In patients with a prior myocardial infarction who are at high risk for ventricular tachyarrhythmia, prophylactic therapy with an implanted defibrillator leads to improved survival as compared with conventional medical therapy.

Drug-induced long QT syndrome (LQTS) is a prevalent disorder of uncertain etiology that predisposes to sudden death. KCNE2 encodes MinK-related peptide 1 (MiRP1), a subunit of the cardiac potassium channel IKr that has been associated previously with inherited LQTS. Here, we examine KCNE2 in 98 patients with drug-induced LQTS, identifying three individuals with sporadic mutations and a patient with sulfamethoxazole-associated LQTS who carried a single-nucleotide polymorphism (SNP) found in Ϸ1.6% of the general population. While mutant channels showed diminished potassium flux at baseline and wild-type drug sensitivity, channels with the SNP were normal at baseline but inhibited by sulfamethoxazole at therapeutic levels that did not affect wild-type channels. We conclude that allelic variants of MiRP1 contribute to a significant fraction of cases of drug-induced LQTS through multiple mechanisms and that common sequence variations that increase the risk of life-threatening drug reactions can be clinically silent before drug exposure.MiRP1 ͉ LQTS ͉ SNP ͉ Bactrim ͉ sulfamethoxazole I nherited long QT syndrome (LQTS) is an uncommon cardiac arrhythmia that predisposes to torsades de pointes (TdP), ventricular fibrillation, and sudden death (1-4). The molecular basis for LQTS is known: delayed repolarization of the myocardium prolongs the cardiac action potential increasing the QT interval measured on the surface electrocardiogram. Mutations in five ion channel genes cause the majority of cases of inherited LQTS. LQTS mutations in SCN5A increase activity of the sodium channel that depolarizes the myocardium to initiate the cardiac action potential (5); LQTS mutations in KCNE1 or KvLQT1 (encoding subunits of I Ks channels) and KCNE2 or HERG (encoding subunits of I Kr channels) diminish potassium fluxes that repolarize the heart to end each beat (6-9).Acquired LQTS is a common disorder caused by drugs and metabolic abnormalities. The risk for acquired LQTS increases when factors that decrease potassium flux act concurrently to impair the ability of the myocardium to repolarize. Wellrecognized conditions that diminish ''repolarization reserve'' include female gender, hypokalemia, and drugs that inhibit cardiac potassium channels (10). Several lines of evidence suggest that patients with drug-induced LQTS have an underlying predisposition to dysrrhythmia. The QT interval measured before drug exposure tends to be longer in patients who later develop drug-induced LQTS than in individuals who receive the same agent safely (11, 12). Moreover, sporadic mutations have been identified in patients with drug-induced TdP (9,13,14). Thus, we demonstrated previously that patients with ''acquired'' LQTS can have a genetic predisposition to arrhythmia because of mutation in the MinK-related peptide 1 (MiRP1) subunit of their I Kr potassium channels (9). In that study, a woman with clarithromycin-induced TdP was found to carry a sporadic missense mutation in KCNE2; channels formed with the altered subunit (Q9E-MiRP1) were abnormal at bas...

Traditional right ventricular (RV) pacing for the management of bradyarrhythmias has been pursued successfully for decades, although there remains debate regarding optimal pacing site with respect to both hemodynamic and clinical outcomes. The deleterious effects of long-term RV apical pacing have been well recognized. This has generated interest in approaches providing more physiological stimulation, namely, His bundle pacing (HBP). This paper reviews the anatomy of the His bundle, early clinical observations, and current approaches to permanent HBP. By stimulating the His-Purkinje network, HBP engages electrical activation of both ventricles and may avoid marked dyssynchrony. Recent studies have also demonstrated the potential of HBP in patients with underlying left bundle branch block and cardiomyopathy. HBP holds promise as an attractive mode to achieve physiological pacing. Widespread adaptation of this technique is dependent on enhancements in technology, as well as further validation of efficacy in large randomized clinical trials.