processed by the Modular ECG
Analysis System (MEANS) to obtain ECG measurements.39 – 41
MEANS determines the QT interval from the start of the QRS
complex until the end of the T wave. MEANS also determines the
presence of right or left bundle-branch block and left ventricular
hypertrophy. To study the association between NOS1AP variants and
QTc duration, all eligible ECGs from subjects with DNA available
were used. ECGs with right or left bundle-branch block were
excluded from analyses. In addition, to minimize confounding by
nongenetic influences on QT duration, all ECGs taken while the
subject was on any QT-altering drugs were excluded from analyses.
Drugs were considered possibly QT prolonging if they appeared on
any of lists 1 through 4 at www.qtdrugs.org.42 We also excluded
ECGs if subjects were on flupentixol, levomepromazine, mefloquine, olanzapine, or sertindole, which may prolong QT interval, or
digoxin, which shortens the QT interval. Up to 3 QTc measurements
were recorded across the 3 examination cycles.
Finally, in additional analyses, the mean QTc interval per individual was divided into 3 gender-specific categories as previously
described. For women, the cut points were ⱕ450 ms (normal), 451
to 470 ms (borderline), and ⬎470 ms (prolonged); for men, the cut
points were ⱕ430 ms (normal), 431 to 450 ms (borderline), and
⬎450 ms (prolonged).19,43
Adjudication of SCD
For the SCD analyses, all genotyped subjects were included. The
ascertainment of SCD cases in the Rotterdam Study has been
described previously.19 SCDs were defined operationally as a witnessed natural death attributable to cardiac causes, heralded by
abrupt loss of consciousness, within 1 hour of onset of acute
symptoms, or as an unwitnessed, unexpected death of someone seen
in a stable medical condition ⬍24 hours previously with no evidence
of a noncardiac cause.44,45
12
Circulation
TABLE 1.
July 3, 2007
Baseline Characteristics
Genotyped Sample
Characteristic
Men
(n⫽2666, 40.6%)
Women
(n⫽3905, 59.4%)
QTc Sample
Men
(n⫽2191, 40.8%)
SCD Cases
Women
(n⫽3183, 59.2%)
Men
(n⫽116, 49.8%)
Women
(n⫽117, 50.2%)
74.4⫾7.7
Age at baseline, y, mean⫾SD
68.2⫾8.2
70.4⫾9.6
67.0⫾7.7
69.0⫾9.1
71.8⫾7.8
Follow-up time, y, mean⫾SD
10.0⫾3.8
10.5⫾3.7
10.6⫾3.4
11.1⫾3.2
6.4⫾3.8
7.3⫾3.8
Current smoking, n (%)
774 (29.0)
680 (17.4)
634 (28.9)
582 (18.3%)
32 (27.6)
15 (12.8%)
1635 (61.3)
1040 (26.6)
1343 (61.3)
872 (27.4)
75 (64.7)
25.7⫾3.0
26.7⫾4.1
25.7⫾3.0
26.7⫾4.0
25.3⫾3.0
27.3⫾3.9
Past smoking, n (%)
Body mass index, kg/m2, mean⫾SD
38 (32.5%)
Systolic blood pressure, mm Hg, mean⫾SD
138.7⫾21.7
139.8⫾22.6
138.3⫾21.5
139.2⫾22.2
144.6⫾24.2
152.8⫾27.7
Diastolic blood pressure, mm Hg, mean⫾SD
74.6⫾11.5
73.2⫾11.4
74.9⫾11.3
73.2⫾11.1
74.0⫾12.5
77.0⫾14.1
Hypertension, n (%)
780 (29.3)
1415 (36.2)
621 (28.3)
1102 (34.6)
53 (45.7)
65 (55.6)
Diabetes mellitus, n (%)
281 (10.5)
422 (10.8)
213 (9.7)
309 (9.7)
14 (12.1)
27 (23.1)
Myocardial infarction, n (%)
447 (16.8)
320 (8.2)
345 (15.7)
243 (7.6)
44 (37.9)
19 (16.2)
81 (3.0)
131 (3.4)
34 (1.6)
75 (2.4)
17 (14.7)
7 (6.0)
Heart failure, n (%)
Shown are characteristics of all individuals with DNA available for genotyping (genotyped sample), of the subset of genotyped subjects with ECGs
without bundle-branch block or use of a QT-prolonging drug or digoxin (QTc sample), and of the SCD cases. The SCD source sample includes all
genotyped subjects.
Statistical Analysis
Genotype frequencies were tested for Hardy-Weinberg equilibrium
with a ␹2 test.
Because the QTc in subsequent ECGs of the same subject are
correlated, we used repeated-measures analyses implemented in
PROC MIXED (SAS 8.2, SAS Institute, Cary, NC). Both allelic and
general genotype models were tested for the 2 polymorphisms,
although the allelic model was considered primary because of the
previously reported rs10494366 –QT relationship.22 Haplotypes were
estimated with the expectation-maximization algorithm implemented
in PHASE 2.0 (University of Washington, Seattle),46,47 and only
individuals with successful genotyping for both SNPs and a posterior
probability of P⬎0.95 for assigned haplotypes were included in
haplotype analyses. In total, we identified 2245 double heterozygotes, all of whom were phased as heterozygous haplotype TC-GG
because these are the major haplotypes, with posterior probabilities
in excess of 0.95. In haplotype analyses, the haplotype with major
alleles for both SNPs was considered the reference to which the other
3 haplotypes were compared individually. QTc was tested for
association with genotype as the sole predictor (crude) and with
adjustment for age and gender (multivariable). To compare the
outcomes of haplotype analysis with individual SNP analysis, the
latter analyses also were performed restricting the analysis to
subjects in whom genotyping was successful for both SNPs. Finally,
a sensitivity analysis was carried out, excluding ECGs with an
abnormally prolonged QTc and using gender-specific cutoff points
of ⬎450 ms for men and ⬎470 ms for women. Jonckheere-Terpstra
tests were used to test whether individuals carrying NOS1AP minor
alleles had an increased frequency of borderline and abnormal mean
QTc.
Hazard ratios for time to SCD from baseline were estimated with
Cox proportional-hazards models. Again, both allelic and general
genotype models were tested for the 2 polymorphisms. In addition to
NOS1AP genotype, known SCD risk factors—including age, gender,
body mass index, smoking, hypertension, diabetes mellitus, heart
failure, and myocardial infarction at baseline and time-dependent
incident diabetes mellitus, heart failure, and myocardial infarction—
were included as predictors. To minimize misclassification of SCD,
we additionally performed a subanalysis restricting the case definition to witnessed deaths only. As we have previously shown, the risk
of SCD for increasing QTc is stronger in the younger than in the
older age group,19 so we determined the hazard ratios for time to
SCD separately in groups stratified by age above and below the
median age at baseline. Finally, we performed a sensitivity analysis,
excluding subjects with a history of myocardial infarction at baseline
from the analysis. All Cox proportional hazards analyses were
performed with SPSS for Windows, version 11.0 (SPSS Inc, Chicago, Ill).
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
Study Subjects
Baseline characteristics for the total study population, consisting of all genotyped subjects from the Rotterdam Study
(n⫽6571), are summarized in Table 1. Within the study
population, 12 967 ECGs were available from 6052 subjects
across up to 3 examination cycles. After exclusion of ECGs
with right or left bundle-branch block (n⫽640) and those
performed in individuals taking QT-prolonging or
-shortening drugs (n⫽1334) or both, a total of 11 108 ECGs
from 5374 subjects remained (on average, 2.1 ECGs per
individual). The 5374 subjects included in the QTc analyses
were 1.3 years younger at baseline, reflecting exclusions
among older participants (Table 1). Women had an 8.9-mslonger age-adjusted QTc interval (431.4 versus 422.5 ms;
P⬍0.0001), as previously shown,38,48 and were 2.2 years
older than men (70.4 versus 68.2 years at baseline;
P⬍0.0001). The numbers of abnormally prolonged QTc in
men and women of our study population were slightly higher
than expected on the basis of numbers from reference
populations.48,49 However, our study population was on
average already considerably older at baseline (69.5 versus 53
and 61 years, respectively), and this mean further increased
when follow-up ECGs were taken.
Genotyping
The G-allele (minor) frequency of rs10494366 T⬎G was
36.4% and of rs10918594 C⬎G was 31.4%. Successful
genotype calls were made in 95.8% and 95.9% of subjects,
respectively. Both SNPs were in Hardy-Weinberg equilibrium (P⫽0.32 for rs10494366 and P⫽0.89 for rs10918594).
The 2 SNPs were in linkage disequilibrium, with an r2 of 0.63
and D⬘ of 0.89. On phasing, we observed 2 common 2-SNP
haplotypes, TC (61.4%) and GG (29.1%), consisting of the 2
Aarnoudse et al
TABLE 2.
NOS1AP Variants Are Associated With QTc Duration
13
Difference in QTc by NOS1AP Genotype
Genotypic Model*
rs10494366 (36.4% MAF)
Subjects, n‡
Crude, ms
Age and gender adjusted, ms
rs10918594 (31.4% MAF)
Subjects, n‡
Crude, ms
Age and gender adjusted, ms
Genotype
Genotype
Genotype
TT
TG
GG
Allelic Model†
P
Per G allele
P
2100
2334
704
Ref
4.2 (3.0–5.5)
7.1 (5.3–8.9)
2.2⫻10⫺17
3.7 (2.9–4.6)
3.3⫻10⫺18
⫺19
3.8 (3.0–4.6)
7.8⫻10⫺20
Ref
4.2 (3.0–5.4)
7.2 (5.5–9.0)
CC
CG
GG
5138
5.9⫻10
2456
2217
530
Ref
4.3 (3.1–5.5)
6.4 (4.4–8.3)
1.7⫻10⫺15
3.6 (2.7–4.5)
6.9⫻10⫺16
6.3 (4.4–8.2)
⫺16
3.6 (2.7–4.4)
6.9⫻10⫺17
Ref
4.3 (3.2–5.5)
5203
1.5⫻10
MAF indicates minor allele frequency; Ref, reference. Values are difference from reference group (95% CI) in milliseconds.
*Linear regression model using dummy variables per genotype.
†Linear regression model entering genotype as an ordinal variable.
‡Because of failures in genotyping for the individual SNPs, genotype counts do not add up to the total of 5374 individuals.
major and 2 minor alleles, respectively, and 2 remaining
haplotypes containing 1 major and 1 minor allele each, GC
(7.2%) and TG (2.3%). Genotype distributions did not differ
between men and women and between quartiles of age at
baseline.
NOS1AP Polymorphisms and QTc
Minor alleles of both NOS1AP SNPs were significantly
associated with an increase in QTc duration. SNP rs10494366
T⬎G was associated with a 3.8-ms increase in multivariableadjusted QTc interval for each additional G allele, and SNP
rs10918594 C⬎G was associated with a 3.6-ms increase per
additional G allele (Table 2). Additional adjustment for ECG
left ventricular hypertrophy did not alter the results (data not
shown). We observed no difference in effect of the SNPs
between men and women. A sensitivity analysis excluding
ECGs with an abnormally prolonged QTc (using genderspecific cut points) resulted in slightly lower estimates (2.9
and 2.7 ms for the allelic models); however, the association of
NOS1AP genotypes with QTc duration remained highly
significant (all P⬍10⫺11).
All 3 haplotypes containing 1 (GC and TG) or 2 (GG)
minor alleles for the 2 SNPs were associated with increased
QTc compared with the homozygous TC reference haplotype.
The GG haplotype was associated with a 4.1-ms-longer
multivariable-adjusted QTc per additional GG haplotype
copy (P⫽2.0⫻10⫺18) using the TC haplotype as reference.
The GC and TG haplotypes were associated with a 3.2-mslonger (P⫽7.0⫻10⫺4) and 4.1-ms-longer (P⫽0.01) multivariable-adjusted QT interval per additional copy, respectively.
None of the haplotypes had a more significant effect than the
individual SNPs.
Furthermore, rs10494366 and rs10918594 were associated
with a larger proportion of borderline and prolonged QTc
intervals using gender-specific cut points19 (test for trend,
both P⬍0.0001; Table 3).
NOS1AP Polymorphisms and SCD
Within the study population (n⫽6571), we identified 233
sudden cardiac deaths, 121 of which were witnessed. Baseline characteristics of all adjudicated SCD cases are shown in
Table 1. After adjustment for known risk factors, the
NOS1AP polymorphisms rs10494366 T⬎G and rs10918594
C⬎G showed nonsignificant trends in the direction of increased hazard of SCD, with hazard ratios per additional
minor allele for time to SCD of 1.09 (95% confidence
interval, 0.90 to 1.33) and 1.10 (95% confidence interval,
0.90 to 1.34), respectively. In the subset of 121 adjudicated
SCD cases that were witnessed, a similar nonsignificant trend
toward increased SCD risk was found (Table 4). Stratification
TABLE 3. Number of Individuals With Normal, Borderline, and Abnormal Mean
QTc per Genotype Group Using Gender-Specific Cut Points
Genotype
rs10494366, n (% within genotype)
Normal
Borderline
Prolonged
P, Test for Trend
⬍0.0001
...
...
...
TT
1679 (80.0)
329 (15.7)
92 (4.4)
TG
1715 (73.5)
447 (19.2)
172 (7.4)
GG
498 (70.7)
144 (20.5)
62 (8.8)
rs10918594, n (% within genotype)
...
...
...
CC
1945 (79.2)
390 (15.9)
121 (4.9)
CG
1609 (72.6)
448 (20.2)
160 (7.2)
GG
385 (72.6)
96 (18.1)
49 (9.2)
⬍0.0001
QTc interval divided into 3 gender-specific categories. For women, the cut points were ⱕ450 ms
(normal), 451 to 470 ms (borderline) and ⬎470 ms (prolonged); for men, they were ⱕ430 ms
(normal), 431 to 450 ms (borderline), and ⬎450 ms (prolonged).19,43
14
Circulation
TABLE 4.
July 3, 2007
Hazard Ratio of All Adjudicated SCD and Witnessed SCD per NOS1AP Genotype or Allele
Genotypic Model*
Genotype
Genotype
Allelic Model†
Genotype
P
Per G Allele
P
All SCD, HR (95% CI)
rs10494366
TT (n⫽90)
Crude
Ref
0.97 (0.72–1.30)
TG (n⫽95)
1.26 (0.85–1.87)
GG (n⫽36)
0.41
1.08 (0.89–1.32)
0.42
Full model
Ref
0.99 (0.74–1.33)
1.27 (0.85–1.89)
0.44
1.09 (0.90–1.33)
0.37
rs10918594
CC (n⫽101)
CG (n⫽103)
Crude
Ref
1.13 (0.85–1.50)
1.11 (0.70–1.76)
0.69
1.08 (0.88–1.32)
0.46
Full model
Ref
1.16 (0.88–1.54)
1.13 (0.71–1.80)
0.58
1.10 (0.90–1.34)
0.37
GG (n⫽24)
Witnessed SCD, HR (95% CI)
rs10494366
TT (n⫽47)
TG (n⫽43)
Crude
Ref
0.82 (0.54–1.24)
1.66 (1.02–2.70)
0.02
1.20 (0.93–1.56)
0.17
Full model
Ref
0.84 (0.55–1.28)
1.68 (1.04–2.74)
0.02
1.22 (0.94–1.58)
0.14
CG (n⫽51)
GG (n⫽26)
rs10918594
CC (n⫽52)
GG (n⫽16)
Crude
Ref
1.11 (0.75–1.64)
1.43 (0.80–2.54)
0.47
1.17 (0.89–1.53)
0.25
Full model
Ref
1.14 (0.77–1.68)
1.45 (0.81–2.59)
0.44
1.18 (0.91–1.55)
0.22
Cox proportional hazards model. HR indicates hazard ratio; Ref, reference; and n, number of cases. Crude model was age and
gender adjusted. Full model included age, gender, body mass index, smoking, hypertension, diabetes mellitus, heart failure, and
myocardial infarction.
*Genotype-specific HR.
†HR entering genotype as an ordinal variable under an allelic model.
for baseline age above and below the median showed no
difference between age groups (data not shown). Finally, a
sensitivity analysis excluding 767 subjects with a history of
myocardial infarction at baseline did not result in a substantial change of the effect estimates or confidence intervals
(data not shown).
Discussion
We observed strong replication in the Rotterdam Study, a
large, well-phenotyped cohort of European ancestry, of the
finding from a prior genome-wide association study22 that
common NOS1AP variants are associated with increased
age-, gender-, and heart rate–adjusted QT-interval duration.
None of the haplotypes showed a more significant effect than
the individual SNPs, which were not specifically selected to
characterize haplotype variation at the locus. The 2 SNPs,
which are 55 kb apart, are not known to be functional, nor are
they highly correlated with any known functional SNP. These
results support the existence of a causal untyped SNP that is
correlated with both rs10494366 and rs10918594.
The association with SCD was not statistically significant.
Although we cannot fully exclude survival bias because of
the older age of our study population, we did not find that the
genotype distribution differed between different age groups at
baseline, making this less likely. The modest QTc prolongation associated with NOS1AP variation, despite the strong
effect of prolonged QTc on SCD risk, suggests that a much
larger study is needed to definitively confirm or rule out an
increased risk of SCD by NOS1AP variants. At least 510
cases would be needed to detect an odds ratio of 1.2 per minor
allele with 80% power. Even if no association with SCD is
ultimately identified, the 7.2-ms increase in QTc interval in
minor homozygotes compared with major homozygotes ap-
proximates the effect of medications that delay myocardial
repolarization and increase liability to ventricular
arrhythmias.
The mechanism by which a common variation in NOS1AP
affects QTc interval duration is unknown at present. However, the statistical evidence supporting the association with
QTc interval of rs10494366 (P⬍10⫺19) and rs10918594
(P⬍10⫺16) in 5374 individuals confirms that this is a genuine
association, consistent with evidence from 4 independent
cohorts totaling ⬎13 000 individuals of European ancestry.
Our study examined the relationship of genetic variation,
present at birth, in an elderly cohort in whom one might
assume that genetic factors play a smaller role than in
younger cohorts. However, these results demonstrate that
genetic factors continue to play a role even at older age.
One major advantage of our study was the availability of
up to 3 ECGs per subject at regular intervals during followup, resulting in more precise long-term ECG measures.
Furthermore, the use of digital ECG recordings all measured
with the MEANS system likely reduced systematic differences in assessment of the QTc interval. In addition, the
intersection of the Rotterdam Study with detailed pharmacy
exposure data allowed us to exclude ECGs recorded in
individuals on QT-prolonging or -shortening drugs, which
could have attenuated the power to detect the association.
Although no information on long-QT syndrome cases was
available, the number of relatives in the Rotterdam Study is
low, and the sensitivity analysis excluding abnormally prolonged QTc further minimized influence of potential familial
long-QT syndrome cases. Another advantage of the Rotterdam Study is the prospective ascertainment of risk factors and
the active surveillance for SCD events over a relatively long
period of follow-up. Thus, extensive information surrounding
Aarnoudse et al
NOS1AP Variants Are Associated With QTc Duration
SCD events was available, including the time between start of
symptoms and death, which enabled rigorous adjudication of
SCD events.
One limitation of the study resides in the variety of
competing causes of abrupt death at increasing age, which
may have led to misclassification, especially in cases in
which death was unwitnessed. Because SCD coding was
blinded to NOS1AP genotype, this would likely have biased
our study to detect no effect. This might explain our finding
of a slightly increased, but still nonsignificant, hazard ratio
when the analyses were restricted to witnessed sudden cardiac deaths. Our results and those of the prior study by Arking
et al22 were restricted to population samples of European
ancestry. Further testing in samples of African and Asian
ancestry is needed to establish the role of genetic variation at
the NOS1AP locus in myocardial repolarization in these
population groups. Moreover, substantial frequency differences are observed among European, African, and Asian
HapMap samples, which raises the possibility of natural
selection in the region.50 Attempts to validate the NOS1AP
association in recently admixed populations, such as African
Americans, will need to account for global and local chromosomal differences in ancestry because of the strong association with continental ancestry and the risk of population
stratification.
Conclusions
We have strongly confirmed the association of NOS1AP
variants with QT-interval duration. With the limited number
of SCD cases in our cohort, it was not possible to demonstrate
that this association translates into an influence on risk of
SCD, although the point estimates suggest that such a risk
increase may truly exist. Additional larger studies are required to determine whether NOS1AP genotype is associated
with SCD.
Acknowledgments
We thank Rowena Utberg for genotyping and Cornelis van der Hooft
and Charlotte van Noord for their help with adjudication of SCD
cases.
Sources of Funding
Dr Newton-Cheh and the genotyping were supported by a Doris
Duke Charitable Foundation Clinical Scientist Development Award
and NIH K23 (HL80025).
Disclosures
None.
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CLINICAL PERSPECTIVE
Sudden cardiac death (SCD) claims 300 000 lives annually in the United States. The ECG QT interval is a noninvasive
measure of ventricular repolarization, and prolongation of the QT interval is an important risk factor for SCD and
drug-induced arrhythmias. Approximately 35% of the variation in QT-interval duration is attributable to heritable factors.
Until recently, the search for sequence variants contributing to QT-interval duration and SCD risk has been restricted to
candidate genes known for their role in arrhythmogenesis. However, in a recent genome-wide association study, a common
variant in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was found to be associated with QT-interval variation.
NOS1AP was not previously known to play a role in repolarization. In the present study, we have strongly confirmed the
association of NOS1AP variants and QT-interval duration with a difference between minor homozygotes and major
homozygotes of 7.2 ms (P⬍10⫺19). We did not find an association of NOS1AP variants with SCD cases in our cohort, but
with 228 SCD events, our study was underpowered to demonstrate such an effect. Even if no association with SCD is
ultimately identified, the 7.2-ms increase in QTc interval in minor allele homozygotes compared with major homozygotes
approximates the effect of medications that delay myocardial repolarization and increase liability to ventricular
arrhythmias. The study underscores the power of association methods to identify novel genes and pathways involved in
myocardial repolarization and to identify genetic variants that could contribute to the risk of cardiac arrhythmias.
Nonsense Mutations in hERG Cause a Decrease in Mutant
mRNA Transcripts by Nonsense-Mediated mRNA Decay in
Human Long-QT Syndrome
Qiuming Gong, MD, PhD; Li Zhang, MD; G. Michael Vincent, MD;
Benjamin D. Horne, PhD, MPH; Zhengfeng Zhou, MD, PhD
Background—Long-QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene (hERG).
More than 30% of the LQT2 mutations result in premature termination codons. Degradation of premature termination
codon– containing mRNA transcripts by nonsense-mediated mRNA decay is increasingly recognized as a mechanism
for reducing mRNA levels in a variety of human diseases. However, the role of nonsense-mediated mRNA decay in
LQT2 mutations has not been explored.
Methods and Results—We examined the expression of hERG mRNA in lymphocytes from patients carrying the R1014X
mutation using a technique of allele-specific transcript quantification. The R1014X mutation led to a reduced level of
mutant mRNA compared with that of the wild-type allele. The decrease in mutant mRNA also was observed in the
LQT2 nonsense mutations W1001X and R1014X using hERG minigenes expressed in HEK293 cells or neonatal rat
ventricular myocytes. Treatment with the protein synthesis inhibitor cycloheximide or RNA interference–mediated
knockdown of the Upf1 protein resulted in the restoration of mutant mRNA to levels comparable to that of the wild-type
minigene, suggesting that hERG nonsense mutations are subject to nonsense-mediated mRNA decay.
Conclusions—These results indicate that LQT2 nonsense mutations cause a decrease in mutant mRNA levels by
nonsense-mediated mRNA decay rather than production of truncated proteins. Our findings suggest that the degradation
of hERG mutant mRNA by nonsense-mediated mRNA decay is an important mechanism in LQT2 patients with
nonsense or frameshift mutations. (Circulation. 2007;116:17-24.)
Key Words: arrhythmia 䡲 ion channels 䡲 long-QT syndrome 䡲 myocytes
L
becoming clear that nonsense and frameshift mutations bearing PTCs can destabilize mRNA transcripts via a mechanism
known as nonsense-mediated mRNA decay (NMD) in many
human diseases, resulting in decreased abundance of mutant
mRNA transcripts rather than in production of truncated
proteins.19,20
ong-QT syndrome is a disease associated with delayed
cardiac repolarization and prolonged QT intervals on the
ECG, which can lead to ventricular arrhythmias and sudden
death.1 The inherited long-QT syndrome type 2 (LQT2) is
caused by mutations in the human ether-a-go-go-related gene
(hERG), which encodes the pore-forming subunit of the
rapidly activating delayed rectifier K⫹ channel (IKr) in the
heart.2,3 More than 250 hERG mutations have been identified
in patients with LQT2.4 –7 The mechanisms of hERG channel
dysfunction in LQT2 mutations have been studied extensively in the last 10 years.8 –11 Most previous studies, however, have focused on the analysis of mutant proteins and
channel function. More than 30% of LQT2 mutations are
nonsense or frameshift mutations that introduce premature
termination codons (PTCs).4 –7 These PTC mutations generally are assumed to result in truncated dysfunctional channel
proteins, and several nonsense and frameshift mutations have
been studied at the protein level.8,12–18 However, it is now
Clinical Perspective p 24
NMD is an RNA surveillance mechanism that selectively
degrades mRNA transcripts containing PTCs resulting from
nonsense or frameshift mutations. The role of NMD as a
disease-causing mechanism of PTC mutations is becoming
increasingly evident.19,20 According to the proposed rule,
NMD occurs when translation terminates ⬎50 to 55 nt
upstream of the 3⬘-most exon-exon junction.21,22 The molecular mechanisms of NMD have been studied extensively.
These studies have shown that pre-mRNA splicing deposits
the exon junction complex ⬇20 to 40 nt upstream of the
exon-exon junction in spliced mRNA. The exon junction
Received October 26, 2006; accepted May 8, 2007.
From the Division of Cardiovascular Medicine, Department of Medicine, Oregon Health and Science University, Portland (Q.G., Z.Z.); and
Departments of Medicine and Cardiology (L.Z., G.M.V.) and Genetic Epidemiology Division (B.D.H.), LDS Hospital, Intermountain Healthcare and
University of Utah, Salt Lake City.
Correspondence to Dr Zhengfeng Zhou, Division of Cardiovascular Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd,
Portland, OR 97239. E-mail zhouzh@ohsu.edu
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.708818
17
18
Circulation
July 3, 2007
Figure 1. Pedigree of the family
with the R1014X mutation.
complex can recruit Upf proteins, which are required for
NMD.22 Several Upf proteins (Upf1, Upf2, Upf3a, Upf3b)
have been identified.23 The Upf1 protein appears to play a key
role in the distinction between proper and improper translation termination. Upf1 is a group 1 helicase that has RNAdependent ATPase and ATP-dependent 5⬘ to 3⬘ helicase
activities. Knockdown of Upf1 by RNA interference (RNAi)
has been shown to inhibit NMD.24,25
The objective of this work was to determine whether NMD
occurs in hERG mutations that contain PTCs. We investigated 2 nonsense mutations, W1001X and R1014X, in the
C-terminal region of the hERG channel. The W1001X and
R1014X mutations have previously been studied at the
protein level using hERG cDNAs.14,15 It was found that both
mutations produced truncated hERG channel proteins and
reduced hERG current amplitude. The R1014X mutation also
caused a dominant-negative effect on the wild-type (WT)
hERG current, which is expected to result in a severe clinical
phenotype. However, the R1014X carriers have presented
with a mild phenotype. In the present study, we demonstrate
that rather than the production of truncated proteins, the
primary defect of the W1001X and R1014X mutations is the
degradation of mutant mRNA by NMD.
Methods
Subjects
The study was approved by the institutional review board and carried
out on receipt of informed consent. The participants were bloodrelated members of a large family previously identified as having the
R1014X mutation.4 The pedigree included 25 blood-related family
members in 4 generations (Figure 1). Phenotyping was performed on
the basis of the history of LQTS-related cardiac events, the assessment of QT intervals and T-wave morphology, and pedigree analysis.26 Genotyping was conducted by sequencing of DNA samples
collected from buccal swabs. Normal control subjects were unrelated
individuals.
RNA and DNA Preparations From Blood Samples
Total RNA was isolated from peripheral blood lymphocytes using
the RiboPure-Blood kit (Ambion, Austin, Tex). The isolated RNA
was treated with RNase-free DNase to remove genomic DNA.
Genomic DNA was isolated from lymphocytes or Epstein Barr
virus–transformed lymphoblastoid cells with the DNeasy tissue kit
(Qiagen, Valencia, Calif).
Allele-Specific Quantification of RNA Transcripts
and Genomic DNA
The relative abundance of RNA transcripts from WT and R1014X
alleles was determined by a modified “hot-stop” polymerase chain
reaction (PCR) method.27,28 In this assay, the regular reversetranscription PCR was carried out using the primers in exon 13
(E13-F, forward 5⬘-GCCTTCTCAGGAGTGTCCAA-3⬘) and exon
14 (E14-R, reverse 5⬘-GAAAGCGAGTCCAAGGTGAG-3⬘). After
35 cycles, [32P]-dCTP was added and subjected to a single cycle of
PCR.28 With hot-stop PCR, only homoduplexes incorporated 32Plabels and any heteroduplexes formed during previous cycles were
unlabeled. Thus, hot-stop PCR will prevent the detection of WT/
mutant heteroduplexes, which are resistant to restriction enzyme
digestion. Because hot-stop PCR analysis yields a relative measure
of transcripts from 2 alleles, normalization to a reference housekeeping gene is unnecessary. The hERG genomic DNA was analyzed by
hot-stop PCR with the same forward primer as used in reversetranscription PCR and a reverse primer in intron 13 (I13-R, 5⬘CTCCGCGCTAGAGGTGTG-3⬘). For analysis of allelic variation in
hERG mRNA expression in normal subjects, the ratio of a common
polymorphism 1692A/G was determined by hot-stop PCR using the
primers in exon 6 (E6-F, forward 5⬘-ATCAACTTCCGCACCCCTA3⬘) and exon 7 (E7-R, reverse 5⬘-TGTGTGGCTGCTCCATGT-3⬘). The
labeled PCR products were treated with TaqI or NheI restriction enzyme
and analyzed by 5% PAGE and autoradiography. For quantitative
analysis, the intensity of each band was quantified with Scion Image
software (Scion Corp, Frederick, Md). The ratio of 2 alleles was
calculated, and a correction factor according to the respective GC
content of each digested product was applied to the ratio.28
Construction of Minigenes
Human genomic DNA was used as a template for PCR amplification
of fragments spanning from hERG exons 12 to 15. The PCR
products were cloned into pCRII vector with the TA cloning kit
(Invitrogen, Carlsbad, Calif) and verified by DNA sequencing. The
minigenes were then subcloned into a mammalian expression vector
pcDNA5/FRT (Invitrogen). The N-terminus of the minigene was
tagged by Myc epitope, which is in frame with the hERG translation
sequence. The W1001X and R1014X mutations in the minigenes
Gong et al
Nonsense-Mediated mRNA Decay in LQT2
19
were generated with the pAlter in vitro site-directed mutagenesis
system (Promega, Madison, Wis) and verified by DNA sequencing.
penicillin (100 U/mL), and streptomycin (100 ␮g/mL). After 1 day
in culture, myocytes were infected with the recombinant
adenoviruses.
Stable Expression of Minigene Constructs in
HEK293 Cells
Statistical Analysis
The minigenes in pcDNA5/FRT vector were stably transfected into
HEK293 cells by using the Flp-In method (Invitrogen). In this
approach, an FRT site sequence is integrated into the genome of
HEK293 cells and recombined by Flp recombinase with the FRT site
of the pcDNA5/FRT vector. The pcDNA5/FRT vector carries the
hygromycin resistance gene, which is used for the selection of stable
cell lines.
RNase Protection Assay of mRNA Transcripts
From Minigene Transfected Cells
RNA isolation and RNase protection assay (RPA) were performed as
previously described.29 Briefly, cytoplasmic RNA was isolated from
HEK293 cells or neonatal rat ventricular myocytes expressing hERG
minigenes with the RNeasy kit (Qiagen). The antisense RNA
riboprobes were transcribed in vitro in the presence of biotin-16-UTP
(Roche, Indianapolis, Ind). RNA (30 ␮g) was analyzed with the
riboprobes using the RPAIII and BrightStart BioDetect kits (Ambion). Yeast RNA was used as control for the complete digestion of
the probes by RNase. The expression level of the hygromycin
resistance gene from the pcDNA5/FRT vector or the E2 gene from
adenovirus was used as a loading control for normalization. The
intensity of each band was quantified with Scion Image software.
RNA Interference
Two plasmids, pSUPERpuro-hUpf1/I and pSUPERpuro-hUpf1/II
(kindly provided by Dr Oliver Mühlemann), were used to inhibit
expression of Upf1 as described by Paillusson et al.25 These plasmids
contain short hairpin RNAs targeting 2 sequences of hUpf1 (5⬘GAGAATCGCCTACTTCACT-3⬘ for pSUPERpuro-hUpf1/I and
5⬘-GATGCAGTTCCGCTCCATT-3⬘ for pSUPERpuro-hUpf1/II).
The HEK293 cells stably expressing WT or R1014X minigenes were
transfected with a mixture of 1 ␮g pSUPERpuro-hUpf1/I and 1 ␮g
pSUPERpuro-hUpf1/II or 2 ␮g pSUPERpuro with scrambled sequence of hUpf1/I using LipofectAmine 2000 (Invitrogen). At 24
hours after transfection, puromycin was added to the final concentration of 1.5 ␮g/mL for 48 hours to eliminate the untransfected cells.
Before analysis, the cells were cultured without puromycin for at
least 24 hours to avoid potential effects of this translation inhibitor
on NMD. The knockdown of the Upf1 protein was analyzed by
Western blot as described.9,25
Construction and Use of Recombinant Adenovirus
The AdEasy vector kit was used to generate WT and R1014X
minigene recombinant adenoviruses (Stratagene, La Jolla, Calif).
First, the WT and R1014X minigenes were subcloned into pShuttleCMV vector and recombined with the pAdEasy plasmid in Escherichia coli strain BJ5183. The pAdEasy/minigene plasmids were
transfected into HEK293 cells. After 2 days, the transfected cells
were cultured in growth medium containing 1.25% Seaplaqueagarose to promote the formation of recombinant viral plaques.
Approximately 2 to 3 weeks later, individual plaques were picked,
amplified in HEK293 cells, and purified over a discontinuous CsCl
gradient.
Primary Culture of Neonatal Rat
Ventricular Myocytes
Neonatal rat ventricular myocytes were prepared as described.30
Briefly, 1- to 3-day-old Sprague-Dawley rat pups were killed under
ether anesthesia by decapitation, and hearts were removed through a
sternotomy. The ventricles were trimmed free of atria, fat, and
connective tissues. Myocytes were dissociated by several 20-minute
cycles of collagenase/pancreatin treatment and serum neutralization.
Myocytes were cultured in Dulbecco’s modified Eagle’s medium
with 17% Media 199, 10% horse serum, 5% fetal bovine serum,
Data are presented as mean⫾SD for QTc intervals or mean⫾SEM
for PCR and RPA analyses. Statistical comparison of QTc intervals
between R1014X mutation carriers and noncarriers was performed
with a family-based analysis approach using the software package
PedGenie, a Monte Carlo simulation– based program.31 ANOVA
with Bonferroni correction for multiple pairwise comparisons between mutation/treatment groups was used for statistical analysis of
RPA data. Values of P⬍0.05 were considered statistically
significant.
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
Patient Description
A total of 22 family members were tested for the presence of
the R1014X mutation. Nine family members were identified
as R1014X mutation carriers (Figure 1). The ECG data were
available for 7 of the mutation carriers, all of which showed
a prolonged QTc interval and typical LQT2 ECG pattern with
the subtle bifid T waves. The mean initial QTc interval in the
mutation carriers was 461⫾7 ms (n⫽7) versus 420⫾13 ms
(n⫽8) in noncarriers (P⬍0.001). Four mutation carriers had
exercise tests, with maximum QTc value of 510⫾10 ms. In
this family, 89% (8 of 9) of the R1014X mutation carriers
were asymptomatic. The only person with a history of cardiac
events is the 71-year-old proband. From 32 to 42 years of age,
she had multiple syncopal episodes and 1 cardiac arrest that
were associated with the presence of hypokalemia (serum K⫹,
2.7 mEq/L) caused by taking a dietary supplement containing
potassium-wasting diuretics or taking QT-prolonging antihistamines. Since then, she has remained asymptomatic by
stopping the potassium-wasting diet, avoiding QT-prolonging
drugs, and taking ␤-blockers.
Analysis of mRNA Isolated From Blood Samples
The R1014X mutation causes premature termination of the
hERG channel protein. This mutation has previously been
studied at the protein level.15 However, it has been known
that nonsense and frameshift mutations that contain PTCs can
lead to the degradation of mRNA transcripts by NMD in
many diseases.19,20 To determine the underlying pathogenic
mechanism of the R1014X mutation, it is important to study
this mutation at the mRNA level. Because the affected heart
tissue from the mutation carriers was not available for this
study, we analyzed hERG mRNA transcripts isolated from
the lymphocytes of patients carrying the R1014X mutation.
To distinguish between WT and R1014X alleles, we performed allele-specific quantification analysis using the hotstop PCR assay. The WT allele contains a TaqI restriction
site, which is destroyed by the R1014X mutation. After
reverse transcription of mRNA, cDNA was amplified by
hot-stop PCR. After digestion of the PCR products with TaqI,
the WT allele should yield 2 fragments of 287 and 72 bp, and
the R1014X allele should give a fragment of 359 bp. As
shown in Figure 2A, cDNA from a normal subject showed a
20
Circulation
July 3, 2007
hERG mRNA expression. To rule out possible allelic variation in hERG expression in the general population, we
examined the allele-specific expression of hERG mRNA in
normal subjects. We analyzed 3 normal subjects who are
heterozygous for a common polymorphism, 1692A/G. To
distinguish between 1692A and 1692G alleles, the relative
levels of mRNA transcripts from 1692A and 1692G alleles
were measured by the hot-stop PCR assay. The 1692A allele
contains an NheI restriction site, which is absent in the 1692G
allele. Thus, digestion with NheI should allow us to determine
the relative ratio of the 2 WT alleles. After digestion of the
PCR products with NheI, the 1692A allele should be cut into
2 fragments of 286 and 46 bp, and the 1692G alleles should
remain uncut (332 bp). As shown in Figure 2B, in subjects 3,
4, and 5 (lanes 3 to 5), there are 2 bands of 268 and 332 bp,
suggesting that they are heterozygous for the 1692A/G
polymorphism. In these 3 normal subjects, the average ratio
of 1692G to 1692A was 0.97⫾0.07. This result suggests that
there is no significant allelic variation in hERG mRNA
expression in normal subjects. Subjects 1 and 2 (lanes 1 and
2) are homozygous for 1692A and 1692G, respectively.
Minigene Analysis of the R1014X and
W1001X Mutations
Figure 2. Hot-stop PCR analysis of mRNA and genomic DNA
isolated from lymphocytes. A, Analysis of WT and R1014X
mutant alleles in a normal subject (NS) and the proband. Schematic diagrams are shown for hot-stop PCR analysis of cDNA
(left) and genomic DNA (right). In cDNA analysis, a forward
primer in exon 13 (E13-F) and a reverse primer in exon 14
(E14-R) were used, and in genomic DNA analysis, the same forward primer and a reverse primer in intron 13 (I13-R) were used.
The position of TaqI and the size of the fragments from WT and
mutant PCR products are shown. After digestion with TaqI, the
32
P-labeled hot-stop PCR products were analyzed by PAGE and
autoradiography. In cDNA analysis (left), the bands from WT and
R1014X alleles are 287 and 359 bp, respectively; in genomic
DNA analysis (right), the bands from WT and R1014X alleles are
275 and 347 bp, respectively (the 72-bp band ran off the gel).
Similar results were obtained in 2 additional R1014X carriers,
and 3 to 5 independent experiments were performed for each
patient. B, Analysis of allelic variation of hERG expression by
analyzing 1692A/G polymorphism in 5 normal subjects. A schematic diagram is shown for the position of NheI and the size of
the fragments from A and G alleles. The 32P-labeled hot-stop
PCR products were digested with NheI. The 286- and 332-bp
bands represent 1692A and 1692G alleles, respectively (the
46-bp band ran off the gel). Results shown are representative of
2 independent experiments.
single band at 287 bp, corresponding to the WT alleles,
whereas in cDNA from the proband, in addition to a WT
287-bp band, a weak 359-bp band from the R1014X mutant
allele was observed. Quantitative analysis of the samples
from 3 patients carrying the R1014X mutation revealed that
the level of the R1014X mutant was reduced to 23⫾1% of the
WT level, suggesting that the mRNA derived from the
R1014X mutant allele is decreased. As a control, we also
analyzed genomic DNA from these 3 patients and showed
that the ratio of R1014X to WT alleles was 1.03⫾0.03, very
close to the expected ratio of 1 (Figure 2A).
The allele-specific quantification analysis depends on the
assumption that there is no significant allelic variation in
To study whether the decrease in the abundance of mRNA
levels in the R1014X mutation is due to NMD, we constructed minigenes containing the hERG genomic sequence
spanning from exon 12 to 15 and expressed the minigenes in
HEK293 cells. In the minigene experiments, the 2 LQT2
nonsense mutations R1014X and W1001X were analyzed by
RPA. Figure 3A shows the structure of the minigene and the
mRNAs after splicing. The R1014X and W1001X mutations
lead to a PTC in exon 13, which is expected to trigger NMD.
As shown in Figure 3B, the mRNA level of the R1014X
minigene was significantly lower than that of the WT
minigene. Because degradation of mRNA by NMD depends
on protein synthesis, we examined whether inhibition of
protein synthesis by cycloheximide (CHX) abrogates NMD
of the mutant mRNA, as has been shown for other PTCcontaining transcripts.32 The cells expressing WT and
R1014X minigenes were treated with CHX for 3 hours before
RNA isolation. Treatment with CHX had no effect on the
level of WT mRNA but significantly increased the level of
R1014X mutant mRNA, suggesting that the mutant mRNA is
degraded by NMD. Similar results were observed in the
W1001X minigene (Figure 3C), suggesting that the degradation of PTC-containing mRNAs by NMD may represent a
common mechanism in LQT2 patients with nonsense
mutations.
Effect of Suppression of Upf1 on NMD of the
R1014X Mutation
Recently, the Upf1 protein has been identified as a key factor
for NMD. Reducing Upf1 expression by RNAi has been used
as a functional assay to assess the NMD sensitivity of
PTC-containing mRNA transcripts.24,25 To study the role of
Upf1 in the reduced mRNA level of the R1014X mutation,
we used the RNAi method to knock down Upf1 protein
expression. In these experiments, HEK293 cells stably ex-
Gong et al
Nonsense-Mediated mRNA Decay in LQT2
21
Figure 3. Analysis of the R1014X and W1001X mutations using minigene constructs. A, The structure of the Myc-tagged minigene
and spliced mRNAs. The positions of WT termination codon (TER) and mutation-induced PTCs are indicated. B, C, Analysis of
mRNA by RPA. HEK293 cells were stably transfected with WT, R1014X (B), or W1001X (C) minigenes, and the expressed mRNA
was analyzed by RPA. Cells expressing WT and mutant minigenes were treated (⫹) or not treated (⫺) with 100 ␮g/mL CHX for 3
hours before RNA isolation. The level of hygromycin resistance gene transcripts (Hygro) served as a loading control. The quantitative data after normalization using protected hygromycin resistance gene mRNA are plotted as percentage of WT control from 4
(B) or 3 (C) independent experiments. Probability values are Bonferroni corrected.
pressing the WT and R1014X minigenes were transfected
with pSUPERpuro-hUpf1/I and pSUPERpuro-hUpf1/II.25
The Upf1 knockdown in the transfected cells was confirmed
by Western blot analysis using anti-Upf1 antibody (a gift
from Dr Jens Lykke-Andersen) (Figure 4A).23 Detection of
tubulin with anti-tubulin antibody served as a loading control.
In the RPA analysis of hERG minigene mRNA transcripts,
the level of R1014X mutant mRNA was significantly increased in Upf1-siRNA–transfected cells (Figure 4B). These
results suggest that mRNA transcripts of the R1014X mutation undergo NMD.
that PTC-containing mRNA transcripts in LQT2 are subject
to NMD. NMD is an evolutionarily conserved mRNA surveillance pathway that detects and eliminates PTC-containing
mRNA transcripts, thereby preventing the synthesis of trun-
Analysis of NMD in Neonatal Rat Myocytes Using
R1014X Adenovirus Minigene
The above experiments indicate that mRNA transcripts of the
R1014X mutation are subject to NMD in lymphocytes and
HEK293 cells. The noncardiac cells may behave differently
from cardiac cells in the degradation of mutant mRNA by
NMD. Therefore, it is important to evaluate whether the
defects observed in noncardiac systems are present in cardiac
myocytes. To test whether NMD of the R1014X mutation
occurs in cardiac myocytes, we infected neonatal rat ventricular myocytes with WT or R1014X minigene adenovirus and
performed RPA analysis. As shown in Figure 5, the mRNA
level of the R1014X mutant was significantly lower than that
of WT. Treatment with CHX had no effect on the level of WT
mRNA but significantly increased the level of R1014X
mutant mRNA, suggesting that the R1014X mutant mRNA is
degraded by NMD in cardiac myocytes. No protected bands
in the control lane indicate that the riboprobe is specific for
exogenous hERG transcripts.
Discussion
The present results demonstrate that the W1001X and
R1014X mutations lead to a reduction of mutant mRNA
transcripts by NMD. Our findings provide the first evidence
Figure 4. Effect of suppression of Upf1 by RNAi on NMD of the
R1014X mutation. HEK293 cells stably expressing the WT and
R1014X minigenes were transfected with pSUPERpuro-hUpf1/I
and pSUPERpuro-hUpf1/II (Upf1) or pSUPERpuro-scrambled
(CON) constructs. A, Western blot analysis of Upf1 protein. B,
Analysis of mRNA by RPA. The quantitative data after normalization using protected hygromycin-resistant gene mRNA are
plotted as percentage of WT control from 4 independent experiments. Probability values are Bonferroni corrected.
22
Circulation
July 3, 2007
Figure 5. Analysis of NMD in neonatal rat ventricular myocytes
using R1014X minigene adenovirus constructs. Myocytes
infected by WT and R1014X mutant minigene adenoviruses
were treated (⫹) or not treated (⫺) with 100 ␮g/mL CHX for 3
hours, and expressed mRNA was analyzed by RPA. The mRNA
from uninfected myocytes was used as control (CON). The level
of E2 transcripts (E2) from adenovirus served as a loading control. The quantitative data after normalization using protected E2
mRNA are plotted as percentage of WT control from 4 independent experiments. Probability values are Bonferroni corrected.
cated and potentially harmful proteins.33 NMD occurs when
translation terminates ⬎50 to 55 nt upstream of the 3⬘-most
exon-exon junction.21,22 According to this rule, ⬎90 LQT2
nonsense and frameshift mutations are potential targets for
NMD. Several LQT2 nonsense and frameshift mutations have
been studied at the functional and protein levels with cDNA
constructs.8,12–18 All previous studies, however, have been
carried out under the assumption that these nonsense and
frameshift mutations lead to the production of truncated
proteins. Because NMD requires introns, the absence of
introns in cDNA constructs would preclude the degradation
of PTC-containing transcripts by NMD. As a result, NMD
effects could not be observed when cDNAs were used in
these studies. In the present study, we used minigene constructs that contain the hERG genomic DNA with both exons
and introns and showed that the W1001X and R1014X
mutations cause a marked decrease in mutant mRNA transcripts. Inhibition of protein synthesis by CHX or knockdown
of Upf1 by RNAi results in the restoration of mutant mRNA
to levels comparable to the WT minigene. These results
strongly suggest that the degradation of mutant mRNA by
NMD is an important mechanism in LQT2 mutations carrying PTCs.
Previous studies have shown that different LQT2 mutations cause hERG channel dysfunction by different mechanisms. This led to a proposed classification of LQT2 mutations according to their underlying mechanisms.11 The
classification scheme (shown in Figure 6) illustrates the
mechanisms underlying LQT2 mutations. Class 1 mutations
cause abnormal protein synthesis by defective transcription or
translation. Class 2 mutations lead to defective protein
trafficking. Class 3 mutations result in abnormal gating
and/or kinetics, and class 4 mutations result in altered or
absent channel selectivity or permeability.11 In the present
study, we show that LQT2 nonsense mutations cause a
decrease in mutant mRNAs by NMD, thereby altering the
amount of mRNA available for subsequent hERG protein
generation. We propose that the degradation of PTCcontaining mRNA transcripts by NMD represents a new class
of LQT2 pathogenic mechanism (class 5).
The mutations that undergo NMD will result in the
degradation of mutant mRNAs before they produce large
quantities of truncated proteins. By eliminating abnormal
mRNA transcripts carrying PTCs, NMD prevents the production of truncated proteins that could act in a dominantnegative manner, leading to deleterious effects on the cells.
One of the physiological roles of NMD is to protect against
severe disease phenotypes by converting the dominantnegative effect to haploinsufficiency.32 NMD as a modifier of
phenotypic severity has been reported in many human diseases.19,20,32,34 For example, in Marfan syndrome, an
autosomal-dominant connective tissue disorder caused by
mutations in the fibrillin 1 gene, nonsense mutations that
result in reduced levels of mutant mRNA are associated with
a mild phenotype. In contrast, patients with nonsense alleles
that escape NMD develop a severe phenotype as a result of
the dominant-negative effect.19,34
Most R1014X mutation carriers in this family have presented with a mild LQT2 phenotype. In contrast to patients
with pore-region mutations, who usually present with a
longer QT interval and more frequent cardiac events,35 the
QTc interval in the R1014X mutation carriers is only mildly
prolonged (461⫾7 ms), and only the proband experienced
arrhythmia-related cardiac events that were always associated
with hypokalemia or the use of QT-prolonging drugs. We
have previously shown that the R1014X mutation causes
hERG channel dysfunction by defective trafficking of the
mutant protein.15 In addition, the truncated mutant protein
exhibits a dominant-negative effect on the WT hERG. This
implies that a severe phenotype would be expected in the
R1014X mutation carriers. However, our present study reveals that the R1014X mutant mRNA transcripts are markedly decreased by NMD, and as a result, the dominantnegative effect caused by the production of truncated proteins
would be minimized. Therefore, haploinsufficiency rather
than a dominant-negative effect is probably the underlying
mechanism for the R1014X mutation, which is consistent
Figure 6. Classification scheme for LQT2
mutations.
Gong et al
with the observed clinical presentation of this family. It is
interesting to note that the W1001X mutation carriers also
present with a mild LQT2 phenotype.35 Moss et al35 reported
that LQT2 patients with mutations in the pore region of
hERG have a significantly higher risk of arrhythmia-related
cardiac events than patients with nonpore mutations. Although the difference may be explained by in vitro electrophysiological effects of reported hERG mutations, with pore
mutations having a greater negative effect on hERG current
than nonpore mutations,35 it also is possible that NMD may
play a role. It is noted that only 6% of LQT2 mutations in the
pore region are nonsense or frameshift mutations, whereas
⬎40% of the mutations in nonpore regions are nonsense or
frameshift mutations. Clearly, further genotype-phenotype
correlation studies are required to test whether NMD contributes to the observed differences in clinical presentations of
pore and nonpore LQT2 mutations.
There are potential limitations to the present study. Our
present experiments analyzed endogenously expressed
mRNA from patients carrying the R1014X mutation, but the
RNA was isolated from lymphocytes rather than the affected
heart tissue. Although we have shown that the R1014X
mutant minigene expressed in neonatal rat ventricular myocytes leads to reduced mRNA levels by NMD, further studies
are required to determine whether the endogenous PTCcontaining mRNA in human heart tissue is subject to NMD.
Verification of our findings in human heart would strengthen
the conclusion that hERG mutations that contain PTCs can
lead to degradation of the mutant mRNA by NMD.
In summary, our findings that nonsense mutations in hERG
lead to a reduced level of mutant mRNA by NMD add to our
understanding of the disease-causing mechanisms of hERG
mutations in LQT2. Thus, in studies of hERG nonsense and
frameshift mutations, it is important to first analyze the
abundance of mRNA to determine whether these PTC mutations are targeted by NMD. Obviously, this important point
had been overlooked in previous studies that analyzed hERG
PTC mutations only at the protein and functional levels.
Because PTC mutations account for ⬎30% of LQT2 mutations, the RNA surveillance imposed by NMD is of fundamental importance in the pathogenesis of LQT2.
Acknowledgment
We thank Dr Kent Thornburg for helpful comments on the
manuscript.
Sources of Funding
The present study was supported in part by NIH grant HL68854 (Dr
Zhou), Deseret Foundation grant DF400 (Dr Vincent), and NIH grant
1UL1RRO24140 – 01 from the National Center for Research
Resources.
Disclosures
None.
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CLINICAL PERSPECTIVE
Congenital long-QT syndrome type 2 (LQT2) is caused by mutations in human ether-a-go-go related gene (hERG), which
encodes a voltage-gated potassium channel (IKr) in the heart. The present work demonstrates that LQT2 nonsense mutations
show a decrease in mutant mRNA transcripts via nonsense-mediated mRNA decay (NMD), an RNA surveillance
mechanism that selectively eliminates the mRNA transcripts that contain premature termination codons. These results
indicate that, contrary to intuition, the predominant consequence of hERG nonsense mutations is not the production of
truncated proteins but rather the degradation of mutant mRNA by NMD. Given that nonsense and frameshift mutations
account for ⬎30% of LQT2 mutations, the RNA surveillance imposed by NMD is of fundamental importance in the
pathogenesis of LQT2. Our findings have important implications for genotype-phenotype correlation investigations in
LQT2. By eliminating abnormal mRNA transcripts carrying premature termination codons, NMD prevents the production
of truncated proteins that could act in a dominant-negative manner. The clinical significance of NMD is the protection
against severe disease phenotypes by converting the dominant-negative effect to haploinsufficiency. Thus, NMD appears
to be an important factor in modifying phenotypic severity in LQT2.
Coronary Heart Disease
Coronary Artery Calcification Progression Is Heritable
Andrea E. Cassidy-Bushrow, PhD, MPH; Lawrence F. Bielak, DDS, MPH; Patrick F. Sheedy II, MD;
Stephen T. Turner, MD; Iftikhar J. Kullo, MD; Xihong Lin, PhD; Patricia A. Peyser, PhD
Background—Coronary artery calcification (CAC), a marker of coronary artery atherosclerosis, can be measured
accurately and noninvasively with the use of electron beam computed tomography. Serial measures of CAC quantify
progression of calcified coronary artery plaque. Little is known about the role of genetic factors in progression of CAC
quantity.
Methods and Results—We quantified the relative contributions of measured risk factors and unmeasured genes to CAC
progression measured by 2 electron beam computed tomography examinations an average of 7.3 years apart in 877
asymptomatic white adults (46% men) from 625 families in a community-based sample. After adjustment for baseline
risk factors and CAC quantity, the estimated heritability of CAC progression was 0.40 (P⬍0.001). Baseline risk factors
and CAC quantity explained 64% of the variation in CAC progression. Thus, genetic factors explained 14% of the
variation [(100⫺64)⫻(0.40)] in CAC progression. After adjustment for risk factors, the estimated genetic correlation
(pleiotropy) between baseline CAC quantity and CAC progression was 0.80 and was significantly different than 0
(P⬍0.001) and 1 (P⫽0.037). The environmental correlation between baseline CAC quantity and CAC progression was
0.42 and was significantly different than 0 (P⫽0.006).
Conclusions—Evidence was found that many but not all genetic factors influencing baseline CAC quantity also influence
CAC progression. The identification of common and unique genetic influences on these traits will provide important
insights into the genetic architecture of coronary artery atherosclerosis. (Circulation. 2007;116:25-31.)
Key Words: atherosclerosis 䡲 calcium 䡲 genetics 䡲 imaging 䡲 population
C
oronary heart disease (CHD) is the leading cause of
death and disability in the United States. Despite recognition of numerous factors contributing to development of
CHD, the ability to predict individuals at risk of CHD events
remains suboptimal. More than one half of CHD deaths occur
in individuals without previous symptoms.1 Traditional risk
factors (high cholesterol, high blood pressure, cigarette smoking, diabetes) are highly prevalent among individuals with
CHD but are also prevalent in individuals without CHD
events.2
CAC quantity measured at a single time point across studies.
Estimated heritability (⫾SE) was 0.42⫾0.13 among asymptomatic white individuals,8 0.40⫾0.08 among sibships enhanced for hypertension,9 and 0.40⫾0.23 among individuals
from families enriched for type 2 diabetes.10
No studies have focused on estimating the genetic contribution to CAC progression, although the complex biology of
progression of calcium appears to be “genetically directed.”11
The purpose of the present investigation was to estimate the
genetic contribution to variation in noninvasively measured
CAC progression among an asymptomatic community-based
sample. Additionally, evidence for pleiotropy, or shared
genetic influences, between CAC quantity at baseline and
CAC progression was examined.
Clinical Perspective p 31
Atherosclerosis is the primary cause of CHD. Coronary
artery calcification (CAC), a measure of coronary atherosclerosis presence and quantity, can be detected noninvasively
and reliably with electron beam computed tomography
(EBCT). CAC predicts CHD events in asymptomatic individuals at intermediate risk on the basis of their CHD risk
factors.3,4 EBCT can be used to serially measure the progression of CAC. CAC progression is associated with CHD.5,6
Family history of premature CHD is associated with CAC.7
Unmeasured genes contribute to interindividual variation in
Methods
Study Participants
The Epidemiology of Coronary Artery Calcification (ECAC) study,
conducted between 1991 and 1998, examined 1240 participants aged
ⱖ20 years from the Rochester Family Heart Study12,13 and 496
individuals living in the vicinity of Rochester, Minn, who were not
Received August 22, 2006; accepted May 8, 2007.
From the Department of Epidemiology, University of Michigan, Ann Arbor (A.E.C.-B., L.F.B., P.A.P.); Department of Biostatistics and Research
Epidemiology, Henry Ford Health System, Detroit, Mich (A.E.C.-B.); Department of Diagnostic Radiology (P.F.S.), Division of Hypertension,
Department of Internal Medicine (S.T.T.), and Division of Cardiovascular Diseases (I.J.K.), Mayo Clinic and Foundation, Rochester, Minn; and
Department of Biostatistics, Harvard University, Boston, Mass (X.L.).
Correspondence to Patricia A. Peyser, PhD, Department of Epidemiology, University of Michigan, 611 Church St, Ann Arbor, MI 48104-3028. E-mail
ppeyser@umich.edu
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.658583
25
26
Circulation
July 3, 2007
pregnant or lactating and who never had coronary or noncoronary
heart surgery.14,15 A total of 1155 ECAC study participants had a
follow-up examination between December 2000 and February 2005.
In general, participants were invited to return for a follow-up
examination on the basis of age (older age first) and longer time
since baseline examination. Study protocols were approved by the
Mayo Clinic and University of Michigan institutional review boards,
and participants gave written informed consent.
One thousand fifty-five white ECAC participants had complete
CAC data at baseline and follow-up and no history of myocardial
infarction, stroke, or positive angiogram at baseline or follow-up.
Individuals with missing baseline or follow-up risk factor data
(n⫽68), 79 individuals aged ⬍45 years at follow-up, and 31
individuals with outlier values (exceeding ⫾4 SDs from sample
mean) for risk factor data were excluded. Individuals were restricted
to being aged ⱖ45 years at follow-up for comparability with other
CAC heritability studies8 and because CAC prevalence in younger
individuals, especially women, is very low.16 The final sample size
consisted of 877 individuals (402 men).
Risk Factor Assessment
During baseline and follow-up examination interviews, participants
reported current medication use, educational attainment, history of
smoking, physician-diagnosed hypertension, myocardial infarction,
angiographic evidence of a blocked coronary artery, stroke, or
diabetes. Family history of CHD was defined as self-reported
myocardial infarction or coronary artery revascularization in a parent
and/or sibling that occurred before age 60 years. Age 60 years was
chosen to represent premature disease.17 Height was measured by a
wall stadiometer, weight was measured by electronic balance, and
body mass index (kg/m2) was calculated. Waist circumference was
measured at the umbilicus, hips were measured at the level of
maximal circumference, and waist-to-hip ratio was calculated.
Standard enzymatic methods were used to measure total cholesterol, high-density lipoprotein cholesterol (HDL-C), plasma glucose,
and triglycerides after overnight fasting.13 Low-density lipoprotein
cholesterol (LDL-C) was calculated by the Friedewald equation.18
Systolic blood pressure (SBP) and diastolic blood pressure (DBP)
levels were measured in the right arm with a random-zero sphygmomanometer (Hawksley and Sons). Three measures at least 2
minutes apart were taken; the average of the second and third
measurements was used. Individuals were considered hypertensive if
they reported a prior diagnosis of hypertension and use of prescription antihypertensive medication or if the average SBP or DBP was
ⱖ140 mm Hg or ⱖ90 mm Hg, respectively. Participants were
considered diabetic if they reported using insulin or oral hypoglycemic agents or if they reported a physician diagnosis of diabetes but
were not currently taking a pharmacological agent to control glucose
levels. The Framingham risk equation was used to estimate the
10-year probability of CHD (10-year CHD risk) at baseline.19
Measurement of CAC
CAC was measured with an Imatron C-150 EBCT scanner (Imatron
Inc, South San Francisco, Calif). Protocols at baseline and follow-up
were identical.20 A dual-scan approach was used beginning in 1993.
A scan run consisted of 40 contiguous 3-mm-thick tomographic
slices from the root of the aorta to the apex of the heart. Scan time
was 100 ms per tomogram. ECG gating was used, and all images
were triggered at end-diastole during 2 to 4 breath-holds. A radiological technologist scored the tomograms with an automated scoring
system without knowledge of other EBCT examination results for
the same participant.21 CAC was defined as a hyperattenuating focus
within 5 mm of the midline of a coronary artery, ⱖ4 contiguous
pixels in size, and having CT numbers ⬎130 Hounsfield units
throughout. Areas ⱖ1 mm2 for all CAC foci were summed to provide
a measure of CAC quantity. When 2 scan runs at a single examination were available, CAC quantity was based on the average.
Statistical Analysis
Baseline CAC quantity was natural logarithm (log) transformed after
adding 1 to reduce nonnormality and is referred to as log baseline
CAC quantity. CAC progression was defined as the log annual
change in CAC area, calculated as follows: log [(difference between
follow-up and baseline CAC area⫹1)/time (in years) between
baseline and follow-up examinations].20 If the difference between
follow-up and baseline CAC area was ⬍0, the difference was set to
0 (to avoid taking the log of a negative number).
Heritability estimates (h2) were calculated for log baseline CAC
quantity and CAC progression with the use of a variance components
approach described previously8 and implemented in SOLAR.22 For
trait y, the value of y for individual i is modeled as:
(1)
yi⫽␮⫹
冘
␤jXij⫹gi⫹ei
where ␮ is the mean of y, Xij is the j-th covariate with associated
regression coefficient ␤j, gi is an additive genetic effect normally
distributed with mean 0 and variance ␴g2, and ei is a random residual
effect normally distributed with mean 0 and variance ␴e2. It is
assumed that ␴g2⫹␴e2⫽1. Any nonadditive genetic and unmeasured
nongenetic effects (as well as measurement and random error) are
incorporated into ei. Heritability is estimated by ␴g2. Likelihood ratio
tests are used to assess significance of a parameter of interest by
comparing the log-likelihood of the model in which the parameter is
estimated with that of the model in which the parameter is fixed to
0.23
Heritability estimates for CAC progression were calculated as follows: (1) unadjusted; (2) adjusted for age and sex; (3) adjusted for age,
sex, and the best subset of the following baseline CHD risk factors: body
mass index, waist-to-hip ratio, triglycerides, LDL-C, HDL-C, fasting
glucose level, SBP, DBP, presence of diabetes, presence of hypertension, college education (ie, any education beyond high school), smoking
history, log (pack-years smoking⫹1), and family history of CHD; and
(4) adjusted for age, sex, log baseline CAC quantity, and the best subset
of the CHD risk factors listed in step 3. Heritability estimates for log
baseline CAC quantity were calculated similarly (steps 1 to 3). Covariates were chosen for similarity to previous h2 studies.8 All 2-way
interaction terms between covariates significantly associated with either
outcome were evaluated. The estimates of h2 and covariate variance
obtained were used to estimate the percentage of total variation
explained by genetic factors: [(1⫺proportion of variance explained by
covariates)⫻h2]⫻100.
The genetic correlation (⌿g) between log baseline CAC quantity
(trait 1) and CAC progression (trait 2) was estimated to assess
pleiotropic genetic effects with the use of maximum-likelihood
estimation in SOLAR.24 –26 The phenotypic correlation between the
2 traits is derived from the ⌿g, the environmental correlation (⌿e),
and the heritabilities of the 2 traits, as follows:
(2)
关 冑h21h22⫻⌿g兴⫹关 冑1⫺h21⫻ 冑1⫺h22⫻⌿e兴
All hypothesis tests were performed with the use of likelihoodratio test statistics.23 The hypothesis tests of interest are whether ⌿g
is different from 0, whether ⌿g is different from 1, and whether ⌿e
is different from 0. If ⌿g is different from 0, the estimate of ⌿g, its
SE, and test of the hypothesis ⌿g⫽1 determine the magnitude of the
shared genetic effects (ie, pleiotropy).27,28 If the hypothesis that
⌿g⫽1 is not rejected, then all genes influencing 1 trait are assumed
to also influence the other trait. Rejection of the null hypothesis that
⌿e⫽0 indicates shared environmental components. Covariates significantly associated with both traits were used to adjust both traits,
whereas covariates only associated with a single trait were used to
adjust for that trait alone. Covariates for CAC progression were
chosen from the model in which log baseline CAC quantity was not
included as a covariate.
The authors had full access to and take responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
Mean baseline age of women was 56.4 years (range, 36.0 to
82.1 years), and that of men was 54.7 years (range, 35.7 to
79.0 years) (Table 1). Mean time between examinations was
Cassidy-Bushrow et al
TABLE 1.
Baseline Characteristics of Study Participants
Women
(n⫽475)
Characteristic
Men
(n⫽402)
P*
Age, y
56.4 (10.4)
54.7 (9.8)
0.016
Body mass index, kg/m2
27.4 (5.5)
27.8 (3.9)
0.196
⬍0.001
Waist-to-hip ratio
0.8 (0.09)
0.9 (0.06)
Triglycerides, mmol/L
1.6 (0.8)
1.6 (0.7)
LDL-C, mmol/L
3.1 (0.8)
3.3 (0.8)
⬍0.001
HDL-C, mmol/L
1.4 (0.4)
1.1 (0.3)
⬍0.001
SBP, mm Hg
122.1 (17.7)
121.6 (15.7)
DBP, mm Hg
75.3 (8.9)
79.3 (9.7)
0.269
0.700
⬍0.001
Fasting glucose, mmol/L
5.0 (0.7)
5.1 (0.6)
0.037
Log (pack-years of smoking⫹1)
0.8 (1.3)
1.6 (1.6)
⬍0.001
10-Year CHD risk, %†
5.5 (4.5)
11.4 (7.1)
⬍0.001
History of smoking, %
35.2
57.7
⬍0.001
Diabetes, %
1.9
2.0
0.919
34.7
34.8
0.978
4.6
6.7
0.180
College education, %
60.0
63.9
0.233
Family history of CHD, %
35.8
31.6
0.191
Hypertension, %
Statin use, %
Data are mean (SD) unless indicated otherwise.
*Sex differences in participant characteristics tested by t test or ␹2 test.
†One man missing 10-year CHD risk because of missing smoking history.
longer for women (7.6⫾3.5 years [range, 1.8 to 13.7 years])
than for men (6.7⫾3.2 years [range, 1.8 to 13.01 years])
(P⫽0.008). The 877 participants belonged to 625 families:
453 singletons and 125 families of size 2, 28 of size 3, 10 of
size 4, 5 of size 5, 3 of size 6, and 1 of size 7. Relationships
consisted of sibships (384 sib pairs), 25 parent-offspring
pairs, and 34 avuncular pairs.
