Mechanisms of hypoxia and contractile dysfunction in ischemia/reperfusion in hiPSC cardiomyocytes: an in silico study.

Interconnected mechanisms of ischemia-reperfusion (I-R) has increased the interest in I-R in vitro experiments using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We developed a whole-cell computational model of hiPSC-CMs including the electromechanics, a metabolite-sensitive sarcoplasmic reticulum Ca2+-ATPase (SERCA), and an oxygen dynamics formulation to investigate I-R mechanisms. Moreover, we simulated the effect and action mechanism of Levosimendan (LEVO) that recently showed promising anti-arrhythmic effects in hiPSC-CMs in hypoxia. The model was validated using hiPSC-CM and in vitro animal data. The role of SERCA in causing relaxation dysfunction in I-R was anticipated to be comparable to its function in sepsis-induced heart failure. Drug simulations showed that LEVO counteracts the relaxation dysfunction by utilizing a particular Ca2+ sensitizing mechanism involving Ca2+ bound troponin C and Ca2+ flux to the myofilament, rather than inhibiting SERCA phosphorylation. The model demonstrates extensive characterization and promise for drug development, making it suitable for evaluating ischemia-reperfusion therapy strategies based on the changing levels of cardiac metabolites, oxygen, and molecular pathways.