Key result
CKM syndrome Stage 4 linked to ~21.8-fold higher cardiovascular mortality vs Stage 0-1.
Why the study?
The American Heart Association recently introduced the cardiovascular-kidney-metabolic (CKM) syndrome staging system, but its distribution in a general population initially free of clinical CVD and its prognostic relevance for cardiovascular mortality remain under discussion.
Cohort (n=1,325)
Advancing American Heart Association cardiovascular-kidney-metabolic (CKM) syndrome stages (specifically stages 3 and 4) are strongly associated with a stepwise increase in the risk of cardiovascular mortality over a median 10-year follow-up.
May refine CV risk stratification in CKM syndrome; leaves open whether staging improves outcomes or warrants practice change.
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
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Sousa et al. (2026) conducted a cohort in Cardiovascular-kidney-metabolic (CKM) syndrome (n=1,325). Cardiovascular-kidney-metabolic (CKM) syndrome Stage 4 (and Stage 3) vs. CKM Stage 0-1 was evaluated on Cardiovascular mortality (HR 21.76, 95% CI 2.87-164.72, p=0.003). CKM syndrome Stage 3 (HR 8.47; 95% CI 1.03-69.70) and Stage 4 (HR 21.76; 95% CI 2.87-164.72) significantly increased cardiovascular mortality vs Stage 0-1.
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