Clinical utility of cardiac innervation imaging in patients with heart failure
Clinical utility of cardiac innervation imaging in patients with heart failure
Jeroen J. Bax 0
0 Reprint requests: Jeroen J. Bax, MD, PhD , Department of Cardiology, Leiden University Medical Center , Leiden , The Netherlands; J Nucl Cardiol 2017;24:1594-7. 1071-3581/ $34.00 Copyright 2017 American Society of Nuclear Cardiology
1 Department of Cardiology, Leiden University Medical Center , Leiden , The Netherlands
WHAT IS THE PROBLEM?
Sudden cardiac death is an important problem in
clinical cardiology. In the USA; the annual incidence of
sudden cardiac death is estimated at 110.8 individuals
per 100,000 population per year.1 In the year 2015, it
was estimated that 356,461 patients died suddenly of
underlying cardiac disease.1 Moreover, in patients with
successful resuscitation, the recurrence rate of sudden
death is high.
Particularly, patients with previous myocardial
infarction and reduced left ventricular (LV) function
are at elevated risk of sudden death.2 With the
introduction of the implantable cardioverter defibrillator
(ICD), a therapy has become available that has been
demonstrated to prevent sudden cardiac death in patients
with ischemic and non-ischemic cardiomyopathy.
In the Multicenter Automatic Defibrillator
Implantation Trial-I (MADIT-I) study, 196 patients with a
history of myocardial infarction (C3 weeks), reduced
LV function (LVEF B 35%) and documented episode of
ventricular tachyarrhythmias, were randomized to either
prophylactic ICD implantation (n = 95) or standard
medical therapy (n = 101).2 Over a 27-month follow-up
period, 15 patients (15.8%; 11 cardiac death) died in the
defibrillator group as compared to 39 patients (38.2%;
27 cardiac death) in the medical group (hazard ratio for
overall mortality, 0.46; 95% confidence interval, 0.26 to
0.82; P = 0.009). Importantly, the use of amiodarone or
beta-blockers did not influence these observations.
In a subsequent study (MADIT-II), 1232 patients
with previous infarction (C1 month) and LVEF B 30%
were randomized in a 3:2 ratio to receive an ICD or
medical therapy.3 During a 20-month follow-up period,
mortality was 19.8% in the patients receiving medical
therapy versus 14.2% in patients receiving an ICD
(hazard ratio for the risk of all-cause mortality, 0.69
(95% confidence interval, 0.51 to 0.93; P = 0.016).
Importantly, age, gender, LVEF, New York Heart
Association class, and QRS duration did not influence
Both these studies paved the way for the European
Society of Cardiology (ESC) to indicate in their 2015
guidelines that an ICD is indicated in patients with
symptomatic heart failure (NYHA class II-III) and
reduced LVEF (B35%)4 (class IA in ischemic heart
disease, and class IB in non-ischemic cardiomyopathy).
Similar recommendations have been issued by the ACC/
It has also become evident from the MADIT-II trial
that a limited number of patients received appropriate
ICD therapy during an average of 21 months of
followup.6 More specifically, of the 720 patients receiving an
ICD in the MADIT-II trial, 169 (23.5%) patients
received antiarrhythmic therapy(anti-tachycardia pacing
in 139 patients, and defibrillator shocks in 30) and 551
(76.5%) patients did not receive ICD therapy.
More recently, Kober et al.7 demonstrated that in
patients with non-ischemic cardiomyopathy, prophylactic
ICD implantation did not improve long-term outcome as
compared to usual clinical care. Specifically, 1116 patients
with non-ischemic cardiomyopathy (LVEF B 35%) were
randomized to ICD implantation (n = 556) or usual care
(n = 560); all-cause death was 21.6% in the ICD group
versus 23.4% in the control group (hazard ratio, 0.87; 95%
confidence interval [CI], 0.68 to 1.12; P = 0.28). Still,
sudden cardiac death was more frequent in the usual care
group (8.2%) versus the ICD group (4.3%) (hazard ratio,
0.50; 95% CI, 0.31 to 0.82; P = 0.005).
Moreover, ICD implantation is associated with
procedural complications, device/lead infections, and
inappropriate shocks.8 Thus, there is significant benefit
from ICDs to prevent sudden cardiac death, but the
criterium of LVEF B35% may be suboptimal for
selecting the patients who may benefit most from ICD
implantation, and a more personalized risk stratification
may be of potential use.9
Various ECG-based criteria have been proposed,
including microvolt T-wave alternans, signal-averaged
ECG, QRS fragmentation, and various measures of
autonomic (dys-)function such as heart rate variability.10
In addition, different imaging techniques have attempted
to better identify the substrate underlying sudden cardiac
death, specifically advanced echocardiographic and
CMR techniques, as well as nuclear imaging with PET
and SPECT. The different imaging techniques reflect
different aspects of the LV substrate underlying the lethal
ventricular arrhythmias; the anatomical substrate is
probably the presence of central homogenous scar tissue
(secondary to myocardial infarction), with a peripheral,
heterogeneous border zone with fibrosis, viable but
jeopardized myocardium and normal tissue.
Contrastenhanced CMR is focused on anatomical imaging
(specifically scar and fibrosis assessment), whereas
echocardiography with strain reflects functional imaging
(LV deformation assessment) and nuclear imaging with
PET and SPECT addresses biological imaging
(specifically innervation and denervation assessment).9 Over the
recent years, the use of cardiac innervation imaging with
123I-metaiodobenzylguanidine (MIBG) and planar
imaging or SPECT has been evaluated for risk
stratification of heart failure patients at risk of sudden cardiac
death. In the current issue of the Journal, two articles are
published regarding the pros and cons of MIBG imaging,
mostly focusing on risk stratification in patients with
heart failure and elevated risk of sudden cardiac
MIBG FOR RISK STRATIFICATION: THE
EVIDENCE OF NEURO-CARDIAC IMAGING
The first article, by Travin, addresses the pros of
MIBG imaging.11 He introduces the concept of the
heartto-mediastinum (H/M) ratio to quantify the tracer uptake in
the heart as compared to the mediastinum on planar
images, reflecting cardiac innervation and denervation.
