JACC: CLINICAL ELECTROPHYSIOLOGY
VOL.
-, NO. -, 2020
ª 2020 PUBLISHED BY ELSEVIER ON BEHALF OF THE
AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
Long-Term Outcomes in Patients With a
Left Ejection Fraction #15% Undergoing
Cardiac Resynchronization Therapy
John Rickard, MD, MPH,a Divyang Patel, MD,a Carolyn Park, MD,b Joseph E. Marine, MD,c Sunil Sinha, MD,c
W.H. Wilson Tang, MD,c Niraj Varma, MD, PHD,a Bruce L. Wilkoff, MD,c David Spragg, MDc
ABSTRACT
OBJECTIVES This study aimed to determine the long-term outcomes and predictors of left ventricular (LV) ejection
fraction (LVEF) improvement in patients with severe cardiomyopathies undergoing cardiac resynchronization therapy
(CRT).
BACKGROUND Whether patients with severe LV dysfunction benefit from CRT or have reached a point in disease
severity past the point at which CRT is beneficial is unknown.
METHODS We collected clinical and echocardiographic data on 420 patients with an LVEF of #15% and a QRS duration
of $120 ms undergoing CRT at the Cleveland Clinic and 2 hospitals in the Johns Hopkins Health System between April
2003 and May 2014. Multivariate models were created to determine factors associated with response to CRT, defined as
an absolute improvement in LVEF of >5% and survival free of LVAD and heart transplant. Procedure-related deaths were
also collected.
RESULTS A total of 298 patients had pre- and appropriately timed post-CRT echocardiograms, of whom 145 (48.7%)
met the criteria for response. In multivariate analysis, LV size and left bundle branch block (LBBB) were associated with
response. Among the most dilated quintile (LV end-diastolic diameter [LVEDD] of >7.8 cm), 30.4% met the criteria for
response. In multivariate analysis, smaller LV end-diastolic dysfunction and presence of LBBB were associated with
improved survival free of heart failure and LVAD over a mean follow-up period of 5.2 years. There were no procedurerelated deaths.
CONCLUSIONS Patients with severe LV dysfunction respond to CRT, although at a lower rate compared to traditional
CRT candidates. Smaller LV size and LBBB are important predictors of positive outcomes in this population. Even among
the most dilated patients, 30.4% realized a meaningful improvement in LVEF with CRT. The CRT implant procedure itself
appears well tolerated. (J Am Coll Cardiol EP 2020;-:-–-) © 2020 Published by Elsevier on behalf of the
American College of Cardiology Foundation.
C
ardiac resynchronization therapy (CRT) rep-
In clinical practice, however, patients with signifi-
resents one of the most important advances
cantly more advanced LV dysfunction are occasion-
in the treatment of patients with electrical
ally encountered. The outcomes of such patients
dyssynchrony and significant left ventricular (LV)
with CRT and the safety of the procedure itself have
dysfunction over the past 20 years (1–4). In clinical
not been reported. In clinical practice, when a CRT
trials of CRT, the mean LV ejection fraction (LVEF)
candidate with an LVEF of #15% presents, the ques-
before implant was approximately 21% to 24% (1–4).
tion often arises of whether a meaningful response
From the aDivision of Cardiology, Heart and Vascular Institute Cleveland Clinic, Cleveland, Ohio; bJohns Hopkins Bayview Medical
Center, Baltimore, Maryland; and the cDivision of Cardiology/Electrophysiology, Johns Hopkins University School of Medicine,
Baltimore, Maryland.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the JACC: Clinical Electrophysiology author instructions page.
Manuscript received March 30, 2020; revised manuscript received July 27, 2020, accepted July 27, 2020.
ISSN 2405-500X/$36.00
https://doi.org/10.1016/j.jacep.2020.07.025
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ABBREVIATIONS
to CRT can be expected given the severity of
implantation of a CRT device at the Cleveland Clinic
AND ACRONYMS
the cardiomyopathy. In addition, it is unclear
(Cleveland, Ohio) and the Johns Hopkins Hospital and
whether improvement in LVEF correlates
Johns Hopkins Bayview Medical Center (both in Bal-
with improved outcomes in this population.
timore, Maryland) between April 2003 and May 2014.
