Sodium current reduction unmasks a structure-dependent substrate for arrhythmogenesis in the normal ventricles

Organ-scale arrhythmogenic consequences of source-sink mismatch caused by impaired excitability remain unknown, hindering the understanding of pathophysiology in disease states like Brugada syndrome and ischemia. We sought to determine whether sodium current (INa) reduction in the structurally normal heart unmasks a regionally heterogeneous substrate for the induction of sustained arrhythmia by premature ventricular contractions (PVCs). We conducted simulations in rabbit ventricular computer models with 930 unique combinations of PVC location (10 sites) and coupling interval (250-400 ms), INa reduction (30 or 40% of normal levels), and post-PVC sinus rhythm (arrested or persistent). Geometric characteristics and source-sink mismatch were quantitatively analyzed by calculating ventricular wall thickness and a newly formulated 3D safety factor (SF), respectively. Reducing INa to 30% of its normal level created a substrate for sustained arrhythmia induction by establishing large regions of critical source-sink mismatch (SF