Does Cardiac Resynchronization Help Patients with Cardiac Sarcoidosis?
Alexandru B. Chicos, MD
Cardiac Electrophysiology
Bluhm Cardiovascular Institute of Northwestern
Associate Professor of Medicine
Feinberg School of Medicine
Northwestern University
251 East Huron Street, Feinberg 8-503B
Chicago, IL 60611
Phone: 312-694-6224
Fax: 312-926-2707
Email: achicos@nm.org
ORCID ID: 0000-0002-0291-4434
-Funding: None
-Conflict of Interest: None
In this issue of the journal, Shabtaie et al present a retrospective
cohort study of the effects of cardiac resynchronization (CRT) in
cardiac sarcoidosis (CS) in 55 patients managed at the Mayo Clinic
enterprise from 2000-2021. A third of the patients had myocardial tissue
diagnosis of CS, while 38% had probable CS and 29% had presumed CS. In
a majority of patients, indications for CRT included QRS greater than
120 milliseconds with low LV ejection fraction (LVEF) <50% in
80% of patients and high degree AV block with reduced LV ejection
fraction in 14.5% of patients. Positive response to CRT, defined as
>5% improvement in LVEF from baseline, was seen in 23
patients (41.8%) at 6-months follow-up and in 26 patients (47.3%) at
the last follow-up (at 4.1 ± 3.7 years). However, in the overall group,
there was no statistically significant improvement in ejection fraction
or left ventricular end-diastolic diameter at 6 months post-implantation
or at the last follow-up. Discussing these results and several other
smaller cohorts, and the relatively poor outcomes of CS patients
receiving CRT, authors raise the possibility of limited benefit of CRT
in CS patients. There are, however, several important caveats that
should prompt caution in drawing a strong conclusion.
This group included a relatively high percentage or cardiac-only
involvement and patients in the category of “presumed CS”. 47% of
patients had extracardiac involvement, while 53% apparently had
isolated cardiac involvement – which is more than was the 12% patients
with isolated cardiac involvement reported in the multicenter registry
from the Cardiac Sarcoidosis Consortium 1. While it is
impossible to ascertain the true incidence, this raises the possibility
that some non-CS patients were included. Other conditions that can
result in a positive PET scan (arrhythmogenic cardiomyopathy,
non-sarcoid myocarditis, recent ablation) cannot be rule out in the
absence of tissue diagnosis. CRT indications included QRS greater than
120 milliseconds with low LV ejection fraction (LVEF) <50% in
80% of patients, and baseline LVEF was 34.8 ± 10.9%. Some of these CRT
devices were therefore implanted in patients with only mildly decreased
LVEF (>35%) and/or only mildly prolonged QRS
(<130-150 ms), therefore limiting the potential observed
benefit of CRT. The authors explored the impact of several baseline
characteristics on the response to CRT, but did not compare baseline
left bundle branch block (LBBB) versus right bundle branch block (RBBB).
9 patients with baseline RBBB (16%) were included in the cohort, though
currently most practitioners would not recommend CRT for these patients
and their inclusion (most likely non-responders) may dilute the apparent
benefit. Detailed information on the extent of LGE on MRI or FDG uptake
on PET in these patients is not available. This might have played a role
in their response to CRT – as the authors mention in their discussion.
In terms of treatment, only 29% of patients were on steroids at the
time of implant – steroids being generally considered the mainstay of
immunosuppression therapy in these patients. However, “at 6 months
post-implant, there was increased utilization of immunosuppression with
70.9% receiving corticosteroids, 23.6% methotrexate and 34.5%
mycophenolate.” We do not know how many patients were on anyimmunosuppressive therapy at a given point in time, the specific
relationship of immunosuppressive therapy and presence of inflammation
on PET, the intensity or duration of immunosuppression or the program of
surveillance of disease activity. The patients included were enrolled as
early as 2000, and PET-guided immunosuppression and surveillance, albeit
not proven in randomized clinical trials, may be used more commonly in
recent years. In any case, immunosuppressive treatment has been neither
standardized, nor uniform by center or time period, therefore adding
potential confounding effects to the results. Medical therapy for
cardiomyopathy, while not specifically studied in CS patients, might
have been suboptimal in this cohort, as suggested by numbers listed in
Table 1 of the study by Shabtaie et al. Only 49.1% of patients were on
ACE inhibitor, 16.45% on angiotensin II receptor blocker and 78.2% on
beta-blocker.
