Circulation. 2001;104:2608-2614
doi: 10.1161/hc4601.099402
doi: 10.1161/hc4601.099402
(Circulation. 2001;104:2608.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Effects of Angiotensin-Converting Enzyme Inhibition on the Development of the Atrial Fibrillation Substrate in Dogs With Ventricular Tachypacing–Induced Congestive Heart Failure
From the Departments of Medicine (D.L., K.S., L.P., S.C., Z.W., S.N.) and Pathology (T.K.L.), Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
Correspondence to Stanley Nattel, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8. E-mail nattel{at}icm.umontreal.ca
Background Atrial structural remodeling creates a substrate for atrial fibrillation (AF), but the underlying signal transduction mechanisms are unknown. This study assessed the effects of ACE inhibition on arrhythmogenic atrial remodeling and associated mitogen-activated protein kinase (MAPK) changes in a dog model of congestive heart failure (CHF).
Methods and Results Dogs were subjected to various durations of ventricular tachypacing (VTP, 220 to 240 bpm) in the presence or absence of oral enalapril 2 mg · kg-1 · d-1. VTP for 5 weeks induced CHF, local atrial conduction slowing, and interstitial fibrosis and prolonged atrial burst pacing–induced AF. Atrial angiotensin II concentrations and MAPK expression were increased by tachypacing, with substantial changes in phosphorylated forms of c-Jun N-terminal kinase (JNK), extracellular signal–regulated kinase (ERK), and p38-kinase. Enalapril significantly reduced tachypacing-induced changes in atrial angiotensin II concentrations and ERK expression. Enalapril also attenuated the effects of CHF on atrial conduction (conduction heterogeneity index reduced from 3.1±0.4 to 1.9±0.2 ms/mm, P<0.05), atrial fibrosis (from 11.9±1.1% to 7.5±0.4%, P<0.01), and mean AF duration (from 651±164 to 218±75 seconds, P<0.05). Vasodilator therapy of a separate group of VTP dogs with hydralazine and isosorbide mononitrate did not alter CHF-induced fibrosis or AF promotion.
Conclusions CHF-induced increases in angiotensin II content and MAPK activation contribute to arrhythmogenic atrial structural remodeling. ACE inhibition interferes with signal transduction leading to the AF substrate in CHF and may represent a useful new component to AF therapy.
Key Words: arrhythmia • remodeling • atrium • electrophysiology • heart failure
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 S. Nattel Antiarrhythmic drugs for atrial fibrillation: Do we need better use, better drugs or a randomized trial of ablation as primary therapy? Can. Med. Assoc. J., September 28, 2004; 171(7): 752 - 753. [Full Text] [PDF]
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 W Anne, R Willems, N Van der Merwe, F Van de Werf, H Ector, and H Heidbuchel Atrial fibrillation after radiofrequency ablation of atrial flutter: preventive effect of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics Heart, September 1, 2004; 90(9): 1025 - 1030. [Abstract] [Full Text] [PDF]
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N. Hanna, S. Cardin, T.-K. Leung, and S. Nattel Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure Cardiovasc Res, August 1, 2004; 63(2): 236 - 244. [Abstract] [Full Text] [PDF]
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P. L. L'Allier, A. Ducharme, P.-F. Keller, H. Yu, M.-C. Guertin, and J.-C. Tardif Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation J. Am. Coll. Cardiol., July 7, 2004; 44(1): 159 - 164. [Abstract] [Full Text] [PDF]
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D. G. Wyse and B. J. Gersh Atrial Fibrillation: A Perspective: Thinking Inside and Outside the Box Circulation, June 29, 2004; 109(25): 3089 - 3095. [Full Text] [PDF]
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S. Nattel Defining "Culprit Mechanisms" in Arrhythmogenic Cardiac Remodeling Circ. Res., June 11, 2004; 94(11): 1403 - 1405. [Full Text] [PDF]
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S. Verheule, T. Sato, T. Everett IV, S. K. Engle, D. Otten, M. Rubart-von der Lohe, H. O. Nakajima, H. Nakajima, L. J. Field, and J. E. Olgin Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-{beta}1 Circ. Res., June 11, 2004; 94(11): 1458 - 1465. [Abstract] [Full Text] [PDF]
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K.-C. Ueng and S.-A. Chen Atrial remodelling in persistent atrial fibrillation: the potential role of aldosterone: Reply Eur. Heart J., June 2, 2004; 25(12): 1087 - 1087. [Full Text] [PDF]
