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See related article, pages 1458 –1465 Defining “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- “Culprit Mechanisms”
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- Potential Pitfalls
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
DOI: 10.1161/

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 Conclusions
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 19. Matsumoto Y, Aihara H, Yamauchi-Kohno R, Reien Y, Ogura T, Yabana 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.
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: References
1. Nattel S, Khairy P, Schram G. Arrhythmogenic ionic remodeling: 22. Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M, adaptive responses with maladaptive consequences. Trends Cardiovasc Guerra PG, Ducharme A. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the 2. Armoundas AA, Wu R, Juang G, Marban E, Tomaselli GF. Electrical and studies of left ventricular dysfunction (SOLVD) trials. Circulation. 2003; structural remodeling of the failing ventricle. Pharmacol Ther. 2001;92: 23. Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, 3. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C. Use of irbesartan to remodeling during atrial fibrillation. Cardiovasc Res. 2002;54:230 –246.
maintain sinus rhythm in patients with long-lasting persistent atrial fibril- 4. Verheule S, Sato T, Everett T, Engle SK, Otten D, Rubart-von der Lohe lation: a prospective and randomized study. Circulation. 2002;106: M, Nakajima H, Nakajima H, Field LJ, Olgin JE. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis due to 24. Ueng KC, Tsai TP, Yu WC, Tsai CF, Lin MC, Chan KC, Chen CY, Wu overexpression of TGF-␤1. Circ Res. 2004;94:1458 –1465.
DJ, Lin CS, Chen SA. Use of enalapril to facilitate sinus rhythm main- 5. Bailey GW, Braniff BA, Hancock EW, Cohn KE. Relation of left atrial tenance after external cardioversion of long-standing persistent atrial pathology to atrial fibrillation in mitral valvular disease. Ann Intern Med.
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Culprit Mechanisms in Arrhythmogenic Remodeling
27. Brundel BJ, Henning RH, Kampinga HH, Van Gelder IC, Crijns HJ.
potassium current in canine cardiomyocytes from pulmonary vein myo- Molecular mechanisms of remodeling in human atrial fibrillation. Car- cardial sleeves and left atrium. J Physiol. 2004;557:583–597.
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31. Samie FH, Berenfeld O, Anumonwo J, Mironov SF, Udassi S, Beaumont 28. Todd DM, Fynn SP, Walden AP, Hobbs WJ, Arya S, Garratt CJ.
J, Taffet S, Pertsov AM, Jalife J. Rectification of the background Repetitive 4-week periods of atrial electrical remodeling promote stability potassium current: a determinant of rotor dynamics in ventricular fibril- of atrial fibrillation: time course of a second factor involved in the lation. Circ Res. 2001;89:1216 –1223.
self-perpetuation of atrial fibrillation. Circulation. 2004;109:1434 –1439.
32. Wu TJ, Ong JJ, Chang CM, Doshi RN, Yashima M, Huang HL, Fishbein 29. Dobrev D, Graf E, Wettwer E, Himmel HM, Hala O, Doerfel C, Christ T, MC, Ting CT, Karagueuzian HS, Chen PS. Pulmonary veins and ligament Schuler S, Ravens U. Human inward rectifier potassium channels in of marshall as sources of rapid activations in a canine model of sustained chronic and postoperative atrial fibrillation. Cardiovasc Res. 2002;54: atrial fibrillation. Circulation. 2001;103:1157–1163.
30. Ehrlich JR, Cha TJ, Zhang L, Chartier D, Villeneuve L, Hebert TE, Nattel 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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