In this foundational episode of the EP Edge Newsletter Podcast, we examine the scientific and engineering principles underlying pulsed field ablation (PFA), a transformative advance in catheter ablation for atrial fibrillation. Unlike radiofrequency or cryoablation, which rely on thermal injury, pulsed field ablation produces myocardial lesions through irreversible electroporation, a non-thermal mechanism that disrupts the cell membrane by applying precisely controlled electric fields. This represents a fundamental shift in ablation biology, where lesion formation is governed not by heat, but by transmembrane voltage thresholds, membrane destabilization, and controlled cellular injury. This episode traces the history of electroporation, from its origins in physics and industrial biotechnology to its adoption in oncology as a non-thermal tumor ablation modality and eventual translation into cardiac electrophysiology. We then explore the Engineering Trinity of pulsed field ablation—the waveform, catheter, and pulse generator—and how these components interact to determine lesion size, safety profile, tissue selectivity, and procedural effectiveness. Understanding this integrated engineering system is essential to interpreting differences between pulsed field ablation platforms and explains why voltage alone does not define lesion durability or procedural success. We also examine the cellular and molecular mechanisms of PFA lesion formation, including nanopore creation within the lipid bilayer, calcium influx, ATP depletion, mitochondrial dysfunction, and regulated cell death pathways. These membrane-driven injury mechanisms produce lesions that differ fundamentally from thermal ablation, preserving extracellular architecture while eliminating cardiomyocytes. This unique biology underlies one of the most important advantages of pulsed field ablation—tissue selectivity, where myocardial cells demonstrate greater susceptibility to irreversible electroporation compared with surrounding structures such as the esophagus, nerves, and vasculature, enabling effective ablation with reduced collateral injury risk. Finally, we review the histopathology and structural evolution of pulsed field ablation lesions, including sharply demarcated injury zones, preserved tissue scaffolding, and progressive fibrocellular remodeling over time. These distinctive lesion characteristics explain both the safety profile and long-term behavior of pulsed field ablation and provide critical insight into how electrophysiologists should interpret acute procedural endpoints and long-term durability. Full references, detailed discussion, figures, and visual summaries are available on the EP Edge Newsletter on LinkedIn, as well as the full long-form edition on Substack at epedge.substack.com. If you have questions, suggestions, or feedback, please email epedgecast@gmail.com
