Understanding torsade de pointes: a bridge to tailored drug therapy?

Abstract

T orsade de pointes secondary to excessive QT prolongation has long been known as a proarrhythmic effect of some antiarrhythmic drugs which act by prolonging the QT interval (Vaughan-Williams class IA and class III) [1]. More recently, this particular kind of polymorphic ventricular tachycardia has received great interest, as its electrophysiological mechanisms have become unveiled [2,3]. The excess mortality associated with class I drugs in the CAST study [4] has contributed to enhancing the interest in the development of antiarrhythmic drugs which act by action potential prolongation (class III) [5]. A major step toward further understanding its pathophysiology came from the recognition that torsade de pointes in drug-induced long QT syndrome has the same mechanisms as in inherited long QT syndrome. In both instances, the basic mechanism is excessive action potential prolongation by reduced repolarizing K channel current (due to drugs or functional alterations resulting from mutations of the ion channel encoding genes) and/or enhanced depolarizing Na channel current, which promotes afterdepolarizations. The emerging interest in torsade de pointes has also led to the recognition that non-antiarrhythmic drugs may result in this life-threatening arrhythmia through the same mechanisms (these drugs reduce the delayed rectifier K current, which is involved in one type of inherited long QT syndrome) [6]. Indeed, these observations have fueled the general interest in torsade de pointes. This usually unexpected but life-threatening arrhythmia is now regarded as a major concern in the development of new drugs and even in the use of some existing ones, as the recent withdrawals from the U.S. market of the prokinetic cisapride and the antihistamine astemizole illustrate. Faced with the challenge of this unpredictable, yet real and even potentially lethal side effect of any (cardiac and noncardiac) drug therapy, the clinician may raise questions which are addressed by 3 review papers in this issue of Cardiovascular Drugs and Therapy [7–9]. What is the pathophysiology of torsade de pointes? How often does drug-induced torsade de pointes occur and how must one manage it? And, at least equally importantly, how can it be avoided, i.e., can its occurrence be predicted in the individual patient? Haverkamp et al. [7] review the current hypotheses regarding the mechanisms of torsade de pointes; they then extensively list the known causes (drugs) and risk factors of QT prolongation and torsade de pointes and present an overview of its modes of therapy. Huikuri [8] emphasizes the role of the autonomic nervous system, dispersion of refractoriness, and their relationship; in addition, he reviews the ways in which they interact to provoke torsade de pointes, and provides an extensive review of the clinical methods to assess dispersion of refractoriness. Importantly, he also discusses their limitations, as some investigators have cast serious doubts on the value of QT dispersion [10]. Priori et al. [9] shed light on some current hypotheses surrounding the molecular basis of torsade de pointes by examining the relationship between acquired (druginduced) long QT syndrome and inherited long QT syndrome and discussing recent and emerging evidence to support the notion that both forms share a genetic basis. Interestingly, all antiarrhythmic drugs which cause torsade de pointes do so by similar incidences of 2–9% [7] (with the exception of amiodarone which rarely causes torsade de pointes presumably due to the fact that it blocks multiple ion channels, including depolarizing currents which are held responsible for triggering afterdepolarizations). In addition, patients who sustain torsade de pointes on one antiarrhythmic drug are at an increased risk of experiencing it on another antiarrhythmic drug. These observations suggest that this type of proarrhythmia afflicts a group of patients who are particularly susceptible to it, perhaps due to their genetic predisposition [11]. The concept of “repolarization reserve” has been developed to this end [12]. Its tenet is that, normally, excess repolarizing forces (carried by a host of different K channels) ensure proper and complete repolarization under a large variety of circumstances to prevent reentrant rhythms and afterdepolarizations. Certain factors or combinations thereof may overwhelm these repolarizing forces. For