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A Surprising New Arrhythmia Mechanism in Heart Failure
Dan M. Roden
H
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eart failure is the most common discharge diagnosis
in the United States, with a prognosis worse than
many cancers.1 Patients with heart failure die for two
reasons: advanced circulatory insufficiency or sudden death.2
We know that continuous online monitoring of cardiac
rhythm from patients with advanced heart failure is inevitably
abnormal and often shows long runs of irregular and/or
polymorphic ventricular tachycardia. Unlike patients with
ventricular tachycardia due to healed myocardial infarction,
those with heart failure rarely have ventricular tachycardia
inducible by programmed stimulation, and when it is, its
prognostic importance is uncertain. Therapy with conventional antiarrhythmics is no more successful in patients with
heart failure than in those with serious ventricular arrhythmias due to healed infarction.
notypes in cellular, animal, and human models include
calcium-mediated activation of transcriptional programs,7,8 a
leaky calcium release channel,9,10 and increased CaM kinase
activity.11
Another common electrophysiological finding both in animal models and in patients with heart failure is reduction in
a range of potassium currents, including ITO, IK1, and the
delayed rectifier components.12 Indeed, this effect, which in
at least some cases has been definitively attributed to decreased ion channel gene transcription,13 contributes to action
potential prolongation and disordered QT regulation, another
characteristic finding in heart failure.14,15 Marbán, Tomaselli,
and colleagues proposed in the mid-1990s16 that such action
potential prolongation would be linked to arrhythmogenesis,
in effect that a torsades de pointes–like mechanism (at the
time not well defined) might be linked to the problem of
serious arrhythmias in heart failure. In this issue of Circulation Research, Akar and Rosenbaum provide evidence for
that link,17 by reporting striking similarities in the electrophysiological properties of “wedge preparations” isolated
from dogs with pacing-induced heart failure, compared with
those from animals treated with drugs causing torsades de
pointes.
Arrhythmias, Disordered [Ca2ⴙ]i Homeostasis,
and Kⴙ Current Downregulation in
Heart Failure
Given the huge public health impact of the problem and the
failure of current pharmacological therapies, one obvious way
forward in attacking the problem of sudden death in heart
failure is to understand the basic molecular mechanisms
underlying arrhythmia susceptibility in this setting. The
disordered contractility that characterizes heart failure naturally suggests abnormal intracellular calcium homeostasis, a
well-recognized feature of the heart failure phenotype,3,4 as a
candidate arrhythmia mechanism, and experimental studies
support this idea. Pogwizd and colleagues have used threedimensional activation mapping in rabbits with volumeoverload heart failure to identify focal triggers and repetitive
focal activity as a major mechanism underlying VT in this
model, 5 behaviors that are highly reminiscent of
afterdepolarization-related triggering due to intracellular calcium overload. Indeed, their further studies indicated that
heart failure–related upregulation of the sodium-calcium
exchanger, in the setting of downregulation of the inward
rectifier and maintained ␤-adrenergic responsiveness, markedly increases the propensity for triggered arrhythmias due to
intracellular calcium overload.6 More upstream mechanisms
implicated as drivers of the “hypertrophy/heart failure” phe-
The Wedge Preparation and Transmural
Heterogeneity of Repolarization
Seminal observations from the laboratory of Antzelevitch
over the past decade have documented the existence of a
previously unrecognized cell type in the midmyocardium
whose unusual response to electrophysiological stressors
such as proarrhythmic drugs is an important contributor to
long QT–associated arrhythmias.18 –20 Indeed, M cells may
constitute up to 40% of the bulk of the ventricular myocardium. The left ventricular “wedge” preparation, originated
and popularized by the Antzelevitch laboratory, has identified
marked drug-induced action potential prolongation in the
M-cell layer as a key contributor to increased transmural
heterogeneity of repolarization that, in turn, appears to
generate the substrate for reentry that is now thought to
underlie typical torsades de pointes.21 The concept that
heterogeneity, or “dispersion,” of action potential durations
creates a substrate for reentry is an older one, but the concept
that this heterogeneity might extend to sites across the
ventricular wall, rather than between adjacent sites located in
the same cell layer, is newer.
In the heart failure wedge preparation, as in the drugtreated wedge preparation, there was marked prolongation of
action potential durations among M cells, with much less
prolongation in endocardial and epicardial cell types, leading
to increased dispersion of repolarization. Further, in both
settings, stimulation from the epicardium (the site with the
shortest action potentials) generates conduction block at the
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Division of Clinical Pharmacology, Vanderbilt University
School of Medicine, Nashville, Tenn.
Correspondence to Dan M. Roden, MD, Professor of Medicine and
Pharmacology, Director, Division of Clinical Pharmacology, Vanderbilt
University School of Medicine, 532 Medical Research Building I,
Nashville, TN 37232. E-mail [email protected]
(Circ Res. 2003;93:589-591.)
