ISHNE zyxw Guidelines for Electrocardiographic Evaluation of Drug-related QT Prolongation and Other Alterations in Ventricular Repolarization: Task Force Summary zyxw A Report of the Tusk Force of the International Society for Holter and Noninvasive Electrocurdiology (ISHNE) zy , Committee on Ventricular Repolarization" Arthur J. Moss, M.D., Chair, Wojciech Zareba, M.D., Ph.D, Jesaia Benhorin, M.D., Jean-Philippe Couderc, Ph.D., Harold Kennedy, M.D., MPH, Emanuela Locati-Heilbron, M.D., Ph.D., and Pierre Maison-Blanche, M.D. 1. INTRODUCTION Quinidine has been used since the beginning of the twentieth century for the conversion of atrial fibrillation to sinus rhythm and for the control of ventricular arrhythmias. Although effective as an antiarrhythmic agent, quinidine is known to pro- long the electrocardiographic QT interval and is associated with unexplained syncope and sudden cardiac death. This drug is the prototype of drug- induced QT prolongation. During the past decade, mutations in several ion channel genes (KVLQT1, HERG, SCN5A, KCNE 1, and KCNE2) have been identified that cause QT prolongation and the hereditary Long QT Syn- drome (LQTS).1-5 LQTS gene mutations cause alter- ations in the ion channel proteins with altered po- tassium or sodium currents that prolong ventricular repolarization. The increased repolar- ization interval is associated with an increased probability of episodic polymorphic ventricular tachycardia (torsades de pointes [TdP]) that is man- ifest as syncope and arrhythmic sudden death. This new knowledge about ionic channel dysfunction occurred almost simultaneously with the clinical recognition of the occurrence of sudden death in otherwise healthy individuals who were taking a new antihistamine, terfenadine, together with an azole antifungal drug.6 Investigations revealed that terfenadine, at high blood concentrations, blocks the HERG potassium repolarization channel with resultant secondary QT prolongation and a propen- sity to malignant ventricular tachyarrhythmias. During the past 5 years, a number of approved and marketed drugs, both cardiovascular and non- cardiovascular agents, have been associated with QT interval prolongation, TdP, and sudden cardiac death.7 Almost all of the noncardiovascular drugs associated with QT prolongation adversely affect the HERG channel. Several of these drugs have been removed from the market or have had restric- tive labeling. This drug-induced QT prolongation problem is of considerable concern to drug regula- tory agencies at the national and international zy "This document, "ISHNE Guidelines for Electrocardiographic Evaluation o f Drug-related QT Prolongation and Other Alterations zy in Ventricular Repolarization: Task Force Suniniary " was developed by the ISHNE Task Force of the Committee on Ventricular Repolarization independent of any input from regulatory agencies, pharmaceutical companies, or device manufacturers. Address for correspondence: Arthur J. zyxwvutsrqpon Moss, M. D., Director, Heart Research Follow-up Program, Box 653, University of Rochester Medical Center, Rochester, New York 14642. Fax: 71 6-2 73-5283; E-niail: heartaimmheart. rochester.edu 333