Mechanistic Links Between Metabolic Dysfunction-Associated Steatotic Liver Disease and Heart Failure with Preserved Ejection Fraction in a Mouse Model

Abstract

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) commonly coexists with heart failure with preserved ejection fraction (HFpEF), yet the mechanisms linking hepatic steatosis to diastolic dysfunction remain unclear. MethodsA combined murine model of pressure overload using transverse aortic constriction (TAC) and diet-induced MASLD was developed to investigate the liver-heart interaction in HFpEF. Cardiac function and structure were assessed by echocardiography and histopathology. Hepatic transcriptomics and cardiac metabolomics were integrated to identify molecular pathways underlying cardiac remodeling and diastolic dysfunction. ResultsWhile left ventricular ejection fraction remained preserved, HFpEF-MASLD mice exhibited significantly worse diastolic function (lower septal e velocity and higher E/e ratio), greater left ventricular hypertrophy, and more extensive myocardial fibrosis compared with HFpEF alone. Immunofluorescence demonstrated augmented myocardial inflammation with increased CD3+ T-cell and CD68+ macrophage infiltration in the combined HFpEF-MASLD group. Transcriptomic analysis demonstrated marked down-regulation of genes implicated in retinoic acid signaling, confirmed by reduced expression of retinoic acid receptors (RAR, RAR{beta}) and retinol dehydrogenases (RDH) in both hepatic and cardiac tissues. Cardiac metabolomics revealed suppression of arginine biosynthesis, the obligate substrate for endothelial nitric oxide (NO) synthase, suggesting a potential link to reduced NO-mediated vascular and myocardial signaling. ConclusionsMASLD aggravates HFpEF through converging inflammatory and metabolic derangements. Disruption of retinoic acid and arginine-NO pathways may represent an important mechanistic link between hepatic steatosis and diastolic dysfunction that warrants further mechanistic and translational investigation.