Molecular therapies for bradyarrhythmias

Loss of sinoatrial node or atrioventricular node function may lead to severe bradyarrhythmias, requiring the implantation of an electronic pacemaker. These devices come with several short comings such as lack of adequate autonomic responsiveness, recurrent need for battery replacement, suboptimal cardiac output, and an increasing risk for device-related infections. To overcome these shortcomings, biological pacemakers are under development exploring the use of gene and cell therapy to restore cardiac pacing. In this setting, viral vectors may be used to introduce pacemaker function-related genes to augment spontaneous activity. Moreover, overexpression of transcription factors is being explored to transdifferentiate resident cells towards a pacemaker phenotype. Alternatively, several different stem cells are being investigated as a vehicle for pacemaker function-related genes, or as a source for cells that are being differentiated towards a pacemaker phenotype before transplantation. At present, robust proof-of-concept data has accumulated supporting the initiation of first-in-human testing of short-term biological pacemakers using adenoviral gene transfer. Ongoing research efforts focus on the optimization of long-term biological pacing comparing viral vector-mediated gene transfer to stem cell-based approaches.