Empagliflozin improves the microRNA signature of endothelial dysfunction in patients with HFpEF and diabetes.

Endothelial dysfunction represents a key mechanism underlying heart failure with preserved ejection fraction (HFpEF), diabetes mellitus (DM), and frailty. However, reliable biomarkers to monitor endothelial dysfunction in these patients are lacking. In this study, we evaluated the expression of a panel of circulating microRNAs (miRs) involved in the regulation of endothelial function in frail older adults with HFpEF and DM that were treated for 3 months with empagliflozin, metformin, or insulin. We identified a unique pattern of miRs that were significantly regulated in HFpEF patients compared to healthy controls and in HFpEF patients after treatment with the SGLT2 inhibitor empagliflozin. Three miRs were significantly downregulated (miR-126, miR-342-3p, and miR-638) and two were significantly upregulated (miR-21 and miR-92) in HFpEF patients compared to healthy controls. Strikingly, two of these miRs (miR-21 and miR-92) were significantly reduced in HFpEF patients after the 3-month treatment with empagliflozin whereas no significant differences in the profile of endothelial miRNAs were detected in patients treated with metformin or insulin. Significance Statement We have identified for the first time a signature of microRNA functionally involved in the regulation of endothelial function that is significantly regulated in frail patients with HFpEF and diabetes. The treatment with the SGLT2 inhibitor empagliflozin caused a modification of some microRNA in a direction that was opposite to what observed in HFpEF patients, indicating a rescue of endothelial function. Our findings are relevant inasmuch as novel biomarkers of disease as well as response to therapy have been established.