Spatiotemporal determinants of stretch-activated channel-induced re-entry in ventricular tissue: An in-silico study

Stretch-activated ion channels (SACs) mediate mechano-electric feedback in cardiomyocytes by coupling mechanical and electrical activity. While SACs activation can induce pro-arrhythmic effects at the cellular level, its impact on tissue-level arrhythmias remains poorly understood. Particularly unclear are the specific stretch characteristics that promote arrhythmogenesis, a knowledge gap largely due to limited experimental control over these parameters. We investigated how SACs activation affects excitation-wave propagation in simulated ventricular tissue and identified parameters promoting arrhythmias, with relevance to commotio cordis, in which a chest impact can trigger ventricular arrhythmias and sudden cardiac death. Our approach employed a validated human ventricular action potential model incorporating three types of SACs (non-selective, potassium-selective, and calcium-selective) applied to a two-dimensional tissue framework. Through systematic multiparameter analysis, we examined the effects of stretch stimulus parameters (amplitude, duration, timing), spatial characteristics (area, location, gradient), and tissue properties (size, conduction velocity). Our simulations revealed that re-entry arises from interactions between stretch-induced depolarization waves and repolarization tails of preceding excitation waves. Acute supra-threshold stretch (i.e., stretch able to trigger an action potential) initiated re-entries with increased likelihood when path lengths were longer and when stretched regions were closer to non-conducting borders oriented perpendicular to the line of block. Furthermore, stretch amplitude gradients attenuated pro-arrhythmic effects, while sustained sub-threshold stretch either reduced conduction velocity or caused conduction block. This in silico analysis demonstrates that tissue-level proarrhythmic effects of stretch depend on complex interactions between stretch stimulus characteristics, spatial parameters, and tissue properties.