Reversible and irreversible cardiac electroporation: Establishing the fundamentals to advance cardiac treatments- REINCARNATION

Cardiovascular diseases are the No. 1 healthcare challenge in the world, among which ischemic heart disease and atrial fibrillation are the most prevalent. Better treatment strategies are greatly needed to reduce the medical, economic, and social burden of these conditions. Electroporation (application of intense pulsed electric field) is showing tremendous potential for treatment of atrial fibrillation, enabling a safer and shorter treatment procedure compared with existing thermal ablation approaches. Moreover, recent pioneering studies provide evidence that electroporation can also be used as a nonviral vector for intracellular delivery of therapeutic nucleic acids that promote cardiac regeneration, potentially offering a way to cure the so-far incurable ischemic heart disease. For treatment of atrial fibrillation, electroporation must be irreversible, resulting in the death of cardiac muscle cells, to locally destroy (ablate) the arrhythmogenic cardiac tissue. Conversely, for treatment of ischemic heart disease electroporation must be reversible, meaning that the pulsed electric field transiently enhances cellular uptake of nucleic acids while the cells are able to survive and express the delivered transgene(s). Due to a lack of fundamental understanding of cardiac electroporation, there are currently no reliable methods able to ensure electroporation (ir)reversibility and the desired treatment outcome. This project is designed to decipher the biophysical mechanisms of cardiac electroporation at the molecular, cellular and tissue level as to develop methodologies that will enable optimal implementation of both irreversible and reversible electroporation. By combining bottom-up experiments in primary cardiac cells and tissue slices with computational modeling and advanced data analysis I will create the foundations needed to streamline further (pre)clinical research and realize the potential of electroporation to advance cardiac treatments.