doi: 10.1161/01.RES.0000133229.19586.bb
© 2004 American Heart Association, Inc.
Editorials |
Defining "Culprit Mechanisms" in Arrhythmogenic Cardiac Remodeling
From the Department of Medicine, Montreal Heart Institute, University of Montreal, and Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Correspondence to Dr Stanley Nattel, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada. E-mail nattel{at}icm.umontreal.ca
Key Words: atrial fibrillation • cardiac ion channels • heart rhythm disorders • antiarrhythmic drug therapy
There has been increasing awareness of the importance of arrhythmogenic remodeling in the pathophysiology of cardiac arrhythmias.1–3 Arrhythmogenic remodeling, involving acquired changes in cardiac structure or function that promote the occurrence of cardiac arrhythmias, occurs in a wide variety of paradigms including congestive heart failure (CHF), atrial fibrillation (AF), hypertensive cardiac disease, acute myocardial infarction, and valvular 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-protein density and distribution; tissue and cell structure; and cardiac-chamber dimension and shape. Progress in the identification of such changes has been impressive: in some cases, hundreds of alterations have been described in response to single well-defined experimental paradigms. A major resulting challenge is to determine which changes are particularly central to the pathophysiology of remodeling-related arrhythmias, and to establish therapeutic implications. In the present issue of Circulation Research, Verheule et al take advantage of a unique transgenic mouse model to address this issue.4
Potential Role of Fibrosis in AF
Interstitial fibrosis has been associated with AF since at least the 1960s.5 Recent studies have demonstrated an association between atrial fibrous-tissue content, conduction abnormalities, and propensity to AF in animals with CHF,6 mitral regurgitation,7,8 and senescence.9,10 These observations point toward fibrosis-induced conduction abnormalities as promoters of local reentry11,12 and thereby AF. However, the evidence has been predominantly circumstantial. Other mechanisms, such as delayed afterdepolarization-related triggered activity,13 favored by the Na+-Ca2+ exchanger upregulation that occurs in CHF,14 could also play a prominent role.
Verheule et al4 studied mice engineered to overexpress a constitutively active mutant form of TGF-ß1, causing atrial-specific interstitial fibrosis in the face of normal ventricular size and histology.15 The mice showed atrial conduction abnormalities and enhanced susceptibility to AF in the absence of abnormalities in atrial action potential properties or connexin protein distribution.4 These observations suggest that atrial fibrosis may itself create a substrate for AF, in agreement with recent studies showing that fibrosis and an AF substrate persist in atria of dogs that have recovered from CHF, despite the disappearance of CHF-induced ventricular dysfunction, hemodynamic alterations, atrial dilation, and ionic-current changes.16,17
Potential Implications of Identifying "Culprit Mechanisms"
The prevention of arrhythmogenic remodeling is emerging as a potential new treatment strategy for cardiac arrhythmias.18,19 If individual components of the many remodeling-associated changes are shown to be particularly important in arrhythmogenesis, they may be worthy of specific targeting. Just as the "culprit lesion" in one coronary artery may be attacked in unstable angina syndromes, it may be possible to target the "culprit mechanism" in specific forms of AF. For example, the effectiveness of angiotensin-converting enzyme inhibition in attenuating fibrosis and AF promotion in experimental CHF20 led to the suggestion that angiotensin-antagonism might be useful in preventing clinical AF due to structural remodeling. Clinical trials have shown that converting-enzyme inhibition prevents AF in patients with left ventricular dysfunction,21,22 and further studies may lead to more effective and specific preventive approaches.
Potential Pitfalls
The idea of a single or limited number of primary mechanisms involved in arrhythmia generation is attractive in its simplicity and tractability; however, reality may prove much more complicated. When an experimental paradigm apparently isolates a single primary factor, like atrial fibrosis in the TGF-ß1 mice or dogs recovered from CHF, it is tempting to identify that factor as established. However, more evidence is needed before fibrosis can be confirmed as causal in AF. It remains conceivable that fibrosis simply accompanies other as-yet unidentified causative factors. The efficacy of angiotensin antagonism in preventing AF associated with left ventricular dysfunction is consistent with the fibrosis hypothesis, but the observation that AF is also prevented by angiotensin-receptor antagonists23 and converting-enzyme inhibitors24 in patients without clear left ventricular dysfunction means either that angiotensin-related structural remodeling is a common feature in AF or that other mechanisms may be involved.
