Download Influence of Ejection Fraction on the Prognostic Value of

JACC: CARDIOVASCULAR IMAGING
VOL. 5, NO. 11, 2012
© 2012 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jcmg.2012.02.019
Influence of Ejection Fraction on the Prognostic
Value of Sympathetic Innervation Imaging With
Iodine-123 MIBG in Heart Failure
Amil M. Shah, MD, MPH,* Mikhail Bourgoun, MD,* Jagat Narula, MD, PHD,†
Arnold F. Jacobson, MD, PHD,‡ Scott D. Solomon, MD*
Boston, Massachusetts; New York, New York; and Princeton, New Jersey
O B J E C T I V E S The aim of this study was to determine whether left ventricular ejection fraction
(LVEF) influences the relationship between abnormal myocardial sympathetic innervation imaging by
iodine 123 meta-iodobenzylguanidine (123I-mIBG) and outcomes in patients with heart failure (HF).
B A C K G R O U N D In systolic HF, both abnormal 123I-mIBG imaging and reduced LVEF are associated
with higher risk of cardiovascular events. Whether
across the LVEF spectrum is unclear.
123
I-mIBG imaging has the same predictive value
M E T H O D S Among 985 patients in the ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) trial with New York Heart Association functional class II or III HF and site-reported
LVEF ⱕ35%, the core laboratory– determined LVEFs were available for 901 subjects, ranging from 20%
to 58% (mean LVEF 34 ⫾ 7%), and was ⬎35% in 386 subjects.
R E S U L T S The mean age of the study population was 62 ⫾ 12 years, 80% were male, and the
majority had New York Heart Association functional class II symptoms and HF of nonischemic etiology.
At all levels of LVEF, the 123I-mIBG heart-to-mediastinum ratio of ⬍1.6 was associated with a higher risk
of death or potentially lethal arrhythmic event and of the composite of cardiovascular death, arrhythmic
event, and HF progression. Comparing subjects with LVEF ⱕ35% and ⬎35%, there was no evidence of
effect modification of LVEF on the risk associated with low heart-to-mediastinum ratio for death or
arrhythmic event (adjusted hazard ratio: 2.39 [95% confidence interval (CI): 1.03 to 5.55] vs. 5.28 [95% CI:
1.21 to 23.02]; interaction p ⫽ 0.48) and for the composite (adjusted hazard ratio: 1.80 [95% CI: 1.01 to
3.23] vs. 2.41 [95% CI: 1.11 to 5.23]; interaction; p ⫽ 0.86). For death or arrhythmic event, the
heart-to-mediastinum ratio appeared to improve the risk discrimination beyond clinical and biomarker
data among both LVEF groups, with improvement in the model C-statistic (0.67 vs. 0.69, p ⫽ 0.03) and
integrated discrimination improvement (p ⫽ 0.0008).
123
I-mIBG imaging has prognostic value across a spectrum of LVEFs. Further
studies may be warranted to prospectively test the prognostic value of 123I-mIBG imaging in patients
with HF and an LVEF ⬎35%. (J Am Coll Cardiol Img 2012;5:1139 – 46) © 2012 by the SIR
CONCLUSIONS
From the *Brigham and Women’s Hospital, Boston, Massachusetts; †Mount Sinai School of Medicine, New York, New York;
and ‡GE Healthcare, Princeton, New Jersey. Dr. Jacobson is an employee of GE Healthcare and has minor ownership of GE
stock. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. H.
William Strauss, MD, served as Guest Editor for this paper.
Manuscript received October 24, 2011; revised manuscript received January 24, 2012, accepted February 8, 2012.
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123
I-mIBG, LVEF, and Outcomes in HF
P
atients with heart failure (HF) are at an
increased risk of death secondary to both
arrhythmia and HF progression regardless of
left ventricular ejection fraction (LVEF) (1,2).
When ⬍45%, LVEF is a powerful predictor of
adverse events in patients with HF (3). However,
few measures are available to risk-stratify HF patients with a normal or mildly reduced LVEF. In
particular, although subjects with HF and an LVEF
⬎35% are at an increased risk of sudden death
compared with persons without HF, there is currently no widely applicable method to risk-stratify
these patients and identify those who may benefit
from advanced therapies such as implantable
cardioverter-defibrillators (4).
