Abstract 15495: Cardiac Structural, Electrical and Mechanical Remodeling Induced by Moderate Endurance Exercise is Sex-Dependent

Abstract

Introduction: While moderate endurance exercise has several health benefits, its effects on cardiac physiology are not fully characterized. By improving metabolism, exercise has been reported to improve cardiac function. However, metabolic changes are sex-specific which could suggest sex dependent modulation of cardiac function by exercise. Hypothesis: Cardiac function modulation by moderate endurance exercise is sex-specific. Methods: Male and female C57BL/6J mice were trained to run on a treadmill for 6 weeks. ECG and echocardiography were performed every two weeks. After 6 weeks of exercise, mice were euthanized and triple parametric optical mapping was performed on Langendorff perfused hearts to assess cardiac physiology. Arrhythmia inducibility was tested by programmed electrical stimulation. Left ventricular (LV) tissue was fixed and RNAseq was performed to determine exercise-induced changes in gene expression. Results: Exercise induced LV dilation in female mice alone as evidenced by increased LV diameter (2.2±0.2 vs 2.5±0.1 mm, p<0.001) and reduced LV wall thickness (1.2±0.1 vs 1.1±0.1 mm, p=0.03). Increased cardiac output (14±1.5 vs 16±1.7 ml/min, p=0.02) and stroke volume were also observed in female mice alone, suggesting improved cardiac mechanical function. Optical mapping revealed further sex differences in exercise-induced modulation of cardiac electrophysiology. In female exercised mice, action potential duration prolongation (59±2 vs 72±7 ms, p=0.01) and decreased voltage-calcium activation delay (-7±3 vs -2±2 ms, p=0.02) were recorded. In males, calcium decay constant was reduced suggesting prolonged calcium reuptake time. Arrhythmia incidences were increased in male and female exercised mice. Lastly, exercise induced changes in gene expression were associated with potassium and calcium ion channels and skeletal muscle genes in females, while metabolism related genes were altered in males. Conclusions: These findings suggest that moderate endurance exercise can significantly alter cardiac physiology. While some of these effects are beneficial like improved cardiac mechanical function, others are pro-arrhythmogenic. Most importantly, exercise-induced cardiac function modulation is sex-specific.