UC Davis

Microgravity has been associated with increased arrhythmia risk in astronauts, yet the mechanisms underlying this vulnerability remain poorly defined. Experimental evidence suggests 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 in microgravity conditions. We adapted a well-established model of the rabbit ventricular myocyte action potential to incorporate experimentally reported microgravity-induced remodeling of L-type Ca2+ channels (LTCCs), ryanodine receptors (RyRs), sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pumps, and Na+/K+ pumps. We then quantified the effects of microgravity remodeling on cardiac alternans. 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 (AP) and Ca2+ transient alternans, and that these changes arise primarily from increased Ca2+ handling instabilities. After isolating the contributions of individual microgravity effects to alternans risk, we found that the remodeling of the LTCC and RyR played a predominant role in mediating the proarrhythmic effects. Our model contributes to understanding the molecular underpinnings of microgravity-induced arrhythmia and provides a platform to evaluate the efficacy of various interventions on heart health. This can accelerate the development and screening of drug strategies to safeguard astronauts’ cardiovascular health, improving the resulting medical outcomes.