Evaluations of LVEF are often imprecise, related
to interobserver variability, differences due to imaging modality, and physiological variation over time
related to changes in loading conditions and heart
rate (5). The use of experienced core
ABBREVIATIONS
laboratories appears to improve the uniAND ACRONYMS
formity of LVEF assessment by echocardiography in multicenter clinical trials,
HF ⴝ heart failure
and profession guidelines for their use are
H/M ⴝ ratio ⴝ heart-tonow available (6). When LVEF cutoffs are
mediastinum ratio
used in multicenter clinic trials, discorIDI ⴝ integrated discrimination
dance in LVEF results between the enrollimprovement
ing site and a core laboratory is not unLV ⴝ left ventricular
common (7).
LVEF ⴝ left ventricular ejection
fraction
Iodine 123 meta-iodobenzylguanidine
123
(123I-mIBG) is a radiopharmaceutical that
I-mIBG ⴝ iodine 123
meta-iodobenzylguanidine
is selectively taken up into pre-synaptic
NYHA ⴝ New York Heart
sympathetic nerve endings via the norepiAssociation
nephrine reuptake system but is not metabolized (8,9). Reductions in 123I-mIBG
uptake therefore may represent abnormalities of
pre-synaptic norepinephrine reuptake or sustained
hyperactivity of the sympathetic nervous system in
HF with pre-synaptic norepinephrine depletion.
Abnormal cardiac sympathetic innervation imaging
using 123I-mIBG is associated with a higher risk of
mortality and morbidity among patients with HF
and an LVEF ⱕ35% (10). Data regarding the
prognostic utility of 123I-mIBG in HF with an
LVEF ⬎35% are limited (11).
We hypothesized that the association of lower
heart-to-mediastinum ratio (H/M ratio) with mortality and potentially lethal arrhythmic events will
be equivalent among HF patients across the spectrum of left ventricular (LV) systolic function. To
gain greater insight into the utility of 123I-mIBG
imaging in HF with EF ⬎35%, we performed a
retrospective analysis of the ADMIRE-HF (Adre-
JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 11, 2012
NOVEMBER 2012:1139 – 46
View Myocardial Imaging for Risk Evaluation in
Heart Failure) trial database using LVEF determined by a core laboratory in which a subset of
patients had an LVEF ⬎35%. Specifically, we
sought to assess for the presence of effect modification of LVEF on the relationship between H/M
ratio and the risk of death or potentially lethal
arrhythmic event and of cardiovascular death, arrhythmic event, or HF progression.
METHODS
Patient population. The ADMIRE-HF trial was
the combination of 2 identical open-label, multicenter trials designed to provide prospective validation of the prognostic role of cardiac sympathetic
innervation imaging using 123I-mIBG in patients
with HF (12). The study enrolled 985 HF subjects
who met the following inclusion criteria: New York
Heart Association (NYHA) functional class II or
III symptoms, an ischemic or nonischemic cardiomyopathy with a site-reported LVEF ⱕ35%, and
receiving evidence-based medical therapy including
a beta-blocker and angiotensin-converting enzyme
inhibitor or angiotensin receptor blocker. All enrolled patients underwent planar imaging of the
anterior thorax at 15 min and 4 h after 123I-mIBG
injection. Subjects were followed for a median of 17
months to the primary composite endpoint of
cardiac death, potentially life-threatening arrhythmic event, or HF progression. The extent of 123ImIBG uptake was quantified at a core reading
facility, and clinical events were adjudicated by an
endpoint adjudication committee as previously described (13). A potentially life-threatening arrhythmic event was defined as an episode of spontaneous
ventricular tachycardia ⬎30 s, resuscitated cardiac
arrest, or appropriate implantable cardioverterdefibrillator discharge (antitachycardia pacing or
defibrillation). HF progression was defined as an
increase in NYHA functional class from II to III or
IV or from III to IV. The primary results of the
ADMIRE-HF trial were previously presented and
published (12).
