Abstract / Summary
Abstract Background Metabolic liver abnormality (here proxied by non-invasive surrogates, specifically imaging-defined steatosis or elevated GGT) is linked to accelerated atherosclerosis and cardiovascular mortality, yet clinical observations reveal a subset of patients with metabolic liver abnormality but preserved coronary patency—an “uncoupled” phenotype whose prognosis remains undefined. We aimed to characterize this phenotype and evaluate its cardiovascular outcomes. Methods In a prospective angiography cohort of 8,182 consecutive patients undergoing coronary angiography, we classified four phenotype groups based on metabolic liver abnormality (fatty liver imaging or GGT > sex-specific upper limit of normal) and coronary atherosclerotic burden (Gensini score; pre-specified cut-off = 20, determined as the sample median of independently recalculated scores): Group A (no metabolic abnormality, low Gensini; n = 2,006), Group B (no metabolic abnormality, high Gensini; n = 2,015), Group C (metabolic abnormality, low Gensini—the uncoupled phenotype; n = 2,213), and Group D (dual burden; n = 1,948). Cox proportional hazards models with sequential covariate adjustment (Models 1–4), interaction tests, FDR-corrected subgroup analyses, Fine–Gray competing risk models, and ten sensitivity analyses (S1–S10) were performed. Results Over a median follow-up of 2.2 years (764 MACE events, 171 deaths), the fully adjusted Model 4 showed that Group B (HR = 2.40 (1.99–2.91)) and Group D (HR = 2.12 (1.74–2.60)) had significantly elevated MACE risk versus Group A, whereas Group C (uncoupled phenotype) did not (HR = 0.84 (0.67–1.05), P = 0.121). The MACE incidence rate ratio for Group C versus Group A was 1.0065 (P = 0.963). Multiplicative interaction was non-significant (P = 0.259). All ten sensitivity analyses confirmed the primary findings. Conclusions The metabolic liver–coronary uncoupled phenotype carries a cardiovascular prognosis comparable to patients with neither risk factor. Coronary atherosclerotic burden, rather than metabolic liver abnormality per se, drives cardiovascular risk. These findings support coronary-centric risk stratification in patients with metabolic liver abnormality.