Empagliflozin significantly reduces the capacity of sera to induce endothelial dysfunction in Ischemia Non-Obstructive Coronary Arteries (INOCA): EMbArk phase II pilot trial

Abstract Introduction Ischemia with Non-Obstructive Coronary Arteries (INOCA) is seen in up to 70% of patients with angina undergoing invasive coronary angiography. In INOCA patients, with coronary microvascular dysfunction (CMD) and underlying endothelial dysfunction (EnD)-induced inflammation and excessive reactive oxygen species (ROS) signaling leads to increased release of cytokines, upregulation of leucocyte adhesion molecules, the release of endothelial microvesicles (eEVs), and ultimately EC apoptosis. In vitro studies have found Sodium Glucose Co-Transporter 2 inhibitors (SGLT2i) reverse EnD. However, the effect of SGLT2i on EnD in an INOCA population with CMD has not been studied. Methods Phase II open label pilot trial in INOCA patients with CMD treated with the SGLT2i Empagliflozin (EMPA, 10mg/daily) for 90 days. Blood samples were collected at baseline and after 45 days of treatment (n = 7), baseline samples were compared to no-CMD controls stored samples (n = 4). Cultured Human Coronary Artery Endothelial Cells (HCAECS) were exposed to sera from the 3 groups at various concentrations (5,10,20%); and cell viability, apoptosis, eEV release, VCAM-1 concentrations, and mitochondrial ROS staining were quantified. Results In an all-female cohort, the mean age was 60 years (SD 12) (Table 1). Compared to no-CMD controls HCAECs, incubated with sera from INOCA patients with CMD had significantly higher apoptosis (Fig. 1A) and lower viability (Fig. 1B) that significantly improved following EMPA treatment (Fig. 1A – 1B). Compared to no-CMD controls HCAECs incubated with 10% sera, INOCA patients with CMD induced significantly higher release of eEVs (concentration, Fig. 1C) with concomitant higher eEV median size (Fig. 1D); and EMPA treated sera significantly reduced the release of eEVs and eEV size (Fig. 1C – 1D). Compared to no-CMD controls, sera of INOCA patients with CMD induced significantly higher levels of VCAM-1 in the supernatant (Fig. 1E) and VCAM-1 protein in the cell lysate (Fig. 1F), which was significantly reduced following treatment (Fig. 1E – 1F). HCAECs incubated with 10% sera from INOCA patients with CMD had significantly elevated Mito-SOX staining compared to non-CMD controls, and this was significantly reduced following treatment (Fig. 1G). Conclusions Sera from INOCA patients with CMD has an increased capacity to induce EnD compared to no-CMD controls and this capacity is reduced following SGLTi treatment. These results suggest SGLT2i’s may target the underlying mechanisms of disease (EnD and CMD) in INOCA patients.