Effect of sacubitril/valsartan and empagliflozin on systemic inflammation and scar remodeling in a swine model of myocardial infarction

Abstract

Abstract Background Angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose cotransporter 2 inhibitors (SGLT2i) lead to reduced cardiovascular death and hospitalization rates for heart failure, but mechanisms of action remain unclear. Purpose To evaluate the effect of ARNI and SLGT2i on cardiac function, systemic inflammation and scar remodeling in a porcine model of acute myocardial infarction (MI). Methods Thirty-three pigs (18 female, 15 male) with non-revascularized MI were randomized to receive treatment with beta-blocker (BB) only (BB group, n=8), empagliflozin + BB (SGLT2i group, n=8), sacubitril/valsartan + BB (ARNI group, n=9) or empagliflozin + sacubitril/valsartan + BB (SGLT2i + ARNI group, n=8) for 30 days post-MI. Cardiac function parameters were studied at 2- and 30-days post-MI by cardiac magnetic resonance imaging. The systemic immune response was analysed at baseline, 2-, 15- and 30-days post-MI to estimate 1) the absolute number of neutrophils and lymphocytes by FSC-A/SSC-A, 2) the circulating monocytes (CD172a+) and their phenotype according to CD73+, and CCR2+ expression. Animals were euthanized at 30 days, interstitial collagen and vascular density of the scar were quantified. Results Left ventricular ejection fraction (LVEF) and stoke volume (LVSV) improved in SGLT2i + ARNI group (P=0.02, P=0.002, respectively, 2 vs 30 days post-MI). Right ventricular ejection fraction (RVEF) and stroke volume (RVSV) improved in ARNI treatment arm (P=0.03; P=0.02, respectively, 2 vs 30 days post-MI). Significant increase in LV mass was only observed in BB group (P=0.02; 2 vs 30 days post-MI). SGLT2i and ARNI treatment prevented the acute increase in circulating leukocytes 2 days post-MI (P=0.0095; P=0.0091, respectively). Moreover, SGLT2i reduced the CCR2+ activated monocytes count at 15 days post-infarction (P=0.01). In contrast, the combined treatment increased the number of circulating monocytes (CD172a+) at 30 days (P=0.008). Reduced collagen I (P=0.04), and Col I/Col III ratio (P=0.02) was observed in ARNI group, and higher collagen III content (P=0.02) in SGLT2i group. Vascular density was significantly increased in SGLT2i + ARNI group (P=0.03). Conclusions SGLT2i modulates systemic inflammatory state. ARNI reduces myocardial fibrosis and improves right ventricular function. Combined treatment improves vascular density and left cardiac function in a post-MI porcine model. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Boehringer Ingelheim Spain, S.A, and Instituto de Salud Carlos III, CIBER Cardiovascular