Association of cardiovascular-kidney-metabolic syndrome with cardiovascular mortality: a prospective cohort study in Madeira Island
F Sousa, M Mendonca, S Freitas, G Abreu, M Ferreira, F Escorcio Silva, E Henriques, M Rodrigues, S Borges, I Ornelas, A Drumond, A C Sousa, R Palma dos ReisAbstract
Background
Cardiovascular disease (CVD) results from interconnected metabolic and renal comorbidities that jointly increase atherosclerotic burden and mortality. The American Heart Association recently introduced the cardiovascular–kidney–metabolic (CKM) syndrome staging system, but its prognostic relevance remains under discussion.
Objective
To assess the distribution of CKM stages in a general population initially free of clinical CVD and evaluate their association with cardiovascular mortality.
Methods
This prospective cohort included 1,325 participants (mean age 57.1±6.6 years; 73.5% male) followed between 2002 and 2025 (median 10 years; IQR 5–15). Participants were classified according to AHA CKM criteria into five stages: 0 (no risk factors), 1 (excess dysfunctional adiposity), 2 (metabolic risk factors and/or CKD), 3 (CKD plus subclinical atherosclerosis), and 4 (established CVD). Multivariate Cox proportional hazards models adjusted for age, sex, smoking, sedentary lifestyle, and alcohol abuse were used to estimate associations with cardiovascular mortality. Kaplan–Meier curves assessed survival differences.
Results
Thirty-five cardiovascular deaths occurred during follow-up. CKM stage distribution shifted with age: Stage 1 predominated at ≤39 years (44.0%); Stage 2 became dominant at 40–49 (41.3%) and remained highest at 50–59 (57.7%) and ≥60 (58.4%); advanced stages (3–4) increased markedly in ≥60 years (16.4% and 15.7%). After adjustment, the CKM stage was strongly associated with cardiovascular mortality, compared with CKM 0–1. Stage 3 conferred an eightfold higher risk (HR=8.47; 95% CI 1.03–69.70; p=0.047) and Stage 4 a twenty-two-fold higher risk (HR=21.76; 95% CI 2.87–164.72; p=0.003). Stage 2 was not significantly different from the reference group. Kaplan–Meier analysis demonstrated a stepwise decline in cardiovascular survival with advancing CKM stage (log-rank p<0.0001).
Conclusion
Our study reveals a high prevalence of CKM syndrome (stages 1 to 4) among the Madeira cohort population, and higher CKM stages were associated with an increased risk of cardiovascular mortality. These findings emphasise that primordial and primary prevention efforts on promoting CKM health should be strengthened to reduce mortality risk.CKMCox Regression