Exercise‐Based Cardiac Rehabilitation Improves Left Ventricular Dysfunction, Mitophagy, and Oxidative Stress Postmyocardial Infarction

<b>Aim:</b> Left ventricular dysfunction, disturbed mitophagy, and persistent oxidative stress after myocardial infarction (MI) are critical drivers of myocardial injury and cardiac remodeling. Exercise-based cardiac rehabilitation (CR) is a cornerstone of post-MI treatment and management, yet its mechanistic effects on myocardial repair remain incompletely elucidated. This study aimed to the effect of exercise-based CR on the left ventricular dysfunction, mitophagy, and oxidative stress post-MI. <b>Methods:</b> Mendelian randomization analysis elucidated causal relationship between six physical activities and MI. Subsequently, 70 MI patients were randomized to control or exercise-based CR groups (moderate-to-vigorous physical activity intensity, 3 days/week, 10-50 min/day, 12 weeks); left ventricular function, cardiopulmonary function, and SF-36 quality of life scale were assessed pre-/postintervention using standardized protocols. Additionally, 21 rats were allocated to Sham, MI, or MI + treadmill running groups (high-intensity interval exercise training, 5 days/week, 30-50 min/day, 10-25 m/min, 4 weeks); left ventricular function, mitophagy, and oxidative stress were detected postintervention. <b>Results:</b> Genetically predicted moderate-to-vigorous intensity physical activity was significantly associated with lower risk of MI (IVW OR = 0.66, 95% CI: 0.54-0.81), with no causal links for other activities. Critically, clinical and animal studies demonstrated that exercise-based CR improved left ventricular systolic function (LVEF) after MI. Four-week exercise in MI rats enhanced mitophagy levels (LC3, FUNDC1, PINK1, and Parkin) and attenuated oxidative injury (MDA, GSH, SOD2, and GPX4) post-MI. Additionally, exercise-based CR also improved cardiopulmonary function (peak VO₂/kg, peakVO₂/pred%, and MET) in patients with MI and ameliorated mitochondrial damage in MI rats. However, GLS, secondary cardiopulmonary parameters (Wmax, HRR1min, peakVO₂/HR, and peakVO₂/HRpred%), and SF-36 (PCS and MCS) showed no significant changes, which may be associated with shorter duration of exercise intervention. <b>Conclusion:</b> Exercise-based CR significantly ameliorated left ventricular dysfunction, enhanced mitophagy levels, and attenuated oxidative stress post-MI, establishing its role in critical pathological mechanisms. Future studies should validate long-term sustainability of exercise-based CR and explore the interaction mechanism between mitophagy and oxidative stress in cardiac remodeling, providing personalized and precise exercise protocols for people at high risk of exercise.