Gene Therapy for Cardiac Arrhythmias.

UNLABELLED: Morbidity and mortality caused by cardiac arrhythmias are a major issue in developed countries. Although conventional therapeutic options including pharmacological therapy, catheter ablation, and implantable devices have shown extensive advances to help reduce morbidity and mortality, a certain segment of these arrhythmias is still refractory to treatment. Therefore, gene therapy was explored as a potential additional or alternative therapy. Gene therapy trials have been developed for bradycardia, atrial fibrillation, and ventricular tachycardia. For the treatment of bradycardia, "biological pacemaker" attempts have been examined utilizing virus vectors to eliminate inward rectifier potassium current, or to overexpress the If current to convert quiescent myocytes into spontaneously active cells. These gene therapy attempts were soon followed by gene and cell hybrid therapies, and cell transplantation therapies utilizing pacemaker cells derived from stem cells. For the treatment of tachycardia, two major strategies were conceived: 1) to increase the effective refractory period, or 2) to recover the conduction velocity. The establishment of a selective and highly efficient gene transfer method would enable us to apply these concepts into the atrial fibrillation and ventricular tachycardia models. Both concepts resulted in an elimination or reduction of tachyarrhythmias in large animal models. Although these trials proved the concept of gene therapy as an adjuvant or alternative approach for the treatment of cardiac arrhythmias, the limitation of these studies is the long-term efficacy and safety. Consequently, an improvement in the gene delivery method is required to overcome these issues. KEY WORDS: Atrial fibrillation; Biological pacemaker; Gene therapy; Ion channel; Ventricular tachycardia.