Abstract 13565: Superoxide Dismutase-loaded Nanoparticles Attenuate Myocardial Ischemia-Reperfusion Injury and Protect Against Chronic Adverse Ventricular Remodeling

Introduction: Revascularization relieves myocardial ischemia but induces additional reperfusion injury by oxidative stress. Superoxide dismutase (SOD) is a potent antioxidant with preclinical promise in reducing reperfusion injury but is not well retained within the myocardium. Hypothesis: Use of SOD-encapsulated nanoparticles (NP-SOD) will improve SOD retention and preserve cardiac function in a rat model of myocardial ischemia-reperfusion (I/R) injury. Methods: Ischemia was maintained for 60 minutes via occlusion of the left anterior descending artery (LAD). Immediately prior to reperfusion, intramyocardial injections of NP-SOD, free SOD or phosphate buffered saline (PBS) were administered along the border of ischemic myocardium. Acute injury was assessed 3 hours post-reperfusion (n=8 per group), and chronic injury at 4 weeks (n=12). Hemodynamics were measured by echocardiography and pressure-volume loops. Acute and chronic injury were examined histologically. Protein isolates at 3 hours measured mediators of cell-death. Intramyocardial enzyme retention analysis was performed by injecting NP or free fluorescent-tagged SOD and explanting hearts for imaging at 0, 24 and 72 hours (n=4 per group). Results: Intramyocardial SOD retention was 25% greater in NP-SOD than free SOD at 24 hours (p<0.01) and 78% greater at 72 hours (p<0.01). NP-SOD exhibited improved ventricular function by ejection fraction at 4 weeks (64%) compared to free SOD (51%; p<0.01) and PBS (43%; p<0.01). Cardiac output, stroke volume and end-systolic elastance were greater in NP-SOD. Histology at 28 days demonstrated 54% less macroscopic fibrosis and 85% less microscopic collagen deposition in NP-SOD compared to PBS, and 33/79% compared to free SOD (all p<0.05). Quantifying RIPK3 protein levels in ‘at risk’ myocardium at 3 hours demonstrated 2.5-fold reduced upstream necrosome activation. Conclusions: NP-SOD provides prolonged enzyme retention within the myocardium. Intramyocardial NP-SOD administration prior to reperfusion attenuates acute myocardial injury and protects against chronic adverse ventricular remodeling. SOD acts by downregulating necrosis. These findings suggest potential for NP-SOD based therapy in mitigating myocardial I/R injury.