Arrhythmia control by prolonging repolarization: the concept and its potential therapeutic impact

Over the last decade, there has been an increasing confluence of experimental and clinical data on the gravity of proarrhythmic effects of class I agents. Over the same period, beta blockers have been shown to reduce mortality in a variety of subsets of patients. The properties of amiodarone and sotalol have also drawn attention to their potential as antifibrillatory compounds, perhaps acting principally by prolonging myocardial repolarization with little or no effect on conduction. However, amiodarone and sotalol are complex molecules and, therefore, attention is also focused 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, as it is a racemic mixture of the levo- and dextro-isomers. The levo-isomer has 50 times the beta-blocking potency of the dextro-isomer, 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 torsade de pointes) actions for a given degree of prolongation of repolarization. These differences currently are not accountable in terms of specificity of their actions on ionic channels. There are differences between the so-called pure class III agents, such as sematilide, dofetilide and E-4031, and more complex compounds, such as sotalol and amiodarone, that also exert antiadrenergic actions. In the development of newer drugs an appropriate balance needs to be struck between proarrhythmic actions and the antifibrillatory properties. At present, it is unclear whether such antifibrillatory compounds should be relatively simple molecules with clearly-defined electrophysiologic profiles in terms of actions on ion channels, currents, receptors and pumps, or whether they need to be those with complex electropharmacologic profiles with multiplicity of actions.