Endometriosis, subclinical cardiac remodeling, and cardiovascular risk: mechanistic insights from cardiac magnetic resonance and mediation analysis

BACKGROUND: Endometriosis is a systemic gynecological disorder affecting ~ 10% of reproductive-aged women and shares pathophysiological features with cardiovascular disease (CVD). However, its associations with cardiac remodeling and CVD risk, as well as underlying mechanisms, remain unclear. METHODS: This study utilized data from the UK Biobank, comprising 6,158 women diagnosed with endometriosis and 229,453 women without the condition. To validate our results, we employed a hospital cohort from the Second Affiliated Hospital of the University of South China, which included 612 women with laparoscopically confirmed endometriosis and 612 age-matched controls. We applied multivariable-adjusted Cox proportional hazards models to investigate the association between endometriosis and the risk of CVD. Additionally, generalized linear models were used to evaluate cardiac magnetic resonance (CMR) metrics. Mediation analyses were conducted to quantify the contributions of 32 biomarkers, with a particular emphasis on metabolic indices (e.g., triglyceride-glucose (TyG)-related indices, lipid accumulation product (LAP)), inflammatory markers (C-reactive protein (CRP), inflammation score (INFLA)), oxidative stress indicators (urate, bilirubin), and hormonal status markers (sex hormone-binding globulin (SHBG)). RESULTS: Over a median 13-year follow-up, 23,239 CVD events occurred. Endometriosis was associated with increased risks of CVD (HR 1.18, 95% CI 1.09-1.29) and coronary heart disease (CHD) (HR 1.25, 95% CI 1.12-1.40). These findings were robust across multiple sensitivity analyses and consistently replicated in the external Chinese cohort, with an additional significant association observed for stroke (HR: 1.19, 95% CI: 1.03-1.40). CMR imaging revealed subclinical concentric remodeling, including increased interventricular septal thickness (1.11%, 95% CI 0.13-2.11), relative wall mass (1.11%, 95% CI 0.05-2.17), and septal-to-lateral wall thickness ratio (0.64%, 95% CI 0.00-1.29). Mediation analyses identified metabolic dysfunction as the primary pathway, with TyG-related indices (15.4%-17.3%), LAP (11.8%), and triglycerides (8.9%) accounting for the largest proportions, followed by inflammation (CRP: 11.1%; INFLA: 3.7%) and oxidative stress (urate: 6.0%). CONCLUSIONS: Endometriosis is associated with increased CVD risk and early subclinical cardiac remodeling, largely mediated by metabolic and inflammatory pathways. These findings underscore the necessity of cardiovascular risk stratification and metabolic monitoring in the clinical management of women with endometriosis.