Contemporary Reviews in Cardiovascular Medicine Drug-Induced Arrhythmia

Prolongation of the QTc interval has been associated with proarrhythmia resulting from a potentially fatal form of polymorphic ventricular tachycardia called torsades de pointes (TdP). Genetic forms of the long-QT syndrome (LQTS) associated with high arrhythmic risk have been causally related to mutations in ion channels responsible for the cardiac action potential; genetic factors associated with milder degrees of QTc prolongation and arrhythmic risk have also been described. Acquired forms of QTc prolongation and proarrhythmia, particularly related to drug therapy, are frequently related to drug effects on the same ion channels involved in genetic forms of LQTS. As is true for genetic forms of LQTS, there is a wide spectrum of potential drug effects on the QTc interval ranging from trivial to potentially lethal. Drug-induced QTc prolongation is a complicated phenomenon related not just to the properties or dose of a particular drug but also to drug-drug interactions and a variety of patient factors, including age, gender, the presence and severity of underlying heart disease, and genetic predisposition. Additionally, drug effects on other ion channels, including blockade of sodium channels (causing prolongation of the QRS interval rather than the QTc interval), are an important cause of drug-induced proarrhythmia. The purpose of this review is to summarize the available data related to acquired forms of LQTS, with particular focus on drug-related LQTS and proarrhythmia. A brief summary is presented here of genetic LQTS because the relevant genes and proteins form the basis for an understanding of the causes of acquired LQTS, and in any given patient, the QTc is determined by genetic, substrate, and environmental factors. Emphasis is placed on practical strategies for clinicians, with the goal of minimizing the risk of dangerous proarrhythmia related to the use of both cardiac and noncardiac drugs with the potential for QTc prolongation. Genetic Basis of LQTS Genetic forms of the LQTS can be associated with a markedly increased risk of TdP and sudden cardiac death (SCD), and the mechanisms elucidated through analysis of genetic LQTS have provided considerable insight into acquired forms of LQTS. Genetic defects associated with profound increases in QTc have frequently been associated with either a reduction in an outward potassium current (via IKs: LQT1 and LQT5; or via IKr: LQT2 and LQT6) or augmentation of an inward sodium current (INa: LQT3) or calcium current. These classic forms of LQTS are associated with different T-wave morphologies and arrhythmic triggers based on the particular form of LQTS, although substantial overlap exists.1 Other variants of genetic LQTS have been associated with proteins that affect trafficking or function of ion channels such as ankyrin 2 (LQT4) or a variety of proteins that affect ion channel kinetics (reviewed elsewhere2,3). Additionally, the genetic short-QT syndrome has been described as being related to gain-of-function mutations in potassium channels or loss-of-function mutations in calcium channels.4–6 Like LQTS, the short-QT syndrome can also be associated with substantial arrhythmic risk. Classic forms of familial LQTS associated with (often) marked prolongation of the QTc interval and arrhythmic risk are relatively rare disorders, even in aggregate. Interestingly, however, recent studies suggest that a substantial proportion of victims of previously unexplained SCD may harbor mutations in proteins encoding ion channels associated with the genetic LQTS. 7–9 Furthermore, missense mutations in genes associated with the LQTS (encoding cardiac sodium and potassium channels) are relatively common in the general population, although the functional impact of most of these mutations is currently unknown. 3,10 Relatively common genetic variants in genes encoding cardiac ion channels have been associated with QTc prolongation, 11–14 and QTc effects have been noted to be associated with mutations in genes not associated with classic forms of LQTS such as NOS1AP.15 Genetic forms of the LQTS therefore represent a wide spectrum of diseases. The classic but relatively rare genetic LQTS may be associated with substantial QTc prolongation and arrhythmic risk, even in the absence of additional risk amplifiers such as the use of QTc-lengthening drugs (although the risk of arrhythmia in the classic forms of genetic LQTS can be markedly increased by the addition of these risk amplifiers). LQTS may exhibit incomplete penetrance based on standard ECG criteria, with a reported penetrance of 25% for gene carriers of classic LQTS mutations and a sensitivity of 38% for conventional clinical diagnostic criteria in detecting these mutations in 1 study of familial LQTS. 16 Patients with classic LQTS mutations but normal or borderline QTc intervals are generally much more susceptible to QTcprolonging medications compared with the general population, yet they may be difficult to detect before drug exposure.