Human in silico clinical trials in post myocardial infarction: mechanistic investigations into phenotypic electromechanical variability and response to treatment (360G-Wellcome-214290_Z_18_Z)

The population of patients with ventricular damage following survival of myocardial infarction (MI) is rising, owing to the increased prevalence of coronary artery disease and improvements in treatment. Post-MI patients suffer from permanent myocardial damage, and this increases risk of sudden death and cardiac mechanical dysfunction, with potential progression to heart failure. Arrhythmic risk stratification is conducted using ventricular ejection fraction, a mechanical marker. However, a significant number of sudden deaths occur in patients with relatively preserved ejection fraction, and patients with low ejection fraction often do not experience serious arrhythmic events. In this Fellowship, I propose to unravel key mechanisms explaining phenotypic variability in post-MI, focusing on the interplay between electrophysiological and mechanical ventricular abnormalities, and their modulation by pharmacological interventions. I propose a Systems Biomedicine approach based on human ventricular computer modelling and simulation of coupled mechanical and electrophysiological function, in iteration with experimental and clinical studies. We will construct populations of thousands of human ventricular electromechanical post-MI models from ionic to whole-organ dynamics, calibrated and validated using rich experimental and clinical datasets. We will conduct in silico clinical trials to dissect key factors determining arrhythmic risk and degree of mechanical dysfunction post-MI, and effects of pharmacological interventions.