Echocardiographic analysis. For trial inclusion, a
site-reported LVEF could be based on assessment
by echocardiography, radionuclide ventriculography, electrocardiography-gated single-photon
emission computed tomography myocardial perfusion imaging, contrast ventriculography, or cardiac
magnetic resonance. For quality assurance purposes,
sites also submitted echocardiograms to an independent core laboratory for quantitative assessment
Shah et al.
I-mIBG, LVEF, and Outcomes in HF
JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 11, 2012
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NOVEMBER 2012:1139 – 46
of LV volumes and LVEFs. All echocardiograms
were evaluated in a core laboratory blinded to both
H/M ratio and clinical status. Ventricular volumes
were determined by the Simpson method in the
apical 4-chamber view, and LVEF was calculated
from volumes in the standard manner (14).
Of 901 patients with a core laboratory–
determined LVEF, 813 (90%) had site LVEF
measured by echocardiography. Of these 813 patients, the same echocardiogram was used for site
assessment and core laboratory analysis in 707
(87%). In the remaining 106 patients (13%), the
study used for site LVEF assessment and core
laboratory analysis were separated by a mean of 32
days (range, 1 to 439 days). In 88 patients (10%),
the site-reported LVEF was based on a modality
other than echocardiography, and in 59 (67%) of
these patients, the study used for site assessment of
LVEF was performed on a different day from the
echocardiogram analyzed by the core laboratory
(mean difference, 26 days; range, 1 to 50 days).
Statistical methods. We dichotomized subjects
based on core laboratory–adjudicated LVEFs
ⱕ35% or ⬎35% to describe baseline clinical and
imaging parameters. Continuous variables are presented as mean and SD unless otherwise specified,
and between-group comparisons were performed
using a Fisher exact test for categorical variables and
a t test for continuous variables. Two-sided p values
⬍0.05 were considered significant. Sample size was
allowed to float.
We assessed for effect modification using 2
methods. First, multivariable Cox proportional hazard models were used to evaluate for effect modification of LVEF on the relationship between H/M
ratio and the following outcomes: arrhythmic event
or death and a composite of cardiac death, HF
progression, and arrhythmic event. All models adjusted for age, sex, baseline NYHA functional class,
HF etiology (ischemic or nonischemic), diabetes
status, history of hypertension, and baseline B-type
natriuretic peptide level. A p value ⬍0.05 was
considered significant.
Second, to better define the magnitude of risk
associated with low H/M ratio across the continuum of observed LVEFs, we used local regression
plots of the adjusted hazard ratio associated with an
H/M ratio ⬍1.6 by LVEF as a continuous measure
using multivariable local regression (15). The hazard ratio associated with a low H/M ratio was
plotted for every second percentile of LVEF incorporating patients with baseline LVEF within the 15
percentiles above and below that point such that
30% of the study population contributed to each
effect estimate.
To assess the incremental value of the H/M ratio
beyond clinical characteristics, biomarker data, and
LVEF, analysis was restricted to 542 subjects (355
with core laboratory LVEFs ⱕ35% and 187 with
LVEFs ⬎35%) with at least 475 days of follow-up.
Multivariable logistic regression models for the
cardiovascular composite outcome and for death or
arrhythmic event were built, either including or
excluding H/M ratio data. All models adjusted for
age, sex, baseline NYHA functional class, HF
etiology (ischemic or nonischemic), diabetes status,
history of hypertension, baseline B-type natriuretic
peptide level, and core laboratory–adjudicated
LVEF. The area under the receiver-operating characteristic curve was expressed as the C-statistic and
tested whether pevent ⬎ pnonevent, where pevent is the
model predicted probability of an event from the
logistic regression model among individuals who
experienced an event and pnonevent is the model
predicted probability of an event among individuals
who did not experience an event. The model
C-statistic was compared among models with versus without H/M ratio. C-statistics were compared
using the Delong test (16). The integrated discrimination improvement (IDI) was calculated
as IDI ⫽ (pwith H/M, event ⫺ pwithout H/M, event) ⫺
(pwith H/M, nonevent ⫺ pwithout H/M, nonevent), where
pwith H/M, event is the predicted probability of an
event from the logistic regression model containing
the H/M ratio data among individuals who experienced an event, pwithout H/M, event is the predicted
probability of an event from the logistic regression model not containing the H/M ratio data
among individuals who experienced an event,
pwith H/M, nonevent is the predicted probability of an
event from the logistic regression model containing
H/M ratio data among individuals who did not
experience an event, and pwithout H/M, nonevent is the
predicted probability of an event from the logistic regression model not containing H/M ratio
data among individuals who did not experience
an event (17).