Table 2 presents baseline data, follow-up data, and annual
change in CAC quantity, by sex. Among women, baseline
CAC prevalence was 38%, and follow-up prevalence was
58%; among men, baseline CAC prevalence was 67%, and
follow-up prevalence was 83%.
Heritability of Baseline CAC Quantity
The best model of log baseline CAC quantity included age
(P⬍0.001), sex (P⬍0.001), LDL-C (P⫽0.107), SBP
(P⬍0.001), DBP (P⫽0.016), log pack-years of smoking
(P⫽0.002), presence of diabetes (P⬍0.001), a positive family
history of CHD (P⫽0.029), and a sex-by–LDL-C interaction
term (P⫽0.020) (Table 3). Higher values of LDL-C were
associated with higher baseline CAC quantity among men but
not women (Figure 1). After adjustment for risk factors,
TABLE 2.
CAC Progression Is Heritable
27
estimated h2 of log baseline CAC quantity was 0.376 (Table
4). Approximately 21% of the total variation in log baseline
CAC quantity was explained by genetic factors not acting
through model covariates.
Risk Factor Associations With CAC Progression
In the best-fitting model of CAC progression, baseline age
(P⬍0.001), waist-to-hip ratio (P⫽0.024), LDL-C (P⬍0.001),
log pack-years of smoking (P⫽0.093), hypertension
(P⬍0.001), and log baseline CAC quantity (P⬍0.001) were
positively significantly associated and female sex (P⫽0.025)
was negatively significantly associated with CAC progression (Table 3). These risk factors together explained ⬇64% of
the variation in CAC progression. The rate of change at any
given baseline age depended on CAC quantity at baseline
(P⬍0.001). Among those with no detectable baseline CAC,
the rate of CAC progression appears slightly higher for older
individuals; at higher CAC quantities, however, the rate of
CAC progression appears higher for younger individuals
(Figure 2).
Heritability of CAC Progression
The estimate of CAC progression h2 was 0.782 (P⬍0.001)
and remained significant after adjustment for baseline age
and sex (h2⫽0.671; P⬍0.001) as well as after adjustment for
baseline CHD risk factors significant at an ␣ ⬍0.1
(h2⫽0.592; P⬍0.001) (Table 4). After adjustment for baseline age, sex, log baseline CAC quantity, waist-to-hip ratio,
LDL-C, log pack-years of smoking, hypertension, and a
baseline age– by– baseline CAC quantity interaction term, the
h2 estimate was 0.396 (P⬍0.001). Baseline risk factors and
CAC quantity explained 64% of the variation in CAC
progression. Thus, genetic factors explained 14% of the
variation [(100⫺64)⫻(0.40)] in CAC progression.
Evidence for Pleiotropy
Log baseline CAC quantity and CAC progression were significantly correlated (Spearman correlation coefficient⫽0.74,
P⬍0.001; Figure 3). The estimated ⌿g between log baseline
CAC quantity and CAC progression was 0.80 and was statistically significantly different from 0 (P⬍0.001) and 1 (P⫽0.037)
(Table 5). The estimated ⌿e between log baseline CAC quantity
and CAC progression was 0.42 and was statistically significantly
different than 0 (P⫽0.006). Thus, there was evidence for shared
environmental factors and genes for variation in log baseline
CAC quantity and CAC progression; however, there also was
evidence for some nonoverlapping genes involved in each of
these measures of atherosclerosis.
Distribution of CAC Quantity at Baseline and Follow-Up and CAC Progression, by Sex
Women
CAC Measure
CAC quantity, mm2
Log (CAC quantity⫹1)
Presence of any detectable CAC, %
Men
Baseline
Follow-Up
Annual Change per Year*
Baseline
Follow-Up
Annual Change per Year*
21.7 (79.7) 关0, 957.6兴
41.3 (118.5) 关0, 1107.2兴
3.7 (9.6) 关⫺3.1, 100.8兴
45.0 (98.3) 关0, 877.6兴
93.0 (153.6) 关0, 980.3兴
8.1 (13.3) 关⫺17.5, 100.3兴
1.1 (1.7) 关0, 6.9兴
1.8 (1.9) 关0, 7.0兴
⫺0.4 (1.8) 关⫺2.6, 4.6兴
2.2 (1.9) 关0, 6.7兴
3.1 (2.0) 关0, 6.9兴
0.8 (1.9) 关⫺2.6, 4.6兴
38.1
58.3
NA
67.2
83.1
NA
Data are mean (SD) 关range兴 or percentage. NA indicates not applicable.
*On scale of mm2/y, defined as (follow-up⫺baseline CAC quantity/time) (mm2/y); on log scale, defined as CAC progression: 关(log(follow-up⫺baseline CAC
quantity⫹1)/time)兴, where (follow-up⫺baseline CAC quantity)⫽0 if (follow-up⫺baseline CAC quantity) ⬍0.
28
Circulation
July 3, 2007
TABLE 3. Baseline Risk Factors Associated With Log Baseline CAC Quantity and/or With
CAC Progression
Log Baseline CAC Quantity
Baseline Covariate
Parameter Estimate (SE)
CAC Progression
P
Parameter Estimate (SE)
P
0.075 (0.006)
⬍0.001
0.022 (0.005)
⬍0.001
⫺1.115 (0.102)
⬍0.001
⫺0.225 (0.117)
0.025
䡠䡠䡠
0.145 (0.087)
䡠䡠䡠
0.107
2.089 (0.613)
0.024
0.226 (0.051)
⬍0.001
SBP, mm Hg
0.023 (0.004)
⬍0.001
DBP, mm Hg
⫺0.016 (0.007)
0.016
Log (pack-years of smoking⫹1)
0.202 (0.033)
0.002
Diabetes
1.984 (0.345)
⬍0.001
Hypertension
䡠䡠䡠
0.262 (0.109)
䡠䡠䡠
0.029
⫺0.255 (0.120)
0.020
Age
Female sex
Waist-to-hip ratio
LDL-C, mmol/L
Family history of CHD
Sex⫻LDL-C
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
0.034 (0.028)
䡠䡠䡠
0.093
䡠䡠䡠
0.349 (0.098)
䡠䡠䡠
⬍0.001
䡠䡠䡠
Log baseline CAC quantity
NA
NA
䡠䡠䡠
0.651 (0.030)
Age⫻log baseline CAC quantity
NA
NA
⫺0.009 (0.002)
䡠䡠䡠
䡠䡠䡠
⬍0.001
⬍0.001
Ellipses refer to variable not selected in stepwise regression procedure in SOLAR. NA indicates not applicable.
Discussion
The present study is the first to estimate the genetic contribution
to CAC progression. There is evidence to suggest a strong,
shared genetic component to both CAC quantity at a single time
point and CAC progression, but there is also evidence suggesting that unique genes are involved in each of these measures of
subclinical coronary artery atherosclerosis. Although no one has
identified candidate genes associated with the rate of progression
of CAC, others have identified candidate genes associated with
CAC progression when defined as a qualitative trait (ie, progressors versus nonprogressors29) in individuals with type 1 diabetes.30,31 It would be important to investigate whether any
identified genes are unique for CAC progression or whether they
also are associated with cross-sectional measures of CAC
prevalence or quantity.
Several clinical trials32–34 examining LDL-C reduction
through statin therapy and CAC progression have recently been
published. These studies evaluated change in CAC over a short
period of time (ⱕ3 years) in study populations with specific
characteristics (hyperlipidemic and postmenopausal women32;
patients with ⱖ2 CAD risk factors plus moderate calcification33;
patients with calcific aortic stenosis34). Despite a reduction in
LDL-C, there was no evidence of a slowing of CAC progression.
In the present study, however, baseline LDL-C was positively
associated with increased CAC progression over a much longer
follow-up period in a community-based sample. This suggests
that LDL-C levels may be important early in the development
and progression of atherosclerosis; our finding is consistent with
that of Kuller et al35 (1999), who showed that premenopausal
LDL-C levels were powerful predictors of CAC measured 8
years after menopause (11 years after LDL-C measurement).
Future work examining the effect of LDL-C reduction on CAC
progression over an extended follow-up period may be warranted. Additionally, studies examining LDL-C reduction in
preventing detectable CAC development among those without
detectable CAC may reveal additional insight into the pathogenesis of LDL-C–mediated CAC development and/or progression.
It may also be of use to examine age- and sex-specific effects of
LDL-C reduction on CAC progression.
Limitations
Figure 1. Relationship between LDL-C and baseline CAC quantity depends on sex. Sex-specific predicted baseline CAC quantities were calculated for hypothetical participants over varying
baseline LDL-C levels, with population mean values of baseline
age, SBP, and DBP, 0 pack-years of smoking, without diabetes,
and without a family history of CHD.
Approximately one half of individuals did not belong to a
sibship. Although these individuals contributed information
to estimation of the mean and variance of the traits being
investigated, as well as to relationships between covariates
and traits of interest, they did not contribute information to
the heritability estimation. However, our baseline h2 estimates
and their SEs closely resemble those obtained by others,8 –10
suggesting that our sample is sufficient for estimating h2 of
CAC progression.
In the present study, h2 estimates may overestimate the
genetic contribution because we have not estimated shared
environments. All siblings reported living in separate households
from one another and their parents at the time of the study.
However, shared environments early in life may contribute to
Cassidy-Bushrow et al
TABLE 4.
CAC Progression Is Heritable
29
Heritability Estimates for Log Baseline CAC Quantity and CAC Progression
Trait
Covariates Adjusted for:
% of Variance
Explained by
Genetic Factors†
0.00
None
48.8
0.35
Age, sex
25.4
0.376 (0.096)
0.43
Age, sex, LDL-C, SBP, DBP, log
(pack-years of smoking⫹1),
diabetes, family history of CHD, sex⫻LDL-C
21.4
0.782 (0.101)
0.00
None
78.2
0.671 (0.108)
0.35
Age, sex
43.6
0.592 (0.109)
0.44
Age, sex, waist-to-hip ratio, LDL-C, log
(pack-years of smoking⫹1),
diabetes, hypertension, family history of CHD
33.2
0.396 (0.133)
0.64
Age, sex, waist-to-hip ratio, LDL-C, log
(pack-years of smoking⫹1),
hypertension, baseline CAC quantity, age⫻baseline CAC quantity
14.3
h2 (SE)
Covariate
Variance*
0.488 (0.104)
0.391 (0.097)
Log baseline
CAC quantity
CAC progression
All h2 estimates were significant (Pⱕ0.001).
*Proportion of variance explained by covariates.
†Calculated as 关(1⫺proportion of variance explained by covariates)⫻h2兴⫻100.
the correlations for CAC quantity8 and CAC progression seen
among adult relatives.
Our study sample was restricted to white individuals; however, CAC burden36 and progression37 vary across different
ethnic populations. Thus, future studies examining the genetic
contribution to CAC progression in other ethnic groups are
warranted.
Participants whose follow-up CAC quantity was less than
CAC quantity at baseline (n⫽52; 5.9%) were treated as having
no change in the definition of CAC progression. The mean
change in this group was ⫺1.3 mm2/y. Individuals with less
detectable CAC at follow-up compared with baseline examination were younger (mean age, 52.8⫾11.7 versus 55.8⫾10.1
years; P⫽0.042), had larger mean body mass index (30.1⫾5.3
versus 27.4⫾4.8 kg/m2; P⬍0.001), had larger mean waist-to-hip
ratio (0.89⫾0.09 versus 0.85⫾0.10; P⫽0.018), and were less
likely to report a family history of CHD (13.5% versus 35.2%;
Figure 2. Relationship between baseline age and annual change
in CAC quantity depends on baseline CAC quantity. Predicted
annual changes in CAC quantity were calculated over varying
baseline ages and CAC quantities for hypothetical women with
population mean values of waist-to-hip ratio, LDL-C, 0 packyears of smoking, and without hypertension.
P⫽0.011) than the remainder of the study sample. Only 28
(46.2%) of these 52 participants had any detectable CAC at
follow-up examination; these 28 individuals had small quantities
of detectable CAC at baseline (mean, 2.7⫾3.1 mm2; range, 0.7
to 12.2 mm2). The negative differences between baseline and
follow-up are likely attributable to measurement errors rather
than being true regression of CAC because larger body size
creates additional noise in CAC measurement,38,39 and ⱖ40% of
those with less detectable CAC at follow-up compared with
baseline had small CAC quantity detected at baseline and no
detectable CAC at follow-up. Furthermore, after we repeated our
analyses removing these 52 participants from the sample, our
inferences remained the same. Thus, treatment of these participants as having no change between baseline and follow-up is
reasonable, particularly because evidence from animal studies
indicates that although calcium progression itself may be slowed
or stopped (eg, through dietary intervention), there is no evidence suggesting that calcium deposits will exhibit a true
regression in the absence of aggressive intervention.40
Although a direct relationship exists between CAC and both
histological and in vivo measures of atherosclerotic plaque on a
Figure 3. Distribution of CAC progression as a function of log
baseline CAC quantity. Linear regression equation is as follows:
CAC progression⫽⫺1.08⫹0.79⫻(log baseline CAC quantity).
P⬍0.0001, R2⫽0.57.
30
Circulation
July 3, 2007
TABLE 5. Evidence of Pleiotropy Between Log Baseline CAC
Quantity and CAC Progression
Estimate (SE)
P for ⌿⫽0
P for ⌿⫽1
Genetic correlation (⌿g)
0.80 (0.11)
⬍0.001
0.037
Environmental correlation (⌿e)
0.42 (0.11)
0.006
Correlation (⌿)
NA
Log baseline CAC quantity and CAC progression were both adjusted for age,
sex, LDL-C, log (pack-years of smoking⫹1), diabetes, and family history of
CHD; log baseline CAC quantity for SBP, DBP, and sex⫻LDL-C; and CAC
progression for waist-to-hip ratio and hypertension. NA indicates not applicable.
heart-by-heart, vessel-by-vessel, and segment-by-segment basis,41– 45 absence of detectable CAC with EBCT does not
necessarily indicate an absence of coronary artery atherosclerosis. This measure likely underestimates total atherosclerosis
quantity and progression in some individuals because CAC
quantity more closely represents calcified plaque burden rather
than atherosclerosis.
Finally, we restricted our analyses to account for baseline
measures of risk factors only; however, change in risk factor
status over time may retard or accelerate CAC progression with
unknown effects on estimation of the role of genetic factors.
Future work should examine time-varying covariates in CAC
progression.
Conclusion
Both individual and familial characteristics (eg, genes) are
important factors in CAC progression. Importantly, there is a
genetic component to CAC progression beyond that captured by
baseline risk factors (including family history of CHD) and
baseline CAC. Baseline risk factors (including family history of
CHD) and baseline CAC may provide useful tools for identifying individuals at otherwise low to moderate risk of a CHD event
who may benefit from serial CAC screening for additional risk
stratification and/or primary prevention of disease.
Identification of specific genes associated with increased
CAC progression may provide insights into molecular mechanisms of atherosclerosis, identify new targets for therapy, and
lead to blood tests for early detection of susceptible individuals
who would benefit from early, individualized therapeutic or
lifestyle interventions for halting or slowing their CAC progression.
Sources of Funding
This research was supported by grant R01 HL46292 from the
National Institutes of Health, by a General Clinic Research Center
grant from the National Institutes of Health (MO1-RR00585)
awarded to Mayo Clinic Rochester, and by National Human Genome
Research Institute grant T32 HG00040.
Disclosures
None.
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CLINICAL PERSPECTIVE
Noninvasively measured progression of quantity of coronary artery calcification (CAC) provides independent information, in
addition to traditional coronary heart disease risk factors, for prediction of risk of future coronary events. Little is known about
factors that influence progression of CAC quantity in a community-based sample of asymptomatic adults. CAC progression over
⬇7 years was influenced by the CAC quantity at the baseline examination as well as older age, male sex, and other traditional
coronary heart disease risk factors (presence of hypertension, higher low-density lipoprotein cholesterol levels, higher
waist-to-hip ratio, family history of coronary heart disease, and smoking more cigarettes). Importantly, there was evidence for
a genetic component unique to CAC progression beyond genes for baseline risk factors and baseline CAC quantity. Identification
of specific genes associated with increased CAC progression may provide insights into molecular mechanisms of coronary
atherosclerosis, identify new targets for therapy, and lead to blood tests for early detection of susceptible individuals who would
benefit from early, individualized therapeutic or lifestyle interventions for halting or slowing their CAC progression. This study
identified measurable factors at a baseline examination that can be used immediately to identify asymptomatic adults likely to
have faster progression of subclinical coronary atherosclerosis.
Epidemiology
Association of Carotid Artery Intima-Media Thickness,
Plaques, and C-Reactive Protein With Future
Cardiovascular Disease and All-Cause Mortality
The Cardiovascular Health Study
Jie J. Cao, MD, MPH; Alice M. Arnold, PhD; Teri A. Manolio, MD, PhD;
Joseph F. Polak, MD, MPH; Bruce M. Psaty, MD, PhD; Calvin H. Hirsch, MD;
Lewis H. Kuller, MD, PhD; Mary Cushman, MD, MSc
Background—Carotid atherosclerosis, measured as carotid intima-media thickness or as characteristics of plaques, has
been linked to cardiovascular disease (CVD) and to C-reactive protein (CRP) levels. We investigated the relationship
between carotid atherosclerosis and CRP and their joint roles in CVD prediction.
Methods and Results—Of 5888 participants in the Cardiovascular Health Study, an observational study of adults aged ⱖ65
years, 5020 without baseline CVD were included in the analysis. They were followed up for as long as 12 years for CVD
incidence and all-cause mortality after baseline ultrasound and CRP measurement. When CRP was elevated (⬎3 mg/L)
among those with detectable atherosclerosis on ultrasound, there was a 72% (95% CI, 1.46 to 2.01) increased risk for
CVD death and a 52% (95% CI, 1.37 to 1.68) increased risk for all-cause mortality. Elevated CRP in the absence of
atherosclerosis did not increase CVD or all-cause mortality risk. The proportion of excess risk attributable to the
interaction of high CRP and atherosclerosis was 54% for CVD death and 79% for all-cause mortality. Addition of CRP
or carotid atherosclerosis to conventional risk factors modestly increased in the ability to predict CVD, as measured by
the c statistic.
Conclusions—In older adults, elevated CRP was associated with increased risk for CVD and all-cause mortality only in
those with detectable atherosclerosis based on carotid ultrasound. Despite the significant associations of CRP and carotid
atherosclerosis with CVD, these measures modestly improve the prediction of CVD outcomes after one accounts for the
conventional risk factors. (Circulation. 2007;116:32-38.)
Key Words: aging 䡲 arteriosclerosis 䡲 atherosclerosis 䡲 cardiovascular diseases 䡲 carotid arteries 䡲 inflammation
B
oth carotid intima-media thickness (IMT) and plaques
are measures of carotid atherosclerosis. Carotid IMT
has been linked to many cardiovascular outcomes, including cerebral and coronary events.1,2 Characteristics of
carotid plaque have been associated with stroke risk3–5 and
coronary events6 in prospective studies. With the growing
interest in cardiovascular disease (CVD) risk stratification
by combining vascular imaging with conventional risk
factors, it is essential to understand the relationship between carotid IMT and plaque and their independent and
combined contribution to the risk of coronary as well
cerebrovascular events.
In addition to ultrasonographic measures of atherosclerosis, C-reactive protein (CRP) has been shown to be a risk
factor for CVD.7–9 Although higher CRP is associated with
Editorial p 3
Clinical Perspective p 38
atherosclerosis measures such as higher carotid IMT10,11 and
complex plaque,12,13 we have shown that the association of
CRP with stroke is more apparent in the presence of a higher
carotid IMT.10 Whether the association of CRP with CVD
risk is modified by the presence of carotid atherosclerosis has
not been explored fully.
In the present study, we evaluated the hypothesis that CRP
is less predictive of CVD outcomes in the absence of
atherosclerosis by investigating the associations of carotid
IMT, carotid plaque, and CRP, alone and in combination,
with incident myocardial infarction, stroke, CVD death, and
all-cause mortality. We also examined the roles of CRP and
carotid atherosclerosis in CVD prediction.
Received June 22, 2006; accepted April 9, 2007.
From the National Heart, Lung, and Blood Institute (J.J.C.), and the National Human Genome Research Institute (T.A.M.), National Institutes of Health,
Bethesda, Md; University of Washington, Seattle (A.M.A., B.M.P.); University of California at Davis (C.H.H.); New England Medical Center, Tufts
University, Boston, Mass (J.F.P.); University of Pittsburgh, Pittsburgh, Pa (L.H.K.); and University of Vermont, Burlington (M.C.).
Correspondence to Jie J. Cao, MD, MPH, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Dr, MSC 1061, Bldg 10,
Room B1D-416, Bethesda, MD 20892. E-mail caoj@nhlbi.nih.gov
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.645606
32
Cao et al
Methods
We studied participants of the Cardiovascular Health Study (CHS),
a population-based, prospective study of men and women aged ⱖ65
years. Between 1989 and 1990, 5201 participants were enrolled from
Medicare eligibility lists in 4 counties: Forsyth County, North
Carolina; Washington County, Maryland; Sacramento County, California; and Allegheny County, Pennsylvania. To increase their
representation, a second cohort of 687 black participants was
enrolled between 1992 and 1993 with the use of similar methods.
Details of the study design have been published.14,15 The study was
approved by the institutional review boards at each participating
center. All participants gave informed consent.
All participants underwent baseline clinical examinations, which
included medical history, physical examination, and carotid ultrasound. Blood was drawn in the morning after an overnight fast.
Samples were promptly centrifuged at 3000g for 10 minutes at 4°C.
Aliquots of plasma were stored in a central laboratory at ⫺70°C.
CRP was measured in all stored baseline plasma samples by a
high-sensitivity immunoassay, with an interassay coefficient of
variation of 6.25%.16 The diagnosis of diabetes mellitus was made
following American Diabetes Association criteria as fasting glucose
ⱖ126 mg/dL or use of insulin or oral glucose-lowering agents.
Impaired fasting glucose was defined as fasting glucose ⬎110 and
⬍126 mg/dL.
The carotid arteries were evaluated at baseline with highresolution B-mode ultrasonography (model SSA-270A; Toshiba
America Medical Systems, Tustin, Calif). One longitudinal image of
the common carotid artery and 3 longitudinal images of the internal
carotid artery were acquired. The maximal IMT of the common
carotid artery and of the internal carotid artery was defined as the
mean of the maximal IMT of the near and far walls on both the left
and right sides. Focal plaques, when present, were included in the
maximum IMT measurement. Carotid IMT was defined as a composite measure that combined the maximum common and internal
carotid wall thickness of the left and right carotid arteries after
standardization (subtraction of the mean and division by the standard
deviation).17 The ultrasound reading center located in Boston, Mass,
was responsible for developing standardized protocols for both
scanning and interpretation of carotid sonographic images. The
ultrasound protocol, including measurement and reading methods,
has been published.18 The interreader variability defined by Spearman correlation coefficients on maximum wall thickness of the
common carotid artery was 0.91 and of the internal carotid artery
was 0.81.18 As for the detection of any carotid lesions, including the
wall thickness and plaque, the ␬ statistics for intrareader and
interreader agreement were 0.69 and 0.58 for the common carotid
artery and 0.73 and 0.65 for the internal carotid artery, respectively.19
Carotid plaque, defined by the appearance of the largest focal
lesion, was classified by surface characteristics, echogenicity, and
texture. Surface characteristics were classified as smooth, mildly
irregular (height variations of ⱕ0.4 mm), markedly irregular (height
variations of ⬎0.4 mm), and ulcerated (a discrete depression of
⬎2 mm in width extended into the media). Lesion echogenicity was
characterized as hypoechoic, isoechoic, hyperechoic, or calcified.
Lesion texture was classified as homogeneous or heterogeneous. In
case of multiple focal lesions, the largest lesion on each side was
measured.20 Participants were then classified as having no plaque,
intermediate-risk plaque, and high-risk plaque. Those with no plaque
were defined as having a smooth intimal surface with no focal
thickening. High-risk plaque was defined as presence of markedly
irregular or ulcerated surface or hypodense or heterogeneous plaques
that occupied ⬎50% of the total plaque volume, those features
reportedly associated with clinical CVD.3–5,20,21 The remaining
plaques, including hyperdense, calcified, or homogeneous plaques or
those with mildly irregular surface, were defined as intermediate
risk. When ⬎1 type of plaque was detected in an individual, the
plaque risk was determined by the more severe type. In some
analyses, we grouped carotid findings into binary variables: detectable and minimal atherosclerosis. Detectable atherosclerosis was
defined as present for participants in the upper 2 tertiles of carotid
wall thickness or in the intermediate- or high-risk plaque groups.
Carotid Atherosclerosis, CRP, and CVD
33
Minimal atherosclerosis was defined as having the lowest tertile of
IMT and no plaque.
The methods of ascertainment and classification of incident stroke
and myocardial infarction have been reported.22 Participants were
examined annually at each clinical site. In addition, telephone
interviews were alternated with clinic visits so that contacts were
every 6 months. Follow-up was complete through June 30, 2001.
Potential vascular events were validated through medical record
review by committees. Myocardial infarction and stroke included
incident fatal and nonfatal events. Composite CVD was defined to
include any incident myocardial infarction, stroke, or CVD death.
Of the 5888 CHS participants, 868 were excluded from analysis
because of prebaseline myocardial infarction or stroke (n⫽765),
missing CRP value (n⫽72), or missing carotid ultrasound (n⫽31).
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Statistical Analysis
Analyses were done with the use of SPSS for Windows, version
11.0.1 (SPSS, Inc, Chicago, Ill) and STATA, version 9.2 (College
Station, Tex). Incidence rates of CVD were calculated by dividing
the total number of events by the total person-years at risk over the
follow-up time within groups defined by the carotid IMT tertile,
plaque risk group, and CRP level. Pearson correlation coefficients
were computed to assess the linear relationships among carotid IMT,
CRP, and plaque. CRP was log-transformed when modeled continuously. Hazard ratios (HRs) from multivariable Cox proportional
hazards models were used to estimate the relative risks (RRs)
associated with high CRP, carotid IMT tertile, and plaque characteristics for CVD outcomes and all-cause mortality. The proportional
hazards assumption was assessed for the 3 measures of interest
(IMT, plaque risk group, and high CRP) by testing each with an
interaction for time in a Cox model. No significant interactions with
time were found. In addition, we examined Kaplan-Meier plots
visually to look for inconsistent effects over time. Participants who
died or were lost to follow-up before the event of interest or June 30,
2001, were censored at the time of death or last follow-up. Multivariable models were adjusted for age and sex and then further adjusted
for race, systolic and diastolic blood pressure, use of antihypertensive medications, body mass index, smoking (never, former, current), and amount smoked [ln(pack-years)], high-density lipoprotein
and low-density lipoprotein cholesterol, and diabetes (none, impaired fasting glucose, diabetes). All conventional risk factors were
measured at the baseline examination and were imputed if missing,
as previously described.23 The maximum percentage missing and
imputed for any variable was 3.2% for pack-years of smoking. All
other variables were imputed for ⬍0.3% of participants. Categorical
measures were modeled with the use of indicator variables for each
level compared with the lowest level, and continuous measures were
modeled linearly, per unit. We examined multiplicative and additive
interactions of CRP with measures of atherosclerosis from ultrasound.
We tested our hypothesis that CRP confers excess risk only in the
presence of atherosclerosis by stratifying on presence of atherosclerosis and by computing the relative excess risk, based on an additive
model,24 using the following 4-level variable: minimal atherosclerosis and CRP ⱕ3 mg/L, detectable atherosclerosis and CRP ⱕ3 mg/L,
minimal atherosclerosis and CRP ⬎3 mg/L, and detectable atherosclerosis and CRP ⬎3 mL/L. On the basis of an additive model,
Rothman24 defined no interaction if the difference in risk between
having both risk factors and having neither is equal to the sum of the
differences in risk between each risk factor alone and neither,
arguing that this presents the interaction in terms of the number of
excess cases, which is an appropriate scale for epidemiological
studies. Dividing by the risk when both risk factors are absent
produces an equality in terms of RR when there is no relative excess
risk due to CRP and atherosclerosis: RR(both)⫺1⫽RR(high
CRP)⫺1⫹RR(atherosclerosis)⫺1. We used Cox proportional hazards models to estimate the RR due to both risk factors and each one
singly and computed the relative excess risk due to interaction
(RERI), defined by RR(both)⫺RR(high CRP)⫺RR(atherosclero-
34
Circulation
TABLE 1.
July 3, 2007
Descriptive Statistics for the Cohort
Age, y
72.6 (5.5)
Female, %
60
Black race, %
15
Body mass index, kg/m2
26.7 (4.7)
Current smokers, %
12
Pack-years (among ever-smokers)*
27 (12 to 49)
Diabetes status, %
Normal
73
Impaired fasting glucose
12
Diabetic
15
Systolic blood pressure, mm Hg
136 (21.7)
Diastolic blood pressure, mm Hg
70.9 (11.4)
Total cholesterol, mg/dL
212 (38.8)
High-density lipoprotein cholesterol, mg/dL
55.1 (15.8)
Low-density lipoprotein cholesterol, mg/dL
CRP, mg/L*
130 (35.7)
1.86 (0.94 to 3.31)
Common carotid IMT, mm
1.06 (0.21)
Internal carotid IMT, mm
1.40 (0.55)
Plaque risk group, %
Low
23
Intermediate
21
High
56
Values expressed as mean (SD) unless otherwise indicated.
*Median (interquartile range).
sis)⫹1 for each outcome. Probability values and 95% CIs were
computed by the delta method.25 The proportion of the disease
related to high CRP and atherosclerosis, either singly or in combination, attributable to their interaction was calculated24 as
(1)
RERI
⫻100.
RERI%⫽
RR(both)⫺1
We assessed the ability of carotid atherosclerosis and CRP to
predict CVD and all-cause mortality by receiver-operating characteristic (ROC) curves and by the c statistic,26 a measure equivalent to
the area under the ROC curve, but allowing for time to event
analysis. The Hosmer-Lemeshow goodness-of-fit test, which compares observed and predicted probabilities,27 was used to assess
model fit. Because the probabilities were derived from a logistic
regression analysis, we used occurrence of events through 8 years of
follow-up, which was available for both cohorts.
Figure 1. Distribution of carotid plaque groups in carotid artery
IMT category with more complex plaque characteristics in the
thicker carotid wall.
tertile (Figure 1). The majority (80.9%) of persons in the
highest IMT tertile had high-risk plaques, with only 1.5%
having no plaque. In contrast, among those in the lowest third
of IMT, 27.4% had high-risk plaque, and 54.3% had no
plaques. The Pearson correlation coefficient between plaque
risk group and carotid IMT was 0.51 (P⬍0.001).
The linear correlation between (ln)CRP level and carotid IMT
was 0.12 and between (ln)CRP and plaque group was 0.08 (both
P⬍0.001). Within each plaque group, higher CRP was correlated with higher IMT (Figure 2). For example, in the
intermediate-risk plaque group, the geometric mean CRP ranged
from 1.58 to 1.85 to 2.20 mg/L across increasing tertiles of IMT.
When the comparison was made across the plaque groups, the
difference in CRP level again varied by IMT tertile.
Risk of CVD Related to Carotid IMT, Plaque
Group, and CRP
HRs increased from the lowest to the highest tertile of carotid
IMT for every CVD outcome and for all-cause mortality (Table
2) after adjustment for the conventional risk factors, carotid
plaque groups, and CRP. The highest tertile was associated with
an 84% increased risk of composite CVD events, 54% increased
risk of all-cause mortality, and doubling of risk for CVD death.
Compared with those with no plaque, participants with
intermediate- or high-risk plaque were at increased risk of every
CVD outcome and of all-cause mortality after adjustment for
Results
Among 5020 individuals in the analysis, the mean age was
72.6⫾5.5 years, and 60.2% were women. Other demographic
data are shown in Table 1. A total of 593 myocardial
infarctions, 613 strokes, 696 CVD deaths, and 1844 all-cause
deaths occurred during a median follow-up time of 11 years
(range, 5 days to 12 years).
Correlation of Carotid IMT Category, Plaque
Groups, and CRP
The frequencies of no plaque, intermediate-risk plaques, and
high-risk plaques were 23%, 21.4%, and 55.6%, respectively.
Carotid IMT category was related to plaque risk group, with
no plaque being more frequent in persons in the lowest IMT
tertile and high-risk plaque more frequent in the highest IMT
Figure 2. Relation of geometric mean CRP (mg/L) with carotid
IMT in tertile and plaque risk group.
Cao et al
TABLE 2.
Carotid Atherosclerosis, CRP, and CVD
35
Hazard Ratios (95% CIs)* of CVD and All-Cause Mortality by CRP, Carotid IMT, and Plaque Groups
Carotid IMT in Tertiles
Plaque Groups
Event
No.
CRP ⬎3 mg/L†
(n⫽1433)
1
(n⫽1673)
Myocardial infarction
595
1.33 (1.11 to 1.60)
1.00
1.41 (1.08 to 1.83) 1.80 (1.37 to 2.38)
1.00
1.41 (1.02 to 1.94) 1.46 (1.08 to 1.98)
Stroke
613
1.26 (1.05 to 1.51)
1.00
1.18 (0.92 to 1.51) 1.77 (1.36 to 2.30)
1.00
1.38 (1.03 to 1.86) 1.31 (0.99 to 1.73)
CVD death
696
1.50 (1.28 to 1.77)
1.00
1.23 (0.95 to 1.59) 2.15 (1.65 to 2.80)
1.00
1.50 (1.10 to 2.05) 1.43 (1.06 to 1.91)
Composite CVD
1904
1.33 (1.18 to 1.50)
1.00
1.28 (1.08 to 1.52) 1.84 (1.54 to 2.20)
1.00
1.41 (1.15 to 1.72) 1.38 (1.14 to 1.67)
All-cause mortality
1844
1.38 (1.25 to 1.53)
1.00
1.16 (1.01 to 1.35) 1.54 (1.32 to 1.79)
1.00
1.28 (1.08 to 1.52) 1.23 (1.04 to 1.44)
2
(n⫽1674)
3
(n⫽1673)
No Plaque
(n⫽1157)
Intermediate Risk
(n⫽1074)
High Risk
(n⫽2789)
*From a model that included age, sex, race, systolic and diastolic blood pressure, use of antihypertensive medications, body mass index, smoking (never, former,
current), and amount smoked (in pack-years), high-density lipoprotein and low-density lipoprotein cholesterol, diabetes (none, impaired fasting glucose, diabetes),
CRP, plaque risk group, and carotid wall thickness.
†Compared with CRP ⱕ3 mg/L.
CVD risk factors, carotid IMT, and CRP (Table 2). Compared
with those with no plaque, the HRs (95% CI) of composite CVD
were 1.86 (1.55 to 2.23) and 2.09 (1.78 to 2.46) for intermediateand high-risk plaques, respectively, after adjustment for age and
gender only but fell to 1.46 (1.21 to 1.77) and 1.42 (1.20 to 1.70),
respectively, after further adjustment for carotid IMT. Additional
adjustment for conventional risk factors and CRP only slightly
attenuated the association, with HRs of 1.41 (1.15 to 1.72) and
1.38 (1.14 to 1.67), respectively. Results were similar for
individual CVD outcomes and for all-cause mortality (Table 2).
Elevated CRP (⬎3 mg/L) was associated with increased
risk of every outcome compared with CRP ⱕ3 mg/L in the
multivariable-adjusted model. The magnitude of association
ranged from a 26% to a 50% increased risk (Table 2).
plus 19.9 for the combination of atherosclerosis and high CRP).
The observed incidence rate for participants with both risk
factors was 46.5/1000 person-years, suggestive of an excess
additive risk due to the interaction of CRP and atherosclerosis.
The total excess additive risk due to CRP, atherosclerosis, and
their interaction was (46.5⫺13.7)⫽32.8/1000 person-years, and
39% of that excess risk [(32.8⫺19.9)/32.8] was due to the
interaction of CRP and atherosclerosis. This excess risk rose to
Cardiovascular Risk Assessment by Detectable
Carotid Atherosclerosis and CRP
In multivariable Cox models stratified by amount of atherosclerosis (detectable versus minimally detectable), elevated
CRP conferred no increased hazard of composite CVD
events, CVD death, or all-cause mortality in individuals with
minimally detectable atherosclerosis, with HRs of 1.05 (95%
CI, 0.70 to 1.56), 1.14 (0.60 to 2.14), and 0.87 (0.62 to 1.23),
respectively. In contrast, the HRs for elevated CRP were
significant in those with detectable atherosclerosis: 1.45 (1.29
to 1.62) for composite CVD events, 1.72 (1.46 to 2.01) for
CVD death, and 1.52 (1.37 to 1.68) for all-cause mortality. A
significant multiplicative interaction between CRP and presence of atherosclerosis was observed for all-cause mortality.
The cumulative event rates for composite CVD and all-cause
mortality are shown in Figure 3. The increased rates associated
with CRP in the presence of atherosclerosis indicated the
possibility of an additive interaction. This finding was consistent
in individual CVD outcome (data not shown). For example, the
incidence of composite CVD in participants with minimal
atherosclerosis and CRP ⱕ3 mg/L was 13.7/1000 person-years.
Among participants with detectable atherosclerosis and CRP ⱕ3
mg/L, it was 32.9/1000 person-years (19.2/1000 person-years
higher than the baseline rate), and with minimal atherosclerosis
and CRP ⬎3 mg/L, it was 14.4/1000 person-years (0.7 personyears higher than the baseline rate). If an additive model held, we
would expect the incidence rate for participants with both risk
factors to be 33.6/1000 person-years (the baseline rate of 13.7
Figure 3. Kaplan-Meier plots of cumulative cardiovascular
events (A) and all-cause mortality (B) over 12-year follow-up
stratified by carotid atherosclerosis and CRP level (low level ⱕ3
mg/L vs high level ⬎3 mg/L). athero indicates atherosclerosis.
36
Circulation
July 3, 2007
TABLE 3. Hazard Ratios and Relative Excess Risk of Cardiovascular Outcomes With and Without Detectable Atherosclerosis and
Elevated CRP
Minimal Atherosclerosis
Detectable Atherosclerosis
Relative Excess Risk
CRP ⬎3 mg/L
(n⫽223)
CRP ⱕ3 mg/L
(n⫽2901)
CRP ⬎3 mg/L
(n⫽1210)
Adjusted Relative
Excess Risk
(95% CI)*
% Attributable
to Interaction†
P
Event
No.
CRP ⱕ3 mg/L
(n⫽686)
Myocardial infarction
595
1.00
1.16
2.24
3.52
0.65 (⫺0.14 to 1.43)
39%
0.11
Stroke
613
1.00
1.04
1.80
2.43
0.51 (⫺0.10 to 1.12)
49%
0.10
0.002
CVD death
696
1.00
1.16
2.22
4.06
1.14 (0.42 to 1.86)
54%
Composite CVD
1904
1.00
1.08
1.99
3.06
0.70 (0.26 to 1.14)
50%
0.002
All-cause mortality
1844
1.00
0.88
1.47
2.36
0.79 (0.47 to 1.12)
79%
⬍0.001
*From a model that included age, sex, race, systolic and diastolic blood pressure, use of antihypertensive medications, body mass index, smoking (never, former,
current), and amount smoked (in pack-years), high-density lipoprotein and low-density lipoprotein cholesterol, diabetes (none, impaired fasting glucose, diabetes),
CRP, plaque risk group, and carotid wall thickness.
†Proportion of disease related to high CRP and atherosclerosis, either singly or together, that is attributable to their interaction, from the multivariable models.
50% after adjustment for CVD risk factors (Table 3). The
adjusted excess risk attributable to interaction was 54% for CVD
death and 79% for all-cause mortality.
CVD Risk Prediction by Carotid Atherosclerosis
and CRP
CVD risk prediction was compared with the use of c statistics
based on models with conventional risk factors alone and
with the sequential addition of CRP ⬎3 mg/L, carotid IMT,
and carotid plaque (Table 4). c Statistics increased only
modestly with each additional risk factor. This observation
was consistent for every CVD outcome and for all-cause
mortality. The final models had excellent fit on the basis of
the Hosmer-Lemeshow goodness-of-fit test (Pⱖ0.28) except
for the stroke outcome (P⫽0.001). As shown in Figure 4,
ROC curves for composite CVD (Figure 4A) and all-cause
mortality (Figure 4B) overlapped for models with conventional risk factors alone and with the addition of CRP ⬎3
mg/L and the further addition of detectable atherosclerosis.
Discussion
In the present large cohort study, we demonstrated that elevated
CRP, carotid IMT, and carotid plaque were all correlated with
one another, yet each remained a significant risk factor for CVD
outcomes and all-cause mortality in the presence of the others.
Furthermore, elevated CRP was associated with increased CVD
and all-cause mortality risk only in those with detectable
atherosclerosis. Addition of CRP or carotid atherosclerosis to
conventional risk factors resulted in a modest increase in the
ability to predict CVD, as measured by the c statistic.
Carotid IMT and plaques are both measures of atherosclerosis,
perhaps having different attributes or risk associations but still
closely related.28,29 Common and internal carotid IMT can be
viewed as an estimate of atherosclerosis quantity. Sonographic
characterization of carotid plaque can be considered a measure of
atherosclerosis quality. Both indices are associated with CVD risk
factors and outcomes. High-risk plaques as defined here were more
common in those with thicker IMT, thus linking atherosclerosis
quality with quantity. The high-risk plaque group had a higher risk
of CVD outcomes in age- and gender-adjusted analyses than the
intermediate-risk plaque group, but this was significantly attenuated
after carotid IMT was taken into account. The definition of high-risk
plaque in the present study was based on features previously
demonstrated to be associated with stroke risk, and high-risk plaque
was common in this older cohort. That the RR of CVD associated
with high-risk plaque was comparable to that of intermediate-risk
plaque after accounting for wall thickness suggests that ultrasound
definition of high-risk or vulnerable plaque can be challenging. We
suggest that future research on plaque quality should evaluate
atherosclerosis quantity when assessing risk of CVD.
CRP-related risk of CVD and all-cause mortality differed by
the severity of atherosclerosis in this cohort of older adults.
Elevated CRP was not associated with increased risk of CVD or
all-cause mortality in the group with minimal atherosclerosis, an
observation that was consistent with our previous report on
stroke risk from the present study.10 However, there was signif-
TABLE 4. c Statistics for Models of Cardiovascular Outcomes and All-Cause
Mortality With Conventional Risk Factors and Additionally With Elevated CRP,
Carotid IMT, and Carotid Plaque
Outcome
Covariates* With CRP ⱖ3 mg/L With Carotid Tertile With Plaque Group
Myocardial infarction
0.6799
0.6829
0.6971
0.6981
Stroke
0.6856
0.6869
0.6984
0.6994
CVD death
0.7424
0.7485
0.7626
0.7632
Composite CVD
0.6840
0.6867
0.7009
0.7017
All-cause mortality
0.7151
0.7188
0.7247
0.7252
*Covariates included age, gender, race, body mass index, smoking status, pack-years of smoking,
diabetes, systolic and diastolic blood pressure, total cholesterol, and high-density lipoprotein and
low-density lipoprotein cholesterol.
Cao et al
0.00
0.25
Sensitivity
0.50
0.75
1.00
A
0.00
0.25
0.50
1-Specificity
0.75
1.00
0.00
0.25
Sensitivity
0.50
0.75
1.00
B
0.00
0.25
0.50
1-Specificity
0.75
1.00
Figure 4. ROC curves for composite cardiovascular outcomes
(A) and for all-cause mortality (B) during 12-year follow-up. The
curves are based on models of the risk prediction with conventional risk factors with or without CRP ⬎3 mg/L and with or
without detectable carotid atherosclerosis. In A, the areas under
the ROC curves are 0.6942, 0.6963, and 0.7086 for models with
cardiovascular risk factors only, with the addition of CRP ⬎3
mg/L, and with the further addition of carotid atherosclerosis,
respectively. In B, the areas under the ROC curves are 0.7508,
0.7543, and 0.7582 for the same 3 models as in A, respectively.
Dotted lines indicate CVD risk factors; dashed lines, plus CRP;
and solid lines, plus atherosclerosis.
Carotid Atherosclerosis, CRP, and CVD
37
prediction by adding CRP to the conventional risk factors, as
shown recently by Bos et al34 and Wang et al.35 We expanded
our observation to the detection of carotid atherosclerosis that
identifies a population at risk for CVD outcomes but does not
seem to significantly increase the ability to predict a CVD event
for an individual patient, as demonstrated by the modest increment in c statistics over conventional CVD risk factors. Similar
findings have been demonstrated previously,36,37 although it is
still debatable whether ROC curve or c statistics is the best way
to assess the power of risk prediction for a given risk factor.38
We recognize the limitations of the present study. The
definition of high-risk plaque was based on published data
linking certain plaque characteristics with clinical events, and by
this definition 53% of participants had high-risk plaques. This
classification was designed to provide a model to study the
interaction of carotid IMT and plaque characteristics, and therefore we caution against the clinical use of this approach. In the
CHS, reproducibility of assessing plaque characteristics by
ultrasound was only moderate3 and would need improvement for
routine clinical application. Finally, a single measure of CRP
was used, which may be subject to error.
To summarize, carotid IMT, plaque, and elevated CRP each
independently contributed to the risk of CVD and all-cause
mortality in models that included all 3 measures. However,
elevated CRP was associated with CVD events and all-cause
mortality only in those with detectable atherosclerosis. Addition
of CRP or carotid atherosclerosis to conventional risk factors
resulted in a modest increase in the ability to predict CVD on the
basis of ROC analysis.
Acknowledgments
A full list of participating CHS investigators and institutions can be
found at http://www.chs-nhlbi.org.
Sources of Funding
This research was supported by contracts N01-HC-85079 through
N01-HC-85086, N01-HC-35129, and N01 HC-15103 from the
National Heart, Lung, and Blood Institute.
Disclosures
icant excess additive risk when CRP was elevated in individuals
with detectable atherosclerosis. This finding supports a complex
relationship among inflammation, subclinical atherosclerosis,
and clinical CVD.30 Determining a patient’s risk for CVD events
or all-cause mortality on the basis of the level of CRP may thus
be clinically challenging if CRP is used in low-risk populations
in whom atherosclerosis burden might be small. This conclusion
is in accord with recent findings in a population of young
women.31 Further research is needed in this area.
In the present study, the increased rates associated with CRP
only in the presence of atherosclerosis indicated the possibility
of an additive interaction. We demonstrated an excess risk of
CVD and all-cause mortality as a result of the additive interaction of elevated CRP and detectable atherosclerosis. Although
most atherosclerosis epidemiology studies use multiplicative
interaction to test effect modification, there are times when
additive effects may reflect the underlying mechanism, as
evident by our data and the data of others.32,33
Despite the significant association between CRP and CVD
outcomes, only modest improvement is made in CVD risk
None.
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CLINICAL PERSPECTIVE
Ultrasound-determined carotid intima-media thickness and presence of plaques are measures of carotid atherosclerosis.
Higher carotid intima-media thickness is a risk marker for future stroke and coronary heart disease. Characteristics of
carotid plaque have also been associated with vascular risk. C-reactive protein (CRP) is also a risk factor for cardiovascular
disease. In the present study we examined the relationship of carotid atherosclerosis and CRP and their joint roles in
cardiovascular risk prediction in 5022 elderly individuals (ⱖ65 years) who were the participants of the Cardiovascular
Health Study. After up to 12 years of follow-up, we found that when CRP was elevated (⬎3 mg/L) among those with
detectable atherosclerosis on ultrasound, there was a significantly increased risk for cardiovascular disease and all-cause
mortality. Elevated CRP in the absence of atherosclerosis did not increase cardiovascular or all-cause mortality risk. We
concluded that determining a patient’s risk for cardiovascular events or all-cause mortality on the basis of the level of CRP
may be clinically challenging if CRP is used in low-risk populations in whom atherosclerosis burden might be small.
Abdominal Visceral and Subcutaneous Adipose
Tissue Compartments
Association With Metabolic Risk Factors in the Framingham Heart Study
Caroline S. Fox, MD, MPH; Joseph M. Massaro, PhD; Udo Hoffmann, MD, MPH; Karla M. Pou, MD;
Pal Maurovich-Horvat, MD; Chun-Yu Liu, PhD; Ramachandran S. Vasan, MD;
Joanne M. Murabito, MD, ScM; James B. Meigs, MD, MPH; L. Adrienne Cupples, PhD;
Ralph B. D’Agostino, Sr, PhD; Christopher J. O’Donnell, MD, MPH
Background—Visceral adipose tissue (VAT) compartments may confer increased metabolic risk. The incremental utility
of measuring both visceral and subcutaneous abdominal adipose tissue (SAT) in association with metabolic risk factors
and underlying heritability has not been well described in a population-based setting.
Methods and Results—Participants (n⫽3001) were drawn from the Framingham Heart Study (48% women; mean age, 50
years), were free of clinical cardiovascular disease, and underwent multidetector computed tomography assessment of
SAT and VAT volumes between 2002 and 2005. Metabolic risk factors were examined in relation to increments of SAT
and VAT after multivariable adjustment. Heritability was calculated using variance-components analysis. Among both
women and men, SAT and VAT were significantly associated with blood pressure, fasting plasma glucose, triglycerides,
and high-density lipoprotein cholesterol and with increased odds of hypertension, impaired fasting glucose, diabetes
mellitus, and metabolic syndrome (P range ⬍0.01). In women, relations between VAT and risk factors were consistently
stronger than in men. However, VAT was more strongly correlated with most metabolic risk factors than was SAT. For
example, among women and men, both SAT and VAT were associated with increased odds of metabolic syndrome. In
women, the odds ratio (OR) of metabolic syndrome per 1–standard deviation increase in VAT (OR, 4.7) was stronger
than that for SAT (OR, 3.0; P for difference between SAT and VAT ⬍0.0001); similar differences were noted for men
(OR for VAT, 4.2; OR for SAT, 2.5). Furthermore, VAT but not SAT contributed significantly to risk factor variation
after adjustment for body mass index and waist circumference (P ⱕ0.01). Among overweight and obese individuals, the
prevalence of hypertension, impaired fasting glucose, and metabolic syndrome increased linearly and significantly
across increasing VAT quartiles. Heritability values for SAT and VAT were 57% and 36%, respectively.
Conclusions—Although both SAT and VAT are correlated with metabolic risk factors, VAT remains more strongly
associated with an adverse metabolic risk profile even after accounting for standard anthropometric indexes. Our
findings are consistent with the hypothesized role of visceral fat as a unique, pathogenic fat depot. Measurement of VAT
may provide a more complete understanding of metabolic risk associated with variation in fat distribution. (Circulation.
2007;116:39-48.)
Key Words: abdominal fat 䡲 diabetes mellitus 䡲 epidemiology 䡲 hypertension 䡲 intra-abdominal fat
䡲 metabolic syndrome X 䡲 obesity
C
ardiovascular disease (CVD) is the leading cause of
morbidity and mortality in the United States, affecting
roughly 70 million people and accounting for nearly 1 million
deaths per year.1 Improvements in CVD risk factor profiles
have led to significant reductions in death from CVD over the
Clinical Perspective p 48
past 50 years, but recent data suggest that the increasing
prevalence of obesity may have slowed this rate of decline.3
Rates of overweight and obesity continue to increase,4 – 6
2
Received November 9, 2006; accepted April 18, 2007.
From the National Heart, Lung and Blood Institute’s Framingham Heart Study (C.S.F., C.J.O.), Framingham, Mass; Division of Endocrinology,
Metabolism, and Diabetes, Department of Medicine (C.S.F., K.M.P.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass;
Boston University, Department of Mathematics (J.M.M.; R.B.D.) and School of Public Health, Division of Biostatistics (C.-Y.L., L.A.C.), Boston, Mass;
Radiology Department (U.H.) and Department of Medicine (J.B.M., C.J.O.), Massachusetts General Hospital, Harvard Medical School, Boston;
Semmelweis University (P.M.-H.), Budapest, Hungary; and Boston University School of Medicine (R.S.V.), Boston, Mass.
Guest Editor for this article was Robert H. Eckel, MD.
The online-only Data Supplement, which consists of a table, is available with this article at http://circ.ahajournals.org/cgi/
content/full/CIRCULATIONAHA.106.675355/DC1.
Correspondence to Caroline S. Fox, MD, MPH, 73 Mt Wayte Ave, Ste 2, Framingham, MA 01702. E-mail foxca@nhlbi.nih.gov
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.675355
40
Circulation
July 3, 2007
which suggests that the full impact of the obesity epidemic
has yet to be realized.
Obesity, defined by a body mass index (BMI) of at least 30
kg/m2, is a risk factor for multiple CVD risk factors, including
hypertension, dyslipidemia, diabetes, and the metabolic syndrome (MetS). BMI is a useful indicator of overall adiposity,
and recent National Health and Nutrition Examination Survey
data demonstrate that two thirds of the US population is either
overweight or obese.6 However, different fat compartments
may be associated with differential metabolic risk.7 In particular, the visceral adipose tissue (VAT) compartment may
be a unique pathogenic fat depot.8 –10 VAT has been termed
an endocrine organ, in part because it secretes adipocytokines
and other vasoactive substances that can influence the risk of
developing metabolic traits.10 –16
Waist circumference (WC) is an easily obtainable but
imprecise measure of abdominal adiposity17 because it is a
function of both the subcutaneous adipose tissue (SAT) and
VAT compartments. Therefore, assessment of VAT requires
imaging with radiographic techniques such as computed
tomography (CT) or magnetic resonance imaging (MRI).
Available studies report relations of greater SAT and VAT
with a higher prevalence of impaired fasting glucose,9,18
diabetes,9,10,19 insulin resistance,9,20,21 hypertension,22–24 lipids,25–29 MetS,30 –32 and risk factor clustering.26 However,
current imaging studies evaluating SAT and VAT are limited
to small, referral-based samples often enriched for adiposityrelated traits.23,25–27,32–34 Furthermore, study samples have
often been limited to either women or men, precluding the study
of sex differences.22,23,25–28,34 –36 Some studies have focused on
Japanese Americans or Southeast Asians,19,22,26,29,35,37 ethnic
groups with more visceral fat than expected for a given overall
BMI.38 We recently demonstrated that multidetector CT permits
highly reproducible volumetric measurements of both SAT and
VAT.39 In addition, this initial observation suggested that volumetric fat measurements, as opposed to previous studies using
single-slice methodology, can accurately characterize the heterogeneity of abdominal fat distribution between individuals and
the differences in fat distribution with age and between women
and men.
Thus, our aims in a community-based sample of women
and men free of CVD across the spectrum of BMI were to
assess whether the volume of SAT and VAT are associated
with metabolic risk factors cross-sectionally, to assess
whether VAT is more strongly associated with metabolic risk
factors than is SAT, and to determine whether sophisticated
volumetric imaging methods of SAT and VAT provide
information about metabolic risk other than that offered by
simpler measures such as BMI and WC.
Methods
Study Sample
Participants for this study were drawn from the Framingham Heart
Study Multidetector Computed Tomography Study, a populationbased substudy of the community-based Framingham Heart Study
Offspring and Third-Generation Study cohorts. Beginning in 1948,
5209 men and women 28 to 62 years of age were enrolled in the
original cohort of the Framingham Heart Study. The offspring and
spouses of the offspring of the original cohort were enrolled in the
Offspring Study starting in 1971. Selection criteria and study design
have been described elsewhere.40,41 Beginning in 2002, 4095 Third
Generation Study participants, who had at least 1 parent in the
offspring cohort, were enrolled in the Framingham Heart Study and
underwent standard clinic examinations. The standard clinic examination included a physician interview, a physical examination, and
laboratory tests. For the present study, the study sample consisted of
Offspring and Third Generation Study participants who were part of
the multidetector CT substudy.
Between June 2002 and April 2005, 3529 participants (2111 third
generation, 1418 offspring participants) underwent multidetector CT
assessment of coronary and aortic calcium. Inclusion in this study
was weighted toward participants from larger Framingham Heart
Study families and those who resided in the greater New England
area. Overall, 755 families were included in our analysis. Men had to
be ⱖ35 years of age; women had to be ⱖ40 years of age and not
pregnant; and all participants had to weigh ⬍350 pounds. Of the
participants, 433 (222 offspring and 211 third generation) were
imaged as participants in an ancillary study using an identical
imaging protocol, the National Heart, Lung, and Blood’s Family
Heart Study.42 Of the total 3529 subjects imaged, 3394 had interpretable CT measures; of those, 3329 had both SAT and VAT
measured; of those, 3124 of them were free of CVD; of those, 3102
attended a contemporaneous examination; and of those, 3001 had a
complete covariate profile. Thus, the overall sample size for analysis
is 3001.
The study was approved by the institutional review boards of the
Boston University Medical Center and Massachusetts General Hospital. All subjects provided written informed consent.
Volumetric Adipose Tissue Imaging
Subjects underwent 8-slice multidetector CT imaging of the abdomen in a supine position as previously described (LightSpeed Ultra,
General Electric, Milwaukee, Wis).39 Briefly, 25 contiguous 5-mmthick slices (120 kVp; 400 mA; gantry rotation time, 500 ms; table
feed, 3:1) were acquired covering 125 mm above the level of S1.
Abdominal Adipose Tissue Measurements
SAT and VAT volumes were assessed (Aquarius 3D Workstation,
TeraRecon Inc, San Mateo, Calif). To identify pixels containing fat,
an image display window width of ⫺195 to ⫺45 Hounsfield units
(HU) and a window center of ⫺120 HU were used. The abdominal
muscular wall separating the visceral from the subcutaneous compartment was traced manually. Interreader reproducibility was assessed by 2 independent readers measuring VAT and SAT on a
subset of 100 randomly selected participants.39 Interclass correlations for interreader comparisons were 0.992 for VAT and 0.997 for
SAT. Similarly high correlations were noted for intrareader
comparisons.
Risk Factor and Covariate Assessment
Risk factors and covariates were measured at the contemporaneous
examination. BMI, defined as weight (in kilograms) divided by the
square of height (in meters), was measured at each index examination. WC was measured at the level of the umbilicus. Fasting plasma
glucose, total and high-density lipoprotein (HDL) cholesterol, and
triglycerides were measured on fasting morning samples. Diabetes
was defined as a fasting plasma glucose level ⱖ126 mg/dL at a
Framingham examination or treatment with either insulin or a
hypoglycemic agent. Participants were considered current smokers if
they had smoked at least 1 cigarette per day for the previous year.
Assessed through a series of physician-administered questions,
alcohol use was dichotomized on the basis of consumption of ⬎14
drinks per week (in men) or 7 drinks per week (in women). Physical
activity, assessed with a questionnaire, is a score based on the
average daily number of hours of sleep and sedentary, slight,
moderate, and heavy activity of the participant. Women were
considered menopausal if their periods had stopped for ⱖ1 year.
Impaired fasting glucose was defined as a fasting plasma glucose
level of 100 to 125 mg/dL among those not treated for diabetes.
Hypertension was defined as systolic blood pressure ⱖ140 mm Hg,
Fox et al
diastolic blood pressure ⱖ90 mm Hg, or on treatment. MetS was
defined from modified Adult Treatment Panel criteria.43
CT Adipose Tissue and Cardiometabolic Risk
TABLE 1. Clinical Characteristics of Study Participants Free of
Clinical CVD Who Underwent Radiographic Assessment of SAT
and VAT Volumes
Statistical Analysis
SAT and VAT were normally distributed. Sex-specific age-adjusted
Pearson correlation coefficients were used to assess simple correlations between SAT and VAT and metabolic risk factors. Multivariable linear and logistic regression was used to assess the significance
of covariate-adjusted cross-sectional relations between continuous
and dichotomous metabolic risk factors and SAT and VAT. For
continuous risk factors, the covariate-adjusted average change in risk
factor per 1–standard deviation (SD) increase in adipose tissue was
estimated; for dichotomous risk factors, the change in odds of the
risk factor prevalence per 1-SD increase in adipose tissue was
estimated. All models were sex specific to account for the strong sex
interactions observed. Covariates in all models included age, smoking (3-level variable: current/former/never smoker), physical activity, alcohol use (dichotomized at ⬎14 drinks per week in men or ⬎7
drinks per week in women), menopausal status, and hormone
replacement therapy. In addition, lipid treatment, hypertension treatment, and diabetes treatment were included as covariates in models
for HDL cholesterol, log triglycerides, systolic and diastolic blood
pressures, and fasting plasma glucose, respectively. R2 values were
computed for continuous models and c statistics were computed for
dichotomous models to assess the relative contribution of SAT and
VAT to explain the outcomes (risk factors). For each risk factor, tests
for the significance of the difference between the SAT and VAT
regression coefficients were carried out within a multivariate standardized regression (in which variables were first standardized to a
mean of 0 and an SD of 1) to assess the relative importance of each
adipose tissue measurement in predicting the risk factor. To assess
the incremental utility of adding VAT to models that contain BMI or
WC, the above multivariate analyses were repeated for VAT with
BMI and WC added as covariates in the multivariate regression
models. Similar models were not examined for SAT because models
with SAT alone did not yield higher R2 or c statistics than models
that included BMI and WC alone. As a secondary analysis, the above
multivariate regressions were rerun using the general estimating
equation linear and logistic regression44 to account for correlations
among related individuals (siblings) in the study sample. SAS
version 8.0 was used to perform all computations; a 2-tailed value of
P⬍0.05 was considered significant.44
Heritability Analysis
Heritability quantifies the proportion of trait variability resulting
from the additive effect of genes; the contributions of both genes and
early common environment cannot be differentiated. Heritability
calculations rely on the assumption that trait variation can be
partitioned into genetic, known covariates and environmental (unknown) components. It is further assumed that the genetic component is polygenic; there is no variation attributable to dominance
components. To determine the heritability of SAT and VAT, we
created sex-specific and cohort-specific residuals from multivariable
regression after adjusting for age, age squared, smoking, and
menopausal status using the overall sample with interpretable CT
scans. Residuals were then pooled, and SOLAR45 was used to
calculate heritabilities using variance-components analysis.
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
41
Women
(n⫽1452)
Age, y
BMI, kg/m2
WC, cm
Triglycerides,* mg/dL
Men (n⫽1549)
51⫾9
49⫾10
26.7⫾5.4
28.3⫾4.4
92⫾14
103⫾11
92 (65, 134)
113 (76, 171)
HDL cholesterol, mg/dL
62⫾17
46⫾12
Total cholesterol, mg/dL
197⫾36
196⫾34
Systolic blood pressure, mm Hg
119⫾17
123⫾14
Diastolic blood pressure, mm Hg
73⫾9
78⫾9
Hypertension, %
Fasting plasma glucose, mg/dL
Impaired fasting glucose,† %
Diabetes mellitus, %
MetS, %
24
95⫾16
18
4.2
28
101⫾20
38
6.1
25
35
12
13
Former
42
34
Never
46
53
Postmenopausal, %
48
䡠䡠䡠
Hormone replacement therapy, %
23
Alcohol use,‡ %
15
䡠䡠䡠
16
Smoking, %
Current
SAT, cm3
3071⫾1444
2603⫾1187
VAT, cm3
1306⫾807
2159⫾967
Data are presented as mean⫾SD when appropriate.
*Median (25th, 75th percentiles).
†Fasting plasma glucose of 100 to 125 mg/dL; percentage is based on those
without diabetes.
‡Defined as ⬎14 drinks per week (men) or ⬎7 drinks per week (women).
The mean SAT volume was 3071⫾1444 cm3 in women
and 2603⫾1187 cm3 in men. The mean VAT volume in
women was 1306⫾807 cm3 and in men was 2159⫾967 cm3.
Correlations With SAT and VAT
Correlations of SAT and VAT with metabolic risk factors are
shown in Table 2. SAT was positively correlated with age in
women (r⫽0.13, P⬍0.001) but not men, and VAT was
positively correlated with age in both sexes (r⫽0.36 in
women and men, P⬍0.001). SAT and VAT were highly
correlated, with an age-adjusted correlation coefficient between SAT and VAT of 0.71 (P⬍0.0001) in women and 0.58
(P⬍0.0001) in men. Both BMI and WC were strongly
correlated with SAT and VAT after adjustment for age (Table
2). All risk factors were highly correlated with both SAT and
VAT, except for serum total cholesterol with SAT in men and
physical activity index with VAT in men.
Results
Overall, 1452 women and 1549 men were available for
analysis. The mean age was 50 years (Table 1); approximately one quarter of the sample was hypertensive, 5% had
diabetes, and approximately one third had MetS. Approximately half of the women were postmenopausal.
Multivariable-Adjusted Regressions With SAT,
VAT, and Metabolic Risk Factor Variables
Results of multivariable-adjusted general linear regression
analyses for SAT and VAT for both continuous and dichotomous metabolic risk factors are shown in Table 3. In
42
Circulation
July 3, 2007
TABLE 2. Age-Adjusted Pearson Correlation Coefficients
Between Metabolic Risk Factors and SAT and VAT Volumes
Women
Men
SAT
VAT
SAT
VAT
Age
0.13†
0.36†
0.03
0.36†
BMI
0.88†
0.75†
0.83†
0.71†
WC
0.87†
0.78†
0.88†
0.73†
Log triglycerides
0.31†
0.46†
0.18†
0.37†
HDL cholesterol
⫺0.25†
⫺0.35†
⫺0.17†
⫺0.33†
Total cholesterol
0.11†
0.15†
0.02
0.08*
Systolic blood pressure
0.26†
0.30†
0.18†
0.24†
Diastolic blood pressure
0.26†
0.28†
0.21†
0.27†
Blood glucose
0.23†
0.34†
0.12†
0.19†
⫺0.14†
⫺0.09*
⫺0.08*
Physical activity index
⫺0.03
*P⬍0.01; †P⬍0.001.
women, per 1-SD increase in SAT, systolic blood pressure
increased on average 3.9⫾0.4 mm Hg (⫾1 SE), whereas
VAT was 4.8⫾0.4 mm Hg higher. For systolic blood pressure
in women, the difference between the magnitude of effect of
the SAT versus VAT was not significant (P⫽0.10; Table 3).
In men, the magnitude of the association of the average
systolic blood pressure increase per 1-SD increase in VAT
was larger than for SAT (3.3 versus 2.3 mm Hg, respectively;
P⫽0.01 for difference in the regression coefficients between
SAT and VAT). Similar results were obtained for diastolic
blood pressure.
In women and men, the association of both SAT and VAT
with continuous measures of metabolic risk factors was
highly significant. For fasting plasma glucose, the effect of
VAT was stronger than that of SAT (P⬍0.0001 for difference
in women, P⫽0.001 in men). Strong and significant results
for log triglycerides and HDL cholesterol followed similar
patterns (Table 3).
Highly significant associations with SAT and VAT also
were noted for dichotomous risk factor variables. Among
women and men, both SAT and VAT were associated with an
increased odds of hypertension (Table 3). In women, the odds
ratio of hypertension per 1-SD increase in VAT (odds ratio,
2.1) was stronger than that for SAT (odds ratio, 1.7; P⫽0.001
for difference between SAT and VAT); similar differences
were noted for men. Similar highly significant differences
also were noted for impaired fasting glucose, diabetes, and
MetS and are presented in Table 3.
The magnitude of association between VAT and all risk
factors examined was consistently greater for women than for
men (Table 3). Weaker sex differences were observed for
SAT.
Residual Effect of VAT in Multivariable Models
That Contain BMI and WC
To address whether radiographic imaging of abdominal
adipose tissue explains variation in metabolic risk factors
over and above the contribution of BMI and WC, we
examined the residual effect size of each metabolic risk factor
from multivariable models that additionally contained BMI
and WC. Because models with BMI and WC routinely
yielded higher R2 or c statistic than models with SAT (Table
I in the online-only Data Supplement), the addition of all 3
variables into one model was not pursued. For example, in
women, SAT plus covariates were associated with 21% of the
variation in log triglycerides (R2⫽0.21), VAT plus covariates
were associated with 30% of the variation in log triglycerides,
and both BMI and WC plus the covariates were associated
with 26% of the variation in triglycerides. Models with VAT,
BMI, and WC demonstrated significant additional contribution of VAT for all variables except diabetes in men.
Statistically significant residual effect sizes for VAT were
observed for all metabolic risk factors except diabetes in men
(Table 3).