Determining the Significance of Specific Remodeling-Induced Changes
Paradigms that cause arrhythmogenic remodeling produce a wide range of alterations in cardiac structure and function. Many of these likely contribute little to the arrhythmia diathesis. Conversely, key arrhythmogenic factors may remain unidentified. Atrial-tachycardia remodeling provides illustrative examples. Atrial tachycardia alters a number of ionic currents, disrupts cellular ultrastructure, impairs atrial contractility, affects the function of many biochemical systems, and may alter intercellular communication via connexins.3,25–27 Which of these many changes plays a role in arrhythmogenesis? Although downregulation of L-type Ca2+-channels is likely involved in the refractoriness abbreviation that contributes to AF promotion, discrepancies in the time-course of refractoriness changes and AF development3,28 suggest the involvement of other factors that remain to be identified. What is the potential role of increases in inward-rectifier currents that are upregulated by atrial tachycardia,29,30 particularly in view of the potentially key role of inward-rectifier currents in ventricular fibrillation?31 What is the mechanism and importance of accelerated activity in the thoracic veins?32 These and other questions need to be answered to develop effective new mechanism-based therapies.
Conclusions
Over the past 5 to 10 years, we have been very successful in describing a host of changes that occur in arrhythmogenic remodeling. We have been less successful in determining which ones matter. We will have to do better in order to improve our understanding of underlying mechanisms and to develop more successful treatment approaches. The Verheule study published in this issue of Circulation Research is a step in that right direction.
Acknowledgments
The author thanks the Canadian Institutes of Health Research, the MITACS Network of Centers of Excellence, and Quebec Heart and Stroke Foundation for financial support and Monique Brouillard for secretarial assistance.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Nattel S, Khairy P, Schram G. Arrhythmogenic ionic remodeling: adaptive responses with maladaptive consequences. Trends Cardiovasc Med. 2001; 11: 295–301.[CrossRef][Medline] [Order article via Infotrieve]
2. Armoundas AA, Wu R, Juang G, Marban E, Tomaselli GF. Electrical and structural remodeling of the failing ventricle. Pharmacol Ther. 2001; 92: 213–230.[CrossRef][Medline] [Order article via Infotrieve]
3. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res. 2002; 54: 230–246.
4. Verheule S, Sato T, Everett T, Engle SK, Otten D, Rubart-von der Lohe M, Nakajima H, Nakajima H, Field LJ, Olgin JE. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis due to overexpression of TGF-ß1. Circ Res. 2004; 94: 1458–1465.
5. Bailey GW, Braniff BA, Hancock EW, Cohn KE. Relation of left atrial pathology to atrial fibrillation in mitral valvular disease. Ann Intern Med. 1968; 69: 13–20.
6. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999; 100: 87–95.
7. Verheule S, Wilson E, Everett T IV, Shanbhag S, Golden C, Olgin J. Alterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation. Circulation. 2003; 107: 2615–2622.
8. Verheule S, Wilson E, Banthia S, Everett IV TH, Shanbhag S, Sih HJ, Olgin J. Direction-dependent conduction abnormalities in a canine model of atrial fibrillation due to chronic atrial dilatation. Am J Physiol Heart Circ Physiol. 2004. In press.
9. Hayashi H, Wang C, Miyauchi Y, Omichi C, Pak HN, Zhou S, Ohara T, Mandel WJ, Lin SF, Fishbein MC, Chen PS, Karagueuzian HS. Aging-related increase to inducible atrial fibrillation in the rat model. J Cardiovasc Electrophysiol. 2002; 13: 801–808.[CrossRef][Medline] [Order article via Infotrieve]
10. Anyukhovsky EP, Sosunov EA, Plotnikov A, Gainullin RZ, Jhang JS, Marboe CC, Rosen MR. Cellular electrophysiologic properties of old canine atria provide a substrate for arrhythmogenesis. Cardiovasc Res. 2002; 54: 462–469.
11. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria. A mechanism for both preventing and initiating reentry. Circ Res. 1989; 65: 1612–1631.
12. Spach MS, Boineau JP. Microfibrosis produces electrical load variations due to loss of side-to-side cell connections: a major mechanism of structural heart disease arrhythmias. Pacing Clin Electrophysiol. 1997; 20: 397–413.[CrossRef][Medline] [Order article via Infotrieve]
13. Stambler BS, Fenelon G, Shepard RK, Clemo HF, Guiraudon CM. Characterization of sustained atrial tachycardia in dogs with rapid ventricular pacing-induced heart failure. J Cardiovasc Electrophysiol. 2003; 14: 499–507.[CrossRef][Medline] [Order article via Infotrieve]
14. Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, Nattel S. Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation. 2000; 101: 2631–2638.
