Abstract 18690: Recombinant Human Relaxin-2 (Serelaxin) Attenuates Ischemic Cardiomyopathy and Improves Left Ventricular Function in Mice

Background: In the RELAX-AHF trial, 48-hour infusion of recombinant human relaxin-2 (serelaxin; SRLX) reduced post-discharge mortality at 180 days in selected patients with acute heart failure. However, the underlying mechanisms remain under investigation. Therefore, we studied the effect of SRLX on attenuation of left ventricular (LV) adverse remodeling following infarction in a mouse model of ischemic cardiomyopathy. Methods and Results: 48 adult male CD-1 mice underwent myocardial infarction (MI) by permanent ligation of the left anterior descending coronary artery and were treated with SRLX (10 μg/Kg/day; sc via osmotic mini-pump) or saline for 4 weeks. Survival at 28 days was 90% in the SRLX group vs. 52% in the saline group (Fig. A). The fibrotic area (% of LV), assessed by Masson’s trichrome staining was reduced to 12.6±1.0% with SRLX as compared to 23.7±3.0% with saline at 28 days post MI (Fig. B). The apoptotic index, measured by TUNEL assay, was 4-fold higher in the saline group vs. SRLX group on day 28 post MI (Fig. C). Fractional shortening (FS) measured using echocardiography on days 7 and 28 post-MI revealed significant LV dysfunction in saline-treated group; however, SRLX markedly preserved FS at both time points (Fig. D). Baseline FS was 43 ± 2%. Although the difference in caveolin-1 expression as assessed by immunofluorescence did not reach statistical significance (P=0.06, not shown) between the groups, there was a promising trend favoring increased capillary density with SRLX at 28 days in the post-infarcted heart. SRLX plasma levels were assessed 7 days after pump implantation using ELISA and the results demonstrate therapeutic levels comparable to plasma relaxin during the first trimester of pregnancy (Fig. E). Conclusion: SRLX improves survival and attenuates cardiomyocyte death and adverse LV remodeling at 28 days post MI. We propose that prolonged SRLX therapy can be explored for treatment of chronic ischemic heart failure in patients.