The question of whether to proceed with
The study was approved by the Institutional Review
resynchronization therapy
CRT becomes even more of a challenge
Boards of the Cleveland Clinic and John Hopkins
ICD = implantable cardioverter
when the patient already has an implantable
Medicine for retrospective medical records review
defibrillator
cardioverter-defibrillator (ICD) and presents
and was performed according to institutional guide-
LBBB = left bundle branch
for consideration for a cardiac implantable
lines. Clinical, electrocardiographic, and echocardio-
block
electrical device (CIED) revision to CRT. As
graphic data were gathered via review of electronic
LV = left ventricular
such, the chances of improvement must be
and physical medical records. For inclusion in the
LVAD = left ventricular assist
weighed against the potential procedural
final cohort, all patients had an LVEF of #15% and a
device
risks, which, given the level of LV dysfunc-
QRS duration of $120 ms. An assessment of all-cause
LVEDD = left ventricular end-
tion, may be significant. In the current study,
mortality was made using the U.S. Social Security
we sought to characterize procedural sur-
Death Index, Ohio death records, chart review, and
vival, long-term outcomes, and reverse ven-
Internet obituary searches. The subsequent implan-
tricular remodeling in patients undergoing
tation of a left ventricular assist device (LVAD) or
CIED = cardiac implantable
electrical device
CRT = cardiac
diastolic diameter
LVEF = left ventricular ejection
fraction
CRT with extremely severe LV dysfunction.
heart transplant was assessed by using current chart
review at both the Cleveland Clinic and Johns Hop-
METHODS
kins Medicine as well as a search of Cleveland Clinic
advanced heart failure therapy registry data.
This retrospective study involved the analysis of a
cohort
of
patients
who
underwent
the
new
Kaplan-Meier curves were constructed, and a
multivariate
model
was
created
to
determine
T A B L E 1 Baseline Characteristics of the Total Cohort*
Total
(N ¼ 420)
Ischemic
Cardiomyopathy
(n ¼ 211)
Nonischemic
Cardiomyopathy
(n ¼ 209)
Age, yrs
63.7 12.3
67.5 10.1
59.8 13.1
0.001
Men
306 (72.9)
172 (81.5)
134 (64.1)
<0.001
Baseline left ventricular ejection fraction, %
13.2 2.4
13.4 2.3
13.0 2.5
0.07
Baseline left ventricular end-diastolic diameter, cm
6.8 1.0
6.6 0.8
6.9 1.2
0.003
<0.001
p Value
6.0 1.5
5.7 1.0
6.3 1.8
CRT-D device, %
409 (97.4)
208 (98.6)
201 (96.2)
0.14
Serum hemoglobin, g/dl
12.7 1.9
12.4 1.9
13.1 1.8
<0.001
<0.001
Baseline left ventricular end-systolic diameter, cm
1.4 0.9
1.6 1.2
1.1 0.5
163.7 26.3
162.4 24.3
165.0 28.1
0.28
Left bundle branch block
222 (52.9)
88 (41.7)
134 (64.1)
<0.001
Paced upgrade
60 (14.3)
32 (15.2)
28 (13.4)
0.68
31 (7.4)
23 (10.9)
8 (3.8)
0.008
0.002
Serum creatinine, mg/dl
QRS duration, ms
Right bundle branch block
Nonspecific intraventricular conduction delay
106 (25.2)
67 (31.8)
39 (18.6)
History of atrial fibrillation, any type
202 (48.1)
107 (50.7)
95 (45.5)
0.29
58 (13.8)
37 (17.5)
21 (10.0)
0.03
Chronic obstructive pulmonary disease
Hypertension
257 (61.2)
131 (62.1)
126 (60.3)
0.76
Hyperlipidemia
234 (55.7)
148 (70.1)
86 (41.1)
<0.001
History of malignancy
44 (10.5)
17 (8.1)
27 (12.9)
0.10
Diabetes mellitus
163 (38.8)
92 (43.6)
71 (34.0)
0.05
0.47
History of stroke or transient ischemic attack
56 (13.3)
31 (14.7)
25 (12.0)
Beta-adrenergic blocker
339 (83.9)
162 (81.0)
177 (86.8)
0.14
ACE inhibitor or angiotensin II receptor blocker
320 (79.2)
144 (72.0)
176 (86.3)
<0.001
Aldosterone antagonist
169 (41.8)
82 (41.0)
87 (42.6)
0.76
Diuretic
351 (86.9)
172 (86.0)
179 (87.7)
0.66
87 (21.5)
53 (26.5)
34 (16.7)
0.02
Anti-arrhythmic medications
Values are mean SD or n (%). *Medications were available in 404 patients: 204 with nonischemic cardiomyopathy and 200 with ischemic cardiomyopathy.