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 transforming growth factor-ß1 transgene in the heart. Circ Res. 2000; 86: 571–579.
16. Shinagawa K, Shi YF, Tardif JC, Leung TK, Nattel S. Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs. Circulation. 2002; 105: 2672–2678.
17. Cha TJ, Ehrlich JR, Zhang L, Shi YF, Tardif JC, Leung TK, Nattel S. Dissociation between ionic remodeling and ability to sustain atrial fibrillation during recovery from experimental congestive heart failure. Circulation. 2004; 109: 412–418.
18. Nattel S. Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management? Cardiovasc Res. 2002; 54: 347–360.
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 cardiomyopathic hamsters. Circulation. 2002; 106: 613–619.
20. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-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 in patients with left ventricular dysfunction. Circulation. 1999; 100: 376–380.
22. Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M, Guerra PG, Ducharme A. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the studies of left ventricular dysfunction (SOLVD) trials. Circulation. 2003; 107: 2926–2931.
23. Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation. 2002; 106: 331–336.
24. Ueng KC, Tsai TP, Yu WC, Tsai CF, Lin MC, Chan KC, Chen CY, Wu DJ, Lin CS, Chen SA. Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation. Results of a prospective and controlled study. Eur Heart J. 2003; 24: 2090–2098.
25. Bosch RF, Nattel S. Cellular electrophysiology of atrial fibrillation. Cardiovasc Res. 2002; 54: 259–269.
26. van der Velden HM, Jongsma HJ. Cardiac gap junctions and connexins: their role in atrial fibrillation and potential as therapeutic targets. Cardiovasc Res. 2002; 54: 270–279.
27. Brundel BJ, Henning RH, Kampinga HH, Van Gelder IC, Crijns HJ. Molecular mechanisms of remodeling in human atrial fibrillation. Cardiovasc Res. 2002; 54: 315–324.
28. Todd DM, Fynn SP, Walden AP, Hobbs WJ, Arya S, Garratt CJ. Repetitive 4-week periods of atrial electrical remodeling promote stability of atrial fibrillation: time course of a second factor involved in the self-perpetuation of atrial fibrillation. Circulation. 2004; 109: 1434–1439.
29. Dobrev D, Graf E, Wettwer E, Himmel HM, Hala O, Doerfel C, Christ T, Schuler S, Ravens U. Human inward rectifier potassium channels in chronic and postoperative atrial fibrillation. Cardiovasc Res. 2002; 54: 397–404.
30. Ehrlich JR, Cha TJ, Zhang L, Chartier D, Villeneuve L, Hebert TE, Nattel S. Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium. J Physiol. 2004; 557: 583–597.
31. Samie FH, Berenfeld O, Anumonwo J, Mironov SF, Udassi S, Beaumont J, Taffet S, Pertsov AM, Jalife J. Rectification of the background potassium current: a determinant of rotor dynamics in ventricular fibrillation. Circ Res. 2001; 89: 1216–1223.
32. Wu TJ, Ong JJ, Chang CM, Doshi RN, Yashima M, Huang HL, Fishbein MC, Ting CT, Karagueuzian HS, Chen PS. Pulmonary veins and ligament of marshall as sources of rapid activations in a canine model of sustained atrial fibrillation. Circulation. 2001; 103: 1157–1163.
This article has been cited by other articles:
 |
|
 |
|
  R. Fischer, R. Dechend, A. Gapelyuk, E. Shagdarsuren, K. Gruner, A. Gruner, P. Gratze, F. Qadri, M. Wellner, A. Fiebeler, et al. Angiotensin II-induced sudden arrhythmic death and electrical remodeling Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1242 - H1253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-J. Cha, J. R. Ehrlich, D. Chartier, X.-Y. Qi, L. Xiao, and S. Nattel Kir3-Based Inward Rectifier Potassium Current: Potential Role in Atrial Tachycardia Remodeling Effects on Atrial Repolarization and Arrhythmias Circulation, April 11, 2006; 113(14): 1730 - 1737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Samarel Costameres, focal adhesions, and cardiomyocyte mechanotransduction Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2291 - H2301. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||