Gene Therapy for Cardiac Arrhythmias

The heart requires a steady rhythm and rate in order tofulfill its physiological role as the pump for the circulation. An excessively rapid heart rate (tachycardia) allowsinsufficient time for the mechanical events of ventricularemptying and filling. Cardiac output drops, the lungs become congested, and, in the extreme, the circulation collapses. An equally morbid chain of events ensues if theheart beats too slowly (bradycardia). Serious disturbances of cardiac rhythm, known as arrhythmias, afflictmore than 3 million Americans and account for > 400,000deaths annually (American Heart Association 2001).Current therapy has serious limitations: Antiarrhythmicdrugs can sometimes be effective, but their utility is limited by their propensity to create new, potentially fatal,arrhythmias while suppressing others (Coplen et al. 1990;Echt et al. 1991; Siebels et al. 1993; Waldo et al. 1996).Ablation of targeted tissue can readily cure simple wiringerrors, but it is less effective in treating more complex andcommon arrhythmias, such as atrial fibrillation or ventricular tachycardia (Richardson and Josephson 1999;Falk 2001). Implantable devices can serve as surrogatepacemakers to sustain heart rate, or as defibrillators totreat excessively rapid rhythms. Such devices are expensive, and implantation involves a number of acute andchronic risks (pulmonary collapse, bacterial infection,lead or generator failure; Bernstein and Parsonnet 2001).In short, arrhythmias are a serious threat of public healthproportions, and current treatment is inadequate. Giventhese limitations, we have begun to develop gene therapyas an alternative to conventional treatment...