Liver fibrosis assessed using non-invasive markers and genetic polymorphisms (PNPLA3 and TM6SF2) predisposing to liver fibrosis, is associated with hospitalization or death from heart failure: a prospective UK Biobank study

BackgroundAside from liver related complications, non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ArLD) are associated with an increased risk of cardiovascular disease (CVD). Liver fibrosis, determined via histology and non-invasive serum fibrosis markers, is associated with cardiovascular events. The association between liver fibrosis and heart failure, and the relationship between PNPLA3 rs738409 and TM6SF2 rs58542926 and heart failure is of particular interest, given the known associations of these genetic polymorphisms with increased risk of liver fibrosis and decreased risk of coronary artery disease. MethodsUsing data from the UK Biobank (UKBB), we examined the relationship between liver fibrosis, determined using non-invasive markers (NAFLD fibrosis score, Fibrosis-4 (FIB-4) and AST to platelet ratio index (APRI score)) and hospitalization or death from heart failure in 413,860 people. Participants were followed up prospectively via electronic linkage to hospital and death records. Cox-regression estimated the hazard ratios (HR) for death or admission with heart failure. The effects of PNPLA3 and TM6SF2 on the association between liver fibrosis and incident heart failure were estimated in an analysis stratified by genotype and by testing for an interaction between genotype and liver fibrosis using a likelihood ratio test. Results12,527 incident cases of heart failure occurred over a median of 10.7 years. Liver fibrosis, determined by single or combination non-invasive tests, was associated with an increased risk of hospitalization or death from heart failure; multivariable adjusted high risk NFS score HR 1.59 [1.45-1.76], 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 NAFLD or harmful alcohol consumption. Polymorphisms linked to liver fibrosis (PNPLA3 rs738409 GG and TM6SF2 rs58542926 TT) further amplified the positive association between non-invasive liver fibrosis markers and heart failure. A statistically significant interaction was found between PNPLA3 rs738409, FIB-4, APRI score and heart failure. ConclusionLiver fibrosis, determined via non-invasive tests, is associated with an increased risk of hospitalization/death from heart failure in a general population cohort with mixed etiologies of chronic liver disease, including individuals with NAFLD and harmful alcohol consumption. Genetic polymorphisms associated with increased risk of liver fibrosis further increased the risk of heart failure. These findings have important mechanistic, clinical, and public health implications.