ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation
- E Kevin Heist, MD, PhD
E Kevin Heist, MD, PhD
- Associate Professor of Medicine
- Harvard Medical School
- Section Editors
- Samuel Lévy, MD
Samuel Lévy, MD
- Section Editor — Cardiac Arrhythmias
- Professor of Cardiology
- University of Marseille, France
- Hugh Calkins, MD
Hugh Calkins, MD
- Section Editor — Cardiac Arrhythmias
- Professor of Medicine
- Johns Hopkins Medical Institutions
Initial studies suggested that angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and (possibly) aldosterone antagonists might either prevent new onset and recurrent atrial fibrillation (AF) or reduce the rate of major adverse cardiovascular outcomes in these patients. However, the available data do not support the use of these drugs solely for these purposes.
In this topic ACE inhibitors and ARBs collectively will be referred to as ‘angiotensin inhibition.’
Mechanisms proposed to explain the benefit of angiotensin blockade found in the early studies included the direct effects of angiotensin blockade on the structural and electrical properties of the atria, as well as the indirect influence of improved control of heart failure and hypertension, both of which are known risk factors for atrial fibrillation (AF) . (See "The electrocardiogram in atrial fibrillation" and "Actions of angiotensin II on the heart" and "Epidemiology of and risk factors for atrial fibrillation".)
The following observations supported the proposed mechanisms:
●Reduction in atrial stretch — Atrial stretch, due to increased left atrial (LA) pressure, is associated with changes in the refractory period and conduction properties of atrial myocardium. These abnormalities provide both potential triggers and the substrate for the initiation and perpetuation of AF. The hemodynamic effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) result in improved ventricular function and also reductions in LA pressure and wall stress .
- Ehrlich JR, Hohnloser SH, Nattel S. Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence. Eur Heart J 2006; 27:512.
- Webster MW, Fitzpatrick MA, Nicholls MG, et al. Effect of enalapril on ventricular arrhythmias in congestive heart failure. Am J Cardiol 1985; 56:566.
- McEwan PE, Gray GA, Sherry L, et al. Differential effects of angiotensin II on cardiac cell proliferation and intramyocardial perivascular fibrosis in vivo. Circulation 1998; 98:2765.
- Li D, Shinagawa K, Pang L, et al. 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.
- Sakabe M, Fujiki A, Nishida K, et al. Enalapril prevents perpetuation of atrial fibrillation by suppressing atrial fibrosis and over-expression of connexin43 in a canine model of atrial pacing-induced left ventricular dysfunction. J Cardiovasc Pharmacol 2004; 43:851.
- Nakashima H, Kumagai K, Urata H, et al. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation 2000; 101:2612.
- Sicouri S, Cordeiro JM, Talarico M, Antzelevitch C. Antiarrhythmic effects of losartan and enalapril in canine pulmonary vein sleeve preparations. J Cardiovasc Electrophysiol 2011; 22:698.
- Zhang Y, Zhang P, Mu Y, et al. The role of renin-angiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Clin Pharmacol Ther 2010; 88:521.
- 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.
- Vermes E, Tardif JC, Bourassa MG, et al. 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.
- Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J 2005; 149:548.
- Ducharme A, Swedberg K, Pfeffer MA, et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J 2006; 152:86.
- Schaer BA, Schneider C, Jick SS, et al. Risk for incident atrial fibrillation in patients who receive antihypertensive drugs: a nested case-control study. Ann Intern Med 2010; 152:78.
- L'Allier PL, Ducharme A, Keller PF, et al. Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation. J Am Coll Cardiol 2004; 44:159.
- Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359:995.
- Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol 2005; 45:712.
- Heckbert SR, Wiggins KL, Glazer NL, et al. Antihypertensive treatment with ACE inhibitors or beta-blockers and risk of incident atrial fibrillation in a general hypertensive population. Am J Hypertens 2009; 22:538.
- Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353:611.
- Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999; 354:1751.
- Yamashita T, Inoue H, Okumura K, et al. Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II study). Europace 2011; 13:473.
- Schneider MP, Hua TA, Böhm M, et al. Prevention of atrial fibrillation by Renin-Angiotensin system inhibition a meta-analysis. J Am Coll Cardiol 2010; 55:2299.
- Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002; 106:331.
- Ueng KC, Tsai TP, Yu WC, et al. 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.
- Yin Y, Dalal D, Liu Z, et al. Prospective randomized study comparing amiodarone vs. amiodarone plus losartan vs. amiodarone plus perindopril for the prevention of atrial fibrillation recurrence in patients with lone paroxysmal atrial fibrillation. Eur Heart J 2006; 27:1841.
- Fogari R, Mugellini A, Destro M, et al. Losartan and prevention of atrial fibrillation recurrence in hypertensive patients. J Cardiovasc Pharmacol 2006; 47:46.
- Belluzzi F, Sernesi L, Preti P, et al. Prevention of recurrent lone atrial fibrillation by the angiotensin-II converting enzyme inhibitor ramipril in normotensive patients. J Am Coll Cardiol 2009; 53:24.
- Galzerano D, Di Michele S, Paolisso G, et al. A multicentre, randomized study of telmisartan versus carvedilol for prevention of atrial fibrillation recurrence in hypertensive patients. J Renin Angiotensin Aldosterone Syst 2012; 13:496.
- GISSI-AF Investigators, Disertori M, Latini R, et al. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009; 360:1606.
- Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol 2005; 45:1832.
- Goette A, Schön N, Kirchhof P, et al. Angiotensin II-antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial. Circ Arrhythm Electrophysiol 2012; 5:43.
- Zhao J, Li J, Li W, et al. Effects of spironolactone on atrial structural remodelling in a canine model of atrial fibrillation produced by prolonged atrial pacing. Br J Pharmacol 2010; 159:1584.
- Dabrowski R, Borowiec A, Smolis-Bak E, et al. Effect of combined spironolactone-β-blocker ± enalapril treatment on occurrence of symptomatic atrial fibrillation episodes in patients with a history of paroxysmal atrial fibrillation (SPIR-AF study). Am J Cardiol 2010; 106:1609.
- Swedberg K, Zannad F, McMurray JJ, et al. Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. J Am Coll Cardiol 2012; 59:1598.
- Ito Y, Yamasaki H, Naruse Y, et al. Effect of eplerenone on maintenance of sinus rhythm after catheter ablation in patients with long-standing persistent atrial fibrillation. Am J Cardiol 2013; 111:1012.
- Klemm HU, Heitzer T, Ruprecht U, et al. Impact of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the long-term outcome after pulmonary vein isolation for paroxysmal atrial fibrillation. Cardiology 2010; 117:14.
- Richter B, Derntl M, Marx M, et al. Therapy with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins: no effect on ablation outcome after ablation of atrial fibrillation. Am Heart J 2007; 153:113.
- Al Chekakie MO, Akar JG, Wang F, et al. The effects of statins and renin-angiotensin system blockers on atrial fibrillation recurrence following antral pulmonary vein isolation. J Cardiovasc Electrophysiol 2007; 18:942.
- ACTIVE I Investigators, Yusuf S, Healey JS, et al. Irbesartan in patients with atrial fibrillation. N Engl J Med 2011; 364:928.
- January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071.
- January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199.
- POSSIBLE MECHANISMS
- PREVENTION OF NEW ONSET AF
- Left ventricular dysfunction or heart failure
- Patients with other risk factors for AF
- Coronary artery bypass graft
- PREVENTION OF RECURRENT AF
- Aldosterone inhibition and AF
- Catheter ablation of AF
- PREVENTION OF CARDIOVASCULAR EVENTS
- RECOMMENDATIONS OF OTHERS
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS