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Abstract
Background: Cardiac arrhythmias, heart failure, and myocarditis are common symptoms associated with coronavirus 2 (SARS-CoV-2) infection. The cytopathic effect of SARS-CoV-2 is initiated by spike protein (S-protein) binding to the ACE2 receptor. However, cellular mechanisms of SARS-CoV-2 causing cardiac complications, particularly in a subset of the population such as diabetic patients, remain unclear. Aims: To determine electrophysiological cytopathic effects of SARS-CoV-2 S-protein in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and Results: CMs were differentiated from WTC-11, then re-plated on 48-well microelectrode array (MEA) plates and cultured under normal or hyperglycemic conditions (Glucose 5 mM (NG), and Glucose 20 mM (HG)) for three days. These HiPSC-CMs were treated with recombinant S-protein with or without insulin supplementation. Cardiac modules in AxIS MEA program were used to acquire and analyze electric and contractile functions. Beat period and field potential duration were significantly prolonged, while conductance velocity and spike slope were accelerated in HG without insulin compared to that in HG with insulin (p<0.05). S-protein-induced perturbations in local extracellular action potential (LEAP) matrices (e.g., LPD30, 50, 90) and Contractility matrices in HG were mitigated by insulin treatment. Higher concentration S-protein induced perturbations in normal hiPSC-CMs (NG+insulin). One day after S-protein treatment, CM functions appeared comparable to the pretreatment state, although changes in some electro-contractile matrices persisted. Conclusion: These results demonstrate SARS-CoV-2 viral structural protein can induce acute electrophysiological dysfunctions in hiPSC-CMs, which is influenced by glucose level. This establishes a new model for dissecting the mechanism of cardiac complications in viral infection.
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