RESULTS
Baseline characteristics. Of 985 subjects enrolled in
the ADMIRE-HF trial, 123I-mIBG imaging results, core laboratory– determined LVEFs, and
complete follow-up were available for 901 subjects
(91.5% of enrolled subjects) who were included in
this analysis. The mean site-reported LVEF was
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I-mIBG, LVEF, and Outcomes in HF
JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 11, 2012
NOVEMBER 2012:1139 – 46
and of death or arrhythmic event compared with
subjects with an LVEF ⬎35%. An H/M ratio ⬍1.6
was associated with an increased relative risk of
both endpoints without evidence of significant effect modification by LVEF category (ⱕ35% or
⬎35%). Figure 2 illustrates the rate of death or
arrhythmic event by H/M ratio among 4 categories
of core laboratory LVEF, demonstrating consistent
trends toward higher event rates with an H/M ratio
⬍1.6 in all categories. As demonstrated in Figure 3,
no significant heterogeneity of the relative risk
associated with an H/M ratio ⬍1.6 was detected
across the continuum of LVEF for either of the
clinical endpoints.
25
Percent of Subjects
20
15
10
5
0
0
20
40
60
Left Ventricular Ejection Fraction (%)
Site reported LVEF
Core lab adjudicated LVEF
Figure 1. LVEF Distribution in the ADMIRE-HF Trial
Distribution of the site-reported (pink columns) and echocardiography core laboratory–
adjudicated left ventricular ejection fraction (LVEF) (green columns). The mean site-reported LVEF was 27.1 ⫾ 6.2. The mean core laboratory–adjudicated LVEF was 34.2 ⫾
6.9, and 386 (43%) subjects had an LVEF of ⬎35%.
27.1 ⫾ 6.2 (Fig. 1). One subject with a reported
LVEF ⬎35% at 2 days before 123I-mIBG imaging
was allowed to remain in the study based on an
earlier determination of 35%. The mean core laboratory–adjudicated LVEF was 34.2 ⫾ 6.9 and 386
(43%) had an LVEF ⬎35%. Using a Bland-Altman
analysis of agreement between site-reported LVEF
and core laboratory–measured LVEF, the bias estimate for site-core laboratory LVEF was ⫺7.1%
with 95% limits of agreement of ⫺21.9% to 7.7%.
The mean LVEF of the 515 subjects with an
LVEF ⱕ35% was 29.5 ⫾ 3.7%, and the mean
LVEF of the 386 subjects with an LVEF ⬎35%
was 40.4 ⫾ 5.0%. Subjects with an LVEF ⬎35%
were more frequently female, more frequently had
HF of ischemic etiology, had lower body mass
index, and had lower baseline B-type natriuretic
peptide levels (Table 1). A modest, although statistically significant, correlation was noted between
LVEF and H/M ratio as a continuous measure
(Pearson correlation coefficient ⫽ 0.23, p ⬍
0.0001).
