Sex differences in cardiovascular-kidney-metabolic syndrome and new onset cardiovascular outcomes

Cardiovascular-Kidney-Metabolic (CKM) syndrome integrates metabolic risk factors, chronic kidney disease (CKD), and cardiovascular dysfunction, and is closely linked to cardiovascular disease (CVD) risk. We aimed to evaluate sex-specific differences in prevalence, components, and outcomes of CKM syndrome to inform strategies for personalized cardiovascular prevention.

We included 6563 participants without established CVD from the Multi-Ethnic Study of Atherosclerosis (MESA). CKM stages were defined according to American Heart Association criteria. We assessed sex-specific prevalence, component distributions, and incidence of coronary heart disease (CHD), heart failure (HF), stroke, and mortality. Incidence rates (IR) per 1000 person-years and Fine-Gray subdistribution hazard ratios (SHR) were estimated.

Among 3095 men and 3468 women (mean age: 62 ± 10 years), men had a higher CKM Stage 3 prevalence (42.4% vs. 36.4% in women). Within Stage 3, subclinical atherosclerotic CVD (coronary artery calcium [CAC] score ≥ 100 Agatston unit) predominated in men (70.5%), whereas subclinical HF (elevated cardiac biomarkers) was more frequent in women (70.1%). During a median follow-up of 13.7 years (IQR 9.0-15.5 years), CHD incidence was higher in men (IR: 20.9 vs. 8.9 in women), followed by HF (IR: 7.2 vs. 4.5) and stroke (IR: 6.7 vs. 6.3). Using women as the reference, SHRs (95% CI) for men were 2.28 (1.84, 2.82) for CHD, 1.66 (1.20, 2.30) for HF, and 1.07 (0.80, 1.43) for stroke.

Men exhibited a higher prevalence of advanced CKM Stages and a substantially greater CHD burden, while women showed a higher subclinical HF phenotype within CKM Stage 3. These findings support sex-specific, stage-based CKM assessment as an actionable framework for early risk stratification and tailored cardiovascular prevention.