Key result
SARS-CoV-2 spike protein induces hiPSC-CM dysfunction worsened by hyperglycemia but alleviated by ROCK and Caspase-3 inhibitors.
Why the study?
Arrhythmias, cardiomyopathy, and myocarditis complicate SARS-CoV-2 infection especially in patients with diabetes, but the underlying cellular and molecular mechanisms remain elusive.
SARS-CoV-2 spike protein induces arrhythmic and contractile dysfunction in hiPSC-CMs under hyperglycemic conditions, which can be mitigated by ROCK and Caspase-3 inhibitors.
Signaling gaps in SARS-CoV-2/DM hearts may underlie arrhythmias; leaves open targeted mechanistic validation before clinical translation.
Background: Arrhythmias, cardiomyopathy, and inflammatory myocarditis are complications occur in cases of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), more so in infected patients having comorbidity such as diabetes mellitus. However, the underlying pathological cellular and molecular mechanisms remains elusive despite advances in this field. Objective: To identify signaling perturbances in SARS-CoV-2 and DM patient heart cells, and assess the electrophysiological cytopathic effects of SARS-CoV-2 spike protein (S-protein) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and Results: We utilized GEO’s bulk and single-nucleus RNA-seq dataset for control or heart failure patients with or without diabetes, COVID-19 patient hearts or hiPSC-CM infected with SARS-CoV-2. Integrated transcriptomic analyses revealed the differentially expressed genes (DEGs) between groups enriched in signaling pathways of inflammation, apoptosis, and cardiac contractility dysfunction. Compared to control (5 mM glucose), mimicked hyperglycemia (HG; 20 mM glucose) caused more profound perturbations in S-protein-treated WTC-11 hiPSC-CMs, including changes in field potential and beat matrices, contractility, and propagation of cardiac syncytium as measured using a microelectrode array (MEA) system. Chroman-1 (0.1 nM)+AcDEVD-CHO (2 uM) improved electrical-contractile functions and reduced apoptotic gene expressions in hiPSC-CMs transfected with S-protein plasmid and cultured in HG. Conclusion: S-protein induces inflammatory and apoptotic signaling cascades leading to arrhythmic and contractile dysfunction in hiPSC-CMs, which can be alleviated by ROCK and Caspase-3 inhibitors. Funding Supports: NIH U54MD007601, P20GM113134, 5P20GM125526, and U24MD015970 (to Y. Zhang) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
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Derderian et al. (2026) studied SARS-CoV-2 cardiomyopathy and arrhythmias. SARS-CoV-2 spike protein and hyperglycemia vs. Control (5 mM glucose) was evaluated on Changes in field potential, beat matrices, contractility, and propagation of cardiac syncytium. SARS-CoV-2 spike protein induced arrhythmic and contractile dysfunction in hiPSC-CMs, which was exacerbated by hyperglycemia and alleviated by ROCK and Caspase-3 inhibitors.
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