LVEF, H/M ratio, and clinical events. Cumulative incidence, event rates, and adjusted hazard ratio for
clinical events by LVEF category and H/M ratio
are shown in Table 2. Subjects with an LVEF
ⱕ35% were at higher risk of both the composite of
cardiac death, arrhythmic event, and worsening HF
Incremental value of H/M ratio beyond clinical characteristics and LVEF in predicting clinical outcomes in
patients with HF and LVEF <35% and >35%. For the
cardiovascular composite endpoint, information on
H/M ratio did not significantly affect the model
C-statistic (Table 3). A small but significant improvement in the IDI was noted, the magnitude of
which was most prominent in the LVEF ⬎35%
group. For the outcome of death or arrhythmic
event, the addition of H/M ratio led to significant improvement in both the C-statistic and the
IDI. For both measures, the magnitude of effect
Table 1. Baseline Characteristics by Core
Laboratory–Adjudicated LVEF
LVEF <35%
(n ⴝ 515)
LVEF >35%
(n ⴝ 386)
LVEF, %
29.5 ⫾ 3.7
40.4 ⫾ 5.0
Age, yrs
61.6 ⫾ 12.0
62.8 ⫾ 11.7
p Value
0.13
Male
423 (82)
296 (77)
0.04
White race
381 (74)
292 (76)
0.59
89 (17)
62 (16)
0.65
321 (62)
267 (69)
NYHA functional class
III
Ischemic etiology
BMI, kg/m2
29.6 ⫾ 6.3
28.7 ⫾ 5.7
0.03
0.02
Diabetes
193 (37)
137 (35)
0.58
Hypertension
326 (63)
257 (67)
0.32
Dyslipidemia
381 (74)
275 (71)
0.37
Smoking
384 (75)
281 (73)
0.59
ACE inhibitor or ARB
483 (94)
358 (93)
0.59
Beta-blocker
475 (92)
350 (91)
0.47
Lipid-lowering
medication
376 (73)
291 (75)
0.44
eGFR, ml/min/1.73 m2
BNP, pg/ml*
58.2 ⫾ 18.2
60.3 ⫾ 18.0
0.10
170 (69–363)
107 (41–232)
⬍0.0001
Values are mean ⫾ SD or n (%). *Median and interquartile range and
Kruskal-Wallis nonparametric test reported. Continuous variables are expressed as mean ⫾ SD.
ACE ⫽ angiotensin-converting enzyme; ARB ⫽ angiotensin receptor blocker;
BMI ⫽ body mass index; BMP ⫽ B-type natriuretic peptide; eGFR ⫽ estimated
glomerular filtration rate; LVEF ⫽ left ventricular ejection fraction; NYHA ⫽
New York Heart Association.
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NOVEMBER 2012:1139 – 46
Table 2. Cumulative Incidence of Cardiovascular Events Among Patients With Core Laboratory–Adjudicated LVEF <35%
Versus >35% by H/M Ratio Category
LVEF <35% (n ⴝ 515)
Death
Overall
H/M
Ratio <1.6
H/M
Ratio >1.6
52 (10)
50 (12)
2 (2)
LVEF >35% (n ⴝ 386)
HR (Range)*
Overall
H/M
Ratio <1.6
H/M
Ratio >1.6
21 (5)
20 (7)
1 (1)
HR (Range)*
p Value
for
Interaction
CV death
33 (6)
32 (7)
1 (1)
13 (3)
12 (4)
1 (1)
Arrhythmic event
48 (9)
44 (10)
4 (5)
14 (4)
13 (5)
1 (1)
117 (23)
106 (24)
11 (13)
48 (12)
40 (14)
8 (7)
95 (18)
89 (21)
6 (7)
2.39 (1.03–5.55)
33 (9)
31 (11)
2 (2)
5.28 (1.21–23.02)
0.48
156 (30)
143 (33)
13 (16)
1.80 (1.01–3.23)
64 (17)
55 (20)
9 (8)
2.41 (1.11–5.23)
0.86
Worsening HF
Arrhythmic event or death
CV composite
Values are n (%) or n (range). *Adjusted for age, sex, heart failure etiology, NYHA functional class, diabetes status, hypertension, and B-type natriuretic peptide level.
CV ⫽ cardiovascular; HF ⫽ heart failure; H/M ratio ⫽ heart-to-mediastinum ratio; HR ⫽ hazard ratio; LVEF ⫽ left ventricular ejection fraction; other abbreviation as in Table 1.
DISCUSSION
Of 901 subjects enrolled in the ADMIRE-HF trial
with H/M ratio data and core laboratory LVEFs,
384 (43%) had an LVEF ⬎35%. We found no
evidence of effect modification of LVEF on the
relationship between H/M ratio and risk, either of
death or arrhythmic event or of the composite
endpoint of cardiac death, arrhythmic event, and
worsening HF. For the outcome of death or arrhythmic event, information on H/M ratio appeared to improve discrimination of predictive
models beyond clinical, biomarker, and LVEF data,
particularly among subjects with an LVEF ⬎35%.
