Liver fibrosis assessed via non-invasive tests is associated with incident heart failure in a general population cohort

Aims To determine whether liver fibrosis is associated with heart failure in a general population cohort, and if genetic polymorphisms (PNPLA3 rs738409; TM6SF2 rs58542926), linked to increased risk of liver fibrosis and decreased risk of coronary artery disease, modify this association. Methods Using UK Biobank data, we prospectively examined the relationship between non-invasive fibrosis markers [NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) and AST to platelet ratio index (APRI)] and incident hospitalization/death from heart failure (n=413,860). Cox-regression estimated hazard ratios (HR) for incident heart failure. Effects of PNPLA3 and TM6SF2 on the association between liver fibrosis and heart failure were estimated by stratifying for genotype, and testing for an interaction between genotype and liver fibrosis using a likelihood ratio test. Results 12,527 incident cases of heart failure occurred over a median of 10.7 years. Liver fibrosis was associated with an increased risk of hospitalization or death from heart failure (multivariable adjusted high risk NFS score HR 1.59 [1.47-1.76], p<0.0001; FIB-4 HR 1.69 [1.55-1.84], p<0.0001; APRI HR 1.85 [1.56-2.19], p<0.0001; combined fibrosis scores HR 1.90 [1.44-2.49], p<0.0001). These associations persisted for people with metabolic dysfunction-associated steatotic liver disease (MASLD), MASLD with alcohol consumption (Met-ALD) and harmful alcohol consumption. PNPLA3 rs738409 GG and TM6SF2 rs58542926 TT did not attenuate the positive association between fibrosis markers and heart failure. For PNPLA3 a statistically significant interaction was found between PNPLA3 rs738409, FIB-4, APRI score and heart failure. Conclusion In the general population, serum markers of liver fibrosis are associated with increased hospitalization/death from heart failure. Genetic polymorphisms associated with liver fibrosis were not positively associated with elevated heart failure risk.