Risk Factor Distribution Based on Quartiles of VAT
Because VAT adds to risk factor variation above and beyond
BMI and WC, we assessed the impact of stratifying individuals by VAT quartile within clinically defined categories of
BMI (normal weight, BMI ⬍25 kg/m2; overweight, BMI of
25 to 29.9 kg/m2; and obese, BMI ⱖ30 kg/m2). Thirty-three
percent of the sample was normal weight, 41% was overweight, and 26% was obese. Among normal-weight, overweight, and obese individuals, there was a highly statistically
significant stepwise linear increase in the prevalence of the
MetS across quartiles of VAT in both women and men (see
the Figure) after adjustment for age and BMI; similar relations were noted for additional risk factors, including hypertension and impaired fasting glucose.
Secondary Analysis
When education status was included as an additional covariate, relations between SAT and VAT and the continuous and
dichotomous metabolic risk factors were not materially different (data not shown). When analyses were rerun using the
general estimating equation procedure, the resulting probability values were not substantively changed from those
discussed above (data not shown).
Heritability Analysis
Heritability for SAT was 57%, whereas heritability for VAT
was 36%.
Discussion
In our community-based sample, volumetric CT measures of
both SAT and VAT were correlated with multiple metabolic
risk factors, although risk factor correlations with VAT were
consistently significantly stronger than those for SAT. VAT,
not SAT, provided information above and beyond simple
clinical anthropometrics, including BMI and WC, and consistently provided differences in risk factor stratification
among individuals who were overweight and obese. VAT
was more strongly associated with metabolic risk factors in
women than in men. Finally, both SAT and VAT are heritable
traits.
VAT has traditionally been considered the more pathogenic adipose tissue compartment compared with SAT, but
data confirming these relations using high-resolution volumetric imaging assessments in large, community-based sam-
Fox et al
CT Adipose Tissue and Cardiometabolic Risk
43
TABLE 3. Sex-Specific Multivariable-Adjusted* Regressions for SAT and VAT With Continuous Metabolic Risk Factors (Top) and
Dichotomous Risk Factors (Bottom)
Women
MV-Adjusted
Residual
Effect Size
P for
Either SAT
or VAT†
Men
P for
SAT vs VAT‡
Residual Effect
Size After
MV/BMI/WC
Adjustment
MV-Adjusted
Residual
Effect Size
䡠䡠䡠
2.5⫾0.7
2.3⫾0.3
⬍0.0001
0.10
3.3⫾0.4
⬍0.0001
䡠䡠䡠
1.4⫾0.4
1.9⫾0.2
⬍0.0001
0.33
2.6⫾0.2
⬍0.0001
1.6⫾0.4
0.0002
⬍0.0001
䡠䡠䡠
3.4⫾0.6
3.1⫾0.5
⬍0.0001
䡠䡠䡠
0.19⫾0.02
0.10⫾0.01
0.003
⬍0.0001
0.22⫾0.01
⬍0.0001
P for Either
SAT or VAT†
P for
SAT vs VAT‡
Residual Effect
Size After
MV/BMI/WC
Adjustment
P for Sex
Interaction
0.01
䡠䡠䡠
1.8⫾0.05
⬍0.0001
0.008
䡠䡠䡠
1.5⫾0.3
0.01
0.001
䡠䡠䡠
1.8⫾0.7
⬍0.0001
䡠䡠䡠
0.22⫾0.02
SBP
SAT
3.9⫾0.4
⬍0.0001
VAT
4.8⫾0.4
⬍0.0001
0.01
DBP
SAT
2.2⫾0.2
⬍0.0001
VAT
2.6⫾0.3
⬍0.0001
SAT
3.4⫾0.3
⬍0.0001
VAT
4.8⫾0.4
⬍0.0001
SAT
0.14⫾0.01
⬍0.0001
VAT
0.23⫾0.01
⬍0.0001
0.77
FPG
0.03
⬍0.0001
Log TG
0.16
0.0002
HDL
SAT
⫺3.9⫾0.4
⬍0.0001
VAT
⫺5.9⫾0.4
⬍0.0001
䡠䡠䡠
⫺4.5⫾0.7
⫺2.0⫾0.3
⬍0.0001
⬍0.0001
⫺4.5⫾0.3
⬍0.0001
䡠䡠䡠
1.6 (1.3–2.0)
1.5 (1.4–1.7)
⬍0.0001
⬍0.0001
1.9 (1.6–2.1)
⬍0.0001
1.5 (1.3–1.7)
⬍0.0001
0.001
䡠䡠䡠
2.1 (1.7–2.6)
1.8 (1.6–2.0)
⬍0.0001
䡠䡠䡠
1.9 (1.3–2.7)
1.6 (1.3–1.9)
⬍0.0001
0.0003
1.6 (1.3–2.0)
⬍0.0001
䡠䡠䡠
1.9 (1.3–2.7)
2.5 (2.2–2.8)
⬍0.0001
⬍0.0001
4.2 (3.5–5.0)
⬍0.0001
⬍0.0001
䡠䡠䡠
⫺3.8⫾0.5
0.006
⬍0.0001
HTN
SAT
1.7 (1.5–2.0)
⬍0.0001
VAT
2.1 (1.8–2.4)
⬍0.0001
SAT
2.0 (1.7–2.3)
⬍0.0001
VAT
2.5 (2.1–2.9)
⬍0.0001
0.89
0.006
䡠䡠䡠
1.6 (1.3–1.9)
0.005
䡠䡠䡠
1.5 (1.2–1.8)
⬍0.0001
0.91
䡠䡠䡠
0.9 (0.7–1.3)
0.03
⬍0.0001
䡠䡠䡠
2.6 (2.1–3.2)
0.002
0.01
IFG
0.04
DM
SAT
1.6 (1.2–2.0)
0.007
VAT
2.1 (1.6–2.6)
⬍0.0001
0.27
MetS
SAT
3.0 (2.6–3.5)
⬍0.0001
VAT
4.7 (3.9–5.7)
⬍0.0001
0.77
MV indicates multivariable; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TG, triglycerides; HTN, hypertension; IFG,
impaired fasting glucose; and DM, diastolic mellitus. Data presented include effect size (the average change in risk factor⫾SE) per 1 SD in adipose tissue for
continuous data, and the change in odds of the condition per 1 SD of adipose tissue with 95% CIs for dichotomous data.
*Adjusted for age, smoking, alcohol use, physical activity, and menopausal status (women only), hormone replacement therapy (women only); for blood pressure,
FPG, HDL cholesterol, and log triglycerides, an additional covariate of treatment for HTN, diabetes, or lipid disorders, respectively, was included.
†For SAT or VAT in the model.
‡For SAT vs VAT difference.
ples of women and men have been lacking. The mechanism
of increased metabolic risk is hypothesized to be related to
the metabolically active adipose tissue found in the visceral
region,7–16 in addition to the drainage of these substances
directly into the portal circulation.46 Multiple small studies
have demonstrated that the visceral fat compartment is
metabolically active, secreting such vasoactive substances as
inflammatory markers,15,47 adipocytokines,10,13,48,49 markers
of hemostasis and fibrinolysis (including plasminogen activator inhibitor-1),50,51 and growth factors (including vascular
endothelial growth factor),52 which may contribute to its role
in cardiometabolic risk factor manifestation.53–55
Our results are consistent with these prior findings in small
studies and extend these findings to a well-characterized,
community-based sample of men and women in that we show
that all cardiometabolic risk factors examined were more
strongly associated with VAT than SAT. We also extend the
current literature to note statistically significant, albeit
weaker, correlations with SAT. Although SAT and VAT are
highly correlated with each other, we used the R2 (for
continuous variables) and c statistic (for dichotomous variables) to determine the total variance explained by SAT and
VAT. We also performed a formal test of the difference in the
␤-coefficients for SAT compared with VAT in relation to the
outcome variables, and in nearly every situation, the
␤-coefficient from the regression model was stronger for
VAT than for SAT. Of note, SAT volume is greater than VAT
volume in both women and men. Therefore, although the
44
Circulation
July 3, 2007
Men
Women
Prevalence (%)
A
40
40
30
30
20
***
**
10
0
IFG
DM
MetS
100
Prevalence (%)
***
***
DM
MetS
*
***
***
20
0
HTN
Prevalence (%)
60
40
***
20
100
80
60
40
20
0
IFG
80
60
40
HTN
100
80
0
C
**
10
0
HTN
B
**
20
IFG
DM
***
**
**
HTN
IFG
DM
HTN
MetS
MetS
*p<0.05 **p<0.01 ***p<0.001
100
80
60
40
20
0
IFG
DM
MetS
***
**
HTN
Q1
IFG
DM
MetS
Q2
Q3
Q4
Prevalence of hypertension (HTN), impaired fasting glucose (IFG), diabetes (DM), and MetS among normal-weight (A), overweight (B),
and obese (C) individuals. Probability values represent those for linear trend across VAT quartiles and are adjusted for age and BMI.
effect sizes between VAT and risk factors may be higher, it is
possible that SAT volume actually contributes to more
absolute risk.
Of interest are recent findings from the Dallas Heart Study,
which examined metabolic risk factors relations in 1934
black and white women and men with SAT and VAT as
assessed by MRI.56 An important difference between our
study and the Dallas Heart Study is the inclusion of percent
body fat in regression models. Given that we do not have a
measure of percent body fat, our findings are not directly
comparable. Nonetheless, the results of Vega et al56 also
show considerably higher R2 for models that include VAT
than for SAT, particularly among white participants, and
increased R2 for models that include VAT above and beyond
percent body fat and WC.
Our results show that both SAT and VAT are associated
positively with prevalence of hypertension, but only VAT
provides significant information above and beyond BMI and
WC. Other studies have demonstrated relations between VAT
and hypertension.22–24,57 Among Japanese Americans and
whites, VAT but not SAT was associated with hypertension,
even after adjustment for BMI and WC,22,57 whereas among
blacks, both SAT and VAT were associated with hypertension in men and women,24 underscoring the relative importance of fat depots among different ethnic groups.38
We also found that both SAT and VAT were associated
with triglycerides and HDL cholesterol in women and men.
Our results build on those of others, which confirm the known
association between VAT and lipids.25,27–29 However, we
extend these findings to include strong and significant relations of SAT with HDL cholesterol and triglycerides. The
primary difference with prior studies may be our large sample
size in a community-based cohort compared with the few
other studies that were adequately powered to compare the
difference between SAT and VAT.25,29
Similarly, for impaired fasting glucose and diabetes, multiple prior studies have demonstrated relations between VAT
and prediabetic hyperglycemia and diabetes,9,10,18,19 but few
have yielded significant relations for SAT. However, SAT
has been shown in multiple studies to be more strongly
associated with insulin resistance than is VAT; this has been
reviewed previously.58 Some studies of insulin resistance
have demonstrated stronger correlations with SAT than with
VAT,20 especially in women. In the Insulin Resistance
Atherosclerosis Study (IRAS), both SAT and VAT were
important correlates of insulin resistance.21 One small study
of 47 women and men demonstrated equivalent correlations
of deep SAT and VAT with respect to cardiometabolic risk
factors.59
Although our results show that VAT is more highly
correlated with MetS than is SAT, SAT was an important
Fox et al
correlate of the MetS. These findings are in contrast to prior
studies, which have reported that SAT is only weakly
associated with MetS. For example, in the Health, Aging, and
Body Composition (Health ABC) Study, SAT was associated
only with MetS in normal-weight and overweight men31;
however, unlike our study, the Health ABC Study focused
primarily on older individuals.32 Therefore, SAT may be an
important adipose tissue compartment that should not be
overlooked. Only 1 very small intervention study has been
conducted to date to examine the relation of SAT reduction
with metabolic variables: In a small study of 15 women who
underwent large-volume liposuction, despite the loss of
nearly 10 kg subcutaneous fat, improvements in cardiometabolic risk factors were not observed.60 However, the small
sample size, associated low power, and inclusion of morbidly
obese study participants make it difficult to rule out a
beneficial effect.
The strong correlation between SAT and cardiometabolic
risk factors may be driven by the results from some20,21,58 but
not all37,61 studies that have shown that insulin sensitivity is
related to SAT and VAT. In addition to insulin resistance,
relations between specific fat depots and adipocytokines may
be responsible for mediating the relations with risk factors. In
particular, leptin has been shown to be equally, if not more,
correlated to SAT compared with VAT.62 Leptin also has
been implicated in vascular dysfunction,63– 66 which suggests
another potential mechanism whereby SAT may be associated with cardiometabolic risk factors.
Despite the statistically significant results observed with
both SAT and VAT, only VAT provided information above
and beyond BMI and WC, suggesting that VAT may be a
unique pathogenic fat depot. Similar findings have been noted
among Japanese Americans, for whom VAT but not SAT was
associated with hypertension, even after adjustment for BMI
and WC.22,57 Unfortunately, we were unable to analyze SAT
in the same models as BMI and WC because of the high
collinearity between the variables. In fact, the R2 of SAT
versus BMI/WC is much higher for SAT than for VAT (0.76
versus 0.54 for men, 0.81 versus 0.64 for women).
Sex Differences
In our study, we found evidence for sex interactions in that
increasing volumes of SAT and of VAT were consistently
and more strongly associated with more adverse risk factors
levels in women than in men. To the best of our knowledge,
our findings are the most comprehensive examination of sex
differences reported to date. In the Health ABC Study, a
significant sex interaction was observed between VAT and
diabetes.10 Among women and men from the Quebec Family
Study and the Health, Risk factors, Exercise Training, and
Genetics (HERITAGE) Family Study, only in women were
higher amounts of VAT associated with adverse CVD risk
factor profiles.67 The cause of these sex differences is
uncertain but may be related to the higher amount of hepatic
free fatty acid delivery derived from lipolysis from VAT that
has been observed in women than in men.16
Heritability
We demonstrate moderate to high heritability for VAT and
SAT, respectively, indicating that a significant portion of the
CT Adipose Tissue and Cardiometabolic Risk
45
variability in these traits is familial. Two prior studies that
investigated the heritability of intra-abdominal fat depots68,69
have found estimates for VAT ranging from 42% to 56% and
estimates for SAT of 42%. Differences between our findings
and prior published work may be due to the inclusion of
younger participants with lower mean BMI, exclusion of
certain metabolic conditions, and inclusion in a fitness study,
which may have biased estimates. Overall, these findings
suggest that a significant proportion of variability in VAT and
SAT may be due to genetic causes. Further research is
warranted to explore this further, including uncovering
genomic regions of linkage and novel candidate genes.
Implications
The relation of MetS and its components with increasing
VAT quartiles, particularly in overweight and obese individuals, suggests that VAT in particular may confer increasing
risk within clinically defined categories of body weight. Two
thirds of our study sample were either overweight or obese,
statistics that mirror national data.6 Our data suggest that
further observational and possibly interventional studies are
warranted to test the impact of weight reduction and, in
particular, the reduction of VAT on metabolic risk factors and
overall CVD risk. Additionally, our work demonstrates
strong and significant results for SAT and VAT in relation to
cardiometabolic risk factors, suggesting that SAT should not
be overlooked in regional adipose tissue research. Nonetheless, we note that the proportion of overall variation of VAT
and of SAT with metabolic risk factors is moderate at best.
This finding, which has been observed previously,56 suggests
that other factors not accounted for in this study may be
responsible for the variation in metabolic risk factors. In fact,
many of these traits have a substantial heritable component,
with reported heritabilities for glucose being 34% to 51%70;
for systolic blood pressure, 53%71; and for total cholesterol,
40%.72 Therefore, the potential role of gene–adiposity interactions should be considered in future research.
Strengths and Limitations
Strengths of our study include the use of a community-based
sample with participants not enriched for adiposity-related
traits. Routine screening of metabolic risk factors was performed, and adjustment was made for several potential
confounders. We used a highly reproducible volumetric
method of SAT and VAT assessment, which accounts for
heterogeneity of fat distribution throughout the abdomen. We
were able to assess the role of SAT and VAT above and
beyond clinical anthropometry. Our study participants were
primarily middle-aged, allowing assessment of relations between fat compartments and risk factors in the absence of
significant comorbidity. Lastly, we have a large sample with
adequate power to detect potentially smaller but significant
relations with SAT. Limitations include the cross-sectional
design; because the associations are not prospective, causality
cannot be inferred. Because the Framingham Offspring Study
is primarily a white sample, generalizability to other ethnic
groups is uncertain. For example, Japanese Americans and
Southeast Asians have groups with more visceral fat than
expected for a given overall BMI,38 whereas blacks have less
46
Circulation
July 3, 2007
visceral fat than do whites for a given BMI.73 Although we
accounted for sibling–sibling correlations, current analytical
methods did not allow us to account for all familial relations.
Because we did not subdivide subcutaneous fat into superficial and deep compartments, we cannot comment on the
relative importance of these compartments. Furthermore, we
measured only abdominal, not truncal, SAT. Truncal SAT has
been shown to be more correlated to insulin resistance than is
abdominal SAT in men.58,74 Finally, we had only radiographic CT measures of intra-abdominal fat, not other techniques
such as MRI or ultrasound. MRI may provide a better
resolution of fat depots, and ultrasound may be a reasonable
alternative to CT75 and is less invasive. Neither MRI nor
ultrasound places patients at risk of radiation exposure, but
MRI is limited by its expense and amount of time needed to
perform the actual scan.
Conclusions
Both SAT and VAT are associated with an adverse metabolic
risk profile. However, only VAT provides information above
and beyond easily obtainable clinical anthropometric measurements. Measurement of VAT may provide a more complete understanding of metabolic risk, and further studies are
warranted to prospectively assess the impact of the lowering
of VAT and SAT on the incidence of MetS and CVD.
Sources of Funding
This work was supported by the National Heart, Lung and Blood
Institute’s Framingham Heart Study (N01-HC-25195). Dr Meigs is
supported by an American Diabetes Association Career Development Award. Dr Vasan is supported in part by 2K24HL04334
(National Heart, Lung, and Blood Institute, National Institutes of
Health).
Disclosures
Dr Meigs has been the recipient of research grants from GlaxoSmithKline, Pfizer, and Wyeth and has served on Advisory Boards for
GlaxoSmithKline, Merck, Pfizer, and Lilly. The other authors report
no conflicts.
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CLINICAL PERSPECTIVE
Visceral adipose tissue (VAT) compartments may confer increased metabolic risk. The incremental utility of measuring
both VAT and subcutaneous abdominal adipose tissue (SAT) in association with metabolic risk factors and underlying
heritability has not been well described in a population-based setting. Participants from the Framingham Heart Study
underwent multidetector computed tomography assessment of SAT and VAT volumes. SAT and VAT were significantly
associated with increased odds of hypertension, impaired fasting glucose, diabetes, and metabolic syndrome. In women,
relations between VAT and risk factors were consistently stronger than in men. VAT was more strongly correlated with
most metabolic risk factors than was SAT. Furthermore, VAT but not SAT contributed significantly to risk factor variation
after adjustment for body mass index and waist circumference. Among overweight and obese individuals, the prevalence
of hypertension, impaired fasting glucose, and metabolic syndrome increased linearly and significantly across increasing
VAT quartiles. Heritability values for SAT and VAT were 57% and 36%, respectively. Although both SAT and VAT are
correlated with metabolic risk factors, VAT remains more strongly associated with an adverse metabolic risk profile even
after accounting for standard anthropometric indices. Our findings are consistent with the hypothesized role of visceral fat
as a unique, pathogenic fat depot. Measurement of VAT may provide a more complete understanding of metabolic risk
associated with variation in fat distribution.
Metoprolol Reverses Left Ventricular Remodeling in
Patients With Asymptomatic Systolic Dysfunction
The REversal of VEntricular Remodeling with Toprol-XL
(REVERT) Trial
Wilson S. Colucci, MD; Theodore J. Kolias, MD; Kirkwood F. Adams, MD;
William F. Armstrong, MD; Jalal K. Ghali, MD; Stephen S. Gottlieb, MD; Barry Greenberg, MD;
Michael I. Klibaner, MD, PhD; Marrick L. Kukin, MD; Jennifer E. Sugg, MS; on behalf of the
REVERT Study Group*
Background—There are no randomized, controlled trial data to support the benefit of ␤-blockers in patients with
asymptomatic left ventricular systolic dysfunction. We investigated whether ␤-blocker therapy ameliorates left
ventricular remodeling in asymptomatic patients with left ventricular systolic dysfunction.
Method and Results—Patients with left ventricular ejection fraction ⬍40%, mild left ventricular dilation, and no symptoms
of heart failure (New York Heart Association class I) were randomly assigned to receive extended-release metoprolol
succinate (Toprol-XL, AstraZeneca) 200 mg or 50 mg or placebo for 12 months. Echocardiographic assessments of left
ventricular end-systolic volume, end-diastolic volume, mass, and ejection fraction were performed at baseline and at 6
and 12 months. The 149 patients randomized to the 3 treatment groups (200 mg, n⫽48; 50 mg, n⫽48; and placebo,
n⫽53) were similar with regard to all baseline characteristics including age (mean, 66 years), gender (74% male),
plasma brain natriuretic peptide (79 pg/mL), left ventricular end-diastolic volume index (110 mL/m2), and left
ventricular ejection fraction (27%). At 12 months in the 200-mg group, there was a 14⫾3 mL/m2 decrease (least square
mean⫾SE) in end-systolic volume index and a 6⫾1% increase in left ventricular ejection fraction (P⬍0.05 versus
baseline and placebo for both). The decrease in end-diastolic volume index (14⫾3) was different from that seen at
baseline (P⬍0.05) but not with placebo. In the 50-mg group, end-systolic and end-diastolic volume indexes decreased
relative to baseline but were not different from what was seen with placebo, whereas ejection fraction increased by
4⫾1% (P⬍0.05 versus baseline and placebo).
Conclusion—␤-Blocker therapy can ameliorate left ventricular remodeling in asymptomatic patients with left ventricular
systolic dysfunction. (Circulation. 2007;116:49-56.)
Key Words: heart failure 䡲 receptors, adrenergic, beta 䡲 remodeling 䡲 ventricles
A
symptomatic left ventricular (LV) systolic dysfunction
is common in the general population, with a prevalence
on the order of 3%,1,2 constituting a high percentage of all
patients with LV dysfunction. For example, in the Olmstead
County population, less than half of all patients with an LV
ejection fraction (EF) ⬍40% had been diagnosed with congestive heart failure (HF).2 Although asymptomatic, these
patients are at high risk for developing clinical HF. In
asymptomatic patients with a LVEF ⬍40% in the Framing-
ham Heart Study population, the annual incidence of symptomatic HF was ⬇6%, and the annual mortality rate was
⬇8%.1 Despite the important consequences of asymptomatic
LV systolic dysfunction, very few clinical trials of therapeutic
agents have been conducted in this population.
In patients with symptoms of HF due to systolic LV
dysfunction, extensive clinical trial data have demonstrated
that ␤-blockers improve survival, decrease hospitalizations
related to HF, and alleviate symptoms.3– 6 The improved
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Received October 5, 2006; accepted April 20, 2007.
From Boston University Medical Center, Boston, Mass (W.S.C.); University of Michigan Medical Center, Ann Arbor (T.J.K., W.F.A.); University of
North Carolina School of Medicine, Chapel Hill (K.F.A.); Wayne State University, Detroit, Mich (J.K.G.); University of Maryland Hospital, Baltimore
(S.S.G.); University of California at San Diego (B.G.); AstraZeneca LP, Wilmington, Del (M.I.K., J.E.S.); and St Luke’s–Roosevelt Hospitals, Columbia
University College of Physicians and Surgeons, New York, NY (M.L.K.).
*All members of the REVERT Study Group are listed in the Appendix.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00038077.
Guest Editor for this article was Martin M. LeWinter, MD.
Correspondence to Wilson S. Colucci, MD, Cardiovascular Medicine, Boston University Medical Center, 88 E Newton St, Boston, MA 02118. E-mail
wilson.colucci@bmc.org
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.666016
50
Circulation
July 3, 2007
outcomes are associated with amelioration of LV remodeling
characterized by decreases in end-diastolic and end-systolic
volumes and an increase in EF.7–10 The studies that have
demonstrated these beneficial effects on outcomes and remodeling have been performed almost exclusively in symptomatic patients in New York Heart Association (NYHA)
functional classes II, III, or IV.
Although an exception would be the Australia/New Zealand Carvedilol Trial, in which approximately one third of
subjects were asymptomatic, the survival benefits of carvedilol in that trial were not analyzed with regard to functional
class.11 Likewise, although some patients in the Carvedilol
Prospective Randomized Cumulative Survival (CAPRICORN) trial had asymptomatic LV dysfunction,12 the impact
of therapy was not analyzed with regard to functional class
and would not be directly applicable to patients with chronic
LV dysfunction.
There have been no randomized controlled trials of the
effects of ␤-blockers on clinical outcomes or remodeling in
patients who have chronic LV systolic dysfunction but are
free of symptoms. Theoretically, patients with asymptomatic
LV dysfunction may be less responsive to ␤-blockers because
the degree of sympathetic nervous system activation is
less.13–15 Alternatively, there is reason to believe that
␤-blockers would be effective in such patients because some
studies have shown clinical benefit in patients with mild (eg,
predominantly NYHA class II) symptoms of HF.16
Because of the lack of direct evidence from randomized
controlled trials, the current recommendation for the use of a
␤-blocker in patients with a chronic reduction in LVEF but no
HF symptoms is based only on expert opinion.17 Furthermore,
it is unlikely that a placebo-controlled study can be performed
to test the effects of ␤-blockade on clinical outcomes in this
population.
There is evidence that the outcome benefits of ␤-blockers
in patients with systolic LV dysfunction are related to the
antiremodeling effect, which might therefore be used as a
reasonable surrogate for clinical benefit.18 Accordingly, we
designed a placebo-controlled, randomized trial, REversal of
VEntricular Remodeling with Toprol-XL (REVERT), to test
the hypothesis that ␤-blocker therapy would ameliorate LV
remodeling in asymptomatic (NYHA functional class I)
patients with LV systolic dysfunction.
Methods
Entry Criteria
To be eligible, patients must have had a LVEF ⬍40% and mild LV
dilatation (LV end-diastolic volume index [LVEDVI] ⬎75 mL/m2)
due to idiopathic, ischemic, or hypertensive cardiomyopathy and
must have had no symptoms of HF for at least 2 months. The
determination of LV systolic dysfunction and dilation was based on
a screening echocardiogram that was performed within 14 days of
randomization and interpreted by the core laboratory. Asymptomatic
LV systolic dysfunction was defined as no limitation of ordinary
physical activity because of fatigue or dyspnea (NYHA functional
class I). Patients previously treated for symptomatic HF were
allowed to participate if they met the inclusion and exclusion criteria
for the study. The use of an angiotensin-converting enzyme (ACE)
inhibitor or angiotensin receptor blocker for at least 3 months, as
tolerated, was required before enrollment. Patients must have had no
changes in the doses of their cardiovascular medications, including
ACE inhibitors, angiotensin receptor blockers, diuretics, digoxin,
and/or vasodilators for at least 3 months before randomization.
Patients were excluded if they had indications for or contraindications to ␤-blocker therapy or took ␤-blockers (including ophthalmic preparations) for ⬎1 week during the 6 months preceding
randomization. Also excluded were patients who, during the 6
months before randomization, had myocardial infarction, unstable
angina, coronary intervention, or hospitalization for cardiovascularrelated causes, as well as patients with heart rate ⬍60 bpm, sitting
blood pressure ⬎140/90 mm Hg, heart block greater than first degree
not treated with a permanent pacemaker, history of ventricular or
atrial fibrillation, or serum creatinine ⬎3 mg/dL. The institutional
review boards of the participating institutions approved the protocol,
and all participants provided written informed consent. The study
was conducted in accordance with the Declaration of Helsinki.
Echocardiographic Measurements
Two-dimensional echocardiograms with Doppler were recorded at
screening (baseline) and at 6 and 12 months, with the same scanner
used for each patient. The videotapes were evaluated in a blinded
fashion by the core echocardiography laboratory at the University of
Michigan.
The echocardiograms were analyzed with the use of a dedicated
offline echocardiography analysis system (TomTec Imaging Systems, Munich, Germany). LV end-systolic volume (LVESV),
LVEDV, and LVEF were measured by Simpson’s method in the
apical 4-chamber view, which was used for the main analyses, as
well as the apical 2-chamber view when possible. LV mass was
calculated from the 2-dimensional parasternal long-axis view with
the use of the Penn cubed formula.19 LVESV index (LVESVI),
LVEDVI, and LV mass index (LVMI) were determined by dividing
volume or mass by body surface area.
Treatment Regimen
Patients who met inclusion/exclusion criteria were randomized in a
1:1:1 ratio to a 52-week treatment with metoprolol succinate
extended-release tablets (metoprolol succinate, TOPROL-XL, AstraZeneca, Wilmington, Del) or placebo as follows: (1) metoprolol
succinate 200 mg/d (high-dose group); (2) metoprolol succinate 50
mg/d (low-dose group); or (3) placebo. The study drug was forcetitrated to the assigned dose over the first 2 months on the basis of
tolerability, and the achieved dose was maintained as tolerated until
the end of the study. Drug blinding was achieved with the use of a
double-blind, double-dummy technique. Treatment compliance was
verified by pill count of returned study medication at each visit.
Brain Natriuretic Peptide
In a substudy that enrolled 82 patients, venous blood was collected
at baseline and at 6 and 12 months for determination of plasma brain
natriuretic peptide, which was measured by radioimmunoassay
(Quest Diagnostics, Van Nuys, Calif).
Statistical Analyses
The change in LVESVI from baseline to 12 months was chosen as
the prespecified primary end point because it reflects changes in both
LV size and systolic function and has been shown to be a sensitive
index of LV remodeling.7 The power calculation was based on a SD
for LVESVI at 12 months of 15 mL/m2 and a dropout rate of 20%.
With an ␣ of 0.050 for a 2-sided test, 150 patients would provide
94% power to detect a change of 12 mL/m2 and 84% power to detect
a change of 10 mL/m2. Prespecified key secondary end points
included the change from baseline in LVESVI at month 6 and
changes from baseline in LVEDVI, LVMI, and LVEF at months 6
and 12. Efficacy was analyzed by a modified intention-to-treat
population (n⫽149 patients) who took at least 1 dose of study
medication after randomization and had at least 1 follow-up echocardiogram. All available data were analyzed, and no substitutions
were made for missing values. Pairwise comparisons were made
between the high-dose group and placebo (primary comparison) and
between the low-dose group and placebo (secondary comparison) for
Colucci et al
TABLE 1.
Metoprolol for Asymptomatic LV Dysfunction
51
Demographic and Clinical Characteristics
Placebo
(n⫽53)
Metoprolol Succinate
50 mg (n⫽48)
Metoprolol Succinate
200 mg (n⫽48)
All Patients
(n⫽149)
Age, mean (SD), y
67 (10)
64 (14)
66 (14)
Men, n (%)
37 (69.8)
38 (79.2)
35 (72.9)
110 (73.8)
66 (13)
White
41 (77.4)
38 (79.2)
36 (75.0)
115 (77.2)
Black
11 (20.8)
9 (18.8)
12 (25.0)
32 (21.5)
Other
1 (1.9)
1 (2.1)
0
BMI, mean (SD), kg/m2
27.2 (4.4)
27.8 (6.0)
28.6 (5.6)
27.8 (5.4)
BSA, mean (SD), m2
1.95 (0.25)
2.02 (0.27)
1.96 (0.31)
1.97 (0.28)
Race, n (%)
NYHA class I, n (%)
2 (1.3)
53 (100.0)
48 (100.0)
48 (100.0)
149 (100.0)
Ischemic
27 (50.9)
27 (56.3)
26 (54.2)
80 (53.7)
Idiopathic
17 (32.1)
12 (25.0)
14 (29.2)
43 (28.9)
Hypertension
7 (13.2)
5 (10.4)
6 (12.5)
18 (12.1)
Other
2 (3.8)
4 (8.3)
2 (4.2)
8 (5.4)
Prior PTCA or CABG, n (%)
21 (39.6)
21 (43.8)
21 (43.8)
63 (42.3)
Diabetes, n (%)
16 (30.2)
12 (25.0)
17 (35.4)
45 (30.2)
Cause of HF, n (%)
Medications, n (%)
ACE inhibitor or ARB
49 (92.5)
44 (91.7)
47 (97.9)
140 (94.0)
Diuretics
31 (58.5)
30 (62.5)
35 (72.9)
96 (64.4)
Digoxin
20 (37.7)
18 (37.5)
24 (50.0)
62 (41.6)
SBP/DBP, mean, mm Hg
125.1/73.9
123.4/73.1
127.1/73.2
125.2/73.4
Heart rate, mean (SD), bpm
78.0 (11.8)
75.4 (10.3)
76.2 (9.7)
76.6 (10.7)
BNP,* mean (SD), pg/mL
88.9 (54.3)
73.9 (65.6)
75.1 (87.9)
79.3 (70.9)
BMI indicates body mass index; BSA, body surface area; PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary
artery bypass grafting; ARB, angiotensin receptor blocker; SBP, systolic blood pressure; DBP, diastolic blood pressure; and BNP, brain
natriuretic peptide.
*BNP samples were collected in a subset of 25 to 30 patients in each group.
all LV end points. Changes from baseline in LV dimensions were
analyzed with a repeated-measures ANOVA, with terms for treat
ment group, time (6 and 12 months), and the interaction between
treatment group and time. Least square means of the interaction term
were used to estimate treatment group effects at each time, to make
pairwise comparisons of the metoprolol groups versus placebo, and
to test whether changes within each treatment group were different
from zero (ie, different from baseline values). All tests were 2-sided
and were performed at a significance level of 0.050. All values are
reported as mean⫾SD unless otherwise specified. All analyses were
conducted with SAS software, version 8.2 (SAS Institute Inc, Cary,
NC).
The authors had full access to the data and take responsibility for
its integrity. All authors have read and agree to the manuscript as
written.
Results
Study Drug Exposure
Of the 164 patients randomized, 149 patients who had at least
1 dose of drug and 1 follow-up echocardiogram were used for
the modified intention-to-treat analysis. Fifteen patients (placebo, n⫽4; low dose, n⫽6; high dose, n⫽5) were excluded
from the intention-to-treat analysis because they did not have
a follow-up echocardiogram. The median (range) duration of
treatment was 357 (9 to 391), 358 (4 to 376), and 358 (15 to
383) days in the placebo, low-dose, and high-dose groups,
respectively. Mean compliance during the 52-week doubleblind treatment period ranged from 97% to 100% in the 3
treatment groups. In the low-dose group, 87% of patients
achieved the 50-mg/d dose (mean dose, 47⫾9 mg/d). In the
high-dose group, 68% of patients achieved the 200-mg/d dose
(mean dose, 155⫾69 mg/d).
Baseline Characteristics
The 149 patients in the intention-to-treat efficacy analysis had
a mean age of 66⫾13 years; 74% were male, and 77% were
white (Table 1). The cause of HF was attributed to ischemia
(54%), idiopathic dilated cardiomyopathy (29%), hypertension (12%), or other causes (5%). Ninety-four percent of
patients were receiving an ACE inhibitor and/or an angiotensin receptor blocker, 64% were receiving a diuretic, and 42%
were receiving digitalis.
At baseline the mean heart rate was 77⫾11 bpm, and the
mean blood pressure was 125/73 mm Hg. Plasma brain
natriuretic peptide averaged 79⫾71 pg/mL. Baseline heart
rate, blood pressure, and brain natriuretic peptide levels were
similar among the 3 treatment groups.
52
Circulation
July 3, 2007
H e a rt ra te (b p m)
5
0
-5
*
-10
*†
*†
*†
-15
Baseline
6 Months
12 Months
Figure 1. Effect of metoprolol succinate on heart rate. Shown
are the mean changes (SE) in heart rate compared with baseline
for patients receiving metoprolol succinate 200 mg (triangles),
50 mg (squares), or placebo (diamonds). *P⬍0.05 vs baseline;
†P⬍0.05 vs placebo.
Effects of Treatment on Heart Rate and
Blood Pressure
Heart rate decreased by 3⫾10, 8⫾10, and 12⫾10 bpm in the
placebo, low-dose, and high-dose groups at 12 months,
respectively (Figure 1). There were no significant changes in
systolic or diastolic blood pressure from baseline to 12
months in any group.
Effects of Treatment on LV Dimensions
At baseline, LV dimensions and EF were similar in the 3
groups (Table 2). At 12 months, LVESVI, the primary end
point, was decreased by 4⫾3, 8⫾3, and 14⫾3 mL/m2 (least
square mean⫾SE) in the placebo, low-dose, and high-dose
groups, respectively (Table 3, Figure 2A). The decrease with
the high dose was significant versus both baseline and
placebo, whereas the decrease with the low dose was signifTABLE 2.
icant only versus baseline. Similar effects were seen at 6
months. There was a similar directional pattern for changes in
LVEDVI with regard to both dose and treatment duration,
although the changes were not statistically different from
placebo (Table 3, Figure 2B).
At 12 months, LVEF was unchanged in the placebo group
and increased by 4⫾1% in the low-dose group and 6⫾1% in
the high-dose group (Table 3, Figure 2C). There were similar
directional changes at 6 months. LVMI tended to increase in
the placebo group and to decrease in both the high-dose and
low-dose groups at both 6 and 12 months, although none of
these differences reached statistical significance (Table 3,
Figure 2D).
Adverse Events and Tolerability
The most common adverse events were fatigue, dizziness,
dyspnea, peripheral edema, and HF. The percentage of
patients discontinuing the study because of adverse events
was 18%, 13%, and 11% in the placebo, low-dose, and
high-dose groups, respectively. There were 2 deaths in the
placebo group, 2 in the low-dose group, and 4 in the
high-dose group. The cause of death was cardiovascular in 7
patients.
Discussion
The REVERT trial shows that treatment with metoprolol
succinate reduces LVESV and improves LVEF in patients
with asymptomatic LV systolic dysfunction. These results
suggest that metoprolol succinate therapy ameliorates and
reverses pathological cardiac remodeling in asymptomatic
patients with LV systolic dysfunction.
Although prior controlled studies have demonstrated that
␤-blockers can reverse LV remodeling in patients with HF,
these studies have been conducted entirely or predominantly
in symptomatic patients. Metoprolol succinate was shown to
LV Echocardiographic Measurements at Baseline, 6 Months, and 12 Months
Baseline
No.
LVESVI, mL/m
Mean
6 Months
95% CI
No.
Mean
12 Months
95% CI
No.
Mean
95% CI
2
Placebo
53
82.5
74.6 to 90.3
52
78.9
69.0 to 88.9
46
77.5
68.7 to 86.3
Metoprolol succinate 50 mg
48
82.5
74.3 to 90.7
46
79.1
69.4 to 88.8
44
75.3
64.7 to 86.0
Metoprolol succinate 200 mg
48
79.8
72.2 to 87.5
45
66.7
58.0 to 75.3
43
66.5
56.7 to 76.3
LVEDVI, mL/m2
Placebo
53
110.7
103.0 to 118.4
52
106.0
95.7 to 116.4
46
104.8
95.5 to 114.1
Metoprolol succinate 50 mg
48
110.9
102.8 to 119.0
47
108.8
98.8 to 118.8
44
104.8
93.5 to 116.1
Metoprolol succinate 200 mg
48
109.0
99.7 to 118.4
45
96.6
86.9 to 106.3
43
96.8
85.7 to 108.0
LVEF, %
Placebo
53
26.8
24.6 to 28.9
52
27.6
25.1 to 30.1
46
27.5
24.7 to 30.4
Metoprolol succinate 50 mg
48
26.6
24.2 to 29.0
46
29.5
26.3 to 32.7
44
30.4
27.1 to 33.7
Metoprolol succinate 200 mg
48
27.2
25.1 to 29.4
45
32.6
29.9 to 35.2
43
33.2
30.3 to 36.2
LVMI, g/m2
Placebo
51
161.5
148.5 to 174.5
51
162.2
148.7 to 175.6
45
169.9
155.8 to 183.9
Metoprolol succinate 50 mg
48
164.3
148.0 to 180.6
46
161.1
144.5 to 177.7
44
160.0
144.3 to 175.7
Metoprolol succinate 200 mg
47
159.9
146.2 to 173.6
44
150.9
137.8 to 164.1
44
151.8
138.6 to 165.1
Colucci et al
TABLE 3.
Metoprolol for Asymptomatic LV Dysfunction
53
Changes in LV Echocardiographic Measurements From Baseline to 6 Months or 12 Months
Baseline to 6 Months
LSM
Change
95%
CI
Baseline to 12 Months
P vs
Placebo
P vs
Baseline
LSM
Change
95%
CI
P vs
Placebo
P vs
Baseline
LVESVI, mL/m2
Placebo
⫺4.5
⫺9.9 to 0.9
⫺3.7
⫺9.2 to 1.9
⫺3.9
⫺9.6 to 1.9
䡠䡠䡠
0.87
0.10
Metoprolol succinate 50 mg
0.18
⫺7.6
⫺13.4 to ⫺1.8
䡠䡠䡠
0.34
Metoprolol succinate 200 mg
⫺13.1
⫺18.8 to ⫺7.4
0.032
⬍0.001
⫺14.5
⫺20.3 to ⫺8.6
0.009
0.20
0.011
⬍0.001
LVEDVI, mL/m2
Placebo
⫺5.6
⫺11.8 to 0.5
⫺5.4
⫺11.7 to 1.0
⫺2.4
⫺9.1 to 3.9
䡠䡠䡠
0.50
0.072
Metoprolol succinate 50 mg
0.43
⫺6.7
⫺13.3 to ⫺0.1
䡠䡠䡠
0.77
Metoprolol succinate 200 mg
⫺11.9
⫺18.5 to ⫺5.4
0.17
⬍0.001
⫺13.5
⫺20.2 to ⫺6.8
0.083
⬍0.001
0.31
0.0
⫺2.5 to 2.5
0.022
3.9
1.4 to 6.5
䡠䡠䡠
0.032
0.003
6.2
3.6 to 8.7
⬍0.001
⬍0.001
0.10
0.047
LVEF, %
Placebo
1.2
⫺1.1 to 3.6
Metoprolol succinate 50 mg
2.9
0.4 to 5.5
䡠䡠䡠
0.32
Metoprolol succinate 200 mg
5.6
3.0 to 8.1
0.014
⬍0.001
0.99
LVMI, g/m2
Placebo
0.5
⫺11.6 to 12.7
⫺4.8 to 20.7
8.0
⫺4.9
⫺17.6 to 7.7
䡠䡠䡠
0.54
0.93
Metoprolol succinate 50 mg
0.44
⫺7.3
⫺20.1 to 5.5
䡠䡠䡠
0.097
0.26
0.22
Metoprolol succinate 200 mg
⫺8.1
⫺20.9 to 4.7
0.34
0.21
⫺8.4
⫺21.2 to 4.5
0.076
0.20
LSM indicates least square mean.
improve survival and decrease hospitalizations in the Metoprolol CR/XL Randomised Intervention Trial in Congestive
Heart Failure (MERIT-HF), a trial that studied predominantly
NYHA class II and III patients and excluded patients in
NYHA class I.4 In the magnetic resonance imaging substudy
of MERIT-HF, treatment with metoprolol succinate for 6
months decreased LVEDVI by 24 mL/m2, decreased LVESVI
by 26 mL/m2, and increased LVEF by 8%.9 Qualitatively and
quantitatively similar effects of metoprolol succinate on LV
volumes and EF were seen in the echocardiographic substudy
of MERIT-HF10 and the Randomized Evaluation of Strategies
for Left Ventricular Dysfunction (RESOLVD) pilot study.20
Likewise, carvedilol has been shown to improve both survival
and remodeling in patients with symptomatic HF. Although
LV dimensions were not reported in the US Carvedilol Trials
Program, treatment with carvedilol for a mean of 213 days
increased LVEF from 22% to 32%.21 In the Australia/New
Zealand Trial, carvedilol decreased LV end-diastolic and
end-systolic dimensions and increased EF.7 Approximately
75% of patients in the Australia/New Zealand Trial were in
class II or III, and the results of that study were not reported
with regard to NYHA class.11
Although the determination of symptoms is subjective,
several observations suggest that the patients in REVERT
differed markedly from those with class II and III symptoms
that are typical of prior ␤-blocker trials. Perhaps the most
objective measure of clinical severity is the average plasma
brain natriuretic peptide level of 75 pg/mL, which is below
the cutoff of 100 pg/mL that has a high level of selectivity for
excluding a diagnosis of HF.22 Another important indicator of
disease severity is mortality rate, which was 5% per year in
this study, a rate well below the rate of ⬇10% to 15% per
year that is typical of symptomatic patients treated with an
ACE inhibitor4,21,23 and similar to the rates observed in
asymptomatic patients in the treatment arm of the Studies of
Left Ventricular Dysfunction (SOLVD) Prevention Trial24 or
a general community population.1 An important indicator of
milder LV dysfunction is the lesser extent of LV remodeling
at baseline. For example, the baseline LVEDVI in REVERT
(110⫾29 mL/m2) is substantially smaller than the LVEDVI
of 153⫾64 mL/m2 in the MERIT-HF substudy.9 Other
indicators of mild disease in this study population are the
relatively low pretreatment heart rate of 77 compared with 82
bpm in MERIT-HF, the relatively preserved systolic blood
pressure of 126 mm Hg, and the need for diuretics of any type
in only ⬇64% of patients. It should be noted that although the
patients in REVERT had to be asymptomatic for at least 2
months before randomization, before that time they may have
had symptoms that responded to therapy with diuretics and/or
renin-angiotensin system blockade.
In REVERT, the effects of metoprolol on LVESVI and
LVEF appear to be dose dependent. Although the study was
not powered to detect a dose-effect relationship, in the
high-dose group the decrease in LVESVI and the increase in
LVEF were significantly different from those seen in the
placebo group at both 6 and 12 months, whereas these
changes in the low-dose group were intermediate in magnitude and, for the most part, not significantly different from
those seen with placebo. Of note, the mean dose achieved in
the high-dose group (155 mg/d) of REVERT is very similar
to the mean dose achieved in MERIT-HF (159 mg/d), which,
like REVERT, had a target dose of 200 mg/d. The vast
majority (94%) of patients in REVERT were receiving an
ACE inhibitor or an angiotensin receptor blocker before
enrollment, indicating that the antiremodeling effect of
␤-blocker therapy in asymptomatic patients is in addition to
54
Circulation
A
July 3, 2007
B
5
0
2
2
LVEDVI (mL/m )
0
-5
*
-10
*†
-15
C
Baseline
6 Months
D
10
LVEF (%)
*†
5
*
*
-10
-20
12 Months
5
*†
0
0
*
*
Baseline
6 Months
12 Months
Baseline
6 Months
12 Months
10
*†
2
-20
-5
-15
*†
LVMI (g/m )
LVESVI (mL/m )
5
-5
-10
-15
-5
Bas eline
6 Months
12 Months
-20
Figure 2. Effect of metoprolol succinate on LV volumes. Shown are the least square mean changes (SE) in LVESVI (A), LVEDVI (B),
LVEF (C), and LVMI (D) compared with baseline for patients receiving metoprolol succinate 200 mg (triangles), 50 mg (squares), or placebo (diamonds). *P⬍0.05 vs baseline; †P⬍0.05 vs placebo.
the benefits afforded by blockade of the renin-angiotensin
system.
A decrease in heart rate, as occurs with ␤-blocker therapy,
may allow more complete LV filling, thereby leading to
increases in stroke volume and EF. A limitation of this study
is that LV dimensions were not repeated after withdrawal of
therapy, which would have allowed the exclusion of a
transient effect due to the decrease in heart rate. However, the
decrease in LVESVI and the increase in LVEF observed with
metoprolol at both 6 and 12 months were associated with a
decrease in LVEDVI, indicating that the observed improvements cannot be attributed to the slowing of heart rate, per se.
In 2001, when REVERT began enrollment, the existing
American College of Cardiology/American Heart Association guidelines, published in 1999, concluded that the benefit
of ␤-blocker therapy beyond the first 3 months after acute
myocardial infarction had not been established conclusively,
and as a result the use of ␤-blockers in patients with moderate
or severe LV failure received only a class IIb recommendation.25 In this setting, REVERT allowed the enrollment of
patients who had a history of a remote myocardial infarction,
defined as ⬎6 months before randomization, if they had not
been treated with ␤-blockers. In practice, no patients were
enrolled in the study who had a myocardial infarction within
the year before randomization. Subsequently, the current
American College of Cardiology/American Heart Association guidelines, published in 2004, recommended that patients who have a history of a myocardial infarction and LV
dysfunction should be treated with ␤-blockers.26 The findings
of REVERT support this recommendation.
REVERT was not designed to test the effect of ␤-blockade
on morbidity or mortality rates. There are very few outcomes
trials in patients with asymptomatic HF. The SOLVD Prevention Trial demonstrated an improvement in symptoms and
a decrease in hospitalization for HF but did not achieve
statistical significance with regard to survival.24 Of note, a
post hoc analysis of the SOLVD Prevention Trial found that
survival was improved significantly in patients who were
randomized to enalapril and were also taking a ␤-blocker.27
It is unlikely that an outcomes trial of ␤-blockers in
patients with asymptomatic LV systolic dysfunction could be
conducted. However, it has been suggested that a beneficial
effect on remodeling may be used as a surrogate for clinical
outcomes in patients with HF due to LV systolic dysfunction.18 It is reasonable to expect that, by ameliorating LV
remodeling, ␤-blocker therapy will delay the emergence or
reemergence of symptoms in asymptomatic patients. This
premise is further supported by the established positive
relationship between improvements in LV remodeling and
survival with ␤-blocker therapy in symptomatic patients.8,18
Colucci et al
The results of REVERT suggest that the survival benefit
observed in symptomatic patients treated with metoprolol
succinate may extend to asymptomatic patients with LV
systolic dysfunction as well.
Appendix
Metoprolol for Asymptomatic LV Dysfunction
7.
8.
REVERT Study Group
Alan Camp, Albert A. Carr, Barry Harold Greenberg, Bruce
K. Jackson, Bruce Kowalski, Chang-seng Liang, Chiayu
Chen, Chris Boylan, D. Marty Denny, Douglas Chapman,
Freny Mody, Garo Garibian, Garrie J. Haas, David R.
Richard, Inder Anand, Jalal K. Ghali, James Zebrack, Jerome
Lyman Anderson, John Murphy, Jose de Jesus Ortiz, Joseph
L. Gelormini, Larry Baruch, Lisa Mendes, Flora Sam, Marc
Jay Kozinn, Mark J. Geller, Marrick L. Kukin, Michael
Benjamin Honan, Michael Lesser, Nancy R. Cho, Ralph M.
Vicari, Raymond Rodriguez, Robert Davidson, Robert E.
Foster, Robert Michael Kipperman, Robert Weiss, Russell
Silverman, Stephen Gottlieb, Steven Hutchins, Thomas D.
Giles, Thomas J. Knutson, Uri Elkayam, W. David Hager,
Wayne David Old, Vince Figueredo.
REVERT Steering Committee
9.
10.
11.
12.
13.
14.
Wilson S. Colucci (Chairman), Kirkwood F. Adams, William
F. Armstrong, Stephen S. Gottlieb, Barry Greenberg, Marrick
L. Kukin.
15.
Sources of Funding
The REVERT study was funded by AstraZeneca, which was responsible for data collection and analysis, which was conducted according to a prespecified analysis plan. Academic leadership was
provided by the Steering Committee, which supervised the management of the study and was responsible for interpretation of the data,
preparation, review, and approval of the manuscript.
Disclosures
16.
17.
Authors who are employees of AstraZeneca are identified as such.
All other authors have received research grants, consultant fees,
and/or honoraria from AstraZeneca.
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Go to http://cme.ahajournals.org to take the CME quiz for this article.
Negative Inotropy of the Gastric Proton Pump Inhibitor
Pantoprazole in Myocardium From Humans and Rabbits
Evaluation of Mechanisms
Wolfgang Schillinger, MD*; Nils Teucher, MD*; Samuel Sossalla, MS; Sarah Kettlewell, PhD;
Carola Werner, PhD; Dirk Raddatz, MD; Andreas Elgner, MS; Gero Tenderich, MD;
Burkert Pieske, MD; Giuliano Ramadori, MD; Friedrich A. Schöndube, MD;
Harald Kögler, MD; Jens Kockskämper, PhD; Lars S. Maier, MD; Harald Schwörer, MD;
Godfrey L. Smith, PhD; Gerd Hasenfuss, MD
Background—Proton pump inhibitors are used extensively for acid-related gastrointestinal diseases. Their effect on
cardiac contractility has not been assessed directly.
Methods and Results—Under physiological conditions (37°C, pH 7.35, 1.25 mmol/L Ca2⫹), there was a dose-dependent
decrease in contractile force in ventricular trabeculae isolated from end-stage failing human hearts superfused with
pantoprazole. The concentration leading to 50% maximal response was 17.3⫾1.3 ␮g/mL. Similar observations were
made in trabeculae from human atria, normal rabbit ventricles, and isolated rabbit ventricular myocytes. Real-time
polymerase chain reaction demonstrated the expression of gastric H⫹/K⫹–adenosine triphosphatase in human and rabbit
myocardium. However, measurements with BCECF-loaded rabbit trabeculae did not reveal any significant
pantoprazole-dependent changes of pHi. Ca2⫹ transients recorded from field-stimulated fluo 3–loaded myocytes (F/F0)
were significantly depressed by 10.4⫾2.1% at 40 ␮g/mL. Intracellular Ca2⫹ fluxes were assessed in fura 2–loaded,
voltage-clamped rabbit ventricular myocytes. Pantoprazole (40 ␮g/mL) caused an increase in diastolic [Ca2⫹]i by
33⫾12%, but peak systolic [Ca2⫹]i was unchanged, resulting in a decreased Ca2⫹ transient amplitude by 25⫾8%. The
amplitude of the L-type Ca2⫹ current (ICa,L) was reduced by 35⫾5%, and sarcoplasmic reticulum Ca2⫹ content was
reduced by 18⫾6%. Measurements of oxalate-supported sarcoplasmic reticulum Ca2⫹ uptake in permeabilized
cardiomyocytes indicated that pantoprazole decreased Ca2⫹ sensitivity (Kd) of sarcoplasmic reticulum Ca2⫹ adenosine
triphosphatase: control, Kd⫽358⫾15 nmol/L; 40 ␮g/mL pantoprazole, Kd⫽395⫾12 nmol/L (P⬍0.05). Pantoprazole
also acted on cardiac myofilaments to reduced Ca2⫹-activated force.
Conclusions—Pantoprazole depresses cardiac contractility in vitro by depression of Ca2⫹ signaling and myofilament
activity. In view of the extensive use of this agent, the effects should be evaluated in vivo. (Circulation. 2007;116:5766.)
Key Words: calcium 䡲 contractility 䡲 heart failure 䡲 inotropic agents 䡲 pharmacology
P
roton pump inhibitors (PPIs) like pantoprazole, omeprazole, esomeprazole, lansoprazole, and rabeprazole are the
most effective pharmacological means of reducing gastric
acid secretion by blocking the final step of proton secretion,
ie, the gastric acid pump, H⫹/K⫹–adenosine triphosphatase
(ATPase). The efficacy of this class of drugs has been
demonstrated in the treatment of a number of acid-related
gastrointestinal diseases, in particular, gastroesophageal reflux and ulcer disease.1 Hence, there is extensive use of these
Clinical Perspective p 66
agents for patients in a variety of settings. In a US Medicaid
population, PPIs accounted for 5.6% of the net pharmacy
expenditures and ranked first in expenditures among all drug
therapy classes during the 12 months before the implementation of the PPI prior-authorization policy.2 Drug shortage
bulletins have been issued repeatedly for intravenous PPIs in
the United States.3
Received September 25, 2006; accepted May 1, 2007.
From the Herzzentrum, Kardiologie und Pneumologie, Universitaet Goettingen, Goettingen, Germany (W.S., S.S., A.E., B.P., H.K., J.K., L.S.M.,
G.H.); Herzzentrum, Thorax-, Herz-, und Gefaesschirurgie, Universitaet Goettingen, Goettingen, Germany (N.T., F.A.S.); Institute of Biomedical and Life
Sciences, University of Glasgow, Glasgow, UK (S.K., G.L.S.); Medizinische Statistik, Universitaet Goettingen, Goettingen, Germany (C.W.);
Gastroenterologie und Endokrinologie, Universitaet Goettingen, Goettingen, Germany (D.R., G.R., H.S.); and Herz- und Diabeteszentrum NordrheinWestfalen, Klinik fuer Thorax- und Kardiovaskularchirurgie, Bad Oeynhausen, Germany (G.T.).
*The first 2 authors contributed equally to this work.
Correspondence to Wolfgang Schillinger, MD, Herzzentrum, Kardiologie und Pneumologie, Georg-August Universitaet Goettingen, Robert-Koch
Strasse 40, 37099 Goettingen, Germany. E-mail schiwolf@med.uni-goettingen.de
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.666008
57
58
Circulation
July 3, 2007
It has been shown recently that the expression of H⫹/K⫹ATPase is not limited strictly to gastric tissue. It has also been
identified in renal4 and colonic epithelial cells,5 vascular
smooth muscle cells,6 and other tissues. In myocardium from
rats, the expression of H⫹/K⫹-ATPase has been demonstrated
at the transcriptional and protein levels.7 Biochemical evidence and physiological evidence for a myocardial H⫹/K⫹ATPase have also been found.8 Furthermore, Beisvag and
coworkers7 showed a contribution from the H⫹/K⫹-ATPase of
⬇25% of total 86Rb⫹ uptake in rat hearts and suggested that
the enzyme could contribute significantly to the regulation of
myocardial K⫹ and H⫹ homeostasis. Inhibition of H⫹/K⫹ATPase might therefore induce cellular acidosis, which is
known to depress myocardial contractility mainly at the level
of myofilament responsiveness to [Ca]i.9
Orally applied PPIs are considered safe1 and have been
found advantageous in regard to cardiovascular side effects
compared with histamine type 2 (H2) receptor antagonists
because of lack of chronotropic and inotropic effects. In
contrast to famotidine, omeprazole did not show any changes
in cardiac performance in healthy volunteers as measured by
impedance cardiography and mechanocardiography after
1-week oral treatment with therapeutic doses.10 Pantoprazole,
lansoprazole, and esomeprazole are currently available as
intravenous formulations in the United States. The rationale
for use has come primarily with the suggested efficacy in
reducing rebleeding after endoscopic hemostasis of bleeding
peptic ulcers (eg, References 11 and 12). The target goal for
gastric pH in these patients has been suggested to be ⬎6 in
order to promote hemostasis and minimize clot lysis, in
contradistinction to the target pH ⬎4 for treating patients to
prevent stress ulcer or heal ulcers or reflux esophagitis.1,11,12
As such, the dosing amounts of intravenous PPI have been
higher than that of oral PPI. Recently, omeprazole and pantoprazole have been dosed at 80 mg followed by 8 mg/h for 72
hours.11,12 However, information regarding the cardiac effects of
high doses is lacking. Moreover, few data are available regarding the direct effect of such agents on the myocardium.
Hence, because of the abundant use of this drug class and
because of the presence of a H⫹/K⫹-ATPase in myocardium,
we sought to investigate the effects of PPI on contractility of
isolated human myocardium using pantoprazole, which is the
most commonly used intravenous formulation. In addition,
the mode of action in cardiac tissue was further analyzed in
isolated cardiac tissue from rabbits.
Methods
Myocardial Tissue
Experiments were performed in left ventricular muscle strips from 8
end-stage failing human hearts obtained from patients undergoing
cardiac transplantation and right atrial trabeculae obtained from 16
patients who underwent cardiac surgery. Additional right ventricular
trabeculae were obtained from adult female Chinchilla Bastard
rabbits (weight, 2.0 to 2.5 kg; Charles River Deutschland, Kisslegg,
Germany). Myocardial trabeculae13 and adult rabbit ventricular
cardiac myocytes14 were isolated and forces of electrically stimulated preparations were investigated as described previously. Experimental procedures with human tissue were reviewed and approved
by the ethical committee of the University Clinics of Goettingen, and
the subjects gave informed consent. Procedures with rabbits were
performed in accordance with institutional guidelines for the care
and use of laboratory animals.
pHi Measurements
Intracellular pH (pHi) was measured in isolated trabeculae from
rabbit hearts as described previously.13 Briefly, trabeculae were
mounted in a cylindrical glass cuvette, connected to an isometric
force transducer, and loaded with 2’,7’-bis(carboxyethyl)-5(6)carboxyfluorescein (BCECF)-AM (15 ␮mol/L) in Tyrode’s solution
by 45-minute incubation at room temperature. Excitation light from
a mercury lamp was passed alternately through 2 bandpass filters
(450 nm/495 nm) and focused on the muscle strip. Fluorescence
emission was collected by a photomultiplier (Scientific Instruments)
after passage through a bandpass filter (535⫾5 nm). Values of pHi
were estimated from the ratio of the BCECF fluorescence signals
(F495/F450) after subtraction of background fluorescence. At the end of
each experiment, the BCECF fluorescence ratio was calibrated in vivo
by means of the high K⫹-nigericin method as previously reported.15
Voltage Clamp and Intracellular [Ca2ⴙ]
Measurements in Rabbit Cardiomyocytes
The cardiomyocytes were superfused with a solution consisting of
(mmol/L) 144.0 NaCl, 5.4 KCl, 0.3 NaH2PO4, 1.0 MgCl2, 5.0
HEPES, 11.1 glucose, 1.8 CaCl2, 0.1 niflumic acid, 5.0 4-AP (pH
7.4) at room temperature in a chamber mounted on the stage of an
inverted microscope. Voltage clamp was achieved with the use of
whole-cell patch-clamp technique with an Axoclamp 2A amplifier
(Axon Instruments, Foster City, Calif) in switch clamp (discontinuous) mode. Pipettes were filled with an intracellular solution of the
following composition (mmol/L): 20.0 KCl, 100.0 K aspartate (DL),
20.0 TEA Cl, 10.0 HEPES, 4.5 MgCl2, 4.0 Na2ATP, 1.0 Na2CrP, 2.5
EGTA (pH 7.25 with KOH) and were of resistance 3 to 6 mol/L⍀.
Intracellular [Ca2⫹] was measured from fura 2 fluorescence signals
by a dual-wavelength spectrophotometer method as previously
described.16 Cytosolic loading of fura 2 was achieved by incubating
cardiomyocytes with 5 ␮mol/L fura 2-AM at room temperature for
12 minutes.
Electrophysiological Protocols
Isolated rabbit cardiomyocytes were held at ⫺80 mV, and the
voltage was stepped to ⫺40 mV (50 ms) to inactivate the inward Na⫹
current before stepping to 0 mV (150 ms). Tetrodotoxin 3⫻10⫺5
mol/L was also used to block INa. This protocol was repeated 40
times at a rate of 1 Hz to achieve steady state Ca2⫹ transients.
Sarcoplasmic reticulum (SR) Ca2⫹ content and Na⫹/Ca2⫹ exchanger
(NCX) activity were then estimated by rapidly switching to
10 mmol/L caffeine to cause SR Ca2⫹ release. In the continued
presence of caffeine (20 seconds), the SR is unable to reaccumulate
Ca2⫹, and therefore Ca2⫹ removal is mainly via NCX. The time
course of the decay of [Ca2⫹] and the NCX-mediated inward current
(INCX) represent rates of extrusion of Ca2⫹ from the cell predominantly by NCX.17 These signals were fitted to exponential decays
over ⬎80% of their amplitude. The magnitude of non-NCX Ca2⫹removal mechanisms was estimated from the Ca2⫹ decay obtained by
rapidly switching to 10 mmol/L caffeine in the presence of
10 mmol/L NiCl2 (which blocks NCX), in which the absence of a
current indicated that the current obtained without NiCl2 was solely
due to NCX.
Simultaneous Measurements of Myocyte
Shortening and Intracellular [Ca2ⴙ]
Shortening and [Ca2⫹]i were measured simultaneously as reported
previously.18 Cells were loaded with 10 ␮mol/L fluo 3-AM (Molecular Probes, Carlsbad, Calif) for 15 minutes. Fluo 3 was excited at
480 nm, and fluorescence was measured at 535 nm. The fieldstimulation frequency was 1 Hz (37°C, pH 7.35). Normalized
amplitude of calcium transients (F/F0) was calculated by dividing
Schillinger et al
TABLE 1.
Negative Inotropy of Pantoprazole
59
Primer Pairs Used in Real-Time PCR
Gene
Human
H⫹/K⫹-ATPase
Sequence
Gene Bank Accession No.
Sense: 5⬘-CCACATCCACACAGCTGACAC-3⬘
M63962
Antisense: 5⬘-TCAAACGTCTGCCCTGACTG-3⬘
Rabbit H⫹/K⫹-ATPase
Sense: 5⬘-ACTCTGCACCGACATTTTCCC-3⬘
X64694
Antisense: 5⬘-TCAGCCTTCTCATACGCCAAG-3⬘
␤-Actin
Sense: 5⬘-CTGGCACCCAGCACAATG-3⬘
M10277
Antisense: 5⬘-CCGATCCACACGGAGTACTTG-3⬘
fluorescence F by the baseline fluorescence F0 after subtraction of
the background fluorescence (IonWizard, IonOptix Corp). Cells
were treated with 0/10/40 ␮g/mL pantoprazole followed by a
washout. Fluorescence and shortening were analyzed at steady state
conditions.
Measurements of SR Ca2ⴙ Uptake Characteristics
Measurements of SR Ca2⫹ uptake were performed as described
previously.14 Ventricular myocytes freshly dissociated from adult
rabbit hearts were permeabilized with 0.1 mg/mL ␤-escin and kept in
mock intracellular solution of the following composition (mmol/L):
100 K⫹, 40 Na⫹, 25 HEPES, 100 Cl⫺, 0.05 EGTA, 5 ATP, 10 CrP
(pH 7.0). To test the influence of pantoprazole on SR Ca2⫹ uptake,
myocytes were divided into 3 groups, and 0 (control), 10 ␮g/mL, and
40 ␮g/mL pantoprazole were added into the cuvette. Oxalate
(10 mmol/L) was included to maintain low and constant intra-SR
[Ca2⫹], and ruthenium red (2.7 ␮mol/L) was included to block SR
Ca2⫹ efflux. Myocyte suspensions were stirred and [Ca2⫹] was
monitored with the use of fura 2 (10 ␮mol/L). The decline of Ca2⫹
signal was used to calculate SR Ca2⫹ uptake characteristics.
Skinned Fibers
Fibers dissected from rabbit right ventricles were skinned by
incubation with Triton (1%) for 24 hours at 4°C. Paired measure-
A
8
Control
(n = 15/12)
ments of calcium sensitivity and force development of the myofilaments were performed with the use of 1 relaxation and 10 activation
solutions containing pantoprazole (10/40 ␮g/mL) or NaCl as control
with increasing Ca2⫹ concentrations (from 1.66⫻10⫺7 mol/L to
5.15⫻10⫺5 mol/L Ca2⫹). Active tension was measured via force
transducer and analyzed at steady state conditions. To exclude that
changes in the active tension were due to rundown of the preparation,
each exposure to pantoprazole was preceded and followed by 1
control step with NaCl 0.9%.
Transcription of Hⴙ/Kⴙ-ATPase in
Human Myocardium
RNA was isolated from myocardial tissue and gastric corpus mucosa
from humans and rabbits with the use of RNeasy Kits (Qiagen).
Quantitative reverse transcription polymerase chain reaction (RTPCR) was performed by real-time PCR as described earlier.19 Primer
pairs for H⫹/K⫹-ATPase and ␤-actin are summarized in the Table.
Each sample was analyzed in duplicate. The investigated number of
cDNA molecules was related to ␤-actin cDNA molecules detected in
the same sample to normalize for the quantity of RNA extracted and
the efficiency of cDNA synthesis. The relative expression was then
calculated as described.19
B
Developed Tension (mN/mm²)
4
Pantoprazole
( n = 16/ 12)
4
*
Pantoprazole
(n = 11/5)
2
1
Human atrium
30
20
D
10
*
Human ventricle
0
0.625 1.25 3.125 6.25 12.5
25
50
Wash-out
6
5
**
Pantoprazole
15
0
50 Wash-out
Control
( n = 11/11)
25
4
3
(n = 11/11)
Esomeprazole
(n = 5/5)
Control
(n = 14/12)
2
5
0
*
3
0 0.625 1.25 3.125 6.25 12.5 25
C
Control
(n = 12/5)
5
6
2
6
Rabbit ventricle
0
0.625 1.25
2.5
5
10
20
40
Wash-out
1
Human atrium
0 0.625 1.25 3.125 6.25 12.5 25
50 Wash-out
Concentration (µg/mL)
Figure 1. Dose dependence of isometric twitch force from pantoprazole (A to C) and esomeprazole (D) in different types of myocardium
as indicated and partial reversibility after washout of the drug. The number of trabeculae and hearts used for each experiment is indicated in parentheses. *P⬍0.025 (only concentrations with potential clinical relevance have been tested).
