Aldosterone Antagonism as an Antiarrhythmic Approach for Atrial Arrhythmias in Heart Failure

The renin–angiotensin–aldosterone system (RAAS) is a critical regulator of blood pressure and electrolyte homeostasis. While essential for normal homeostasis, excessive RAAS activation is implicated in the development of hypertension and may underlie the pathophysiology of heart failure (HF). Thus, current AHA/ACC treatment guidelines recommend treatment of heart failure patients with an ACE inhibitor or angiotensin II receptor antagonist and a beta-adrenergic receptor blocker.1 Atrial fibrillation (AF) is the most common arrhythmia and a common comorbidity, occurring frequently in heart failure patients.2 As in heart failure, activation of the RAAS has an important role in the etiology of AF.3 In human AF, tissue angiotensin converting enzyme (ACE) is upregulated, correlating with increased atrial angiotensin II production.4 ACE inhibition has been shown to attenuate atrial structural remodeling (interstitial fibrosis) in a canine rapid ventricular pacing (RVP) model5-7 and to reduce the prevalence of AF in patients with left ventricular dysfunction post-myocardial infarction (MI).8 Other studies in the canine RVP model emphasize the role of fibrosis as an important mediator of increased atrial arrhythmia persistence.5 In the canine RVP-induced heart failure model, AF duration was increased relative to controls both before and following recovery of pacing-induced atrial electrical remodeling. This suggests that tissue fibrosis creates a substrate for increased arrhythmia persistence that is independent of action potential duration. It is interesting to note that, while enalapril attenuated the development of interstitial fibrosis, it had no impact on the atrial effective refractory period, conduction velocity, or wavelength of conduction in the canine rapid ventricular pacing model.6 This suggests that, while angiotensin II may contribute to the development of atrial fibrosis, it is unlikely to have prominent electrophysiologic effects. Another key component of the RAAS axis is the mineralocorticoid aldosterone. Serum aldosterone levels have been reported to be elevated in AF patients, and aldosterone levels