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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