Many smaller studies have used this parameter to
demonstrate the use of MIBG for risk stratification of heart failure
patients. Agostini and colleagues13 performed a large
analysis including 290 heart failure patients who
previously underwent MIBG imaging (between 199
). During a 2-year follow-up, 67 patients (26%)
experienced a major cardiac event (death, cardiac
transplantation, potentially lethal arrhythmias). These patients
had a lower H/M ratio (1.51 ± 0.30) as compared with the
patients without events (1.97 ± 0.54, P \ 0.001).
Dr Travin then referred to the ADMIRE-HF
(AdreView Myocardial Imaging for Risk Evaluation in Heart
Failure) trial and its sub-studies.14 The ADMIRE-HF
study included 961 heart failure patients (NYHA II-III)
and LVEF B35% who underwent MIBG imaging, and
the H/M ratio was assessed from the 4-hour delayed
image; a value of 1.60 was used as the normal value.
Patients were followed up for 2 years and the end-points
included time to first occurrence of NYHA functional
class progression, potentially life-threatening arrhythmic
event, or cardiac death. During a median follow-up, 237
patients (25%) experienced events; the 2-year event rate
was 15% for H/M C1.60 and 37% for H/M \1.60, and
the H/M ratio was predictive of all end-points. On
multivariate analysis, H/M ratio, LVEF, B-type
natriuretic peptide, and NYHA class were predictive of
outcome. Addition of the H/M ratio enabled further
stratification in patients with high B-type natriuretic
peptide (140 ng/l) and low LVEF (B30%).
More recently, a pooled analysis from Japan was
reported, including 6 cohorts with 1322 heart failure
patients, with a follow-up of 78 months, and primary
outcome being all-cause mortality.15 The mortality was
5.6% at 1 year, and 19.7% at 5-year follow-up. On the
multivariate analysis, age, NYHA class, LVEF and the
late MIBG H/M ratio were predictive of outcome.
All these data have built a strong case supporting
the use of MIBG for risk stratification in heart failure
patients, and have shown the incremental value of the
H/M ratio over the routine risk markers. One important
issue is the predictive value. This remains to be further
explored in future studies. As with any technique, a high
negative predictive value is important: ‘‘to rule out.’’
This could imply not providing a certain therapy or less
close monitoring. In the ADMIRE-HF study, the
allcause mortality was 1% (2 patients of 201) in the
patients with an H/M ratio C1.6. Moreover, in the
highrisk groups (according to BNP [140 ng/l and LVEF
B30%) with a H/M ratio C1.6 there were no cardiac
deaths. These data are supportive of the conception that
MIBG imaging could serve as gate-keeper for ICD
WHAT ARE THE UNCERTAINTIES
Drs Liga and Scholte discuss the limitations of
MIBG imaging hampering the widespread acceptance of
this technique in clinical practice.12 The first issue
discussed by these authors concerns the need for a
standardized protocol. The main parameter used in the
clinical setting is the H/M ratio, which reflects cardiac
innervation and denervation. At present, an early
(15 min after tracer injection) and late MIBG scan
(4 hour after tracer injection) are obtained, and the H/M
ratio can be derived from both scans. It is currently not
clear which scan provides the optimal prognostic
information. From a practical point of view, it would be
ideal to use the scan obtained within the first hour after
tracer injection. Finally, the cut-off value of 1.6 needs
further, prospective evaluation.
Other parameters from planar MIBG imaging have
also been used, such as the washout rate, and these are
less well validated as compared to the H/M ratio.
Moreover, with planar imaging, the global
sympathetic innervation of the heart can be evaluated, but
regional information may be more important. SPECT
provides information on regional variations in
sympathetic innervation, but regional physiological variations
also occur, with less tracer uptake in the inferior wall in
normal individuals. Also, in patients with severe heart
failure, tracer uptake may be low resulting in poor
SPECT image quality, and in general, data acquisition
with SPECT is more time-consuming than planar
WHAT EVIDENCE IS MISSING AND NEEDED?
Prospective, randomized controlled trials will be
needed to establish the role of MIBG in risk
stratification of heart failure patients. From a clinical point of
view, the ADMIRE-HF study provided strong
prognostic data in a prospective cohort of heart failure patients,
but an important question remains whether MIBG could
direct therapy in these patients and specifically guide
ICD implantation. As outlined above, the current
selection criterium of LVEF B35% does not optimally
include and exclude patients who need an ICD for
primary prevention in ischemic and non-ischemic
cardiomyopathy. As Dr Travin points out, this trial is
planned, including [2,000 heart failure patients (LVEF
between 30% and 35%, and NYHA class II-III) who will
receive MIBG-guided ICD implantation or
guidelinedirected ICD implantation; this trial will compare the
outcomes (primary outcome all-cause mortality) over
2.75 to 3 years, but will only be completed in 2019.16
However, Dr Travin also points out, this trial will take
time to be completed, but there is currently significant
evidence that MIBG contributes to risk stratification in
heart failure patients, probably more evidence than has
been obtained with other imaging techniques that are
used in clinical practice.
The department of Cardiology, Leiden University Medical
Center, The Netherlands, has received unrestricted research
grants of Medtronic, Biotronik, Boston Scientific and Edwards
Journal of Nuclear Cardiology
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