Treatment with a CD31 agonist peptide improves the outcome of experimental heart failure with either reduced or preserved ejection fraction

Introduction CD31 is a mechanosensory receptor and recent studies in CD31 knockout mice have suggested a protective role for CD31 in condition of altered mechanic stress such as in heart failure. Objective To directly assess the impact of CD31 signaling on the outcome of heart failure (HF) with both reduced and preserved ejection fraction (HFrEF and HFpEF, respectively). Method Permanent ligature of the proximal left coronary in C57Bl6 mice was used for modeling experimental HFrEF. Five days after surgery, mice displaying a myocardial infarction involving > 30% of the left ventricle (LV) at echocardiography were randomized to receive either a CD31 agonist peptide (P8RI, 2.5 mg/kg) or placebo by subcutaneous continuous infusion (osmotic pumps). Low dose angiotensin II infusion was applied to apolipoprotein E knockout (ApoE KO) mice as a model of HEpEF. The osmotic pumps delivered angiotensin II (200 μg/Kg/day) alone or together with P8RI. The Ejection Fraction (EF%) and the E/E’ ratio were evaluated by echocardiography. Results In the HFrEF model, the daily treatment with the CD31 agonist peptide starting from the 5th day after the myocardial infarction, improved both the EF% (68 ± 3% vs. 47 ± 4%, P  = 0.05) evaluated 30 days later. Also, the LV filling pressure was improved by the treatment, as reflected by the E/E’ ratio (24.6 ± 2.4% vs. 49.7 ± 7.5, P  = 0.05). An even more striking beneficial effect was observed in the model of HEpEF, in which the CD31 agonist treatment prevented the development of the diastolic LV dysfunction induced by the low dose of angiotensin II infusion as determined by the variation of the E/E’ ratio at the end of the treatment period (6 ± 7 in P8RI treated mice vs. 37 ± 8 in controls, P Conclusion CD31 agonist drugs can contribute to improve function of the heart in experimental conditions of myocardial mechanic stress and may represent a novel therapeutic strategy for heart failure with both reduced and preserved ejection fraction.