© 2003 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org
DOI: 10.1161/01.RES.0000095382.50153.7D
589
590
Circulation Research
October 3, 2003
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epicardial-midmyocardial junction with polymorphic arrhythmias arising as a result of conduction around this region of
functional block. Extending the link to heart failure are
studies in the wedge and other preparations that have implicated disordered intracellular calcium homeostasis as a potential contributor to drug-induced torsades de pointes.22,23
M cells display long basal action potentials, suggesting
reduced net inward current, and this may underlie their
susceptibility to display such marked prolongation with
QT-prolonging drugs (or pacing-induced heart failure). However, it is not yet established why M cells display long action
potentials under normal conditions; suggested possibilities
include reduced K⫹ current, increased inward current, altered
intracellular calcium handling, or altered gap junction protein
function.17,24,25 Most importantly, we have yet to understand
how a disease like heart failure, however defined, engenders
changes in expression or function of not only these candidate
proteins, but a myriad of others that together make up the
complex signaling pathways that we call normal electrophysiology. Even more fundamentally, we do not understand the
signals that tell a cell to become an M cell or the mechanisms
that determine their unusual, and not totally homogeneous,
distribution within the midmyocardium; obviously, their location and their electrophysiological properties will be linked
in some as yet poorly understood fashion. Indeed, a difficulty
with this field is an exact definition of what constitutes a
normal M cell. It is a cell with a long action potential, like
those in the endocardium, but with a prominent phase 1
notch, as in the epicardium. These gross morphological
descriptors of action potential configuration reflect balancing
acts among a multitude of inward and outward currents, but
how big a notch constitutes a notch or how long an action
potential one must have before an M cell becomes an M cell
and is no longer an epicardial cell is not so clear. The
gradients described by Akar and Rosenbaum17 suggest that
these distinctions are continuous rather than abrupt, and thus
we should expect gradients of expression of channels and
other proteins important for electrogenesis in the same
fashion.
Implications for Heart Failure Research and
Patient Care
Any investigator studying heart failure or any clinician caring
for patients with heart failure will immediately recognize that
the diagnosis of “heart failure” itself represents a highly
heterogeneous mixture of clinical diagnoses, presentations,
and responses to therapies. Thus, an interesting and important
question raised by the present study is how commonly
increased transmural dispersion of repolarization occurs in
heart failure and to what extent it contributes to generating
the associated arrhythmia-prone substrate. As a corollary, one
can turn the question around: having implicated heterogeneity
of repolarization as an important mechanism in clinically
important polymorphic tachycardias such as classical torsades de pointes and ventricular tachycardia in heart failure,
how often does this mechanism underlie other polymorphic
tachycardias?
Many insults cause the contractile dysfunction/arrhythmia
phenotype we call heart failure. Intervening once this pheno-
type is in place has the appeal that the disease is readily
recognized, and many therapies aimed at symptoms—regardless of the underlying cause—provide some benefit. However, early intervention to correct the molecular dysfunction
that leads to arrhythmias in this setting seems more appealing.
This presents the problem that we have to think about
advanced clinical phenotypes like heart failure as many
separate diseases, each with its own molecular triggers and
specific therapies that should be curative if applied early. This
is not so different from the way oncologists are approaching
the problem of “cancer.”
Finally, what does any of this mean for patient care? One
interesting characteristic of the wedge preparation is that
polymorphic ventricular tachycardia is most readily induced
by programmed electrical stimulation from the site with the
shortest action potentials, the epicardium. Whether this is the
case in patients is not certain. In whole animal models of
torsades de pointes, the arrhythmias have been reported to be
initiated by endocardial foci, possibly representing afterdepolarizations in the Purkinje network.26 More recently, a proarrhythmic effect of epicardial pacing (as now increasingly
used clinically in patients with heart failure and biventricular
pacing devices) has been reported.27 The early experience
with biventricular pacing, however, suggests that overall
mortality is not increased.28 Is it possible that techniques of
programmed stimulation using epicardial approaches could
be used to stratify arrhythmia risk among patients with heart
failure? Or patients with the long-QT syndromes, where
conventional electrophysiological testing (that uses endocardial stimulation) has also not proven terribly helpful? Thus,
description of an unexpected role of exaggerated transmural
heterogeneity of repolarization in this study identifies both
clinical opportunities as well as an interesting new starting
point for development and evaluation of new therapies to deal
with the challenge of sudden death in heart failure.
Acknowledgments
This work was supported in part by grants from the United States
Public Health Service (HL46681, HL49989, and HL65962). Dr
Roden is the holder of the William Stokes Chair in Experimental
Therapeutics, a gift from the Dai-ichi Corporation.
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KEY WORDS: arrhythmia
䡲
heart failure
䡲
long QT
A Surprising New Arrhythmia Mechanism in Heart Failure
Dan M. Roden
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Circ Res. 2003;93:589-591
doi: 10.1161/01.RES.0000095382.50153.7D
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