Multiple single-center studies have demonstrated
an association between abnormal cardiac sympathetic innervation imaging, reflected in a low H/M
ratio, and worse outcomes among patients with HF
(10). However, the majority of studies evaluated
patients with HF and low LVEF, and only limited
data exist regarding the performance of this test in
HF patients with normal or only slightly reduced
LVEF (18 –20). In a multicenter study of 290
patients, Agostini et al. (18) demonstrated a relationship between H/M ratio and cardiovascular
events among the 191 subjects with an LVEF
ⱕ35% but not among the 99 patients with an
LVEF ⬎35%. Studies have demonstrated that the
washout rate, but not the H/M ratio, was predictive
of events among patients with an LVEF ⬎35% to
40% (19,21). Among HF patients with a broad
range of core laboratory–adjudicated LVEFs, including 386 subjects with an LVEF ⬎35%, we did
not detect evidence of heterogeneity by LVEF in
the association between low H/M ratio and risk of
cardiovascular events.
Although the risk of sudden death is especially
pronounced among HF patients with significant
LV dysfunction, it is also the most common cause
of cardiovascular death among patients with HF
and normal or slightly reduced systolic function,
accounting for 26% to 28% of total mortality (1,2).
However, the ability to effectively risk-stratify these
patients is limited. Although LVEF is a powerful
predictor of mortality and sudden death when
significantly reduced, it is less useful in riskstratifying those patients with normal or only
slightly reduced LVEF (⬎45%) (3). Given the role
HR 3.4
HR 1.6
Event Rate for Death or Arrhythmic Event
(per 100 person-years)
appeared greater among subjects with an LVEF
⬎35%.
17.1
N = 44 (21 %)
18
HR 3.3
13.9
N = 45 (20 %)
16
11.0
N = 22 (13 %)
14
12
10
8
7.5
N = 9 (9%)
6.3
N = 3 (10 %)
6
3.9
N = 3 (6 %)
4
3.0
N = 2 (4 %)
2
0
<1.6
0
<30
(N = 251)
30- 35
(N = 264)
≥1.6
35- 40
(N = 229)
H / M Ratio
>40
(N = 157)
Category of Core Lab LVEF (%)
Figure 2. Event Rates by LVEF and H/M Ratio
Rates of death or arrhythmic event by 4 categories of core laboratory–adjudicated left
ventricular ejection fraction (LVEF) and heart-to-mediastinum ratio (H/M ratio). Values
above each column represent the event rate per 100 person-years, number of events,
and percentage of patients experiencing an event. Hazard ratios (HRs) were determined
using multivariable Cox proportional hazards models adjusting for baseline New York
Heart Association (NYHA) functional class and log of baseline B-type natriuretic peptide
(BNP) level.
1144
Adjusted* Hazard Ratio (95% CI)
for Cardiovascular Death, Arrhythmic Event,or Heart
Failure Progression Associated with H/M Ratio <1.6
A
Shah et al.
123
I-mIBG, LVEF, and Outcomes in HF
JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 11, 2012
NOVEMBER 2012:1139 – 46
10
9
8
7
6
5
4
3
2
1
0
25
27
29
31
33
35
37
39
41
37
39
41
Core Lab Adjudicated LVEF (%)
Adjusted* Hazard Ratio (95% CI)
for Death or Arrhythmic Event Associated with
H/M Ratio <1.6
B
25
20
15
10
5
0
25
27
29
31
33
35
Core Lab Adjudicated LVEF (%)
Figure 3. Risk of H/M Ratio <1.6 Across the LVEF Continuum
Local regression plots of the adjusted HR associated with an H/M ratio ⬍1.6 by LVEF as a
continuous measure using multivariable Cox proportional hazards models. Refer to the
Methods section for details of plot derivation. All HR point estimates are adjusted for age,
sex, heart failure etiology, NYHA functional class, diabetes status, hypertension, and BNP
level. (A) Clinical cardiovascular composite of cardiovascular death, arrhythmic event, or
heart failure progression; (B) death or arrhythmic event. CI ⫽ confidence interval; other
abbreviations as in Figure 2.
