See related article, pages 1458 –1465Defining “Culprit Mechanisms” in Arrhythmogenic Cardiac Remodeling
Therehasbeenincreasingawarenessoftheimportance abnormalities and enhanced susceptibility to AF in the
of arrhythmogenic remodeling in the pathophysiology
absence of abnormalities in atrial action potential properties
of cardiac arrhythmias.1–3 Arrhythmogenic remodel-
or connexin protein distribution.4 These observations suggest
ing, involving acquired changes in cardiac structure or
that atrial fibrosis may itself create a substrate for AF, in
function that promote the occurrence of cardiac arrhythmias,
agreement with recent studies showing that fibrosis and an
occurs in a wide variety of paradigms including congestive
AF substrate persist in atria of dogs that have recovered from
heart failure (CHF), atrial fibrillation (AF), hypertensive
CHF, despite the disappearance of CHF-induced ventricular
cardiac disease, acute myocardial infarction, and valvular
dysfunction, hemodynamic alterations, atrial dilation, and
heart disease. In many of these contexts, changes occur at
many levels: ion-channel density, distribution, and function;ion-transporter (pumps and exchanges) function; connexin-
Potential Implications of Identifying
protein density and distribution; tissue and cell structure; andcardiac-chamber dimension and shape. Progress in the iden-
tification of such changes has been impressive: in some cases,
The prevention of arrhythmogenic remodeling is emerging as
hundreds of alterations have been described in response to
a potential new treatment strategy for cardiac arrhyth-
single well-defined experimental paradigms. A major result-
mias.18,19 If individual components of the many remodeling-
ing challenge is to determine which changes are particularly
associated changes are shown to be particularly important in
central to the pathophysiology of remodeling-related arrhyth-
arrhythmogenesis, they may be worthy of specific targeting.
mias, and to establish therapeutic implications. In the present
Just as the “culprit lesion” in one coronary artery may be
issue of Circulation Research, Verheule et al take advantage
attacked in unstable angina syndromes, it may be possible to
of a unique transgenic mouse model to address this issue.4
target the “culprit mechanism” in specific forms of AF. Forexample, the effectiveness of angiotensin-converting enzyme
Potential Role of Fibrosis in AF
inhibition in attenuating fibrosis and AF promotion in exper-
Interstitial fibrosis has been associated with AF since at least
imental CHF20 led to the suggestion that angiotensin-
the 1960s.5 Recent studies have demonstrated an association
antagonism might be useful in preventing clinical AF due to
between atrial fibrous-tissue content, conduction abnormali-
structural remodeling. Clinical trials have shown that
ties, and propensity to AF in animals with CHF,6 mitral
converting-enzyme inhibition prevents AF in patients with
regurgitation,7,8 and senescence.9,10 These observations point
left ventricular dysfunction,21,22 and further studies may lead
toward fibrosis-induced conduction abnormalities as promot-
to more effective and specific preventive approaches.
ers of local reentry11,12 and thereby AF. However, theevidence has been predominantly circumstantial. Other mech-
anisms, such as delayed afterdepolarization-related triggered
The idea of a single or limited number of primary mecha-
activity,13 favored by the Naϩ-Ca2ϩ exchanger upregulation
nisms involved in arrhythmia generation is attractive in its
that occurs in CHF,14 could also play a prominent role.
simplicity and tractability; however, reality may prove much
Verheule et al4 studied mice engineered to overexpress a
more complicated. When an experimental paradigm appar-
constitutively active mutant form of TGF-␤1, causing atrial-
ently isolates a single primary factor, like atrial fibrosis in the
specific interstitial fibrosis in the face of normal ventricularsize and histology.15 The mice showed atrial conduction
TGF-␤1 mice or dogs recovered from CHF, it is tempting toidentify that factor as established. However, more evidence isneeded before fibrosis can be confirmed as causal in AF. Itremains conceivable that fibrosis simply accompanies other
The opinions expressed in this editorial are not necessarily those of the
as-yet unidentified causative factors. The efficacy of angio-
editors or of the American Heart Association.
From the Department of Medicine, Montreal Heart Institute, Univer-
tensin antagonism in preventing AF associated with left
sity of Montreal, and Department of Pharmacology and Therapeutics,
ventricular dysfunction is consistent with the fibrosis hypoth-
McGill University, Montreal, Quebec, Canada.
esis, but the observation that AF is also prevented by
Correspondence to Dr Stanley Nattel, Montreal Heart Institute, 5000
Belanger St E, Montreal, Quebec H1T 1C8, Canada. E-mail
angiotensin-receptor antagonists23 and converting-enzyme in-
hibitors24 in patients without clear left ventricular dysfunction
(Circ Res. 2004;94:1403-1405.)
means either that angiotensin-related structural remodeling is
2004 American Heart Association, Inc.
a common feature in AF or that other mechanisms may be
Circulation Research is available at http://www.circresaha.org DOI: 10.1161/01.RES.0000133229.19586.bb 1403 1404 Circulation Research June 11, 2004 Determining the Significance of Specific
model of chronic atrial dilatation due to mitral regurgitation. Circulation. Remodeling-Induced Changes
8. Verheule S, Wilson E, Banthia S, Everett IV TH, Shanbhag S, Sih HJ,
Paradigms that cause arrhythmogenic remodeling produce a
Olgin J. Direction-dependent conduction abnormalities in a canine model
wide range of alterations in cardiac structure and function.
of atrial fibrillation due to chronic atrial dilatation. Am J Physiol Heart
Many of these likely contribute little to the arrhythmia
Circ Physiol. 2004. In press.
