Platelet dysfunction, liver fibrosis and adverse outcomes in individuals with ischemic heart disease: a post-hoc analysis of the prospective observational EVA study

Background Subclinical liver fibrosis, assessed using the Fibrosis-4 (FIB-4) index, has emerged as a robust prognostic marker across cardiovascular conditions. Large prospective cohort studies and meta-analyses have shown that elevated FIB-4 values are associated with a higher risk of cardiovascular events and mortality in individuals, both with and without metabolic dysfunction–associated steatotic liver disease. However, the biological mechanisms linking liver fibrosis to adverse outcomes in ischemic heart disease (IHD) remain incompletely understood. We hypothesize that platelet dysfunction, a key determinant of atherothrombosis and inflammation, may serve as a mechanistic link between liver fibrosis and cardiovascular risk. Methods This study is a post-hoc analysis of the prospective observational Endocrine Vascular disease Approach (EVA) study. Adults undergoing coronary angiography for acute coronary syndrome or stable angina were prospectively enrolled and included in this study, and the FIB-4 index for liver fibrosis was calculated. Platelet function was evaluated using platelet count–adjusted soluble P-selectin and mean platelet volume (MPV), biomarkers previously shown to reflect platelet activation in IHD. All-cause and cardiovascular death were recorded during follow-up. Results Among 462 individuals (mean age: 66.8±11.4 years; 30.9% females) with IHD included in the analysis, 54 (11.7%) patients showed a FIB-4 > 2.67, indicating a high risk of advanced fibrosis. Patients with higher FIB-4 were older and had a higher prevalence of heart failure (HF). In the multivariable logistic regression analysis, C-reactive protein (OR 1.10, 95% CI 1.02–1.20, per mg/dL increase) and PLT-adjusted soluble P-selectin levels (OR 1.83, 95% CI 1.30–2.60, per increasing quartile) were independently associated with FIB-4 > 2.67. Among the 440 (95.2%) individuals with available follow-up data, all-cause mortality was higher among patients with FIB-4 >2.67 (Figure 1); similar results were observed for cardiovascular mortality. Higher FIB-4 values were independently associated with all-cause and cardiovascular mortality in a multivariable Cox regression model. Conclusions In individuals with IHD, FIB-4 identifies a high-risk phenotype characterized by enhanced platelet activation and systemic inflammation; higher FIB-4 values are independently associated with adverse outcomes. These findings support platelet dysfunction as a potential biological link between subclinical liver fibrosis and cardiovascular risk.