Key result
Empagliflozin ameliorates diastolic dysfunction and cuts blood glucose ~43% in obese-diabetic HFpEF mice.
Why the study?
Although empagliflozin provides cardiovascular benefits in HFpEF, SGLT2 expression is virtually absent in cardiomyocytes, leaving its exact protective mechanism unclear.
Does empagliflozin improve excitation-contraction coupling, electrophysiology, and gene transcription in a two-hit HFpEF mouse model?
Does empagliflozin improve excitation-contraction coupling, electrophysiology, and gene transcription in a two-hit HFpEF mouse model?
Absolute Event Rate: 13% vs 23%
Empagliflozin restores cardiomyocyte electrophysiological properties and ameliorates diastolic function in a cardiometabolic HFpEF mouse model, providing mechanistic insights into its clinical benefits.
Supports cardiometabolic HFpEF benefits in mice; leaves open translation to patients.
Effective treatments for heart failure with preserved ejection fraction (HFpEF) are limited. Empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, provides cardiovascular benefits for patients with HFpEF. SGLT2 expression is virtually absent in cardiomyocytes, hence the exact protective mechanism of empagliflozin is unclear. We aimed to study the effect of in vivo empagliflozin treatment on excitation–contraction coupling (ECC), electrophysiology, and gene transcription in a translational two-hit HFpEF mouse model that combines the obese-diabetic leptin receptor-deficient db/db mice with chronic aldosterone infusion ( db/db + Aldo). We performed morphometry, echocardiography, cardiomyocyte electrophysiology, intracellular Ca 2+ imaging, and whole-heart RNA-sequencing in empagliflozin-treated db/db + Aldo and vehicle control mice. In db/db + Aldo mice, empagliflozin (in vivo, 4 weeks) reduced the elevated plasma blood glucose (13 ± 5 mmol/L versus 23 ± 8 mmol/L) and BNP levels, prevented pulmonary congestion, and ameliorated diastolic dysfunction. However, empagliflozin did not reduce cardiac hypertrophy and obesity. In healthy control mice, empagliflozin had no functional effect. Chronic in vivo empagliflozin treatment in db/db + Aldo also normalized the changes in cardiomyocyte electrophysiology and Ca 2+ handling properties measured in the absence of empagliflozin in the perfusion solution during cell experiments, indicating a true phenotypic rescue. Differentially expressed gene clusters were identified characteristic of the db/db genotype, aldosterone, and empagliflozin treatments. Interestingly, empagliflozin did not just reverse the HFpEF-altered gene expression but shifted it further away from control to a new expression profile. We conclude that chronic in vivo empagliflozin treatment restores cardiomyocyte electrophysiological and ECC properties, ameliorates diastolic function in cardiometabolic HFpEF, and induces complex gene expression changes.
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Hernández et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF) (n=45). Empagliflozin vs. Vehicle was evaluated on Plasma blood glucose (mmol/L). Chronic in vivo empagliflozin treatment reduced elevated plasma blood glucose (13 vs 23 mmol/L), prevented pulmonary congestion, and ameliorated diastolic dysfunction in obese-diabetic HFpEF mice.
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