Abstract 4366367: Cardioprotection in a Rat Model of Ischemic Injury by a Novel Anti-CD47 Fusion Protein

Abstract

Background: To prevent secondary necrosis and prolonged inflammation following cardiac ischemia, efficient clearance of dying cardiomyocytes must occur. CD47 is a “don’t eat me” signal that negatively modulates phagocyte-mediated clearance of dying cells through binding and activation of its cognate receptor SIRPα (signal-regulatory protein alpha). CD47 is upregulated in ischemic heart disease. As such, increased CD47 expression on the surface of dying cardiomyocytes may impair their efficient removal by phagocytes. Hypothesis: Blocking CD47 with a recombinant, high affinity SIRPα-Fc fusion protein, will promote the efficient removal of dying cardiomyocytes and prevent the decrease in cardiac function typically observed following an ischemic event. Methods: Myocardial infarction (MI) was induced in Sprague Dawley rats by temporary ligation of their left coronary artery for 45 minutes. Rats received the SIRPα-Fc fusion protein (n=27) or IgG placebo (n=27) by intravenous infusion (3 mg/kg) 2 hours before MI. Three additional weekly subcutaneous injections (3 mg/kg) of SIRPα-Fc fusion protein or IgG were administered. Cardiac function was assessed by left ventricular pressure-volume loops 28 days after MI. At that time, the heart was harvested and sectioned at six levels to quantify the scar area by histology with Masson trichrome staining. Results: Treatment with SIRPα-Fc fusion protein improved cardiac contractility and hemodynamics 28 days after MI compared to IgG. Specifically, statistically significant increases in ejection fraction by 29% (p<0.001), end-systolic elastance by 35% (p<0.05), preload recruitable stroke work by 25% (p<0.05), stroke volume by 24% (p<0.01) and a decrease in end-systolic volume by 28% (p<0.001) were observed following treatment with SIRPα-Fc fusion protein vs. IgG. Moreover, scar area was also decreased by 22% in rats treated with SIRPα-Fc fusion protein compared to IgG-treated animals. Conclusion: These results suggest that CD47 blockade has potential as a novel therapy for ischemic heart diseases.