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B. J.J.M Brundel, H. H Kampinga, and R. H Henning Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial fibrillation Cardiovasc Res, June 1, 2004; 62(3): 521 - 528. [Abstract] [Full Text] [PDF]
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C.-T. Tsai, L.-P. Lai, J.-L. Lin, F.-T. Chiang, J.-J. Hwang, M. D. Ritchie, J. H. Moore, K.-L. Hsu, C.-D. Tseng, C.-S. Liau, et al. Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation Circulation, April 6, 2004; 109(13): 1640 - 1646. [Abstract] [Full Text] [PDF]
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 S. Wasson, H. K. Reddy, and M. L. Dohrmann Current Perspectives of Electrical Remodeling and Its Therapeutic Implications Journal of Cardiovascular Pharmacology and Therapeutics, April 1, 2004; 9(2): 129 - 144. [Abstract] [PDF]
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A. Khan, G. W. Moe, N. Nili, E. Rezaei, M. Eskandarian, J. Butany, and B. H. Strauss The cardiac atria are chambers of active remodeling and dynamic collagen turnover during evolving heart failure J. Am. Coll. Cardiol., January 7, 2004; 43(1): 68 - 76. [Abstract] [Full Text] [PDF]
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H. Heidbuchel A paradigm shift in treatment for atrial fibrillation: from electrical to structural therapy? Eur. Heart J., December 1, 2003; 24(23): 2077 - 2078. [Full Text] [PDF]
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K.-C. Ueng, T.-P. Tsai, W.-C. Yu, C.-F. Tsai, M.-C. Lin, K.-C. Chan, C.-Y. Chen, D.-J. Wu, C.-S. Lin, and S.-A. Chen 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., December 1, 2003; 24(23): 2090 - 2098. [Abstract] [Full Text] [PDF]
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A. Boldt, U. Wetzel, J. Weigl, J. Garbade, J. Lauschke, G. Hindricks, H. Kottkamp, J. F. Gummert, and S. Dhein Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1785 - 1792. [Abstract] [Full Text] [PDF]
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S. Cardin, D. Li, N. Thorin-Trescases, T.-K. Leung, E. Thorin, and S. Nattel Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways Cardiovasc Res, November 1, 2003; 60(2): 315 - 325. [Abstract] [Full Text] [PDF]
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P. Sanders, J. B. Morton, N. C. Davidson, S. J. Spence, J. K. Vohra, P. B. Sparks, and J. M. Kalman Electrical Remodeling of the Atria in Congestive Heart Failure: Electrophysiological and Electroanatomic Mapping in Humans Circulation, September 23, 2003; 108(12): 1461 - 1468. [Abstract] [Full Text] [PDF]
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C. Boixel, V. Fontaine, C. Rucker-Martin, P. Milliez, L. Louedec, J.-B. Michel, M.-P. Jacob, and S. N. Hatem Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat J. Am. Coll. Cardiol., July 16, 2003; 42(2): 336 - 344. [Abstract] [Full Text] [PDF]
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K. Kumagai, H. Nakashima, H. Urata, N. Gondo, K. Arakawa, and K. Saku Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2197 - 2204. [Abstract] [Full Text] [PDF]
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H. U. Klein and A. Goette Blockade of atrial angiotensin II type 1 receptors: A novel antiarrhythmic strategy to prevent atrial fibrillation? J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2205 - 2206. [Full Text] [PDF]
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E. Vermes, J.-C. Tardif, M. G. Bourassa, N. Racine, S. Levesque, M. White, P. G. Guerra, and A. Ducharme Enalapril Decreases the Incidence of Atrial Fibrillation in Patients With Left Ventricular Dysfunction: Insight From the Studies Of Left Ventricular Dysfunction (SOLVD) Trials Circulation, June 17, 2003; 107(23): 2926 - 2931. [Abstract] [Full Text] [PDF]
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 Y.-M. Cha, P. P. Dzeja, W. K. Shen, A. Jahangir, C. Y. T. Hart, A. Terzic, and M. M. Redfield Failing atrial myocardium: energetic deficits accompany structural remodeling and electrical instability Am J Physiol Heart Circ Physiol, April 1, 2003; 284 (4): H1313 - H1320. [Abstract] [Full Text] [PDF]
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S. Nattel Atrial Electrophysiology and Mechanisms of Atrial Fibrillation Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1_suppl): S5 - S11. [Abstract] [PDF]
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