Circulation
July 3, 2007
Pantoprazole (µg/mL):
Force (mN/mm²)
A
11
10
9
8
7
6
5
4
3
2
1
0
0
0
500
11
10
9
8
7
6
5
4
3
2
1
0
1000 0
10
500
11
10
9
8
7
6
5
4
3
2
1
0
1000 0
20
500
11
10
9
8
7
6
5
4
3
2
1
0
1000 0
40
500
11
10
9
8
7
6
5
4
3
2
1
0
1000 0
B
160
500
1000
Developed Tension (mN/mm2)
60
6
4
2
1
Force (mN/mm²)
C
6
6
6
6
6
5
5
5
5
5
4
4
4
4
4
3
3
3
3
3
2
2
2
2
2
1
1
1
1
1
0
0
500
10
100
Pantoprazole [µg/mL]
0
1000 0
500
0
1000 0
500
0
1000 0
Time (ms)
500
0
1000 0
D
500
1000
Developed Tension (mN/mm2)
Time (ms)
6
4
2
0
1
10
100
Pantoprazole [µg/mL]
Figure 2. Determination of EC50 for contractile depression of pantoprazole in human myocardium. Single twitches of original recordings
of typical experiments in human atrial (A) and ventricular (C) trabeculae are shown. Mean force values in atrial (B) (n⫽8 trabeculae from
4 hearts) and ventricular (D) (n⫽6/3) trabeculae are shown. Curves have been fitted to yield EC50 values as detailed in Results.
Statistical Analysis
Data are expressed as mean⫾SEM. Student paired t test (Figures 3
and 5) or repeated-measures ANOVA (Figures 1, 4, 6, and 7) were
performed to test for statistically significant differences between
different interventions. In general, a value of P⬍0.05 was accepted
as statistically significant; for post hoc analysis, probability values
were adjusted according to Bonferroni (Figures 1 and 4), or the
Tukey test was used (Figure 6).
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
Dose-Response Relationship of PPIs in Isolated
Trabeculae From Human and Rabbit Myocardium
Figure 1A and 1B demonstrates a dose-dependent reduction
of isometric twitch force of electrically stimulated trabeculae
from nonfailing human atrial and failing ventricular myocardium under the influence of pantoprazole. Negative inotropy
was at least partially reversible after washout of the drug. The
pantoprazole-dependent negative inotropy was also present in
ventricular myocardium from healthy adult rabbits (Figure
1C). Moreover, a similar dose-dependent effect was found
with esomeprazole in human atrial myocardium (Figure 1D).
The effect was highly reproducible, and the maximum effect
usually occurred within a few minutes after exposure to
pantoprazole. To yield EC50 values of the negative inotropic
effect, additional dose-response experiments with maximum
pantoprazole concentrations of 160 ␮g/mL have been performed that induced nearly complete suppression of contractile force. Data points have been fitted with the use of logistic
curve fit with OriginPro 7 scientific software (OriginLab
Corp). The EC50 was 30.6⫾1.8 ␮g/mL in atrial human
myocardium (Figure 2B) and 17.3⫾1.3 ␮g/mL in ventricular
human myocardium (Figure 2D). Compared with control, at
doses of 6.25 and 12.5 ␮g/mL of pantoprazole, the contractile
forces in human ventricular myocardium were 3.0⫾0.4 versus 4.2⫾0.7 mN/mm2 and 2.4⫾0.3 versus 4.0⫾0.6 mN/mm2
(P⬍0.025, each). This corresponds to a depression of contractile forces by 27⫾9% and 42⫾8%, respectively. In
human atrial myocardium, forces in the presence of 12.5
␮g/mL pantoprazole were 5.1⫾0.8 versus 5.7⫾0.4 mN/mm2
compared with control (P⬍0.025, depression by 12⫾14%).
Preincubation of trabeculae with ouabain (0.2 ␮mol/L) in-
Figure 3. pHi measurements in ventricular trabeculae from rabbits. A, pHi
changes after application of pantoprazole (40 ␮g/mL) in an individual rabbit
ventricular muscle strip. B, Average
changes of pHi (left) and developed force
(right) induced by 20-minute treatment
with 40 ␮g/mL pantoprazole. Data were
obtained from 5 ventricular trabeculae
isolated from 5 rabbit hearts. **P⬍0.01
vs initial control.
Schillinger et al
A
10 µg/mL
Negative Inotropy of Pantoprazole
61
40 µg/mL Wash-out
Length (µm)
1.90
1.85
1.80
1.75
0
B
1 00
Time (s)
200
300
Length (µm)
1.90
1.85
1.80
Figure 4. Dependence of myocyte shortening and [Ca2⫹]i from pantoprazole in rabbit
myocytes. Original chart files of myocyte
shortening with (A) and without (B) addition
of pantoprazole are shown. C, Original recordings of Ca2⫹ transients in an isotonically contracting myocyte. D, Mean values
of fractional shortening. E, Ca2⫹ transient
measurements (n⫽16 myocytes from 10
animals for pantoprazole, and n⫽15/8 for
control). *P⬍0.025 vs control.
1.75
0
100
200
300
Time (s)
C
10
40
[Ca²+]i; 400 rel.
Fluorescence Units
PP (µg/mL): 0
1s
E
1.6
*
1
0
Control
2
0
[Ca2+]i (F/F0)
3
10
40
Wash-out
Concentration (µg/mL)
*
1.4
1.2
1.0
Control
*
Pantoprazole
4
Pantoprazole
Fractional Shortening (%)
D
0
10
40
Wash-out
Concentration (µg/mL)
duced an increase in contractile force by 31.1%. After
exposure to pantoprazole (40 ␮g/mL), force decreased by
65.2% compared with ouabain treatment and by 54.4%
compared with baseline values (P⬍0.05 each).
with ventricular myocardium was 1.2⫻106 times higher in
humans (1.3⫾0.8 versus 1.1⫻10⫺6⫾0.7⫻10⫺6; n⫽3) and
2.2⫻106 times higher in rabbits (1262⫾673 versus
580⫻10⫺6⫾217⫻10⫺6; n⫽3), respectively.
Expression of Hⴙ/Kⴙ-ATPase in Myocardium and
Gastric Mucosa From Humans and Rabbits
Pantoprazole Does Not Affect pHi
H⫹/K⫹-ATPase mRNA expression was detectable in both
gastric corpus mucosa and ventricular myocardium from
humans and rabbits. However, the expression was very low in
ventricular myocardium from both species. The relative
expression of H⫹/K⫹-ATPase in corpus mucosa compared
pHi is an important modulator of contractility. Therefore, we
tested whether pantoprazole induced changes in pHi that
might explain the observed negative inotropic effect. Figure
3A shows pHi changes of a BCECF-loaded rabbit ventricular
muscle strip before and in the presence of pantoprazole (40
Circulation
July 3, 2007
A
B
Em (mV)
[Ca ] (nM)
800
600
Average changes
**
40
2+
Diastolic [Ca ]i
2+
Systolic [Ca ]i
Transient amplitude
20
0
-20
**
400
1
0
400ms
% change (+/-SEM)
Current (nA)
Current (nA)
2+
0
-40
-80
(ii) Pantoprazole
% change (+/-SEM)
C ont r o l
(i)
0
-1
0
-1
-20
**
ICa,L amplitude
**
-40
2+
Ca influx via ICa,L
50ms
C
D
(i)
Im (nA) [Ca2+] (nM)
i
1000
Control
(ii) Pantoprazole
Caffeine (10mM)
Caffeine (10mM)
500
0
0.0
-0.1
Average changes
% change (+/-SEM)
62
INCX.time integral
20
2+
Ca transient amplitude
2+
Rate of Ca transient decay
0
-20
*
*
2s
Figure 5. Depolarization-induced Ca2⫹ transients recorded from rabbit ventricular cardiomyocytes. A, Records of membrane voltage
(Em), membrane current, and [Ca2⫹]i from single cardiomyocytes (average of 4 sequential signals) during control conditions (i) and after
perfusion with pantoprazole (40 ␮g/mL) (ii). B, Mean⫾SEM of the percent change in diastolic [Ca2⫹]I, systolic [Ca2⫹]i, and Ca2⫹ transient
amplitude (**P⬍0.01). C, Recordings of [Ca2⫹]i and membrane current recorded on rapid application of 10 mmol/L caffeine (as indicated
above the records) during control conditions (i) and after perfusion with pantoprazole (40 ␮g/mL) (ii). D, Mean⫾SEM of the percent
change in INCX · time integral diastolic [Ca2⫹]I, Ca2⫹ transient amplitude, and rate constant for the decay of the Ca2⫹ transient. *P⬍0.05.
␮g/mL). In this example, pHi was increased slightly by ⬇0.1
pH units. Simultaneously, developed force declined from
12.0 to 5.6 mN/mm2 or by 53% within the 20-minute
recording period (not shown). Average results from a total of
5 muscle strips (Figure 3B) revealed that pantoprazole did not
induce any significant alterations in pHi (⌬pHi⫽0.07⫾0.10;
P⫽NS), whereas developed force was reduced by 55⫾4%
(P⬍0.01). Thus, the negative inotropic effect of pantoprazole
was not accompanied by changes in pHi.
Ca2ⴙ Homeostasis in Isolated Rabbit Myocytes
Similar to the findings in isolated trabeculae, pantoprazole
induced a dose-dependent reduction of isotonic shortening of
isolated rabbit myocytes by 32.3⫾5.8% at 10 ␮g/mL and
65.4⫾3.4% at 40 ␮g/mL. This was paralleled by a depression
of Ca2⫹ transient amplitude measured by fluorescence of fluo
3–loaded myocytes (F/F0) by 9.0⫾2.6% and 10.4⫾2.1% at 10
and 40 ␮g/mL, respectively (Figure 4). Effects of pantopra-
zole on intracellular Ca2⫹ cycling were further investigated in
voltage-clamped and fura 2–loaded rabbit myocytes (Figure
5A and 5B). On addition of 40 ␮g/mL pantoprazole, diastolic
[Ca2⫹]i was increased by 33⫾12% (P⬍0.05; n⫽13), with no
significant change in peak systolic [Ca2⫹]i (4⫾7%; n⫽14). As
a result of these changes, Ca2⫹ transient amplitude was
reduced by 25⫾8% (n⫽14; P⬍0.05) compared with control
cells. These changes were paralleled by a reduction in ICa,L
amplitude (by 35⫾5%; P⬍0.05; n⫽14). To measure SR and
NCX function, the intracellular Ca2⫹ signals and the associated INCX were analyzed on rapid application of 10 mmol/L
caffeine (Figure 5C and 5D). A reduction in both the
amplitude of the caffeine induced Ca2⫹ release (by 18⫾6%;
n⫽10; P⬍0.05) and the associated time integral of INCX (by
21⫾6%; n⫽10; P⬍0.05) on exposure to pantoprazole (40
␮g/mL) indicated that pantoprazole decreased SR Ca2⫹ content. No changes in the rate of decay of the caffeine induced
Ca2⫹ transient (1⫾8%; n⫽10) and INCX (2⫾7%; n⫽10) were
Downloaded from circ.ahajournals.org at Mohammed Mahboob on July 15, 2007
Schillinger et al
Negative Inotropy of Pantoprazole
Kd of SR Ca2+ uptake
Control
Low Panto
High Panto
Contr ol
l ow P a n t o
High Panto
450
0.3
Kd (nmol/L)
Vmax (fmol/s/106 cells)
Vmax of SR Ca2+ uptake
0.4
63
0.2
0.1
*
400
*
350
A
B
Figure 6. Characteristics of SR Ca2⫹-ATPase activity as determined by use of a cuvette assay. Vmax (A) and Kd (B) of Ca2⫹ transport
activity in the presence of either 0 (control), 10 (low), or 40 (high) ␮g/mL of pantoprazole (Panto) are shown. *P⬍0.05 vs control.
␮g/mL (P⫽NS) and 26.5⫾2.8% at 40 ␮g/mL (P⬍0.05). In
addition, a small but significant rightward shift of the Ca2⫹
response curve indicating a decrease of Ca2⫹ sensitivity was
found. The EC50 was 1.44 mol/L Ca2⫹ at 0 ␮g/mL and 1.59
mol/L Ca2⫹ at 40 ␮g/mL pantoprazole (P⬍0.05).
observed after pantoprazole administration, indicating that
the sarcolemmal extrusion processes (particularly NCX) were
unaffected by the drug.
SR Ca2ⴙ Uptake Data
Figure 6 demonstrates the effects of pantoprazole on oxalatesupported Ca2⫹ uptake in permeabilized rabbit ventricular cardiomyocytes. In the presence of either carrier solution or low (10
␮g/mL) or high (40 ␮g/mL) concentrations of pantoprazole, the
[Ca2⫹] at which half maximal Ca2⫹ uptake occurred (Kd) and the
value of the maximum rate of Ca2⫹ uptake (Vmax) were estimated
with a fura 2– based SR Ca2⫹ uptake assay. Neither low nor high
concentration of pantoprazole influenced the Vmax value. However, the Kd values of SR Ca2⫹ uptake were increased significantly at both concentrations of pantoprazole (nmol/L: control,
358⫾15; low pantoprazole, 406⫾15; high pantoprazole,
395⫾12; P⬍0.05).
Discussion
The present study shows a negative inotropic effect of
pantoprazole in isolated myocardium. This was dose dependent, induced nearly complete inhibition of twitch force at
very high doses, and was partially reversible. Negative
inotropy of pantoprazole was present in myocardium from
different species (human and rabbit) and in myocardium from
different origins (atrial and ventricular), and it was found in
different myocardial preparations (multicellular and single
cells). The EC50 for contractile force depression was
30.6⫾1.8 ␮g/mL in nonfailing human atrial and 17.3⫾1.3
␮g/mL in failing human ventricular myocardium, respectively. Moreover, similar results could be obtained with
esomeprazole, which is suggestive of a class effect of PPIs.
Furthermore, we could reveal 2 underlying mechanisms for
the pantoprazole-dependent inhibition of contractile force: (1)
reduction in the amplitude of Ca2⫹ transients as a consequence of impaired SR Ca2⫹ uptake and reduced Ca2⫹ influx
Effects of Pantoprazole in Skinned
Fiber Preparations
The effect of pantoprazole in skinned fibers is shown in
Figure 7. There was a reduction of the maximum active
tension at saturating Ca2⫹ concentration by 7.8⫾0.8% at 10
[Ca
2+
]o (mol/L)
40 µg/mL
Pantoprazole
[Ca 2+ ]o (mol/L)
10
-4
0
10
-5
10
-4
10
-5
10
-6
10
-7
0
*
Control
10
10
-6
10 µg/mL
Pantoprazole
20
10
-7
Control
10
30
10
-8
20
Active Tension (mN/mm²)
B
30
10
-8
Active Tension (mN/mm²)
A
Figure 7. Measurements in skinned fibers. Dose
dependence of active tension at increasing Ca2⫹
concentrations in skinned fiber preparations at 10
␮g/mL (A) and 40 ␮g/mL (B) of pantoprazole is
shown. Maximal active tension at saturating Ca2⫹
concentration and Ca2⫹ sensitivity was significantly
lower at 40 ␮g/mL. *P⬍0.05.
64
Circulation
July 3, 2007
via ICa,L and (2) reduced Ca2⫹ responsiveness of the myofilaments as a result of a reduced maximal active tension and a
slightly lower Ca2⫹ sensitivity. In contrast, despite the expression of the H⫹/K⫹-ATPase at the transcriptional level in
human and rabbit myocardium, no significant changes in pHi
could be detected in the presence of pantoprazole.
Note that the mechanisms underlying the effects of pantoprazole in myocardium are completely different from the mechanisms of the drug in gastric parietal cells and probably do not
involve inhibition of H⫹/K⫹-ATPase. In regard to gastric proton
pump inhibition, all PPIs are prodrugs and require acid to
become protonated and converted into the active form.1 After
intravenous administration or intestinal absorption, when orally
administered the lipophilic unprotonated form readily penetrates
cell membranes, including that of gastric parietal cells and
myocytes. In parietal cells, as it transverses the cell it is exposed
to the acidic environment in the secretory canaliculus of the
gastric site and becomes protonated, converting it to a hydrophilic drug that can no longer permeate cell membranes. The
drug becomes trapped in the canaliculus of the parietal cell. For
this reason, in parietal cells PPIs exhibit a substantial accumulation versus plasma at low pH, eg, 1000-fold for omeprazole
and 10000-fold for rabeprazole at a pH of 1. Moreover, protonation of the drug initiates a series of chemical reactions that
culminates in covalent binding of the drug with selected cysteine
residues of the H⫹/K⫹-ATPase.1
The present study is the first one reporting on the expression of H⫹/K⫹-ATPase in human and rabbit ventricular
myocardium. Recently, it has been suggested that H⫹/K⫹ATPase may contribute to pH homeostasis in rat myocardium.7 We therefore investigated the hypothesis that cellular
acidosis subsequent to proton pump inhibition might explain
the negative inotropy of PPIs. However, our measurements
with the H⫹-sensitive fluorescence dye BCECF did not reveal
any significant influence of pantoprazole on pHi. Moreover,
the absence of acidic compartments in cardiac tissue with pH
⬍1 precludes significant accumulation of pantoprazole in the
myocardium. In moderately acidic compartments like lysosomes, slow activation of pantoprazole theoretically may
occur with an activation half-life of 4.7 hours.20 However,
negative inotropy in our experiments usually occurred
quickly within several minutes. Moreover, the effect was at
least partially reversible after washout of the drug, whereas
the recovery of the gastric proton pump from pantoprazole
has a half-life of ⬇46 hours21 and was suggested to depend
mainly on the synthesis of new pump protein.1,22 In addition,
the expression of H⫹/K⫹-ATPase in myocardium was very
low compared with gastric mucosa. Therefore, it is unlikely
that the negative inotropy of pantoprazole in myocardium is
the consequence of H⫹/K⫹-ATPase inhibition.
We investigated the effects of pantoprazole on intracellular
Ca2⫹ homeostasis and myofilament Ca2⫹ responsiveness,
which are the 2 principal physiological mechanisms of the
myocardium to alter contractility. We found a reduction in the
Ca2⫹ transient amplitude in field-stimulated ventricular myocytes. Interpretation of this result in terms of Ca2⫹ signaling is
complicated by possible effects of pantoprazole on the action
potential. With fixed depolarizing pulses in voltage-clamped
myocytes, pantoprazole caused a rise in diastolic [Ca2⫹]i and
minimal changes in systolic [Ca2⫹]i, the net effect being a
reduced Ca2⫹ transient amplitude. Independent evidence for
pantoprazole-dependent inhibition of SERCA as an underlying mechanism was obtained with a fura 2– based SR calcium
uptake assay in permeabilized cardiomyocytes. Moreover,
Ca2⫹ influx via ICa,L was also depressed by pantoprazole. The
combination of reduced SR calcium uptake and reduced Ca2⫹
influx would explain the reduction in SR Ca2⫹ content
observed and raised diastolic [Ca2⫹]i.
We also investigated the influence of pantoprazole in
skinned fibers. These preparations allow for the investigation
of drug effects directly at the myofilament level under
well-defined in vitro conditions. Hence, it can be excluded
that the observed effects are mediated by changes in [Ca2⫹]i or
pHi. We were able to show a significant reduction in maximal
active tension of the contractile proteins at saturating Ca2⫹
concentrations by 26.5⫾2.8% at 40 ␮g/mL. Moreover, at 40
␮g/mL there was a slight but significant reduction in myofilament Ca2⫹ sensitivity. However, when the marked negative inotropy in multicellular trabeculae is considered, these
effects were too faint to explain entirely the mode of action of
pantoprazole in myocardium. Therefore, the negative inotropy of pantoprazole observed at 10 ␮g/mL mainly results
from decreased intracellular [Ca2⫹]. At the higher dose (40
␮g/mL), depression of myofilament responsiveness appears
to contribute to the negative inotropic effect. We also suggest
that the effects of pantoprazole in myocardium depend on the
native unprotonated form of the drug and do not require
activation by low pH because all effects occurred at pH 7.3
to 7.4.
In contrast to our data, Yenisehirli and Onur23 found a positive
inotropic effect of 3 different PPIs in rat atria that was potentiated by pretreatment with the Na⫹/K⫹-ATPase inhibitor ouabain.
Moreover, lansoprazole induced a prolongation of the action
potential. The authors speculated that this could be mediated by
inhibition of H⫹/K⫹-ATPase promoting altered intracellular
Ca2⫹ handling. In our study with human and rabbit myocardium,
pantoprazole decreased tension and reduced shortening and Ca2⫹
transient amplitude in “unclamped” trabeculae and single cells.
When single rabbit myocytes were clamped with a fixed voltage
clamp duration, pantoprazole decreased the Ca2⫹ transient amplitude to a degree similar to that seen in “unclamped” preparations. This suggests that in humans and rabbits, action potential
duration changes are not instrumental in the decreased Ca2⫹
transient and subsequent mechanical response caused by pantoprazole application. Moreover, a significant contribution of
H⫹/K⫹-ATPase to the action potential is unlikely because of the
low degree of expression. The different responses to PPIs may
therefore be related to species. Compared with human and rabbit
myocardium, in rats the action potential is short and intracellular
sodium is high. In particular, the latter condition favors Ca2⫹
entry by reverse-mode Na⫹-Ca2⫹ exchange, which contributes to
SR Ca2⫹ load and contractility when action potential duration
increases.9 In contrast to the study by Yenisehirli and Onur, the
negative inotropic effect of pantoprazole in rabbit myocardium
observed by us was not influenced by blockade of Na⫹/K⫹ATPase, and the magnitude of the effect was similar to that in
experiments without ouabain.
Schillinger et al
Finally, although this was beyond the scope of the present
study, we would like to speculate whether our findings might be
of clinical relevance. Because the negative inotropic effect was
partially reversible after washout of the drug and significant
accumulation in the myocardium is unlikely, the effect of
pantoprazole in vivo probably depends on plasma concentrations. Maximal pantoprazole plasma concentrations of 4.6 ␮g/
mL24 and 10.4 ␮g/mL (Altana Pharma AG, written communication, July 23, 2004) have been found after administration of
common oral (40 mg) and intravenous (80 mg) doses. In the
present work, similar concentrations induced a reduction of
contractile force of isolated trabeculae by 27⫾9% (6.25 ␮g/mL)
and 42⫾8% (12.5 ␮g/mL), which might indicate a potential
clinical relevance of our findings. However, the duration of
cardiac side effects is temporally limited because all PPIs are
quickly eliminated from blood with plasma elimination half-life
periods of ⬇1 to 2 hours.20,24 Moreover, cardiac side effects may
be attenuated in vivo because the activity of the active free
compound may be substantially lower because of high plasma
protein binding.20 On the other hand, particular conditions may
be associated with increased duration and intensity of side
effects. Patients with heart failure must be investigated for PPI
tolerance. These patients are much more susceptible to negative
inotropic drugs because of blunted contractile reserve subsequent to decreased sympathetic sensitivity25 or negative forcefrequency relationship.26 In addition, the dependence of H⫹
elimination from H⫹/K⫹-ATPase may be increased in heart
failure because of the impaired function of the Na⫹/H⫹ exchange
subsequent to increased [Na⫹]i.27 Moreover, all PPIs undergo
extensive hepatic biotransformation before elimination. In
CYP2C19-poor metabolizers that represent ⬇3% to 5% of
whites, a similar percentage of blacks, and 12% to 25% of
different Asian populations, much higher plasma concentrations
and longer elimination half-life periods have been found.1 The
same holds true for patients with severe liver impairment.28
Recent American29 and Canadian30 studies have shown that
appropriate use of intravenous PPIs was seen in less than half
of the patients. In view of our data, PPIs should be prescribed
carefully. We have recently initiated a clinical study for the
investigation of cardiac side effects of pantoprazole in
healthy volunteers. Moreover, we encourage clinical studies
to identify individuals with increased intrinsic risk for cardiac
side effects of PPIs.
Acknowledgments
We gratefully acknowledge the expert assistance of Hanna Schotola,
Astrid Steen, Aileen Rankin, Gudrun Muller, Elke Neumann, and
Michael Kothe.
Sources of Funding
This work was supported by grants from the Wellcome Trust (to Dr
Kettlewell), the British Heart Foundation (to Dr Smith), and the
Deutsche Forschungsgemeinschaft (to Dr Maier).
Disclosures
None.
Negative Inotropy of Pantoprazole
65
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Ng EK, You JH, Lee CW, Chan AC, Chung SC. Effect of intravenous
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13. Luers C, Fialka F, Elgner A, Zhu D, Kockskamper J, von Lewinski D,
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P, Wagner S, Kogler H, Inesi G, Bers DM, Hasenfuss G, Smith GL.
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15. Hasenfuss G, Maier LS, Hermann HP, Luers C, Hunlich M, Zeitz O,
Janssen PM, Pieske B. Influence of pyruvate on contractile performance
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18. DeSantiago J, Maier LS, Bers DM. Frequency-dependent acceleration of
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Comparative pharmacokinetic/pharmacodynamic analysis of protein
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effects of proton pump inhibitors in isolated rat atrium. Eur J Pharmacol.
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Lurie K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivity and beta-adrenergic receptor density in failing human
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Meyer M, Just H, Hasenfuss G. Influence of SR Ca2⫹-ATPase and
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1998;93(suppl 1):38 – 45.
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Rate dependence of [Na⫹]i and contractility in nonfailing and failing
human. Circulation. 2002;106:447– 453.
28. Ferron GM, Preston RA, Noveck RJ, Pockros P, Mayer P, Getsy J,
Turner M, Abell M, Paul J. Pharmacokinetics of pantoprazole in
patients with moderate and severe hepatic dysfunction. Clin Ther.
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30. Kaplan GG, Bates D, McDonald D, Panaccione R, Romagnuolo
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CLINICAL PERSPECTIVE
The proton pump inhibitor pantoprazole was evaluated for its effects on cardiac contractility in isolated myocardium from
humans and rabbits. We found a dose-dependent negative inotropic effect mainly resulting from alterations in intracellular
Ca2⫹ handling. At higher concentrations of the drug, depression of myofilament Ca2⫹ responsiveness was also observed.
However, despite the expression of the gastric proton pump in human and rabbit hearts, no relevant changes in pH
homeostasis could be detected. Moreover, expression of the pump was very low in myocardium compared with gastric
tissue. A similar effect was observed with esomeprazole. Thus, proton pump inhibitors affect cardiac contractility by
intracellular mechanisms that are distinct from their effects in gastric parietal cells. The effects in isolated myocardium
were observed at concentrations that might be of potential clinical relevance. Thus, cardiac effects of proton pump
inhibitors should be evaluated in vivo because of their extensive use for acid-related gastrointestinal diseases.
Interventional Cardiology
Emergency Department Physician Activation of the
Catheterization Laboratory and Immediate Transfer to an
Immediately Available Catheterization Laboratory Reduce
Door-to-Balloon Time in ST-Elevation Myocardial Infarction
Umesh N. Khot, MD; Michele L. Johnson, RN; Curtis Ramsey, MS; Monica B. Khot, MD;
Randall Todd, MD; Saeed R. Shaikh, MD; William J. Berg, MD
Background—Consensus guidelines and hospital quality-of-care programs recommend that ST-elevation myocardial
infarction patients achieve a door-to-balloon time of ⱕ90 minutes. However, there are limited prospective data on
specific measures to significantly reduce door-to-balloon time.
Methods and Results—We prospectively determined the impact on median door-to-balloon time of a protocol mandating
(1) emergency department physician activation of the catheterization laboratory and (2) immediate transfer of the patient
to an immediately available catheterization laboratory by an in-house transfer team consisting of an emergency
department nurse, a critical care unit nurse, and a chest pain unit nurse. We collected door-to-balloon time for 60
consecutive ST-elevation myocardial infarction patients undergoing emergency percutaneous intervention within 24
hours of presentation from October 1, 2004, through August 31, 2005, and compared this group with 86 consecutive
ST-elevation myocardial infarction patients from September 1, 2005, through June 26, 2006, after protocol
implementation. Median door-to-balloon time decreased overall (113.5 versus 75.5 minutes; P⬍0.0001), during regular
hours (83.5 versus 64.5 minutes; P⫽0.005), during off-hours (123.5 versus 77.5 minutes; P⬍0.0001), and with transfer
from an outside affiliated emergency department (147 versus 85 minutes; P⫽0.0006). Treatment within 90 minutes
increased from 28% to 71% (P⬍0.0001). Mean infarct size decreased (peak creatinine kinase, 2623⫾3329 versus
1517⫾1556 IU/L; P⫽0.0089), as did hospital length of stay (5⫾7 versus 3⫾2 days; P⫽0.0097) and total hospital costs
per admission ($26 826⫾29 497 versus $18 280⫾8943; P⫽0.0125).
Conclusions—Emergency department physician activation of the catheterization laboratory and immediate transfer of the
patient to an immediately available catheterization laboratory reduce door-to-balloon time, leading to a reduction in
myocardial infarct size, hospital length of stay, and total hospital costs. (Circulation. 2007;116:67-76.)
Key Words: angioplasty 䡲 myocardial infarction 䡲 quality of health care 䡲 stents 䡲 quality indicators, health care
E
mergency percutaneous intervention (PCI) is increasingly used in the management of ST-elevation myocardial infarction (STEMI). The benefits of emergency PCI are time
dependent, with door-to-balloon time delays associated with
increasing mortality.1 Therefore, consensus guidelines recommend that STEMI patients achieve a door-to-balloon time of
ⱕ90 minutes.2 More recently, the American College of Cardiology, American Heart Association, the Centers for Medicare
and Medicaid Services, and the Joint Commission on Accreditation of Healthcare Organizations have all included door-toballoon time as a core hospital quality-of-care indicator.3–5
Despite the increased emphasis on achieving appropriate
door-to-balloon times, only 32% of patients overall in the
United States receive PCI within 90 minutes.6,7 In addition,
there has been limited temporal improvement in door-to-
Editorial p 6
Clinical Perspective p 76
balloon time,8 leading some to suggest that future improvements in door-to-balloon time are unlikely.9 Interestingly,
select hospitals have achieved improvements in door-toballoon times, and recent studies have highlighted qualitative
characteristics unique to these institutions.10 More recently, a
survey of hospital strategies revealed that activation of the
catheterization laboratory by the emergency department physician rather than cardiologist was associated with faster
door-to-balloon times.11 Prior studies actually implementing
emergency department physician activation have shown improvements in door-to-balloon time. One report revealed a
reduction in median door-to-balloon from 88 to 61 minutes.12
Received November 20, 2006; accepted April 20, 2007.
From the Indiana Heart Physicians, Indianapolis (U.N.K., M.B.K., S.R.S., W.J.B.); St. Francis Hospital and Health Centers, Beech Grove (M.L.J.);
Curtis Ramsey and Associates, Indianapolis (C.S.); and Emergency Physicians of Indianapolis, Beech Grove (R.T.), Ind.
Correspondence to Umesh N. Khot, MD, Indiana Heart Physicians/St. Francis Heart Center, 5330 E Stop 11 Rd, Indianapolis, IN 46237. E-mail
khot@cvresearch.net
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.677401
67
68
Circulation
July 3, 2007
However, the results of that study were confounded by
simultaneous conversion of reperfusion strategy from a combination of thrombolytics and PCI to solely PCI. In addition,
the study excluded data from a 6-month transition period
between strategies. In a recent retrospective study, emergency
department physician activation reduced door-to-balloon time
from 118 to 89 minutes.13 There are limited prospective data
on the effect of adopting emergency department physician
activation of the catheterization laboratory on door-to-balloon
time in centers already dedicated to primary PCI. We therefore prospectively determined the impact on door-to-balloon
time of emergency department physician activation of the
catheterization laboratory, combined with a novel strategy of
immediate physical transfer of the patient to an immediately
available catheterization laboratory by in-house nursing staff.
Methods
Study Design
The present prospective study was conducted between October 1,
2004, and June 26, 2006, at St Francis Hospital and Health Center
(Beech Grove and Indianapolis, Ind), a 591-bed tertiary care community hospital consisting of 2 campuses 7 miles apart (13-minute
drive). Both campuses have emergency departments staffed with
emergency medicine residency–trained physicians; cardiology services are located within the Indianapolis campus. During the study
period, the hospital performed primary PCI for all STEMI patients
presenting at either campus. A single 20-physician group provides
cardiology services at both campuses (Indiana Heart Physicians,
Indianapolis). Cardiologists take in-hospital call. Call consists of a
noninterventional cardiologist on call with interventional cardiologist on backup call at home ⬇80% of the time; the other 20% of the
time, an interventional cardiologist takes primary call. Call pattern
was unchanged during the study period. Four catheterization staff
members take home call during off-hours and are expected to arrive
to the hospital within 30 minutes of laboratory activation.
We prospectively enrolled consecutive patients who presented to
either the Beech Grove or Indianapolis emergency department with
STEMI who received PCI within 24 hours of presentation.4,5 We
excluded STEMI patients who were hospital inpatients at the time of
diagnosis.
Protocol During Cardiology Activation/Routine
Transfer Period (October 1, 2004, Through August
31, 2005)
Emergency department physicians requested immediate cardiology
evaluation for all STEMI patients. After patient evaluation, the
cardiologist activated the catheterization laboratory by contacting the
catheterization laboratory coordinator during regular hours (7 AM to
5 PM weekdays) or the hospital operator during off-hours (weekends
and 5 PM to 7 AM weekdays). During regular hours, the catheterization laboratory coordinator notified the emergency department to
transfer the patient when a catheterization room became available.
During off-hours, transfer to the catheterization laboratory occurred
on arrival of 2 catheterization staff members.
Protocol During Emergency Department
Activation/Immediate Transfer Period (September
1, 2005, Through June 26, 2006)
On September 1, 2005, at 7 AM, we implemented a protocol mandating
(1) emergency department physician activation of the catheterization
laboratory and (2) immediate transfer of the patient to an immediately available catheterization laboratory by an in-house emergency
heart attack response team (EHART) consisting of an emergency
department nurse, a critical care unit nurse, and a chest pain unit
nurse. The only exceptions to immediate transfer by the nursing staff
were hemodynamic compromise (requiring pressors, temporary pac-
ing, or balloon pump) and ongoing cardiopulmonary resuscitation;
these patients were prepared for immediate transfer but transferred
by the nursing staff with the cardiologist. The emergency department
physician contacted the hospital operator to activate the catheterization laboratory. The operator subsequently paged the cardiology
physician assistant, catheterization laboratory coordinator, and critical care unit nurse during regular hours or the on-call cardiologist,
interventional cardiologist, critical care unit nurse, chest pain unit
nurse, and on-call catheterization team during off-hours. On catheterization laboratory activation, the critical care unit nurse proceeded
to the emergency department and subsequently transferred the
patient to the catheterization laboratory with the emergency department nurse. During transfer, in case of sustained hypotension or
arrest, the critical care unit nurse could administer dopamine or
norepinephrine intravenous drips, perform defibrillation, and request
intubation by respiratory therapy, all without prior physician approval. The critical care unit modified the work requirements for the
EHART nurse by assigning the nurse 1 patient instead of 2 patients.
To make the catheterization laboratory immediately available
during regular hours, the catheterization laboratory coordinator
identified a catheterization room and staff for the patient. The
catheterization laboratory coordinator could remove an elective
patient from the catheterization laboratory if the case had not started
(defined as cardiologist fully scrubbed at bedside obtaining access).
If all rooms were occupied with cases in progress, then the STEMI
patient went to the first available room. On patient placement on the
catheterization laboratory table, the EHART team members transferred the patient’s nursing care to the catheterization team.
To make the catheterization laboratory immediately available
during off-hours, the chest pain unit nurse proceeded to the catheterization laboratory, activated the catheterization laboratory imaging equipment, and confirmed that the temporary pacemaker, balloon
pump, defibrillator, and activated clotting time machine were in
working order. This individual subsequently assisted the critical care
unit nurse and emergency department nurse in the initial setup of the
patient, including placement on the catheterization table, monitoring
equipment setup, prepping of groin, and assistance with the sterile
catheterization laboratory table. The emergency department nurse
and critical care nurse monitored the patient until the third and fourth
catheterization staff members arrived and subsequently transferred
nursing care to the catheterization team. If the patient was unstable,
all staff attended to the patient until safe transfer of care was
possible. Table 1 compares the processes in the 2 time periods.
All activities in the emergency department, during the transfer to
the catheterization laboratory, and during initial setup in the catheterization laboratory did not require cardiologist presence or input
(see the order set available at www.stfrancishospitals.org/heart). The
cardiologist evaluated the patient and determined the appropriateness
for emergency catheterization in the emergency department, en route
to the catheterization laboratory, or in the catheterization laboratory.
Study End Points and Statistical Analysis
The primary end point was median door-to-balloon time.3 Door time
represented the arrival time at the initial emergency department.
Secondary end points included the individual components of doorto-balloon time (ie, door-to-ECG time), infarct size measured by
peak creatinine kinase within the first 24 hours,14 hospital costs
(total, direct, and indirect), hospital length of stay, and all-cause
in-hospital mortality. Hospital cost data reflect the actual costs
involved in the delivery of care to each patient and were determined
by the cost-accounting software of the hospital (Alliance for Decision Support, Avega, El Segundo, Calif). Cost data for all patients
(including outliers) were analyzed. All-cause in-hospital mortality
was presented in unadjusted fashion. We determined the prevalence
of “false-positive” activation, defined as a patient sent to the
catheterization laboratory by the emergency department physician
but who subsequently was determined to be an inappropriate
activation by the cardiologist. All patients provided informed consent. Our institutional review board approved the study.
Time values are presented as medians with interquartile ranges
and were analyzed using 2-sample Wilcoxon rank sum tests. Other
Khot et al
TABLE 1.
Improving Door-to-Balloon Time in STEMI
69
Summary of Processes During the 2 Study Time Periods
Cardiology Activation Routine Transfer, October 1,
2004, Through August 31, 2005
ED Activation Immediate Transfer, September 1,
2005, Through June 26, 2006
Yes
Yes
No
No
PCI as primary reperfusion strategy for all STEMI
Routine availability of prehospital ECG in
ambulances
Activation of cath lab based on prehospital ECG
No
No
Standing order for obtaining ECG in triage area
Yes
Yes
ED physician activation of cath lab
1 Call activates cath lab*
Immediate transfer of patient to immediately
available cath lab
Cath lab staff arrives within 30 min of activation
No
Yes
Yes
Yes
No
Yes
Yes
Yes
Cardiologist in-house call
Yes
Yes
Door-to-balloon time feedback to staff and
physicians
Yes
Yes
ED indicates emergency department; cath lab, catheterization laboratory.
*In the first period, the 1 call to activate the cath lab was to the cath lab coordinator during daytime and through the operator at night. In the second time period,
all calls went through the operator.
continuous data are presented as mean⫾SD and were analyzed by
2-sample t tests. Categorical data are presented as proportions and
were analyzed by Fisher exact test. Values of P⬍0.05 were considered statistically significant. Stata software was used for statistical
analyses (version 8.2, Stata Corp, College Station, Tex).
The authors had full access to and take responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
From October 1, 2004, to August 30, 2005, 68 consecutive
patients presented with STEMI, and 60 patients met the
inclusion criteria (Figure 1). From September 1, 2005, to June
26, 2006, 96 consecutive patients presented with STEMI, and
86 patients met the inclusion criteria. The proportions of
patients with normal/mild coronary artery disease (4.4%
versus 5.2%; P⫽1), significant coronary artery disease
(⬎50% stenosis) managed medically (1.5% versus 1%;
P⫽1), or coronary artery bypass grafting (2.9% versus 1%,
P⫽0.57) were similar. Unadjusted all-cause in-hospital mortality was similar (intention to treat, 7.4% versus 5.2%,
P⫽0.74; post-PCI, 5% versus 4.7%, P⫽1).
Demographics, initial presentation details, and treatments
were similar (Table 2). Emergency department physician
catheterization laboratory activation increased from 0% to
87% (P⬍0.0001).
Median door-to-balloon time decreased from 113.5 to 75.5
minutes (P⬍0.0001) (Table 3). Reductions in door-to-balloon
time were seen during regular hours, during off-hours, and
with transfer from 1 campus to another (Table 3). Improvements were seen regardless of gender, ambulance or nonambulance presentation, or need for additional procedures (defibrillation, pacemaker, balloon pump) before PCI. Patients
presenting during regular hours had a median door-to-balloon
time of 45 minutes.
The most substantial decrease occurred in time spent in the
emergency department and in transportation to the catheterization laboratory (Table 3). Door-to-ECG and catheterization laboratory–to–sheath placement times showed no
change, although there was a modest but statistically significant decrease in sheath-to-balloon time. Mean infarct size
and hospital length of stay decreased. Total hospital costs,
direct hospital costs, and indirect hospital costs all decreased.
The proportion of patients treated within 90 minutes
increased from 28% to 71% (P⬍0.0001) (Table 4). There was
a ⬎2-fold increase in the treatment within 60 minutes and a
nearly 10-fold reduction in treatment requiring ⬎120 minutes
(P⬍0.0001).
During the 10-month emergency department activation/
immediate transfer period, the prevalence of “false-positive”
activation by an emergency department physician was 1% (1
of 97). A patient with flash-pulmonary edema was misrouted
to the catheterization laboratory instead of the critical care
unit. This case occurred early in the implementation of the
program, and focused review indicated that emergency department physician-cardiologist misunderstanding was the
root cause of the problem (patient not included in Figure 1).
Discussion
Emergency department physician activation of the catheterization laboratory and immediate transfer of the patient to an
immediately available catheterization laboratory by an inhouse nursing team led to a substantial reduction in door-toballoon time. This reduction was seen regardless of time of
day, ambulance or nonambulance presentation, and clinical
characteristics of the patient (Table 3). The success of our
protocol came from transforming a rigid system of stepwise
serial processes into a parallel process system with nearly
simultaneous performance of catheterization laboratory activation, physical transfer to catheterization laboratory, initial
catheterization laboratory setup, and cardiology evaluation
(Figure 2). In addition, our data confirm a recent survey of
hospital practices highlighting the importance of emergency
department physician activation of the catheterization laboratory and add an immediate transfer process to the list of
strategies that reduce door-to-balloon time.11 Finally, the
present study is one of the first prospective studies to reveal
70
Circulation
July 3, 2007
Figure 1. Summary of enrollment and outcomes in study during the 2 time periods. PCI denotes percutaneous intervention. Significant
coronary artery disease indicates a stenosis ⬎50%. ED indicates emergency department; CCU, coronary care unit; CAD, coronary
artery disease; and CABG, coronary artery bypass grafting.
that decreasing door-to-balloon time leads to decreased infarct size, length of stay, and hospital costs.
Providing timely emergency PCI is a complex undertaking
demanding rapid coordination of care by multiple physicians,
nurses, and hospital staff. In prior reports, an audit process,
in-depth continuous quality control improvement analysis,
and multidisciplinary quality initiatives have all improved
door-to-balloon time.15–19 However, the specific steps recommended have varied between these studies, making it challenging for other institutions to adopt specific protocols to
improve their door-to-balloon time. In addition, the recom-
mended measures have been multiple and often complex,
typically requiring months to years for full implementation.18,19 In contrast, the present study showed that 2 simple,
focused modifications rapidly reduced door-to-balloon time
and could be implemented rapidly within a day.
Our protocol was resisted initially because of concerns that
emergency department physician activation of the catheterization laboratory would not reduce door-to-balloon time
since our cardiologists took in-house call. However, this
simple change allowed catheterization laboratory staff to
arrive 20 to 40 minutes earlier (Table 3), indicating that there
Khot et al
TABLE 2.
Improving Door-to-Balloon Time in STEMI
Demographics, Initial Presentation Characteristics, and Treatment Outcomes
Cardiology Activation Routine Transfer, October 1,
2004, Through August 31, 2005 (n⫽60)
ED Activation Immediate Transfer, September 1,
2005, Through June 26, 2006 (n⫽86)
P
0.31
Demographics
Age, y
58⫾13
60⫾13
17 (28.3)
25 (29.1)
1
Private
28 (46.7)
48 (55.8)
0.51
Medicare
21 (35)
29 (33.7)
䡠䡠䡠
Medicaid
3 (5)
3 (3.5)
䡠䡠䡠
Self-pay
8 (13.3)
6 (7)
䡠䡠䡠
Female gender
Health insurance
Medical history
Current smoker
31 (51.7)
48 (55.8)
0.74
Diabetes
10 (16.7)
17 (19.8)
0.67
Hypertension
34 (56.7)
46 (53.5)
0.74
Hypercholesterolemia
19 (31.7)
31 (36.1)
0.60
Family history of CHD
22 (36.7)
28 (32.6)
0.72
Congestive heart failure
0 (0)
0 (0)
COPD
4 (6.7)
9 (10.5)
䡠䡠䡠
0.56
Prior PCI
10 (16.7)
23 (26.7)
0.17
Prior CABG
5 (8.3)
5 (5.8)
0.74
PVD
3 (5)
8 (9.3)
0.53
Stroke
0 (0)
5 (5.8)
0.08
Initial presentation
Regular hours
26 (43.3)
30 (34.9)
0.39
Transferred for PCI
12 (20)
22 (25.6)
0.55
ⱕ1 h
20 (33.3)
39 (45.4)
0.40
⬎1–2 h
14 (23.3)
22 (25.6)
䡠䡠䡠
⬎2–6 h
12 (20)
8 (9.3)
䡠䡠䡠
⬎6–12 h
4 (6.7)
4 (4.7)
䡠䡠䡠
⬎12 h
6 (10)
6 (7)
䡠䡠䡠
Unknown
4 (6.7)
7 (8.1)
Symptom onset to arrival
Chest pain at presentation
Prehospital ECG
Ambulance arrival
54 (90)
2 (3.3)
䡠䡠䡠
0.24
7 (8.1)
0.31
31 (36.1)
0.31
85⫾21
79⫾23
0.10
Systolic blood pressure, mm Hg
137⫾26
137⫾34
0.99
Diastolic blood pressure, mm Hg
83⫾19
83⫾22
0.89
Heart rate, bpm
27 (45)
71 (82.6)
Location of infarct
Anterior
24 (40)
26 (30.2)
0.29
Inferior
34 (56.7)
56 (65.1)
0.39
Lateral (isolated)
2 (3.3)
4 (4.7)
1
LBBB
2 (3.3)
0 (0)
0.17
ECG leads with ST-elevation
2
16 (27.1)
19 (22.1)
0.80
3–4
29 (49.2)
45 (52.3)
䡠䡠䡠
ⱖ5
14 (23.7)
22 (25.6)
4 (6.7)
5 (5.8)
䡠䡠䡠
1
Cardiogenic shock
Cath lab activation
ED physician
0 (0)
75 (87.2)
⬍0.0001
Cardiologist
60 (100)
11 (12.8)
䡠䡠䡠
71
72
Circulation
TABLE 2.
July 3, 2007
Continued
Cardiology Activation Routine Transfer, October 1,
2004, Through August 31, 2005 (n⫽60)
ED Activation Immediate Transfer, September 1,
2005, Through June 26, 2006 (n⫽86)
P
Treatment
Aspirin
57 (95)
85 (98.8)
0.31
␤-Blocker
53 (88.3)
75 (87.2)
1
Heparin
59 (98.3)
86 (100)
0.41
Glycoprotein IIb/IIIa inhibitor
0.27
60 (100)
83 (96.5)
Defibrillation before PCI
5 (8.3)
8 (9.3)
1
Temporary pacemaker before
PCI
4 (6.7)
3 (3.5)
0.45
IABP before PCI
1 (1.7)
1 (1.2)
1
0 (0)
0.32
Catheterization results
Infarct-related artery
Left main
Left anterior descending
2 (3.3)
23 (38.3)
33 (38.4)
Left circumflex
5 (8.3)
13 (15.1)
Right coronary
27 (45)
38 (44.2)
3 (5)
2 (2.3)
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
Bypass graft
Treatment
Balloon angioplasty only
10 (16.6)
11 (12.8)
0.63
Balloon angioplasty/stent
50 (83.3)
75 (87.2)
䡠䡠䡠
0.64
Type of stent
Bare metal stent
11 (22)
13 (17.3)
Drug-eluting stent
39 (78)
62 (82.7)
䡠䡠䡠
Values are expressed as mean⫾SD or n (%). ED indicates emergency department; CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease;
CABG, coronary artery bypass grafting; PVD, peripheral vascular disease; cath lab, catheterization laboratory; and IABP, intra-aortic balloon pump.
are considerable delays associated with even waiting for
in-house cardiology evaluation. In addition, although emergency department physician interpretation of ST-segment
elevation typically is accurate,20 our cardiologists were concerned about inappropriate activation of the catheterization
laboratory by the emergency department physicians. We
overcame this resistance by emphasizing that the decision to
activate the laboratory and the decision to perform catheterization and intervention were distinct. Thus, the final decision
regarding appropriateness for emergency catheterization remained with cardiology, and our cardiologists were instructed
to perform catheterization only if they agreed with the
emergency department assessment. We further audited all
cases for appropriateness and provided this information to the
emergency department physicians and cardiologists. Ultimately, inappropriate activations occurred rarely11 and were
eventually accepted as necessary to improve the overall care
of STEMI patients.
The largest component of door-to-balloon time is the
time spent within the emergency department and transferring to the catheterization laboratory.15,18 Transfer out of
the emergency department to the catheterization laboratory
often is hampered by structural impediments such as strict
requirements for cardiology consultation or catheterization
laboratory readiness before transfer.11 Furthermore, during
day hours, the catheterization laboratory can be occupied
by elective cases, further impeding the STEMI patient’s
access to the catheterization laboratory. The importance of
addressing the transfer process was underscored by a
report showing that simply preparing patients for transfer
to the catheterization laboratory reduced emergency department time.15 Although a recent survey of hospital
practices did not identify transfer process as a factor in
door-to-balloon time, this is likely related to the fact that
93% of hospitals practiced in a manner similar to the
routine transfer period of the present study and required
the catheterization laboratory to notify the emergency
department when it was ready before transfer. In fact, none
of the hospitals in the survey had an immediate transfer
policy in place.11 The present study shows that the decision
to transfer the patient should originate in the emergency
department and that the catheterization laboratory should
be immediately prepared to receive the patient.
Any transfer of a critically ill patient within the hospital is
associated with a potential risk of decompensation or adverse
event during transfer, and there was concern regarding the
safety of transfer without a cardiologist. To maximize patient
safety during transfer, the transfer team included a critical
care nurse who had standing orders for events such as
unstable heart rhythms or hypotension. We also excluded
from immediate transfer patients with ongoing cardiopulmonary resuscitation or hemodynamic instability. In addition,
because our cardiologists were in-house, the time without
cardiologist presence was minimized. Finally, even in critically ill patients, proceeding to the catheterization laboratory
Khot et al
TABLE 3.
Improving Door-to-Balloon Time in STEMI
73
Primary and Secondary End Points
No.
Cardiology Activation Routine
Transfer, October 1, 2004,
Through August 31,
2005 (n⫽60)
No.
ED Activation Immediate
Transfer, September 1,
2005, Through June 26,
2006 (n⫽86)
P
Primary end point door-to-balloon time, min
All patients
⬍0.0001
60
113.5 (83, 143)
86
75.5 (64, 94)
Regular hours
26
83.5 (63, 129)
30
64.5 (42, 85)
Off-hours
34
123.5 (108, 157)
56
77.5 (69.5, 100)
⬍0.0001
⬍0.0001
All patients, excluding outside transfers
0.0048
47
109 (79, 130)
64
73.5 (54, 91)
Regular hours
21
79 (61, 125)
23
45 (39, 75)
0.0019
Off-hours
26
120.5 (106, 139)
41
76 (68, 94)
⬍0.0001
13
147 (114, 157)
22
85 (75, 98)
0.0006
Outside transfer patients
Regular hours
5
Off-hours
8
114 (83, 134)
152.5 (133.5, 239.5)
7
87 (78, 98)
0.3709
15
84 (74, 107)
0.0004
Female
17
139 (122, 149)
25
84 (74, 99)
0.0004
Male
43
108 (73, 126)
61
74 (61, 89)
⬍0.0001
Ambulance arrival
27
106 (67, 125)
31
71 (44, 84)
0.0007
Nonambulance arrival
33
125 (97, 149)
55
78 (68, 99)
⬍0.0001
9
134 (114, 153)
11
75 (68, 77)
0.0002
Defibrillation, temporary pacemaker, or IABP before PCI
Secondary end points
Door-to-balloon components, min
Door to ECG
60
5 (1, 9)
86
4 (1, 6)
ECG to cath lab arrival, overall
60
71 (45, 88)
86
39 (25, 54)
⬍0.0001
Regular hours
26
48.5 (36, 75)
30
27.5 (19, 52)
0.0006
Off hours
34
81.5 (66, 107)
56
41.5 (33, 54.5)
47
67 (43, 83)
64
33 (21.5, 47.5)
⬍0.0001
Regular hours
21
44 (36, 69)
23
25 (16, 31)
⬍0.0001
Off hours
26
77.5 (58, 97)
41
37 (28, 50)
⬍0.0001
ECG to cath lab arrival, excluding outside transfer patients
ECG to cath lab arrival, outside transfer patients
Regular hours
Off hours
0.2328
⬍0.0001
13
85 (78, 108)
22
55 (43, 62)
0.0012
5
78 (34, 79)
7
56 (42, 70)
0.5698
8
100 (81.5, 199)
15
52 (43, 61)
0.0002
Cath lab arrival to sheath placement
60
16 (10.5, 22)
86
16 (10, 21)
0.3833
Sheath placement to balloon
60
17.5 (12.5, 25)
86
13 (9, 18)
ECG to first cath lab staff arrival off-hours, overall
30
51 (42, 70)
51
30 (24, 39)
⬍0.0001
23
48 (35, 58)
39
28 (24, 39)
0.0003
7
74 (59, 157)
12
32 (27.5, 38)
0.0007
Excluding Outside Transfers
Outside Transfers Only
ECG to second cath lab staff arrival off-hours, overall
Excluding outside transfers
Outside transfers only
0.0045
30
56.5 (46, 75)
51
34 (28, 42)
⬍0.0001
23
54 (39, 63)
39
32 (27, 42)
0.0011
7
75 (70, 170)
12
36 (30.5, 42)
0.0005
Mean infarct size, peak creatinine kinase, IU/L
60
2623⫾3329
83
1517⫾1556
0.0089
Mean total hospital costs, $
60
26 826⫾29 497
86
18 280⫾8943
0.0125
Mean direct hospital costs, $
60
19 585⫾21 946
86
13 060⫾6438
0.0102
Mean indirect hospital costs, $
60
7240⫾7571
86
5220⫾2518
0.0228
Mean hospital length of stay, d
60
5⫾7
86
3⫾2
0.0097
68⫾86
86
48⫾37
0.0574
Mean time in coronary care unit, h
60
All-cause in-hospital mortality, intention to treat
68
5 (7.4)
96
5 (5.2)
0.74
All-cause in-hospital mortality post-PCI
60
3 (5)
86
4 (4.7)
1
All time values are median (25th and 75th percentiles). IABP indicates intra-aortic balloon pump; cath lab, catheterization laboratory.
as soon as possible was believed to allow more timely
delivery of lifesaving interventions, outweighing the potential
risk of transfer.
The present study included patients who were transferred
for emergency PCI from another emergency department at
our other campus. Such transfer patients are typically ex-
74
Circulation
TABLE 4.
July 3, 2007
Proportion of Patients Treated Within Various Time Points
Door-to-Balloon (min)
⬍60
Cardiology Activation/ Routine Transfer, October
1, 2004, Through August 31, 2005 (n⫽60)
ED Activation/Immediate Transfer, September 1,
2005, Through June 26, 2006 (n⫽86)
P
⬍0.0001
5 (8.3)
17 (19.8)
60–90
12 (20)
44 (51.2)
91–120
16 (26.7)
20 (23.3)
⬎120
27 (45)
5 (5.8)
Values are expressed as n (%).
cluded from most analyses15,18 and are specifically excluded
from public reporting of quality indicators despite having the
longest door-to-balloon times.4,5 In the National Registry of
Myocardial Infarction, transfer patients had a median doorto-balloon time of 180 minutes, with only 4.2% achieving
reperfusion within 90 minutes.7 With our new protocol, the
median door-to-balloon time decreased to 85 minutes, and
62% of these patients were treated within 90 minutes. Thus,
our protocol leads to improvement in the care of STEMI
patients transferred directly for PCI.
Most patients undergoing emergency PCI present during
off-hours, and only 26% undergo reperfusion in ⱕ90 minutes.6 It has been suggested that hospitals that perform PCI
have catheterization staff on site 24 hours to ensure timely
revascularization or to cross-train in-house staff to perform
catheterization staff duties.6 However, even in high-volume
centers, 24-hour coverage would be prohibitively expensive,
and maintaining proficiency of cross-trained staff exposed to
nighttime myocardial infarction cases only would be challenging. Our use of an in-house transfer team allowed us to
substantially improve the care of off-hours patients while
maintaining the delivery of care by a highly trained catheterization staff.
Study Limitations
Although the 2 cohorts were similar, baseline differences
cannot be completely accounted for between the 2 time
periods because of the nonrandomized nature of the present
study. Nevertheless, the present study design reflects the
“real-life” manner in which physicians and hospitals implement process improvements and is similar to other process
improvement studies.21 The present study was performed in a
community hospital setting with cardiologists taking in-house
call. However, the protocol could be adapted for cardiologists
taking home call only or for the inclusion of residents and
fellows in academic settings. Our results could be explained
by increased attention to door-to-balloon time; however, our
results during the baseline time period were widely presented
to physician and hospital staff with no door-to-balloon time
improvement. Our transfer patients traveled a 7-mile distance, and our results may not be applicable to longer transfer
distances. Emergency medicine residency–trained physicians
Figure 2. Serial vs parallel processing in achieving
door-to-balloon time. Simultaneous performance of
catheterization laboratory activation, physical
transfer to catheterization laboratory, initial catheterization laboratory setup, and cardiology evaluation leads to a reduction in door-to-balloon time.
Khot et al
staffed our emergency departments, and staffing by a different mix of physicians may not be able to duplicate our results.
Our results occurred with limited availability of prehospital
ECG, but we believe the use of ECGs is complementary and
could further reduce door-to-balloon time. However, 50% of
STEMI patients nationwide do not present by ambulance,
underscoring the importance of protocols that improve the
care of all patients.22
Emergency department activation of the catheterization
laboratory and immediate transfer of the patient to an immediately available catheterization laboratory by an in-house
transfer team are 2 specific measures that allow the delivery
of PCI in a timely fashion to a broad population of patients.
Additional benefits include reductions in myocardial infarct
size, hospital length of stay, and total hospital costs. Widespread implementation of this simple strategy can substantially improve the quality of care of STEMI patients undergoing emergency PCI. An electronic copy of the order set
used in the EHART protocol is available at www.
stfrancishospitals.org/heart.
Improving Door-to-Balloon Time in STEMI
3.
4.
5.
6.
Appendix
The following individuals participated in the present study.
Indiana Heart Physicians, Indianapolis: A. Akinwande, M.
Barron, J. Christie, H. Genovely, J. Graham, D. Hadian, M.
Jones, S. Karanam, D. Kovacich, I. Labin, S. Lall, J. Mossler,
G. Revytak, and R. Shea. Emergency Physicians of Indianapolis, Beech Grove, Ind: S. Antoine, D. Blank, S. Boha, M.
Brown, W. Corbett, D. Debikey, B. Dillman, K. Ernsting, M.
Fitzpatrick, G. Godfrey, C. Hartman, B. Johnston, S. Kistler,
H. Levitin, R. Mara, W. McDaniel, E. Olson, M. Overfelt, M.
Russell, A. Stern, M. Stone, and E. Weinstein.
7.
Acknowledgments
10.
We are indebted to Mechelle L. Peck, RN; Diana L. Brown, RN;
Mark Manning, CCT; Patricia L. Wray, RN; Stephen H. Kliman,
MD; Juan E. Weksler, MD; Carl L. Rouch, MD; and Horace O.
Hickman, MD, who were intimately involved in the implementation
of the present study.
8.
9.
11.
Sources of Funding
Indiana Heart Physicians and St Francis Hospital and Health Centers
provided funding for the present study. The funding organizations
had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Disclosures
None.
12.
13.
14.
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CLINICAL PERSPECTIVE
The relationship between delays in door-to-balloon time and increased mortality is well established and has led to
consensus guidelines and hospital quality-of-care programs recommending that ST-elevation myocardial infarction patients
achieve a door-to-balloon time of ⱕ90 minutes. However, most patients do not receive treatment within the recommended
90 minutes, and there are limited prospective data on specific measures to significantly reduce door-to-balloon time. In the
present study, we prospectively determined the impact on median door-to-balloon time of a protocol mandating (1)
emergency department physician activation of the catheterization laboratory and (2) immediate transfer of the patient to an
immediately available catheterization laboratory by an in-house transfer team consisting of an emergency department
nurse, a critical care unit nurse, and a chest pain unit nurse. With this protocol, median door-to-balloon time fell
substantially, and this reduction was seen regardless of time of day, ambulance or nonambulance presentation, and clinical
characteristics of the patients. In addition, patients transferred from an outside affiliated emergency department to our main
hospital also saw substantial reductions in door-to-balloon time. Treatment within 90 minutes increased from 28% to 71%.
Other benefits included reductions in mean infarct size, hospital length of stay, and total hospital costs per admission. The
present study identifies a simple and widely applicable strategy that leads to improvements in both door-to-balloon time
and the quality of care of ST-elevation myocardial infarction patients undergoing emergency percutaneous intervention.
The Brain–Heart Connection
Martin A. Samuels, MD
N
eurocardiology has many dimensions, but it may be
conceptualized as divided into 3 major categories: the
heart’s effects on the brain (eg, cardiac source embolic
stroke), the brain’s effects on the heart (eg, neurogenic heart
disease), and neurocardiac syndromes (eg, Friedreich disease). The present review deals with the nervous system’s
capacity to injure the heart. This subject is inherently important but also represents an example of a much more widespread and conceptually fascinating area of neurovisceral
damage in general.
History of Learning the Nature of the
Brain–Heart Connection
In 1942, at the culmination of his distinguished career as
Professor of Physiology at Harvard Medical School, Walter
B. Cannon published a remarkable paper entitled “‘Voodoo’
Death,”1 in which he recounted anecdotal experiences,
largely from the anthropology literature, of death from fright.
These often remote events, drawn from widely disparate parts
of the world, had several features in common. They were all
induced by an absolute belief that an external force, such as
a wizard or medicine man, could, at will, cause demise and
that the victim himself had no power to alter this course. This
perceived lack of control over a powerful external force is the
sine qua non for all the cases recounted by Cannon, who
postulated that death was caused “by a lasting and intense
action of the sympathico-adrenal system.” Cannon believed
that this phenomenon was limited to societies in which the
people were “so superstitious, so ignorant, that they feel
themselves bewildered strangers in a hostile world. Instead of
knowledge, they have fertile and unrestricted imaginations
which fill their environment with all manner of evil spirits
capable of affecting their lives disastrously.” Over the years
since Cannon’s observations, evidence has accumulated to
support his concept that “voodoo” death is, in fact, a real
phenomenon but, far from being limited to ancient peoples,
may be a basic biological principle that provides an important
clue to understanding the phenomenon of sudden death in
modern society as well as providing a window into the world
of neurovisceral disease (also known as psychosomatic
illness).
George Engel collected 160 accounts from the lay press of
sudden death that were attributed to disruptive life events.2
He found that such events could be divided into 8 categories:
(1) the impact of the collapse or death of a close person; (2)
during acute grief; (3) on threat of loss of a close person; (4)
during mourning or on an anniversary; (5) on loss of status or
self-esteem; (6) personal danger or threat of injury; (7) after
danger is over; (8) reunion, triumph, or happy ending.
Common to all is that they involve events impossible for the
victim to ignore and to which the response is overwhelming
excitation, giving up, or both.
In 1957, Curt Richter reported on a series of experiments
aimed to elucidate the mechanism of Cannon’s “voodoo”
death.3 Richter, a former student of Cannon, pursued an
incidental discovery of an epidemic of sudden death in a
colony of rodents, which was induced when a colleague,
Gordon Kennedy, had clipped the whiskers of the animals to
prevent contamination of the urine collection. Richter studied
the length of time that domesticated rats could swim at
various water temperatures and found that at a water temperature of 93°C these rats could swim for 60 to 80 minutes.
However, if the animal’s whiskers were trimmed, it would
invariably drown within a few minutes. When carrying out
similar experiments with fierce wild rats, he noted that a
number of factors contributed to the tendency for sudden
death, the most important of which was restraint, which
involved holding the animals and confinement in a glass
swimming jar with no chance of escape. By trimming the
rats’ whiskers, a procedure that destroys possibly their most
important proprioceptive mechanism, the tendency for early
demise was exacerbated. In the case of the calm domesticated
animals in which restraint and confinement were apparently
not significant stressors, removal of whiskers rendered these
animals as fearful as wild rats with a corresponding tendency
for sudden death. ECGs taken during the process showed
development of a bradycardia prior to death, and adrenalectomy did not protect the animals. Furthermore, atropine
protected some of the animals, and cholinergic drugs led to an
even more rapid demise. All this was taken as evidence that
overactivity of the sympathetic nervous system was not the
cause of the death but rather it was caused by increased vagal
tone.
We now believe that the apparently opposite conclusions
of Cannon and Richter are not mutually exclusive, but rather
that a generalized autonomic storm, which occurs as a result
of a life-threatening stressor, will have both sympathetic and
parasympathetic effects. The apparent predominance of one
From the Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Dr Martin A. Samuels, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston,
MA 02115. E-mail msamuels@partners.org
(Circulation. 2007;116:77-84.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI:10.1161/CIRCULATIONAHA.106.678995
77
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July 3, 2007
over the other depends on the parameter measured (eg, heart
rate, blood pressure) and the timing of the observations in
relation to the stressor (eg, early events tend to be dominated
by sympathetic effects, whereas late events tend to be
dominated by parasympathetic effects). Cerebral hemispheral
dominance with regard to autonomic control (right predominantly sympathetic and left predominantly parasympathetic)
probably also contributes to the dominant mechanism of
sudden death (ie, sympathetic versus vagal) in a given
person.4
In human beings, one of the easily accessible windows into
autonomic activity is the ECG. Edwin Byer and colleagues
reported 6 patients whose ECGs showed large upright T
waves and long QT intervals.5 Two of these patients had
hypertensive encephalopathy, 1 patient had a brain stem
stroke with neurogenic pulmonary edema, 1 patient had an
intracerebral hemorrhage, 1 patient had a postpartum ischemic stroke possibly related to toxemia of pregnancy, and 1
patient had no medical history except a blood pressure of
210/110 mm Hg. On the basis of experimental results of
cooling or warming the endocardial surface of a dog’s left
ventricle, Byer and colleagues concluded that these ECG
changes were caused by subendocardial ischemia. Harold
Levine reported on several disorders other than ischemic
heart disease that could produce ECG changes reminiscent of
coronary disease.6 Among these was a 69-year-old woman
who was admitted and remained in coma. Her admission
ECG showed deeply inverted T waves in the anterior and
lateral precordial leads. Two days later, it showed ST segment elevation with less deeply inverted T waves, a pattern
suggestive of myocardial infarction. However, at autopsy a
ruptured berry aneurysm was found and no evidence of
myocardial infarction or pericarditis was noted. Levine did
not propose a specific mechanism but referred to experimental work on the production of cardiac arrhythmias by basal
ganglia stimulation and ST and T-wave changes induced by
injection of caffeine into the cerebral ventricle.
