Keeping up the pace: developing gene and cell-based biological pacemakers

Abstract

Every year, around 18 million people die of cardiovascular diseases (CVD) worldwide. About 25-50% of CVD-related fatalities is related to sudden cardiac death, of which the majority are caused by lethal cardiac arrhythmias, including severe bradyarrhythmias. Bradyarrhythmias are characterized by a resting heartbeat below 60 beats per minute, often originating from age-related electrical and fibrotic remodeling of the cardiac pacemaker and conduction system. When conduction from the sinoatrial node and/or the atrioventricular node fails, pacing rates drop, leading to symptoms like dizziness, fatigue or fainting. Often, these patients require the implantation of an electronic pacemaker to maintain a normal heart rate. Around 1 million electronic pacemaker devices are implanted every year worldwide. While highly effective, electronic pacemakers come with their own set of limitations, such as the need for periodic battery replacements, risks of infection, and a limited device lifespan. To overcome these limitations, researchers aim to develop biological pacemakers. In this thesis, we have been exploring innovative approaches or the optimization of existing methodologies to further develop long-term biological pacing. We have brought new insights on two approaches: a cell-gene hybrid approach of gene therapy via a cardiac stem cell-based delivery platform or functional reengineering using AAV and lentiviruses.