ACE ¼ angiotensin-converting enzyme; CRT-D ¼ cardiac resynchronization therapy defibrillator.
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predictors of survival free of LVAD and heart transplant. In patients in whom an appropriately timed
T A B L E 2 Multivariate Cox Proportional Hazards Model for Survival Free of LVAD or
Heart Transplant
follow-up echocardiogram was available, an assessHazard Ratio
(95% Confidence Interval)
ment of reverse remodeling was made. The echocar-
p Value
diogram closest to 9 months and at least >3 months
Baseline left ventricular end-diastolic diameter
1.19 (1.03–1.36)
0.01
post-procedure was chosen. Response was defined as
Age
1.02 (1.00–1.03)
<0.001
an absolute improvement in LVEF of >5%. Variables
Male
1.44 (1.06–2.00)
0.02
selected for the models were selected based on a
History of atrial fibrillation
1.15 (0.89–1.48)
0.277
priori data obtained from review of past studies. In
Ischemic cardiomyopathy
1.45 (1.11–1.90)
0.07
the cohort as a whole, CRT device implantations were
Serum creatinine
1.06 (0.96–1.17)
0.25
performed transvenously in the vast majority of patients by electrophysiologists targeting a lateral or
posterolateral vein for the LV lead position. Medica-
QRS duration
0.996 (0.991–1.001)
0.63 (04.7–0.85)
Paced upgrade
0.88 (0.59–1.30)
0.51
NYHA functional class
2.10 (1.51–2.86)
<0.001
tions were recorded immediately before implantation
of the CRT device, with subsequent titration of
LVAD ¼ left ventricular assist device; NYHA ¼ New York Heart Association.
medications made at the discretion of patients’
outpatient physicians.
STATISTICAL ANALYSIS. Continuous variables were
was 13.2 2.4%, and patients were more commonly
presented as a mean SD and dichotomous variables
men (72.1%) with left bundle branch block (LBBB)
as an absolute number with percentage. Comparisons
(53.1%). Over a mean follow-up period of 5.2 years,
between 2 continuous variables were made using
there were 291 endpoints (17 LVADs, 20 heart trans-
Student’s t-test for parametric variables and a Mann-
plants, and 254 deaths). In multivariate analysis,
Whitney test for nonparametric variables. Compari-
younger age, female sex, smaller baseline LV end-
sons among more than 2 continuous variables were
diastolic diameter (LVEDD), and presence of LBBB
made using an analysis of variance test for parametric
were independently associated with improved sur-
variables and the Kruskal-Wallis test for nonpara-
vival free of LVAD and heart transplant (Table 2,
metric
were
Central Illustration). There was a nonsignificant trend
compared using the chi-square test. Kaplan-Meier
toward improved survival in patients with non-
curves using the log-rank test were created to assess
ischemic cardiomyopathy compared with ischemic
survival free of LVAD or heart transplant over the
cardiomyopathy (Table 2, Figure 1).
variables.
Dichotomous
variables
duration of follow-up. A multivariate Cox propor-
A total of 298 patients had an available pre-CRT
tional hazards model was created to determine fac-
and appropriately timed follow-up echocardiogram,
tors associated with long-term survival free of LVAD
of whom 145 met the criteria for response (48.7%)
and heart transplant, controlling for multiple vari-
(Table 3). Responders tended to have a smaller LVEDD
ables selected based on a priori knowledge. To test
and more often have LBBB (Table 3). There were 66
the Cox assumption that the hazard ratio between
patients who were revised from ICD to CRT-D, of
individuals is constant, a time-varying covariate was
whom 30 met the criteria for response (45.5%;
entered into the model for each variable, with a p
p ¼ 0.58). In multivariate logistic regression, a smaller
value of >0.05 needed to satisfy this assumption. In
LV size was associated with improved response
those patients in whom an appropriately timed
(Table 4). There was a nonsignificant trend toward
follow-up echocardiogram was available, a multivar-
presence of LBBB and improved response to CRT.
iate logistic regression analysis was performed to
Patients whose LVEF improved demonstrated a sig-
determine factors associated with response. All ana-
nificant survival advantage over those whose LVEF
lyses were performed with SPSS Inc. (Chicago, Illi-
failed to improve (Figure 2). When stratified by
nois). A procedure-related death was defined as a
LVEDD quintile, patients in the highest stratum (7.8
death before discharge from the hospital.
