Drug induced QT prolongation and torsades de pointes

n 1966, Francois Dessertenne described a specific electrocardiographic form of polymorphic ventricular tachycardia, which he termed ''torsades de pointes'' (TdP).w1 w2 The word ''torsades'' refers to an ornamental motif imitating twisted hairs or threads as seen on classical architectural columns, and ''pointes'' referred to points or peaks.w1 w2 In the seminal article, Dessertenne made no attempt to suggest the mechanism of TdP and, until recently, there has been considerable conjecture as to the pathophysiology of this arrhythmia. CAUSES OF TORSADES DE POINTES cSince the original work by Dessertenne, it has been well recognised that many conditions may cause prolonged or abnormal repolarisation (that is, QT interval prolongation and/or abnormal T or T/U wave morphology), which is associated with TdP.If TdP is rapid or prolonged, it can lead to ventricular fibrillation and sudden cardiac death (fig 1).Essentially, TdP may be caused by either congenital or acquired long QT syndrome (LQTS).In recent years, there has been considerable renewed interest in the assessment and understanding of ventricular repolarisation and TdP.There are several reasons for this.Firstly, the cloning of cardiac ion channels has improved the understanding of the role of ionic channels in mediating cardiac repolarisation, the pathophysiological mechanism of LQTS (congenital and acquired forms), and the pathogenesis of TdP.Secondly, modern molecular techniques have unravelled the mutations in genes encoding cardiac ion channels that cause long QT syndrome, although the genetic defects in about 50% of patients are still unknown.Thirdly, there has been considerable enthusiasm for the development and use of class III antiarrhythmic drugs, which prolong repolarisation and cardiac refractoriness.Unfortunately, drugs that alter repolarisation have now been recognised to increase the propensity for TdP.Finally, an increasing number of drugs, especially non-cardiac drugs, have been recognised to delay cardiac repolarisation and to share the ability with class III antiarrhythmics to cause TdP occasionally.Many of the drugs that were initially known to prolong the QT interval were antiarrhythmics, and quinidine was the most commonly implicated agent.Surprisingly, many non-cardiac drugs have also been reported to cause QT prolongation and/or TdP recently.In a survey in both the UK and Italy, non-cardiac drugs that have pro-arrhythmic potential (that is, have an official warning on QT prolongation or TdP, or with published data on QT prolongation, ventricular tachycardia, or class III effect) alone represented 3% and 2% of total prescriptions in both countries, respectively. 1 The danger of drug induced pro-arrhythmia is therefore serious.This issue has been identified as a considerable public health problem and has attracted attention from the drug regulatory authorities.The exact incidence of drug induced TdP in the general population is largely unknown.Most of our understandings of the incidence, risk factors, and drug interaction of pro-arrhythmic drugs are derived form epidemiological studies, anecdotal case reports, clinical studies during drug development, and post-marketing surveillance.The awareness of drug induced TdP in the last few years has resulted in an increase in the number of spontaneous reports.Nevertheless, the absolute total number remains very low, although it has been suggested that the system of spontaneous reporting under-reports the true incidence of serious adverse reactions by a factor of at least 10. 2 Between 1983 and December 1999, 761 cases of TdP, of which 34 were fatal, were reported to the World Health Organization Drug Monitoring Centre by the member states. 3 The WHO data provide an insight into the incidence of TdP on the most commonly reported pro-arrhythmic drugs 3 (table 1).However, such a reporting system is undermined by the widely variable content and clinical information between different countries and sources.It is also compounded by various factors such as the patient's underlying disease, whether the adverse drug reaction is well known or has not been previously described, and the amount of attention paid by the medical community on a specific adverse drug reaction.In this article, we will review the risk of drug induced QT prolongation and/or TdP.