Strenuous Exercise Elicits Sex-Specific Cardiovascular Maladaptation in a Rodent Model: Atrial Fibrillation and Vascular Risk in Females

Abstract Aims We aimed to investigate in a rodent model whether the detrimental cardiovascular effects of chronic strenuous exercise observed in males (atrial fibrillation, right ventricle and vascular maldaption) also occur in females. Methods Male and female Wistar rats underwent a 16-week high-intensity treadmill regimen or remained sedentary. Structural and functional cardiac parameters were assessed through echocardiography, electrocardiography, invasive hemodynamics, histology, molecular biology, and transcriptomic profiling. Results Exercise induced comparable physiological left ventricular remodeling in both sexes, alongside systolic and diastolic right ventricular dysfunction. Notably, females developed atrial fibrosis and exhibited a similar propensity for atrial fibrillation as their male counterparts. However, transcriptional remodeling in the atria was sex- and chamber-specific, with exercise-induced gene expression changes being more pronounced in the left atrium of females. In the vasculature, sedentary females displayed superior endothelial function, but unlike males, failed to improve after training. Furthermore, exercised females developed tunica media fibrosis without accompanying oxidative stress, suggesting divergent mechanisms of vascular injury. Plasma proteomic profiling at rest identified Ccl20 as a candidate biomarker of exercise-induced cardiovascular damage; acute post-exercise responses revealed numerous sex-specific alterations in circulating biomarkers, including those associated with inflammation and fibrosis. Conclusions Females engaged in regular strenuous endurance exercise are at an increased risk of atrial fibrillation and vascular harm, similar to males. However, underlying mechanisms and phenotypic expressions are strongly sex-dependent. These findings highlight the importance of incorporating sex-specific approaches into the diagnostic and prognostic evaluation of cardiovascular adaptations and risks associated with endurance training.