Investigating the heart-liver-axis in metabolic dysfunction-associated steatohepatitis and acute myocardial infarction

Abstract

Progression in metabolic dysfunction-associated steatotic liver disease (MASLD) to the inflammatory, profibrotic subphenotype metabolic dysfunction-associated steatohepatitis (MASH) is linked with increased mortality and incidence of heart failure post-myocardial infarction. Currently, the mechanisms underlying this apparent accelerated progression to heart failure are poorly defined. We hypothesise that pre-existing MASH dysregulates post-MI wound healing, leading to aberrant collagen deposition and worsened cardiac function.

Here, we developed a combined Western-style diet-induced MASH (WD) and isoprenaline-induced myocardial injury/infarction (MI) model in Sprague-Dawley rats. Concurrently, we conducted a systems-level bioinformatics analysis of heart and liver global transcriptomic data from ~100 mouse strains in the Hybrid Mouse Diversity Panel (HMDP) and a preclinical model of heart failure with preserved-ejection fraction (HFpEF).

Acute myocardial injury, assessed by plasma cardiac troponin I (cTnI), did not differ between WD and control diet groups post-isoprenaline administration (mean±SEM; WD – 6009±1224 ng/L; Control – 4405±670 ng/L; Mann-Whitney test; p=0.57). By day 7 post-MI, the WD group had greater histological myocardial collagen deposition than controls (WD – 5.88±1.09%; Control – 3.90±0.18%; Mann-Whitney test; p=0.04). At 12-weeks, the WD group had impaired systolic function on echocardiography, indicated by reduced left ventricular ejection fraction (LVEF) (WD – 54.78±2.86%; Control – 63.31±1.34%; Mann-Whitney test; p=0.01). Our bioinformatics analysis ranked genes encoding liver-secreted proteins by their cross-tissue correlations with cardiac genes and pathways, leveraging natural variation across the HMDP and changes observed in HFpEF1,2. To explore the translational relevance, we analysed a publicly available plasma proteomics dataset from patients with MASLD and MASH3, identifying several liver-derived factors potentially implicated in adverse myocardial remodelling, including afamin, lumican, and orosomucoid 2. Using the SteatoSite patient cohort (n=707) with histologically staged MASLD fibrosis and bulk RNA-sequencing data4, we assessed whether hepatic gene expression correlates with fibrosis severity and are now investigating whether these secreted factors are associated with major adverse cardiovascular events.

Collectively, these data support that pre-existing MASH exacerbates post-MI collagen deposition and cardiac dysfunction, despite comparable initial injury. We are now characterising myocardial remodelling with whole-heart clearing and 3D imaging, and validating hepatic gene expression and plasma levels of candidate liver-secreted factors implicated in adverse remodelling.