Controlling cardiac arrhythmias by lengthening repolarization: historical overview

An increasing confluence of experimental and clinical data on the gravity of proarrhythmic effects of class I agents has led to a shift to other electrophysiologic classes of agents for treating cardiac arrhythmias. The fact that beta blockers reduce mortality in a variety of subsets of patients has suggested a wider role for this class of agents. Recent investigations have focused on the potential role of sotalol and amiodarone, 2 agents that not only block sympathetic antagonism, but also prolong cardiac repolarization. They have been test drugs in an increasing number of controlled and uncontrolled trials in patients at risk for arrhythmic deaths. Their properties have formed the basis for the hypothesis that arrhythmias may be effectively controlled independently of changes in conduction; they are prototypes of compounds that may favorably influence electrical instability in the myocardium. Amiodarone and sotalol are, however, complex molecules with attendant side effects; therefore, attention is also focusing on compounds that act simply by selective prolongation of cardiac repolarization. These agents have been termed "pure" class III agents. The properties of sotalol, the prototype of class III agents, are of particular interest because it is a racemic mixture with the levo-isomer having 50 times the beta-blocking potency of the dextro-isomer; both have equipotent class III actions. Studies of the antiarrhythmic properties of beta blockers, D- and D,L-sotalol, and amiodarone may provide insights into the nature of class III actions. There is clinical evidence indicating that class III drugs exert a varying spectrum of antifibrillatory and proarrhythmic (characterized by torsades de pointes) actions for a given degree of prolongation of repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)