Project Summary/Abstract For patients with symptomatic bradyarrhythmias, the current and only treatment is to implant an electronic pacemaker. Nearly all of the current research regarding rhythm management, including the leadless pacemakers, are invested in incremental progress in miniaturizing the indwelling devices. While the devices can provide stable and long-term pacing, the technology is far from ideal with problems inherent to the pacing technology and to foreign body issues due to the indwelling hardware. The problems can be severe for pediatric patients with congenital heart block as multiple and invasive surgeries are needed for replacement or revision of the implanted devices over the patients’ lifetime. Device-related acute problems are rising as well, include infections with the generator and/or leads wire, which require surgical removal of the entire implanted device. Bioengineered pacemakers, in contrast, transcend all current modalities by creating hardware-free cardiac pacing. We have previously demonstrated that minimally-invasive delivery of a natural transcription factor gene could pace the ventricles in both small and large animal models of complete heart block. The enabling technology is based on regenerative tissue engineering in which ordinary heart muscle is converted to specialized pacemaker tissue construct in situ with a focally delivered genetic construct. To advance this concept to clinical practice, two questions need to be answered: 1) how long can the bioengineered pacemaker retain its function, and 2) how well the bioengineered pacemaker be able to function in diseased myocardium since most patients with a pacemaker are also presented with underlying diseases in the myocardium. In this proposal, we will directly answer these questions by employing chronic heart block models that are known to elicit traits of heart failure, and examining the efficacy and durability of the gene therapy in a longitudinal study.