A Translational Model of MASLD-Associated HFpEF Defines Mitochondrial Dysfunction and Cardiac Plasticity During Disease Progression and Regression.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are strongly linked to heart failure with preserved ejection fraction (HFpEF), yet the mechanisms underlying this association remain unclear because robust integrative preclinical models are lacking and the liver and heart are rarely studied as a coordinated system. Here we show that Alms1 -/- (Foz/Foz) mice fed a Western diet develop MASH with advanced liver fibrosis accompanied by a HFpEF phenotype characterized by left ventricular hypertrophy, impaired cardiomyocyte contractility, reduced β-adrenergic reserve, elevated BNP, and increased mortality despite ejection fraction >50. Liver fibrosis emerged as a strong predictor of cardiac dysfunction. Remarkably, dietary reversal restored hepatic architecture, normalized cardiac function, and improved survival, revealing marked plasticity of the liver-heart axis. Mechanistic analyses revealed coordinated mitochondrial dysfunction, altered substrate utilization, and extracellular matrix remodeling in the left ventricle, with strong concordance to human HFpEF transcriptomic signatures. Ultrastructural studies confirmed mitochondrial injury and sarcomeric disorganization, linking metabolic failure to impaired cardiomyocyte performance. Together, these findings identify mitochondrial dysfunction as a central mediator of MASLD-associated HFpEF and establish the Foz/Foz model as a powerful platform for dissecting liver-to-heart signaling pathways and testing mechanism-based therapeutic strategies.