Benefits of sacubitril/valsartan alone and in combination with dapagliflozin in a preclinical female model of cardiometabolic and age-related cardiac dysfunction

Heart failure with preserved ejection fraction (HFpEF) disproportionately affects elderly women and is closely associated with central obesity and metabolic dysfunction. Although sodium-glucose co-transporter-2 inhibitors (SGLT2i) are recommended in all HFpEF patients, the potential benefit of angiotensin receptor-neprilysin inhibitors (ARNi) alone or in combination with SGLT2i remain underexplored. ARNi may be particularly effective because of the reduced natriuretic peptides availability and heightened renin-angiotensin-aldosterone system (RAAS) activation associated with aging and central obesity, particularly in postmenopausal women. Aged female F344 rats, which recapitulate features of metabolic stress, visceral adiposity, and cardiac aging observed in HFpEF patients, were used as a model of dysmetabolic aging heart failure (DAHF). From 15 months of age, animals received long-term treatment with sacubitril/valsartan (S/V; 60 mg/kg/day) alone or in combination with dapagliflozin (D; 0.1 mg/kg/day) for 45 weeks. Cardiac structure and function were assessed by echocardiography and invasive hemodynamic analysis. Histological and molecular analyses of cardiac tissue were used to investigate fibrosis, inflammation, oxidative stress, mitochondrial antioxidant activity, senescence markers, and cardiometabolic signalling pathways. Angiotensin II an Ang-(1–7), NT-pro-BNP, BNP, leptin and aldosterone were measured in plasma by enzyme-linked immunosorbent assay. Freshly isolated cardiomyocytes form young and middle-aged rats were used as in vitro model to investigate the effects of drugs on the AMPK/NAMPT/SIRT1 pathways. Positive effects were observed with S/V monotherapy, but S/V + D combination further improved diastolic function, reduced left ventricular filling pressures, and enhanced chamber compliance. Functional improvements were paralleled by reductions in plasma NT-proBNP and myocardial BNP. Both treatments attenuated cardiac fibrosis and inflammation by downregulating TGF-β1/SMAD3 signalling and pro-inflammatory cytokines (IL-6, TNF-α, NF-κB). Only the combination therapy significantly enhanced endothelial nitric oxide synthase (eNOS) expression and boosted myocardial antioxidant defences. The benefit of S/V + D was associated with reactivation of the Nrf2/Keap1 and the AMPK/NAMPT/SIRT axes and reduced markers of cellular senescence, including p53 acetylation and p21CIP1, and suppressed senescence-related microRNAs. S/V alone conferred significant myocardial protection which was further amplified when combined with D in a female model of cardiometabolic and age-related cardiac dysfunction. These findings support the hypothesis that long-term S/V + D combination therapy synergistically recruits interconnected antioxidant, metabolic, and anti-senescent pathways, establishing a positive molecular feedback loop. Together, these effects provide mechanistic insight into sex-specific therapeutic strategies and support a precision medicine approach for elderly women with HFpEF and central obesity.