Ganguly, S.; Gunes, B.; Gu, Y.; Suarez, J.; Gupta, G.; Ishizuka, K.; Murad, R.; Kisseleva, T.; Dillmann, W.; Peterson, K.; Adler, E.; Brenner, D.; Dhar, D.

Background: Metabolic dysfunction associated steatotic liver disease (MASLD) and its advanced form, MASH, are closely linked to heart failure with preserved ejection fraction (HFpEF). However, the mechanisms driving MASLD-associated HFpEF and its reversibility remain poorly understood, largely due to the lack of robust preclinical models. Here, we established a translational model of MASLD-associated HFpEF and applied functional and transcriptomic analyses of the left ventricle (LV) to define the mechanisms underlying cardiac dysfunction and its reversibility. Methods: Alms1-/- (Foz/Foz) mice and wild-type littermates were fed normal chow (NC) or Western diet (WD) for up to 34w. Reversibility was modeled by switching WD-fed Foz/Foz mice at 12w back to NC for 12w. Cardiac assessment included echocardiography, invasive hemodynamics with dobutamine stimulation, histopathology, electron microscopy and isolated cardiomyocyte contractility. LV transcriptomes were profiled by bulk RNA sequencing and analyzed by differential expression and pathway enrichment. Result: Foz/Foz mice on WD for 24w developed metabolic syndrome and MASH with advanced liver fibrosis. Cardiac phenotyping showed LV hypertrophy, impaired cardiomyocyte contractility, reduced {beta}-adrenergic reserve, elevated plasma BNP, and increased mortality while the ejection fraction was preserved (>50%), consistent with HFpEF. Liver fibrosis was a strong predictor of HFpEF. Switching WD-fed Foz/Foz mice at 12w to normal chow diet reversed hepatic fibrosis, restored LV function, and reduced mortality, demonstrating plasticity of the liver-heart axis. LV transcriptome during disease progression and regression revealed mitochondrial dysfunction, altered substrate utilization, extracellular matrix remodeling, and metabolic stress as central drivers of HFpEF, with strong overlap to human HFpEF signatures. Cardiac electron microscopy revealed swollen mitochondria with disrupted cristae, which normalized following dietary intervention. Conclusions: Mitochondrial dysfunction and fibroinflammatory remodeling are central mediators of MASLD-associated HFpEF. Reversal of hepatic and cardiac phenotypes with dietary intervention, together with elucidation of underlying pathways, establish the Foz/Foz model as a robust translational platform for mechanistic and therapeutic discovery targeting the liver-heart axis.