of cardiac autonomic innervation in the pathogenesis of ventricular arrhythmias (22), sympathetic
innervation imaging has the potential to identify
subjects at increased risk of life-threatening arrhythmia, although data regarding the relationship
between H/M ratio and spontaneous arrhythmias in
patients with implantable cardioverter-defibrillators (23)
or inducible arrhythmias on electrophysiological testing
(24) has been inconsistent. Our findings suggest that a
low H/M ratio is associated with a higher risk of
death or arrhythmic event across the spectrum of
LVEFs, including HF patients with an LVEF
⬎35%. Also, although limited by power, our exploratory analysis of the impact of H/M ratio data
on model performance (C-statistic) and reclassification indexes (IDI) suggests that for the outcome
of death or arrhythmic event, information on the
H/M ratio improves risk discrimination beyond
clinical, biomarker, and LVEF data. These findings
suggest that 123I-mIBG imaging may hold promise
to improve risk stratification among HF patients
with an LVEF ⬎35% if future adequately powered
prospective studies can confirm these hypothesisgenerating findings.
Study limitations. All patients had a site-reported
LVEF of ⱕ35%. Although we noted a quantitative
core laboratory LVEF ⬎35% in 386 patients (43%
of the trial population), the core laboratory LVEF
was still ⬍40% in the majority of these (n ⫽ 229,
59%) and was ⬍45% in a large majority (n ⫽ 324,
84%). These differences may partly relate to a
difference in timing and/or modality of study used
by site and core laboratory in nearly one-fourth of
subjects because the confidence limits for serial
assessments of the LVEF in an individual at 2 time
points are approximately 10% (25). Differences in
the remainder of cases may partly relate to interreader variability, which approximates 7%, even
when both assessments are measured quantitatively
(5,25). Finally, in multicenter clinical trials using
LVEF cutoffs for inclusion, discordance between
enrolling site and core laboratory assessment is not
unusual (7). Although this analysis provides information on the performance of sympathetic innervation imaging in HF patients with lesser degrees of
impairment in LV systolic function, it does not
represent the HF with preserved ejection fraction
population. The timing between performance of the
echocardiogram read by the core laboratory and the
123
I-mIBG imaging varied. The relationship between appropriate implantable cardioverterdefibrillator therapy and sudden death is unclear.
HF progression determined by increased NYHA
functional class is subjective, although this endpoint
was centrally adjudicated. The analyses were underpowered to detect an interaction by LVEF on the
relationship between the H/M ratio and clinical
events. They were similarly underpowered to detect
incremental benefit of the H/M ratio beyond
LVEF, biomarkers, and clinical data, especially
when stratified by LVEF. For the LVEF ⬎35%
subgroup, adjusted effect estimates for death or ar-
Shah et al.
I-mIBG, LVEF, and Outcomes in HF
JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 11, 2012
123
NOVEMBER 2012:1139 – 46
Table 3. Indexes of the Incremental Value of H/M Ratio Beyond Clinical, Echocardiographic, and Biomarker Data in Predicting
Occurrence of Cardiovascular Events Among Patients With LVEF <35% and Those With LVEF >35%
Overall
p Value
LVEF <35%
p Value
LVEF >35%
p Value
Cardiovascular composite
C-statistic
Without H/M ratio
0.72
With H/M ratio
0.73
IDI
0.14
0.75
0.20
0.76
1.09%
0.007
Without H/M ratio
0.67
0.03
With H/M ratio
0.69
0.71
0.55
0.72
0.89%
0.04
0.70
0.07
2.25%
0.03
0.67
0.08
Arrhythmic event or death
C-statistic
IDI
1.29%
0.71
0.0008
1.16%
0.74
0.02
3.36%
0.008
IDI ⫽ Integrated discrimination improvement; other abbreviations as in Table 2.
rhythmic event may be overfitted, although results
were qualitatively similar as observed in unadjusted
analyses. However, this population is the largest to our
knowledge with data on the H/M ratio and clinical
outcomes in HF patients with an LVEF ⬎35%.
CONCLUSIONS
Myocardial sympathetic innervation imaging with
123
I-mIBG has prognostic value across a broad
spectrum of LVEFs for death or arrhythmic event
and for cardiovascular death, arrhythmic event, and
HF progression. For the outcome of death or
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Key Words: ejection fraction y
heart failure y metaiodobenzylguanidine y prognosis
y sympathetic nervous system.