Tissue-specific metabolomics in experimental HFpEF reveals hepatic remodelling modulated by SGLT2 inhibition

Background Recent favourable clinical trials of sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like-peptide-1 (GLP-1) agonists have substantially changed the management landscape for heart failure with preserved ejection fraction (HFpEF) patients. However, the organ-level metabolic mechanisms underpinning these benefits remain incompletely understood and it is unclear how these therapies reshape inter-organ metabolic crosstalk in HFpEF. In many patients, the HFpEF phenotype appears to result from an intersection between abnormal cardiovascular physiology together with metabolic and inflammatory changes. Methods Experimental HFpEF was induced in 18-month-old female C57BL/6J mice with a high-fat diet for 12 weeks, an angiotensin II infusion beginning at week 6, with age-matched controls, to establish a cardiometabolic phenotype. Treatment with the SGLT2 inhibitor Dapagliflozin (Dapa) was administered for 6 weeks, concurrently with AngII administration. In addition to comprehensive cardiovascular and inflammatory phenotyping, we conducted metabolomic profiling of the heart, liver and plasma and performed 16S rRNA sequencing to characterise alterations in the gut microbiome. Results Characteristic cardiometabolic and inflammatory profiles were observed in experimental HFpEF, including obesity, hypertension, diastolic dysfunction, hepatic steatosis, and gut dysbiosis. Despite no detectable improvement in echocardiographic function at endpoint, Dapa induced distinct hepatic remodelling, with increased citraconate, restoration of succinate, modulation of branched-chain amino acid and ketone pathways and reduced oxidative stress markers. Aromatic amino acid metabolism and gut-derived metabolites were broadly disrupted across heart, liver, and plasma. Conclusion HFpEF is defined by complex, tissue-specific metabolic derangements. SGLT2 inhibition primarily remodeled the hepatic metabolome, positioning the liver as a central hub of cardio-renal-liver crosstalk. These findings suggest that extra-cardiac metabolic pathways, particularly liver-centered mechanisms, may contribute to the therapeutic benefits of SGLT2 inhibitors in HFpEF and provide new insights into inter-organ metabolic regulation.