Biophysical principles of pulsed field ablation

Pulsed field ablation (PFA) is emerging as a major advance in cardiac ablation because it induces irreversible electroporation rather than relying primarily on thermal injury. This article provides an overview of the core biophysical principles underlying PFA, focusing on concepts broadly relevant across systems and clinical applications. Externally applied pulsed electric fields interact with biological tissues and affect their transmembrane potential. When a critical threshold is exceeded, nanoscale aqueous pores form in the lipid bilayer, initiating electroporation. Depending on pulse amplitude, duration, number, repetition frequency, waveform, and tissue characteristics, membrane permeabilization may remain reversible or progress to irreversible injury and cell death. This article focuses on the fundamental biophysical principles of electroporation that underpin PFA. The article outlines how membrane charging, cell geometry, and tissue heterogeneity influence electric field distribution and biological response and explains why lesion formation depends on both field intensity and exposure conditions. It also summarizes the molecular basis of pore formation, the potential contribution of lipid peroxidation and membrane proteins, and the downstream processes linking sustained permeability to loss of homeostasis and delayed cell death. Finally, it places cardiac PFA in the broader context of electroporation-based therapies developed in oncology, drug delivery, and gene transfer, while highlighting the remaining need for cardiomyocyte-specific mechanistic evidence to further optimize safety, precision, and durability.