Authors discuss possible reasons for limited benefits of CRT in CS
patients. They discuss the possibility that extensive scar may limit
benefits of CRT, similar to observations in ischemic cardiomyopathy
(ICM). The potential role of scar also highlights the need and potential
benefit of earlier diagnosis. In fact, the timing of diagnosis likely
has improved over time, including during the duration of recruitment for
this cohort. Earlier diagnosis may result in different patient
characteristics and perhaps less extensive myocardial scarring, on
average, in a more recent cohort. It is also worth mentioning that areas
of scar noted in CS are often not transmural, so the same caveats seen
in ICM patients with large, dense, transmural LV scars may not
necessarily apply. Furthermore, areas of increased FDG uptake on PET
scans are dynamic and may respond to immunosuppression. Suboptimal CRT
pacing percentage (for example due to premature ventricular beats or
atrial fibrillation) can also limit its benefits and attempts to
maximize it should be part of routine clinical care. In this cohort, CRT
pacing percentage was 95% initially and 97% at 6 months follow-up.
Most importantly, there has been no study of patients with CS and
indication for CRT comparing outcomes between those who receive CRT and
those who do not. Given these limitations, it is difficult to interpret
the data and impossible to derive practice-changing conclusions. We are
currently using recommendations for CRT based on data obtained in other
populations and extrapolated to patients with CS.
CS is different from ICM with fixed scar or from other NICM. CS is often
an active disease that has the potential to progress due to persistent
and progressive inflammatory activity. Cardiomyopathy, LV systolic
dysfunction and arrhythmia could progress or fail to improve due to
multiple mechanisms, including disease inflammatory activity,
dyssynchrony from LBBB or RV pacing or progressive remodeling in the
presence of irreversible myocardial damage. Consistent with other
published data, the patients in this study had a high incidence of
adverse outcomes: 20.0% went on to cardiac transplantation, 1.8%
received left ventricular assist devices, and there was a high burden of
ventricular arrhythmias during the follow-up period: by last follow up,
20.0% of patients had sustained ventricular tachycardia, 18.2% of
patients had ICD shocks, and 16.4% of patients underwent ventricular
tachycardia ablation. The relatively poor prognosis of these patients
underscores the importance of optimizing and maximizing their
management, and, along with the multidimensional nature of CS, leads us
towards using a multipronged approach with all the tools that we have at
our disposal: immunosuppression with the goal of adequate control of
inflammation in order to prevent disease progression; optimal medical
therapy of cardiomyopathy and CHF (as extrapolated from other
populations of patients with cardiomyopathy); CRT and optimization of
CRT pacing percentage (also by extrapolation from other studied
populations). Inadequately addressing any of these aspects can lead to
poor outcomes that may confound the results and dilute the apparent
benefits of CRT.
It is true that same criteria and approaches we use in other
cardiomyopathy populations may not extrapolate identically to CS. We
need randomized clinical trials to inform and guide immunosuppressive
therapy, the possible role of PET-guided immunosuppression or other
medical therapy, or to identify the best candidates for device therapy.
In this sense, this study tries to address an important question. It is
worth repeating here the authors’ call for “formulating prospective
multicenter studies designed to assess the ideal CS patient to benefit
from CRT therapy”, and to extend it to other interventions and
therapies in patients with CS. In the absence of better CS-specific
data, recommendations for CRT in CS should continue to be based on data
and guidelines from other populations of patients with
cardiomyopathy2-5.
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