Cell therapy approaches for treatment of bradyarrhythmias

Abstract In the myocardium, impulse generation is initiated in the sinoatrial node (SAN) which represents the dominant pacemaker. Therefore, the SAN determines the rhythm and rate of the heartbeat. This crucial function is based on spontaneous diastolic depolarization which generates electrical impulses that rely on ion channels that are connected by molecular, electrophysiological, and histological processes. Overall, these impulses permit automaticity of the cells forming the cardiac conduction system. Subsequently, the action potentials (AP) initiated within the SAN are propagated via the atrioventricular node (AVN), the bundles and the Purkinje fibers to the ventricles by electrical coupling of the various myocyte subtypes. In a healthy heart, impulse initiation and conduction are safe and very effective, properly responding to a person’s physiological needs. SAN dysfunction can lead to severe bradycardia with obstructive and life-threatening consequences. Failure of normal pacing due to pathological SAN or AVN typically requires implantation of an electronic pacemaker. Over the last few decades, pacemaker implantations have increased worldwide, primarily because of aging populations, leading to growing numbers of patients with degenerative heart disease. Modern electronic pacemakers are very reliable, but still have disadvantages, such as restricted battery life, hazards from infections and metal allergies, lack of autonomic responsiveness to physiological needs, and interference with other electronic devices. Biological pacemakers could help solve these problems, in the future. To this end, scientists are working on developing options based on cell and gene therapies, with the goal of recreating reliable biological pacemakers. This article discusses the state-of-the-art of these approaches, which have the potential to yield viable therapies for pacemaker dysfunction via forward stem cell programming and direct reprogramming. Tools for cell and gene vector delivery to restore biological pacing, as well as novel OMICS approaches to improve cell programming will be addressed.