George Burch and colleagues7 reported on 17 patients who
were said to have “cerebrovascular accidents” (ie, strokes). In
14 of the 17, hemorrhage was demonstrated by lumbar
puncture. It is not possible to determine which of these
patients had hemorrhagic infarction, intracerebral hemorrhage, and subarachnoid hemorrhage, and no data about the
territory of the strokes are available. The essential features of
the ECG abnormalities were: (1) long QT intervals in all
patients; (2) large, usually inverted, T waves in all patients;
and (3) U waves in 11 of the 17 patients.7
Cropp and Manning8 reported on the details of ECG
abnormalities in 29 patients with subarachnoid hemorrhage.
Twenty-two of these patients survived. Two of those who
died had no postmortem examination, which left 5 patients in
whom autopsies confirmed the presence of a ruptured cerebral aneurysm. In 3 of these 5 patients, the heart and coronary
arteries were said to be normal, but the details of the
pathological examination were not revealed. The point is
made that ECG changes seen in the context of neurological
disease do not represent ischemic heart disease but are merely
a manifestation of autonomic dysregulation, possibly caused
by a lesion that affected the cortical representation of the
autonomic nervous system. The authors argued that Brodmann area 13 on the orbital surface of the frontal lobe and
area 24 on the anterior cingulate gyrus were the cortical
centers for cardiovascular control.
There is clear evidence that cardiac lesions can be produced as the result of nervous system disease. The concept of
visceral organ dysfunction that occurs as a result of neurological stimuli can be traced to Ivan Pavlov. Hans Selye, a
student of Pavlov, described electrolyte–steroid– cardiopathy
with necroses (ESCN).9 Selye’s view was that this cardiac
lesion was common and often described by different names in
the literature. He argued that this lesion was distinct from the
coagulation necrosis that occurred as a result of ischemic
disease, but that it could exist in the same heart. Selye
demonstrated that certain steroids and other hormones created
a predisposition for the development of ESCN, but that other
factors were required for ESCN to develop. The most
effective conditioning steroid was 2- ␣ -methyl-9- ␣ fluorocortisol. Among the factors that led to ESCN in
steroid-sensitized animals were certain electrolytes (eg,
NaH2PO4), various hormones (eg, vasopressin, adrenaline,
insulin, thyroxine), certain vitamins (eg, dihydrotachysterol),
cardiac glycosides, surgical interventions (eg, cardiac reperfusion after ischemia), and psychic or nervous stimuli (eg,
restraint, fright). The cardiac lesions could not be prevented
by adrenalectomy, which suggests that the process, if related
to sympathetic hyperactivity, must exert its influence by
direct neural connection to the heart rather than by a bloodborne route.
Cardiac lesions may be produced in rats by pretreatment
with either 2-␣-methyl-9-␣-fluorohydrocortisone (fluorocortisol), dihydrotachysterol (calciferol), or thyroxine and then
restraint of the animals on a board for 15 hours or with cold
stress.10 Agents that act by inhibition of the catecholaminemobilizing reflex arc at the hypothalamic level (eg, chlorpromazine) or by blockade of only the circulating but not the
neurogenic intramyocardial catecholamines (eg, dibenamine)
were the least effective for protection of cardiac muscle,
whereas those drugs that act by ganglionic blockade (eg,
mecamylamine) or by direct intramyocardial catecholaminedepletion (eg, reserpine) were the most effective. Furthermore, it is clear that blood catecholamine levels are often
normal but that identical ECG findings are seen with high
systemic catecholamines. These clinical and pharmacological
data support the concept that the cardiac necrosis is caused by
catecholamine toxicity and that catecholamines released directly into the heart via neural connections are much more
toxic than those that reach the heart via the bloodstream,
though clearly the 2 routes could be additive in the intact,
nonadrenalectomized animal. Intracoronary infusions of epinephrine reproduce the characteristic ECG pattern of neurocardiac disease, which is reminiscent of subendocardial
ischemia, though no ischemic lesion can be found in the
hearts of dogs euthanized after several months of infusions.11
In the years that followed, numerous reports emanated from
around the world that documented the production of cardiac
repolarization abnormalities in the context of various neurological catastrophes and that proposed that this was caused by
an autonomic storm. It seemed likely that the connection
Samuels
between neuropsychiatric illness and the visceral organs
would be provided by the autonomic nervous system.
Melville et al12 produced ECG changes and myocardial
necrosis by stimulation of the hypothalamus of cats. With
anterior hypothalamic stimulation, parasympathetic responses
occurred, predominantly in the form of bradycardia. Lateral
hypothalamic stimulation produced tachycardia and ST segment depressions. With intense bilateral and repeated lateral
stimulation, persistent irreversible ECG changes occurred and
postmortem examination revealed a stereotyped cardiac lesion characterized by intense cytoplasmic eosinophilia with
loss of cross-striations and some hemorrhage. The coronary
arteries were normal without occlusion. Although Melville
referred to this lesion as “infarction,” it is probably best to
reserve that term for coagulation necrosis caused by ischemia.
This lesion is probably identical to Selye’s ESCN and would
now be called coagulative myocytolysis, myofibrillar degeneration, or contraction band necrosis. More recently, Oppenheimer and Cechetto have mapped the chronotropic organizational structure in the rat insular cortex, which
demonstrates that sympathetic innervation arises from a more
rostral part of the posterior insula then causes parasympathetic innervation.13 The insula and thalamus had already
been shown to have a sensory viscerotropic representation
that included the termination of cardiopulmonary afferents.14
The central role of the insula in the control of cardiovascular
function has been supported by a robust experimental and
clinical literature.15,16
Despite the fact that myocardial damage could definitely
be produced in animals, until the mid-1960s there was little
recognition that this actually occurred in human beings with
acute neurological or psychiatric illness until Koskelo and
colleagues17 reported on 3 patients with ECG changes caused
by subarachnoid hemorrhage who were noted on postmortem
examination to have several small subendocardial petechial
hemorrhages. Connor18 reported focal myocytolysis in 8% of
231 autopsies, with the highest incidence seen in patients who
suffered fatal intracranial hemorrhages. The lesion reported
by Connor conforms to the descriptions of Selye’s ESCN or
what might now be called myofibrillar degeneration, coagulative myocytolysis, or contraction band necrosis. Connor
pointed out that previous pathology reports probably overlooked the lesion because of the fact that it was multifocal,
with each individual focus being quite small, which would
require extensive tissue sampling. It is clear now that even
Connor underestimated the prevalence of the lesion and that
serial sections are required to rigorously exclude its presence.
Greenshoot and Reichenbach19 reported on 3 new patients
with subarachnoid hemorrhage and a review of 6 previous
patients from the same medical center. All 9 of these patients
had cardiac lesions of varying degrees of severity that ranged
from eosinophilia with preservation of cross-striations to
transformation of the myocardial cell cytoplasm into dense
eosinophilic transverse bands with intervening granularity,
sometimes with endocardial hemorrhages. Both the ECG
abnormalities and the cardiac pathology could be reproduced
in cats given mesencephalic reticular formation stimulation.
Adrenalectomy did not protect the hearts, which supports the
The Brain–Heart Connection
79
contention that the ECG changes and cardiac lesions are due
to direct intracardiac release of catecholamines.
Hawkins and Clower20 injected blood intracranially into
mice, which thereby produced the characteristic myocardial
lesions. The number of lesions could be reduced but not
obliterated by pretreatment with adrenalectomy and the use of
either atropine or reserpine, which suggested that the cause of
the lesions was in part caused by sympathetic overactivity
(humoral arrival at the myocardium from the adrenal and by
direct release into the muscle by intracardiac nerves) and in
part caused by parasympathetic overactivity. This supports
the concept that the cause is an autonomic storm with a
contribution from both divisions to the pathogenesis.
Jacob et al21 produced subarachnoid hemorrhage experimentally in dogs and carefully studied the sequential hemodynamic and ultrastructural changes that occurred. The hemodynamic changes occurred in 4 stages and directly
paralleled the effects seen with intravenous norepinephrine
injections. These stages were: (1) dramatic rise in systemic
blood pressure; (2) extreme sinus tachycardia with various
arrhythmias (eg, nodal or ventricular tachycardia, bradycardia, atrioventricular block, ventricular premature beats, ventricular tachycardia, ventricular fibrillation with sudden
death), all of which could be suppressed by bilateral vagotomy or orbital frontal resection; (3) rise in left ventricular
pressure parallel to rise in systemic pressure; and (4) up to
2-fold increase in coronary blood flow.
Ultrastructurally, a series of 3 stereotyped events occurred
that could be imitated exactly with norepinephrine injections.
These were: (1) migration of intramitochondrial granules that
contained Ca2⫹ to the periphery of the mitochondria; (2)
disappearance of these granules; and (3) myofilament disintegration at the I bands while the density of the I band was
increased in the intact sarcomeres.21
Partially successful efforts to modify the developments of
neurocardiac lesions were made with reserpine pretreatment
in mice subjected to simulated intracranial hemorrhage22 and
by Hunt and Gore,23 who pretreated a group of rats with
propranolol and then attempted to produce cardiac lesions
with intracranial blood injections. No lesions were found in
the control animals, but they were found in 21 of the 46
untreated rats and in only 4 of the 22 treated rats. This
suggested that neurological influences via catecholamines
may be at least partly responsible for cardiac cell death. More
modern studies have confirmed the fact that myocardial
injury occurs in the context of subarachnoid hemorrhage and
that the likelihood of myocardial necrosis was correlated with
the severity of the clinical neurological state as judged by the
standard Hunt-Hess grading system for subarachnoid
hemorrhage.24
The phenomenology of the various types of myocardial
cell death was articulated most clearly by Baroldi,25 who
pointed out that there were 3 main patterns of myocardial
necrosis: (1) coagulation necrosis, the fundamental lesion of
infarction, in which the cell loses its capacity to contract and
dies in an atonic state with no myofibrillar damage; (2)
colliquative myocytolysis, in which edematous vacuolization
with dissolution of myofibrils without hypercontraction occurs in the low-output syndromes; and (3) coagulative myo-
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Circulation
July 3, 2007
Figure 1. The neurocardiac lesion: Gross specimen of a patient
who died during an acute psychological stress shows fresh
endocardial hemorrhages (1 of many is shown by the arrow).
Figure 3. Intense mineralization within minutes of the onset of
contraction band necrosis.
cytolysis, in which the cell dies in a hypercontracted state
with early myofibrillar damage and anomalous irregular
cross-band formations.
Coagulative myocytolysis is seen in reperfused areas
around regions of coagulation necrosis in transplanted hearts,
in “stone hearts,” in sudden unexpected and accidental death,
and in hearts exposed to toxic levels of catecholamines, such
as in patients with pheochromocytoma. This is probably the
major lesion described by Selye as ESCN and is likely to be
the major lesion seen in animals and people who suffer acute
neurological or psychiatric catastrophes. Although coagulative myocytolysis is probably the preferred term, the terms
myofibrillar degeneration and contraction band necrosis are
commonly used in the literature. This lesion tends to calcify
early and to have a multifocal subendocardial predisposition
(Figure 1, 2, and 3).
Intense rapid calcification makes it likely that the subcellular mechanisms that underlie the development of coagulative myocytolysis involve calcium entry. Zimmerman and
Hulsmann26 reported that the perfusion of rat hearts with
calcium-free media for short periods of time creates a
situation such that on readmission of calcium there is a
massive contracture followed by necrosis and enzyme release. This phenomenon, known as the calcium paradox, can
be imitated almost exactly with reoxygenation after hypoxemia. The latter, called the oxygen paradox, has been linked
to the calcium paradox by pathological calcium entry.27 This
major ionic shift is probably the cause of the dramatic ECG
changes seen in the context of neurological catastrophe, a fact
that could explain the phenomenon of sudden unexpected
death (SUD) in many contexts.
Although SUD is now recognized as a medical problem of
major epidemiological importance, it has generally been
assumed that neurological disease rarely results in SUD. In
fact, it has been traditionally held that neurological illnesses
almost never cause sudden demise, with the occasional
patient who dies during an epileptic convulsion or rapidly in
the context of a subarachnoid hemorrhage as the exception.
Further, it has been assumed that the various SUD syndromes
(eg, sudden death in middle-aged men, sudden infant death
syndrome, sudden unexpected nocturnal death syndrome,
frightened to death (“voodoo” death), sudden death during an
epileptic seizure, sudden death during natural catastrophe,
sudden death associated with recreational drug abuse, sudden
death in wild and domestic animals, sudden death during
asthma attacks, sudden death during the alcohol withdrawal
syndrome, sudden death during grief after a major loss,
sudden death during panic attacks, sudden death from mental
stress, and sudden death during war) are entirely separate and
have no unifying mechanism. For example, it is generally
accepted that sudden death in middle-aged men is usually
caused by a cardiac arrhythmia (ie, ventricular fibrillation),
which results in functional cardiac arrest, whereas most work
on sudden infant death syndrome focuses on immaturity of
the respiratory control systems in the brain stem.
However, the connection between the nervous system and
the cardiopulmonary system provides the unifying link that
allows a coherent explanation for most, if not all, of the forms
of neurocardiac damage. Powerful evidence from multiple
disparate disciplines allows for a neurological explanation for
many forms of SUD.28
Figure 2. Cardiac contraction band necrosis (also known as
coagulative myocytolysis, myofibrillar degeneration). The arrow
shows 2 of the contraction bands.
Samuels
Neurogenic Heart Disease
Definition of Neurogenic
Electrocardiographic Changes
A wide variety of changes in the ECG is seen in the context
of neurological disease. Two major categories of change are
regularly noted: arrhythmias and repolarization changes. It is
likely that the increased tendency for life-threatening arrhythmias found in patients with acute neurological disease is a
result of the repolarization change, which increases the
vulnerable period during which an extrasystole would be
likely to result in ventricular tachycardia and/or ventricular
fibrillation. Thus, the essential and potentially most lethal
features of the ECG, which are known to change in the
context of neurological disease, are the ST segment and T
wave, which reflect abnormalities in repolarization. Most
often, the changes are seen best in the anterolateral or
inferolateral leads. If the ECG is read by pattern recognition
by someone who is not aware of the clinical history, it will
often be said to represent subendocardial infarction or anterolateral ischemia. The electrocardiographic abnormalities usually improve, often dramatically, with death by brain criteria.
In fact, any circumstance that disconnects the brain from the
heart (eg, cardiac transplantation, severe autonomic neuropathies caused by amyloidosis or diabetes, stellate ganglionectomy for treatment of the long QT syndrome) blunts neurocardiac damage of any cause.
The phenomenon is not rare. In a series of 100 consecutive
stroke patients, 90% showed abnormalities on the ECG
compared with 50% of a control population of 100 patients
admitted for carcinoma of the colon.29 This of course does not
mean that 90% of stroke patients have neurogenic ECG
changes. Obviously, stroke and coronary artery disease have
common risk factors, so that many ECG abnormalities in
stroke patients represent concomitant atherosclerotic coronary disease. Nonetheless, a significant number of stroke
patients have authentic neurogenic ECG changes.
Mechanism of the Production of Neurogenic
Heart Disease
Catecholamine Infusion
Josué30 first demonstrated that epinephrine infusions could
cause cardiac hypertrophy. This observation has been reproduced on many occasions, which documents the fact that
systemically administered catecholamines are not only associated with ECG changes reminiscent of widespread ischemia
but with a characteristic pathological picture in the cardiac
muscle that is distinct from myocardial infarction. An identical picture may be found in human beings with chronically
elevated catecholamines, as seen with pheochromocytoma.
Patients with stroke often have elevated systemic catecholamine levels, a fact that may in part account for the high
incidence of cardiac arrhythmias and ECG changes seen in
these patients. On light microscopy, these changes range from
increased eosinophilic staining with preservation of crossstriations to total transformation of the myocardial cell
cytoplasm into dense eosinophilic transverse bands with
intervening granularity. In severely injured areas, infiltration
The Brain–Heart Connection
81
of the necrotic debris by mononuclear cells is often noted,
sometimes with hemorrhage.
Ultrastructurally, the changes in cardiac muscle are even
more widespread than they appear to be in light microscopy.
Nearly every muscle cell shows some pathological alteration,
which range from a granular appearance of the myofibrils to
profound disruption of the cell architecture with relative
preservation of ribosomes and mitochondria. Intracardiac
nerves can be seen and identified by their external lamina,
microtubules, neurofibrils, and the presence of intracytoplasmic vesicles. These nerves can sometimes be seen immediately adjacent to an area of myocardial cell damage. The
pathological changes in the cardiac muscle are usually less at
a distance from the nerve, often with a complete return to
normalcy by a distance of 2 to 4 ␮m away from the nerve
ending.21
Myofibrillar degeneration (also known as coagulative
myocytolysis and contraction band necrosis) is an easily
recognizable form of cardiac injury, distinct in several major
respects from coagulation necrosis, which is the major lesion
of myocardial infarction.25,31 In coagulation necrosis, the cells
die in a relaxed state without prominent contraction bands.
This is not visible by any method for many hours or even
days. Calcification only occurs late, and the lesion elicits a
polymorphonuclear cell response. In stark contrast, in myofibrillar degeneration the cells die in a hypercontracted state
with prominent contraction bands (Figures 2 and 3). The
lesion is visible early, perhaps within minutes of its onset. It
elicits a mononuclear cell response and may calcify almost
immediately.31,32
Stress Plus or Minus Steroids
A similar, if not identical, cardiac lesion can be produced
with various models of stress. This concept was applied to the
heart when Selye published his monograph The Chemical
Prevention of Cardiac Necrosis in 1958.9 He found that
cardiac lesions probably identical to those described above
could be produced regularly in animals that were pretreated
with certain steroids, particularly 2- ␣ -methyl-9- ␣ fluorohydrocortisone (fluorocortisol) and then subjected to
various types of stress. Other hormones, such as dihydrotachysterol (calciferol) and thyroxine, could also sensitize animals
for stress-induced myocardial lesions, though less potently
than fluorocortisol. This so-called stress could be of multiple
types such as restraint, surgery, bacteremia, vagotomy, and
toxins. He believed that the first mediator in the translation of
these widely disparate stimuli into a stereotyped cardiac
lesion was the hypothalamus and that it, by its control over
the autonomic nervous system, caused the release of certain
agents that were toxic to the myocardial cell. Since Selye’s
original work, similar experiments have been repeated in
many different types of laboratory animals with comparable
results. Although the administration of exogenous steroids
facilitates the production of cardiac lesions, it is clear that
stress alone can result in the production of morphologically
identical lesions.
Whether a similar pathophysiology could ever be repeated
in human beings is, of course, of great interest. Many
investigators have speculated on the role of stress in the
82
Circulation
July 3, 2007
pathogenesis of human cardiovascular disease and, in particular, on its relationship to the phenomenon of SUD. A few
autopsies on patients who experienced sudden death have
shown myofibrillar degeneration. Cebelin and Hirsch33 reported on a careful retrospective analysis of the hearts of 15
victims of physical assault who died as a direct result of the
assault, but without sustaining internal injuries. Eleven of the
15 individuals showed myofibrillar degeneration. Age- and
cardiac disease–matched controls showed little or no evidence of this change. This appears to represent human stress
cardiomyopathy. Whether such assaults can be considered
murder has become an interesting legal correlate of the
problem.
Because the myofibrillar degeneration is predominantly
subendocardial, it may involve the cardiac conducting system, which thus predisposes to cardiac arrhythmias. This
lesion, combined with the propensity of catecholamines to
produce arrhythmias even in a normal heart, may well raise
the risk of a serious arrhythmia. This may be the major
immediate mechanism of sudden death in many neurological
circumstances, such as subarachnoid hemorrhage, stroke,
epilepsy, head trauma, psychological stress, and increased
intracranial pressure. Even the arrhythmogenic nature of
digitalis may be largely mediated by the central nervous
system. Further evidence for this is the antiarrhythmic effect
of sympathetic denervation of the heart for cardiac arrhythmias of many types.
Furthermore, it is known that stress-induced myocardial
lesions may be prevented by sympathetic blockade with many
different classes of antiadrenergic agents, most notably,
ganglionic blockers such as mecamylamine and catecholamine-depleting agents such as reserpine.10 This suggests that
catecholamines, which are either released directly into the
heart by sympathetic nerve terminals or reach the heart
through the bloodstream after release from the adrenal medulla, may be excitotoxic to myocardial cells.
Some people who are subjected to an extreme stress may
develop an acute cardiomyopathy that presents with chest
pain and/or symptoms of heart failure. This process is most
commonly seen in older women, whose echocardiograms and
ventriculograms show a typical pattern of left ventricular
apical ballooning, which was named takotsubo-like cardiomyopathy34 because of the similarity in the appearance the
left ventricle to the Japanese octopus trapping pot, the
takotsubo. If a lethal arrhythmia does not intervene, the
process is potentially completely reversible. Some debate
exists regarding whether this syndrome (variously described
as myocardial stunning or myocardial hibernation) could be
explained by ischemia, but it is striking that this pattern of
dysfunction is most consistent with a neural rather than a
vascular distribution.35,36 Wittstein and colleagues37 reported
a series of such patients and referred to the problem as
myocardial stunning. In patients in whom endocardial biopsies were performed, contraction band lesions were found.
The finding of contraction bands suggests either catecholamine effect and/or reperfusion. The 2 mechanisms are not
mutually exclusive in that a neural stimulus could produce
both catecholamine release and coronary vasospasm followed
by vasodilation. There is no direct evidence that the nervous
system can cause coronary vasospasm, but the possibility
remains. Regardless of the precise mechanism, the fact
remains that takotsubo-like cardiomyopathy occurs after an
acute psychological stress and thereby represents an example
of a neurocardiac lesion. It seems likely that this dramatic
condition may be the tip of an iceberg under which lurks a
much larger, albeit less easily demonstrable, problem; namely
neurocardiac lesions that are not sufficiently severe and
widespread to produce gross heart failure but may predispose
to serious cardiac arrhythmias.
Nervous System Stimulation
Nervous system stimulation produces cardiac lesions that are
histologically indistinguishable from those described for
stress and catecholamine-induced cardiac damage. It has been
known for a long time that stimulation of the hypothalamus
can lead to autonomic cardiovascular disturbances,38 and
many years ago lesions in the heart and gastrointestinal tract
have been produced with hypothalamic stimulation.39,40 It has
been clearly demonstrated that stimulation of the lateral
hypothalamus produces hypertension and/or electrocardiographic changes reminiscent of those seen in patients with
central nervous system damage of various types. Furthermore, this effect on the blood pressure and ECG can be
completely prevented by C2 spinal section and stellate
ganglionectomy, but not by vagotomy, which suggests that
the mechanism of the electrocardiographic changes is sympathetic rather than parasympathetic or humoral. Stimulation
of the anterior hypothalamus produces bradycardia, an effect
that can be blocked by vagotomy. Unilateral hypothalamic
stimulation does not result in histological evidence of myocardial damage by light microscopy, but bilateral prolonged
stimulation regularly produces myofibrillar degeneration indistinguishable from that produced by catecholamine injections and stress, as previously described.41
Other methods to produce cardiac lesions of this type
include stimulation of the limbic cortex, the mesencephalic
reticular formation, the stellate ganglion, and regions known
to elicit cardiac reflexes such as the aortic arch. Experimental
intracerebral and subarachnoid hemorrhages can also result in
cardiac contraction band lesions. These neurogenic cardiac
lesions will occur even in an adrenalectomized animal,
although they will be somewhat less pronounced.20 This
evidence argues strongly against an exclusively humoral
mechanism in the intact organism. High levels of circulating
catecholamines exaggerate the electrocardiographic findings
and myocardial lesions, but high circulating catecholamine
levels are not required for the production of pathological
changes. These electrocardiographic abnormalities and cardiac lesions are stereotyped and identical to those found in the
stress and catecholamine models already outlined. They are
not affected by vagotomy and are blocked by maneuvers that
interfere with the action of the sympathetic limb of the
autonomic nervous system, such as C2 spinal section, stellate
ganglion blockade, and administration of antiadrenergic
drugs such as propranolol.
The histological changes in the myocardium range from
normal muscle on light microscopy to severely necrotic (but
not ischemic) lesions with secondary mononuclear cell infil-
Samuels
The Brain–Heart Connection
83
tration. The findings on ultrastructural examination are invariably more widespread, often involving nearly every
muscle cell, even when the light microscopic appearance is
unimpressive. The electrocardiographic findings undoubtedly
reflect the total amount of muscle membrane affected by the
pathophysiological process. Thus, the ECG may be normal
when the lesion is early and demonstrable only by electron
microscopy. Conversely, the ECG may be grossly abnormal
when only minimal findings are present by light microscopy,
since the cardiac membrane abnormality responsible for the
electrocardiographic changes may be reversible. Cardiac
arrhythmias of many types may also be elicited by nervous
system stimulation along the outflow of the sympathetic
nervous system.
Reperfusion
The fourth and last model for the production of myofibrillar
degeneration is reperfusion, as is commonly seen in patients
who die after a period of time on a left ventricular assist pump
or after they undergo extracorporeal circulation. Similar
lesions are seen in hearts that were reperfused with angioplasty or fibrinolytic therapy. The mechanism by which
reperfusion of ischemic cardiac muscle produces coagulative
myocytolysis (also known as myofibrillar degeneration and
contraction band necrosis) involves entry of calcium after a
period of relative deprivation.41
Sudden calcium influx by one of several possible mechanisms (eg, a period of calcium deficiency with loss of
intracellular calcium, a period of anoxia followed by reoxygenation of the electron transport system, a period of ischemia followed by reperfusion, or opening of the receptoroperated calcium channels by excessive amounts of locally
released norepinephrine) may be the final common pathway
by which the irreversible contractures occur, which leads to
myofibrillar degeneration. Thus reperfusion-induced myocardial cell death may be a form of apoptosis (programmed cell
death) analogous to that seen in the central nervous system, in
which excitotoxicity with glutamate results in a similar, if not
identical, series of events.42
The precise cellular mechanism for the electrocardiographic change and the histological lesion may well reflect
the effects of large volumes of norepinephrine released into
the myocardium from sympathetic nerve terminals.43 The fact
that the cardiac necrosis is greatest near the nerve terminals in
the endocardium and is progressively less severe as one
samples muscle cells near the epicardium provides further
evidence that catecholamine toxicity produces the lesion.19
This locally released norepinephrine is known to stimulate
synthesis of adenosine 3⬘,5⬘-cyclic phosphate, which in turn
results in the opening of the calcium channel with influx of
calcium and efflux of potassium. This efflux of potassium
could explain the peaked T waves (a hyperkalemic pattern)
often seen early in the evolution of neurogenic electrocardiographic changes.21 The actin and myosin filaments interact
under the influence of calcium but do not relax unless the
calcium channel closes. Continuously high levels of norepinephrine in the region may result in failure of the calcium
channel to close, which leads to cell death, and finally to
leakage of enzymes out of the myocardial cell. Free radicals
Figure 4. Cascade of events that lead to neurocardiac damage.
released as a result of reperfusion after ischemia or by the
metabolism of catecholamines to the known toxic metabolite,
adrenochrome, may contribute to cell membrane destruction,
which leads to leakage of cardiac enzymes into the blood.44,45
Thus, the cardiac toxicity of locally released norepinephrine
falls on a continuum that ranges from a brief reversible burst
of electrocardiographic abnormalities to a pattern that resembles hyperkalemia and then finally to an irreversible failure of
the muscle cell with permanent repolarization abnormalities,
or even the occurrence of transmural cardiac necrosis with
enzyme (eg, troponin, creatine kinase) release and Q waves
seen on the ECG.
Histological changes would also represent a continuum
that ranges from complete reversibility in a normal heart
through mild changes seen only by electron microscopy to
severe myocardial cell necrosis with mononuclear cell infiltration and even hemorrhages. The amount of cardiac enzymes released and the electrocardiographic changes would
roughly correlate with the severity and extent of the pathological process. This explanation, summarized in Figure 4,
rationalizes all the observations in the catecholamine infusion, stress plus or minus steroid, nervous system stimulation,
and reperfusion models.
Concluding Remarks and Potential Treatments
In conclusion, there is powerful evidence to suggest that
overactivity of the sympathetic limb of the autonomic nervous system is the common phenomenon that links the major
cardiac pathologies seen in neurological catastrophes. These
profound effects on the heart may contribute in a major way
to the mortality rates of many primarily neurological conditions such as subarachnoid hemorrhage, cerebral infarction,
status epilepticus, and head trauma. These phenomena may
also be important in the pathogenesis of SUD in adults,
sudden infant death, sudden death during asthma attacks,
cocaine- and amphetamine-related deaths, and sudden death
during the alcohol withdrawal syndrome, all of which may be
linked by stress and catecholamine toxicity.
Investigations aimed at alteration of the natural history of
these events with catecholamine receptor blockade, calciumchannel blockers, free-radical scavengers, and antioxidants
84
Circulation
July 3, 2007
Figure 5. Possible therapeutic approaches aimed to prevent neurocardiac damage. GABA indicates gamma aminobutyric acid.
are in progress in many centers around the world and are
summarized in Figure 5.
Disclosures
None.
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19. Greenshoot JH, Reichenbach DD. Cardiac injury and subarachnoid haemorrhage. J Neurosurg. 1969;30:521–531.
20. Hawkins WE, Clower BR. Myocardial damage after head trauma and
simulated intracranial haemorrhage in mice: the role of the autonomic
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35. Angelakos ET. Regional distribution of catecholamines in the dog heart.
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36. Murphree SS, Saffitz JE. Quantitative autoradiographic delineation of the
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Gerstenblith G, Wu KC, Rade JJ, Bivalaqua TJ, Champion HC. Neurohumoral features of myocardial stunning due to sudden emotional stress.
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39. Karplus JP, Kreidl A. Gehirn und Sympathicus. Sympathicusleitung im
Gehirn und Halsmark [German]. Pflugers Arch. 1912;143:109 –127.
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Hypothalamaszentren zu Blutdruck und innerer Sekretion [German].
Pflugers Arch. 1927;215:667– 674.
41. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged
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42. Gottlieb R, Burleson KO, Kloner RA Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest.
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43. Eliot RS, Todd GL, Pieper GM, Clayton FC. Pathophysiology of catecholamine-mediated myocardial damage. J S C Med Assoc. 1979;75:
513–518.
44. Singal PK, Kapur N, Dhillon KS, Beamish RE, Dhalla NS. Role of free
radicals in catecholamine-induced cardiomyopathy. Can J Physiol
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Adv Myocardiol. 1983;4:3–21.
KEY WORDS: antioxidants 䡲 apoptosis 䡲 cardiomyopathy 䡲 cerebral
infarction 䡲 death, sudden 䡲 nervous system, autonomic 䡲 nervous system,
sympathetic
Cardiovascular Involvement in General Medical Conditions
Chronic Kidney Disease
Effects on the Cardiovascular System
Ernesto L. Schiffrin, MD, PhD, FRSC, FRCPC; Mark L. Lipman, MD, FRCPC; Johannes F.E. Mann, MD
Abstract—Accelerated cardiovascular disease is a frequent complication of renal disease. Chronic kidney disease promotes
hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Furthermore, diabetic
nephropathy is the leading cause of renal failure in developed countries. Together, hypertension, dyslipidemia, and
diabetes are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis.
Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in chronic kidney
disease, which likely contributes through enhanced production of reactive oxygen species to the accelerated
atherosclerosis observed in chronic kidney disease. Promoters of calcification are increased and inhibitors of
calcification are reduced, which favors metastatic vascular calcification, an important participant in vascular injury
associated with end-stage renal disease. Accelerated atherosclerosis will then lead to increased prevalence of coronary
artery disease, heart failure, stroke, and peripheral arterial disease. Consequently, subjects with chronic renal failure are
exposed to increased morbidity and mortality as a result of cardiovascular events. Prevention and treatment of
cardiovascular disease are major considerations in the management of individuals with chronic kidney disease.
(Circulation. 2007;116:85-97.)
Key Words: atherosclerosis 䡲 hypertension 䡲 kidney 䡲 vasculature
I
addressed because the emphasis will be on CKD before
ESRD is reached. In addition, the CV complications associated with dialysis will not be discussed. The different stages
of CKD according to the level of glomerular filtration rate
(GFR) are shown in Table 1. ESRD corresponds to the stage
where patients need renal replacement therapy (ie, dialysis or
renal transplantation), whereas stage 1 is mostly recognized
by either albuminuria or structural renal abnormality (eg,
hyperechoic renal parenchyma on ultrasound). Table 2 provides the approximate odds ratios (univariate) of CVD
according to stages of CKD on the basis of the literature cited
below. The increase in risk in comparison to people without
CKD depends on the age of the population studied: the
younger the person, the higher the relative risk. Microalbuminuria increases the CV risk 2- to 4-fold.
t is increasingly apparent that individuals with chronic
kidney disease (CKD) are more likely to die of cardiovascular (CV) disease (CVD) than to develop kidney failure.1,2 A
large cohort study comprising ⬎130 000 elderly subjects
showed that increased incidence of CV events could be in
part related to the fact that persons with renal insufficiency
are less likely to receive appropriate cardioprotective treatments.3 However, beyond the effects of lack of appropriate
therapy, it is clear that accelerated CVD is prevalent in
subjects with CKD. The first part of the present review will
therefore focus on the epidemiological links between impairment of renal function and adverse CV events, between
albuminuria and CV events, and between serum cystatin C
and CVD. The second part of the present review will address
the mechanisms that lead to the association of renal and CVD,
which include hypertension, dyslipidemia, activation of the
renin-angiotensin system, endothelial dysfunction and the
role of asymmetric dimethyl arginine (ADMA), oxidative
stress, and inflammation. Finally, mechanisms that are involved in vascular calcification often found in CKD and
end-stage renal disease (ESRD) will be described. Additionally, ESRD is associated with several specific complications
caused by the uremic state per se, which can contribute to the
development and progression of CVD through volume overload with consequent hypertension, anemia, uremic pericarditis, and cardiomyopathy. However, these issues will not be
Epidemiological Links Between Impaired
GFR and Adverse Cardiovascular Events
Evidence for the relationship between renal dysfunction and
adverse CV events was perhaps first recognized in the
dialysis population in whom the incidence of CV death is
strikingly high. Approximately 50% of individuals with
ESRD die from a CV cause,2,4,5 a CV mortality that is 15 to
30 times higher than the age-adjusted CV mortality in the
general population.4,6 This disparity is present across all ages,
but it is most marked in the younger age group (25 to 34 years
From the Department of Medicine (E.L.S., M.L.L.), Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada;
and the Department of Nephrology and Hypertension (J.F.E.M.), Schwabing General Hospital, Ludwig Maximilians University, Munich, Germany.
Correspondence to Ernesto L. Schiffrin, MD, PhD, FRSC, FRCPC, Sir Mortimer B. Davis Jewish General Hospital, B-127, 3755 Côte Ste-Catherine
Rd, Montreal, Quebec, Canada H3T 1E2. E-mail ernesto.schiffrin@mcgill.ca
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.678342
85
86
Circulation
July 3, 2007
TABLE 1.
Stages of CKD
Stage
GFR, mL/min per 1.73 m2
Description
1*
Kidney damage with normal or increased GFR
ⱖ90
2
Kidney damage with mildly decreased GFR
60 to 89
3
Moderately decreased GFR
30 to 59
4
Severely decreased GFR
15 to 29
5
Kidney failure
⬍15 or dialysis
ESRD is defined as the need for renal replacement therapy (ie, need for dialysis or renal
transplantation).
*Stage 1 CKD is mostly recognized by either albuminuria or structural renal abnormality (eg,
hyperechoic renal parenchyma on ultrasound).
old), where the CV mortality is 500-fold greater in ESRD
patients compared with age-matched controls with normal
renal function.1 It is therefore unsurprising that established
CVD is easily demonstrable in CKD. For example, 40% of
patients who have started dialysis treatments have evidence
of coronary artery disease, and 85% of these patients have
abnormal left ventricular structure and function.7
The relationship between renal disease and CV mortality
has also been shown to extend to subjects with more
moderate degrees of renal functional impairment. In fact, the
majority of patients with stage 3 to 4 CKD (ie, a GFR⬍60
mL/min per 1.73 m2) die of CV causes rather than progress to
ESRD. Here too, objective evidence of structural and functional cardiac abnormalities has been demonstrated by echocardiography. Levin et al determined left ventricular mass
index in a population of 115 men and 60 women with an
average creatinine clearance (CrCl) of 25.5⫾17 mL/min with
2-dimensional targeted M-mode echocardiography. The population was stratified into 3 groups according to renal
function. The prevalence of left ventricular hypertrophy
(LVH) was 26.7% in subjects with CrCl⬎50 mL/min, 30.8%
in those with CrCl between 25 and 49 mL/min, and 45.2% in
individuals with CrCl⬍25 mL/min.8
Tucker et al9 reported a similar finding in a population of
85 persons with renal insufficiency. With the same echocardiographic techniques, as well as comparable criteria for the
diagnosis of LVH, these investigators found an LVH prevalence of 16% in subjects with a CrCl⬎30 mL/min and 38% in
those with a CrCl⬍30 mL/min. These studies demonstrate
that LVH is common in patients with renal insufficiency even
before they progress to dialysis, and that the prevalence of
LVH correlates with the degree of renal functional
impairment.
TABLE 2.
CV Risk According to Stages of CKD
Stage
CV Risk (Odds Ratio, Univariate)
1
Depending on degree of proteinuria
2
1.5
3
2 to 4
4
4 to 10
5
ESRD
10 to 50
20 to 1000
The increase in risk in comparison with people free of CKD depends on the
age of the population studied: The younger the person, the higher the relative
risk. Microalbuminuria increases the CV risk 2- to 4-fold.
A growing number of studies have demonstrated that the
relationship between renal dysfunction and increased CV
morbidity and mortality extends across the spectrum of renal
dysfunction to encompass the mildest degrees of renal impairment. Moreover, this relationship appears to hold across
populations with widely varying degrees of baseline CV
health.
CVD Associated With Renal Disease in the
General Population
The Framingham Heart Study was among the first to assess
mild renal insufficiency and its association with death and
adverse CV events in the general population.10 Of the 6233
participants in the study, mild renal insufficiency was present
in 246 men and 270 women (serum creatinine, 1.4 to 3.0
mg/dL). Of these individuals, 81% had no prevalent CVD at
entry. Over the 15-year follow-up period, there was no
significant association between mild renal insufficiency and
either death or adverse CV events in women. However, in
men there was a trend toward more CV events with mild renal
insufficiency, and a significant association was demonstrated
with age-adjusted all-cause mortality (hazard ratio, 1.42).
Given the relatively small number of subjects followed in this
study and the low number of outcome events, these findings
were suggestive but not definitive of a correlation between
mild renal dysfunction and increased CV morbidity and
mortality.
More recently, Go et al11 examined the relationship of
GFR and adverse CV events in a low-risk population. They
analyzed the database of a large healthcare provider in
northern California and used the Modification of Diet in
Renal Disease (MDRD) formula12 to estimate the baseline
GFR from measurements of serum creatinine in ⬎1.1
million adults, with only those who were on dialysis or
who had undergone a kidney transplant excluded. The
primary outcomes examined included death from any
cause, CV events, and hospitalizations. The end-point
information was obtained from the health-plan database
and the California death registry with a mean follow-up
period of 2.84 years. After adjustment for age, sex, race,
coexisting illnesses, and socioeconomic status, a stepwise
increase in the rate of each of the 3 primary outcomes was
seen for every sequential decrease in GFR. With the best
cohort (GFR⬎60 mL/min per 1.73 m2) as the point of
reference, the adjusted hazard ratio for death from any
cause and any CV event increased to 1.2 and 1.4, respec-
Schiffrin et al
tively, for a GFR between 45 to 59 mL/min per 1.73 m2;
1.8 and 2.0 for a GFR between 30 to 44 mL/min per 1.73
m2; 3.2 and 2.8 for GFR between 15 to 29 mL/min per 1.73
m2; and 5.9 and 3.4 for a GFR⬍15 mL/min per 1.73 m2.
The adjusted risk of hospitalization with a reduced GFR
followed a similar pattern. This large study, which incorporated a diverse population of adults, clearly demonstrated an independent and graded (inverse) correlation
between decreasing levels of renal function and increasing
event rates of CV morbidity and death.
CVD Associated With Renal Disease in
Hypertensive Subjects
The association between renal function and mortality in the
hypertensive population was evaluated by the Hypertension
Detection and Follow-up Program Cooperative Group, which
followed and treated 10 940 hypertensive subjects to compare
stepped care to referred care.13 The primary end point of the
study was all-cause mortality. Persons with a baseline serum
creatinine ⱖ1.7 mg/dL experienced an 8-year mortality rate
that was ⬎3 times higher than that of all other participants.
Data from the Hypertension Optimal Treatment (HOT)
study support this finding. In the HOT study, 18 790 hypertensive subjects, only 10% of whom had evidence of atherosclerotic disease, were assigned to 3 diastolic blood pressure
target groups and followed for a mean of 3.8 years. Persons
with a serum creatinine ⬎3 mg/dL were excluded and the
Cockroft-Gault14 equation was used to calculate baseline
GFR. The adjusted relative risks for total mortality and for
major CV events (nonfatal myocardial infarction [MI], nonfatal stroke, CV death) were 1.65 and 1.58, respectively, in
subjects with GFR⬍60 mL/min compared with those with a
GFR⬎60 mL/ min.15
Effect of Renal Disease on Individuals With
Preexisting Stable CVD or Risk Factors for CVD
A post hoc analysis of the Heart Outcomes and Prevention
Evaluation (HOPE) study examined the impact of baseline
serum creatinine on the incidence of the composite primary
outcome (CV death, MI, or stroke).16 The HOPE population
included individuals with objective evidence of vascular
disease or diabetes combined with another CV risk factor and
was designed to test the benefit of add-on ramipril versus
placebo in this population. Patients with heart failure or a
serum creatinine concentration ⬎2.3 mg/dL were excluded.
The follow-up period was ⬇5 years. There were 980 subjects
with mild renal insufficiency (serum creatinineⱖ1.4 mg/dL)
and 8307 subjects with normal renal function (serum creatinine⬍1.4 mg/dL). The cumulative incidence of the primary
outcome was 22.2% in individuals with mild renal insufficiency versus 15% in those with normal renal function
(P⬍0.001). The impact of renal insufficiency was independent of both the baseline CV risk factors as well as the
treatment group.
A similar relationship between renal function and CV
events was demonstrated in the Prevention of Events with
Angiotensin-Converting Enzyme Inhibition (PEACE) trial.17
In PEACE, add-on trandolapril was compared with placebo in
a population with chronic stable coronary artery disease and
Kidney Disease and the Cardiovascular System
87
LVEF⬎40%. The primary end point was a composite of
death from CV causes, MI, and coronary revascularization.
Patients with a serum creatinine ⬎2.0 mg/dL were excluded
and the median duration of follow-up was 4.8 years. A post
hoc analysis of 8280 subjects, in whom baseline renal
function was separated into quartiles with the MDRD formula, demonstrated significant stepwise increases in event
rates as the baseline GFR declined. Interestingly, unlike in
HOPE, there was a significant interaction between GFR and
treatment group with respect to CV and all-cause mortality in
that the angiotensin-converting enzyme inhibitor benefited
only those individuals with a GFR⬍60 mL/min per 1.73 m2.
Effect of Renal Disease in Patients With Established
Heart Failure or Postmyocardial Infarction
Hillege et al examined whether renal dysfunction was a
predictor of mortality in stable patients with advanced heart
failure.18 They studied 1906 subjects with New York Heart
Association class III and IV heart failure and evidence of left
ventricular dysfunction (LVEF⬍35%) who were enrolled in
the Second Prospective Randomized study of Ibopamine on
Mortality and Efficacy (PRIME II).19 Hillege et al correlated
baseline GFR, as calculated with the Cockroft-Gault equation, with overall mortality after a median follow-up of 277
days. The authors found that patients in the lowest quartile of
GFR (⬍44 mL/min) had relative risk of mortality of 2.85
compared with subjects in the highest quartile (⬎76 mL/min).
Somewhat surprisingly, baseline GFR was independent of
impaired LVEF and was a stronger predictor of mortality than
either LVEF or New York Heart Association class. In fact,
GFR was the strongest predictor of mortality of all factors
analyzed, which included parameters of neurohormonal
activation.
Hillege et al also explored the prognostic ability of baseline
renal function to predict the development of heart failure after
an anterior-wall MI.20 Patients with a serum creatinine ⬎180
␮mol/L (2.0 mg/dL) were excluded. Baseline GFR was
calculated with the Cockroft-Gault formula, and the 298
patients were divided into tertiles of renal function. At 1 year
of follow-up the incidence of congestive heart failure by
tertile of decreasing GFR was 24.0%, 28.9%, and 41.2%.
Risk of de novo congestive heart failure was 1.86-fold higher
in the lowest tertile (⬍81 mL/min) than in the highest tertile
(⬎103 mL/min). As the mean GFR in the lowest tertile was
67.0 mL/min, the study by Hillege et al highlights the impact
of even mild GFR reductions on cardiac outcomes.
In a post hoc analysis of the Valsartan in Acute Myocardial
Infarction Trial (VALIANT), Anavekar et al examined the
relationship between baseline renal function and adverse
outcomes in 14 527 subjects with acute MI complicated by
clinical or radiologic signs of heart failure and/or left ventricular dysfunction.21 Subjects were randomly assigned to
receive captopril, valsartan, or both, and they were followed
for a mean of 24.7 months. Individuals with a serum
creatinine ⬎2.5 mg/dL were excluded from the study. The
primary end point was death from any cause, and secondary
end points included death from CV causes, heart failure,
recurrent MI, resuscitation after cardiac arrest, stroke, and a
composite of these.22 Anavekar et al21 stratified these subjects
88
Circulation
July 3, 2007
into 4 groups; the investigators used the MDRD formula to
estimate baseline GFR (mL/min per 1.73 m2) and found that,
irrespective of treatment group, there was a progressive
increase in both the primary end point as well as each of the
secondary end points as GFR declined across the 4 groups.
These findings remained significant even when an extensive,
70-candidate, variable model was used to adjust for higher
comorbidities in patients with the poorest renal function. If
the group with a GFR ⬎75 mL/min per 1.73 m2 is considered
the reference point, the adjusted hazard ratio for adverse CV
events was 1.10 in the GFR group between 60.0 to 74.9
mL/min per 1.73 m2 and 1.49 in the GFR group ⬍45.0
mL/min per 1.73 m2. When GFR was analyzed as a continuous variable, each decrease in GFR of 10 mL/min per 1.73
m2 below 81.0 was associated with a 1.1-fold increase in risk
of death and nonfatal CV complications.21
Epidemiological Links Between Albuminuria
and Adverse Cardiovascular Events
Renal disease may not only be identified by low GFR but also
by the presence of abnormal quantities of albumin in the
urine. In fact, the appearance of pathological albuminuria
often precedes the functional deterioration that is evidenced
by a decline in GFR. Importantly, albuminuria has also been
shown to be a potent independent marker of CV risk in both
diabetic and nondiabetic persons. Similar to GFR, the link
between albuminuria and adverse CV events was first recognized in the more overt situations of macroalbuminuria (urine
albumin:creatinine ratio [ACR] ⬎300 mg/g),23,24 and then
this link was extended to more modest elevations such as
microalbuminuria (ACR, 30 to 300 mg/g).25 More recently, it
has become increasingly recognized that CV risk begins to
rise within currently defined normal levels of albuminuria
(ACR⬍30 mg/g). Thus, urinary albumin is a continuous CV
risk factor, whereas microalbuminuria is a designated threshold for renal functional deterioration in individuals with and
without diabetes.
CVD in Patients With Macroalbuminuria
The Irbesartan Diabetic Nephropathy Trial (IDNT) enrolled
subjects with type 2 diabetes, hypertension, and macroalbuminuria.26 A total of 1715 subjects with mean urine ACR of
1416.2 mg/g were randomized into 3 treatment groups that
received irbesartan, amlodipine, or placebo and were followed for a mean period of 2.6 years. The primary outcome
of the main trial was a renal-centric composite of serum
creatinine doubling, ESRD, or death. Although irbesartan
proved to be the superior treatment with respect to the
primary outcome, no difference was detected between treatment groups on the secondary outcome of CV events. With
this data, a post hoc analysis was performed by Anavekar et
al27 to assess the relationship between baseline albumin
excretion and the CV composite (CV death, nonfatal MI,
hospitalization for heart failure, stroke, amputation, and
coronary and peripheral revascularization). A univariate analysis revealed that the proportion of patients who experienced
the CV end point progressively increased with increasing
quartiles of baseline urine ACR. A multivariate analysis
confirmed albuminuria as an independent risk factor for CV
events with a 1.3-fold increased relative risk for each natural
log increase of 1 U in urine ACR.
A similar population was studied in the Reduction of End
points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL). Here, 1513 persons with type 2 diabetes,
hypertension, and macroalbuminuria (mean baseline ACR,
1810 mg/g) were randomized to either losartan or placebo
and followed for a mean of 3.4 years. The primary end point
was the same as in IDNT, namely a composite of mainly
adverse nephrological events (serum creatinine doubling,
ESRD, or death), and, consistent with IDNT, the angiotensin
antagonist provided superior nephroprotection but conferred
no statistically significant benefit on the secondary CV
outcomes,28 although de novo heart failure was less frequently noted in the losartan group. Nevertheless, in a post
hoc analysis of RENAAL, baseline albuminuria was again
shown to be a predictor of both the prespecified composite
CV end point (composite of MI, stroke, first hospitalization
for heart failure or unstable angina, coronary or peripheral
revascularization, or CV death) as well as of heart failure
alone. With subjects stratified into 3 groups on the basis of
baseline ACR (⬍1500, 1500 to 3000, ⬎3000 mg/g), comparison of the highest tertile with the lowest revealed an adjusted
hazard ratio of 1.92 for the composite CV end point and 2.70
for heart failure. In multivariate analysis, baseline albuminuria was the strongest independent predictor of both these
outcomes. Perhaps more significant was the finding that the
change in urine albumin excretion from baseline to 6 months
was the only dynamic correlate of adverse CV outcomes. A
50% reduction in baseline albuminuria translated into an 18%
reduction in the composite CV end point and a 27% reduction
in the risk of heart failure. Thus, albuminuria is not only a risk
factor for adverse CV outcomes but may also be a therapeutic
target or an indicator of therapeutic response.29
CVD in Patients With Microalbuminuria
Microalbuminuria also correlates with adverse CV events. In
a multivariate analysis of CHD mortality in a type-2 diabetic
population, Mattock et al reported that microalbuminuria was
the strongest predictor of adverse CV outcomes with an odds
ratio of 10.02, which outranked smoking (odds ratio, 6.52),
diastolic blood pressure (odds ratio, 3.20), and serum cholesterol (odds ratio, 2.32).30
The HOPE study investigators reported on the risk of CV
events associated with baseline ACR ⬎2.0 mg/mmol (equivalent to 17.7 mg/g). This amount of albuminuria was present
at baseline in 1140 (32.6%) subjects of the diabetic cohort
and in 823 (14.8%) subjects of the nondiabetic cohort. In the
overall population a baseline ACR ⬎2.0 mg/mmol increased
the adjusted relative risk of CV events (1.83), all-cause death
(2.09), and hospitalization for congestive heart failure (3.23).
The impact of microalbuminuria on the primary composite
outcome (CV death, MI, or stroke) was significant in both
diabetics (relative risk, 1.97) and nondiabetics (relative risk,
1.61).31
The ability of microalbuminuria to predict adverse CV
events is not restricted to a high-risk population like that of
the HOPE trial. In fact, Hillege et al demonstrated the ability
of microalbuminuria to predict CV and non-CV mortality in
Schiffrin et al
the general population.32 The investigators mailed medical
questionnaires and a vial to collect early morning urine
samples to all inhabitants of the city of Groningen between
1997 and 1998. More than 40 000 subjects responded and
were followed for a mean period of 961 days. Vital statistics
and the causes of death were available from government
registries. The percentage of subjects who manifested baseline microalbuminuria was 22.5% in those who succumbed to
CV death, 16.0% in patients who died as a result of non-CV
death, and 7.0% in patients who remained alive at the end of
the study period. After adjustment for other known CV risk
factors, a doubling of the urine albumin excretion rate was
associated with a relative risk of 1.29 for CV mortality and
1.12 for non-CV mortality. Here again, microalbuminuria
outranked the predictive power of other classic CV risk
factors.
CVD in Patients With Albuminuria in the
Normal Range
The relationship between CV events and albuminuria has
been extended further by several studies that suggest CV risk
associated with increased levels of urinary albumin excretion
begins to emerge at levels previously defined as normal
(ACR⬍30 mg/g). Here too, the association appears to apply
to a wide spectrum of patient populations. Analysis of the
HOPE study population supports albuminuria as a continuous
risk factor for adverse CV events from an ACR as low as 0.5
mg/mmol (equivalent to 4.4 mg/g).33 For every subsequent
0.4 mg/mmol increase in the ratio, the adjusted hazard of
major CV events increased by 5.9%.
Similarly, Klausen et al34 reported that the risk of CV
events in the general population began to increase at urinary
albumin excretion levels below the defined threshold for
microalbuminuria. Klausen et al followed subjects in the
Third Copenhagen City Heart Study, which included
⬇10 200 randomly selected participants who underwent a
detailed CV investigation program and provided a timed
overnight urine sample. Subjects were classified into quartiles
on the basis of urinary albumin with a follow-up period that
ranged from 5 to 7 years. A urinary albumin excretion above
the upper quartile of 4.8 ␮g/min (equivalent to ACR ⬇9
mg/g) was associated with an increased adjusted relative risk
of 2.0 for CHD and 1.9 for death.
A post hoc analysis of the Losartan Intervention for
Endpoint Reduction in Hypertension (LIFE) study related not
just baseline albuminuria to CV risk but also the impact of
reduction of urinary albumin excretion on CV events.35 The
LIFE study followed 8206 hypertensive individuals with
LVH for a mean period of 4.8 years. The principal finding of
LIFE was that losartan proved superior to atenolol in the
reduction of the composite primary end point (CV death,
nonfatal stroke, nonfatal MI) for the same degree of blood
pressure reduction.36 In the post hoc study by Ibsen et al,35 the
LIFE population was stratified into 4 groups according to
mean ACR at baseline (1.21 mg/mmol, equivalent to 10.6
mg/g) and at year 1 (0.67 mg/mmol, equivalent to 5.9 mg/g).
The percentage of subjects who experienced an adverse CV
event was reported on the basis of whether their ACR was
above or below the mean values. This analysis demonstrated
Kidney Disease and the Cardiovascular System
89
a statistically significant stepwise increase in the primary
composite end point that started with the group with the low
baseline/low year-1 group ratios (5.5%). Intermediate risk
was found in the groups with low baseline/high year-1 (8.6%)
ratios and high baseline/low year-1 ratios (9.4%). The highest
risk group had high baseline/high year-1 values (13.5%).
These results were independent of in-treatment blood pressure and indicated that reductions in urine ACR over time
translated into diminished CV risk.
Epidemiological Links Between Serum Cystatin C
and Adverse Cardiovascular Events
Recently, serum cystatin C has gained recognition as an
excellent endogenous marker of kidney function. Cystatin C
is a cysteine proteinase with a molecular weight of 13 kDa
that is produced by almost all human cells and released into
the blood. Cystatin C is freely filtered by the glomerulus and
metabolized by proximal tubular cells, but it is not secreted
into the tubules. Cystatin C does not appear to be affected by
age, gender, or muscle mass, and there is evidence to suggest
that it may be a more sensitive detector of incipient renal
dysfunction than creatinine-based estimates of GFR such as
the Cockroft-Gault or MDRD formulas.37 Several recent
reports have indicated that cystatin C may be a better
predictor of adverse CV events and all-cause mortality than
either serum creatinine or creatinine-based estimating equations.38 – 41 Ix et al categorized a population of 990 ambulatory
persons with stable coronary heart disease into quartiles on
the basis of baseline serum cystatin C levels and followed
these subjects for a median of 37 months.42 Subjects in the
highest cystatin C quartile (ⱖ1.30 mg/dL), when compared
with the lowest quartile (ⱕ0.91 mg/dL), had a hazard ratio of
3.6 for all-cause mortality, 2.0 for CV events (composite of
CHD death, MI, and stoke), and 2.6 for incident heart failure.
These statistically significant results were adjusted for traditional CV risk factors. Potentially the most important finding
in this study was that higher cystatin C levels were predictive
of these adverse outcomes even among people without
microalbuminuria or a diminished GFR as estimated by the
MDRD formula (ⱕ60 mL/min per 1.73 m2). Currently
cystatin C is not routinely measured in clinical practice.
In summary, the presence of renal dysfunction, whether
detected by GFR, urine albumin excretion, or serum cystatin
C, predicts adverse CV outcomes. These relationships appear
to extend to individuals with and without diabetes, those with
and without preexisting CVD, and subjects with minimal to
marked perturbations in their renal parameters.
Mechanisms of Cardiovascular Complications
in Renal Disease
As described in the preceding paragraphs, there is growing
evidence that relatively minor renal abnormalities such as a
slightly reduced GFR or microalbuminuria even within the
normal range may be associated with increased risk of CV
events. One of the principal pathophysiological mechanisms
involved in this association has been proposed to be endothelial dysfunction. Whether micro- or macroalbuminuria is
an expression of generalized endothelial cell dysfunction
remains to be demonstrated. However, many studies have
90
Circulation
July 3, 2007
demonstrated the correlation of albuminuria with endothelial
dysfunction as measured in peripheral blood vessels. Many of
the traditional and nontraditional CV risk factors that could
affect endothelial function can be found in association with
CKD. Related conditions such as diabetes, obesity, and
hypertension, as well as the presence of renal dysfunction per
se lead to activation of the renin-angiotensin system, oxidative stress, elevated ADMA, low-grade inflammation with
increased circulating cytokines, and dyslipidemia, which are
all common pathophysiological mechanisms that play a role
in the association of renal failure and CVD.43
Hypertension
Hypertension in and of itself represents a powerful risk factor
for CVD in CKD and is almost invariably present in patients
with renal failure. Sodium retention and activation of the
renin-angiotensin system have been considered the most
important mechanisms involved in the elevation of blood
pressure in subjects with kidney disease.44 Sympathetic nervous system activation also plays a role. Plasma catecholamine concentrations are elevated, and increased nerve sympathetic traffic has been demonstrated in renal failure.45,46
The participation of the sympathetic system has become more
complex with the recent discovery of renalase, a new regulator of cardiac function and blood pressure produced by the
kidney. Xu et al47 screened libraries of the Mammalian Gene
Collection Project and identified a 37.8-kDa oxidase, which
contained flavin-adenine-dinucleotide, expressed mainly in
glomeruli and proximal tubules of the kidney but also in
cardiomyocytes and other tissues; the investigators called this
oxidase renalase. Renalase metabolizes catecholamines in the
following order: dopamine 3 epinephrine 3 norepinephrine.
In contrast to other oxidases, renalase is secreted into plasma
and urine of healthy persons. However, it is not detectable in
uremic individuals. Recombinant renalase exerts a powerful
and rapid hypotensive effect on rats. To what extent the
impairment of renalase production contributes to sympathetic
hyperactivity and blood pressure elevation in CKD remains to
be established. Also, endothelial dysfunction48 –52 (see below)
and remodeling of blood vessels53 may participate not only in
vascular complications in patients with kidney disease but
also in the maintenance of elevated blood pressure.
Hypertension also plays a major role in cardiac damage in
CKD via LVH induction.54,55 In addition, a reduction in
coronary reserve and capillary density that occurs in CKD
patients exposes them to coronary ischemia,56 which in turn
leads to worsening of ventricular dysfunction.
Endothelial Dysfunction, Nitric Oxide
Bioavailability, and ADMA in Renal Disease
Impairment of endothelial function is recognized as one of
the initial mechanisms that lead to atherosclerosis. Endothelial dysfunction, which occurs in both large and small
arteries, is present in renal disease.51 Microalbuminuria, a
marker of glomerular hyperfiltration, has been correlated with
and may be a manifestation of impaired endothelial function.57 Experimental evidence suggests that microvascular
endothelial dysfunction participates in the mechanisms that
lead to progression of renal disease,58 which in turn may
exacerbate endothelial dysfunction and contribute to acceleration of atherogenesis. It has been postulated that glomerular
endothelial dysfunction is an early feature of essential hypertension that may precede blood pressure elevation. Microalbuminuria may itself contribute to renal dysfunction, which
progresses with uncontrolled blood pressure elevation. Endothelial dysfunction in turn may contribute to CV mortality
already in mild renal insufficiency as suggested by the Hoorn
Study.59 Reduced bioavailability of nitric oxide (NO) appears
to be one of the main factors involved in chronic renal
failure–associated endothelial dysfunction,48,52,60 in large
measure because of increased oxidative stress in the vascular
wall (see Dyslipidemia, Inflammation, and Oxidative Stress
in Renal Disease).48,49 Prevalence of impaired endothelial
function, low-grade inflammation, and dyslipidemia associated with incipient and progressive renal disease may explain
the acceleration of atherosclerosis and, together with hypertension, may explain the high prevalence of coronary ischemia and CV events in CKD. The presence of hypertension,
sometimes difficult to control, in subjects with the previously
mentioned risk factors may underlie the prevalence of cerebrovascular disease and stroke in patients with renal disease.
Paradoxically, a recent report showed that lowest systolic
blood pressure was associated with stroke in stage 3 to 4
CKD.61
ADMA is a competitive inhibitor of NO synthase.62
ADMA is synthesized potentially in many tissues, but in the
CV system it is produced in the heart, endothelium, and
smooth muscle cells. It is derived from the catabolism of
proteins that contain methylated arginine residues, and it is
released as the proteins are hydrolyzed. The synthesis of
ADMA requires the enzyme protein arginine methyltransferase type I, which methylates arginine residues, and the
protein arginine methyltransferase type II forms symmetric
dimethylarginine, which is a stereoisomer of ADMA and is
not an inhibitor of NO synthase. ADMA and symmetric
dimethylarginine enter endothelial cells through the cationic
amino acid y⫹ transporter. The activity of this transporter
colocalizes with caveolin-bound NO synthase, which suggests that y⫹ transporter activity may be a determinant of the
local concentrations of ADMA. The ADMA and symmetric
dimethylarginine compete with each other and L-arginine for
transport into the cell. Thus, ADMA may block entry of
L-arginine, with the resulting decrease in synthesis of NO.
ADMA is metabolized mainly by dimethylarginine dimethylaminohydrolase and cleared by the kidney. Exogenous
ADMA inhibits NO generation in vitro, and in humans it
reduces forearm blood flow and cardiac output and increases
systemic vascular resistance and blood pressure.63 Subpressor
ADMA infusion increases renovascular resistance, induces
intimal hyperplasia, and affects small and large vessels.64 – 66
Plasma concentrations of ADMA are increased in association
with endothelial dysfunction and/or reduced NO production,
particularly in renal failure.67,68 Increased ADMA in renal
failure may result from both increased activity of protein
arginine methyltransferase and decreased metabolism by
dimethylarginine dimethylaminohydrolase.69 It is unclear
whether endogenous ADMA concentrations increase sufficiently to inhibit NO production in vivo. Interestingly, plasma
Schiffrin et al
Kidney Disease and the Cardiovascular System
norepinephrine and ADMA concentrations are closely correlated in patients with ESRD and are likely to act through
common mechanisms that contribute to CV events.70 ADMA
is now considered one of the strongest markers of atherosclerosis.71 Elevated plasma concentrations of ADMA are associated not only with endothelial dysfunction and atherosclerosis72 but predict mortality and CV complications in CKD
and ESRD.68 In subjects with mild to advanced CKD, plasma
ADMA was inversely related to GFR73 and was an independent risk marker for progression to ESRD and mortality.74 In
the Mild to Moderate Kidney Disease Study, ADMA was
significantly associated with progression of nondiabetic kidney disease.75 Elevated plasma ADMA has been shown to be
a marker of CV morbidity in early nephropathy associated
with type 1 diabetes.76 In the Ludwigshafen Risk and Cardiovascular Health Study, ADMA independently predicted
total and CV mortality in individuals with angiographic
coronary artery disease.77 Although reduced bioavailability of
NO and accumulation of ADMA cause endothelial dysfunction, there is little evidence for coronary artery endothelial
dysfunction in renal failure. Recently, Tatematsu et al78
induced renal failure in dogs and evaluated coronary vasodilator response to acetylcholine, which demonstrated blunted
responses in the CKD dogs. mRNA expression of dimethylarginine dimethylaminohydrolase-II and endothelial NO synthase in coronary arteries were downregulated, which demonstrated a possible mechanism for coronary endothelial
dysfunction in early stages of CKD.
TABLE 3. Effects of Renal Failure and Inflammation on
Lipoprotein and Endothelial Structure and Function
Dyslipidemia, Inflammation, and Oxidative Stress
in Renal Disease
to reduce proteinuria modestly, and results in a small reduction in the rate of loss of kidney function, especially in
populations with CVD.82
The changes in lipoprotein composition and structure as
well as angiotensin II–mediated alterations in endothelial
function stimulate and amplify the effect of inflammatory
mechanisms.83 Between 30 and 50% of CKD patients have
elevated serum levels of inflammatory markers such as
C-reactive protein, fibrinogen, interleukin-6, tumor necrosis
factor-␣, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, D-dimer, and the adhesion molecules E-selectin,
VCAM-1 and ICAM-1.84,85 Mechanisms are unclear but
increased inflammatory mediators have been attributed to
increased oxidative stress, accumulation of postsynthetically
modified proteins, advanced glycation end products, and
other agents normally cleared by the kidney. Thus, causes of
inflammation may include comorbidities, oxidative stress,
infections, and hemodialysis-related factors that depend on
membrane biocompatibility and the dialysate.86 Progressive
deterioration of renal function in CKD may lead to dyslipidemia or accumulation of uremic toxins, which can stimulate
oxidative stress and inflammation, which in turn may contribute to endothelial dysfunction and progression of
atherosclerosis.
A major contributor to the increase in circulating inflammatory biomarkers in CKD may be enhanced oxidative
stress.85– 87 Mechanisms of oxidative stress in uremia may
involve activation of reduced nicotinamide adenine dinucleotide (NAD(P)H) oxidase, xanthine oxidase, uncoupled endothelial NO synthase, myeloperoxidase (MPO), and mito-
Individuals with CKD become progressively malnourished,
as evidenced by low levels of albumin, prealbumin, and
transferrin, which has been suggested to be a mechanism for
activation of inflammation.79 Diseases in which low-grade
inflammation is found, such as diabetes and hypertension, are
often associated with CKD. Thus it is difficult to conclude
whether there is a direct effect of renal failure on inflammation in early CKD. Renal failure causes changes in plasma
components and endothelial structure and function that favor
vascular injury, which may play a role as a trigger for
inflammatory response. Dyslipidemia associated with
CKD80,81 contributes to the inflammatory response in renal
failure. The changes in blood-lipid composition and their
relation to renal dysfunction and inflammation are summarized in Table 3. Hepatic apolipoprotein A-I synthesis decreases and high-density lipoprotein levels fall. High-density
lipoprotein is an important antioxidant and also protects the
endothelium from the effects of proinflammatory cytokines.
Apolipoprotein C-III, a competitive inhibitor of lipoprotein
lipase, is increased in CKD. Serum triglyceride levels increase as a result of accumulation of intermediate-density
lipoprotein, which comprise very low-density lipoprotein and
chylomicron remnants. These impair endothelial function and
are associated with CVD.
Because dyslipidemia associated with CKD appears to play
a role in the enhanced CV risk of these patients, treatment of
dyslipidemia conversely should reduce proteinuria and ameliorate the progression of CKD. Indeed, statin therapy appears
91
HDL
Effects of renal failure: decreased synthesis of apoA-I; decreased LCAT
activity; increased apoC-III; increased triglycerides; decreased levels of
mature HDL
Effects of inflammation: replacement of apoA-I with serum amyloid A;
decreased levels of mature HDL; decreased paroxynase and AHH activity;
decreased ability to protect against cytokine action of endothelium;
decreased ability to reduce oxidized LDL
Remnants
Effects of renal failure: increased levels linked to increase apoC-III;
decreased clearance; interaction with blood vessels to induce
vasoconstriction
LDL
Effects of renal failure: accumulation of small dense atherogenic LDL;
results in increased AngII and also upregulation of the AT1 receptor
Activation of the renin-angiotensin system
Stimulates NAD(P)H oxidase, xanthine oxidase, etc., which leads to
production of superoxide; induces IL-6 and other cytokines as well as
PAI-1 gene expression; increased superoxide leads to decreased
bioavailability of nitric oxide, endothelial dysfunction, vascular remodeling,
and hypertension
HDL indicates high-density lipoprotein; apo, apolipoprotein; LACT, decreased
lecithin cholesterol ester transferase; AHH, aryl hydrocarbon hydrolase; LDL,
low-density lipoprotein; AT, angiotensinogen; and PAI-1, plasminogen activator
inhibitor 1. Adapted from Kaysen and Eiserich80 with permission from the
American Society of Nephrology. Copyright 2004.
