Unravelling the Mechanistic Links between Pro-Arrhythmia and Mechanical Function

Sudden cardiac death (SCD) from ventricular arrhythmias is a leading cause of mortality. Accurate arrhythmic risk stratification is vital for preventative clinical interventions. Ejection fraction (EF) is the primary metric used, but its accuracy is under debate, as many SCD cases exhibit preserved EF. Thus, identifying clear links between EF and arrhythmic risk is critical. Here, as a step forward, we investigate the ionic processes determining cellular pro-arrhythmic mechanisms and their relationship with active tension. A population of 2500 human ventricular electromechanical cellular models was created, and stimulated to produce pro-arrhythmic behaviour. We quantified their susceptibility to develop early afterdepolarizations (EADs) and action potential duration (APD) shortening, as key arrhythmic markers. The relationship between both arrhythmic markers and tension amplitude was found to be highly dependent on ionic mechanism. Variability in L-type calcium current was the primary determinant of active tension and arrhythmia susceptibility, alongside SERCA and hERG expression. Models with low tension could exhibit both high and low EAD susceptibility. APD shortening, however, displayed a weak positive correlation with active tension amplitude.