Objective: Microvascular dysfunction and mitochondrial impairment in endothelial cells (ECs) are recognized as early drivers of heart failure (HF) progression. This study aimed to characterize the bioenergetic deficits and mitochondrial dysfunction of ECs and to investigate whether SGLT2 inhibitors (SGLT2i) could reverse these abnormalities. Design and method: Human primary coronary microvascular ECs were isolated from human hearts of healthy donors (n=6) excluded from transplantation procedure. Murine cardiac microvascular cell line (H5 V) was also used. Direct effects of SGLT2i were evaluated in these cells treated with dapagliflozin. Mitochondrial respiration was measured using Seahorse XFp technology, reactive oxygen species were determined by using mitoSOX (mtROS) and dedicated kit (ctROS). Intracellular adenine nucleotides (ATP, ADP, AMP) were quantified via liquid chromatography. In vivo, male C57BL/6 mice were administered dapagliflozin (35 mg/kg) for 6 weeks. Real-time coronary nitric oxide (NO) production was quantified using intravital microscopy with DAF2-DA fluorescent staining across various vessel diameters. Patients with chronic HF (n=16, EF>40%) were prospectively evaluated at baseline, 1 and 3 months after initiating SGLT2i therapy (dapagliflozin 10 mg/day). Peripheral microvascular function was assessed using Flow-Mediated Skin Fluorescence (FMSF). Plasma amino acids (L-arginine, L-citrulline, ADMA, SDMA) were measured via mass spectrometry coupled to liquid chromatography. NO stable degradation products were assessed calorimetrically. Results: In vitro, human and mouse coronary ECs after dapagliflozin treatment showed higher energy status related to improved mitochondrial respiration and modulated both cytoplasmic and mitochondrial ROS production. In vivo, dapagliflozin led to a marked increase in NO bioavailability within the coronary microvasculature. Clinically, SGLT2i therapy resulted in a significant reduction in plasma L-arginine and a trend toward increased NO metabolites. Most importantly, patients demonstrated an improvement in the Normoxia Oscilatory Index (NOI) parameter after 1 and 3 months. NOI correlated negatively with endogenous NO synthase inhibitors asymmetric and symmetric dimethylarginines: with ADMA (r=-0.52) and SDMA (r=-0.59). Conclusions: These findings demonstrate that SGLT2i treatment exert potent vasculoprotective effects by reversing endothelial mitochondrial dysfunction and enhancing the L-arginine/NO pathway. It reveals a novel cardiometabolic mechanism where these drugs restore microvascular efficiency, offering a promising target for treating microcirculatory abnormalities in HF.
Walczak et al. (Fri,) studied this question.