SGLT2 inhibitors promote electrical remodeling in heart failure patients undergoing cardiac resynchronization therapy: a clinical and metabolomic analysis

Recent randomized controlled trials have highlighted the significant prognostic benefits of sodium/glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) in heart failure (HF) patients. The DAPA-HF study demonstrated that dapagliflozin reduced HF worsening and cardiovascular death by 26%. Similarly, the EMPEROR trial reported a 22% reduction in cardiovascular mortality or HF-related hospitalizations with empagliflozin. Notably, these benefits were consistent in patients with and without diabetes, underscoring the broad therapeutic potential of SGLT2i in HF management.

This study evaluates the impact of SGLT2i on energy metabolism in heart failure with reduced ejection fraction (HFrEF), specifically examining the metabolic shift from glucose to lipid utilization. By analyzing metabolic biomarkers, it seeks to provide insights into the therapeutic effects of SGLT2i in HF, potentially improving diagnostic and treatment strategies. Additionally, SGLT2i may address elevated intracellular sodium levels in HF, which disrupt calcium handling, impair contractility, and contribute to arrhythmias. By modulating sodium and calcium dynamics, SGLT2i could improve cardiac function and increase the response rate to cardiac resynchronization therapy (CRT).

This prospective, observational, randomized study included non-diabetic HFrEF patients eligible for CRT. The treatment group received SGLT2i (dapagliflozin or empagliflozin) for over three months, while the control group comprised patients optimized for HF therapy without SGLT2i. Blood samples were collected from peripheral, central venous, and arterial sites during CRT implantation and analyzed using mass spectrometry for metabolomic profiling. Follow-up evaluations were conducted at 3, 6, and 12 months, including additional venous blood sampling and transthoracic echocardiography to assess left ventricular ejection fraction (LVEF), CRT response, biventricular stimulation efficacy.

Metabolomic profiling revealed significant changes in energy metabolism pathways in SGLT2i-treated patients. Increases in tricarboxylic acid (TCA) cycle intermediates, beta-hydroxybutyrate, and short-chain carnitines indicated a shift toward lipid utilization, while long-chain carnitines were reduced. Cardiovascular stress markers, including polyols and ceramides, were lower in treated patients, suggesting decreased metabolic burden and oxidative stress.

This study provides novel insights into the metabolic effects of SGLT2i in non-diabetic HFrEF patients, identifying biomarkers that may inform diagnostic and therapeutic strategies in HF. The findings enhance understanding of SGLT2i mechanisms in modulating ion channel activity and cardiomyocyte function, potentially improving CRT outcomes and promoting reverse electrical remodeling. These results underscore the potential of SGLT2i to improve HF management and optimize CRT response.

Metabolomics results