Mendelian randomization unravels bidirectional effects of NAFLD and heart failure across subtypes

Background The association between heart failure (HF) and non-alcoholic fatty liver disease (NAFLD) is increasingly noted; however, whether it reflects a direct causal relationship remains uncertain. Using Mendelian randomization (MR), this study explored potential bidirectional links between NAFLD and HF. Methods We conducted bidirectional MR using summary statistics from large European-ancestry Genome-wide association studies (GWAS). The inverse-variance weighted (IVW) estimator was primary, with weighted median, Mendelian randomization–Egger (MR-Egger) regression, and weighted mode as complementary analyses. Horizontal pleiotropy was evaluated and adjusted via Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global and outlier tests. Analyses were conducted in a stepwise manner, beginning with the effect of NAFLD on HF overall, followed by subtype-specific evaluations for HFrEF and HFpEF. We then examined the reverse direction, assessing the effect of HF on stage-specific NAFLD outcomes (simple steatosis, inflammatory–fibrotic stages, and cirrhosis), and finally focused on HF-subtype–specific associations with cirrhosis. Results After adjusting for horizontal pleiotropy, MR indicated that NAFLD was not statistically significantly associated with HF, either overall or by subtype. In contrast, HF showed no effect on simple steatosis but was associated with a higher risk of fibrotic NAFLD (OR = 2.04, 95% CI 1.51–2.74, P < 0.001) and cirrhosis (OR = 1.30, 95% CI 1.12–1.50, P < 0.001). Notably, when stratified by HF subtype, HFrEF—but not HFpEF—was causally linked to cirrhosis (HFrEF OR = 1.14, 95% CI 1.02–1.28, P < 0.05; HFpEF OR = 1.07, 95% CI 0.90–1.27, P = 0.42). Conclusions This bidirectional MR provides robust genetic evidence that NAFLD is unlikely to be an independent causal risk factor for HF. Conversely, HF—particularly HFrEF—may promote the progression of NAFLD to advanced stages and increase cirrhosis risk, informing prevention, risk stratification, and therapies for HF-related hepatic complications.