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BACKGROUND: Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes HFD+L-NAME (ad libitum high-fat diet and 0.5% N[ω]-nitro-L-arginine methyl ester), we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to HFD+L-NAME.METHODS: Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein (nicotinamide nucleotide transhydrogenase), we established an isogenic model of loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of HFD+L-NAME. Twelve-week-old mice cross-bred to isolate wild-type () or loss-of-function () in the C57BL/6N background were challenged with HFD+L-NAME for 9 weeks (N=6-10).RESULTS: mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via noninvasive echocardiographic quantification of early diastolic pulse-wave velocity (E) to mitral annular velocity (e') ratio (E/e') (42.8 versus 21.5, =1.2×10), E/A (early-to-late mitral inflow velocity ratio) (2.3 versus 1.4, =4.1×10), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, =5.1×10), and myocardial fibrosis (=2.3×10). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD (=8.4×10) and a 38.8% reduction in the ratio of reduced-to-oxidized glutathione (GSH: GSSG, =2.6×10) among mice after HFD+L-NAME feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling in myocardial fibrosis.CONCLUSIONS: Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.