Mechanically Induced Ectopy via Stretch-Activated Cation-Nonselective Channels Is Caused by Local Tissue Deformation and Results in Ventricular Fibrillation if Triggered on the Repolarization Wave Edge (Commotio Cordis)

External chest impacts (commotio cordis) can cause mechanically induced premature ventricular excitation (PVE_M) and, rarely, ventricular fibrillation (VF). Because block of stretch-sensitive ATP-inactivated potassium channels curtailed VF occurrence in a porcine model of commotio cordis, VF has been suggested to arise from abnormal repolarization caused by stretch activation of potassium channels. Alternatively, VF could result from abnormal excitation by PVE_M, overlapping with normal repolarization-related electric heterogeneity. Here, we investigate mechanisms and determinants of PVE_M induction and its potential role in commotio cordis-induced VF. Methods and Results - Subcontusional mechanical stimuli were applied to isolated rabbit hearts during optical voltage mapping, combined with pharmacological block of ATP-inactivated potassium or stretch-activated cation-nonselective channels. We demonstrate that local mechanical stimulation reliably triggers PVE_M at the contact site, with inducibility predicted by local tissue indentation. PVE_M induction is diminished by pharmacological block of stretch-activated cation-nonselective channels. In hearts where electrocardiogram T waves involve a well-defined repolarization edge traversing the epicardium, PVE_M can reliably provoke VF if, and only if, the mechanical stimulation site overlaps the repolarization wave edge. In contrast, application of short-lived intraventricular pressure surges neither triggers PVE_M nor changes repolarization. ATP-inactivated potassium channel block has no effect on PVE_M inducibility per se, but shifts it to later time points by delaying repolarization and prolonging refractoriness. Conclusions - Local mechanical tissue deformation determines PVE_M induction via stretch-activation of cation-nonselective channels, with VF induction requiring PVE_M overlap with the trailing edge of a normal repolarization wave. This defines a narrow, subject-specific vulnerable window for commotio cordis-induced VF that exists both in time and in space.