Microcirculatory and metabolic adaptations to SGLT2 inhibitor therapy in chronic heart failure

Background

Sodium glucose cotransporter 2 inhibitors (SGLT2i) reveal positive effects on cardiovascular events in heart failure (HF) patients. The impairment of microcirculation and mitochondrial function has been reported in HF. SGLT2i improves microcirculation and most probably mitochondrial biogenesis in these patients, which may be vital for managing HF and related circulatory issues. However, the mechanisms underlying these effects are not fully elucidated.

Purpose

This study aims to investigate the mechanisms of SGLT2i on global microvascular function using non-invasive flow mediated skin fluorescence (FMSF) technique in patients with chronic HF. The analyses were enriched with targeted metabolomic profiling of serum amino acid compounds.

Methods

Microvascular function and blood analysis were performed before, one and three months after adding dapagliflozin (10mg/day) or empagliflozin (10mg/day) in twenty-four outpatients with chronic HF. Microvascular reactivity was assessed using FMSF, which reflects overall microcirculatory function and metabolic conditions by measuring a reduced form of nicotinamide adenine dinucleotide (NADH) fluorescence in the skin. Targeted serum metabolomics was conducted using mass spectrometry.

Results

Treatment with SGLT2i was associated with a significant improvement in peripheral microvascular reactivity (Figure 1). The Normoxia Oscillatory Index (NOI) increased significantly at one and three months compared to baseline. The Reactive Hyperemia Response (RHR) showed an upward trend during treatment, indicating improved endothelial-dependent vasodilation. Subgroup analysis revealed differential responses according to NYHA functional class (Figure 2).

Targeted metabolomic analysis of branched amino acids related to mitochondrial metabolism showed significant increase after one (64.2 ± 3.0 µM) and three months (64.5 ± 2.3 µM) of the treatment as compared to baseline (58.7 ± 1.8 µM). Leucine and valine concentrations demonstrated upward trends during SGLT2i. In addition, there were beneficial changes in serum methylated L-arginine metabolites, such as asymmetric (ADMA) and symmetric (SDMA) dimethylarginine, reflecting endothelial function improvement.

Conclusion

SGLT2i therapy is associated with significant improvement in peripheral microvascular reactivity in patients with chronic HF, as assessed by FMSF. The observed enhancement of NOI and ischemic response, particularly in patients with lower NYHA class, supports the concept of partially reversible microvascular and mitochondrial dysfunction in earlier stages of heart failure. Importantly, concomitant favorable changes in circulating branched-chain amino acids and methylated L-arginine derivatives, together with their negative correlations with microvascular function parameters, suggest that SGLT2i may improve endothelial function via modulation of mitochondrial metabolism and nitric oxide bioavailabilityFigure 1For image description, please refer to the figure legend and surrounding text.Figure 2For image description, please refer to the figure legend and surrounding text.