In silico optimization of regenerative cell therapy in the infarcted human ventricles to mitigate arrhythmic burden

Myocardial infarction remains a frequent cause of heart failure and mortality. Cell therapy has shown promise in regenerating the damaged tissue, but delivered cells may beat spontaneously and produce ventricular arrhythmias, hindering clinical application. Here, we conducted multiscale computer simulations of the electrical activity of the infarcted human ventricles including the cardiac conduction system to identify and mitigate pro-arrhythmic mechanisms following cell delivery. Firstly, our simulations show how arrhythmic risk increases from before to after cell injection and further during the first two weeks post-delivery. Secondly, we suggest that concurrently targeting the funny current, the inward rectifier potassium current, the sodium-potassium pump current, and the rapid delayed outward rectifier potassium current may reduce automaticity and re-entry while maximizing calcium transient amplitude and thus contractility. Our study demonstrates how modeling and simulation enables the design of anti-arrhythmic strategies to improve therapy safety while preserving efficacy.