92
Circulation
July 3, 2007
chondrial oxidases. NAD(P)H oxidase is probably the most
important source in the vasculature, and it is stimulated by
angiotensin II and other agents (see Renin-Angiotensin System).88 Increased production of reactive oxygen species
(ROS) by uncoupled endothelial NO synthase49 as well as
reduced inactivation of ROS by antioxidant systems such as
superoxide dismutase87 also play an important role. MPO is
present in neutrophils and monocytes/macrophages, and has
been shown to be expressed to a significant degree in human
atheroma.89 It may thus play a role in the accelerated
atherosclerosis of renal failure. It has recently been reported
that a single nucleotide polymorphism in the promoter region
of the MPO gene associated with reduced expression of MPO
is accompanied by a lower prevalence of CVD in ESRD
patients.90 Active MPO is released from white blood cells
during hemodialysis, and this could be a mechanism whereby
MPO plays a role in vascular injury in subjects with ESRD.
TABLE 4.
Renin-Angiotensin System
Adapted from Qunibi93 with permission from the American Society of
Nephrology. Copyright 2005.
Activation of the renin-angiotensin system occurs in many
forms of renal disease. Angiotensin II stimulates NAD(P)H
oxidase, which leads to generation of superoxide anion and
contributes to endothelial dysfunction and vascular remodeling and growth.91 Mechanisms whereby the renin-angiotensin
system may be activated by kidney disease are multiple and
beyond the scope of the present review, but such mechanisms
may in part depend on the adaptation to loss of renal mass that
results in changes in renal hemodynamics. When angiotensin
II acts through the AT1 receptor, it stimulates generation of
ROS by NAD(P)H oxidase and other enzymes systems,
which leads to upregulation of inflammatory mediators,
which include cytokines, chemokines, adhesion molecules,
and plasminogen activator inhibitor 1, and superoxide scavenging of NO. These events, together with the mechanisms
already mentioned, promote endothelial dysfunction, vascular
remodeling, and the progression of atherosclerosis.92
Vascular Calcification, Inducers and Inhibitors
of Calcification, and the Role of Phosphate in
Renal Failure
Accelerated calcifying atherosclerosis and valvular heart
disease occur with high frequency in CKD.93–95 A recent
study showed that 40% of patients with CKD and a mean
GFR 33 mL/min exhibited coronary artery calcification
compared with 13% in matched control subjects with no renal
impairment.96 Calcification can be found in atherosclerotic
plaques and in the vascular media, smooth muscle cells, and
elastic laminae of large elastic and medium muscular arteries
as well as in cardiac valves.93–95 Subjects with renal failure
who exhibit medial calcification are typically middle-aged
and have been dialyzed for some time, although some
individuals may already have calcified vessels before dialysis.97 There is a specific dialysis-related type of vascular
calcification called calciphylaxis, or calcific uremic arteriopathy, that is characterized by diffuse calcification of the media
of small to medium arteries and arterioles with intimal
proliferation and thrombosis that results in skin ulcers98 and
can lead to life-threatening skin necrosis or acral gangrene.
Calciphylaxis is the result of an elevated calcium (Ca) ⫻
Promoters and Inhibitors of Vascular Calcification
Promoters of calcification
Traditional factors
Older age, male gender, hypertension, diabetes, smoking high LDL
cholesterol, low HDL cholesterol, genetics
Uremia-related factors
Uremic serum, hyperphosphatemia, increased Ca⫻P product,
exogenous vitamin D therapy, elevated parathyroid hormone levels,
dialysis vintage, calcium load and hypercalcemia, chronic inflammation,
warfarin, elevated leptin levels
Inhibitors of calcification
Circulating inhibitors
Fetuin-A, bone morphogenetic protein-7, parathyroid hormone–related
peptide, HDL, magnesium
Locally acting inhibitors
Matrix Gla protein, osteopontin, pyrophosphate, osteoprotegerin,
genetics
phosphate (P) product without presence of an active osteogenic process, and it must be differentiated from other forms
of calcification of the skin that do not affect blood vessels and
from medial calcific sclerosis, which affects larger vessels. It
is a rare complication of renal failure present in up to 4% of
hemodialysis patients, typically in obese diabetic females,
associated often with secondary hyperparathyroidism, hypercalcemia, hyperphosphatemia, malnutrition, and sometimes
with warfarin therapy or hypercoagulability. However, although warfarin and hypercoagulability have both been implicated, the latter on the basis of an association of protein C
deficiency and calciphylaxis, some studies suggest that neither hypercoagulability nor warfarin play a role in this rare
condition.99 Similarly, parathyroidectomy has been reported
to lead to the resolution of the skin ulcers of calciphylaxis in
some series100 but not all.101
Mechanisms involved in vascular calcification in CKD
include passive precipitation of Ca and P in the presence of
excessively high extracellular concentrations, effects of inducers of osteogenic transformation and hydroxyapatite formation, and deficiency of calcification inhibitors.94,102 Table
4 summarizes some of the inducers and inhibitors of vascular
calcification that induce an osteoblast phenotype in vascular
smooth muscle cells in CKD. Patients with ESRD often have
severe changes in their Ca⫻P product, which induces a trend
toward ectopic calcification. Aortic stiffening associated with
calcification103 will cause LVH, which results in increased
CV risk. Increased phosphate levels are also a source of
increased CV risk, probably as a result of worsening vascular
calcification.104 Precipitation associated with a raised Ca⫻P
product may contribute to soft-tissue calcification, but calcification of the media of blood vessels appears to involve
active transport through the Na-P cotransporter PiT-1 which
occurs in part as a result of a phenotypic switch of vascular
smooth muscle cells into osteoblast-like cells as a consequence of high intracellular Ca and P, which induce osteogenic differentiation of smooth muscle cells.94,95 In an in vitro
model, elevated Ca or P induced human vascular smooth
Schiffrin et al
muscle cell calcification, which was initiated by release of
membrane-bound matrix vesicles and apoptotic bodies.105
Vesicles released by cells exposed to Ca and P calcified to an
important degree, but those released in the presence of serum
were minimally calcified and were found to contain the
calcification inhibitors fetuin-A and matrix Gla protein
(MGP) (see next paragraph). Thus, vascular calcification is a
cell-mediated process regulated by calcification inhibitors,
functional impairment of which leads to accelerated vascular
calcification.
Among the inhibitors of calcification, fetuin-A (␣2-Schmid
Heremans glycoprotein; molecular weight, 60 kDa), which is
produced by the liver and circulates in blood, appears to be of
prime importance. Fetuin-A has a transforming growth
factor-␤ receptor II–like domain and may function as a
soluble transforming growth factor-␤ antagonist that interferes with insulin receptor autophosphorylation and tyrosine
kinase activity.106 It forms stable colloidal spheres with Ca
and P (calciprotein particles) and is the main component of a
high molecular mass complex that contains Ca, P, and
MGP.107 Low serum fetuin-A levels in subjects with CKD
have been associated with enhanced vascular calcification102
and increased CV mortality.108,109 MGP belongs to a family
of N-terminal ␥-carboxylated (Gla) proteins that require a
vitamin K– dependent ␥-carboxylation for their biological
activation and prevent bone morphogenetic protein (BMP)2/BMP receptor-2 (BMPR2) interactions. 110 The
␥-carboxylated MGP, but not the non–␥-carboxylated MGP,
is carried in plasma by fetuin-A. Mice that lack MGP develop
spontaneous calcification of arteries and cartilage.111 Elevated concentrations of MGP may be found in the vicinity of
atherosclerotic plaques112 and have been shown to be associated with calcification of vascular smooth muscle cells in
vitro.113 MGP levels in blood have been reported to correlate
negatively with coronary artery calcification.114
Osteoprotegerin regulates osteoclast activation. It acts as a
soluble decoy receptor that prevents the binding of the
osteoclast stimulator receptor activator of nuclear factor-␬B
ligand to its receptor. Osteoprotegerin deficiency in mice
leads to vascular calcification, but its mechanism of action
has not been elucidated.115 Osteoprotegerin levels are elevated in ESRD,116 correlate with vascular calcification, and
predict mortality in hemodialysis patients, in particular in
individuals with high C-reactive protein levels.117 Interestingly, lower soluble receptor activator of nuclear factor-␬B
ligand concentrations were associated with better
outcomes.117
Elevated pyrophosphate (PPi) concentrations prevent hydroxyapatite crystal formation and calcification. PPi is synthesized by the rate-limiting enzyme nucleotide pyrophosphatase phospho-diesterase-1. Mice that lack nucleotide
pyrophosphatase phospho-diesterase-1 develop PPi deficiency, which results in an altered vascular smooth muscle
cell phenotype and vascular calcification.118 The cellular PPi
exporter ankyrin, which is encoded by the transmembrane
transporter progressive ankylosis locus, mediates PPi exit
from cells.119 Vascular calcification may also result from
enhanced activity of the membrane-bound tissue-nonspecific
alkaline phosphatase, which degrades PPi to P. PPi deficiency
Kidney Disease and the Cardiovascular System
93
may occur in ESRD as a consequence of removal of PPi
during hemodialysis,120 which may be one of the mechanisms
that contribute to accelerated vascular calcification in hemodialysis patients.
BMPs are important regulators of bone formation. They are
members of the largest subclass of the transforming growth
factor-␤ superfamily and have been localized in areas of
vascular calcification.121 BMP-2 is generated from a 60-kDa
precursor, which is processed to an 18-kDa monomer that
associates with another monomer to form the active homodimer, which then binds to its receptor. The BMPR is a
heterodimer that consists of types 1 and 2 serine/threonine
kinases. BMPR2 phosphorylates BMPR1, which in turn
phosphorylates the Smad 1/5/8 complex, which, with Smad 4,
then modulates target gene expression.122 Of the different
BMPs, BMP-2 or BMP-4 may induce osteogenic differentiation of vascular smooth muscle cells through induction of
transcription factors Cbfa1, osterix, and the msh homeobox
homolog MSX-2. Other effects of BMP-2/BMP-4 that contribute to calcification of the vasculature are the triggering of
apoptosis and inhibitory effects on MGP. In addition, BMP-4
has been shown to exert vascular effects that lead to increased
oxidative stress and impaired endothelial function, and to
what extent these effects are related to media calcification
remains to be established. BMP-7 on the other hand inhibits
vascular calcification by upregulation of ␣-smooth muscle
actin expression via induction of p21 and upregulation of
Smad 6 and 7. BMP-7 is expressed mainly in the kidney, and
its expression decreases with progression of renal failure,
which results in reduction of its ability to inhibit calcification.
Lowering of BMP-7 affects bone metabolism with consequent increase in serum phosphate levels, which adversely
affects the Ca⫻P product and induces phenotypic changes in
vascular smooth muscle cells, which leads to metastatic
calcification.
Increased leptin levels may participate in the process of
vascular calcification in CKD because serum leptin concentrations are increased in renal failure as a result of reduced
leptin excretion. Leptin induces heterotopic calcification via
its receptors in the hypothalamus that induce an increased
sympathetic activity, which stimulates osteoblast
␤-adrenergic receptors.123 Leptin increases bone marrow
stem cell differentiation into an osteoprogenitor phenotype
and may act on vascular smooth muscle cells to induce
calcification,124 in part by an increase in ROS generation and
induction of BMP-2.95
In summary, BMP-2/BMP-4 binds the BMPR1/BMPR2
receptor complex and phosphorylates the regulatory Smads,
which then signal downstream to upregulate the expression of
transcription factors Cbfa1, osterix, and MSX-2. BMP-4 also
stimulates generation of ROS. Cbfa1 expression is also
enhanced by ROS, leptin, vitamin D, high phosphate levels,
and PiT-1.87 The result is a phenotypic change in vascular
smooth muscle cells to an osteogenic phenotype. These cells
express alkaline phosphatase and produce hydroxyapatite
crystals. Calcification inhibitors such as fetuin-A, MGP,
osteoprotegerin, osteopontin, BMP-7, and Smad 6 antagonize
BMP-2/BMP-4 signaling and metastatic calcification
(Figure).
94
Circulation
July 3, 2007
Angiotensin II
Thrombosis
Endothelium
Inflammation
Fetuin-A
LOX-1
PO4
Ca x P
BMP-2/4
Pit-1
Calcification
Leptin
promoters Vitamin D
Osteogenic
VSMC
ALP
ROS
Hydroxyapatite
VSMC
AT1R
Fetuin-A
OPG
Calcification
MGP
inhibitors
OPN
BMP-7
PPi
NADH/
NADPH
oxidase
Mechanisms depicted here are some of those involved in vascular calcification in chronic kidney disease. Activation of the reninangiotensin system results in stimulation of AT1R, which stimulates reduced NAD(P)H oxidase, the main source of vascular ROS. BMP2/4 binds the BMP receptor BMPR1/BMPR2 receptor complex and phosphorylates the Smad 1/5/8 complex, which, with Smad 4, signals downstream to upregulate expression of transcription factors Cbfa1, osterix, and MSX-2. Cbfa1 expression is also enhanced by
ROS, leptin, vitamin D, increased Ca⫻P product, or high PO4 levels induced by Pit-1, the sodium-phosphate cotransporter, activated in
part as a result of the phenotypic switch of VSMCs into osteoblast-like cells. VSMCs that have acquired an osteogenic phenotype
express ALP and produce hydroxyapatite crystals. Calcification inhibitors such as PPi inhibit hydroxyapatite precipitation, whereas
fetuin-A, MGP, OPG, OPN, BMP-7, and Smad 6 antagonize BMP2/4 signaling and calcification. AT1R indicates angiotensin AT1 receptor; NAD(P)H, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; BMP, bone morphogenic protein; PO4, phosphate;
VSMC, vascular smooth muscle cells; ALP, alkaline phosphatase; PPi, pyrophosphate; MGP, matrix Gla protein; OPG, osteoprotegerin;
and OPN, osteopontin.
Conclusion
The present review underlines the CV risk to which patients
with CKD are exposed and summarizes some of the mechanisms that lead to the increased risk of adverse CV events. It
is also clear that some of this risk is modifiable and can be
improved with currently available therapy by reduction of
blood pressure according to guidelines, aggressive treatment
of dyslipidemia, control of protein intake, minimization of
bone resorption, optimization of Ca and P metabolism, and
combat of hypercoagulability, with the caveat that warfarin
may be implicated in calciphylaxis of the latter. Therapeutic
aspects that may require new approaches include management of the increased oxidative stress and low-grade inflammation, as well as development of novel strategies to increase
the concentrations of inhibitors of calcification and to moderate the agents that promote calcification.
Sources of Funding
The work by Dr Schiffrin was supported by a Canada Research Chair
on Hypertension and Vascular Research, and by grants 37917 and
82790 from the Canadian Institutes of Health Research.
Disclosures
None.
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ACCF/AHA/SCAI Clinical Competence Statement
ACCF/AHA/SCAI 2007 Update of the Clinical Competence
Statement on Cardiac Interventional Procedures
A Report of the American College of Cardiology Foundation/American
Heart Association/American College of Physicians Task Force on
Clinical Competence and Training (Writing Committee to Update the
1998 Clinical Competence Statement on Recommendations for
the Assessment and Maintenance of Proficiency in
Coronary Interventional Procedures)
WRITING COMMITTEE MEMBERS
Spencer B. King III, MD, MACC, FAHA, FSCAI, Chair;
Thomas Aversano, MD, FACC; William L. Ballard, MD, FACC, FSCAI;
Robert H. Beekman III, MD, FACC, FAHA;
Michael J. Cowley, MD, FACC, FSCAI*; Stephen G. Ellis, MD, FACC;
David P. Faxon, MD, FACC, FAHA, FSCAI*; Edward L. Hannan, PhD, FACC;
John W. Hirshfeld, Jr, MD, FACC, FAHA; Alice K. Jacobs, MD, FACC, FAHA, FSCAI;
Mirle A. Kellett, Jr, MD, FACC, FSCAI; Stephen E. Kimmel, MD, FACC, FAHA;
Joel S. Landzberg, MD, FACC; Louis S. McKeever, MD, FACC, FSCAI;
Mauro Moscucci, MD, FACC; Richard M. Pomerantz, MD, FACC, FSCAI;
Karen M. Smith, MD, FACC, FSCAI; George W. Vetrovec, MD, FACC, FSCAI*
TASK FORCE MEMBERS
Mark A. Creager, MD, FACC, FAHA, Chair; John W. Hirshfeld, Jr, MD, FACC, FAHA†; David R.
Holmes, Jr, MD, FACC; L. Kristin Newby, MD, FACC, FAHA; Howard H. Weitz, MD, FACC,
FACP; Geno Merli, MD, FACP; Ileana Piña, MD, FACC, FAHA;
George P. Rodgers, MD, FACC, FAHA; Cynthia M. Tracy, MD, FACC†
*Society for Cardiovascular Angiography and Interventions Representative.
†Former Task Force member during the writing effort.
This document was approved by the American College of Cardiology Board of Trustees in May 2007, the American Heart Association Science
Advisory and Coordinating Committee in May 2007, and the Society for Cardiovascular Angiography and Interventions in May 2007.
When this document is cited, the American College of Cardiology, American Heart Association, and Society for Cardiovascular Angiography and
Interventions would appreciate the following citation format: King SB III, Aversano T, Ballard WL, Beekman RH III, Cowley MJ, Ellis SG, Faxon DP,
Hannan EL, Hirshfeld JW Jr., Jacobs AK, Kellett MA Jr., Kimmel SE, Landzberg JS, McKeever LS, Moscucci M, Pomerantz RM, Smith KM, Vetrovec
GW. ACCF/AHA/SCAI 2007 update of the clinical competence statement on cardiac interventional procedures: a report of the American College of
Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Clinical Competence and Training (Writing
Committee to Update the 1998 Clinical Competence Statement on Recommendations for the Assessment and Maintenance of Proficiency in Coronary
Interventional Procedures). Circulation. 2007;116:98 –124.
This article has been copublished in the July 3, 2007, issue of the Journal of the American College of Cardiology.
Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org), the American Heart
Association (www.americanheart.org), and the Society for Cardiovascular Angiography and Interventions (www.scai.org). For copies of this document,
please contact Elsevier Inc. Reprint Department, fax (212) 633-3820, e-mail reprints@elsevier.com. To purchase Circulation reprints, call 843-216-2533
or e-mail kelle.ramsay@wolterskluwer.com.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express
permission of the American College of Cardiology or the American Heart Association. Instructions for obtaining permission are located at http://
www.americanheart.org/presenter.jhtml?identifier⫽4431. A link to the “Permission Request Form” appears on the right side of the page.
(Circulation. 2007;116:98-124.)
© 2007 by the American College of Cardiology Foundation and the American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.185159
98
King et al
ACCF/AHA/SCAI Clinical Competence Statement
99
TABLE OF CONTENTS
Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .99
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .100
Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101
Writing Group Composition . . . . . . . . . . . . . . . . . . . . .101
Literature Review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101
Percutaneous Coronary Intervention . . . . . . . . . . . . . . . . .101
Evolution of Competence and Training
Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101
Evolution of Coronary Interventional
Capabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
Procedural Success and Complications of
Coronary Interventional Procedures . . . . . . . . . . . . . . .102
Patient, Lesion, and Institutional Variables
Influencing Success and Complication
Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .103
Measures/Definitions of Success . . . . . . . . . . . . . . . .103
Patient and Lesion Characteristics Related
to Procedural Success and Complication
Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .104
Strategies for Risk Stratification and
Operator Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . .104
Impact of the Facility on Procedural
Success . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .104
Components of Operator Competence . . . . . . . . . . . . .105
Cognitive Knowledge Base . . . . . . . . . . . . . . . . . . . .105
Technical Skills . . . . . . . . . . . . . . . . . . . . . . . . . . . . .106
Nonballoon Devices . . . . . . . . . . . . . . . . . . . . . . . . . .106
Relationships of Operator and Institutional
Experience and Activity to Outcomes in
Coronary Interventional Procedures . . . . . . . . . . . . . . .106
Evidence Reviewed . . . . . . . . . . . . . . . . . . . . . . . . . .106
Relationship of Institutional Volume to
Procedural Outcome. . . . . . . . . . . . . . . . . . . . . . . . . . . .107
Volume and Outcomes Relationship for
Primary PCI in Acute MI . . . . . . . . . . . . . . . . . . . . . . .108
Relationship of Individual Operator
Volume to Procedural Outcome . . . . . . . . . . . . . . . .109
Combination of Individual Operator
Volume and Institutional Volume on
Procedural Outcome. . . . . . . . . . . . . . . . . . . . . . . . . . . .110
Ongoing Quality Improvement and
Maintenance of Competence . . . . . . . . . . . . . . . . . . . . .111
Institutional Maintenance of Quality. . . . . . . . . . . . .111
Individual Maintenance of Quality . . . . . . . . . . . . . .112
Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112
Definition of Quality in PCI . . . . . . . . . . . . . . . . . . .112
Institutional Quality Assurance
Requirement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112
Role of Risk Adjustment in Assessing
Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112
Challenges in Determining Quality . . . . . . . . . . . . . .112
Requirement for Institutional Resources
and Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113
The Quality Assessment Process. . . . . . . . . . . . . . . .113
Conclusions and Recommendations
for PCIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113
Success and Complication Rates . . . . . . . . . . . . . . . .113
Risk Adjustment. . . . . . . . . . . . . . . . . . . . . . . . . . . . .114
Volume–Activity Relationships . . . . . . . . . . . . . . . . .114
Recommendations for Institutional
Maintenance of Quality . . . . . . . . . . . . . . . . . . . . . . .114
Recommendations for Individual
Maintenance of Quality . . . . . . . . . . . . . . . . . . . . . . .114
Percutaneous Noncoronary Interventions . . . . . . . . . . . . .114
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .114
Disorders of the Atrial Septum . . . . . . . . . . . . . . . . . . .115
Criteria for Competency . . . . . . . . . . . . . . . . . . . . . .115
Cardiologists in Training Programs . . . . . . . . . . . . .115
Cardiologists in Practice . . . . . . . . . . . . . . . . . . . . . .115
Maintenance of Competency for
Percutaneous ASD/PFO Closure . . . . . . . . . . . . . . . .115
Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . .115
Hypertrophic Cardiomyopathy and
Alcohol Septal Ablation . . . . . . . . . . . . . . . . . . . . . . . .116
Criteria for Competency . . . . . . . . . . . . . . . . . . . . . .116
Valvular Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . .116
Cognitive Knowledge Base . . . . . . . . . . . . . . . . . . . .116
Criteria for Competency . . . . . . . . . . . . . . . . . . . . . .116
Percutaneous Ventricular Assist
Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .116
Laboratory and Staff Competence. . . . . . . . . . . . . . . . .116
Conclusions and Recommendations . . . . . . . . . . . . . . .117
Percutaneous Noncoronary
Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117
Appendix 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121
Appendix 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .122
Preamble
The granting of clinical staff privileges to physicians is a
primary mechanism used by institutions to uphold the quality
of care. The Joint Commission on Accreditation of Health
Care Organizations requires that the granting of continuing
medical staff privileges be based on the criteria specified in
the medical staff bylaws. Physicians themselves are thus
charged with identifying the criteria that constitute professional competence and with evaluating their peers accordingly. Yet, the process of evaluating physicians’ knowledge
and competence is often constrained by the evaluator’s own
knowledge and ability to elicit the appropriate information,
problems compounded by the growing number of highly
specialized procedures for which privileges are requested.
The American College of Cardiology Foundation/American Heart Association/American College of Physicians
(ACCF/AHA/ACP) Task Force on Clinical Compe-
100
Circulation
July 3, 2007
tence and Training was formed in 1998 to develop
recommendations for attaining and maintaining the cognitive and technical skills necessary for the competent performance of a specific cardiovascular service, procedure, or
technology. These documents are evidence based and,
where evidence is not available, expert opinion is utilized to
formulate recommendations. Indications and contraindications for specific services or procedures are not included in
the scope of these documents. Recommendations are intended to assist those who must judge the competence of
cardiovascular health care providers entering practice for the
first time and/or those who are in practice and undergo
periodic review of their practice expertise or who apply for
privileges at a new institution. The assessment of competence is complex and multidimensional, therefore, isolated
recommendations contained herein may not necessarily be
sufficient or appropriate for judging overall competence.
The current document addresses competence in cardiac
interventional procedures and is authored by representatives
of the ACCF, the AHA, and the Society for Cardiovascular
Angiography and Interventions (SCAI). This document
applies to specialists trained in internal medicine and/or
adult cardiology and is not meant to be a clinical competence statement on procedures for congenital heart disease
in the child or young adult.
The ACCF/AHA/ACP Task Force makes every effort to
avoid any actual or potential conflicts of interest that might
arise as a result of an outside relationship or personal interest
of a member of the ACCF/AHA/ACP Writing Committee. Specifically, all members of the Writing Committee
were asked to provide disclosure statements of all such
relationships that might be perceived as real or potential
conflicts of interest relevant to the document topic. These
statements were reviewed by the Writing Committee and
updated as changes occurred. The relationships with industry for authors and peer reviewers are published in the
appendices of the document.
Mark A. Creager, MD, FACC, FAHA
Chair, ACCF/AHA/ACP Task Force on
Clinical Competence and Training
Introduction
Coronary intervention has evolved from an investigational
procedure to a widely practiced, mature mainstream clinical
therapy (1). Conventional balloon angioplasty, while still a
core procedure in interventional cardiology, has been augmented by adjunctive stenting, which greatly improves
procedure efficacy and modestly reduces the risk of restenosis (2). Bare-metal stents have been replaced by drug-eluting
stents in the majority of cases, which further reduce the risk
of restenosis (3). Because stents or other interventional
devices are commonly used, the coronary angioplasty procedure is more aptly termed “percutaneous coronary intervention” (PCI).
The AHA estimated that more than 1,000,000 PCIs
were performed in the United States in 2003 (4). Physicians
performing these procedures represent approximately 25%
of board-certified cardiologists in the United States (5).
As a result of the maturation of PCI as a discipline and
the ongoing clarification of its role in the management of
coronary heart disease, the public can and should appropriately expect consistent access to high-quality PCI capability.
However, there is potential for substantial variation in the
quality of PCI services. PCI is often a complex, demanding
procedure. To perform PCI optimally, an operator must
possess a substantial cognitive knowledge base as well as
considerable technical skill. In addition, the technical difficulty of a particular procedure can vary greatly from one
patient to another. Furthermore, serious complications of
coronary interventional procedures may occur unpredictably
in procedures that initially appear to be straightforward.
Recognition and management of complications are critical
components of PCI procedures that require skill, knowledge, experience, and judgment. Since there can be variation
among operators in cognitive knowledge and skill and
among procedures in technical difficulty, there is a potential
for substantial variation in procedure safety and efficacy.
Credentialing physicians to perform procedures is the
responsibility of the governance of the local health care
facility. The Joint Commission on the Accreditation of
Health Care Organizations requires that medical staff privileges be granted to applicants only after assessment based
on professional criteria. Physicians are charged with the
responsibility to establish the criteria that constitute professional competence and to evaluate their peers on the basis of
such criteria. The U.S. health care system relies, in part, on
this process of granting and renewing clinical privileges to
maintain quality.
The issue of determining quality standards and credentialing criteria has presented a major challenge to the
medical profession. Developing standards has been difficult
because, until recently, there were few data available on
which to base them and because PCI techniques, indications, and capability have evolved rapidly. During the past
several years, documents have been published that have
offered guidelines and standards for the training and maintenance of competence (6 –15). Because of the paucity of
clinical data, the earlier standards were developed principally
through observation, experience, and intuition. These standards relied heavily on operator activity level as a surrogate
for skill and quality.
The most recent document published by the ACC was
based on the information available in 1998 (16). The
recommendations of this and other similar documents
require updating as technology and training evolve (17).
Percutaneous noncoronary cardiac interventions, such as
aortic and mitral valvuloplasty, atrial septal defect (ASD)
and patent foramen ovale (PFO) closure, and alcohol septal
ablation therapy, were not addressed in the previous document (16). These procedures, although constituting a
King et al
small minority of interventional activity, are performed
by interventional cardiologists and are included in the
Accreditation Council on Graduate Medical Education
(ACGME) curriculum and the American Board of Internal Medicine (ABIM) certifying exam. There have
been no statements addressing clinical competence in
noncoronary interventions.
The ACC, the ACP, the SCAI, the Society for Vascular
Medicine and Biology (SVMB), and the Society for Vascular Surgery (SVS) have jointly developed a document on
acquisition and maintenance of competence in vascular
medicine and catheter-based vascular interventions (18);
however, PCI and other percutaneous cardiac procedures
are not addressed by the current document. This document
is divided into 2 sections: PCI and percutaneous noncoronary cardiac interventions.
Purpose
This document was developed to review the currently
available scientific data with the following purposes:
1. To characterize the expected success and complication
rates for coronary interventional procedures when performed by highly skilled operators.
2. To identify comorbidities and other risk factors that may
be used for risk adjustment when assessing procedurespecific expected success and complication rates.
3. To assess the relationship between operator activity level
and success rates in PCI procedures as assessed by
risk-adjusted outcome statistics.
4. To assess the relationship between institutional activity
level and success rates in PCI procedures as assessed by
risk-adjusted outcome statistics.
5. To develop recommendations for standards to assess
operator proficiency and institutional program quality.
These include standards for data collection to permit
monitoring of appropriateness and effectiveness of PCI
procedures both at the level of the operator and the
institution.
6. To expand the scope of this competency document,
previously limited to coronary procedures, to also include
noncoronary cardiac interventions.
Writing Group Composition
The Writing Group was selected to represent a broad range
of experience and expertise to bear on this issue. The
members of the Writing Group were identified on the basis
of 1 or more of the following attributes: PCI operators with
a broad range of experience (in practice and in academic
settings); individuals who have performed clinical research
studying the outcome of PCI procedures; individuals who
direct catheterization laboratories with a broad cross section
of interventional operators; and individuals with broad
clinical experience who have had considerable previous
involvement with PCI.
ACCF/AHA/SCAI Clinical Competence Statement
101
Literature Review
A literature search was conducted with 5 goals:
1. To identify published coronary and other cardiac interventional outcomes data that could be used as benchmarks for quality assessment. In addition, the process
sought to identify those risk adjustment variables that
affect the likelihood of success and complications. This
review focused on outcomes of coronary interventions,
including the latest interventional devices as of the date
of this revision.
2. To identify data that examines the relationships between
operator and institutional experience, and activity levels,
and their impact on procedural success and complication
rates.
3. To assess the issues and problems associated with judging operator and institutional proficiency based on outcome statistics—in particular, the challenge of accurately
assessing the performance of low-volume operators and
institutions.
4. To expand the recommendations beyond coronary interventions to other cardiac interventional procedures.
5. To identify methods for monitoring appropriateness of
performance of PCI.
Percutaneous Coronary Intervention
Evolution of Competence and Training Standards
Initially, because experience was limited, the coronary angioplasty technique was disseminated informally among
physicians who were highly experienced at diagnostic cardiac catheterization. During this period, physicians acquired
angioplasty skills through “on-the-job” experience, and no
standards existed for either training requirements or for
demonstration of competence.
As the coronary angioplasty knowledge base grew and
techniques evolved, standards were developed for training
(19). Formal angioplasty training programs were first organized in the early 1980s. The most recent recommendations
were published by the ACC in 1999 (20). The ABIM
developed an Examination in Interventional Cardiology
that was first administered in 1999. As of 2005, 5,020
physicians had successfully passed the examination and
become board certified in interventional cardiology. Currently, eligibility to sit for the ABIM interventional cardiology examination requires completion of a fourth-year
fellowship in interventional cardiology in an ACGMEaccredited program. During academic year 2004 to 2005,
there were 122 accredited interventional cardiology programs in the United States that had 240 filled training
positions.
Professional organizations have addressed the issue of
standards and criteria for proficiency in PCI procedures
since 1986, with an increasing focus on the issue of
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July 3, 2007
maintenance of proficiency and skills (6 –15). These documents have universally endorsed an annual caseload goal for
maintenance of proficiency. The most commonly endorsed
activity level has been 75 procedures per year per operator.
This standard was initially based on general consensus of
experts. In recent years, considerable research has examined
the volume– outcome relationship and, in general, has affirmed it (21,22).
Since the previous guidelines were published, there has
been debate over the relationship between volume and
quality. While a relationship between volume and outcomes
exists, volume alone does not determine quality. Also, the
ABIM interventional cardiology board exam has been
established to certify a level of knowledge and experience in
the field. This competency document addresses these factors
as they relate to determinations of overall operator and
institutional quality.
Evolution of Coronary Interventional Capabilities
The cognitive and technical knowledge base required for
proficiency in PCI has expanded. The fundamental concepts of coronary angioplasty technique, namely the coaxial
guide catheter and the dilation catheter with a minimally
compliant cylindrical balloon, were formulated by Andreas
Gruntzig (23). Because of the initial comparatively primitive
equipment design and capability, coronary angioplasty was
only applicable to readily accessible discrete proximal coronary stenoses. Subsequent refinement in instrumentation
has greatly enhanced procedural success and extended the
indications for the performance of PCI. Complex anatomic
situations now considered technically suitable for PCI
procedures include multivessel disease (24 –30), distal and
bifurcation stenoses, total occlusions (31), saphenous vein
graft stenoses (32), and complex stenoses. Challenging
clinical situations now considered appropriate for coronary
intervention include patients with unstable angina (33,34)
and myocardial infarction (MI) (35,36) and those who are
not considered candidates for coronary bypass surgery.
Nonballoon devices, including coronary stents, and directional, rotational, and laser atherectomy devices, have been
introduced. These devices augment conventional balloon
angioplasty and extend its capability; however, they all
require specific training and mentoring by a previously
experienced operator. To become competent in the use of
any of these newer interventional devices, an operator must
acquire the additional knowledge and technical skills specific to each device.
A number of adjunctive antithrombotic and antiplatelet
medications have been introduced for the purpose of reducing acute thrombus-related treatment site complications.
Understanding the appropriate indications for and complications associated with the use of these medications, which
are powerful anticoagulants, requires knowledge of hemostatic mechanisms.
Procedural Success and Complications
of Coronary Interventional Procedures
Recent clinical studies have demonstrated that despite a
continuing increase in clinical and angiographic complexity,
procedural and clinical success rates have remained high and
complication rates have remained low (37– 45) (Table 1).
Angiographic success occurs in over 95% of patients.
Among patients without ST-segment elevation myocardial
infarction (STEMI), PCI is associated with an average
mortality rate of less than 1%, a Q-wave MI rate of less than
1%, and an emergency coronary artery bypass surgery
(CABG) rate of less than 1%. Table 1 contains data from 5
large contemporary registries of PCI procedures and the
first 2 National Heart, Lung, and Blood Institute (NHLBI)
registries for historical comparison. These data constitute a
point of departure for developing benchmarking standards.
Adverse events related to PCI procedures are categorized
either by the mechanism of the complication or by the
adverse event caused by the procedure. A given adverse
event, such as death, may be caused by a variety of
complications.
Complications can be divided into 3 mechanistic categories:
1. Coronary vascular injury. Coronary arterial injury can
occur when devices are introduced into coronary vessels
or result from embolization of thrombotic or atherosclerotic material from devices or vessel walls. Examples
include coronary dissection, thrombosis, perforation, and
embolization.
2. Other vascular events. Other vascular events are caused
either by injury to a peripheral vessel by catheter insertion, manipulation, or removal, or by embolization of
thrombotic or atherosclerotic material. Examples include
pseudoaneurysm, retroperitoneal hemorrhage, arteriovenous fistula, and stroke.
3. Systemic nonvascular events. Systemic nonvascular adverse events are caused by the procedure but are not due
to vascular injury. They include all the systemic hazards
of cardiovascular radiographic angiography procedures.
Examples include contrast agent-induced nephropathy
and acute pulmonary vascular congestion.
For the purpose of assessing clinical competence, complications may be divided into 8 basic outcome categories:
1.
2.
3.
4.
5.
6.
7.
8.
Death: related to the procedure, regardless of mechanism
Stroke
MI: related to the procedure, regardless of mechanism
Ischemia requiring emergency CABG: either as a result
of procedure failure or a procedure complication
Vascular access site complications
Contrast agent nephropathy
Excessive bleeding, requiring treatment
Other (such as coronary perforation and tamponade)
The first 4 of these categories are generally considered
major adverse cardiac and cerebral events (MACCE). Be-
Reprinted with permission from Smith SC Jr., Feldman TE, Hirshfeld JW Jr., et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention—summary article: a report of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006;47:216 –35 (15).
ACC ⫽ American College of Cardiology; CABG ⫽ coronary artery bypass graft surgery; MCD ⫽ multicenter database; MI ⫽ myocardial infarction; NA ⫽ not available; NHLBI ⫽ National Heart, Lung, and Blood Institute.
0.54
3.25
0.20
0.36
0.51
1.27
1.17
0.4
0.4
1.33
1.2 unadjusted rate
1.00
1.0
1.2
3.40
5.80
Mortality (%)
94
2005: stented lesions: 99;
nonstented lesions: 86
93
91
68
Angiographic success (%)
Emergency CABG (%)
97.5
97.5
NA
53
0
Success and Complication Indicators
25
ST-segment elevation MI (%)
0
0
13
12
18.9
60
83.6
27.8
43
44
37
Unstable angina (%)
49
35
32.0
92.7
65
62
63
54
Mean patient age (yrs)
58
61
63
14,946
87.5
84.0
86
91.6
0
Stent use (%)
78
2001–2003
124,096
2002
36,831
5,901
2000–2004
1,082,690
6,183
1998–2005
1997–2002
1,802
1,155
No. of patients
1985–1986
1977–1981
Years of entry
Variable
NHLBI-1
(40)
NHLBI-2
(38,39)
Clinical Characteristics
Northern New
England
Consortium
(43)
ACC National
Cardiovascular Data
Registry
(42)
NHLBI
Dynamic
Registry
(41)
Table 1. Changes in Coronary Interventional Practice and Outcome From Registry Data
0
Emergent
Nonemergent
Michigan Blue
Cross
Consortium
(44)
New York State Registry
(45)
King et al
ACCF/AHA/SCAI Clinical Competence Statement
103
cause adverse events are definite end points, they are easily
recognized and captured for statistical summary purposes.
The ACC-National Cardiovascular Data Registry
(NCDR)® has developed a comprehensive data dictionary
with rigorous definitions of recognized adverse events (46).
It may be impossible to determine conclusively whether
death or a complication was caused by a procedure. Nonetheless, for the purposes of monitoring performance, rate of
complications or deaths substantially above that expected,
after adjustment for patient risk factors, is a cause for
concern.
Patient, Lesion, and Institutional Variables
Influencing Success and Complication Rates
A number of factors have improved the overall success and
complication rates of PCI procedures. These include increased operator experience, modifications in conventional
instrumentation (balloon catheters, guide catheters, guide
wires), newer interventional devices (stents and embolization protection devices), and advances in adjunctive pharmacologic therapy. Concurrently, these improvements have
led to the extension of interventional treatment to higherrisk patients with more complex coronary anatomy and
comorbid disease. These factors have influenced overall
acute and long-term outcome associated with PCI procedures.
Measures/Definitions of Success
Anatomic success. The definition of anatomic success
focuses exclusively on the enlargement of the lumen at the
target site and blood flow through the epicardial coronary
artery. Although there has been disagreement, the current
definition of success of PCI with stenting is the achievement of a minimal diameter stenosis of less than 20% as
visually assessed by angiography and maintenance of
Thrombolysis In Myocardial Infarction (TIMI) flow grade
3 (15). Anatomic success of PCI without stenting is defined
as stenosis diameter reduction greater than 20% with residual stenosis less than 50%. Notably, there is frequently a
disparity between the visual estimate of lumen diameter and
quantitative measurements (47,48).
Procedural success. Procedural success has been defined as
the achievement of anatomic success of all treated lesions
without the major complications of death, MI, or emergency CABG (14,40). Although emergency CABG during
hospitalization and death are easily identified end points,
the definition of periprocedural MI has been more problematic. Some definitions require the development of Q
waves in addition to a threshold value for creatine kinase
(CK) elevation. However, more recent reports have included
non-STEMIs with CK elevations greater than 3 or 5 times
the upper limit of normal as clinically significant, since they
have been shown to correlate with long-term mortality (49).
Although major adverse cardiac events (MACE) have been
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July 3, 2007
used to judge success, some recent studies also include
MACCE.
Short-term clinical success. Short-term clinical success
requires, in addition to procedural success, the relief of signs
and symptoms of myocardial ischemia.
Longer-term clinical success. Longer-term clinical success
requires that the initial clinical success remains durable and
that the patient has persistent relief of signs and symptoms
of myocardial ischemia for 6 to 9 months after the procedure. Restenosis remains the principal cause of a lack of
clinical success over the first year following a successful
procedure. This directly leads to target lesion revascularization (TLR), target vessel revascularization, and target vessel
failure. Thereafter, clinical events are usually caused by
progression of disease at other sites. Clinically important
restenosis may be judged by the frequency with which
subsequent TLR procedures are performed after the index
procedure. Incomplete revascularization, new lesion formation, and stent thrombosis may also limit long-term clinical
success, especially in subsequent years (50).
Patient and Lesion Characteristics Related to
Procedural Success and Complication Rates
Angioplasty procedural success and complication rates are
influenced by a variety of patient and target lesion characteristics. These characteristics must be taken into consideration through risk adjustment when assessing adverse event
rates. In addition, they must also be weighed in determining
procedure appropriateness.
Patient clinical characteristics. The clinical factors associated with an increased risk of an adverse outcome after
intervention include advanced age, female gender, acute
coronary syndrome (especially STEMI), chronic renal insufficiency, heart failure, and multivessel coronary disease
(7,12,14,15). Patients with impaired renal function, particularly patients with diabetes, are at increased risk for
contrast-induced nephropathy (51).
Target lesion anatomic factors. Particular lesion morphologic characteristics are predictive of immediate outcome
with coronary intervention (7,12,14,52). Lesion length,
presence of thrombus, and degenerated saphenous vein
grafts are independently associated with abrupt vessel closure and major ischemic complications. Chronic total occlusions (greater than or equal to 3 months) are associated
with a lower procedural success rate. On the basis of these
observations, a previous ACC/AHA Clinical Task Force on
Clinical Privileges in Cardiology (13) proposed a classification scheme based on lesion morphology to estimate the
likelihood of procedural success and complications. This
scheme was subsequently modified by others (52) and has
served as a useful guide for assessing the risk of an adverse
outcome associated with a particular lesion. More recent
experience indicates that improved devices and techniques
have higher success rates in more complex lesions (53–56).
As a result, lesion morphology may be less predictive of
complications currently than it has been in the past (57).
Strategies for Risk Stratification
and Operator Evaluation
Several large retrospective studies of patients undergoing
PCI have identified clinical and angiographic characteristics
that correlate with procedural success, in-hospital morbidity, and mortality (21,22,44) (Table 2). These observations
have been used to develop multivariate logistic regression
models that can stratify patients before the procedure.
Model reliability is best assessed by relative predictive
accuracy (C-statistic: moderate is greater than 0.80, excellent is greater than 0.90) and scaling accuracy (the HosmerLemeshow statistic). Several models predict periprocedural
mortality with C-statistic greater than 0.80 (Table 2).
Prediction of other events is typically less accurate (58 – 60).
Model utility also must consider the frequency and clinical
importance of the event measured. Very infrequently occurring events, even if severe, may not allow adequate evaluation of operators with low volume. Results of several years of
experience should be considered in order to have sufficient
numbers of events to be adequately assessed from a statistical standpoint. Operators and catheterization laboratories
should be encouraged to submit information to large databases that allow for evaluation of risk-adjusted outcomes.
Impact of the Facility on Procedural Success
Physical facility requirements. The physical facility in
which interventional procedures are performed has an important impact on procedural success. The facility must
provide radiologic equipment, monitoring, and patient support equipment to enable operators to perform at the best of
their ability. The video and “cine” image quality of radiologic imaging equipment must be optimal to facilitate
accurate catheter and device placement and enable proper
assessment of procedure results. Physiologic monitoring
equipment must provide continuous, accurate information
about the patient’s condition. Requisite support equipment
must be available and in good operating order to respond to
emergency situations.
Overall institutional system requirements. The interventional laboratory must have an extensive support system of
specifically trained laboratory personnel. Cardiothoracic
surgical, respiratory, and anesthesia services should be available to respond to emergency situations in order to minimize detrimental outcomes. The institution should have
systems for credentialing, governance, data gathering, and
quality assessment. Prospective, unbiased collection of key
data elements on consecutive patients and consistent feedback of results to providers brings important quality control
to the entire interventional program. The ACC/AHA/
SCAI 2005 Guideline Update for PCI (15) recommends
that each interventional program performing elective PCI
King et al
ACCF/AHA/SCAI Clinical Competence Statement
105
Table 2. Odds Ratios* for Significant Independent Risk Factors† for Short-Term Mortality Related to PCI
Source
No. of patients
New York
State
50,046
Northern
New England
15,331
Michigan
BMC2
10,796
ACC-NCDR
100,253
ACC-NCDR Update
No acute MI
Acute MI
(142,817)
(30,926)
COAP
19,358
Incidence (%)
0.58
1.1
1.6
1.4
N/A
N/A
1.6
Years
2003
1994–1996
1997–1999
1998–2000
1998–2001
1998–2001
1999–2000
Acute MI less than 12–24 h
8.6
5.5
2.8
1.3
Age
⫹
⫹
⫹
⫹
⫹
⫹
⫹
3.2
8.6
1.3
1.7
1.5
1.8
1.4
1.25
Clinical
Cardiac arrest
CHF
3.7
1.6
COPD
Diabetes
Female
⫹
1.5
IABP pre
1.8
26.2
Peripheral vascular disease
2.6
Prior CABG
1.4
3.3
1.4
1.7
1.9
1.6
⫹
1.6
⫹
⫹
⫹
⫹
Renal insufficiency
3.1
6.4
5.5
3.0
3.5
2.0
3.5
Shock
22.1
32.2
11.5
8.5
9.8
8.8
9.8
⫹
Priority (salvage, emergent urgent, elective)
Anatomic
ACC lesion score, C
2.9
⫹
⫹
⫹
2.0
1.5
2.1
Prox LAD lesion
2.0
1.3
1.3
SCAI lesion score
⫹
⫹
⫹
Ejection fraction
⫹
⫹
LMT lesion
Number of diseased vessels
⫹
⫹
⫹
⫹
Thrombus
Procedural
Lytic use
1.4
Nonstent use
1.6
1.6
1.4
0.89
0.85
0.87
C-statistic
0.905
0.88
0.90
1.25
0.87
*Values are odds ratios for binary variables unless otherwise noted; †specific definitions of risk factors may vary from series to series; ⫹relationship exists for continuous or ordinal variables (61– 66).
ACC-NCDR ⫽ American College of Cardiology National Cardiovascular Data Registry; BMC2 ⫽ Blue Cross Blue Shield of Michigan Cardiovascular Consortium; CABG ⫽ coronary artery bypass graft;
CHF ⫽ congestive heart failure; COAP ⫽ clinical outcome assessment program; COPD ⫽ chronic obstructive pulmonary disease; IABP ⫽ intra-aortic balloon pump; LAD ⫽ left anterior descending; LMT
⫽ left main trunk; MI ⫽ myocardial infarction; PCI ⫽ percutaneous coronary intervention; SCAI ⫽ Society for Cardiovascular Angiography and Interventions.
should have in-house surgical support. Institutions that do
not have in-house surgical support and are performing
primary PCI only for STEMI, should have an established,
well-organized system for emergency transfer to surgery at
another institution.
Components of Operator Competence
Cognitive Knowledge Base
The knowledge needed to perform PCI, including that
expected to be acquired in ACGME-approved interventional training programs, has been addressed by expert
panels (7,8,20,67,68). The core knowledge is now tested by
the ABIM Interventional Cardiology certifying examination which has been administered since 1999. Through
2003, physicians trained by a nontraditional pathway were
eligible to take the examination based on either practicebased procedure activity and experience or by completion of
an interventional training program. Since 2003, only individuals who have completed an ABIM-qualified training
program are eligible to take the certifying examination.
Individuals who train in interventional cardiology should
become ABIM certified in interventional cardiology.
Training programs and the qualifying examination
(20,69) require that interventional cardiologists be knowledgeable in anatomy, physiology, and pathophysiology of
the cardiovascular system. In particular, one should understand the biology of coronary artery disease, be knowledgeable about the pathophysiology of myocardial ischemia and
MI, and understand the dynamics of cardiac dysfunction.
Interventionalists should possess a fundamental knowledge
of stents and be familiar with the polymers and drugs that
are incorporated into stents, coagulation cascade, thrombosis, and the pharmacology, therapeutic application, and risks
of antiplatelet, antithrombin, and fibrinolytic drugs that are
used in association with PCI. Competent operators must
have knowledge of the indications for PCI and adjunctive
and alternative use of medical therapy and surgery for
patients with coronary artery disease based on an in-depth
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understanding of published clinical trials. Coronary interventionalists must understand the role of primary angioplasty compared with fibrinolytic therapy for STEMI and
the alternative therapeutic approaches for treating STEMI
that depend upon the time of presentation, anticipated
door-to-balloon time, and the presence or absence of
ongoing symptoms and/or electrocardiographic abnormalities.
Cognitive knowledge must be bolstered by clinical skills
and experience that support the rational selection of optimal
treatment strategies for each patient. Such decisions are
based on symptoms, anatomy, and associated risk factors.
Thus, equally important to knowing the indications for PCI
is an understanding of its limitations and contraindications,
particularly as these relate to comorbid systemic diseases and
special anatomical subsets. Physicians performing these
procedures should be conversant with the applicable guidelines (e.g., PCI, CABG, STEMI, unstable angina/
NSTEMI [15,70 –72]).
Coronary interventionalists must also have a thorough
knowledge of specialized equipment, techniques, and devices used to perform PCI competently, including:
1. The theoretical and practical aspects of X-ray imaging,
radiation physics and safety, and other equipment to
generate digital images; quality control of images; image
archiving; consequences of exposure of patients and
personnel to ionizing radiation; and methods of reducing
patient and staff radiation exposure (73).
2. Specialized catheterization recording and safety equipment (physiological data recorders, pressure transducers,
blood gas analyzers, defibrillators) (74).
3. Catheters, guide wires, balloon catheters, stents,
atherectomy devices, ultrasound catheters, intra-aortic
balloon pumps, puncture site sealing devices, contrast
agents, distal protection devices, and thrombus extraction devices.
Operators must be knowledgeable about the prevention,
prompt recognition, and treatment of procedural complications. It is extremely important to have the knowledge and
skills to diagnose and manage vessel perforation, no reflow,
coronary dissection, expanding hematoma, pseudoaneurysm, arterial venous fistulas, and retroperitoneal hemorrhage. Interventionalists must also be cognizant of systemic
complications, including cerebrovascular events and
contrast-related nephropathy.
Technical Skills
Many of the skills required to perform coronary interventional procedures are closely related to those needed to
perform diagnostic cardiac catheterization and coronary
angiography. These include manual dexterity and the ability
to obtain percutaneous arterial and venous access and
maintain sterile surgical technique.
Most of the other required technical skills are unique to
coronary interventional procedures and can only be acquired
during training and by performing actual procedures under
the direction of an experienced interventionalist. These
include the manipulation and operation of guide catheters,
coronary angioplasty guide wires, coronary angioplasty balloon catheters, specialized atherectomy devices, stents, and
intracoronary ultrasound catheters. Such training appropriately occurs in standardized training programs that are
ACGME-approved and lead to eligibility for board
certification.
Nonballoon Devices
A special area of competence involves use of lesion assessment tools. Intracoronary devices commonly used by interventional cardiologists for assessment of intraluminal coronary anatomy and/or physiology include intravascular
ultrasound (IVUS) or intracoronary ultrasound (ICUS),
Doppler flow wires, and pressure wires. Competency in the
use of angioscopy, optical coherence tomography, spectroscopy, intravascular thermography, and intravascular magnetic resonance imaging is beyond the scope of this document. Expertise in device manipulation and image
interpretation is required to use these intravascular assessment devices safely and effectively. The risks of these devices
is the same as those with PCI and include vessel spasm;
myocardial ischemia; coronary artery dissection; plaque
disruption; thrombosis; air, plaque, or thrombotic embolization; acute occlusion; coronary artery perforation; and
contrast nephropathy, stroke, and access site complications.
Therefore, only an interventional cardiologist skilled in
transluminal coronary techniques such as balloon angioplasty and stenting who is able to diagnose and treat
complications of interventional procedures should employ
these devices. Recommendations regarding the use of
IVUS, Doppler flow wires, and pressure wires are published
in Appendix C of the ACC/AHA Guidelines for Coronary
Angiography (75).
It is also important to ensure quality image acquisition,
measurement, and reporting for each of the intravascular
assessment devices. For ICUS, the reader is referred to the
ACC Clinical Expert Consensus Document on Standards
for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (76). No such documents are
available for Doppler analysis of coronary flow reserve and
pressure wire analysis of fractional flow reserve, but many of
the general principles in the IVUS document may be of
some benefit in guiding appropriate use of these other
modalities.
Relationships of Operator and Institutional
Experience and Activity to Outcomes
in Coronary Interventional Procedures
Evidence Reviewed
Computerized literature searches of English language publications, review of recent abstract publications, and solicitation of manuscripts under review for publication from
King et al
ACCF/AHA/SCAI Clinical Competence Statement
107
Table 3. Published Data Relating Hospital Coronary Angioplasty Volume to Complication Rates
Data Source
No. of Patients/
Hospitals Studied
Hartz et al. (78)
1989–1991 Wisconsin Medicare
2,091/16
No relation between volume and outcome
Ritchie et al. (86)
1989 California State (Adm)
24,883/110
Increased CABG (not death) less than 20
cases per yr; finding is valid for both
acute MI and nonacute MI patients
Jollis et al. (85)
1987–1990 MEDPAR (Adm)
217,836/1,194
Kimmel et al. (84)
1992–1993 SCAI
GUSTO (llb) Angioplasty
Substudy Group (36)
GUSTO llb trial
Kato et al. (79)
1991 HCFA (RAND Corp.)
Stone et al. (80)
PAMI II trial
Jollis et al. (77)
1992 Medicare (Adm)
Tiefenbrunn et al. (83)
Second National Registry of MI
(U.S.)
Hannan et al. (82)
1991–1994 NY State
Zahn et al. (81)
Study
19,594/48
565/59
Conclusions
Comments
Very low number of cases
and hospitals examined
Death and CABG increased with low
volume (risk increases with Medicare
patient volume* (less than 100–200
total per yr for death, 200–300 per yr for
CABG)
Fewer major complications for labs with
greater than 400 cases per yr
Able to risk adjust more
completely than most
other analyses
No difference, 200–625 vs. greater than
625 cases per yr for acute MI patients
All operators greater than or
equal to 50 cases per yr
113,576/862
Except for Medicare volume* less than 50,
higher volume hospitals had higher
mortality rates
1,100/34
No difference, less than 500, 501–1,000,
greater than 1,000 cases per yr for
acute MI patients
97,498/984
Incremental decrease in death and bypass
surgery as hospital Medicare volume*
less than 100, 100–200, greater than
200 per yr
4,939/?
Increased acute MI mortality for hospital
less than 25 acute MI cases per yr
62,670/31
Death alone and same-stay CABG
increased with annual caseloads less
than 600
Risk-adjusted
1992–1995 German Hospital
Consortium
4,625/?
For patients with acute MI; increased
mortality in hospitals with less than or
equal to 40 acute MI PTCA per yr
No risk-adjusted
Moscucci et al. (22)
1998–1999 NY State and MI
11,374/8
In-hospital death increased for hospital
volume less than 400
Risk-adjusted
Hannan et al. (21)
1998–2000 NY State
Death, same-day CABG, same-stay CABG
increased for hospital volume less than
400
Risk-adjusted
107,713/34
*Medicare patients usually constitute 35% to 50% of total interventional caseload.
Adm ⫽ administrative data set; CABG ⫽ coronary artery bypass graft; GUSTO ⫽ Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes; HCFA ⫽ Health Care
Financing Administration; MEDPAR ⫽ Medicare provider analysis and review; MI ⫽ myocardial infarction; PAMI ⫽ Primary Angioplasty in Myocardial Infarction; PTCA ⫽ percutaneous transluminal coronary
angioplasty; SCAI ⫽ Society for Cardiovascular Angiography and Interventions.
many physicians and epidemiologists expert in the field were
used to compile the relevant available scientific evidence
relating institutional and operator activity level to outcomes
(Table 3). In general, greater weight was given to recent,
fully peer-reviewed publications of high quality. No single
work was considered definitive. It was recognized that many
analyses were limited to some extent by lack of capacity to
fully adjust expected outcomes for differences in patient
characteristics, changes and advances in the field of interventional cardiology, and inability to generalize the results
to a broader population.
Relationship of Institutional Volume
to Procedural Outcome
The preponderance of data suggest that, on average, hospitals in which fewer coronary interventions are performed
have a greater incidence of procedure-related complications,
notably death and need for bypass surgery for failed intervention, than hospitals performing more procedures. Multiple data sources support the existence of a curvilinear,
perhaps logarithmic, statistical relation between caseload
and outcome (Fig. 1). However, for CABG, the continued
importance of the relationship between volume and outcomes has been recently confirmed using contemporary
clinical data (87). For PCI, the majority of the studies
available either predate the widespread introduction in
interventional practice of coronary stenting and adjunctive
use of glycoprotein receptor blockers, or were obtained
through analysis of Medicare claims data or other administrative data. Recognized limitations of Medicare data
include the need to extrapolate the total number of proce-
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Circulation
July 3, 2007
2.0
1.8
Risk-Adjusted Mortality Rate (%)
1.6
1.4
1.2
1.0
State-Wide Rate
0.8
0.6
0.4
0.2
0.0
0
200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000
Mean Annual Volume
Figure 1. Mean Annual Hospital PCI Volume and Risk-Adjusted In-Hospital Mortality Rate in New York State, 1998 –2000
Reprinted with permission from Hannan EL, Wu C, Walford G, et al. Volume-outcome relationships for percutaneous coronary interventions in the stent era. Circulation 2005;
112:1171–9 (21). PCI ⫽ percutaneous coronary intervention.
dures from the number of Medicare procedures, the incomplete reporting in Medicare claims of comorbidities that
might be important predictors of adverse outcomes (16,17),
and the possibility of miscoding complications as comorbidities (18).
The direct relationship between institutional volume and
outcomes has been recently confirmed by 2 more contemporary analyses of large clinical registries. The first study
compared data collected between 1998 and 1999 in a
multicenter PCI registry in Michigan with data from the
New York State data registry (22). An institutional annual
volume less than 400 cases per year was found to be
independently associated with an increased risk of inhospital death compared with hospitals with annual volumes
of at least 400 (adjusted odds ratio [OR] 1.77, 95%
confidence interval [CI] 1.16 to 2.70). The second study
(21), based on the New York State data registry, evaluated
107,713 procedures performed in 34 hospitals in New York
State during 1998 to 2000. The same hospital volume
threshold of less than 400 procedures per year was found to
be associated with an increased risk of in-hospital mortality
(adjusted OR 1.98, 95% CI 1.17 to 3.35), “same day”
CABG surgery (adjusted OR 2.07, 95% CI 1.36 to 3.15) or
“same stay” CABG surgery (adjusted OR 1.51, 95% CI 1.03
to 2.21). Figure 1 from the New York study presents the
continuous relationship between hospital volume and riskadjusted in-hospital mortality.
It is important to underscore that advancements in
technology have resulted in a progressive improvement in
outcomes of PCI, and that this improvement has at least in
part offset the adverse institution volume– outcome relationship. In a recent study evaluating temporal trends in the
volume– outcome relationship in the state of California, it
was found that over time, the disparity in outcomes between
low- and high-volume hospitals had narrowed, and that
outcomes had improved significantly for all hospitals (88).
The author of this study concluded that given these improvements, lower minimum volume standards might be
justifiable in less populated areas, where the alternative is no
access to angioplasty at all. Importantly, procedural volume
is only one of many factors contributing to the variability of
measured outcomes (58,82,89). Furthermore, there is no
clear “cut-off ” above or below which hospitals, or groups of
hospitals in aggregate, perform well or poorly. There are
institutions with low volumes that appear to achieve very
acceptable results. For an individual institution, however,
such an impression must be tempered by the statistical
imprecision of the estimate of risk.
Volume and Outcomes Relationship
for Primary PCI in Acute MI
The relationship between operator and institutional volume
and outcome of primary PCI for acute MI has been
examined nearly exclusively at hospitals with onsite cardiac
surgery. In an analysis including 62,299 patients with acute
MI and enrolled in the National Registry of Myocardial
Infarction, Magid et al. (90) analyzed data from 446
acute-care hospitals providing primary angioplasty services.
Hospitals were classified as low volume (less than 16
procedures per year), intermediate volume (17 to 48 procedures per year), and high volume (more than 49 procedures
per year). In high-volume hospitals, mortality for acute MI
patients was significantly lower with primary angioplasty
when compared with fibrinolysis, while in low-volume
hospitals, there were no differences in mortality rates between primary angioplasty and fibrinolysis. Two other
King et al
ACCF/AHA/SCAI Clinical Competence Statement
analyses from the same registry and 2 studies using the New
York State data registry have shown a direct relationship
between hospital volume of primary angioplasty and mortality. In the analysis by Canto et al. (91), hospital volume
was divided in quartiles. In-hospital mortality was 28%
lower in patients treated in the highest volume quartile
(greater than 33 primary PCIs per year) when compared
with patients treated in the lowest volume quartile (less than
12 primary PCIs per year). Similar results were obtained by
Cannon et al. (92). In this analysis, a procedure volume
greater than 3 PCIs per month was found to be associated
with a lower in-hospital mortality rate when compared with
a procedure volume of less than 1 PCI per month, or with
a procedure volume between 1 and 3 PCIs per month.
Recently, Hannan et al. (21) reported data from the New
York State Coronary Angioplasty Reporting System Registry collected in the years 1998 to 2000, a period when
stenting was used in a large majority of the STEMI
patients. A trend toward an increased odds ratio of inhospital mortality was observed for low-volume operators
when compared with high-volume operators both for a
volume cut of 8 procedures per year (OR 1.40, 95% CI 0.89
to 2.20) and with a volume cut of 10 procedures per year
(OR 1.27, 95% CI 0.87 to 1.87). Importantly, a significant
increase in the odds of in-hospital mortality was observed
with lower institutional volume of primary PCI, regardless
of whether the institutional volume cut point was set at 36
procedures per year (OR 2.01, 95% CI 1.27 to 3.17), 40
procedures per year (OR 1.73, 95% CI 1.1 to 2.71), or 60
procedures per year (OR 1.45, 95% CI 1.01 to 2.09).
Volume and outcomes relationship for PCI in hospitals
without onsite cardiac surgery. There is only 1 report
indicating a relationship between institutional PCI volume
and outcome in hospitals without onsite cardiac surgery.
Wennberg et al. (93) reported that among Medicare recipients, there was no difference in mortality after primary/
rescue PCI (emergency procedure on the same day for
STEMI) performed at hospitals with or without cardiac
surgery onsite. However, they did report a higher mortality
for PCI patients, excluding primary/rescue PCI, at hospitals
without cardiac surgery onsite (adjusted OR 1.38, 95% CI
1.14 to 1.67; p ⫽ 0.001). The relationship between institutional volume and PCI affecting this outcome was confined mainly to hospitals without cardiac surgery onsite
performing 50 or fewer nonprimary/rescue PCIs in Medicare recipients per year. Among hospitals performing more
than 100 PCIs in Medicare recipients, mortality was not
higher in hospitals without surgery onsite (adjusted OR
0.76, 95% CI 0.52 to 1.11; p ⫽ 0.16). These hospitals likely
perform more than 200 PCIs per year based on the
assumption that 100 Medicare PCIs represent approximately 200 total PCIs per year.
Taken together, these data suggest that the relationship
between institutional volume of PCI patients (excluding
primary/rescue PCI) and mortality in hospitals without
109
surgery onsite may be similar to the relationship in hospitals
with surgery onsite. For facilities without onsite surgery, it
is mandatory that there be an established, well-organized
plan for transfer for surgery if needed.
Relationship of Individual Operator Volume to
Procedural Outcome
Several large studies have assessed the potential relation
between individual operator caseload and procedural complications (93). Recently, McGrath et al. (94) analyzed
relatively contemporary data (calendar year 1997) from the
Medicare database. Based on a slightly different assumption
than Wennberg et al. (93) that Medicare patients represent
35% to 45% of total PCI procedure volume, they estimated
that 30 PCIs per operator per year on Medicare patients
could be extrapolated to a total procedure volume of 70
PCIs per operator per year (94). A significant relationship
between operator volume and outcomes was also reported in
their study, with better outcomes observed in patients
treated by high-volume operators when compared with
patients treated by low-volume operators. Similar results
were obtained in the study by Hannan et al. (21) in the
analysis of data collected from the 107,713 procedures
performed in the 34 hospitals performing PCI in New York
State during 1998 to 2000. Operator volume thresholds
were set at 75 procedures per year based on ACC/AHA
recommendations, and at slightly higher levels of 100 and
125 procedures per year. There were no differences in
risk-adjusted mortality between patients undergoing PCI
performed by lower volume operators and patients undergoing PCI performed by higher volume operators for any of
the 3 volume thresholds that were examined. However, for
all 3 volume thresholds, significant differences for “same
day” CABG surgery and for “same stay” CABG surgery
were observed. For example, patients undergoing PCI with
operators performing less than 75 procedures per year had a
65% increased odds of undergoing same-day CABG surgery, and a 55% increased odds of undergoing “same-stay”
CABG surgery.
Further confirmation of the adverse operator volume–
outcome relationship with contemporary PCI comes from
an analysis by Moscucci et al. (95) of another regional,
audited, clinical PCI registry. In that analysis including
18,504 procedures performed in 14 Michigan hospitals in
calendar year 2002, operator volume was subdivided in
quintiles (1 to 33 PCIs per year, 34 to 89 PCIs per year, 90
to 139 PCIs per year, 140 to 206 PCIs per year, and 207 to
582 PCIs per year). The primary end point was a composite
of MACE, including death, CABG, stroke, transient ischemic attack, MI, and repeat PCI at the same lesion site.
Stent utilization was greater than 80%, and greater than
70% of patients received a glycoprotein (GPIIb/IIIa) receptor
inhibitor. After adjustment for comorbidities, patients
treated by operators in the 2 lower volume quintiles (Quintiles 1 and 2) had a 63% increase in the odds of MACE
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Adjusted Odds ratios for MACE in Quintiles of Operator Volume vs. Quintile 5
(Clustering model by Hospital)
2.5
Adjusted OR and 95% CI
2
**
1.63
**
1.63
1.5
1.24
1.10
1
1
0.5
0
Quintile 1
Quintile 2
Quintile 3
Quintile 4
Quintile 5
1-33
34-89
90-139
140-206
207-582
Quintiles of Operator Volume with Ranges. ** P<0.0001
Figure 2. Adjusted Odds Ratios for MACE by Quintile of Operator Volume
Reprinted with permission from Moscucci M, Share D, Smith D, et al. Relationship between operator volume and adverse outcome in contemporary percutaneous coronary
intervention practice: an analysis of a quality-controlled multicenter percutaneous coronary intervention clinical database. J Am Coll Cardiol 2005; 46:625–32 (95). MACE ⫽
major adverse cardiac events.
(Fig. 2). No significant relationship was observed between
operator volume and risk of in-hospital death. The adverse
relationship between operator volume and outcomes appeared to be relatively independent of patient risk. A
detailed analysis of individual operator risk-adjusted outcomes revealed the presence of several low-volume operators
with better than expected outcomes, and of a few highvolume operators with worse than expected outcomes, thus
suggesting that there are exceptions to the rule, and that
low-volume operators should be tracked over a longer
period of time to ascertain their true performance (Fig. 3).