to 11 cm) had a 30.4% chance of response, which was
lower than the other strata (Table 5), When response
RESULTS
0.14
Left bundle branch block
was defined by an LVEF improvement of $10%, patients in the highest stratum (7.8 to 11 cm) had a 19.6%
Between April 2003 and May 2014, 420 patients met
chance of response, which was lower than the other
inclusion criteria. The baseline characteristics of the
strata (Table 6). There were no procedure-related
cohort are shown in Table 1. The mean baseline LVEF
deaths. There were 122 patients in whom complete
0.002
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C E N T R A L IL L U ST R A T I O N Kaplan-Meier Curves for Survival Free of LV Assist Device or Heart
Transplant Based on Baseline LV End-Diastolic Diameter Tertile
Rickard, J. et al. J Am Coll Cardiol EP. 2020;-(-):-–-.
Blue indicates LV end-diastolic diameter (LVEDD) of $7.2 cm, green indicates LV end-diastolic diameter of 6.4 to 7.2 cm, and tan indicates LV
end-diastolic diameter of <6.4 cm. Log-rank p < 0.01. LV ¼ left ventricular.
echocardiographic
unavailable
Of the 122 patients, 32 (24.2%) died within 1 year of
(Table 7). Such patients had a higher baseline serum
follow-up
was
CRT implant. Baseline characteristics based on QRS
creatinine (1.6 1.3 mg/dL vs. 1.3 0.7 mg/dL;
morphology are characterized in Table 8. Patients
p < 0.001), more ischemic cardiomyopathy (68.0% vs.
with LBBB had improved survival compared to the
42.6%; p < 0.001), and more non-LBBB than those
other QRS morphologies (Figure 3). Response was
with complete echocardiographic follow-up (Table 7).
noted in 54.3% of patients with LBBB, 20.0% with
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F I G U R E 1 Kaplan-Meier Curves for Survival Free of LVAD or Heart Transplant Based on Cardiomyopathy Subtype
Blue indicates nonischemic cardiomyopathy, and green indicates ischemic cardiomyopathy. Log-rank p < 0.001. LVAD ¼ left ventricular assist
device.
right bundle branch block, 46.8% with a paced
those who did not. Finally, the procedure itself
morphology, and 45.1% with a nonspecific intraven-
appears safe, with no procedural deaths.
tricular conduction delay.
Patients with a severely depressed LVEF who present for CRT implant present a treatment challenge.
DISCUSSION
Current implant guidelines offer no guidance as to
whether CRT is futile or potentially harmful in pa-
Patients with an extremely reduced LVEF (defined
tients with an extremely poor ejection fraction (5–7).
here as an LVEF of #15%) have been underrepre-
First, it is unclear how much benefit such patients
sented in clinical trials of CRT. Therefore, outcomes
derive from CRT once their LV function has dropped
and safety of CRT implantation in such patients are
to such an extreme level. The mean LVEF in clinical
unknown. The current study has multiple note-
trials has been in the range of 20% to 30% (1–4). In the
worthy findings. First, 48.9% of patients with se-
MADIT-CRT (Cardiac-Resynchronization Therapy for
vere
significant
the Prevention of Heart-Failure Events) trial, the
improvement in LVEF with CRT, a number some-
baseline LVEF was 24%; in the RAFT (Cardiac-
what lower than that previously reported in pa-
Resynchronization
tients with better baseline LV function. Second, LV
Heart Failure) trial, it was 23%; in the COMPANION
size is an important predictor of both ventricular
