AH Maass

AJ Moss

Alexander H. Maass

AM Jong De

AS Tang

AY Patwala

BA Schaer

DJ Veldhuisen van

ES Chung

FZ Khan

K Dickstein

KA Ellenbogen

MD Bogaard

MD Smit

PW Foley

S Buck

WJ Remme

English

PubMed

Springer - Publisher Connector

EDITORIAL
Cardiac Resynchronization in Mild Heart Failure:
All Issues Resolved?
Editorial to “Cardiac Resynchronization Therapy in Patients with Mild Heart Failure:
A Systematic Review and Meta-Analysis of Randomized Controlled Trials” by Ronghui
Tu et al.
Alexander H. Maass
Published online: 19 July 2011
# The Author(s) 2011. This article is published with open access at Springerlink.com
Cardiac resynchronization therapy (CRT) can improve heart
failure symptoms and reduce mortality in advanced heart
failure. Implantation rates have been shown to increase
steadily in Europe [1, 2] and it is expected they will
increase further after the recent updated European guide-
lines on device therapy in heart failure [3]. What is the
evidence for CRT in patients with depressed systolic
function but little heart failure symptoms? Until recently
there were several studies that demonstrated improvement
in symptoms, reduction of heart failure hospitalizations but
no significant effect on mortality. The RAFT study was the
first randomized study demonstrating a reduction of
mortality in patients with NYHA functional class I or II
[4]. In this issue of Cardiovascular Drugs and Therapy, Tu
et al. present a meta analysis of all trials including patients
in this functional class [5]. These include trials that were
designed to include mild heart failure patients but also trials
where only part of the patients were in better functional
classes. This meta-analysis shows that CRT in these patients
reduces mortality and leads to reverse remodeling, and
reduces hospitalizations or worsening heart failure at the
cost of a somewhat higher rate of complications.
Can we now close the books on CRT in mild heart
failure? Patient selection remains a critical issue. Subanalyses
of the 2 biggest trials, MADIT-CRT and RAFT showed that
only patients with QRS durations of >150 ms benefit from
CRT [4, 6]. In addition to QRS duration, QRS morphology
seems to be important to identify patients most likely to
respond to CRTwith classical left bundle branch block being
more likely than aspecific intraventricular conduction delay
or right bundle branch block. To define specific and sensitive
criteria identifying possible responders to CRT is the next
critical issue as using the current criteria only 50–70% of
patients show reverse remodeling of the left ventricle.
Reverse remodeling, however, is the prerequisite for reduc-
tion of hard endpoints such as heart failure hospitalization
and mortality [7]. In addition to QRS duration and
morphology, there are other known predictors of response,
such as etiology of heart failure with better response in non-
ischemic cardiomyopathy. Echocardiographic dyssynchrony
indexes have some predictive value but have failed to be
used in daily clinical practice, mostly due to low specificity
and high interobserver variability [8]. In addition to finding
new parameters to predict response, we might have to move
away from classical parameters. It has been recently shown
that in patients with an left ventricular ejection fraction
(LVEF) of above 35% the rate of response is comparable to
patients with low LVEF [9]. The effects of CRT could even
be beneficial in a subgroup of patients with diastolic heart
failure since systolic as well as diastolic dyssynchrony can
contribute to the pathophysiology of this disorder [10].
Instead of only focusing on patient selection, optimal
delivery of CRT is of critical importance [11]. There is an
ongoing discussion on the importance of lead position.
Even though there is abundant contradicting literature from
subanalyses of the landmark trials as well as other
retrospective databases, we will have to wait for the results
of ongoing randomized trials. First promising results of the
TARGET study comparing echocardiography guided lead
positioning have been presented at the meeting of the
American College of Cardiology this year [12]. The debate
is also ongoing about the importance of device programming.
A. H. Maass (*)
Department of Cardiology, Thoraxcenter,
University Medical Center Groningen, University of Groningen,
P.O. Box 30.001, 9700 RB Groningen, The Netherlands
e-mail: a.h.maass@umcg.nl
Cardiovasc Drugs Ther (2011) 25:281–283
DOI 10.1007/s10557-011-6318-4
A recent large prospective study has doubted the importance
of AV delay optimization even though the magnitude of
reverse remodeling seemed higher in patients undergoing
optimization [13]. Optimal VV delay is less likely to
significantly contribute to CRT response, especially in
patients with optimal left ventricular lead positions. An
overlooked parameter that can influence response to CRTand
is also important to improve exercise capacity is the heart
rate [14]. Chronotropic incompetence is an important
pathophysiological mechanism in heart failure due to
desensitization of beta-adrenergic signaling as well as due
to drug treatment such as beta-blockers and/or amiodarone.
Utilizing the rate sensor of the CRT device can overcome
this problem and new physiological rate sensors will be
incorporated in the next generation of devices leading to a
further improvement of this issue. CRT optimization at
higher heart rates is an exciting area of research as most
patients are only symptomatic during exercise. There is some
literature available but we need more prospective studies to
prove that it is worthwhile during these cumbersome
optimizations [15].
CRT follow-up is also a chance to optimize pharmaco-
logical and physical therapy. Doses of heart failure
medication in real life often do not reflect those given in
randomized clinical trials. There are multiple reasons for
this, including orthostatic symptoms due to hypotension
and bradycardia due to beta-blocker treatment. After CRT
implantation bradycardia is not an issue any more and
reverse remodeling often also improves hypotension and
congestion. Follow-up after CRT should routinely include
optimization of drug treatment such as trials of reducing
diuretics and increasing doses of ACE inhibitors and
beta-blockers [16]. Cardiac rehabilitation programs with
structured exercise training can also be used after CRT and
has been shown to improve exercise capacity and quality
of life [17].
Lastly, the occurrence of arrhythmias is important for
CRT response. Part of the reduced mortality can be
explained by a reduction in life-threatening arrhythmias.
In fact it has been shown that response to CRT dramatically
reduces the occurrence of ICD therapies [18]. If CRT can
also induce reverse remodeling in the atria and reduce the
occurrence of atrial fibrillation (AF) remains controversial.
Atrial remodeling is more severe than ventricular remodeling
and might not be reversible once it has progressed too far [19].
New-onset AF on the other hand is associated with non-
response and worse outcome in CRT patients [20, 21]
probably related to loss of biventricular stimulation. It seems
thus important to aggressively treat AF with a rhythm
control strategy and the effecT study (NCT00811382) is
currently investigating prospectively if aggressive treatment
of AF episodes detected via remote monitoring will improve
outcome of these patients.
In conclusion, proving that CRT is efficacious in mildly
symptomatic heart failure patients will create more ques-
tions than it answers. Extending the indication for CRTwill
make patient selection, optimization of CRT delivery and
programming as well as improvement of drug therapy and
treatment of atrial fibrillation even more important. Cardiac
resynchronization therapy will more and more become a
team effort between specialists in heart failure, echocardiog-
raphy, and electrophysiology with special interest in device
therapy.
Conflicts of Interest A.H.M. has received lecture fees from
Medtronic, Biotronik, Boston Scientific, and Sorin.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which permits
any noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
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Cardiovasc Drugs Ther (2011) 25:281–283 283


