Electrophysiological effects of stretch-activated ion channels: a systematic computational characterization

Cardiac electrophysiology and mechanics are strongly interconnected. Their interaction is, among others, mediated by mechano-electric feedback through stretch-activated ion channels (SACs). The electrophysiological changes induced by SACs may contribute to arrhythmogenesis, but the precise SAC-induced electrophysiological changes remain incompletely understood. Here, we provide a systematic characterization of stretch effects through three distinguished SACs on cardiac electrophysiology using computational modelling. We implemented potassium-selective, calcium-selective and non-selective SACs in the Tomek-Rodriguez-O'Hara-Rudy model of human ventricular electrophysiology. The model was calibrated to experimental data from isolated cardiomyocytes undergoing stretch, considering inter-species differences, and disease-related remodelling of SACs. SAC-mediated effects on the action potential (AP) were analysed by varying stretch amplitude, application timing and/or duration. Afterdepolarizations of different amplitudes were observed with transient 10-ms stretch stimuli of 15-18% applied during phase 4, while stretch ≥18% during phase 4 elicited triggered APs. Longer stimuli shifted the threshold of AP trigger during phase 4 to lower amplitudes, while shorter stimuli increased it. Continuous stretch provoked electrophysiological remodelling. Furthermore, stretch shortened duration or changed morphology of a subsequent electrically evoked AP, and, if applied during a vulnerable time window with sufficient amplitude, prevented its occurrence because of stretch-induced modulation of sodium and L-type calcium channel gating. These effects were more pronounced with disease-related SAC remodelling due to increased stretch sensitivity of diseased hearts. We showed that SACs may induce afterdepolarizations and triggered activities, and prevent subsequent AP generation or change its morphology. These effects depend on cardiomyocyte stretch characteristics and disease-related SACs remodelling and may contribute to cardiac arrhythmogenesis. KEY POINTS: The interplay between cardiac electrophysiology and mechanics is mediated by mechano-electric feedback through stretch-activated ion channels (SACs). These channels may be pro-arrhythmic, but their precise effect on electrophysiology remains unclear. Here we present a systematic in silico characterization of stretch effects through three SACs by implementing inter-species differences as well as disease-related remodelling of SACs in a novel computational model of human ventricular cardiomyocyte electrophysiology. Our simulations showed that, at the cellular level, SACs may provoke electrophysiological remodelling, afterdepolarizations, triggered activities, change the morphology or shorten subsequent electrically evoked action potentials. The model further suggests that a vulnerable window exists in which stretch prevents the following electrically triggered beat occurrence. The pro-arrhythmic effects of stretch strongly depend on disease-related SAC remodelling as well as on stretch characteristics, such as amplitude, time of application and duration. Our study helps in understanding the role of stretch in cardiac arrhythmogenesis and revealing the underlying cellular mechanisms.