(Cardiac-Resynchronization Therapy With or Without
remodeling and long-term outcomes in this patient
an Implantable Defibrillator in Advanced Chronic
population. Nevertheless, 30% of patients in the
Heart Failure) trial, it was 21%; and in the MIRACLE
highest quintile of LV dilatation still realized an
(Cardiac Resynchronization in Chronic Heart failure
echocardiographic benefit. Third, patients whose
trial) trial, it was 22% (1–4). In subgroup analysis from
LVEF improved had better long-term outcomes than
MADIT-CRT, patients with an LVEF of #25% were
LV
dysfunction
realized
a
Therapy for
Mild-to-Moderate
5
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T A B L E 3 Baseline Characteristics Based on Response*
Total (n ¼ 298)
Responders (n ¼ 145)
Nonresponders (n ¼ 152)
Age, yrs
63.2 12.9
63.4 12.1
63.1 13.6
0.87
Men
209 (70.1)
97 (66.9)
113 (74.3)
0.20
Baseline left ventricular ejection fraction, %
13.1 2.4
13.1 2.4
13.1 2.4
0.95
Baseline left ventricular end-diastolic diameter, cm
6.9 1.1
6.7 1.0
7.1 1.1
0.001
0.001
p Value
Baseline left ventricular end systolic diameter, cm
6.0 1.2
5.8 1.2
6.2 1.2
Upgrade from ICD to CRT-D
66 (22.1)
30 (23.4)
36 (23.7)
0.58
Ischemic cardiomyopathy
127 (42.6)
59 (40.7)
68 (44.7)
0.49
Serum hemoglobin, g/dl
12.9 1.8
12.8 1.7
12.9 1.9
0.60
Serum creatinine, mg/dl
1.3 0.7
1.3 0.7
1.4 0.7
0.40
QRS duration, ms
165.3 26.7
165.6 25.1
165.0 28.3
0.86
QRS post, ms
160.6 23.6
158.8 23.1
162.4 24.0
0.19
QRS change, ms
4.6 27.6
6.7 26.8
2.6 28.3
0.20
Left bundle branch block
0.048
164 (42.6)
89 (61.4)
75 (49.3)
Paced rhythm
47 (15.8)
22 (15.2)
25 (16.4)
0.75
Right bundle branch block
15 (5.0)
3 (2.1)
12 (7.9)
0.03
0.50
Nonspecific intraventricular conduction delay
71 (23.8)
32 (22.1)
39 (25.7)
History of atrial fibrillation (any type)
151 (50.7)
80 (55.2)
71 (46.7)
0.17
CRT-D (vs CRT-P)
290 (97.3)
144 (99.3)
146 (96.0)
0.28
II
23 (7.7)
13 (9.0)
10 (6.6)
III
124 (81.6)
NYHA functional class
0.66
245 (82.2)
121 (83.4)
III-IV
11 (3.7)
4 (2.8)
7 (4.6)
IV
19 (6.4)
8 (5.5)
11 (7.2)
Chronic obstructive pulmonary disease
43 (14.4)
17 (11.7)
26 (17.1)
0.19
Hypertension
188 (63.1)
89 (61.4)
90 (59.2)
0.19
Hyperlipidemia
167 (56.0)
76 (52.4)
91 (60.0)
0.20
35 (11.7)
14 (9.7)
21 (13.8)
0.28
116 (38.9)
65 (44.8)
51 (33.6)
0.06
0.50
History of malignancy
Diabetes mellitus
History of stroke or transient ischemic attack
39 (13.1)
17 (11.7)
22 (15.2)
Beta-adrenergic blocker
245 (85.1)
122 (87.1)
123 (83.1)
0.41
ACE inhibitor or angiotensin II receptor blocker
236 (81.9)
119 (85.0)
117 (79.1)
0.20
Diuretic
253 (87.8)
126 (90.0)
127 (85.8)
0.29
Antiarrhythmic medications
58 (20.1)
29 (20.7)
29 (19.6)
0.90
Nitrates
66 (22.9)
32 (22.9)
34 (23.0)
1.00
Hydralazine
37 (12.8)
16 (11.4)
21 (14.2)
0.60
Values are mean SD or n (%). *Medications were available in 288 patients: 140 responders and 148 nonresponders.
CRT-P ¼ cardiac resynchronization therapy pacemaker; ICD ¼ implantable cardioverter defibrillator; other abbreviations as in Tables 1 and 2.
noted
T A B L E 4 Multivariate Logistic Regression Model for Response
to
have
improved
outcomes
with
CRT
compared to ICD alone (8). This benefit, however, was
less than patients with a higher LVEF (8). The number
Odds Ratio
(95% Confidence
Interval
p Value
Left ventricular end-diastolic diameter
0.68 (0.53–0.97)
0.002
Male
0.95 (0.55–1.65)
0.85
of patients in the MADIT-CRT trial with an LVEF
of #15% was very small (8).
