SARS‐CoV‐2 Spike Protein‐Mediated Cardiac Dysfunction: Structural Abnormalities, Impaired Calcium Dynamics, and Gene Expression Changes in Human Stem Cell‐Derived Cardiomyocytes

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has resulted in more than 7.1 million deaths worldwide since 2019 and is increasingly recognized for its cardiovascular complications beyond respiratory disease. Growing evidence suggests that the SARS-CoV-2 spike protein itself, present during infection or after vaccination, may directly contribute to cardiac dysfunction, including myocarditis, through interaction with angiotensin-converting enzyme 2 (ACE2) receptors expressed in cardiomyocytes. To investigate these effects, we established a lentiviral-based SARS-CoV-2 pseudovirus system expressing spike proteins from the Wuhan and Delta variants and examined their impact on human embryonic stem cell-derived cardiomyocytes (ESC-CMs). Exposure to pseudovirus resulted in significant increases in sarcomere length and promoted syncytium formation in ESC-CMs. Moreover, infection with either Wuhan or Delta spike pseudoviruses caused marked early disturbances in intracellular calcium transient dynamics as early as 1.5 hours post-infection, with partial recovery observed by 24 hours. Transcriptomic analyses further revealed significant dysregulation of key cardiac-related genes involved in cell junction organization, structural integrity, ion channel function, and calcium handling. Together, these findings demonstrate the utility of a lentiviral pseudovirus platform for modeling SARS-CoV-2-induced cardiac injury and highlight a direct pathogenic role of the spike protein in cardiac structural, functional, and molecular abnormalities.