Combination of Individual Operator Volume and
Institutional Volume on Procedural Outcome
The combined impact of hospital volume and operator
volume on adverse outcomes was assessed by Hannan et al.
(21). Patients undergoing PCI performed by operators with
volumes below 75 per year in hospitals with volumes below
400 per year were found to have significantly higher odds of
dying in the hospital than patients undergoing PCI performed by operators with volumes of 75 or more in hospitals
with volumes of 400 or more (OR 5.92, 95% CI 3.25 to
Figure 3. Linear Plot of Standardized MACE Ratios (Observed/Predicted Rates) Versus Annual Operator Volume
Reprinted with permission from Moscucci M, Share D, Smith D, et al. Relationship between operator volume and adverse outcome in contemporary percutaneous coronary
intervention practice: an analysis of a quality-controlled multicenter percutaneous coronary intervention clinical database. J Am Coll Cardiol 2005; 46:625–32 (95). MACE ⫽
major adverse cardiac events.
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ACCF/AHA/SCAI Clinical Competence Statement
10.97). Also, patients undergoing PCI performed by operators with annual volumes of below 75 in hospitals with
annual volumes below 400 experienced significantly higher
same-day CABG rates than patients with high-volume
operators (greater than 75 annually) in high-volume hospitals (greater than 400 annually), with an OR of 4.02. For
same-stay CABG surgery the respective OR was 3.19. It
should be noted that the magnitude of these ORs demonstrates that the increase in adverse outcomes compound
when patients undergo PCIs performed by low-volume
operators (less than 75 annually) in low-volume hospitals
(less than 400 annually).
In summary, analysis of more contemporary data supports
the hypothesis that technological advancements have not
completely offset the influence of “practice” in determining
proficiency of contemporary PCIs. However, procedure
volume is only a poor substitute for quality and outcomes;
therefore, it should not be used as a replacement for
appropriately risk-adjusted outcomes. Nevertheless, it is
easy to measure, and its potential implications are easily
understood by patients undergoing PCI. As such, it seems
appropriate to continue to include procedure volume among
the several indirect quality indicators of contemporary PCI
practice.
However, it is also important to underscore that there are
significant limitations to the simplistic interpretation of
procedure volume statistics as a measure of competence and
quality. First, it is uncertain whether this relationship is a
result of the “practice makes perfect” principle, or the fact
that patients are more frequently referred to high-quality
operators. Second, it remains unclear where the “cut-off”
number should be set. Third, studies have shown significant
variability in the volume– outcome relationship within the
same registry, with some low-volume operators having
better than expected outcomes, and a few high-volume
operators having worse-than-expected outcomes. Furthermore, at present, few or no data exist linking operator
volume to case selection, appropriateness of procedures,
periprocedural MI, long-term clinical outcome, or costeffectiveness, each of which measures a component of
quality of care, or linking clinical outcomes to operator
experience as measured by the number of years in practice,
total procedure volume over a lifetime career, or board
certification.
The development of national, regional, and state registries for outcome assessment is also promoting a shift of the
paradigm surrounding quality of PCI from a mere collection
of procedure volume to objective assessment of clinical
outcomes. In addition, the past decade has been characterized by substantial advancement in methodology, scientific
rigor, and acceptance of risk adjustment. Factors related to
in-hospital mortality following PCI are now well defined,
and progress is being made toward the development of
statistical models for other outcomes. Clearly, the calculation of risk-adjusted outcomes using data from clinical
registries is a more accurate way to assess outcomes than
111
using volume as a surrogate, and as more registry data
become available, procedure volume will likely no longer be
used as a replacement or a surrogate for quality assessment.
Yet, limitations related to the effect of random variation
and to the evaluation of rare events continue to exist. These
limitations make it difficult to assess the true performance of
very-low-volume operators. In such situations, close scrutiny of case selection and close monitoring of outcomes on
a case-by-case basis might serve as a substitute/complement
to risk adjustment.
In summary, while there are inherent limitations in using
procedure volume as a surrogate of quality and outcomes,
recent data suggest that there is still a relationship between
experience and outcomes. In the analysis of the New York
State data, the relationship appeared to be at a level of 75
procedures per year, with further improvement in outcomes
observed at a volume threshold of greater than 100 procedures per year. In the analysis of the Michigan data, the
relationship was at a level of 100 procedures per year. On
the basis of these data, it is recommended that the operator
volume threshold continue to be 75 procedures per year.
Independent of procedure volume, all operators should
participate in a regional or national program for outcome
assessment and quality improvement. In addition, it is
recognized that there are limitations in the application of
the risk-adjustment methodology in the evaluation of rare
events and of low-volume operators, and that there might be
substantial variations in the volume– outcome relationship.
For operators that do not meet a threshold of 75 cases per
year measured in 2-year intervals, it is recommended that a
case-by-case review, case selection, and prior experience
including the total number of cases in a lifetime career be
included in their evaluation. They could also partner with
higher volume operators to perform cases together to gain
further experience.
Ongoing Quality Improvement and
Maintenance of Competence
Maintenance of competence in interventional procedures
should be accomplished for both the individual physician
operator and for the institutions in which cardiac interventional procedures are performed. The goals in setting
criteria for maintaining competence include:
1. Ensuring quality of patient care and outcomes;
2. Enabling quality interventionalists and institutions to
continue to perform PCI;
3. Providing standards that all institutions and operators
should strive to achieve.
Institutional Maintenance of Quality
It is recommended that all institutions have a regular (at
least monthly) catheterization laboratory conference. The
opportunity for ongoing dialogue and collaboration among
angiographers, interventional operators, and cardiothoracic
surgical colleagues is highly desirable. New developments in
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July 3, 2007
the angioplasty literature should be reviewed, and procedural complications should be discussed.
Maintenance of competence also requires that patient
outcomes be determined longitudinally for each procedure
by the institution’s quality assessment program. Participation in a state, regional, or national database is highly
encouraged. This allows institutions to measure riskadjusted outcomes and compare them to regional and
national benchmarks for improving quality of care.
It is recommended that lower volume institutions (less
than 400 interventions per year) consider holding conferences with a partnering, more highly experienced institution. It is also recommended that any institution that falls
outside the risk-adjusted national benchmarks in mortality
or emergency same-stay CABG during 2 of 3 contiguous
6-month periods have an external audit looking for opportunities to improve quality of care.
Individual Maintenance of Quality
To maintain a cognitive knowledge base, it is recommended
that individual operators attend at least 30 h of interventional cardiology continuing medical education (CME)
every 2 years. This could include catheterization conferences
and PCI meetings in addition to expanding the use of
simulation cases for procedure use and competence.
To ensure appropriate patient selection and quality of
technical skills, it is recommended that all operators have 5
randomly selected cases and all major complications reviewed each year by the catheterization laboratory director
or a Quality Assessment Committee at the institution. Any
operator performing less than 75 cases per year should have
10 cases reviewed per year. These performance evaluations
should include feedback to the operator. If it is determined
that the quality of PCI care being provided does not meet
national benchmarks, the catheterization laboratory director
should have the discretion of making recommendations for
improving quality and reassessing over the next 6 months. If
disagreements concerning corrective action occur, external
review is often helpful.
Quality Assurance
Definition of Quality in PCI
Satisfactory quality in PCI may be defined as selecting
patients appropriately for the procedure and achieving
risk-adjusted outcomes that are comparable to national
benchmark standards in terms of procedure success and
adverse event rates. To achieve optimal quality and outcomes in PCI it is necessary that both the physician operator
and the supporting institution be appropriately skilled and
experienced.
Institutional Quality Assurance Requirement
In the United States, responsibility for quality assurance is
vested in the health care institution that is responsible to the
public to ensure that patient care conducted under its
jurisdiction is of acceptable quality. Quality assessment
review should be conducted both at the level of the entire
program and at the level of the individual practitioner.
Each institution that performs PCI must establish an
ongoing mechanism for valid peer review of its quality and
outcomes. The program should provide an opportunity for
interventionalists as well as physicians who do not perform
angioplasty, but are knowledgeable about it, to review its
overall results on a regular basis. The review process should
tabulate the results achieved both by individual physician
operators and by the overall program and compare them to
national benchmark standards with appropriate risk adjustment. Valid quality assessment requires that the institution maintain meticulous and confidential records that
include the patient demographic and clinical characteristics necessary to assess appropriateness and to conduct
risk adjustment.
Role of Risk Adjustment in Assessing Quality
A raw adverse event rate that is not appropriately risk
adjusted has little meaning. Data compiled from large
registries of procedures performed in recent years have
generated multivariate risk adjustment models for adverse
event rates for PCI in the current era. Six multivariate
models of the risk of mortality following PCI have been
published (62,64,96 –99).
Although these models differ somewhat, they are consistent in identifying acute MI, shock, and age as important
risk stratification variables for mortality. The ACCNCDR® reported an univariate in-hospital mortality of
0.5% for patients undergoing elective PCI, mortality of
5.1% for patients undergoing primary PCI within 6 h of the
onset of STEMI and mortality of 28% for patients undergoing PCI for cardiogenic shock (64). Thus, it is clear that,
in order to assess PCI mortality rates, patients should be
stratified by whether they are undergoing elective PCI,
primary PCI for acute STEMI without shock, or primary
PCI for STEMI with shock.
Challenges in Determining Quality
Given the complexity of case selection and procedure
conduct, quality is difficult to measure in PCI and is not
determined solely by adverse event rates even when properly
risk adjusted. Accurate assessment of quality becomes more
problematic for low-volume operators and institutions because absolute event rates are expected to be small. Thus,
particularly in low-volume circumstances, quality may be
better assessed by an intensive case-review process conducted by recognized experts who can properly judge all of
the facets of the conduct of a case. Case review also has
merit in high-volume situations as it can identify subtleties
of case selection and procedure conduct that may not be
reflected in pooled statistical data.
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113
Table 4. Key Components of a Quality Assurance Program
Clinical proficiency
●
General indications/contraindications
●
Institutional and individual operator complication rates, mortality, and emergency coronary artery bypass grafting
●
Institutional and operator procedure volumes
●
Training and qualifications of support staff
Equipment maintenance and management
●
Quality of laboratory facility (see ACC/SCAI Expert Consensus Document on Catheterization Laboratory Standards [100])
Quality improvement process
●
Establishment of an active concurrent database to track clinical and procedural information and patient outcomes for individual operators and the institution.
Participation in multicenter database is highly encouraged.
Radiation safety
●
Educational program in the diagnostic use of X-ray
●
Patient and operator exposure
Requirement for Institutional Resources and Support
A high-quality PCI program requires appropriately trained,
experienced, and skilled physician operators. However, the
operator does not work in a vacuum. An operator needs a
well-maintained high-quality cardiac catheterization facility
to practice effectively. In addition, the operator depends on
a multidisciplinary institutional infrastructure for support
and response to emergencies. Thus, to provide quality PCI
services, the institution must ensure that its catheterization
facility is properly equipped and managed, and that all of its
necessary support services, including data collection, are of
high quality and are readily available.
The Quality Assessment Process
Quality assessment is a complex process that includes more
than a mere tabulation of success and complication rates.
Components of quality in coronary interventional procedures include appropriateness of case selection; quality of
procedure execution; proper response to intraprocedural
problems; accurate assessment of procedure outcome both
short- and long-term; and appropriateness of postprocedure
management. It is important to consider each of these
parameters when conducting a quality assessment review. A
quality program performs appropriately selected procedures
while achieving risk-adjusted outcomes, in terms of procedure success and complication rates, that are comparable to
national benchmark standards. It is accepted that quality
assurance monitoring is best conducted through the peerreview process despite the political challenges associated
with colleagues evaluating each other. There has been
considerable controversy surrounding efforts to define standards, criteria, and methodologies for conducting quality
assessment. There are many challenges to conducting this
process in a fair and valid manner.
The cornerstone of quality assurance monitoring is the
assessment of procedure outcomes in terms of success and
adverse event rates. Other components of quality assurance
monitoring include establishing criteria for assessing procedure appropriateness and applying proper risk adjustment to
interpret adverse event rates. As adverse events should be
rare, a valid estimate of a properly risk-adjusted adverse
event rate generally requires tabulating the results of a large
number of procedures. This adds an additional challenge to
the valid assessment of low-volume operators and institutions. The responsible supervising authority should monitor
the issues outlined in Table 4.
In addition, mere tabulation of adverse event rates, even
with appropriate risk adjustment, is inadequate to judge
operator or program quality. Such tabulations do not address numerous other quality issues—in particular, appropriateness. Thus, the quality assessment process should also
conduct detailed reviews of both cases that have adverse
outcomes, to determine the cause(s) of the adverse event,
and of uncomplicated cases, in order to judge case selection
appropriateness and procedure execution quality. These
reviews should be conducted by recognized experienced
interventionalists, drawn either from within the institution
or externally, if a requisite number of appropriately qualified
unconflicted individuals are not available.
Conclusions and Recommendations for PCIs
In formulating conclusions and recommendations it is
important to emphasize that the ultimate goal of setting
standards is to facilitate the attainment of optimal patient
outcomes. Optimal outcome is most likely when operators
select clinically appropriate patients for interventional procedures and perform these procedures at a requisite level of
proficiency. Institutional and programmatic quality is ultimately determined by its success in achieving that goal.
Success and Complication Rates
Coronary interventional procedures may be complex and
technically demanding to perform. Complications of these
procedures may be life-threatening and can occur unpredictably. Nonetheless, recent clinical studies have demonstrated that despite increased clinical and angiographic
complexity, procedural and clinical success has remained
high and complications have remained low. Angiographic
success (at least 1 lesion successfully dilated by greater than
20%, with a residual stenosis of less than 50%), excluding
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STEMI patients, occurs in over 95% with an average
mortality rate of less than 1%, a Q-wave MI rate of less than
1%, and an emergency CABG rate of less than 1%.
Risk Adjustment
Several large retrospective studies have identified both
clinical and angiographic characteristics of PCI that correlate with procedural success, hospital morbidity, and mortality. These studies have been used to develop multivariate
logistic regression models that can stratify patients into risk
groups before the procedure which have moderate predictive
value for mortality (C-statistic 0.85 to 0.90), and slightly
less predictive value for morbidity (C-statistic 0.67 to 0.78).
Volume–Activity Relationships
Analysis of more contemporary data supports the hypothesis
that technological advancements have not offset the influence of “practice” in determining proficiency of contemporary PCIs. There are statistical associations between activity
levels and short-term complication rates (emergency CABG
and mortality) (17,58,85,89,97,101) for both institutions
and for individual operators. In particular, low-volume
operators operating at low-volume hospitals had an increased mortality rate. However, procedural volume is only
one of many factors contributing to the variability of
measured outcomes. Furthermore, there is no clear “cut-off”
above or below which hospitals or individual operators
perform well or poorly. Procedural volume continues to be
correlated with outcomes, but should not serve as a substitute for a well-controlled analysis of results and does not
ensure quality. The development of national, regional and
state registries for outcome assessment is promoting objective assessment of clinical outcomes.
The expected low complication rate for coronary interventional procedures presents a major statistical power
problem when attempting to estimate the true complication
rate of the low-volume operator with meaningful precision.
In such situations, close scrutiny of case selection and close
monitoring of outcomes on a case-by-case basis would serve
as a complement to risk adjustment.
Highly complex procedures require much more skill and
experience, and should be undertaken by operators possessing these attributes. Complex cases appropriate for interventions should be referred, not denied.
Recommendations for Institutional Maintenance
of Quality
It is recommended that all institutions have a regular (at
least monthly) catheterization laboratory conference. Patient outcomes should be determined longitudinally for each
procedure by the institution’s quality assessment program.
Participation in a state, regional, or national registry is
highly encouraged to allow institutions to measure riskadjusted outcomes and compare them to national benchmarks for improving quality of care.
For both institutional and individual volume assessments,
ongoing 2-year volumes should be measured, then averaged
to arrive at annual statistics. It is recommended that lower
volume institutions (less than 400 per year) consider holding
conferences with a more experienced partnering institution,
with all staff expected to attend on a regular basis.
It is also recommended that any institution that falls more
than 2 standard deviations outside the risk-adjusted national
benchmarks in mortality or emergency same-stay CABG
during 2 of 3 contiguous 6-month periods have an external
audit looking for opportunities to improve quality of care.
An institution offering coronary interventional procedures should have a physician-director who is responsible
for the program’s overall quality. The director should be
certified in interventional cardiology by the ABIM, with a
career experience of more than 500 procedures. The director
should perform procedures at the facility that he or she
directs.
Recommendations for Individual Maintenance
of Quality
To maintain an appropriate cognitive knowledge base for
PCIs, it is recommended that individual operators attend at
least 30 h of PCI CME every 2 years. The overall performance of physicians whose complication rates exceed national benchmark standards for 2 of 3 contiguous 6-month
periods should be reviewed by the program director, with
careful attention to statistical power and risk-adjustment
issues. It is recommended that the operator volume threshold continue to be 75 procedures per year. Monitoring of
physicians with an annual procedural volume of less than 75
should be particularly detailed because of the difficulty of
estimating their true complication rate. These performance
evaluations should include feedback to the operator.
If it is determined that the quality of PCI care being
provided does not meet national benchmarks, the catheterization laboratory director should have the discretion of
making recommendations for improving quality and reassessing over the next 6 months. These recommendations
could include establishing a defined mentoring relationship
with an experienced operator. If the operator in question
disputes this assessment, then external review may be
helpful in determining the most appropriate methods of
assuring quality performance.
Percutaneous Noncoronary Interventions
Introduction
Noncoronary interventions are a growing and important
contribution to the field of interventional cardiology. The
majority of procedures have had their origin in the pediatric
population, and several have expanded to the adult patient.
The purpose of this section is to discuss the training and
experience necessary for the safe and successful performance
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ACCF/AHA/SCAI Clinical Competence Statement
of valvuloplasty, alcohol septal ablation, and percutaneous
repair of ASD/PFO.
The knowledge, skills, and training necessary for competency in noncoronary interventional procedures are different
from that required for coronary interventions. Therefore,
special study of the anatomy, physiology, and pathology of
these conditions is a prerequisite for safe and effective
treatment. Furthermore, an in-depth understanding of the
clinical indications for treatment and the unique complications of these treatments are essential.
Although the scope of this document is focused on
competency, this section will expand the discussion somewhat to describe some anatomical and procedural details.
Such details are well known for PCI, and their performance
is widespread, whereas these noncoronary procedures, in the
estimation of this Writing Committee, warrant some discussion of background information and procedural alternatives.
Disorders of the Atrial Septum
Criteria for Competency
The knowledge base required for performing PCI is different than that required for percutaneous closure of ASD and
PFO. Extensive knowledge of structural cardiac anatomy,
especially that of the atrial septum and the adjacent structures, is required, as is the understanding of the impact of
abnormal anatomy and function, and the relative value of
therapeutic options (85,101–105). Therefore, specific training and experience is necessary to safely and successfully
treat this subgroup of patients. The Food and Drug Administration guidelines on the use of device closure of PFOs
in these patients state that only patients who have failed
anticoagulation or have a compelling medical reason to not
be anticoagulated are appropriate for device closure. These
guidelines should be fully discussed with patients during the
informed consent process. In addition, complications such
as cardiac perforation, device embolization, thrombus formation on the device, infective endocarditis, arrhythmias,
and early as well as late erosion of the device through the
atrial wall or aorta should be disclosed. Currently, 2 studies
are underway comparing percutaneous closure of PFO to
standard oral anticoagulation, which should clarify the
indications for interventional treatment.
Since these procedures are relatively new to interventionalists trained in adult cardiology, no pre-existing guidelines
are available on which to base current opinion. In the
absence of such guidelines, we arrived at these recommendations from discussions with colleagues actively performing
these percutaneous closures.
115
mum number of cases required for maintenance of competency and proficiency. A survey of Pediatric Cardiology
Interventional Catheterization training programs concluded
that a minimum of 10 percutaneous ASD closures is
necessary for a trainee to gain clinical competence with the
procedure (102).
With this in mind, it is recommended that interventional
cardiologists who intend to perform these procedures independently, should be involved in these procedures during
training with at least 10 of these cases being secundum ASD
closures. Furthermore, as part of the procedure, the fellow
should be fully conversant in the use of transesophageal
echocardiography and/or intracardiac echocardiography. He
or she should understand how to obtain the appropriate
views to image necessary structures in order to perform the
procedure safely and to exclude other anatomical problems
such as a primum or sinus venosus ASD, anomalous
pulmonary venous drainage, fenestrated or multiple ASD,
or lipomatous hypertrophy of the septum. Obviously, not all
fellows in training will be able to gain this experience and,
therefore, concentrating the experience in training should be
limited to a few trainees.
Cardiologists in Practice
Interventional cardiologists in practice who were not specifically trained in ASD/PFO closure but would like to perform
these procedures should be fully credentialed in interventional
techniques in their institution. The first several cases should be
done with a proctor. To ensure safety and success, it seems
prudent that the first 10 cases be proctored by someone fully
credentialed in these techniques such as a pediatric cardiologist
or adult cardiologist trained in congenital heart disease. Proctors should also be present for the first 3 to 5 cases if a different
device is to be used after the initial credentialing proctorship.
Maintenance of Competency for Percutaneous
ASD/PFO Closure
To maintain physician proficiency and competency in percutaneous ASD/PFO closure, a minimum of 10 cases per year is
recommended. Similarly, to maintain catheterization laboratory proficiency, a minimum of 10 cases per year should be
performed in each institution each year. To achieve this
experience, it may be necessary to concentrate the procedures
in the hands of only a few operators. A multidisciplinary
program, including neurology consultation for PFO closure,
prospective evaluation of case selection, and evaluation of
clinical outcomes is critical to ensure appropriateness and
maintain safety and efficacy. Laboratories and individual operators that are not active enough to maintain quality outcomes
should reconsider treating these patients.
Cardiologists in Training Programs
Quality Assurance
Acquisition of the knowledge and skills necessary to perform percutaneous procedures to treat ASD and PFO
should be incorporated into the formal training of interventional cardiologists. There are no data regarding the mini-
The quality improvement process used for oversight of ASD/
PFO closure should include concurrent case review, and will
also benefit from regular case conferences to discuss indications, procedural techniques, and case outcomes. It is particu-
116
Circulation
July 3, 2007
larly useful in any developing procedural area to share results
with other institutions through informal and formal conferences. Because there are, as of yet, no large databases of
outcomes for these procedures, participation in local, regional,
and national registries is encouraged. Focusing the performance of these procedures in the hands of a few experienced
operators is also recommended.
Hypertrophic Cardiomyopathy and
Alcohol Septal Ablation
Hypertrophic cardiomyopathy is the most common genetic
cardiovascular disease, with a prevalence in the general population estimated to be 0.2% (103). Physicians performing these
procedures should have extensive knowledge of the outcomes,
limitations and complications of medical therapy (104), dual
chamber pacing and surgical myectomy (105–107), and alcohol
septal ablation (105–114). No comparative trial against surgical
myectomy has been performed.
Criteria for Competency
Acquisition of competence. It is strongly recommended that
alcohol septal ablation be offered within a multidisciplinary
program that includes the contribution of experienced cardiac
surgeons, echocardiographers, general cardiologists, and electrophysiologists. Although there are currently no data regarding the minimum number of procedures required for training
and for credentialing, a minimum number of 10 procedures
seems to be appropriate.
Maintenance of competence. It is recommended that individual operators perform a minimum of 6 cases per year to
maintain competence in performance of septal ablation for
hypertrophic cardiomyopathy. Each institution should employ
a multidisciplinary program with prospective evaluation of case
selection and clinical outcomes. Such an approach is critical for
any institution offering alcohol septal ablation as a treatment
option for symptomatic patients with hypertrophic obstructive
cardiomyopathy.
Quality assurance. Quality assurance in such low-volume
procedures requires an approach similar to that outlined for
ASD and PFO closures, as previously described.
Valvular Heart Disease
Cognitive Knowledge Base
Physicians performing invasive procedures on stenotic cardiac
valves must have extensive knowledge of the pathoanatomy,
the hemodynamic alterations, the clinical course, and the
outcomes of various therapeutic options. Complications of
aortic (115,116) and mitral (117–119) valvuloplasty should be
well understood.
Criteria for Competency
Acquisition of competence. Mitral valvuloplasty is one of
the most challenging cardiac procedures. The presence of a
“learning curve” has been well described (120,121). Thus,
training in the performance of mitral valvuloplasty requires the
acquisition of clinical skills for the evaluation of indications for
the procedure and the assessment of suitable valve morphology.
It requires the development of proficiency in the performance
of transseptal cardiac catheterization, device manipulation, and
online evaluation of hemodynamic parameters. The interventionalist must be able to recognize and manage complications
specific to mitral valvuloplasty, including acute mitral regurgitation, cardiac perforation, pericardial tamponade, and stroke.
Although a learning curve has been well described, there are
currently no specific data regarding the minimum numbers
needed for competency. Nonetheless, 5 to 10 cases should be
done with an experienced colleague before attempting to
perform balloon valvuloplasty independently. Any program
offering mitral valvuloplasty as an alternative to mitral valve
replacement or surgical commissurotomy for the treatment of
mitral stenosis should include a thorough quality assurance
program and close monitoring of case selection and clinical
outcomes. As with other infrequently performed procedures,
concentration of experience among a small subset of interventional cardiologists within an institution is appropriate.
Maintenance of competence. With the low prevalence of
mitral stenosis in the United States, maintaining experience
is difficult. Given this limitation, concentration of this
experience among institutional and perhaps regional centers
may be appropriate.
Quality assurance. Quality assurance in such low-volume
procedures requires an approach similar to that outlined for
ASD and PFO closures, as previously described.
Percutaneous Ventricular Assist Devices
Percutaneous ventricular assist devices are becoming available. They require training and proctored supervision to
attain competence, as well as periodic use or refresher drills
to maintain competence. As with other seldom-used techniques, experience should be concentrated among a limited
number of operators and laboratory staff who have received
appropriate training.
Laboratory and Staff Competence
In order for laboratories to become competent in the
performance of noncoronary cardiac procedures, the supervising or performing operator should be fully credentialed in
the procedure. Initially, this may require off-site training,
simulation training, a visiting proctor, or a combination of
these approaches. The operator responsible for the performance of the procedure in the catheterization laboratory
should supervise the staff in acquiring the necessary skills
and equipment for the procedure. As is the case for the
operators of lower volume procedures, there should be a
small number of dedicated staff members trained to perform
specific noncoronary interventions, concentrating the experience. If and when a specific procedure becomes more
common, then the training may be expanded to the remainder of the staff and operators.
King et al
ACCF/AHA/SCAI Clinical Competence Statement
Conclusions and Recommendations
Percutaneous Noncoronary Interventions
Noncoronary cardiac interventions require special training
that is not possible for all operators to obtain because of the
small number of these procedures. Therefore, it is necessary
to concentrate the activity both in training and practice so
that adequate experience can be obtained to allow for quality
performance. Hospitals should develop clear credentialing
criteria, despite the small number of cases and empiric data
from which to judge appropriateness, as well as success and
complication rates of these procedures.
The quality improvement process used for oversight of
percutaneous noncoronary interventions should include
concurrent case review, and will also benefit from regular
case conferences to discuss indications, procedural techniques, and case outcomes. It is particularly useful in any
developing procedural area to share results with other
institutions through informal and formal conferences. Since
there are, as of yet, no large databases of outcomes for these
procedures, participation in local, regional, and national
registries is encouraged. Focusing the performance of these
procedures in the hands of a few experienced operators is
also recommended.
Staff
American College of Cardiology Foundation
John C. Lewin, MD, Chief Executive Officer
Thomas E. Arend, Jr, Esq., Chief Operating Officer
Lisa Bradfield, Associate Director, Practice Guidelines
Erin A. Barrett, Senior Specialist, Clinical Policy and
Documents
American Heart Association
M. Cass Wheeler, Chief Executive Officer
Rose Marie Robertson, MD, FACC, FAHA, Chief
Science Officer
Kathryn A. Taubert, PhD, FAHA, Senior Scientist
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88. Ho V. Evolution of the volume-outcome relation for hospitals
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277:892– 8.
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septal ablation for hypertrophic obstructive cardiomyopathy. Catheter Cardiovasc Interv 2002;56:503–7.
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114. Nagueh SF, Ommen SR, Lakkis NM, et al. Comparison of ethanol
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hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2001;
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in 170 consecutive patients. N Engl J Med 1988;319:125–30.
117. The National Heart, Lung, and Blood Institute Balloon Valvuloplasty Registry Participants. Multicenter experience with balloon
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King et al
ACCF/AHA/SCAI Clinical Competence Statement
121
APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY—ACCF/AHA/SCAI WRITING COMMITTEE TO UPDATE
THE CLINICAL COMPETENCE STATEMENT ON CARDIAC INTERVENTIONAL PROCEDURES
Name
Research
Grant
Consultant
Scientific
Advisory Board
Speakers’
Bureau
Steering
Committee
Stock Holder
Other
Dr. Thomas
Aversano
None
None
None
None
None
None
None
Dr. William L.
Ballard
None
None
None
None
None
None
None
Dr. Robert H.
Beekman, III
●
None
None
None
None
None
None
Dr. Michael J.
Cowley
None
None
None
None
None
None
None
Dr. Stephen G.
Ellis
●
Boston
Scientific
● Celera
● Cordis
● Guidant
● Viacon
●
Celera
Centacor/Lilly
● Cordis
●
Boston Scientific
Cordis
● Viacon
None
None
None
None
●
●
Dr. David P.
Faxon
●
None
●
Boston Scientific
None
None
●
Dr. Edward L.
Hannon
None
None
None
None
None
None
None
Dr. John W.
Hirshfeld, Jr.
None
None
●
None
None
None
None
Dr. Alice K.
Jacobs
None
None
None
None
None
None
●
Dr. Mirle A.
Kellett, Jr.
None
None
None
None
None
None
None
Dr. Stephen E.
Kimmel
None
None
None
None
None
None
None
Dr. Spencer B.
King, III
●
Bristol-Myers
Squibb
● CV Therapeutics
● Sanofi/Aventis
None
●
●
Bristol-Myers
Squibb
● Sanofi
None
None
●
Dr. Joel S.
Landzberg
None
None
None
None
None
None
None
Dr. Louis S.
McKeever
None
None
None
None
None
None
None
Dr. Mauro
Moscucci
None
●
None
●
●
Dr. Richard M.
Pomerantz
●
Dr. Karen M.
Smith
Dr. George W.
Vetrovec
AGA Medical
Bristol-Myers
Squibb/Sanofi
●
Medacorp.
Sanofi/Aventis
BlueCross/
BlueShield
Bracco Inc.
Bristol-Myers
Squibb/Sanofi
Medtronic
Aventis
Pfizer
None
None
●
Sanofi/Aventis
None
●
None
None
None
●
None
None
●
None
None
None
None
Merck
●
Cordis/Johnson
& Johnson
● NHLBI
None
●
●
Medical Technology
Informational
●
Lilly
Pfizer
Pfizer
Johnson & Johnson
None
Wyeth–Spouse’s
Employer
Novoste–Royalties
Cordis–Fellowship
Training Grant
None
None
None
This table represents the relationships of committee members with industry that were reported orally at the initial writing committee meeting and updated in conjunction with all meetings and conference
calls of the writing committee during the document development process. It does not necessarily reflect relationships with industry at the time of publication.
122
Circulation
July 3, 2007
APPENDIX 2. PEER REVIEWER RELATIONSHIPS WITH INDUSTRY—ACCF/AHA/SCAI 2007 UPDATE OF THE
CLINICAL COMPETENCE STATEMENT ON CARDIAC INTERVENTIONAL PROCEDURES
Name
Representation
Consultant
Scientific
Advisory
Board
Research Grant
Speakers’
Bureau
Steering
Committee
Stock
Holder
Other
Dr. John C. Giacomini
●
Official–AHA
None
None
None
None
None
None
Dr. Lawrence Laslett
●
Official–ACC
Board of
Governors
None
None
None
None
None
●
Dr. Carl J. Pepine
●
Official–ACC
Board of
Trustees
●
Abbott
AstraZeneca
Berlex
Laboratories
● Pfizer
None
None
None
None
●
●
Abbott
CV Therapeutics
●
General
Electric
None
None
●
●
Educational grant–
AstraZeneca,
CV Therapeutics,
GlaxoSmithKline,
King
Pharmaceuticals,
Monarch
Pharmaceuticals,
Pfizer,
Sanofi-Aventis,
Schering-Plough,
Wyeth-Ayerst
Laboratories
Dr. Albert P. Rocchini
●
Official–AHA
None
None
None
None
None
None
None
Dr. Samuel J. Shubrooks
●
Official–ACC
Board of
Governors
None
None
None
None
None
None
None
Dr. Alan Yeung
●
Official–AHA
●
Abbott
Boston
Scientific
● Cordis
None
None
●
None
None
None
None
None
None
Boston
Scientific
GE Medical
● Lilly
● RADI Medical
● Volcano Corp
●
GE Medical
Pfizer
None
●
Technology
Solutions
Group
● BioInfo
Accelerator
Fund
● Volcano
Corp
●
None
None
●
RADI
Medical
None
None
None
Medtronic
●
●
Dr. Gregory Dehmer
●
Organizational–
Society for
Cardiovascular
Angiography
and
Interventions
None
Dr. John Hodgson
●
Organizational–
Society for
Cardiovascular
Angiography
and
Interventions
●
Organizational–
Society for
Cardiovascular
Angiography
and
Interventions
●
Dr. Morton J. Kern
●
Volcano Corp
Abbott
Boston
Scientific
●
●
●
Volcano Corp
●
●
●
●
●
Bracco Inc.
Meritt Medical
Therox Inc.
Boston
Scientific
None
Management–
Mytogen
Technology
Solutions Group
● BioInfo Accelerator
Fund
Dr. Ronald Krone
●
Organizational–
Society for
Cardiovascular
Angiography
and
Interventions
None
None
None
None
None
None
None
Dr. Douglass A. Morrison
●
Organizational–
Society for
Cardiovascular
Angiography
and
Interventions
None
None
None
None
None
None
None
Dr. Mark Reisman
●
Organizational–
Society for
Cardiovascular
Angiography
and
Interventions
None
None
●
Abbott
Boston
Scientific
● Cordis
● Medtronic
●
None
None
None
●
●
Boston
Scientific
Cordis
Dr. Barry Uretsky
●
Organizational–
Society for
Cardiovascular
Angiography
and
Interventions
None
None
None
None
None
None
None
Dr. Mazen Abu-Fadel
●
Content–ACCF
Cardiac
Catheterization
and
Intervention
Committee
None
None
None
None
None
None
None
Dr. Peter Berger
●
Content–
Individual
Reviewer
●
Boston
Scientific
Cordis/Johnson
& Johnson
● Genentech
● Guilford
●
Cardiokinetix
Conor
Cordis/Johnson
& Johnson
● Datascope
● Guilford
● Lilly
● The Medicine
Company
● Medtronic
● Sankyo
● Sanofi-Aventis
●
Arginox
Bristol-Myers
Squibb
● SanofiAventis
● ScheringPlough
None
None
●
●
●
●
●
Lumen, Inc
None
Continued on next page
King et al
ACCF/AHA/SCAI Clinical Competence Statement
123
APPENDIX 2. Continued
Name
Representation
Consultant
Research Grant
Scientific
Advisory
Board
Speakers’
Bureau
Steering
Committee
Stock
Holder
Other
Dr. Robert O. Bonow
●
Content–PCI
Guideline
Writing
Committee
None
None
None
None
None
None
None
Dr. Jose G. Diez
●
Content–ACCF
Cardiac
Catheterization
and
Intervention
Committee
None
None
None
None
None
None
None
Dr. Ted E. Feldman
●
Content–ACCF
Cardiac
Catheterization
and
Intervention
Committee
●
Boston
Scientific
Cardiac
Dimensions
● Cordis
● Myocor
●
Abbott
Atritech
Boston
Scientific
● Cardiac
Dimensions
● Cordis
● Evalve
None
None
None
None
None
●
●
●
Dr. James Ferguson
●
Content–
Individual
Reviewer
None
None
None
None
None
None
None
Dr. Tommaso Gori
●
Content–AHA
Diagnostic &
Interventional
Cardiac
Catherization
Committee
None
None
None
None
None
None
None
Dr. Hani Jneid
●
Content–AHA
Diagnostic &
Interventional
Cardiac
Catheterization
Committee
None
Pfizer
None
None
None
None
None
Dr. Fred M. Krainin
●
Content–ACCF
Cardiac
Catheterization
and
Intervention
Committee
None
None
None
None
None
●
Boston
Scientific
Johnson &
Johnson
● Medtronic
None
●
Dr. Glenn Levine
●
Content–AHA
Diagnostic &
Interventional
Cardiac
Catheterization
Committee
None
None
None
None
None
None
None
Dr. Charanjit S. Rihal
●
Content–ACCF
Cardiac
Catheterization
and
Intervention
Committee
None
None
None
None
None
None
None
Dr. Dan M. Roden
●
Content–
Individual
Reviewer
●
Abbott
Alza
Arpida
● AstraZeneca
● Bristol-Myers
Squibb
● CV Therapeutics
● EBR Systems
● First Genetic
Trust
● GlaxoSmithKline
● Genzyme
● Johnson &
Johnson
● Lexicon
● Lundbeck
● Medtronic
● Merck
● NPS
Pharmaceuticals
● Novartis
● Pfizer
● SanofiSynthelabo
Groupe
● Solvay
● Thornton
Medical
● Wyeth
● Yamanouchi
None
None
None
None
None
None
●
●
Dr. Carlos Ruiz
●
Content–ACCF
Cardiac
Catheterization
and
Intervention
Committee
None
None
None
None
None
None
None
Dr. Michael J. Silka
●
Content–
Individual
Reviewer
None
None
None
None
None
None
●
General Electric
Continued on next page
124
Circulation
July 3, 2007
APPENDIX 2. Continued
Name
Representation
Consultant
Research Grant
Dr. Thoralf M. Sundt
●
Content–ACCF
Cardiac
Catheterization
and
Intervention
Committee
None
None
Dr. Cynthia M. Tracy
●
Content–
Individual
Reviewer
None
●
●
Guidant Corp
Medtronic
Scientific
Advisory
Board
Speakers’
Bureau
Steering
Committee
Stock
Holder
Medtronic
(son has
stock)
Other
None
None
None
●
None
None
None
None
None
None
Dr. E. Murat Tuzcu
●
Content–AHA
Diagnostic &
Interventional
Cardiac
Catheterization
Committee
None
None
None
None
None
None
None
Dr. Matthew Wolff
●
Content–ACCF
Cardiac
Catheterization
and
Intervention
Committee
None
None
None
None
None
None
None
Dr. Yerem Yeghazarans
●
Content–
Individual
Reviewer
None
None
None
●
None
None
None
●
Pfizer
SanofiAventis
This table represents the relationships of peer reviewers with industry that they reported as relevant to this topic. It does not necessarily reflect relationships with industry at the time of publication.
Participation in the peer review process does not imply endorsement of the document. Names are listed in alphabetical order within each category of review.
An Unusual Site for a Common Disease
Maysaa Alzetani, MRCP, MSc; Joseph J. Boyle, MRCP, PhD;
David Lefroy, MA, MB, BChir, FRCP; Petros Nihoyannopoulos, MD, FRCP
A
75-year-old Asian woman presented with a 5-month
history of night sweats, lethargy, and malaise. On
admission she was found to have low-grade pyrexia and
elevated inflammatory markers. Septic screen, which included repeated blood cultures and chest x-ray (Figure 1),
were negative. A transthoracic and transesophageal echocardiography revealed a doughnut-shaped mass (online Data
Supplement Movie I) that surrounded the mitral valve annulus and extended up to the left atrial walls and atrial septum.
A surgical biopsy was taken (Figure 2), which showed
epithelioid and langhans giant cell granulomas with central
caseating necrosis consistent with tuberculosis. Special staining with high-sensitivity immunoperoxidase confirmed the
diagnosis of tuberculosis. The patient was treated for tuberculosis with complete resolution of her symptoms. Repeated
echocardiography 6 months later showed a dramatic reduction of the mass size (Data Supplement Movies II and III).
Isolated cardiac tuberculosis is extremely rare. However it
should be included in the differential diagnosis of intracardiac
masses.
Figure 1. Posterior-anterior chest x-ray, taken on admission,
shows clear lung fields and no signs of infection.
Figure 2. Biopsy taken from the mass that surrounded the
mitral valve annulus and extended up to the left atrial walls
and atrial septum. Hematoxylin and eosin staining. Magnification, ⫻20. Ep indicates epithelioid macrophages; L, Langhans
giant cells; and N, necrosis. Inset, immunohistochemistry with
monoclonal antibody to mycobacterium (Dako, Glostrup, Denmark) and immunoperoxidase (Menarini Diagnostic, Wokingham, UK). B indicates bacillus; M, macrophage. Magnification,
⫻100 (cropped for space).
Sources of Funding
Dr Boyle has received research support from the British Heart
Foundation, KRUK, HHRTC, and the Broad Foundation.
Disclosures
Dr Boyle has received honoraria from the International Journal of
Experimental Pathology, has served as a speaker for the Histochemical
Society and the British Atherosclerosis Society as a member of the
editorial board for the International Journal of Experimental Pathology,
and as an expert witness to UK coroners and mesothelioma panels.
From the Hammersmith Hospital NHS Trust (M.A.), and the Histopathology Department (J.J.B.) and Hammersmith Hospital (D.L., P.N.), Imperial
College, London, UK.
The online-only Data Supplement, consisting of movies, is available with this article at http://circ.ahajournals.org/cgi/content/full/116/1/e1/DC1.
Correspondence to Dr Maysaa Alzetani, 42 Tryfan Close, Ilford, London IG4 5JY, United Kingdom. E-mail maysaazetani@msn.com
(Circulation. 2007;116:e1.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.677120
Sine-Wave Pattern Arrhythmia and Sudden Paralysis That
Result From Severe Hyperkalemia
Maurice J.H.M. Pluijmen, MD; Ferry M.R.J. Hersbach, MD
A
54-year-old man with a history of end-stage renal
disease treated with hemodialysis presented to the emergency department because of a sudden inability to move his
limbs.
Physical examination revealed a complete quadriplegia.
Blood pressure was 145/90 mm Hg, with a regular pulse of 45
beats per minute. Initial 12-lead electrocardiography showed
a sinus bradycardia with atrial, atrioventricular, and intraventricular conduction delay (Figure 1). Subsequently, the patient developed several episodes of a nonsustained widecomplex tachycardia with a right bundle-branch block
configuration that gradually evolved into and from a “sinewave” pattern (Figures 2 and 3). Remarkably, the patient
remained hemodynamically stable. Because hyperkalemia
was suspected, serum potassium was determined in venous as
well as arterial blood samples to be 9.9 mmol/L. Calcium
gluconate was administered, and emergency hemodialysis
was performed. After normalization of the serum potassium
concentration, sinus rhythm was maintained, the cardiac
conduction times returned to normal (Figure 4), and the
quadriplegia resolved completely.
This case illustrates some typical features of severe hyperkalemia. Initial characteristic electrocardiographic abnormalities in hyperkalemia are tall and peaked T waves, followed
by an increasing cardiac conduction delay. As demonstrated
in this case, this results in flattened and broadened P waves,
an atrioventricular block of first or higher degrees, and
widening of the QRS complex. In rare instances, ST-segment
elevation may occur, which leads to a “pseudoinfarction”
pattern.1 Progression of hyperkalemia causes further widening of
the QRS complex, often with the configuration of a left or right
bundle-branch block. Eventually, merger of QRS complex and T
wave will lead to the appearance of a typical sine-wave pattern.
Contrary to our patient, a sine-wave pattern often precedes
ventricular fibrillation or asystole.2 Furthermore, rapidly progressing flaccid motor weakness may result in a quadriplegia,
which was the presenting symptom in this case and is an
uncommon manifestation of severe hyperkalemia that may
ultimately result in respiratory failure.2,3
Recognition of the combination of sudden paralysis and
electrocardiographic abnormalities as demonstrated in this
case can lead to early diagnosis and treatment of severe
hyperkalemia.
Disclosures
None.
References
1. Sims DB, Sperling LS. Images in cardiovascular medicine. ST-segment
elevation resulting from hyperkalemia. Circulation. 2005;111:
e295– e296.
2. 2005 American Heart Association Guidelines for Cardiopulmonary
Resuscitation and Emergency Cardiovascular Care, Part 10.1. Lifethreatening electrolyte abnormalities. Circulation. 2005;112:
IV121–IV125.
3. Freeman SJ, Fale AD. Muscular paralysis and ventilatory failure caused
by hyperkalaemia. Br J Anaesth. 1993;70:226 –227.
From the Department of Cardiology, Medisch Centrum Rijnmond-Zuid, Rotterdam, the Netherlands.
Correspondence to Dr Maurice J.H.M. Pluijmen, Groene Hilledijk 315, 3075EA Rotterdam, The Netherlands. E-mail m_pluijmen@hetnet.nl
(Circulation. 2007;116:e2-e4.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.687202
Pluijmen and Hersbach
Severe Hyperkalemia
e3
Figure 1. The initial 12-lead ECG (25 mm/sec, 5 mm/mV) obtained on presentation to the emergency department demonstrates a sinus
bradycardia with prolonged atrial conduction (flattened and broadened P waves, see arrows), a first-degree atrioventricular block (PQ,
300 ms), and an intraventricular conduction delay (QRS, 160 ms).
Figure 2. Rhythm strip recording of lead II, with a wide-complex tachycardia with right bundle-branch block configuration that gradually
evolves into a sine-wave pattern.
e4
Circulation
July 3, 2007
Figure 3. This 12-lead ECG (25 mm/sec, 10 mm/mV) of the wide-complex tachycardia (QRS, 240 ms) demonstrates the right bundlebranch block configuration that evolves into and from a sine-wave pattern.
Figure 4. The 12-lead ECG (25 mm/sec, 5 mm/mV) after normalization of the serum potassium concentration reveals the normalization
of atrial, atrioventricular (PQ, 140 ms), and intraventricular (QRS, 80 ms) conduction times, as well as a preexistent left ventricular hypertrophy pattern.
Images in Cardiovascular Medicine
Lipomatous Metaplasia in Ischemic Cardiomyopathy
A Common but Unappreciated Entity
Matthias Schmitt, MD, PhD, MRCP; Nilesh Samani, BSc, MB, ChB, MD, FRCP, FmedSci;
Gerry McCann, BSc, MB, ChB, MD, MRCP
A
idiopathic dilated cardiomyopathy, or chronic valvulopathy,
respectively.1 Myocardial perfusion imaging (lipohilic myocardial perfusion agents such as tetrofosmin and sestamibi
may well be taken up into fat cells) and echocardiography fail
to diagnose LM (which accounts for the lack of recognition of
this not uncommon entity) with the consequent implications
for overestimation of viable myocardium or underestimation
of scar size.
Importantly, LM on magnetic resonance imaging must not
be mistaken for late enhancement after gadolinium contrast.
68-year-old man with a 14 1year prior history of anterior
myocardial infarction was referred for viability assessment. He had established 3-vessel coronary artery disease
with a proximally occluded left anterior descending coronary
artery. He complained of worsening shortness of breath and
diminishing exercise tolerance. Cardiac magnetic resonance
imaging demonstrated a nondilated left ventricle with minor
aneurysmal transformation that affected the mid-anterior wall
and extended into mid- and antero-septum as well as the apex.
Gradient (Figure, A) and T1-weighted spin-echo images
demonstrated bright signal intensity in the mid-myocardium
of the anterior wall (see arrows in Figure, B), which disappeared with fat saturation (see arrows in Figure, C and D).
These findings are indicative of lipomatous metaplasia (LM).
The term LM describes fat that is present in and seemingly
replaces scar tissue in the myocardium. The exact etiology of
LM is unknown, but it is not seen in the absence of
substitutive myocardial fibrosis. Histological evidence of LM
has been found in up to 68%, 24%, and 37% of areas of left
ventricular myocardial scars in explanted hearts of patients
who underwent transplantation for ischemic heart disease,
Disclosures
None.
References
1. Baroldi G, Silver MD, De Maria R, Parodi O, Pellegrini A. Lipomatous metaplasia in left ventricular scar. Can J Cardiol. 1997;13:
65–71.
From the Department of Cardiology, Glenfield Regional Cardiac Centre, Leicester University Hospital Trust, Leicester, UK.
The online-only Data Supplement, consisting of movies, is available with this article at http://circ.ahajournals.org/cgi/content/full/116/1/e5/DC1.
Correspondence to Dr Matthias Schmitt, Department of Cardiology, Glenfield Regional Cardiac Centre, Leicester University Hospital Trust, Groby
Road, Leicester LE3 9QP, UK. E-mail matthschmitt@doctors.org.uk
(Circulation. 2007;116:e5-e6.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.690800
e5
e6
Circulation
July 3, 2007
Short-axis images at mid-cavity level (A
and C) and long-axis images (B and D).
White arrows mark high signal intensity
(no gadolinium given) in the anterior wall
(A and B) that turns black in corresponding fat suppression sequence (C and D).
Correspondence
Letter by Brewster and van Montfrans
Regarding Article, “Risks Associated With
Statin Therapy: A Systematic Overview of
Randomized Clinical Trials”
Disclosures
None.
Lizzy M. Brewster, MD
Gert A. van Montfrans, MD
Departments of Internal and Vascular Medicine
Academic Medical Center F4-222
University of Amsterdam
Amsterdam, The Netherlands
To the Editor:
Kashani et al1 report that in randomized trials, statin
therapy (with the exclusion of cerivastatin) did not result in
significant absolute increases in myalgias (risk difference per
1000 patients, 2.7 (95% CI, ⫺3.2 to 8.7), or mild creatine
kinase (CK) elevations 0.2 (95% CI, ⫺0.6 to 0.9). The authors
used data from published trials to reach this conclusion.
However, Kashani et al did not take into account that many
statin trials disclose that eligible patients with muscle complaints,
previous adverse responses to cholesterol-lowering therapy, or
even a mild asymptomatic elevation of CK (⬎1.5 to 6.0 times the
upper limit of normal) are not randomized.2–5
On the basis of the complete exclusion criteria, up to 76% of
the screened participants in statin trials are not randomized and
excluded.2–5 Thus, the incidence of hyperCKemia with the use of
statins that emerges from these trials may mainly concern
subjects in the lower part of the CK distribution, with a low
a priori risk to develop highly elevated CK levels.
The exclusion of these patients before randomization may lead
to biased reports on the frequency of occurrence of side effects
with statin use. This should be acknowledged to be a limitation
when adverse effects associated with statins are assessed in
published trials.
1. Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT,
Krumholz HM. Risks associated with statin therapy: a systematic overview
of randomized clinical trials. Circulation. 2006;114:2788 –2797.
2. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto
AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New
Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in
patients with stable coronary disease. N Engl J Med. 2005;352:1425–1435.
3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection
Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.
4. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM,
Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW,
Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ,
Twomey C, Westendorp RG; PROSPER Study Group. Pravastatin in
elderly individuals at risk of vascular disease (PROSPER): a randomised
controlled trial. Lancet. 2002;360:1623–1630.
5. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW,
McKillop JH, Packard CJ. Prevention of coronary heart disease with
pravastatin in men with hypercholesterolemia. West of Scotland Coronary
Prevention Study Group. N Engl J Med. 1995;333:1301–1307.
(Circulation. 2007;116:e7.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.689497
e7
Correspondence
drug could still account for myalgias in ⬎250 000 patients—
not quite an insignificant number!
Letter by Rosenberg and Uretsky Regarding Article,
“Risks Associated With Statin Therapy: A
Systematic Overview of Randomized Clinical Trials”
To the Editor:
In regard to the article by Kashani et al,1 the authors
conclude that “...statin therapy is associated with small excess
risk of transminase elevations, but not of myalgias, creatine
kinase elevations, rhabdomyolysis...”. We think this conclusion is misleading. On closer inspection of the data, atorvastatin has 3 times the occurrence of myalgias compared with
placebo (P⬍0.04). According to the authors’ data, these
adverse events seem to be unique to atorvastin and were not
observed with other statins. Admittedly the absolute risk is
small; however, when one considers that in the US alone ⬇5
million patients are presently treated with atorvastatin, this
Disclosures
None.
Lauren Rosenberg, MD
Seth Uretsky, MD
St Luke’s-Roosevelt Medical Center
Columbia University College of Physicians and Surgeons
New York, NY
1. Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, Krumholz
HM. Risks associated with statin therapy: a systematic overview of randomized
clinical trials. Circulation. 2006;114:2788–2797.
(Circulation. 2007;116:e8.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.690867
e8
Correspondence
Response to Letters Regarding Article, “Risks
Associated With Statin Therapy: A Systematic
Overview of Randomized Clinical Trials”
Amir Kashani, MS, MD
JoAnne M. Foody, MD
Yongfei Wang, MS
Harlan M. Krumholz, MD, SM
Section of Cardiovascular Medicine
Department of Medicine
Yale University School of Medicine
New Haven, Conn
The letters that address our analysis of risks associated with statin
therapy1 raise 2 important points: the generalizability of the data and
the excess incidence of myalgias observed with atorvastatin therapy.
Although inclusion/exclusion criteria required for clinical trials limit
generalizability to patients in clinical practice, randomized controlled trials remain the best unbiased source of data to assess
adverse effects.2,3 However, there remains a need for additional,
large, safety studies in populations previously not studied.
In their letter, Drs Brewster and van Montfrans indicate that
some statin trials exclude patients with elevated creatine kinase
levels (⬎1.5 to 6 times the upper limit of normal). We believe
that these patients are appropriately excluded, as patients with
extreme creatine kinase elevations have an underlying pathology
and may represent a population inappropriate for statin therapy.
The issue of excess incidence of myalgia observed with
atorvastatin, raised in the letter from Drs Rosenberg and Uretsky,
merits further investigation. This observation reached marginal
statistical significance (P⫽0.04) and was based on only 567
patients (19 of 375 patients versus 3 of 192 patients in the
treatment and placebo groups, respectively). Accordingly, this
finding is worth further pursuit, but should not be considered
definitive at this time.
Christopher O. Phillips, MD, MPH
Department of General Internal Medicine
The Cleveland Clinic Foundation
Cleveland, Ohio
Sandeep Mangalmurti, MD
Ambulatory Health Clinic
United States Navy
Groton, Conn
Dennis T. Ko, MD
Schlich Heart Centre
Sunnybrook Health Sciences Centre
Ontario, Canada
1. Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT,
Krumholz HM. Risks associated with statin therapy: a systematic
overview of randomized clinical trials. Circulation. 2006;114:
2788 –2797.
2. Curtin F, Altman DG, Elbourne D. Meta-analysis combining parallel
and cross-over clinical trials. I: Continuous outcomes. Stat Med.
2002;21:2131–2144.
3. Curtin F, Elbourne D, Altman DG. Meta-analysis combining parallel and
cross-over clinical trials. III: The issue of carry-over. Stat Med.
2002;21:2161–2173.
Disclosures
Dr Foody received honoraria from and served as a consultant/
advisory board member for Merck, BMS/Sanofi, and Pfizer. The
other authors have nothing to disclose.
(Circulation. 2007;116:e9.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.697227
e9
Acknowledgment of Reviewers
The editors express appreciation to the following referees who served from July 1, 2006, though December 31, 2006.
