Modulación de la polarización de macrófagos con administración aguda de Vericiguat después de un infarto de miocardio

Vericiguat (Merck, marketed as Verquvo) is a soluble guanylate cyclase stimulator that is FDA-approved for use in heart failure patients with reduced or mildly reduced ejection fraction (HFrEF, HFmrEF) to decrease heart failure hospitalization and cardiovascular mortality. We hypothesized that earlier administration of vericiguat post-MI would reduce the workload of the viable cardiomyocytes, leading to an earlier switch towards anti-inflammatory macrophages and reduced adverse remodeling. Male and female C57BL/6J mice (n=6/sex/group) underwent permanent occlusion of the left anterior descending coronary artery followed by implantation of a subcutaneous osmotic mini-pump (vericiguat or saline) 24 hours later. Echocardiography and histological assessment were performed for cardiomyocyte size (wheat germ agglutinin), vascularity (g. simplicifolia lectin I), and collagen area fraction (picrosirius red). Macrophages were isolated from the infarct at day 3 post-MI and conditioned media was collected. While cardiomyocyte size did not significantly differ between treatment groups, female drug-treated mice trended toward smaller cardiomyocytes in the border zone compared to males. Macrophage numbers were not affected, however proteomic analysis demonstrated a pro-angiogenic phenotype with vericiguat. In vitro stimulation of endothelial cells with the macrophage conditioned media from female drug-treated mice demonstrated a more organized and robust tubule network. Drug-treated female trended towards greater collagen in the infarct at day 7 post-MI, whereas drug-treated males had decreased vessel density in the remote area compared to controls. Despite the molecular changes observed, no significant differences in cardiac function were observed at day 7 post-MI. Our data demonstrates that acute administration of vericiguat post-MI stimulates macrophages towards a pro-angiogenic phenotype that was more exaggerated in females.