Myocardial electrophysiological, contractile and metabolic properties of hypertrophic cardiomyopathy: Insights from modelling

Hypertrophic cardiomyopathy (HCM) is characterised by cellular dysfunction, asymmetric left ventricular (LV) hypertrophy, ventricular arrhythmias and sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to investigate the mechanisms by which HCM alters electrophysiological activity, contractility and energy metabolism regulation at the single cell and organ levels. We developed a human ventricular, electromechanical, mitochondrial energetics (EMME) myocyte model incorporating electrophysiology, metabolism and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by a) remodelling of several ion channels and Ca²⁺ handling proteins arising from altered Ca²⁺ /calmodulin kinase 11 (CAMKlI) signaling pathways; and b) increased Ca²⁺ sensitivity of the myofilament proteins. Our simulation results showed energy metabolism was impaired, as indicated by a decreased phosphocreatine to ATP ratio (-9%) and there was energy expenditure beyond supply. 3D EMME human L V model simulation incorporating septal hypertrophy showed ejection fraction was not significantly altered but contractile efficiency was reduced.