Long-Acting Fc-elabela Improves Heart Functional Performance and Markedly Reduces the Infarction Area in a Non-Human Primate Model of Myocardial Infarction

Introduction: Agonists for the apelin receptor APJ have exhibited cardioprotective and anti-heart failure effects in numerous basic and clinical studies. Besides apelin, elabela is a new endogenous peptide ligand for APJ. In a previous study, we have shown that Fc-Elabela (Fc-ELA) has an in vivo half-life of 44 hours in mice and mitigates heart dysfunctions in the rat model of myocardial infarction. Hypothesis: We hypothesized that we could reproduce Fc-ELA’s cardioprotective effects in non-human primates. Methods: Sixteen 3-6 kg male cynomolgus monkeys were divided into 2 groups of vehicle (Veh, n=9) and Fc-ELA (n=7), each with a mean LVEF of 73%. The animals were subjected to ligation of the LAD for 60 min of ischemia and reperfusion to induce myocardial infarction (MI) and heart failure, and received administration of Fc-ELA at 1 mg/kg, s.c., daily for 4 weeks or vehicle, starting at reperfusion. Ultrasound was performed before operation, after reperfusion, and 1, 2, 3 and 4 weeks after operation. Hemodynamics were measured before and 4 weeks after the procedure. At the end of the experiment, TTC staining for the infarction area and CD31staing for microvessels were performed. Results: LVEF decreased from baseline 73% to 64% after MI, gradually decreasing to 50% by the end of week 4 in the Veh group, whereas LVEF remained between 63% and 66% in the entire 4 weeks of Fc-ELA treatment (p <0.001 vs. Veh at Week 2, 3 and 4). dP/dt increased from 2,235 to 3,975 mmHg/s with Veh, but from 2,249 to 5,893 mmHg/s with Fc-ELA (p < 0.05 between groups). LVEDP decreased by 63% with Fc-ELA, but did not change with Veh (p < 0.05 between groups). Systolic BP increased with Fc-ELA as compared to Veh . Fc-ELA reduced the infarct area by 48.2% (MI area ratio: Veh vs. Fc-ELA; 5.0% vs 2.6%, p < 0.01. In addition, the Fc-ELA treatment increased the expression of CD31, a vascular endothelial marker, by 26.3% (p < 0.01), compared to the Veh group. Conclusions: In non-human primates, Fc-ELA showed significant cardioprotective effects. Fc-ELA markedly reduced MI infarction area and significantly increased the microvessel density in the model, supporting Fc-ELA as a potential therapeutic for heart failure and MI.