SHS Phase 6 – Cornell Imaging Center
Richard B. Devereux, MD
Professor of Medicine
Weill Cornell Medical College
Cornell Center – Cardiovascular
Phenotyping in SHS Phases 2 to 5
• Phase 2 – 3501 echocardiograms (91% LV mass)
• Phase 3 – 3715 carotid ultrasounds, 3820 computerized
ECGs, central BP 3560
• Phase 4 – 3629 echocardiograms (97% LV mass), 3582
carotid ultrasounds, 3645 computerized ECGs, central BP
2540
• Phase 5 – 3074 echocardiograms, 3080 carotid ultrasounds,
3038 popliteal ultrasounds, 3203 computerized ECGs
• CV pheonotype of SHFS participants assessed
systematically by ~31,500 standardized ultrasounds,
ECGs or central BP recordings in members of 95 families
in SHS phases 3 to 5.
SHS Cardiovascular Reading Center –
Peer-Reviewed Publications
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SHS Phase 6 - Cornell Center
Weill Cornell Medical College – Richard B. Devereux, M.D, P.I.
MR
Centers in
AZ,
ND/SD,
OK
Prior CV Exams
Carotid Ultrasound
Cardiac Echo
Popliteal Ultrasound
Computerized ECG
In SHFS at 3rd to 5th
SHS Exams
MR Reading
Center
UCSD
Claude Sirlin,
MD
Hepatic
Triglycerides
Subcutaneous Fat
Intra-Abdominal Fat
Abdominal Aortic
Diameter
Applanation
Tonometry
Cold Pressor
Test
Heart Rate
Variability
Mary
Roman, MD
Jason
Umans, MD
Peter Okin,
MD
Brachial and
Central BP
Reactivity
Reactivity of
Pulse
Pressure
Amplification
Time Domain
(mean RR,
PNN50, etc)
Freq Domain
(LF, HR.
LFHF ratio)
Central
Arterial
Pressure
Pulse
Pressure
Amplification
Change from
4th SHS
Exam
Adiposity, Metabolic Abnormalities and Atherosclerosis
• The SHS has assessed adiposity indirectly measures (BMI, waist
circumference, bioelectric impedence).
• Hepatic steatosis (trigyceride deposition):
– increasing in prevalence.
– instigating feature of non-alcoholic and alcoholic fatty liver
disease
– associated with risks of cancer, CV disease and diabetes
– may contribute to emergence of diabetes
• SHS Phase 6 will directly measure hepatic, intra-abdominal and
subcutaneous fat in SHFS - - unique opportunity to assess relations
of organ adiposity to metabolic disturbance, preclinical CV disease
and CV events.
Closer Association of Hepatic than Visceral
Adipose Tissue with Metabolic Abnormalities
•
•
•
•
•
Visceral adipose tissue (VAT) and intrahepatic triglyceride (IHTG) content
measured.
Association of IHTG and VAT to metabolic function assessed by evaluating
groups of obese subjects, with high vs. normal IHTG content but matched
on VAT volume or had high vs. normal VAT volume matched on IHTG
content.
Stable isotope tracer techniques and the euglycemic-hyperinsulinemic
clamp procedure were used to assess insulin sensitivity and very-lowdensity lipoprotein-triglyceride (VLDL-TG) secretion rate.
Adipose tissue and muscle insulin sensitivity were 41, 13, and 36%
lower (P < 0.01), and VLDL-triglyceride secretion rate was almost
double (P < 0.001), in subjects with higher than normal IHTG content,
matched on VAT. No differences in insulin sensitivity or VLDL-TG
secretion were observed between subjects with different VAT
volumes, matched on IHTG content.
Thus IHTG, not VAT, is a better marker of the metabolic derangements
associated with obesity.
Fabbrini et al.: Proc Natl Acad Sci U S A. 2009;106:15430-15435
MR1. Measurement
Fatof–hepatic
Prooftriglyceride
of Concept
MRby
Fig.
