Abstract
Myocardial ischemia, arising from severe blockages in coronary arteries, poses a significant global health risk due to its potential to cause arrhythmia and heart failure, often leading to sudden cardiac death. During acute myocardial ischemia, profound changes occur in cardiac electrophysiology and anatomy, influencing action potential morphology and propagation, which increased susceptibility to arrhythmias. Sex differences play a critical role in myocardial ischemia and arrhythmogenesis. Females exhibit distinct genetic and hormonal influences on ion channel expression and cardiac function, affecting susceptibility to arrhythmias like Torsade de Pointes. Using the O'Hara-Rudy dynamic (ORd) model, this study shows that females are more likely than males to exhibit cardiac alternans (2:2), a periodic variation in action potential duration between consecutive heartbeats, as well as 2:1 arrhythmic behaviors-characterized by inexcitability in the even beats-under ischemic conditions. Additionally, hormones further exacerbate these gender differences. Moreover, females show a higher propensity than males to terminate 2:2 and 2:1 arrhythmic responses during ischemia treatment. This manuscript aims to uncover sex-specific disparities in electrophysiological responses and drug reactions during myocardial ischemia using the optimized ORd model. These findings underscore the importance of considering sex-specific factors in cardiovascular research and clinical practice.