In silico study of the mechanisms of hypoxia and contractile dysfunction during ischemia and reperfusion of hiPSC cardiomyocytes

ABSTRACT Interconnected mechanisms of ischemia and reperfusion (IR) has increased the interest in IR 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 IR mechanisms. Moreover, we simulated the effect and action mechanism of levosimendan, which 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 IR was anticipated to be comparable to its function in sepsis-induced heart failure. Drug simulations showed that levosimendan 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 IR therapy strategies based on the changing levels of cardiac metabolites, oxygen and molecular pathways.


Fig. S2 .
Fig. S2.The effect of metabolite changes on the SERCA model behavior.SERCA pump rate (A) and Ca 2+ sensitivity (B).

Fig. S4 .
Fig. S4.Ca 2+ sensitivity of SERCA pump rate in response to different Kd,h coefficients.

Fig. S10 .
Fig. S10.Ca 2+ sensitivity of SERCA pump rate in response to different n h coefficients.

Fig. S11 .
Fig. S11.Ca 2+ sensitivity of normal and calibrated SERCA pump rates at different pH levels.

Fig. S12 .
Fig. S12.The model simulates effects of the ischemic insult in total and separated by mechanisms on oxygen consumption rate.Simulated action potentials (A) and oxygen dynamics in control and ischemic conditions: severities 1 and 2 (B), the effect of separate mechanisms of ischemia on oxygen consumption rate (C), and time-dependent behavior of oxygen consumption rate at severity 2 at the onset of ischemia (D).

Table S3 . Parameters used to model the effect of Levosimendan
(LEVO).INaF: fast Na + current, ICaL: L-type Ca 2+ current, IKr: Rapid delayed rectified K + current, Kon: rate constant for Ca 2+ to troponin C binding affinity