Experimental set-upof
forHepatic
measurements
(HTG)by
content
proton magnetic
resonance spectroscopy
(1H MRS)
Spectroscopy
Measurement
in Individual
Voxels
Szczepaniak, L. S. et al. Am J Physiol Endocrinol Metab 288: E462-E468 2005;
doi:10.1152/ajpendo.00064.2004
Copyright ©2005 American Physiological Society
Weak Relation between body mass index and Hepatic Triglyceride
Content in the Dallas Heart Study
Szczepaniak, L. S. et al. Am J Physiol Endocrinol Metab 288: E462-E468 2005;
doi:10.1152/ajpendo.00064.2004
Copyright ©2005 American Physiological Society
MRI Assessment of Hepatic Fat Content
• Spectroscopy is most accurate method of calculating
triglyceride content of individual 3-dimensional voxels.
• However, spectroscopy of large numbers of individual
voxels to assess overall hepatic TG content is too complex
for application in multi-center population-based studies
• 20 second MRI can measure proton-density fat fraction in
2-D pixels. By drawing multiple dispersed regions of
interest can calculate whole liver fat fraction.
• Images of entire liver can be stored for more labor intensive
precise measurement of whole-liver and segmental fat
fraction/volume.
Method to Quantify Liver Triglyceride in SHS Phase 6
MRI-based approach
•Six magnitude MR images
acquired at echo times of 1.15,
2.3, 3.45, 4.60, 5.75, 6.90 msec
•Parameters are selected to avoid
the errors that confound
conventional MRI techniques
•Entire liver imaged in 20 sec
Post-processing (UCSD)
•Signal intensity is modeled as a
function of echo time
•Corrections done for multi-speak
spectral interference and
exponential signal decay
Yokoo T, … Sirlin C: Radiology 2009; 251:67-76
•Output (UCSD)
•Maps of proton-density fat
fraction (PDFF)
•PDFF = quantitative biomarker of
liver TG concentration
•Abdominal aortic diameter
MRI-Determined Proton Density Fat Fraction Agrees Closely
with MR Spectroscopy
LIPO_Quant FF(%) vs. MRS FF(%)
LIPO_Quant FF(%)
50.0
40.0
30.0
20.0
10.0
0.0
0.0
10.0
20.0
30.0
40.0
MRS FF(%)
Spectroscopy
Fat Fraction (%)
Yokoo T, … Sirlin C: Radiology 2009; 251:67-76
50.0
MRI Protocol for SHS Phase 6
• Localizers and planning sequences – 3
minutes
• MRI fat quantification – 20 seconds
• MRI adiposity images – 20 seconds
• MRI aorta diameter – 20 seconds
• Total exam time including subject set up,
localization, prescribing, acquisition = 30
minutes
Blood Pressure Variation
• BP varies over time – 24-hour ambulatory BP
• However, 40-50% of variability of brachial BP
remains unexplained
– Genetic effects
– Autonomic nervous system effects
• BP highly responsive to activity – e.g.,
treadmill exercise and other forms of stress
• BP varies importantly between central aorta
and brachial artery - due to pulse pressure
amplification
Top, Difference between simultaneously recorded central aortic and radial pressure
waveforms
O'Rourke M F, Seward J B Mayo Clin Proc. 2006;81:1057-1068
• Because
of effect of wave reflections, systolic BP is higher in the
brachial and other peripheral arteries than in the central aorta
• Increase in systolic BP greatest in young individuals and in those
with more compliant arteries at any age
• Central arterial pressure reflects load imposed on the LV and the
coronary and cerebral circulations more directly
O'Rourke M F, Seward J B Mayo Clin Proc. 2006;81:10571068
• Therefore, central BP may be of greater prognostic significance
© 2006 Mayo Foundation for Medical Education and Research
METHODS: Tonometry
Applanation Tonometry: SphygmoCor®
METHODS: Waveforms
Independent Associations of Aortic and Brachial
BP with CVD in the Strong Heart Study
Age (p<0.001), diabetes (p<0.001), heart rate (p<0.05) and creatinine
(p<0.05 to <0.001) ± fibrinogen (p=0.06 to 0.008) entered all models.
