Proarrhythmia.

The concept that antiarrhythmic drugs can exacerbate the cardiac rhythm disturbance being treated, or generate entirely new clinical arrhythmia syndromes, is not new. Abnormal cardiac rhythms due to digitalis or quinidine have been recognized for decades. This phenomenon, termed "proarrhythmia," was generally viewed as a clinical curiosity, since it was thought to be rare and unpredictable. However, the past 20 years have seen the recognition that proarrhythmia is more common than previously appreciated in certain populations, and can in fact lead to substantially increased mortality during long-term antiarrhythmic therapy. These findings, in turn, have moved proarrhythmia from a clinical curiosity to the centerpiece of antiarrhythmic drug pharmacology in at least two important respects. First, clinicians now select antiarrhythmic drug therapy in a particular patient not simply to maximize efficacy, but very frequently to minimize the likelihood of proarrhythmia. Second, avoiding proarrhythmia has become a key element of contemporary new antiarrhythmic drug development. Further, recognition of the magnitude of the problem has led to important advances in understanding basic mechanisms. While the phenomenon of proarrhythmia remains unpredictable in an individual patient, it can no longer be viewed as "idiosyncratic." Rather, gradations of risk can be assigned based on the current understanding of mechanisms, and these will doubtless improve with ongoing research at the genetic, molecular, cellular, whole heart, and clinical levels.