A question that has often been raised is whether
History of atrial fibrillation
1.34 (0.82–2.90)
0.24
there is a degree of LV dysfunction that is so severe
Ischemic cardiomyopathy
0.88 (0.53–1.46)
0.88
that the cardiomyopathic process has surpassed the
QRS duration
1.001 (0.99–1.01)
0.80
ability of CRT to demonstrate a meaningful benefit
1.70 (0.92–3.11)
0.09
(9). Although improvement in LVEF has been shown
Paced rhythm
1.14 (0.477–2.88)
0.77
NYHA functional class
0.86 (0.45–1.64)
0.86
Left bundle branch block
NYHA ¼ New York Heart Association.
to translate into a survival benefit in a traditional CRT
population, whether such improvement translates
into a survival benefit in patients with extreme LV
dysfunction is unclear (10–12). Finally, the safety of
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F I G U R E 2 Kaplan-Meier Curves for Survival Free of LVAD or Heart Transplant Based on Change in LVEF
Yellow indicates LVEF of >10%, green indicates LVEF of 5% to 10%, and blue indicates LVEF of <5%. Log-rank p < 0.001. LVAD ¼ left
ventricular assist device; LVEF ¼ left ventricular ejection fraction.
the procedure itself has been called into question.
tion or general anesthesia in patients with extremely
CRT has been shown to be a safe procedure in more
poor LV function adds to the considerations of
traditional candidates (13). In some patients, CRT
whether CRT is appropriate. When patients already
implantation can be difficult and time consuming,
have an ICD and the indication is a revision to CRT-D,
especially in patients with LV dilatation and severe
the decision is even more challenging. We found that
LV dysfunction, in whom coronary venous anatomy
patients with an LVEF of #15% had a 48.9% chance of
can be distorted. Coupling a more challenging
improvement in LVEF of at least >5% and that such
implant with the risks of prolonged conscious seda-
improvement translated into a long-term survival
T A B L E 5 Percent Responders Based on LVEDD Quintile
T A B L E 6 Improvement in Left Ventricular Ejection Fraction
$10% Based on LVEDD Quintile
LVEDD (cm) by Quintile
Response
11–7.8
17/56 (30.4)
LVEDD (cm) by Quintile
7.7–7.1
27/56 (48.2)
11–7.8
7.0–6.6
28/59 (47.5)
7.7–7.1
23/56 (41.1)
6.5–6.1
34/52 (65.4)
7.0–6.6
27/59 (45.8)
#6.0
35/63 (55.6)
6.5–6.1
31/52 (59.6)
#6.0
30/63 (47.6)
Values are n/N (%).
LVEDD ¼ left ventricular end-diastolic diameter.
Values are n/N (%).
LVEDD ¼ left ventricular end-diastolic diameter.
Response
11/56 (19.6)
7
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T A B L E 7 Baseline Characteristics of the Total Cohort*
No Follow-Up
Echocardiogram
(n ¼ 122)
Follow-Up
Echocardiogram
(n ¼ 298)
64.7 10.8
63.2 12.9
0.25
Men
88 (72.1)
210 (70.5)
0.09
Baseline left ventricular ejection fraction
13.4 2.3
13.1 2.4
0.59
Baseline left ventricular end-diastolic diameter, cm
6.6 1.0
6.9 1.1
0.29
Ischemic cardiomyopathy
83 (68.0)
127 (42.6)
<0.001
CRT-D device
119 (97.5)
290 (97.3)
>0.99
Serum hemoglobin, g/dl
12.3 2.0
12.9 1.8
0.22
Serum creatinine, mg/dl
1.57 1.3
1.34 0.7
<0.001
0.07
Age, yrs
p Value
160.3 24.9
165.3 26.7
Left bundle branch block
58 (47.5)
164 (55.0)
0.16
Paced upgrade
13 (10.7)
47 (15.8)
0.22
Non–left bundle branch block
49 (40.2)
84 (28.2)
0.02
History of atrial fibrillation, any type
51 (41.9)
151 (50.7)
0.11
Chronic obstructive pulmonary disease
15 (12.3)
43 (14.4)
0.64
0.23
QRS duration, ms
Hypertension
69 (56.6)
188 (63.1)
Hyperlipidemia
67 (54.9)
167 (56.0)
0.91
9 (7.4)
35 (11.7)
0.22
History of malignancy
Diabetes mellitus
48 (39.3)
16 (5.4)
>0.99
History of stroke or transient ischemic attack
17 (13.9)
39 (13.1)
0.88
Beta-adrenergic blocker
95 (77.9)
245 (85.1)
0.37
ACE inhibitor or angiotensin II receptor blocker
85 (73.3)
236 (81.9)
0.06
Aldosterone antagonist
53 (45.7)
117 (40.6)
0.37
Diuretic
98 (84.5)
253 (87.8)
0.42
Antiarrhythmic medications
28 (24.1)
58 (20.1)
0.42
Values are mean SD or n (%). *Medications were available in 404 patients: 116 with no follow-up echocardiogram and 288 with follow-up echocardiogram.
