Trajectory of liver-related events following incident cardiovascular disease in MASLD: A 15-year population-based cohort study

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a risk factor for cardiovascular disease (CVD). However, the risk of liver-related events (LREs) after CVD is often overlooked. We investigated the association between incident CVD and subsequent long-term LRE risk among individuals with MASLD. Methods: We used UK Biobank data to examine whether incident CVD (coronary heart disease [CHD], myocardial infarction [MI], heart failure [HF], or atrial fibrillation [AF]) was associated with subsequent long-term LREs (cirrhosis, decompensation, hepatocellular carcinoma, or liver-related death) in MASLD. Semi-Markov multi-state and time-dependent Cox regression models estimated transition rates and adjusted hazard ratios (aHRs). Imaging and proteomic data explored biological mechanisms. Results: Among 142,454 individuals with MASLD, 22,630 (15.9%) developed incident CVD, and 2635 (1.8%) developed subsequent LREs over a median of 15.1 years. The transition rate from CVD to LREs was higher than the direct progression from MASLD to LREs (3.56 vs. 1.08 per 1000 person-years). Time-dependent Cox regression showed that incident CVD was associated with a higher risk of subsequent LREs (aHR 1.93, 95%CI 1.73-2.14). The risk varied by CVD subtypes, with HF highest, followed by AF, CHD, and MI (all P < 0.001). Exploratory integrated multi-omics analyses revealed associations between cardiac dysfunction and hepatic parameters, and identified a shared proteomic signature enriched in immune and fibrotic pathways. Conclusions: Individuals with MASLD who experience a CVD event have a higher subsequent risk of long-term LREs. These findings underscore the value of targeted liver monitoring for high-risk individuals after CVD and integrated heart-liver co-management.