Dapagliflozin Attenuates Heart Failure With Preserved Ejection Fraction Remodeling and Dysfunction by Elevating...

Area of Science:

• Cardiology
• Metabolic Diseases
• Pharmacology

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a prevalent condition with high mortality.
• Current guidelines recommend SGLT2 inhibitors (SGLT2i) for HFpEF, but their precise mechanisms remain unclear.
• Understanding SGLT2i's role is crucial for HFpEF pathophysiology and therapeutic development.

Purpose of the Study:

• To investigate the therapeutic mechanisms of SGLT2 inhibitors, specifically dapagliflozin (DAPA), in a preclinical HFpEF model.
• To elucidate how DAPA impacts cardiac remodeling, dysfunction, and metabolic pathways in HFpEF.
• To correlate preclinical findings with observed changes in HFpEF patients receiving DAPA therapy.

Main Methods:

• An HFpEF rat model was established using a high-fat diet and L-NAME administration (2-Hit model).
• Dapagliflozin (DAPA) was administered to assess its effects on cardiac structure, function, and molecular markers.
• Metabolic analyses, including β-hydroxybutyric acid (β-OHB), citrate synthase, acetyl-CoA, ATP, and mitochondrial oxidative phosphorylation, were performed in vivo and in patient blood samples.

Main Results:

• DAPA treatment significantly attenuated cardiomyocyte hypertrophy, apoptosis, inflammation, oxidative stress, and fibrosis in the HFpEF model.
• DAPA improved both diastolic and systolic cardiac function in late-stage HFpEF.
• Mechanistically, DAPA normalized energy metabolism by increasing β-OHB, activating citrate synthase, reducing acetyl-CoA, modulating ATP production, and enhancing mitochondrial oxidative phosphorylation.

Conclusions:

• SGLT2 inhibitors, exemplified by dapagliflozin, offer significant benefits in preventing and treating cardiac remodeling and dysfunction in HFpEF.
• DAPA exerts its protective effects by ameliorating cardiometabolic dysregulation, particularly through modulation of fatty acid metabolism and mitochondrial function.
• Clinical data supports the observed metabolic benefits of DAPA in HFpEF patients, highlighting its therapeutic potential.