Abbreviations as in Table 1.
benefit. In addition, no procedure-related mortalities
extreme LV dilatation (LVEDD of 7.8 to 11 cm) had a
were noted. Patients revised from a previous ICD to
30.4% chance of demonstrating significant LVEF
CRT-D had similar rates of response. These data
improvement. This suggests that although the chan-
suggest that CRT in patients with extremely severe
ces of benefit are lower compared to a traditional CRT
LV dysfunction is safe and that these patients have a
population, benefit is still possible (15). This refutes
reasonable chance to improve cardiac function and
the notion that there may be a point at which LV
survival free of LVAD and heart transplant. In addi-
function has become so poor and LV diameter so
tion, we found that many of the same predictors of
dilated that the disease process has moved past the
outcomes seen in a more traditional CRT population
point of at least partial mitigation with CRT.
(e.g.,
cardiomyopathy
morphology)
were
subtype,
similarly
gender,
predictive
in
QRS
this
population.
STUDY LIMITATIONS. First, this is a cohort from 3
large tertiary care referral centers and, therefore, may
Patients with extreme LV dysfunction typically
not be indicative of other cohorts. The retrospective
have significant LV dilatation, which was indeed
nature cannot account for all confounders, despite
noted in the current study. In a more traditional pa-
our best effort to do so, although the large number of
tient population undergoing CRT, LV size has been
patients reported in this study allowed us to control
shown to correlate with long-term outcomes (9).
for many potential confounders. Echocardiographic
Some investigators have suggested normalizing the
information was obtained via chart review, and the
QRS duration to LV dimension as a means of pre-
imaging studies could not be readjudicated. However,
dicting outcomes (14). We found that among patients
both the Cleveland Clinic and John Hopkins Medicine
with severe LV dysfunction, even patients with
have served as echocardiographic core labs, with
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Severe Cardiomyopathy and CRT
T A B L E 8 Baseline Characteristics Based on Bundle Branch Block Morphology*
Paced
(n ¼ 67)
Right Bundle
Branch Block
(n ¼ 32)
Nonspecific
Intraventricular
Conduction Delay
(n ¼ 107)
p Value
64.6 12.5
66.4 12.2
64.4 12.7
59.9 11.0
0.002
Men
139 (65.0)
52 (77.6)
29 (90.6)
86 (80.4)
0.001
Ischemic cardiomyopathy, %
86 (40.2)
33 (49.3)
24 (75.0)
68 (63.6)
<0.001
Baseline left ventricular ejection fraction, %
13.1 2.4
13.3 2.3
13.8 1.9
13.0 2.5
0.32
Baseline left ventricular end diastolic diameter, cm
6.7 1.0
6.9 1.1
6.3 0.9
7.0 1.0
0.01
Age, yrs
Left Bundle
Branch Block
(n ¼ 214)
Baseline left ventricular end systolic diameter, cm
6.0 1.7
5.9 1.3
5.6 0.9
6.1 1.2
0.36
CRT-D device
209 (97.7)
64 (95.5)
32 (100.0)
104 (97.2)
0.60
Serum hemoglobin, g/dl
12.7 1.9
12.8 1.7
12.2 2.0
12.8 2.1
0.51
Serum creatinine, mg/dl
1.4 1.0
1.6 1.0
1.4 0.8
1.4 0.7
0.42
<0.001
164.8 21.1
189.7 28.6
162.6 14.7
146.1 22.7
History of atrial fibrillation, any type
97 (45.3)
39 (58.2)
16 (50.0)
50 (46.7)
0.32
Chronic obstructive pulmonary disease
30 (14.0)
9 (13.4)
3 (9.4)
16 (15.0)
0.88
Hypertension
137 (64.0)
42 (62.7)
18 (56.3)
60 (56.1)
0.51
Hyperlipidemia
113 (52.8)
36 (53.7)
24 (75.0)
61 (57.0)
0.13
History of malignancy
21 (9.9)
10 (14.9)
5 (15.6)
8 (7.5)
0.33
Diabetes mellitus
81 (37.9)
30 (44.8)
10 (31.3)
42 (39.3)
0.60
History of stroke or transient ischemic attack
22 (10.3)
11 (16.4)
3 (9.4)
20 (18.7)
0.15
Beta-adrenergic blocker
178 (86.4)
54 (85.7)
22 (71.0)
85 (81.7)
0.15
ACE inhibitor or angiotensin II receptor blocker
168 (81.6)
52 (82.5)
21 (67.7)
79 (76.0)
0.24
Aldosterone antagonist
81 (39.3)
28 (44.4)
15 (48.4)
45 (43.3)
0.72
Diuretic
177 (85.9)
55 (87.3)
25 (80.6)
94 (90.4)
0.50
32 (15.5)
17 (5.9)
3 (9.7)
35 (33.7)
0.001
QRS duration, ms
Antiarrhythmic medications
Values are mean SD or n (%). *Medications were available in 404 patients: 206 with left bundle branch block, 63 paced, 31 with right bundle branch block, and 104 with
nonspecific intraventricular conduction delay.