Einari Aavik
Inmaculada B. Aban
Nicola Abate
Amr E. Abbas
Antonio Abbate
Jinnette Dawn Abbott
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Piergiuseppe Agostoni
Eustachio Agricola
Pietro Maria G. Agricola
David Aguilar
Seyedhossein Aharinejad
Ferhaan Ahmad
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Alsir A.M. Ahmed
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Acknowledgment of Reviewers
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Acknowledgment of Reviewers
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Victor G. Davila-Roman
Bryce H. Davis
Roger B. Davis
Robin L. Davisson
Kevin P. Davy
Buddhadeb Dawn
Jeffrey D. Dawson
Jonathan R.S. Day
Mariza de Andrade
Dirk De Bacquer
Jacques de Bakker
Bernard De Bruyne
Marco De Carlo
Raffaele De Caterina
Carlos R. De Diego
Sarah D. de Ferranti
Pim J. de Feyter
Dominique P. de Kleijn
Peter W. de Leeuw
James A. de Lemos
Moniek P.M. de Maat
Ramon de Nooijer
Anne-Cornelie J.M. de Pont
Albert de Roos
Giovanni de Simone
Bianca L. De Stavola
Pieter P. de Tombe
Roberto De Vogli
Leon J. De Windt
Robbert J. de Winter
Dick de Zeeuw
Barbara J. Deal
John Eric Deanfield
Arjun Deb
G. William Dec
Jeanne M. DeCara
Carole J. Decker
Ulrich K.M. Decking
Prakash C. Deedwania
Carolin Deiner
Etienne Delacrétaz
Brian P. Delisle
Mario Delmar
Anthony N. DeMaria
Linda L. Demer
Nikolaos Demiris
Martin den Heijer
Mario C. Deng
David DeNofrio
Christophe Depre
Akshay S. Desai
Milind Desai
Anne M. Deschamps
Christopher A. DeSouza
Jean-Pierre Despres
Alexander Deten
Christian Detter
Marcelo F. Di Carli
Michele Di Mauro
Nuno V. Dias
David A. Dichek
Hans Dieplinger
D.B. Diercks
Rodney J. Dilley
Wolfgang H. Dillmann
Vasken Dilsizian
J. Michael DiMaio
John P. DiMarco
Pawel Petkow Dimitrow
Stefanie Dimmeler
Robert A.E. Dion
Donald J. DiPette
Dobromir Dobrev
Douglas W. Dockery
Frances Dockery
Jean-Michel P.N. Dogné
Anuja Dokras
Raul J. Domenech
J. Kevin Donahue
Rosario Donato
Acknowledgment of Reviewers
Chunming Dong
G.A. Donnan
Marjo Donners
Vincent Dor
Andrea Doria
Paul Dorian
Pedro D’orléans-Juste
Gerald W. Dorn
Mirko Doss
John S. Douglas
Pamela S. Douglas
James M. Downey
Luciano Ferreira Drager
Christopher Drake
Mark H. Drazner
Helmut Drexler
Daniel L. Dries
Dayue Duan
Naihua Duan
Raghvendra K. Dubey
Anique Ducharme
Stephen J. Duffy
Jean G. Dumesnil
Brian W. Duncan
J. Michael Duncan
Daniel Duprez
Jocelyn Dupuis
William Durante
Greg Dusting
Lance D. Dworkin
Jason R. Dyck
Peter Dyck
Kim A. Eagle
Mark J. Earley
Cara A. East
Robert T. Eberhardt
Franz R. Eberli
Shah Ebrahim
Dwain L. Eckberg
Robert H. Eckel
Elazer R. Edelman
Sarah Eder
Thomas S. Edgington
Richard Edwards
Igor R. Efimov
Kensuke Egashira
Hannelore Ehrenreich
Oliver Eickelberg
Andreas Eicken
Benjamin W. Eidem
John F. Eidt
John W. Eikelboom
Michael Eikmans
Graeme Eisenhofer
David A. Eisner
Tony Eissa
Daniel T. Eitzman
Ulf Ekelund
Garabed Eknoyan
Amir Elami
John A. Elefteriades
Suzette Elias-Smale
Uri Elkayam
Ronald C. Elkins
Kenneth A. Ellenbogen
C. Gregory Elliott
Stephen G. Ellis
R Curtis Ellison
Costanza Emanueli
Michael Emerson
Mary Emond
Jean-Philippe Empana
Masao Endoh
Matthias Endres
S. Engeli
Richard M. Engelman
Marguerite M. Engler
Robert L. Engler
Mark L. Entman
Andrew Epstein
Stephen E. Epstein
Raimund R. Erbel
Sandra Erbs
John M. Erikson
Urs K. Eriksson
Aycan F. Erkan
Korhan Erkanli
David Erlinge
Sabine Ernst
Georg Ertl
Nilda Gladys Espinola
Christine Espinola-Klein
Katherine Esposito
Barry C. Esrig
Faadiel Essop
Mohammed Rafique Essop
N.A. Mark Estes
Anthony L. Estrera
Susan P. Etheridge
Charles J. Everett
Gordon A. Ewy
Vernat Exil
Michael D. Ezekowitz
Gianluca Faggioli
Colomba Falcone
Pierre-Emmanuel Falcoz
Erling Falk
Rodney H. Falk
James A. Fallavollita
John T. Fallon
James C. Fang
James I. Fann
Søren Fanø
Frank Faraci
Andrew Farb
Jeronimo Farre
Marc Fatar
Farzin F. Fath-Ordoubadi
Diane Fatkin
Rossella Fattori
Desiderio Favarato
William P. Fay
Zahi A. Fayad
Sergio Fazio
William F. Fearon
Paul W.M. Fedak
Martin Feelisch
Jeffrey A. Feinstein
Frederick Feit
Arthur M. Feldman
David S. Feldman
Ted Feldman
Peter Ferdinandy
Maros Ferencik
James J. Ferguson
T. Bruce Ferguson
Francisco Fernandez-Aviles
Olivier Feron
Christiane Ferran
Carlos M. Ferrario
Victor A. Ferraris
Paolo Ferrazzi
Robert E. Ferrell
Julio J. Ferrer-Hita
Andreas Festa
Loren J. Field
David S. Fieno
Hans R. Figulla
Marcin Fijalkowski
Janos G. Filep
Kristian B. Filion
Jeffrey R. Fineman
Toren Finkel
Joel Finkelstein
Louis D. Fiore
Paolo Fiorina
Christian Firschke
Peter Fischbach
Roman Fischbach
Marcus Fischer
Uwe M. Fischer
Rodolphe Fischmeister
Céline Fiset
Michael C. Fishbein
Edward A. Fisher
Marc Fisher
Patrick W. Fisher
Steven A. Fisher
Garret A. FitzGerald
Peter J. Fitzgerald
Greg C. Flaker
Scott D. Flamm
Marcus D. Flather
Jerome L. Fleg
Lee A. Fleisher
Ingrid Fleming
Danilo Fliser
John S. Floras
Alan M. Fogelman
Robert N. Foley
Warren Foltz
Gregg C. Fonarow
Guo-Hua Fong
e13
Thomas Joseph Forbes
Thomas Force
Ian Ford
Daniel Forman
Myriam Fornage
James S. Forrester
Tom Forsen
Elyse Foster
Jean-Claude Fouron
Caroline S. Fox
Keith A.A. Fox
Harry A. Fozzard
Gabriele Fragasso
Renerio Fraguas
Alain Fraisse
Mark W. Frampton
Gary S. Francis
Veronica Franco
John V. Frangioni
Nikolaos G. Frangogiannis
John A. Frangos
Barry A. Franklin
Charles Fraser
Sohrab Fratz
Gunilla Nordin Fredrikson
David S. Freedman
S. Ben Freedman
Brent A. French
John K. French
Michael P. Frenneaux
Ulrich H. Frey
Gary S. Friedman
Matthias G. Friedrich
Soren Friis
M. Kent Froberg
Victor Froelicher
Edward D. Frohlich
Jiri J. Frohlich
Peter C. Frommelt
Alexandra Theresia Fuchs
Flavio Danni Fuchs
Robert C. Fuhlbrigge
Bianca Fuhrman
Yoshihiro Fukumoto
John W. Funder
Colin D. Funk
Curt D. Furberg
George Fust
Valentin Fuster
William H. Gaasch
Alain-Pierre Gadeau
James V. Gainer
Peter A. Gaines
Maurizio Galderisi
Catharine R. Gale
Zorina S. Galis
William Gallo
Apoor S. Gami
Ronald Gangnon
Peter Ganz
Feng Gao
e14
Susan M. Gapstur
Mario J. Garcia
Julius M. Gardin
Timothy J. Gardner
Alistair N. Garratt
Peter Garred
Daniel J. Garry
Jean-Michel Théodule Gaspoz
Michael A. Gatzoulis
Glenn R. Gaudette
Kimberlee Gauvreau
Haralambos P. Gavras
Irene Gavras
J. William Gaynor
David C. Gaze
Thomas Gaziano
Raul J. Gazmuri
Carmine Gazzaruso
Carolyn L. Geczy
Bruce D. Gelb
Caroline Genco
Yong-Jian Geng
Thomas L. Gentles
Alfred L. George
James F. George
Sarah Jane George
Bernhard L. Gerber
Bernard J. Gersh
Welton M. Gersony
Gary Gerstenblith
Edward P. Gerstenfeld
Robert E. Gerszten
Leonard S. Gettes
Godfrey S. Getz
Tal Geva
Henry Gewirtz
Michael Gewitz
Mihai Gheorghiade
Giorgio Ghilardi
Raymond J. Gibbons
C. Michael Gibson
Frank C. Gibson
Samuel S. Gidding
Stephan Gielen
Wayne R. Giles
Linda D. Gillam
Brenda W. Gillespie
A. Marc Gillinov
Matthew W. Gillman
Richard F. Gillum
Robert F. Gilmour
Jeffrey M. Gimble
Frank J. Giordano
Domenico Girelli
Adriana C. Gittenberger-de
Groot
Robert P. Giugliano
Carla Giustetto
Michael M. Givertz
David Gjertson
Mark T. Gladwin
Acknowledgment of Reviewers
Stanton A. Glantz
Ruchira Glaser
Christopher Glass
Stephen J. Glatt
David K. Glover
Peter D. Gluckman
Robert J. Glynn
Alan S. Go
David C. Goff
Noyan Gokce
Diane R. Gold
Jeffrey P. Gold
Alexander Goldberg
Andrew P. Goldberg
Jeffrey J. Goldberger
Ilan Goldenberg
Joshua I. Goldhaber
Samuel Z. Goldhaber
Lee Goldman
Martin E. Goldman
Steve Goldman
James A. Goldstein
Larry B.Goldstein
Sidney Goldstein
Paolo Golino
Jonathan Golledge
Michael H. Gollob
Gershon Golomb
Ana M. Gomez
Celso E. Gomez-Sanchez
Philimon Gona
Isabel Goncalves
Mario D. Gonzalez
Mark O. Goodarzi
John Gorcsan
Tommaso Gori
Agnes Gorlach
Joseph H. Gorman
Shinya Goto
Roberta A. Gottlieb
K. Lance Gould
Andrew A. Grace
Juan F. Granada
Scott Grandy
Christopher B. Granger
Augustus O. Grant
Richard A. Gray
William A. Gray
Paul A. Grayburn
J. Thomas Grayston
Sally C. Greaves
Barry Greenberg
Roy K. Greenberg
Stephen E. Greenwald
Darren C. Greenwood
Kathy K. Griendling
Brian P. Griffin
John H. Griffin
Cindy L. Grines
Steven K. Grinspoon
Johannes C. Grisar
William J. Groh
Christian Grohe
Garrett J. Gross
Gil J. Gross
Paul D. Grossfeld
Eugene A. Grossi
Blair P. Grubb
Eberhard Grube
Scott M. Grundy
Gary L. Grunkemeier
William H. Guilford
Christian Guilleminault
Gerard Marcel Guiraudon
Giosue Gulli
Paul A. Gurbel
Geoffrey C. Gurtner
Björn I. Gustafsson
David D. Gutterman
Robert A. Guyton
Tomasz J. Guzik
Constance Kay Haan
Judith Haendeler
Steven M. Haffner
Dominik Georg Haider
David E. Haines
Michel Haissaguerre
Katherine Hajjar
Roger J. Hajjar
Julian P.J. Halcox
Charles A. Hales
Andrew Halestrap
Michael E. Halkos
Hermann Haller
Michael Hallman
Alfred P. Hallstrom
Naomi M. Hamburg
Mohamed H. Hamdan
Christian W. Hamm
Wayne W. Hancock
Aase Handberg
Anthony J. Hanley
Edward L. Hannan
Tim Hanson
Goran K. Hansson
Tomonori Haraguchi
Violet I. Haraszthy
Joshua M. Hare
Robert A. Harrington
William S. Harris
David G. Harrison
Paul Harrison
David Hasdai
Gerd Hasenfuss
Vic Hasselblad
Richard N.W. Hauer
Paul J. Hauptman
Derek J. Hausenloy
Richard J. Havel
Axel Haverich
Edward P. Havranek
Nat Hawkins
Robert A. Haworth
Kenshi Hayashi
Toshio Hayashi
Michael R. Hayden
David L. Hayes
Daniel Hayoz
Stanley L. Hazen
Mary Fran Hazinski
Guo-Wei He
Jiang He
Geoffrey Head
John P. Headrick
Susan R. Heckbert
Markus Hecker
Timothy Heeren
Christopher Heeschen
Robert A. Hegele
Paul A. Heidenreich
Jay W. Heinecke
Christian Heiss
Claes Held
Johanna Helmersson
Harry Hemingway
Jeroen Hendrikse
Marc Hendrikx
Timothy D. Henry
Moonseong Heo
Dirk Hermann
Ramon C. Hermida
Adrian F. Hernandez
Victoria L.M. Herrera
Amy Herring
David M. Herrington
Howard C. Herrmann
Ray E. Hershberger
Charles A. Herzog
Otto M. Hess
Gerd Heusch
Stephane Heymans
William R. Hiatt
Charles B. Higgins
Robert Higgins
Thomas Hilberg
Karl F. Hilgers
John S. Hill
Joseph A. Hill
Hans L. Hillege
L. David Hillis
Gerhard Hindricks
Aroon D. Hingorani
Rabea Hinkel
Loren F. Hiratzka
Yoshitaka Hirooka
Karen K. Hirschi
Valeria Hirschler
John W. Hirshfeld
Mark A. Hlatky
Michael Ho
Judith S. Hochman
Morrison Hodges
Barbara H. Hoffmann
Acknowledgment of Reviewers
Martin H. Hoffmann
Udo Hoffmann
Peter Höglund
Thomas Hohlfeld
Stefan H. Hohnloser
Brian D. Hoit
Fernando Holguin
David R. Holmes
Paul Holvoet
Michael Holzer
Shunichi Homma
Yuling Hong
L.N. Hopkins
Paul N. Hopkins
Richard Hopkins
Susan Hopkins
Maria T.E. Hopman
Masatsugu Hori
Masatsugu Horiuchi
Benjamin D. Horne
John D. Horowitz
Keith A. Horvath
Lawrence D. Horwitz
Akiko Hosler
Barbara V. Howard
George Howard
Vicky Y. Hoymans
Patrick C.H. Hsieh
Daphne T. Hsu
Fang-Chi Hsu
Priscilla Hsue
Chengcheng Hu
Gang Hu
Howard Hu
Rae-Chi Huang
Johnny Huard
Sally Ann Huber
Susanna Y. Huh
James C. Huhta
Heikki V. Huikuri
P.P. Hujoel
Roger Hullin
Per M. Humpert
William Gregory Hundley
Judy Hung
Sharon Ann Hunt
Stephen Hunyor
Ahsan Husain
Gianluca Iacobellis
Ioannis Iakovou
Fumito Ichinose
Raymond E. Ideker
Masaaki Ii
John S. Ikonomidis
Erkki Ilveskoski
Armin Imhof
Akihiro Inazu
Robin Ingalls
Julie R. Ingelfinger
Erik Ingelsson
Joanne S. Ingwall
John P. Ioannidis
Carlos Iribarren
Thomas A. Ischinger
Shun Ishibashi
Masaharu Ishihara
Tetsuya Ishikawa
Ami E. Iskandrian
Hiroyasu Iso
Mitsuaki Isobe
Hideki Itoh
Bernard Iung
D. Dunbar Ivy
Kohichiro Iwasaki
Gregory T. Jones
Robert H. Jones
Steven P. Jones
Habo J. Jongsma
Jens Jordan
Marit Eika Jørgensen
Jacob Joseph
Mark E. Josephson
Pekka Jousilahti
Michael J. Joyner
J. Wouter Jukema
Philip Jung
Suh-Hang Hank Juo
Wael A. Jaber
Edwin K. Jackson
Alice K. Jacobs
David R. Jacobs
Marshall L. Jacobs
Donald W. Jacobsen
Paul Jacques
Sae Young Jae
Michael R. Jaff
Allan S. Jaffe
Farouc A. Jaffer
Mukesh Kumar Jain
Jose Jalife
Richard W. James
Konrad Jamrozik
Ik-Kyung Jang
Joseph S. Janicki
Warren R. Janowitz
Maurits A. Jansen
Stefan P. Janssens
Craig T. January
James Louis Januzzi
Patrick Y. Jay
John Jefferies
J. Richard Jennings
Jong Hyeon Jeong
Jamie Yancey Jeremy
Tomas Jernberg
Michael Jerosch-Herold
Paula Jerrard-Dunne
Ashish K. Jha
Ishwarlal Jialal
Hongyu Jiang
Zhihua Jiang
Zhezhen Jin
Hanjoong Jo
Magnus Carl Johansson
Roger A. Johns
Arnold Johnson
B. Delia Johnson
Jason L. Johnson
Lynne L. Johnson
Paula A. Johnson
Richard J. Johnson
Robert L. Johnson
Robert Graham Johnson
Timothy D. Johnson
James G. Jollis
Stefan Kaab
Ramanathan Kadirvel
Alan H. Kadish
Hiroyuki Kageyama
Richard Kahn
Hisashi Kai
Jan Kajstura
Afksendiyos Kalangos
Jonathan M. Kalman
Timothy J. Kamp
David E. Kandzari
Sachiko Kanki-Horimoto
Prince J. Kannankeril
Ronald J. Kanter
Jørgen K. Kanters
Emmanouil Ioannis Kapetanakis
Tara Karamlou
Richard H. Karas
Elissavet Kardami
Tom R. Karl
Johan Karlberg
Joel S. Karliner
Aly Karsan
S. Ananth Ananth Karumanchi
David Alan Kass
Robert S. Kass
Jerome P. Kassirer
Adnan Kastrati
Sekar Kathiresan
Masahiko Kato
Tomohiro Katsuya
Hugo A. Katus
Zvonimir S. Katusic
Stuart D. Katz
Marc P. Kaufman
Philipp A. Kaufmann
Padma Kaul
Sanjiv Kaul
Rae-Ellen Kavey
Chuichi Kawai
Ziya Kaya
David M. Kaye
Mark T. Kearney
Bernard Keavney
Daniel P. Kelly
Darren J. Kelly
Ralph A. Kelly
Kenneth M. Kent
e15
Rosemary J. Keogh
Richard E. Kerber
Dean J. Kereiakes
Karl B. Kern
Morton J. Kern
Steven J. Keteyian
Paul Khairy
Amit Khera
Ali Reza Khoshdel
Stefan Kiechl
Jan T. Kielstein
Shinji Kihara
Lois A. Killewich
Philip J. Kilner
David Kilpatrick
Hyo-Soo Kim
Shokei Kim-Mitsuyama
Spencer B. King
Bronwyn A. Kingwell
Scott Kinlay
Margaret L. Kirby
Paulus F. Kirchhof
James Kirklin
Lorrie A. Kirshenbaum
Toru Kita
Masafumi Kitakaze
Michelle Kittleson
Arthur L. Klatsky
Neal S. Kleiman
Allan L. Klein
George J. Klein
Lloyd W. Klein
Michael D. Klein
Charles S. Kleinman
Paul D. Kligfield
Uwe Klima
Francis J. Klocke
Robert A. Kloner
John L. Knight
Anne A. Knowlton
Juhani Knuuti
Jon A. Kobashigawa
Lars Kober
Colleen Gorman Koch
Walter J. Koch
Werner Koch
Patrick M. Kochanek
Paul V. Kochupura
Todd M. Koelling
Wolfgang Koenig
Theo Kofidis
Kwang Kon Koh
Martin Köhrmann
Pipin Kojodjojo
Pappachan E. Kolattukudy
Theodore J. Kolias
Frank D. Kolodgie
MichelM. K. Komajda
Tatsuya Komaru
Masashi Komeda
Issei Komuro
e16
Takahisa Kondo
Marvin A. Konstam
Stavros V. Konstantinides
Michael C. Kontos
Marianne Eline Kooi
Willem J. Kop
Bruce A. Koplan
Gideon Koren
Andreas Koster
Thomas Erling Kottke
Darrell N. Kotton
Alexei Kouroedov
Petri T. Kovanen
Peter R. Kowey
Jun Koyama
Andrew D. Krahn
Dara L. Kraitchman
Aldi Kraja
Christopher M. Kramer
Evangelia G. Kranias
William E. Kraus
Ronald M. Krauss
Eswar Krishnan
Steen Dalby Kristensen
Michael H. Kroll
Irving L. Kron
Mitchell W. Krucoff
Warren Kruger
Henry Krum
Isao Kubota
Karen Kuehl
Nino Kuenzli
Donald M. Kuhn
Helena Kuivaniemi
Thomas J. Kulik
Lewis H. Kuller
Iftikhar J. Kullo
Koichiro Kumagai
Cheng-Deng Kuo
Christian Kupatt
Sabina Kupershmidt
Hiromi Kurosawa
Tobias Kurth
Irving Kushner
Johanna Kuusisto
Jeffrey T. Kuvin
Masafumi Kuzuya
Martijn Kwaijtaal
Raymond Y. Kwong
Yoshiki Kyo
Alan Patrick Kypson
David E. Laaksonen
Carlos Alberto Labarrere
Vinod Labhasetwar
Arthur Labovitz
Daniel Lackland
Karl J. Lackner
Peter S. Lacy
Stephanie Laeer
Huichuan Lai
Shenghan Lai
Acknowledgment of Reviewers
Wyman W. Lai
Edward G. Lakatta
Evanthia Lalla
Karen S.L. Lam
Benoit Lamarche
John J. Lamberti
Michael J. LaMonte
Rachel Lampert
Kathryn G. Lamping
Steve Lancel
R. Clive Landis
Ulf Landmesser
Michael J. Landzberg
Florian Lang
Irene Marthe Lang
Roberto M. Lang
Jonathan Langberg
Elisabetta Lapenna
Gina LaRocca
John C. LaRosa
Martin Larson
Warren K. Laskey
Robert D. Lasley
Johan P.E. Lassus
Roberto Latini
Wei C. Lau
Michael S. Lauer
Ulrich Laufs
Jari A. Laukkanen
Lenore J. Launer
Geoffrey J. Laurent
Kenneth R. Laurita
Peter C. Laussen
Michael LaValley
Carl Lavie
Debbie A. Lawlor
Harold L. Lazar
Mitchell A. Lazar
Thierry H. Le Jemtel
Bruce J. Leavitt
Alexander Wolfgang Leber
Nathan K. LeBrasseur
Sandrine Lecour
Amanda J. Lee
Douglas S. Lee
Duk-Hee Lee
Hon-Chi Lee
I-Min Lee
Kerry L. Lee
Richard T. Lee
Frans H.H. Leenen
David J. Lefer
Michael H. Lehmann
Stephan E. Lehnart
Stephanie Lehoux
James M. Leiper
Paul LeLorier
Karl B. Lemstrom
Steven R. Lentz
David A. Leon
Philipp M. Lepper
Amir Lerman
Bruce B. Lerman
Lilach O. Lerman
Michelle Letarte
Hanno H. Leuchte
Adeera Levin
Max Levin
Benjamin D. Levine
R.J. Levine
Robert A. Levine
Sidney Levitsky
Bodo Levkau
Bruce D. Levy
Daniel Levy
Finn Olav Levy
Jerrold H. Levy
Robert J. Levy
Wayne C. Levy
Marilyne Lévy
Elad I. Levy
E. Douglas Lewandowski
Martin M. LeWinter
Eldrin F. Lewis
Gary F. Lewis
Chuanfu Li
Fan Li
Gui-Rong Li
Liang Li
Na Li
Nan Li
Ren-Ke Li
Ronald A. Li
Chang-seng Liang
James K. Liao
Ronglih Liao
Peter Libby
Andrew H. Lichtman
David Richard Light
Chee Chew Lim
Valter C. Lima
Marian C. Limacher
Jing Ping Lin
Julie Lin
JoAnn Lindenfeld
Marshall D. Lindheimer
Jes S. Lindholt
Jonathan R. Lindner
Karl H. Lindner
Ken A. Lindstedt
Mark S. Link
Axel Linke
MacRae F. Linton
Gregory Y.H. Lip
Steven E. Lipshultz
Lewis A. Lipsitz
Richard Lipton
William C. Little
Laszlo Littmann
Kiang Liu
Donald M. Lloyd-Jones
Cecilia Wen-Ya Lo
Eng H. Lo
Amanda Lochner
James E. Lock
Andrew J. Lodge
Frank W. LoGerfo
Barry London
Gérard M. London
Eva M. Lonn
Gary D. Lopaschuk
Matthias W. Lorenz
Douglas W. Losordo
Stavros P. Loukogeorgakis
Gordon D. Lowe
Tse Min Lu
Russell V. Luepker
Friedrich C. Luft
Ketil Lunde
Kathryn Lunetta
Keith G. Lurie
Thomas F. Luscher
Aldons J. Lusis
Deborah Lyn
John W. Lynch
Xin Liang Ma
Christoph Maack
David M. Maahs
Charles A. Mack
Michael J. Mack
Wendy J. Mack
Todd A. MacKenzie
Rachel H. Mackey
Nigel Mackman
Michael I. Mackness
Kenneth N. MacLean
William Robb MacLellan
Paolo Madeddu
Aldo P. Maggioni
William T. Mahle
William T. Mahle
Jonathan D. Mahnken
Lynn Mahony
Lars S. Maier
Willibald Maier
Francesco Maisano
William H. Maisel
Amy S. Major
Koon-Hou Mak
Jonathan C. Makielski
Marek Malik
Robert T. Mallet
Giuseppe Mancia
Donna M. Mancini
G.B. John Mancini
Kaushik Mandal
Ravi Mandapati
Jayawant N. Mandrekar
Dennis T. Mangano
Arduino A. Mangoni
Douglas L. Mann
Giovanni E. Mann
Stewart Mann
Acknowledgment of Reviewers
Warren J. Manning
Teri A. Manolio
Nicolas Mansencal
Alberto Mantovani
Michael Stephen Marber
Francis E. Marchlinski
Frank I. Marcus
Andrew O. Maree
Raffaele Marfella
James R. Margolis
Kenneth B. Margulies
Daniel B. Mark
Roger Markwald
Jonathan D. Marmur
Barry J. Maron
David J. Maron
Martin Maron
Luc Maroteaux
Philip A. Marsden
Steven P. Marso
Randolph P. Martin
Ulrich Martin
Thomas H. Marwick
Gerald R. Marx
Nikolaus Marx
Daniele Maselli
Attilio Maseri
Frederick A. Masoudi
Joseph M. Massaro
Barry M. Massie
Serge Masson
Kazuko Masuo
Fiona Mathews
Knut Matre
Hiroaki Matsubara
Hikaru Matsuda
Akira Matsumori
Francesco U.S. Mattace-Raso
Christian M. Matter
Marco L.S. Matteucci
Nilanjana Maulik
Mathew S. Maurer
Laura Mauri
Simon Maxwell
Charles Maynard
Bongani Mawethu Mayosi
Todor N. Mazgalev
PatrickM. McCarthy
Michael V. McConnell
Michael Leon McCormick
Brian W. McCrindle
Peter A. McCullough
David H. McDermott
Mary McGrae McDermott
Doff B. McElhinney
CarmelM. McEniery
Edward Mcfalls M.D.
Daniel McGee
John C. McGiff
John L. McGregor
Darren K. McGuire
William J. McKenna
Vallerie V. McLaughlin
C. Alex McMahan
John J.V. McMurray
Elizabeth M. McNally
Robert L. McNamara
Helene McNulty
Charles F. McTiernan
Mandeep R. Mehra
Roxana Mehran
Jawahar L. Mehta
Shamir R. Mehta
Bernhard Meier
James B. Meigs
Silke Meiners
Cynthia J. Meininger
Christa Meisinger
Daniel Meldrum
Russell H. Mellor
Philippe Menasche
Ulrike Mende
Jean-Jacques Mercadier
Patrick Mercie
Yahye Merhi
Alan F. Merry
C. Noel Merz
Emmanuel Messas
Franz H. Messerli
Luisa Mestroni
Peter Meyer
Theo E. Meyer
J.A. Michaels
Evangelos D. Michelakis
Erin Donnelly Michos
Shigetoshi Mieno
Richard V. Milani
D. Douglas Miller
D. Craig Miller
Jordan D. Miller
Leslie W. Miller
Todd D. Miller
Virginia M. Miller
Susumu Minamisawa
L. LuAnn Minich
Kenji Minoguchi
Gary S. Mintz
Israel Mirsky
Manisha Mishra
Seema Mital
Brett M. Mitchell
Gary F. Mitchell
R. Scott Mitchell
Richard N. Mitchell
Arnold Mitnitski
Suneet Mittal
Friedrich Mittermayer
Murray A. Mittleman
Hiroto Miura
Mihaela M. Mocanu
Peter Mohler
Emile R. Mohler III
Ali H. Mokdad
Ernesto Molina
Giuseppe Molinari
David J. Moliterno
Jeffery D. Molkentin
Nico R. Mollet
Tom E. Mollnes
Donald A. Molony
Laurent Monassier
Nicola Montano
Farouk Mookadam
Jeffrey Moore
Samia Mora
Martin Morad
Fred Morady
Pierre Moreau
L.A. Moreno
Marie-Claude Morice
Carlos A. Morillo
Ryuichi Morishita
Toshisuke Morita
Gregory E. Morley
Nicholas W. Morrell
Brian J. Morris
Laurie J. Morrison
David A. Morrow
Richard Mortensen
Ralph S. Mosca
Mauro Moscucci
Jeffrey W. Moses
Ivan P. Moskowitz
Arthur J. Moss
Karen S. Moulton
J. Paul Mounsey
Matthew Movsesian
Dariush Mozaffarian
Thomas Muenzel
Andreas Mugge
Andrew Mugglin
Debabrata Mukherjee
Rupak Mukherjee
Douwe J. Mulder
James E. Muller
Jochen Muller-Ehmsen
Michael J. Mulvany
Tomoatsu Mune
Paul Muntner
Elizabeth Murphy
Timothy P. Murphy
Charles E. Murry
Anthony J. Muslin
Aviva Must
Robert J. Myerburg
Daniel D. Myers
Jonathan Myers
Leann Myers
Elizabeth G. Nabel
Koonlawee Nademanee
Ryozo Nagai
Shoichiro Nagasaka
Eike Nagel
e17
Sherif F. Nagueh
Matthias Nahrendorf
Samer Najjar
Hiroshi Nakagawa
Brahmajee K. Nallamothu
Bin Nan
Claudio Napoli
Carlo Napolitano
Sanjiv M. Narayan
Jagat Narula
David Nash
Andrea Natale
Peter Nathanielsz
Stanley Nattel
Matthew T. Naughton
Mohamad Navab
Frank Naya
Mona Nemer
Dario Neri
Richard W. Nesto
Stefan Neubauer
Donna S. Neuberg
Ellis J. Neufeld
Franz-Josef Neumann
Joachim Neumann
Peter Newburger
David E. Newby
L. Kristin Newby
John H. Newman
Mark F. Newman
Christopher H. Newton-Cheh
Ludwig Neyses
Dusko G. Nezic
Stephen James Nicholls
Wilmer W. Nichols
Georg Nickenig
Martin John Nicklin
Alfred C. Nicolosi
James T. Niemann
Christoph A. Nienaber
Petros Nihoyannopoulos
Sigrid Nikol
Rick A. Nishimura
Steven E. Nissen
Dorothea Nitsch
Timothy David Noakes
Yoshihiro Noji
Georg Nollert
Fumikazu Nomura
Lars Norgren
Sharon-Lise T. Normand
Kari E. North
Gavin R. Norton
Michael G.A. Norwood
Ann-Trude With Notø
Gian M. Novaro
William C. Nugent
Satoshi Numata
Jürg Nussberger
Pirjo Nuutila
e18
Timothy Daniel O’Connell
Christopher M. O’Connor
Gerald T. O’Connor
Christopher J. O’Donnell
Peter Oettgen
Patrick T. O’Gara
Jae K. Oh
Seil Oh
Takahiro Ohara
Ann M. O’Hare
Patrick Ohlmann
E. Magnus Ohman
John Ohrvik
Peter M. Okin
Johannes Oldenburg
Donal S. O’Leary
Jeffrey W. Olin
Michael Hecht Olsen
Eric N. Olson
Lyle J. Olson
Anders G. Olsson
Ray A. Olsson
Patrick G. O’Malley
Eileen O’Meara
Steve R. Ommen
James O. O’Neill
Henry Ooi
Suzanne Oparil
Lionel H. Opie
Hakan Oral
E. John Orav
Jose M. Ordovas
Joseph P. Ornato
Michael F. O’Rourke
Leiv Ose
Clive Osmond
Yutaka Otsuji
David Ott
Harald C. Ott
Catherine M. Otto
Noriyuki Ouchi
Michel Ovize
Al Ozonoff
Pal Pacher
Sandosh Padmanabhan
Francis D. Pagani
Massimo Pagani
Richard L. Page
Jennifer Pai
Paolo Palatini
Wulf Palinski
Julio C. Palmaz
Colin N.A. Palmer
Demosthenes Panagiotakos
Natesa G. Pandian
James S. Pankow
Nazareno Paolocci
Domenico Paparella
Carlo Pappone
Thomas G. Parker
Juan C. Parodi
Acknowledgment of Reviewers
Michele Pasotti
Gerard Pasterkamp
Amit N. Patel
Anushka Alankar Patel
Ayan Patel
Jeetesh V. Patel
Carlo Patrono
Richard D. Patten
Cam Patterson
Walter J. Paulus
Aimée D.C. Paulussen
Jeffrey M. Pearl
Jeremy D. Pearson
Daniel Pella
Patricia A. Pellikka
Michael Pencina
Marc S. Penn
Dudley J. Pennell
Carl J. Pepine
Paul E. Peppard
Emerson C. Perin
John Pernow
James C. Perry
Stephen D. Persell
Sharina D. Person
G. Rutger Persson
Inga Peter
Karlheinz Peter
Nicholas S. Peters
Eric D. Peterson
Linda R. Peterson
Pamela Peterson
Eva Petkova
Michael E. Phelps
Gerald B. Phillips
Richard P. Phipps
Colin K. Phoon
Robert N. Piana
Philippe Pibarot
Eugenio Picano
Michael H. Picard
J. Geoffrey Pickering
Thomas G. Pickering
Luc A. Pierard
Burkert Pieske
Bruce Pihlstrom
Nico H.J. Pijls
Louise Pilote
David R. Pimentel
Ileana Pina
H. Michael Piper
Tobias Pischon
Bertram Pitt
Jeffrey L. Platt
Jonathan F. Plehn
Mark J. Pletcher
Jorge Plutzky
Bruno K. Podesser
Gerald M. Pohost
Paul Poirier
Joseph F. Polak
Don Poldermans
Jaimie W. Polson
Giulio Pompilio
Philip A. Poole-Wilson
Barry M. Popkin
Thomas R. Porter
Wendy S. Post
Luciano Potena
Lincoln Potter
Jeffrey T. Potts
Neil Poulter
Andrew J. Powell
Janet T. Powell
Ashwin Prakash
Abhiram Prasad
Sanjay K. Prasad
Susan J. Pressler
Jack F. Price
Ronald Prineas
Frits W. Prinzen
Silvia G. Priori
Kirkwood A. Pritchard, Jr.
Vincent Probst
Karin Przyklenk
William T. Pu
John D. Puskas
Reed Pyeritz
Kalevi Pyorala
Zhaohui Steve Qin
Miguel A. Quiñones
Ton J. Rabelink
Alejandro A. Rabinstein
Vittorio Racca
Frank E. Rademakers
Daniel J. Rader
R. Radermecker
Martha J. Radford
Paolo Raggi
Shahbudin H. Rahimtoola
Leopoldo Raij
Elaine W. Raines
Olli T. Raitakari
Sanjay Rajagopalan
Nalini M. Rajamannan
Venkatesh Rajapurohitam
Harry Rakowski
Vivek Rao
Ursula Rauch
Ursula Ravens
Reza S. Razavi
Peter Razeghi
Richard Re
Patricia Reant
Rita F. Redberg
Margaret M. Redfield
Josep Redon
Thomas C. Register
Jalees Rehman
Nathaniel Reichek
Muredach Reilly
Azaria J.J.T. Rein
Olaf Reinhartz
Steven E. Reis
Willem J. Remme
Serge C. Renaud
Frederic S. Resnic
Kathyrn M. Rexrode
Matthew R. Reynolds
Shereif H. Rezkalla
Edward K. Rhee
Jonathan Rhodes
Jorge P. Ribeiro
Fernando F. Ribeiro-Filho
Paul M. Ribisl
Ken Rice
Jean-Paul Richalet
Vincent Richard
Paul M Ridker
Johannes Rieger
Nader Rifai
Charanjit S. Rihal
Eric B. Rimm
P.A. Ringleb
Rasmus Sejersten Ripa
James M. Ritter
Eberhard Ritz
Alain Rivard
Jeffrey Robbins
Robert Roberts
William C. Roberts
Sander J. Robins
Jennifer G. Robinson
Simon C. Robson
Frederic Roche
Dan M. Roden
Brian Rodrigues
Alfredo E. Rodriguez
Alicia Rodriguez-Pla
Matthew T. Roe
Mark Roest
Marco Roffi
Veronique L. Roger
Campbell Rogers
Joseph G. Rogers
Mary J. Roman
Mats Rönnback
Dieter Ropers
Wayne D. Rosamond
Eric A. Rose
Noel R. Rose
Michael R. Rosen
David S. Rosenbaum
Gary A. Rosenberg
Michael E. Rosenfeld
Robert S. Rosenson
David N. Rosenthal
Anthony Rosenzweig
Bernard Rosner
Allan M. Ross
David L. Ross
Gian Paolo D. Rossi
Acknowledgment of Reviewers
Marco L. Rossi
J.E. Rossouw
Stephen J. Roth
Dietrich Rothenbacher
Richard B. Rothman
Peter M. Rothwell
Joris Rotmans
Melvyn Rubenfire
Frederick L. Ruberg
Lewis J. Rubin
Israel Rubinstein
Neil B. Ruderman
Goran Rudez
Marc Ruel
Luis M. Ruilope
Carlos E. Ruiz
Pilar Ruiz-Lozano
John S. Rumsfeld
Marschall S. Runge
Frank Ruschitzka
Raymond R. Russell
Vincenzo Russo
Wolfgang Rutsch
Carolyn Rutter
Elfriede Ruttmann
Thomas Ryan
Thomas J. Ryan
Jack Rychik
Lars Ryden
Tobias Saam
Samir Saba
Hani N. Sabbah
Joseph F. Sabik
Ralph L. Sacco
Michael N. Sack
Frank M. Sacks
Michael S. Sacks
J. Evan Sadler
Junichi Sadoshima
Michel E. Safar
Jeffrey E. Saffitz
Robert D. Safian
Alexander Sagie
David J. Sahn
Genichi Sakaguchi
Sanjeev Saksena
Tomas A. Salerno
Veikko Salomaa
Flora Sam
Frederick F. Samaha
Nilesh J. Samani
Jeffrey Samet
Jonathan M. Samet
Jane-Lise Samuel
Timothy Allen Sanborn
Dirk Sander
Mikael Sander
Stephen P. Sanders
John E. Sanderson
Anthony J. Sanfilippo
Michael C. Sanguinetti
John Lewis Sapp
Dennis Sarabi
Wim Saris
Ferdinando Carlo Sasso
Masataka Sata
Naveed Sattar
Kurt W. Saupe
Giorgio Savazzi
Stephen G. Sawada
Tatsuya Sawamura
Douglas B. Sawyer
Leslie A. Saxon
Tiziano Scarabelli
Pierre-Yves Scarabin
Volker Schachinger
Thomas Schachner
Alvin Schadenberg
Hartzell V. Schaff
Martin J. Schalij
Bernhard Schaller
Wolfgang Schaper
Doug E. Schaubel
Patrick Schauerte
Debra Ann Schaumberg
Dierk Scheinert
Melvin M. Scheinman
Sebastian M. Schellong
Benjamin J. Scherlag
Ralph Theo Schermuly
Bernhard Schieffer
Giuseppe Schillaci
Martin Schillinger
Alexandru Schiopu
Thomas Schlosser
Alvin Schmaier
Axel Schmermund
Claudia Schmidtke
Neil Schneiderman
Albert Schoemig
Frederick J. Schoen
Mark Howard Schoenfeld
Jurgen Schrader
Richard B. Schuessler
Gerhard C. Schuler
Kevin A. Schulman
Heinz-Peter Schultheiss
Richard Schulz
Eric Schulze-Bahr
Heribert Schunkert
Arnold Schwartz
Gary L. Schwartz
Kenneth A. Schwartz
Peter J. Schwartz
Robert Stockton Schwartz
David S. Schwartzman
Ernst R. Schwarz
P.E. Schwarz
Karie Scrogin
Paola Sebastiani
Christine E. Seidman
Jonathan G. Seidman
Christian Seiler
Akira Sekikawa
Donald F. Sellitti
Frank W. Sellke
Elizabeth Selvin
Andrew P. Selwyn
Craig H. Selzman
Gregg L. Semenza
Marc J. Semigran
Chris Sempos
Chandan K. Sen
Roxy Senior
Victor L. Serebruany
Charles N. Serhan
Patrick W. Serruys
Marc J. Servant
Sudha Seshadri
Howard D. Sesso
Magnus Settergren
Ralph Shabetai
Robert E. Shaddy
Ajay M. Shah
Maully J. Shah
Pravin M. Shah
Prediman K. Shah
David M. Shahian
Catherine M. Shanahan
Richard P. Shannon
Behrooz G. Sharifi
Arya M. Sharma
Samin K. Sharma
Ken Sharpe
Palma Shaw
Amanda M. Shearman
Michael Shechter
Soren P. Sheikh
Prem S. Shekar
Rhidian John Shelton
Stanton K. Shernan
Mark V. Sherrid
Guo-Ping Shi
Weibin Shi
Rei Shibata
Mei-Chiung Shih
Koichi Shimizu
Tatsuya Shimizu
Wataru Shimizu
Hiroaki Shimokawa
Ichiro Shiojima
Girish S. Shirali
Kalyanam Shivkumar
Michael G. Shlipak
Yehuda Shoenfeld
Stephen R. Shorofsky
Matthias Siepe
Hans-H. Sievers
Ulrich Sigwart
Donald S. Silverberg
David I. Silverman
Jean-Sebastien Silvestre
Robert D. Simari
e19
Daniel I. Simon
Joel A. Simon
Michael Simons
Maarten L. Simoons
Paul C. Simpson
Ross J. Simpson
Alan R. Sinaiko
Mervyn Singer
Krishna Singh
Michael N. Singh
Steven N. Singh
Tajinder P. Singh
Albert J. Sinusas
Deborah A. Siwik
Allan C. Skanes
Susan A. Slaugenhaupt
Karen Sliwa
Richard W. Smalling
Otto A. Smiseth
Craig Smith
George Davey Smith
Grace L. Smith
Jonathan Smith
Nicholas L. Smith
Stephen Mark Smith
Timothy William Smith
Warren Morrison Smith
Ryszard T. Smolenski
David B. Snead
Allan D. Sniderman
Burton E. Sobel
Birgitta Söder
Stefan Soderberg
Kyoko Soejima
Manoocher Soleimani
Scott D. Solomon
Virend K. Somers
Robert J. Sommer
Ali Sonel
Dan Sorescu
Vincent L. Sorrell
P.C. Souverein
Arthur A. Spector
J. David Spence
Markus Sperandio
John A. Spertus
Martin Spiecker
Bruce Spiess
Francis G. Spinale
Paolo Spirito
David H. Spodick
Martinus Spoor
Matthew L. Springer
Henri M.H. Spronk
Francesco Squadrito
Iain B. Squire
Ray W. Squires
V.S. Srinivas
Martin G. St. John Sutton
Earl R. Stadtam
Jan A. Staessen
e20
Meir J. Stampfer
Kenneth Stanley
William C. Stanley
William Stanley
Alice V. Stanton
Norbert Stefan
Michael W. Steffes
Philippe Gabriel Steg
Coen D. Stehouwer
Helmut O. Steinberg
Julia Steinberger
Robin H. Steinhorn
Steve R. Steinhubl
Kurt R. Stenmark
Andrew Steptoe
Michael P. Stern
Lynne Warner Stevenson
William G. Stevenson
Duncan J. Stewart
Julian M. Stewart
Ralph A.H. Stewart
Simon Stewart
Roland Stocker
Karen Stokes
Monika Stoll
Gregg W. Stone
Peter H. Stone
Roslyn A. Stone
Julie St-Pierre
Ruth H. Strasser
Bodo E. Strauer
H. William Strauss
Bruno H. Stricker
Erik S.G. Stroes
Matthias Stuber
Christian Stumpf
Rodney Sturdivant
Yan Ru Su
Krishnankutty Sudhir
Cathie L.M. Sudlow
Koichi Sughimoto
M.-Saadeh Suleiman
Jerome L. Sullivan
Lisa M. Sullivan
Jack C.J. Sun
Thoralf M. Sundt III
H. Robert Superko
Mark A. Sussman
Thomas M. Suter
Allison J. Sutherland
Kim Sutton-Tyrrell
Erik J. Suuronen
Alan F. Sved
Lars G. Svensson
Elisabet Svenungsson
Michael O. Sweeney
E.R. Swenson
Bernard Swynghedauw
Koichi Tabayashi
Stefano Taddei
Heinrich Taegtmeyer
Acknowledgment of Reviewers
David P. Taggart
Peter Taggart
Masato (Mike) Takahashi
Shinji Takai
Satoshi Takeshita
Johanna J.M. Takkenberg
William T. Talman
Masashi Tanaka
Toshihiro Tanaka
Lilong Tang
Rajendra K. Tangirala
Lloyd Y. Tani
Laszlo B. Tanko
Felix C. Tanner
Masaya Tanno
Yoshihisa Tanoue
Kahraman Tanriverdi
Victor F. Tapson
Jean-Claude Tardif
Giovanni Targher
Mark B. Taubman
Ahmed Tawakol
Allen J. Taylor
Andrew M. Taylor
Anne L. Taylor
Alain Tedgui
Usha Tedrow
John R. Teerlink
Paul S. Teirstein
David F. Teitel
George Tellides
Martin Tepel
Masahiro Terashima
Ronald L. Terjung
Norma Terrin
Dellara F. Terry
Pierre Theroux
Aravinda Thiagalingam
Perumal Thiagarajan
Ravi R. Thiagarajan
Chris Thiemermann
Gaetano Thiene
Anita C. Thomas
James D. Thomas
Randal J. Thomas
Shane R. Thomas
William Thomas
Douglas Thompson
MaryLou Thompson
Paul D. Thompson
Richard Thompson
Jens Jakob Thune
Johan Thyberg
Lu Tian
Rong Tian
Tomasz Timek
Brian Timmons
Laurence Tiret
Asa Tivesten
Geoffrey H. Tofler
Cheng-Hock Toh
Gordon F. Tomaselli
Naruya Tomita
Marcello Tonelli
Andrew M. Tonkin
Eric J. Topol
Per Tornvall
Robert Daniel Toto
Rhian M. Touyz
Jeffrey A. Towbin
Dwight A. Towler
Jonathan N. Townend
Kazunori Toyoda
Russell P. Tracy
John K. Triedman
Han-Mou Tsai
Thomas T. Tsai
Teresa S.M. Tsang
Sotirios Tsimikas
Tim K. Tso
Yukiomi Tsuji
Igor Tudorache
Paul A. Tunick
José Tuñón
Tanya N. Turan
Fiona Turnbull
Alexander G.G. Turpie
E. Murat Tuzcu
Volkan Tuzcu
James S. Tweddell
Christophe Tzourio
Thomas Unger
Zoltan Ungvari
Philip Urban
Zsolt Urban
Barry F. Uretsky
Masuko Ushio-Fukai
Viola Vaccarino
Miguel Valderrabano
Marco Valgimigli
Patrick J.T. Vallance
Jesus G. Vallejo
Joannis E. Vamvakopoulos
Eric Van Belle
Peter Van Buren
Ruud M.A. Van de Wal
Frans J. Van de Werf
Greta Van den Berghe
Johanna Gerarda van der bom
Yvonne T. van der Schouw
Ernst E. van der Wall
Berry M. van Gelder
Bethany Van Guelpen
George F. Van Hare
Linda Van Horn
Johannes J. van Lieshout
Joost P. van Melle
A.M. van Rij
J. Peter van Tintelen
Dirk J. van Veldhuisen
David R. van Wagoner
Thomas E. Vanhecke
Mani A. Vannan
Cristina Varas-Lorenzo
Nerea Varo
Mariuca Vasa-Nicotera
Thomas A. Vassiliades
Dorothy E. Vatner
Stephen F. Vatner
Mary S. Vaughan Sarrazin
Hector O. Ventura
Paolo Verdecchia
Freek W.A. Verheugt
Subodh Verma
Cees Vermeer
Richard L. Verrier
Sara Vesely
George W. Vetrovec
Victoria Vetter
Aristidis Veves
Flordeliza S. Villanueva
Francisco Villarreal
Karen A. Vincent
Jakob Vinten-Johansen
Renu Virmani
Sami Viskin
Eric Vittinghoff
Gus J. Vlahakes
Robert A. Vogel
Manfred Vogt
Pierre Voisine
Arnold von Eckardstein
Finn Edler von Eyben
Marc A. Vos
Robert Voswinckel
Sari Voutilainen
Naren Vyavahare
Bernard Waeber
Anja Wagner
Ron Waksman
Albert L. Waldo
Lars Wallentin
Susanna M. Wallerstedt
Reidar Wallin
Edward P. Walsh
Thomas Walther
Paul J. Wang
Ping H. Wang
Qing Wang
Thomas J. Wang
Wenyu Wang
Xuejun Wang
Yun Wang
James W. Warnica
Manabu Watanabe
Mari A. Watanabe
Nozomi Watanabe
David D. Waters
Sergio Waxman
W. Douglas Weaver
Catherine Webb
David J. Webb
Acknowledgment of Reviewers
Gary D. Webb
John G. Webb
Steven A. Webber
Christian Weber
Karl T. Weber
Michael A. Weber
Mark W.I. Webster
Kevin Wei
L. Wei
Wei Wei
Franz Weidinger
Dorothee Weihrauch
Max Harry Weil
Myron Weinberger
Neal L. Weintraub
William S. Weintraub
Richard D. Weisel
Mary C. Weiser-Evans
Eric S. Weiss
Harvey Richard Weiss
Robert G. Weiss
Robert M. Weiss
Neil J. Weissman
Jeffrey I. Weitz
Carrie Welch
David J. Welsh
Frederick G. Welt
Peter Wenaweser
Nanette Kass Wenger
Jolanda J. Wentzel
Nikos S. Werner
Malcolm West
Cynthia M. Westerhout
Dirk Westermann
Cornelia M. Weyand
Andrew S. Weyrich
Gillian A. Whalley
John Wharton
Christopher J. White
Guy StJ. Whitley
J. Lindsay Whitton
Mark H. Wholey
Samuel A. Wickline
Julian Widder
Susan E. Wiegers
William Wijns
David J. Wilber
Arthur A.M. Wilde
Ian B. Wilkinson
Bruce L. Wilkoff
Andrew R. Willan
Walter C. Willett
Bryan Williams
David O. Williams
David M. Williams
Mark A. Williams
Scott R. Willoughby
Andrew M. Wilson
Peter W. Wilson
Stephan Windecker
Karl Winkler
Jeffrey A. Winkles
Jonathan Allan Winston
Jacqueline C.M. Witteman
Janet Wittes
Joseph L. Witztum
Stephen D. Wiviott
Philip A. Wolf
Eugene E. Wolfel
Michael S. Wolin
Paul Wolkowicz
Kai C. Wollert
Lennie Wong
Nathan D. Wong
John C. Wood
Mark A. Wood
Elizabeth A. Woodcock
Angela Woodiwiss
R. Scott Wright
Alan H.B. Wu
Chuntao Wu
Joseph C. Wu
Kenneth K. Wu
D. George Wyse
Xiao Xiao
Susan Xu
Magdi H. Yacoub
Hitoshi Yaku
Hafize Yaliniz
Norikazu Yamada
Yoshiji Yamada
Takashi Yamaki
Clyde W. Yancy
Homer Yang
Qinglin Yang
Zhihong Yang
Katsusuke Yano
Masafumi Yano
Jack Yanovski
Derek M. Yellon
Midori Anne Yenari
Seppo Yla-Herttuala
Paul G. Yock
Mervin C. Yoder
e21
Mitsuhiro Yokoyama
Shi-Joon Yoo
Young-sup Yoon
Lawrence H. Young
Cheuk-Man Yu
Chun Yuan
Ian C. Zachary
Ralf Zahn
Peter Zahradka
Andrew Zalewski
Faiez Zannad
Wojciech Zareba
Barry L. Zaret
Alan M. Zaslavsky
Cuihua Zhang
Jianyi Zhang
Rong Zhang
Shetuan Zhang
Zefeng Zhang
Li-Ru Zhao
Shankuan Zhu
Xinsheng Zhu
Felix Zijlstra
Michael R. Zile
Thomas Zimmer
M. Bridget Zimmerman
Jean-Marc Zingg
Douglas P. Zipes
Edgar Zitron
Carmine Zoccali
Irving H. Zucker
Jay L. Zweier
AHA Issues New Products
The following new products for the public and the healthcare
professional are available through your local American Heart
Association or by calling 1-800-AHAUSA1.
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AHA Conference Proceedings: Understanding the Complexity of Trans Fatty Acid Reduction in the American Diet:
American Heart Association Trans Fat Conference 2006.
Read about the current status and future implications of
reducing trans fatty acids without increasing saturated fats
in the food supply, while functionality and consumer
acceptance of packaged, processed, and prepared foods are
maintained. Product code 71-0326.
AHA Guideline: Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women: 2007 Update. This
update provides the most current clinical recommendations
for the prevention of cardiovascular disease in women ⱖ20
years of age and is based on a systematic search of the
highest-quality science, interpreted by experts in the fields
of cardiology, epidemiology, family medicine, gynecology,
internal medicine, neurology, nursing, public health, statistics, and surgery. These guidelines also cover the primary
and secondary prevention of chronic atherosclerotic vascular diseases. Product code 71-0401.
AHA Guideline: Prevention of Infective Endocarditis. This
guideline updates the recommendations for the prevention
of infective endocarditis that were last published in 1997.
Product code 71-0407.
AHA Policy Statement: Nonfinancial Incentives for Quality. Four principles were crafted to guide the structure and
metrics used in pay-for-quality programs, and they identified at least 6 areas that required additional research to
serve as criteria that should be considered when designing
and evaluating pay-for-quality programs. Product code
71-0387.
AHA Scientific Statement: Acute Coronary Care in the
Elderly, Part I: Non–ST-Segment-Elevation Acute Coronary Syndromes. The first part of this 2-part statement
summarizes evidence on patient heterogeneity, clinical
presentation, and treatment of non–ST-segment elevation
acute coronary syndromes in relation to age (⬍65, 65 to 74,
75 to 84, and ⱖ85 years). Product code 71-0404.
AHA Scientific Statement: Acute Coronary Care in the
Elderly, Part II: ST-Segment-Elevation Myocardial Infarction. This second part summarizes evidence on presentation
and treatment of ST-segment– elevation myocardial infarction in relation to age (⬍65, 65 to 74, 75 to 84, and ⱖ85
years). Product code 71-0405.
AHA Scientific Statement: Cardiovascular Risk Reduction
in High-Risk Pediatric Patients. A panel of experts reviewed what is known about very premature cardiovascular
disease in 8 high-risk pediatric diagnoses and, from the
science base, developed practical recommendations for
management of cardiovascular risk. Product code 71-0378.
AHA Scientific Statement: Drug Therapy of High-Risk
Lipid Abnormalities in Children and Adolescents. This
statement examines new evidence on the association of
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lipid abnormalities with early atherosclerosis, discuss challenges with previous guidelines, and highlight results of
clinical trials with statin therapy in children and adolescents with familial hypercholesterolemia or severe hypercholesterolemia. Product code 71-0406.
AHA Scientific Statement: Essential Features of a Surveillance System to Support the Prevention and Management
of Heart Disease and Stroke. This statement provides a
brief overview of the Healthy People 2010 goals, prevention and management strategies, and the role of surveillance in monitoring the impact of prevention and treatment
efforts. It also provides a review of the existing surveillance system for monitoring progress toward preventing
heart disease and stroke in the United States and recommendations for filling important gaps in that system.
Product code 71-0386.
AHA Scientific Statement: Exercise and Acute Cardiovascular Events: Placing the Risks Into Perspective. This
scientific statement discusses the potential cardiovascular
complications of exercise, their pathological substrate, and
their incidence and suggests strategies to reduce these
complications. Product code 71-0400.
AHA Scientific Statement: Genetic Basis for Congenital
Heart Defects: Current Knowledge. This statement provides the clinician with a summary of what is currently
known about the contribution of genetics to the origin of
congenital heart disease. Product code 71-0376.
AHA Scientific Statement: Indications for Heart Transplantation in Pediatric Heart Disease. Learn about the
evaluation that led to the development and refinement of
indications for heart transplantation for patients with congenital heart disease and pediatric cardiomyopathies in
addition to indications for pediatric heart retransplantation.
Product code 71-0393.
AHA Scientific Statement: Noninherited Risk Factors and
Congenital Cardiovascular Defects: Current Knowledge.
This statement summarizes the currently available literature on potential fetal exposures that might alter risk for
cardiovascular defects. Product code 71-0377.
AHA Scientific Statement: Physical Activity Intervention
Studies: What We Know and What We Need to Know. An
overview is provided of existing physical activity intervention research, focusing on subpopulations and intervention
modalities. New ideas and recommendations are also
offered to improve the state of the science within each area
and, where possible, to propose ideas to help bridge the
gaps between these existing categories of research. Product
code 71-0369.
AHA Scientific Statement: Recommendations and Considerations Related to Preparticipation Screening for Cardiovascular Abnormalities in Competitive Athletes: 2007 Update. Preparticipation cardiovascular screening is the
systematic practice of medically evaluating large, general
populations of athletes before participation in sports for the
purpose of identifying (or raising suspicion of) abnormalities that could provoke disease progression or sudden
death. Identifying the relevant diseases may prevent some
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instances of sudden death after temporary or permanent
withdrawal from sports or targeted treatment interventions.
Product code 71-0399.
AHA Scientific Statement: Relevance of Genetics and
Genomics for Prevention and Treatment of Cardiovascular
Disease. Approaches that researchers are using to advance
understanding of the genetic basis of cardiovascular disease are discussed, as well as details of the current state of
knowledge regarding the genetics of myocardial infarction,
atherosclerotic cardiovascular disease, hypercholesterolemia, and hypertension. Product code 71-0410.
AHA Scientific Statement: Treatment of Hypertension in
the Prevention and Management of Ischemic Heart Disease. This statement summarizes the published data relating to the treatment of hypertension in the context of coronary
artery disease prevention and management and attempts, on
the basis of the best available evidence, to develop recommendations that will be appropriate for blood pressure reduction and the management of coronary artery disease in its
various manifestations. Product code 71-0412.
AHA Scientific Statement: Use of Nonsteroidal Antiinflammatory Drugs: An Update for Clinicians. Read about the
current evidence that indicates that selective COX-2 inhibitors have important adverse cardiovascular effects, which
include increased risk for myocardial infarction, stroke,
heart failure, and hypertension. Product code 71-0396.
AHA/ASA Guideline. Guidelines for the Early Management
of Adults With Ischemic Stroke. This guideline is an
overview of the evaluation and treatment of adults with
acute ischemic stroke for physicians and other emergency
healthcare providers who treat patients within the first 48
hours after stroke. Information for healthcare policy makers is included. Recommendations for management from
the first contact by emergency medical services personnel
through initial admission to the hospital are also provided.
Product code 71-0398.
AHA/ASA Guideline: Guidelines for the Management of
Spontaneous Intracerebral Hemorrhage in Adults: 2007
Update. Current and comprehensive recommendations are
presented for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage. Product code 71-0411.
AHA/AACVPR Scientific Statement: Core Components of
Cardiac Rehabilitation/Secondary Prevention Programs:
2007 Update. This updated statement presents current
information on the evaluation, interventions, and expected
outcomes in each of the core components of cardiac
rehabilitation/secondary prevention programs, in agreement with the 2006 update of the American Heart Associ-
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ation/American College of Cardiology Secondary Prevention Guidelines, including baseline patient assessment,
nutritional counseling, risk factor management (lipids,
blood pressure, weight, diabetes mellitus, and smoking),
psychosocial interventions, and physical activity counseling and exercise training. Product code 71-0394.
AHA/ACC/HRS Scientific Statement: Recommendations for
the Standardization and Interpretation of the Electrocardiogram: Part I: The Electrocardiogram and Its Technology. This statement examines the relation of the resting
ECG to its technology and to foster an understanding of
how the modern ECG is derived and displayed so that
standards are established that will improve the accuracy
and usefulness of the ECG in practice. Product code
71-0389.
AHA/ACC/HRS Scientific Statement: Recommendations for
the Standardization and Interpretation of the Electrocardiogram: Part II: Electrocardiography Diagnostic Statement List. This statement provides a concise list of diagnostic terms for ECG interpretation that can be shared by
students, teachers, and readers of electrocardiography. An
intended outcome of this statement list is greater uniformity of ECG diagnosis and a resultant improvement in
patient care. Product code 71-0390.
AHA/ACC/SCAI/ACS/ADA Science Advisory: Prevention
of Premature Discontinuation of Dual Antiplatelet Therapy
in Patients With Coronary Artery Stents. This advisory
stresses the importance of dual antiplatelet therapy after
placement of a drug-eluting stent and educating the patient
and healthcare providers about hazards of premature discontinuation. Product code 71-0395.
AHA/ADA Scientific Statement: Primary Prevention of
Cardiovascular Diseases in People With Diabetes Mellitus.
The ADA and AHA have issued separate recommendations
for each of the cardiovascular risk factors in patients with
diabetes. This statement attempts to harmonize the recommendations of both organizations where possible and
recognizes areas in which AHA and ADA recommendations differ. Product code 71-0379.
AHA/HRS Scientific Statement: Addendum to “Personal
and Public Safety Issues Related to Arrhythmias That May
Affect Consciousness: Implications for Regulation and
Physician Recommendations: A Medical/Scientific Statement From the American Heart Association and the North
American Society of Pacing and Electrophysiology”: Public
Safety Issues in Patients With Implantable Defibrillators. This
statement extends the original 1996 recommendations and
provides specific recommendations on driving for individuals
with implantable cardioverter-defibrillators (implanted for
primary prevention). Product code 71-0392.
Meetings Calendar
AHA Meetings
forum in which to present recent scientific work
related to stroke and cerebrovascular disease. More
than 600 abstract presentations and lectures will be
featured. This year, special symposia will focus on
numerous topics, including controversies in vascular
cognitive impairment, genetics of stroke, getting
therapies across the blood– brain barrier, metabolic
down regulation in cerebral ischemia, stroke in
neonates, stroke in women, platelet resistance in
stroke prevention, diagnosis and management of
AVM, aneurysm and intracranial hemorrhage, the
role of exercise in stroke rehabilitation, the latest in
stroke prevention, advancing stroke systems of care,
and other informative symposia. Sessions in clinical
categories will center on diagnosis, acute management, in-hospital treatment, rehabilitation and recovery, pediatric stroke, prevention and community/risk
factors, outcomes, vascular cognitive impairment,
and systems of stroke care. Experimental categories
will address neurons/glia/inflammation and vascular
pathophysiology/thrombosis. See Web site:
http://www.heart.org/presenter.jhtml?identifier⫽3045505
Mar 11–15: Joint Conference – 48th Cardiovascular
Disease Epidemiology and Prevention and the
Nutrition, Physical Activity, and Metabolism
Conference 2008. Colorado Springs, Colo. The
Annual Conference offers participants the opportunity to learn about: population trends in cardiovascular diseases and their risk factors; causes and
mechanisms of atherosclerosis and other vascular
diseases; results of cardiovascular disease treatment
and prevention trials; methods of population surveillance for cardiovascular disease and risk factors;
techniques in preventive cardiology nutrition and
cardiovascular disease; and outcomes research in
cardiovascular disease. See Web site: http://www.
heart.org/presenter.jhtml?identifier⫽3046690
Many of these meetings are sponsored by the American
Heart Association (AHA) and its Scientific Councils. For
information, contact AHA, Scientific Meetings, 7272
Greenville Avenue, Dallas, TX 75231-4596; Fax 214373-3406; E-mail scientificconferences@heart.org; or
visit the Web site http://my.americanheart.org/portal/
professional/conferencesevents
2007
July 30 –Aug 2: 4th Annual Symposium of the American Heart Association Council on Basic Cardiovascular Sciences: Cardiovascular Repair and
Regeneration: Structural and Molecular Approaches in the Cellular Era. Keystone, Colo. This
3.5-day conference is a multifaceted symposium
highlighting research under development in the cardiovascular community targeted at slowing and/or
reversing the pathogenesis of disease. The conference will focus on how cellular-based approaches
are being manipulated to enhance the repair and
regeneration capabilities of the cardiovascular system with the goal of therapeutic based interventions.
See Web site: http://www.heart.org/presenter.
jhtml?identifier⫽3044056
Sept 26 –29: 61st Annual High Blood Pressure Research
Conference 2007. Tucson, Ariz. The 2.5-day scientific program gives physicians and research investigators an opportunity to enhance their knowledge,
advance their skills, and learn about the latest
developments in research pertaining to hypertension, stroke, kidney function, obesity, and genetics.
The program will include state-of-the-art lectures
and more than 350 oral and poster abstract presentations and discussions led by authorities. See Web site:
http://www.heart.org/presenter.jhtml?identifier⫽3043476
Nov 4 –7: Scientific Sessions 2007. Orlando, Fla. Scientific Sessions encompasses 4 days of invited lectures
and investigative reports. Simultaneous presentations represent all fields of cardiovascular and related disciplines. The program will include more
than 4,000 basic, clinical, and population science
abstract presentations; plenary, special, and how-to
sessions, morning programs and cardiovascular
seminars; clinical practice sessions focusing on current standards of care for practicing clinicians;
translational science sessions that bring together
basic scientists and clinicians; and Ask the Experts
luncheons and in-depth subspecialty updates. There will
also be 7 pre-Sessions symposia. See Web site: http://
scientificsessions.americanheart.org
Other Meetings of Interest—Domestic
2007
Sept 5– 8: 8th Annual New Cardiovascular Horizons
and Management of the Diabetic Foot & Wound
Healing. New Orleans, La. For more information,
contact conference@newcvhorizons.com, phone
337-261-0944, or fax 337-572-9778. See Web site:
http://www.newcvhorizons.com
Other Meetings of Interest—International
2007
Sept 17–20: 4th European Meeting on Vascular Biology
and Medicine. Bristol, United Kingdom. Keynote
and plenary speakers’ topics include atherosclerosis
treatment, heart disease treatment, clinical modula-
2008
Feb 20 –22: International Stroke Conference 2008. New
Orleans, La. This 2.5-day conference provides a
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B4
Meetings Calendar
tion of angiogenesis, vulnerable plaque, and phenotype of vascular cells. Tracks include atherosclerosis, endothelium and angiogenesis, and cellular
dysfunction. For more information, contact
wheldonevents@btconnect.com, phone ⫹44-1922457-984, or fax ⫹44-1922-455-238. See Web site:
http://2007.emvmb.org
Oct 7–10: 7th International Congress on Coronary
Artery Disease–From Prevention to Intervention
(ICCAD 7). Venice, Italy. The meeting will follow
the format of the very successful previous ICCAD
Coronary Artery Disease meetings and will provide
a comprehensive update on coronary disease in all
its aspects. Keynote lectures will be delivered by a
distinguished international faculty, while a large
number of selected free communications will report
new data from basic research laboratories and clinical centers around the globe. The program will
include sessions on molecular mechanisms, gene
therapy and cell therapy, epidemiology and prevention, and clinical aspects. There will be a major
focus on new frontiers in interventional cardiology
and to the surgical management of coronary disease.
A new feature will be a fast track for recent and
“about to break” clinical trials. For more information, contact coronary@kenes.com or phone ⫹4122-908-0488. See Web site: http://www.kenes.com/cad7
Oct 7–10: 20th Annual Congress of the European
Society of Intensive Care Medicine. Berlin, Ger-
many. A series of thematic lectures will run throughout the congress that describe progresses and innovations from 14 separate topics. Pre-conference
meetings are also offered. Educational sessions will
take the form of lectures, round tables, pro-con
debates, clinical presentations, core competencies,
tutorials, and interactive education. For more information, contact public@esicm.org, phone ⫹32-2559-03-55, or fax ⫹32-2-527-00-62. See Web site:
http://www.esicm.org
Oct 14 –16: 5th International Meeting on Intensive
Cardiac Care. Tel Aviv, Israel. Three parallel
sessions, with more 100 presentations, will be featured. A parallel nursing stream will also be provided. For details, contact seminars@isas.co.il. See
Web site: http://isas.co.il/cardiaccare2007
Nov 8 –11: Fifth International Congress on Vascular
Dementia. Budapest, Hungary. Attendees shall
have an opportunity to deliberate on large and
small vessel brain diseases and how they contribute to cognitive decline. There will also be an
opportunity to identify the specific psychological
markers, if any, of vascular dementia, and also the
genetic factors involved. The overlap with Alzheimer’s disease will be a central issue, as will
be the white matter changes frequently seen in
vascular dementia. For details, contact
vascular@kenes.com. See Web site: http://www.
kenes.com/vascular
The American Heart Association welcomes announcements of interest to physicians, scientists, researchers, and
others concerned with cardiovascular and cerebrovascular medicine. All copy is reviewed by the Scientific
Publishing Department. Content may be edited for style, clarity, and length. Copy should be sent to Publications–
AHA News & Meetings Calendar, American Heart Association, 7272 Greenville Ave, Dallas, TX 75231-4596; Fax
214-691-6342; E-mail Scientific.Publishing@heart.org
American Heart Association Newly Elected Fellows, Spring 2007
Sixty-six Premium Professional Members were elected Fellows and International Fellows of the American Heart
Association (AHA) in the spring 2007. Fellows are elected on the basis of their outstanding credentials, achievements, and
community contributions to the study of cardiovascular disease and stroke. Persons elected to fellowship are entitled to use
FAHA, Fellow of the American Heart Association, as a professional designation. Fellows who reside outside the United
States and Canada are designated International Fellows. For more information on the AHA Fellowship program, please visit
our Web site at http://www.americanheart.org/presenter.jhtml?identifier⫽3033104
COUNCIL ON CLINICAL
CARDIOLOGY
MARTIN R. BERK, MD, FAHA
Partner/Physician
Cardiology & Interventional
Vascular Associates
Dallas, Tex
David J. D’Agate, DO,
FACC, FCCP, FAHA
Suffolk Heart Group, LLP
Smithtown, NY
Harold L. Dauerman, MD,
FAHA
Director, CV Catheterization
Labs
University of Vermont
Burlington, Vt
Mark H. Drazner, MD, MSc,
FAHA
Associate Professor/Medical
Director
University of Texas Southwest
Medical Center
Dallas, Tex
Mark B. Effron, MD, FAHA
Medical Fellow
Lilly Corporate Center
Indianapolis, Ind
Victor A. Ferrari, MD,
FAHA
Associate Director, Non
Invasive Imaging
University of Pennsylvania
Medical Center
Philadelphia, Pa
Robert A. Harrington, MD,
FAHA
Professor of Medicine
Director, Duke Clinical
Research Institute
Duke University Medical
Center
Durham, NC
John A. Hildreth, MD,
FAHA
Medical Director, FPL Group
Palm Beach Gardens, Fla
Eileen Michelle Hsich, MD,
FAHA
Assistant Professor
Case Western Reserve
University
Cleveland, Ohio
Ira S. Nash, MD, FAHA
Associate Professor
Cardiovascular Institute
Mount Sinai Medical Center
New York, NY
Jeffrey W. Olin, DO, FAHA
Professor and Director,
Vascular Medicine
Mount Sinai School of Medicine
New York, NY
Atul R. Hulyalkar, MD,
FAHA
Cardiologist
North Ohio Heart Center, Inc.
Westlake, Ohio
Armen Ovsepian, MD, FAHA
Staff Physician
Suffolk Heart Group, LLP
Smithtown, NY
Birgit Kantor, MD, PhD,
FAHA
Senior Associate Consultant III
Mayo Clinic, Rochester
Rochester, Minn
Robert A. Pelberg, MD,
FAHA
Ohio Heart and Vascular
Center
Cincinnati, Ohio
Kelley D. Kennedy, MD,
FAHA
Cardiologist
Bloomington Heart Institute
Normal, Ill
Jan J. Piek, MD, PhD, FAHA
Professor, Cardiology
Academic Medical Center
Amsterdam, the Netherlands
Daniel M. Kolansky, MD,
FAHA
Associate Professor of
Medicine
University of Pennsylvania
Philadelphia, Pa
Manuel A. Quiles-Lugo, MD,
FACC, FAHA
Cardiologist
San Juan, Puerto Rico
Srinivas Ramaka, MBBS,
MD, DM, FAHA
Consultant Cardiologist
Srivinvas Heart Centre
India
Robert J. Lederman, MD,
FAHA
Investigator, CV Branch
National Heart, Lung, and
Blood Institute
National Institutes of Health
Division of Intramural
Research
Bethesda, Md
Dimitrius Richter, MD,
FAHA
Head of Cardiac Department
Athens Gurolliwic
Athens, Greece
Pedro Lozano, MD, FAHA
Assistant Professor of Medicine
University of Oklahoma Health
Sciences Center
Oklahoma City, Okla
Spanos Vassilios, MD, FAHA
Consultant, Interventional
Cardiology
Euroclinic Hospital
Athens, Greece
Wayne L. Miller, MD, PhD,
FAHA
Associate Professor of
Medicine
Mayo Clinic and Foundation
Rochester, Minn
Laurence S. Sperling, MD,
FAHA
Director, Preventive Cardiology
Emory University Hospital/The
Emory Clinic
Atlanta, Ga
B5
Martin St. John Sutton,
MBBS, FAHA
Director, Cardiovascular Imaging
Department of
Medicine/Cardiology
Hospital of the University of
Pennsylvania
Philadelphia, Pa
Jon Walter Wahrenberger,
MD, FAHA
Assistant Professor of Medicine
Dartmouth Hitchcock Medical
Center
Lebanon, NH
Pavlos Toutouzas, MD, FAHA
Athens, Greece
Dimitrios N. Tziakas, MD,
FAHA
Assistant Professor in Cardiology
Alexandropolis, Greece
Yee Guan Yap, BMedSci,
MBBS, MD, FAHA
Assoc. Professor/Head of
Cardiology
University of Putra Malaysia
Petaling Jaya, Selangor,
Malaysia
COUNCIL ON
CARDIOVASCULAR
DISEASE
IN THE YOUNG
Luis E. Alday, MD, FAHA
Head, Division of Cardiology
Hospital Acronautico
Argentina
Stuart Berger, MD, FAHA
Medical Director, Herma Heart
Center
Professor of Pediatrics
Medical College of Wisconsin
Milwaukee, Wis
David Jonathan Sahn, MD,
FAHA
Professor, Pediatrics
(Cardiology)
Oregon Health and Science
University
Portland, Ore
B6
Craig Andrew Sable, MD,
FAHA
Director, Echocardiography,
Fellowship Training, and
Telemedicine
Children’s National Medical
Center
Washington, DC
L. LuAnn Minich, MD, FAHA
University of Utah School of
Medicine
Children’s Medical Center
Pediatrics
Salt Lake City, Utah
COUNCIL ON
CARDIOVASCULAR
RADIOLOGY AND
INTERVENTION
David A. Bluemke, MD, PhD,
MSB, FAHA
Clinical Director, MRI
Associate Professor, Radiology
and Medicine
Johns Hopkins University
School of Medicine
Baltimore, Md
Seung Woon Rha, MD, PhD,
FAHA
Professor
Korea University Guro Hospital
Seoul, South Korea
COUNCIL ON CV
SURGERY
AND ANESTHESIA
Jerrold Henry Levy, MD,
FAHA
Professor and Director, CT
Anesthesia
Emory Healthcare
Atlanta, Ga
Yoshitaka Hayashi, MD,
PhD, FAHA
Overseas Surgeon
Department of Cardiothoracic
Surgery
Monash Medical Centre
Monash University
Clayton, Victoria, Australia
Hitoshi Hirose, MD, PhD,
FAHA
Faculty Staff
Cardiothoracic Surgery
Drexel University College of
Medicine
Philadelphia, Pa
AHA Newly Elected Fellows, Spring 2007
Madhav Swaminathan, MD,
FASE, FAHA
Assistant Professor
Duke University Medical
Center
Durham, NC
Yasuyuki Shimada, MD,
PhD, FAHA
Director, Cardiovascular Surgery
Yuri General Hospital
Japan
COUNCIL ON
EPIDEMIOLOGY
PREVENTION
AND
Javed Butler, MD, MPH,
FAHA
Associate Professor of
Medicine
Department of
Medicine/Cardiology
Emory University
Atlanta, Ga
J. Jeffrey Carr, MD, MSCE,
FAHA
Professor/Vice Chair
Division of Radiologic
Sciences/Clinical Research
Wake Forest University
Durham, NC
Ellen Demerath, PhD, FAHA
Associate Professor
Community Health
Boonshoft School of Medicine
Wright State University
Kettering, Ohio
James M. Galloway, MD,
FAHA
Director, Native American
Cardiology
Program & Senior Cardiologist
Indian Health Service
Flagstaff, Ariz
Jiang He, MD, PhD, FAHA
Professor and Chair
Department of Epidemiology
Tulane University School of
Public Health
and Tropical Medicine
New Orleans, La
Angela Dorthea Liese, PhD,
MPH, FAHA
Associate Director
Epidemiology and Biostatistics
University of South Carolina
Columbia, SC
Hirotsugu Ueshima, MD,
PhD, FAHA
Professor, Health Sciences
Shiga University of Medical
Science
Tsukinowa-cho, Otsu
Japan
COUNCIL FOR HIGH
BLOOD PRESSURE
RESEARCH
Keiichiro Atarashi, MD, PhD,
FAHA
Physician of the Crown
Prince’s Household
Imperial Household Agency
Tokyo, Japan
Olakunle O. Akinboboye,
MD, MPH, MBA, FAHA
Associate Director
New York Hospital/Queens
Roslyn, NY
Anil K. Bidani, MD, FAHA
Professor of Medicine and
Division Director
Loyola University Medical
Center and
Hines VA Hospital
Maywood, Ill
STROKE COUNCIL
Erfan A. Albakri, MD,
FAHA
Medical Director
Florida Neuro Vascular
Institute
Tampa, Fla
Andrew Butler, PhD, PT,
FAHA
Emory University School of
Medicine
Atlanta, Ga
Sherene Schlegel, Associate
RN, FAHA
Stroke Program Clinical
Effectiveness Coordinator
Swedish Medical Center
Seattle, Wash
Tammy L. Cress, RN, BSN,
MSN, FAHA
Stroke Program Manager
Swedish Medical Center
Seattle, Wash
Afshin Andre Divani, MSc,
PhD, FAHA
Director, Zeenat Qureshi
Stroke Research Center
UMDNJ – New Jersey Medical
School
Newark, NJ
Wende N. Fedder, RN, BSN,
MBA, FAHA
Director of Nursing, Stroke
Center
Alexian Brothers Hospital
Network
Chicago, Ill
Elias A. Giraldo, MD, FAHA
Director, UTHSC Stroke
Program
Department of Neurology
University of Tennessee
Memphis, Tenn
Keith Lowell Hull, Jr, MD,
FAHA
Partner, Raleigh Neurology
Associates, PA
Raleigh, NC
Robert H. Rossenwasser,
MD, FAHA
Professor and Chairman
Thomas Jefferson University
Philadelphia, Pa
Joseph Y. Chu, MD, FRCPC,
FACP, FAHA
Neurologist
University of Toronto
Toronto, Ontario, Canada
Sandeep Sachdeva, MBBS,
MD, FAHA
Lead Hospitalist Stroke
Program
Swedish Medical Center
Seattle, Wash
Niloufar Hadidi, RN, MS,
CNS, FAHA
Neuroscience Clinical Nurse
Specialist
University of Minnesota
Medical Center
Shoreview, Minn
Sean Isaac Savitz, MD, FAHA
Neurologist, Stroke Service
Assistant Professor, Neurology
Beth Israel Deaconess Medical
Center
Harvard Medical School
Boston, Mass