Cardio-hepatic axis in metabolic dysfunction-associated steatotic liver disease: Mechanisms, clinical implications and therapeutic opportunities

Figure 1 Schematic diagram of bidirectional crosstalk and systemic regulatory networks in the cardio-hepatic axis in metabolic dysfunction-associated steatotic liver disease. The central white circle illustrates the direct bidirectional dialogue between the liver and the heart: The liver acts on the heart through extracellular vesicles, while the heart reciprocally regulates the liver through the secretion of atrial natriuretic peptide and B-type natriuretic peptide, accompanied by target organ phenotypes. The grey annular band encircling the core region summarizes the pathogenic mediators intertwined with the systemic amplification networks that drive shared core pathways underlying concurrent cardiac and hepatic injury. The outermost four modules, immunometabolic network, gut signaling network, circadian rhythm network, and genetic/epigenetic/CHIP, further exacerbate the vicious cycle of the cardio-hepatic axis by amplifying pathological molecular levels within the loop. For a detailed list of all specific molecules mediating these interactions, see Table 1. PCSK9: Proprotein convertase subtilisin/kexin type 9; FXI: Factor XI; FGF21: Fibroblast growth factor 21; ANGPTL3: Angiopoietin-like protein 3; SAA1/4: Serum amyloid A1/A4; EVs: Extracellular vesicles; ANP: Atrial natriuretic peptide; BNP: B-type natriuretic peptide; HSC: Hepatic stellate cell; MASH: Metabolic-dysfunction-associated steatohepatitis; AngII: Angiotensin II; GDF15: Growth differentiation factor 15; CHIP: Clonal hematopoiesis of indeterminate potential.

Figure 2 Integrated cardio-hepatic risk stratification workflow for metabolic dysfunction-associated steatotic liver disease. All patients receive annual screening for type 2 diabetes mellitus, hypertension and dyslipidaemia plus baseline atherosclerotic cardiovascular disease risk assessment via the PREVENT equation. Step 1: Fibrosis-4 (FIB-4) index initial fibrosis screening (low: FIB-4 < 1.3; grey zone: 1.3 ≤ FIB-4 ≤ 2.67; high: FIB-4 > 2.67). Grey zone patients proceed to vibration-controlled transient elastography liver stiffness measurement (LSM) measurement (exclude advanced fibrosis: LSM < 8 kPa; grey zone: 8 kPa ≤ LSM < 12 kPa; advanced fibrosis: LSM ≥ 12 kPa); enhanced liver fibrosis score (cutoff ≥ 9.8) serves as a vibration-controlled transient elastography substitute. Three management tiers are defined: (1) Routine biennial follow-up for low-risk patients; (2) Annual monitoring with coronary artery calcium recalibration for intermediate-risk individuals; and (3) Urgent multidisciplinary specialist referral for high-risk patients. All patients with type 2 diabetes mellitus or established cardiovascular disease require yearly fibrosis reassessment. XL probe is suggested for obese patients to measure controlled attenuation parameter steatosis grade simultaneously. MASLD: Metabolic dysfunction-associated steatotic liver disease; T2DM: Type 2 diabetes mellitus; FIB-4: Fibrosis-4; ELF: Enhanced liver fibrosis; LSM: Liver stiffness measurement; CVD: Cardiovascular disease; CAC: Coronary artery calcium; VCTE: Vibration-controlled transient elastography.

Figure 3 Mechanism-targeted therapeutic strategies for cardio-hepatic crosstalk in metabolic dysfunction-associated steatotic liver disease. Central panel: Bidirectional cardio-hepatic pathogenic signalling loops. Four therapeutic modules encircle the core: (1) Upper left: Agents blocking liver-derived pathogenic mediators; (2) Upper right: Therapies reversing heart-induced hepatic injury; (3) Lower left: Interventions suppressing systemic amplification pathways; (4) Lower right: Synergistic combination regimens. Key therapeutic agents are listed within each corresponding module. Full molecular mediators are detailed in Table 1; evidence grading of each intervention is summarised in Table 2. GLP-1: Glucagon-like peptide-1; GIP: Glucose-dependent insulinotropic polypeptide; THR-β: Thyroid hormone receptor-β; pan-PPAR: Pan-peroxisome proliferator-activated receptor; PPARγ: Peroxisome proliferator-activated receptor-γ; FGF21: Fibroblast growth factor 21; PCSK9: Proprotein convertase subtilisin/kexin type 9; EVs: Extracellular vesicles; SGLT2: Sodium-glucose cotransporter 2; RAAS: Renin-angiotensin-aldosterone system; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; MRA: Mineralocorticoid receptor antagonist; GLP-1RA: Glucagon-like peptide-1 receptor agonist; SGLT2i: Sodium-glucose cotransporter 2 inhibitor; FXR: Farnesoid X receptor; RNAi: RNA interference; PNPLA3: Patatin-like phospholipase domain-containing protein 3; HSD17β13: Hydroxysteroid 17-beta dehydrogenase 13.