Effects of acute myocardial ischemia in mathematical models of heterogeneous myocardium

It has been shown that isolated sub-epicardial (EPI) and sub-endocardial (ENDO) myocytes have distinct electrical and mechanical properties in normal heart ventricle and differently respond to interventions. We utilized our electromechanical models of EPI and ENDO myocytes to simulate their responses to the acute ischemia and to predict effects of cell electromechanical coupling within a heterogeneous 1D tissue model. Intracellular effects of acute ischemia were simulated via a combination of two hypoxic consequences - a time-dependent increase in [K⁺]o and a reduction in [ATP]i which affected the activity of ATP-sensitive and other potassium channels. In cellular models we showed that the higher sensitivity of ATP -sensitive potassium currents provided for a greater action potential (AP) shortening and force decrease in EPI versus ENDO cells under hypoxia. In a 1D heterogeneous myocardial strand comprising segments of EPI, ENDO and intermediate cell type, the hypoxic consequences also resulted in a decrease in the force production, while the dispersion of repolarisation between the coupled cells increased significantly above the difference in AP duration in uncoupled cells. Our modeling results suggest significant increase in the transmural electrical and mechanical heterogeneity between isolated cells under hypoxia, which further increases due to cell interactions within the tissue creating substrate for arrhythmia.