Cardiac Resynchronization in Mild Heart Failure: All Issues Resolved?

Maass, Alexander H.

Dissertations of the University of Groningen

Cardiac Resynchronization in Mild Heart Failure:All Issues Resolved? Editorial to "Cardiac Resynchronization Therapy in Patients with Mild Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials" by Ronghui Tu et al.

Proceedings - University of Groningen

NARCIS 

Cardiac Resynchronization in Mild Heart Failure: All Issues Resolved? Editorial to "Cardiac Resynchronization Therapy in Patients with Mild Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials" by Ronghui Tu et al.

University of Groningen

University of Groningen Research Database

Crossref

Cardiovascular Drugs and Therapy

Cardiac resynchronization therapy in patients with mild heart failure: a systematic review and meta-analysis of randomized controlled trials. Cardiovasc Drugs Ther. 2011;25: this issue.

Cardiac resynchronization therapy may benefit patients with left 282 Cardiovasc Drugs Ther (2011) 25:281–283ventricular ejection fraction >35%: a PROSPECT trial substudy.

Cardiac-resynchronization therapy for mildto-moderate heart failure.

Cardiac-resynchronization therapy for the prevention of heart-failure events.

Close connection between improvement in left ventricular function by cardiac resynchronization therapy and the incidence of arrhythmias in cardiac resynchronization therapy-defibrillator patients.

Device therapy in patients with heart failure and preserved ejection fraction (HFPEF): a new frontier?

focused update of ESC guidelines on device therapy in heart failure: an update of the 2008 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure and the

Left ventricular reverse remodelling, long-term clinical outcome, and mode of death after cardiac resynchronization therapy.

Maximizing patient benefit from cardiac resynchronization therapy with the addition of structured exercise training: a randomized controlled study.

Results of the predictors of response to CRT (PROSPECT) trial.

Should we optimize cardiac resynchronization therapy during exercise?

Targeted left ventricular lead placement using speckle tracking echocardiography improves the acute hemodynamic response to cardiac resynchronization therapy: a randomized controlled trial.

The European cardiac resynchronization therapy survey. Eur Heart J.

V an Gelder IC. Cardiac resynchronisation therapy and the role of optimal device utilisation.

V an Gelder IC. Importance of heart rate during exercise for response to cardiac resynchronization therapy.

V an V eldhuisen DJ, V an Gelder IC. Cardiac resynchronization therapy in patients with heart failure and atrial fibrillation: importance of new-onset atrial fibrillation and total atrial conduction time.

V an V eldhuisen DJ, V an Gelder IC. Prognosticimportanceofnatriureticpeptidesand atrial fibrillation in patients receiving cardiac resynchronization therapy.

V an V eldhuisen DJ, V an Gilst WH, V an Gelder IC. Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation. Cardiovasc Res.

Which beta-blocker is most effective in heart failure? Cardiovasc Drugs Ther.

Cardiac Resynchronization in Mild Heart Failure: All Issues Resolved?: Editorial to “Cardiac Resynchronization Therapy in Patients with Mild Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials” by Ronghui Tu et al.

Cardiac Resynchronization in Mild Heart Failure: All Issues Resolved?: Editorial to “Cardiac Resynchronization Therapy in Patients with Mild Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials” by Ronghui Tu et al.

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Dissertations of the University of Groningen

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