Microgravity increases arrhythmogenesis through poorly defined mechanisms. Studies suggest that cardiomyocytes under microgravity conditions exhibit changes in ion channel expression and function, mediated by alterations in biochemical signaling and oxidative stress, which could destabilize cardiac action potentials and increase arrhythmia vulnerability. Here, we aim to develop a model of cardiomyocyte electrophysiology that integrates experimental results to understand the mechanisms of heightened arrhythmia risk under microgravity. We used an established model of rabbit ventricular myocytes and modify it to reflect the experimentally reported microgravity-induced remodeling of L-type Ca 2+ channels (LTCCs), ryanodine receptors (RyRs), and SERCA pumps. We then quantified susceptibility to alternans by identifying the longest pacing period that induces alternans, and evaluated afterdepolarization susceptibility by determining the shortest pacing period at which early afterdepolarizations can arise. Using population-based modeling approaches, we assessed the robustness of microgravity-induced effects across a range of cellular phenotypes. We found that microgravity-induced changes lower the pacing threshold for the onset of action potential alternans, and that the increased action potential alternans under microgravity conditions are secondary to enhanced Ca 2+ transient alternans. Microgravity-induced changes also increase cellular susceptibility to afterdepolarizations. Population of models allowed us to systematically evaluate how each molecular alteration, and their combinations, modulate the threshold for alternans and predisposes cells to afterdepolarizations. Our model provides a stepping-stone to understanding the molecular underpinnings of microgravity-induced arrhythmia, thereby providing a tool to evaluate the efficacy of various interventions on heart health. This can accelerate the screening of various cardioprotective drugs that may be available for astronauts, improving the resulting medical outcomes. Future studies will couple our microgravity-remodeled ventricular myocyte model with a model of cardiovascular hemodynamics to evaluate the impact of multi-system interactions on arrhythmogenesis.
Bak et al. (Sun,) studied this question.