PARAMETER
HR
95% CI
p value
Aortic pulse pressure*
1.15
(1.07-1.24)
<0.001
Aortic systolic pressure*
1.07
(1.01-1.14)
<0.05
Brachial pulse pressure*
1.10
(1.03-1.18)
<0.01
Brachial systolic pressure*
1.08
(1.02-1.14)
<0.05
*per 10 mmHg
Remained significant after addition of carotid atherosclerosis and brachial pulse pressure
Roman MJ et al. Hypertension 2007;50:197-203.
Associations of Carotid and Brachial BP with
Incident CVD in the Dicomano Study
Adjusted for age (p<0.0001) and male gender (p=0.001)
PARAMETER
HR
95% CI
p value
Carotid PP*
1.23
(1.10-1.37)
<0.0001
Carotid SBP*
1.19
(1.08-1.31)
<0.0001
Brachial PP*
0.063
Brachial SBP*
0.119
*per 10 mmHg
Pini et al. J Am Coll Cardiol 2008;51:2432-2439.
Associations of Carotid and Brachial BP with
Incident CVD in Taiwan
1272 healthy normotensive or untreated hypertensive Taiwanese aged 30-79,
followed for 10 years; 130 all-cause deaths and 37 cardiovascular deaths
Wang et al. J Hypertens 2009;27:461-7.
Central Blood Pressure
Measurement in SHS Phase 6
• Re-measure central systolic, pulse pressure,
waveform after ~10 years after 4th SHS exam –
largest population-based long-term follow-up
• Examine effects of obesity, diabetes,
dyslipidemia, renal function at baseline and
intermediate 5th SHS exam on increase of
central systolic and pulse pressure
• Examine associations of intra-abdominal,
subcutaneous and hepatic fat with central BP
and pulse pressure amplification
Cold Pressor Test
• Widely used measure of brachial BP reactivity to
stress, predominate α–adrenergic mediation
• Strong heritability in Heredity and Phenotype
Intervention Heart Study in a population with
strong founder effects: additive genetic effect 1225%.
• Strong association with genes in small
physiologic studies.
• Impact of cold pressor BP response on central
BP and association with candidate genes
unknown in large population-based samples.
Familial Resemblance of SBP Response to
Cold Pressor Test in the HAPI Study
Protocol for Assessment of Brachial and Central
BP, Their Reactivity to Cold Pressor Test and
Heart Rate Variability in SHS Phase 6
• Brachial BP by Omron automated device,
applanation tonometry to measure central BP
and heart rate variability from 5-minute ECG
recording assessed at rest
• Cold pressor test protocol modified from
Heredity and Phenotype Intervention Heart
Study to record BP by Omron at baseline and at
1, 2, 3, 4 and 5 minutes of cold pressor test
• Repeat applanation tonometry between minute 2
and 3 of cold pressor test.
SHS Phase 6 – Heart Rate Variability (HRV)
• 5 minute supine ECG recording using
SphygmoCor HRV system
• Time-Domain HRV measures
– Mean and SD of mean RR interval
– PNN50 (% of consecutive RR intervals differing by >50
ms)
– RMS-SDD (root mean square of successive RR intervals
• Frequency-Domain HRV measures
– Fast Fourier transform of RR interval data
– Low Frequency (LF) power (0.04-0.15 Hz, sympathetic ±
vagal tone)
– High Frequency (HF) power (0.15-0.4 Hz, vagal tone)
– LF/HF ratio (balance of vagal/sympathetic tone)
Unique Features
• Relate hepatic fat fraction by MRI proton density (and
intra-abdominal & subcutaneous fat) to metabolic
abnormalities and extensive prior CV phenotypes.
• Relate abdominal aortic diameter to risk factors and prior
CV phenotypes
• Characterize long-term evolution of central arterial
pressure and waveform
• Relate heart rate variability as measure of autonomic
tone to metabolic & CV phenotypes
• Relate stress response of brachial & central BP & HR to
above phenotypes and autonomic tone
• Provide these phenotypes in members of 95 families to
Genetics Component of SHS Phase 6.