Empagliflozin Improves the MicroRNA Signature of Endothelial Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Diabetes

Abstract

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 (miRNAs, 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 distinctive 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 miRs were detected in patients treated with metformin or insulin. Taken together, our findings demonstrate for the first time that specific circulating miRs implied in the regulation of endothelial function are significantly regulated in frail HFpEF patients with DM and in response to empagliflozin treatment.

Cost-effectiveness of adding empagliflozin to the standard therapy for Heart Failure with Preserved Ejection Fraction from the perspective of healthcare systems in China

“…Empagliflozin was the first to be proved to improve HFpEF by a randomized controlled trial with sufficient statistical efficacy. Some molecular mechanisms proposed that empagliflozin could improve the specific circulating microRNA to regulate the endothelial function significantly and empagliflozin could reduce inflammatory and oxidative stress in HFpEF to decrease pathological cardiomyocyte stiffness by inhibiting NHE1 (Na+/H+ exchanger 1), which supported the wide use of empagliflozin in HFpEF (37)(38)(39). However, over 86% of HFpEF were using ACE-I/ARBs, 80% were using beta-blockers, and over 24% were using spironolactone in reality (7), which increased the burden of treating HFpEF to some extent.…”

Functional role of miR-34a in diabetes and frailty

“…Indeed, diabetes leads to a higher risk of cardiovascular complications and functional and physical impairment driving adverse outcomes (Fadini and Avogaro, 2010;Prattichizzo et al, 2018;Yun et al, 2018;Jarvie et al, 2019;Yu et al, 2019;Gulsin et al, 2020). microRNAs (miRNAs) are small non-coding RNAs that act as post-transcriptional gene regulators (Ambros, 2004;Krol et al, 2010;Santulli, 2015;Ferrante and Conti, 2017;Fridrichova and Zmetakova, 2019;Stavast and Erkeland, 2019;Mone et al, 2021b;Mone et al, Forthcoming 2022c); miRNAs exert their activity in many biological processes and have been proposed as biomarkers and therapeutic strategies (Creemers et al, 2012;Wronska et al, 2015;Barwari et al, 2016;Chen et al, 2018;Wong et al, 2018;Mone et al, 2021b;Fonseca et al, 2021;Mone et al, Forthcoming 2022c). Many miRNAs have been associated to mitochondrial dysfunction, inflammation, and oxidative stress and their concentration may vary in physiological conditions (Zhang et al, 2014;Hathaway et al, 2018;Wei et al, 2018;Rusanova et al, 2019;Song et al, 2019;Gambardella et al, Forthcoming 2022).…”

Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms

“…A different, recently proposed biomarker of aging trajectories is miR-21, which is increased during aging and in age-related diseases [ 96 ]. Of note, a 3-month treatment with empagliflozin was recently reported to restore the blood circulating quantities of this miRNA in frail older adults with heart failure and diabetes mellitus; the study also demonstrated that this effect was specific for the SGLT-2i, compared with treatment with insulin, or also metformin in the same patients [ 97 ].…”