Antiarrhythmic Impact of Anti-Ischemic, Anti-Failure and Other Cardiovascular Strategies

For nearly two decades, the clinical management of ventricular arrhythmias has been predominantly characterized by the use of pharmacological antiarrhythmic agents either prescribed empirically or guided by electrophysiologic studies. Initially, in the absence of adequate, prospective, placebocontrolled assessment, enthusiasm for these approaches were high but recent data has been sobering. Empiric use of class I antiarrhythmic agents [1,2] and d-sotalol, a class III agent devoid of β-blockade [3], have been associated with increased mortality and sudden/arrhythmic death in patients post myocardial infarction. The class III agent dofetilide has been recently shown to be mortality neutral in both post-infarction [4] and congestive heart failure [5] populations. Agents with class III and β-blocking properties (sotalol and amiodarone) have been mortality neutral (with potentially a small decrease in sudden/arrhythmic death) in this population [6–8]. While class III antiarrhythmic therapy guided by electrophysiologic evaluation has been shown to be superior to class I agents [9,10], they have not been proven convincingly superior to placebo [11]. There is, however, convincing data that pharmacological therapy, not typically thought of as “antiarrhythmic”, can decrease total and, more surprisingly, sudden and arrhythmic death. These agents may be effective, at least in part, because of their long-term effects on myocardial structure and cardiac remodeling. Reversal or limitation of remodeling may occur with beta-blockers, angiotensin converting enzyme (ACE) inhibitors, nitrates, and hydralazine. Moreover, activation of the autonomic nervous system and reninangiotensin-aldosterone axis may promote the occurrence of ventricular tachyarrhythmias [12,13]. A shift in focus from agents that suppress ventricular arrhythmias to agents that alter or limit the arrhythmogenic milieu in some ways parallels the evolution of the management of congestive heart failure. Initially congestive heart failure was viewed as a problem of edema and sodium retention (with widespread utilization of diuretics and digitalis) or as a hemodynamic problem (with use of agents which improved myocardial contractile function but failed to improve symptoms and increased mortality). Only when management was directed at the neurohormonal and structural aspects of congestive failure have significant improvements in outcome been realized. There are fundamental problems inherent in the assessment of the antiarrhythmic impact of any cardiovascular intervention. First, although overall mortality is a distinct endpoint, assignment of total deaths to cardiac and especially sudden cardiac designations may be fraught with classification error. Second, while sudden death is for all intents and purposes essentially arrhythmic, the specific arrhythmic mechanism may be different in different situations. It is easy to imagine that agents which might have a beneficial effect on one mechanism may exacerbate another. Nevertheless, many agents utilized in the treatment of congestive heart failure (CHF) or coronary artery disease (e.g., β-blockers, ACE inhibitors, etc.) may have important antiarrhythmic actions and will be discussed in this selective review.