Effects of angiotensin converting enzyme inhibition in patients with stable coronary artery disease: The prevention of events with angiotensin converting enzyme inhibition (PEACE) trial: the PEACE Study investigators (original) (raw)

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 Ϫ1 • d Ϫ1. 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 tachypacinginduced changes in atrial angiotensin II concentrations and ERK expression. Enalapril also attenuated the effects of CHF on atrial conduction (conduction heterogeneity index reduced from 3.1Ϯ0.4 to 1.9Ϯ0.2 ms/mm, PϽ0.05), atrial fibrosis (from 11.9Ϯ1.1% to 7.5Ϯ0.4%, PϽ0.01), and mean AF duration (from 651Ϯ164 to 218Ϯ75 seconds, PϽ0.05). 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. (Circulation. 2001;104:2608-2614.) Key Words: arrhythmia Ⅲ remodeling Ⅲ atrium Ⅲ electrophysiology Ⅲ heart failure A trial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. Although antiarrhythmic agents promote sinus rhythm maintenance, they can cause potentially serious proarrhythmia. 1 A potential new approach to AF therapy is to target the underlying substrate. 2 We recently found that dogs with ventricular tachypacing (VTP)induced congestive heart failure (CHF) have a substrate for AF maintenance, 3 with interstitial fibrosis that resembles atrial pathology in many patients with AF. 4 The renin-angiotensin system is involved in myocardial fibrosis in hypertensive heart disease, 5 CHF, 6 myocardial infarction, 7 and cardiomyopathy. 8 Angiotensin II (Ang II) stimulates collagen synthesis in rat cardiac fibroblasts. 9,10 Mitogen-activated protein kinases (MAPKs) are important mediators of Ang II effects on tissue structure. 11,12 The 3 best-characterized MAPK subfamilies are extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38-MAPKs. 12,13 Recent studies showed ERK activation 14 and angiotensin receptor changes 15 in patients with AF. We speculated that Ang II and MAPK activation might be involved in AFpromoting atrial structural remodeling. We therefore designed this study to determine (1) the changes in atrial Ang II and MAPKs during the development of VTP-induced CHF in dogs, (2) the effect of ACE inhibition on atrial Ang II and MAPKs, and (3) the impact of ACE inhibition on AF substrate development. Methods Enalapril Effects on the CHF-Induced AF Substrate The following groups of mongrel dogs (25 to 33 kg) were studied: controls (nϭ7), placebo-VTP group (nϭ10), and enalapril-VTP group (nϭ10). The placebo and enalapril groups were subjected to VTP 3 for 5 weeks (240 bpm for 3 weeks, 220 bpm 2 weeks) and given either placebo or enalapril (2 mg • kg Ϫ1 • d Ϫ1 , Merck Frosst)