Integrated Transcriptomic and Functional Dissection of Reversible Liver-Heart Dysfunction in a Preclinical MASLD-HFpEF Model

We applied functional and transcriptomic analyses of the left ventricle (LV) to define the pathways associated with 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 36 weeks (wk). Reversibility was modeled by switching WD-fed Foz/Foz mice at 12wk back to NC for 12wk. 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. Results Foz/Foz mice on WD for 24wk developed metabolic syndrome and MASH with advanced liver fibrosis. Cardiac phenotyping showed LV hypertrophy, impaired cardiomyocyte contractility, reduced β-adrenergic reserve, elevated plasma BNP, and increased mortality while the ejection fraction was preserved (>50%), consistent with HFpEF.

The progression of cardiac dysfunction was closely associated with liver fibrosis that developed during MASH. Switching WD-fed Foz/Foz mice at 12wk to normal chow diet reversed hepatic fibrosis, restored LV function, and reduced mortality, demonstrating plasticity of the liver-heart axis. LV transcriptomic analysis revealed that cardiac impairment in these mice was associated with mitochondrial dysfunction, altered substrate utilization, extracellular matrix remodeling, and metabolic stress; pathways that are similarly dysregulated in human HFpEF.

Cardiac electron microscopy revealed swollen mitochondria with disrupted cristae, which improved following dietary intervention. Conclusions Mitochondrial dysfunction and fibroinflammatory remodeling are prominent features of MASLD-associated cardiac dysfunction. Reversal of hepatic and cardiac phenotypes with dietary intervention, together with elucidation of underlying pathways, establish the Foz/Foz model as a useful translational platform for studying liver-heart axis in MASLD.