Abbreviations as in Table 1.
standard methods of LVEF and LVEDD reporting.
severely dysfunctional that mitigation with CRT is
Patients
echocardiogram
completely precluded. Improvement in LVEF translates
appeared to have more comorbidities than those with
into improved survival in this population. LV size and
complete
Overall,
bundlebranchblockmorphologyareimportantfactorsin
24.2% of patients without an echocardiographic
predicting outcomes, and the CRT implant procedure it-
follow-up met the primary endpoint within 1 year. As
selfinthesepatientsappearswelltolerated.
without
a
follow-up
echocardiographic
follow-up.
such, some selection bias may be present. There was
no non-CRT control arm; therefore, a direct compar-
AUTHOR RELATIONSHIP WITH INDUSTRY
ison with or without CRT could not be made. Finally,
Dr. Rickard has performed consulting for Medtronic; and has per-
the number of patients who underwent defibrillation
formed research for Abbott. Dr. Varma has performed research for
threshold testing or who had other types of proce-
St. Jude. Dr. Wilkoff is a speaker for Boston Scientific and Con-
dural complications was not collected.
vaTec; consultant to Phillips, Medtronic, and Abbott; and provides
research support to Phillips. All other authors have reported that
they have no relationships relevant to the contents of this paper to
CONCLUSIONS
disclose.
Patients with severe LV dysfunction derive benefit from
ADDRESS FOR CORRESPONDENCE: Dr. John Rick-
CRT, although at lower rates than traditionally studied
ard, Heart and Vascular Clinic, Cleveland Clinic, 9500
patients with higher LVEFs. These data argue against a
Euclid
specific point at which cardiac function becomes so
rickarj2@ccf.org.
Avenue,
Cleveland,
Ohio
44195.
E-mail:
9
10
Rickard et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
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Severe Cardiomyopathy and CRT
F I G U R E 3 Kaplan-Meier Curves for Survival Free of LVAD or Heart Transplant Based on Baseline QRS Morphology
Blue indicates left bundle branch block, green indicates paced, yellow indicates right bundle branch block, and purple indicates nonspecific
intraventricular conduction delay. Log-rank p < 0.001. LVAD ¼ left ventricular assist device.
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: CRT re-
gauge the presence of electrical dyssynchrony, the pri-
mains an important tool for many patients with systolic
mary target for CRT. Better tools are needed to measure
heart failure and evidence of electrical dyssynchrony.
electrical dyssynchrony noninvasively to gauge CRT can-
Occasionally in clinical practice, patients with extreme LV
didacy and CRT effect. Such tools are especially pertinent
dysfunction despite good medical therapy are encoun-
in patients with severe LV dysfunction who often have a
tered, and the utility and safety of CRT are questioned.
concomitantly elevated LV mass. Determining how much
The results of this study suggest that CRT is a reasonable
QRS widening is due to true electrical dyssynchrony
and well-tolerated procedure in patients with severe LV
versus slow conduction due to a combination of scar and
functional impairment.
mass effect will be useful to guide therapy.
TRANSLATIONAL OUTLOOK: CRT candidacy continues to hinge on the use of 12-lead echocardiography to
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
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Severe Cardiomyopathy and CRT
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KEY WORDS cardiac resynchronization
therapy, reverse remodeling, severe
cardiomyopathy, survival
11