National Cheng Kung University Tainan, Taiwan (Republic of China)
Abstract: Recent studies suggest that maternal SARS-CoV-2 infection may influence the cardiovascular health of infants, potentially contributing to heart disease after infection as well as impacting early cardiac development. Human pluripotent stem cell–derived cardiomyocytes (PSC-CMs), which retain an immature phenotype resembling fetal/neonatal heart cells, offer a valuable model to investigate how the spike protein of SARS-CoV-2 might alter cardiac function. Here, we employed lentiviral pseudoviruses encoding spike proteins from the Wuhan, Delta, and Omicron strains of SARS-CoV-2 to elucidate spike-mediated effects in human embryonic stem cell–derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). After a 24-hour exposure, transcriptomic profiling revealed dysregulation of calcium-handling and ion channel genes, hinting at compromised electrophysiological stability. Functional assays demonstrated irregular contractions and enhanced beat-to-beat oscillations, indicating a proarrhythmic risk. Fluorescence microscopy further showed sarcomeric disarray and syncytia formation, consistent with structural remodeling. Notably, each spike variant triggered distinct disruptions in calcium homeostasis, underscoring the variant-specific nature of spike protein pathogenicity. By using lentiviral pseudoviruses to isolate the effects of the spike protein, our findings offer insights into how SARS-CoV-2 variants can directly affect fetal/neonatal-like cardiomyocytes and potentially contribute to both post-infection heart disease and developmental cardiac abnormalities. These results underscore the utility of PSC-CMs in modeling virus-induced cardiac dysfunction within a developmentally relevant context, ultimately informing strategies to mitigate cardiovascular risks in young populations, including those born to SARS-CoV-2–infected mothers.
