Angiotensin Converting Enzyme Inhibition in Heart, Kidney, and Serum Studied Ex Vivo after Administration of Zofenopril, Captopril, and Lisinopril (original) (raw)
European Heart Journal, 2005
Atrial fibrillation (AF) is a common arrhythmia that is difficult to treat. Anti-arrhythmic drug therapy, to maintain sinus-rhythm, is limited by inadequate efficacy and potentially serious adverse effects. There is increasing interest in novel therapeutic approaches that target AF-substrate development. Recent trials suggest that angiotensin converting-enzyme (ACE)-inhibitors and angiotensin-receptor blockers (ARBs) may be useful, particularly in patients with left ventricular hypertrophy or failure. The clinical potential and mechanisms of this approach are under active investigation. Angiotensin-II is involved in remodelling and may have direct electrophysiological actions. Experimental studies show protection from atrial structural and possibly electrical remodelling with ACE-inhibitors and ARBs, as well as potential effects on cardiac ion-channels. This article reviews information pertaining to the clinical use and mechanism of action of ACE-inhibitors and ARBs in AF. A lack of prospective randomized double-blind trials data limits their application in AF patients without another indication for their use, but studies under way may alter this in the near future. This exciting field of investigation may lead to significant improvements in therapeutic options for AF patients.
Journal of The American College of Cardiology, 2005
This study was designed to identify all randomized clinical trial data evaluating angiotensinconverting enzyme inhibitors or angiotensin receptor blockers for the prevention of atrial fibrillation (AF), to estimate the magnitude of this effect and to identify patient subgroups most likely to benefit. BACKGROUND Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce morbidity and mortality in patients with heart failure, vascular disease, and hypertension. Several reports suggest that they may also prevent the development of AF.
Journal of the American …, 2005
This study was designed to identify all randomized clinical trial data evaluating angiotensinconverting enzyme inhibitors or angiotensin receptor blockers for the prevention of atrial fibrillation (AF), to estimate the magnitude of this effect and to identify patient subgroups most likely to benefit. BACKGROUND Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce morbidity and mortality in patients with heart failure, vascular disease, and hypertension. Several reports suggest that they may also prevent the development of AF.
Circulation
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)
The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin converting enzyme inhibitors (ACEis) suppress angiotensin II (ANG II) concentrations, whereas angiotensin receptor blockers (ARBs) block the binding of ANG II to AT 1 receptors. ACEis and ARBs are both effective anti-hypertensive agents and have similar risk reductions in stroke — a blood pressure dependent phenomenon. ACEis also reduce the risk of myocardial infarction (MI) and mortality in high risk hypertensive patients, as well as in diabetics, the elderly, those with vascular disease, and in congestive heart failure. ARBs, in contrast, do not reduce the risk of MI or death in clinical trials where the comparator has been another active therapy or even a placebo. Systematic reviews of ARBs that include meta-analyses or meta-regression analyses confirm that ARBs lack the cardiovascular protective effects of ACEis, which in part are " independent " of blood pressure lowering. Practice guidelines, especially those in high risk hypertensive patients, should reflect the evidence that ACEis and ARBs have divergent cardiovascular effects — ACEis reduce mortality, whereas ARBs do not. ACEis should be the preferred RAAS inhibitor in high risk patients. Angiotensin converting enzyme inhibitors (ACEis) and angioten-sin II type 1 (AT 1) receptor blockers (ARBs) are anti-hypertensive (HTN) agents that modulate the renin angiotensin aldosterone system (RAAS) by targeting angiotensin II (ANG II), each with a unique mode of action. ACEis suppress the production of ANG II, whereas ARBs block the ANG II stimulation of the AT 1 receptor; therefore each is a unique therapeutic class. ACEis and ARBs do have similar blood pressure (BP) lowering effects, with a positive impact on stroke, 1 diabetic kidney disease, 2 symptoms of congestive heart failure (HF), 3 and at least in post hoc analyses of large clinical trials, reduce the incidence of diabetes mellitus(DM) and atrial fibrillation. 4 This shared efficacy has led to the conclusions in many practice guidelines that ACEis and ARBs are equivalent, interchangeable, and alternative