9. Hayashi H, Wang C, Miyauchi Y, Omichi C, Pak HN, Zhou S, Ohara T,
diathesis. Conversely, key arrhythmogenic factors may re-
Mandel WJ, Lin SF, Fishbein MC, Chen PS, Karagueuzian HS. Aging-
main unidentified. Atrial-tachycardia remodeling provides
related increase to inducible atrial fibrillation in the rat model. J Car-
illustrative examples. Atrial tachycardia alters a number of
diovasc Electrophysiol. 2002;13:801– 808.
10. Anyukhovsky EP, Sosunov EA, Plotnikov A, Gainullin RZ, Jhang JS,
ionic currents, disrupts cellular ultrastructure, impairs atrial
Marboe CC, Rosen MR. Cellular electrophysiologic properties of old
contractility, affects the function of many biochemical sys-
canine atria provide a substrate for arrhythmogenesis. Cardiovasc Res.
tems, and may alter intercellular communication via connex-
ins.3,25–27 Which of these many changes plays a role in
11. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of
repolarization with anisotropic propagation in dog atria. A mechanism for
arrhythmogenesis? Although downregulation of L-type Ca2ϩ-
both preventing and initiating reentry. Circ Res. 1989;65:1612–1631.
channels is likely involved in the refractoriness abbreviation
12. Spach MS, Boineau JP. Microfibrosis produces electrical load variations
that contributes to AF promotion, discrepancies in the time-
due to loss of side-to-side cell connections: a major mechanism of
course of refractoriness changes and AF development3,28
structural heart disease arrhythmias. Pacing Clin Electrophysiol. 1997;20:397– 413.
suggest the involvement of other factors that remain to be
13. Stambler BS, Fenelon G, Shepard RK, Clemo HF, Guiraudon CM. Char-
identified. What is the potential role of increases in inward-
acterization of sustained atrial tachycardia in dogs with rapid ventricular
pacing-induced heart failure. J Cardiovasc Electrophysiol. 2003;14:499 –507.
tachycardia,29,30 particularly in view of the potentially key
14. Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, Nattel S. Effects
role of inward-rectifier currents in ventricular fibrillation?31
of experimental heart failure on atrial cellular and ionic electrophys-
What is the mechanism and importance of accelerated activ-
iology. Circulation. 2000;101:2631–2638.
ity in the thoracic veins?32 These and other questions need to
15. Nakajima H, Nakajima HO, Salcher O, Dittie AS, Dembowsky K, Jing S,
Field LJ. Atrial but not ventricular fibrosis in mice expressing a mutant
be answered to develop effective new mechanism-based
transforming growth factor-␤1 transgene in the heart. Circ Res. 2000;86:
16. Shinagawa K, Shi YF, Tardif JC, Leung TK, Nattel S. Dynamic nature of
atrial fibrillation substrate during development and reversal of heartfailure in dogs. Circulation. 2002;105:2672–2678.
Over the past 5 to 10 years, we have been very successful in
17. Cha TJ, Ehrlich JR, Zhang L, Shi YF, Tardif JC, Leung TK, Nattel S.
describing a host of changes that occur in arrhythmogenic
Dissociation between ionic remodeling and ability to sustain atrial fibril-
remodeling. We have been less successful in determining
lation during recovery from experimental congestive heart failure. Cir-
which ones matter. We will have to do better in order to
culation. 2004;109:412– 418.
18. Nattel S. Therapeutic implications of atrial fibrillation mechanisms: can
improve our understanding of underlying mechanisms and to
mechanistic insights be used to improve AF management? Cardiovasc
develop more successful treatment approaches. The Verheule
study published in this issue of Circulation Research is a step
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H, Masuda Y, Sato T, Komuro I, Nakaya H. Long-term endothelin a
receptor blockade inhibits electrical remodeling in cardiomyopathichamsters. Circulation. 2002;106:613– 619. Acknowledgments
20. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S.
The author thanks the Canadian Institutes of Health Research, the
Effects of angiotensin-converting enzyme inhibition on the development
MITACS Network of Centers of Excellence, and Quebec Heart and
of the atrial fibrillation substrate in dogs with ventricular tachypacing-
Stroke Foundation for financial support and Monique Brouillard for
induced congestive heart failure. Circulation. 2001;104:2608 –2614.
21. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces
the incidence of atrial fibrillation after acute myocardial infarction inpatients with left ventricular dysfunction. Circulation. 1999;100:
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KEY WORDS: atrial fibrillation Ⅲ cardiac ion channels Ⅲ heart rhythm
S. Characterization of a hyperpolarization-activated time-dependent
disorders Ⅲ antiarrhythmic drug therapy
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