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Life sciences · Journal article
Disease Models & Mechanisms · October 19, 2026
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BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome in which translational progress is limited by experimental models that insufficiently reflect the cardiometabolic phenotype while affecting endogenous endothelial function. We aimed to characterize a cardiometabolic "two-hit" HFpEF model combining metabolic stress (db/db) with chronic mineralocorticoid excess (d-aldosterone), focusing on integrated cardiac, vascular, and pulmonary phenotyping. METHODS: Female db/db mice received 4-week d-aldosterone (0.3 µg/h) or vehicle via osmotic minipumps. Metabolic profiling, high-resolution echocardiography including strain and left atrial mechanics, invasive right-heart catheterization, and thoracic aortic wire myography were performed. RESULTS: Aldosterone-treated db/db mice developed cardiac hypertrophy and pulmonary congestion with preserved LVEF but marked diastolic dysfunction, left atrial remodeling with increased stiffness, and impaired global longitudinal LV strain. Pulmonary hypertension with right ventricular dysfunction was evidenced by elevated RVSP/estimated mPAP, reduced PAT/PET, and reduced TAPSE. Thoracic aortae from untreated db/db mice already showed impaired endothelium-dependent relaxation, which was further aggravated by aldosterone, whereas maximal endothelium-independent relaxation remained largely preserved. CONCLUSIONS: The db/db+d-aldosterone model recapitulates key features of cardiometabolic HFpEF across the cardiac-vascular-pulmonary axis and provides a translational platform for mechanistic and therapeutic studies targeting endothelial and ventricular-vascular dysfunction in HFpEF. New & Noteworthy: Current HFpEF animal models often limit the investigation of vascular dysfunction, a central component of cardiometabolic HFpEF. We provide a comprehensive functional characterization of a db/db+d-aldosterone two-hit model demonstrating obesity, diabetes, diastolic dysfunction, atrial remodeling, endothelial dysfunction, pulmonary hypertension, and right ventricular impairment. By preserving endogenous endothelial nitric oxide signaling, this model offers a translational platform for studying vascular and cardiopulmonary mechanisms in cardiometabolic HFpEF.