Association between cardiorespiratory fitness and risk of incident venous thromboembolism: a prospective cohort study.

BACKGROUND: Venous thromboembolism (VTE) is a leading cardiovascular disease with substantial burden, yet the association between cardiorespiratory fitness (CRF) and VTE risk remains inconclusive. OBJECTIVES: This study is aimed to investigate the association of CRF with incident VTE, and quantify the mediating effects of circulating biomarkers. METHODS: A total of 63,755 participants from the UK Biobank without prior VTE were included. CRF was estimated using a submaximal cycle ergometer test and classified into low (<20th percentile), moderate (20th-60th percentile), and high (>60th percentile) categories, standardized by sex and 10-year age groups. VTE was ascertained through linkage to national health records. Cox proportional hazards models adjusted for potential confounders were used to estimate hazard ratios (HRs) and 95% CIs. Polygenic risk scores for VTE were categorized into low, middle, and high tertiles. Mediation analyses were performed to assess the contribution of circulating biomarkers. RESULTS: During a median follow-up of 12.5 years, 1744 incident VTE cases were documented. Each 1-metabolic equivalents increment in CRF was associated with an 8% lower VTE risk (HR 0.92, 95% CI 0.89-0.95). Compared with low CRF, high CRF was associated with a 27% lower risk (HR 0.73, 95% CI 0.63-0.84). The inverse association was consistently observed across all genetic risk strata. C-reactive protein, alkaline phosphatase, gamma-glutamyl transferase, cystatin C, and creatinine were estimated to account for 21.5% of this association. CONCLUSION: Higher CRF is associated with a lower VTE risk, regardless of genetic susceptibility. Inflammation, hepatobiliary enzymes, and renal function markers may account for a portion of this association.