Association between cardiovascular-kidney-metabolic syndrome, inflammatory biomarkers, and cardiovascular outcomes: Insights from the MESA study

Background: This study investigated the association between cardiovascular-kidney-metabolic (CKM) syndrome stages 0–3 and atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF), as well as whether this association varies by interleukin-6 and high-sensitivity C-reactive protein (hsCRP). Methods: 6579 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) were included. Restricted mean survival time (RMST) differences in ASCVD and HF-free survival by CKM syndrome stage, stratified by inflammatory markers, were estimated. Results: Over a median follow-up of 17.5 years (IQR: 10.5–18.4 years), participants with CKM stage 3 demonstrated significantly shorter ASCVD-free survival compared to stage 0 (−1.94 years; 95 % CI: −2.27, −1.61). Subgroup analysis by IL-6 levels demonstrated differential RMST across CKM stages, with participants having above-median IL-6 levels showing greater survival reduction (−2.5 years; 95 % CI: −3.50, −1.85) than those with below-median levels (−1.46 years; 95 % CI: −1.84, −1.07) (interaction p = 0.002). For heart failure outcomes, categorization by IL-6 levels displayed similar patterns by CKM stage (interaction p = 0.006). Among participants with elevated IL-6, both CKM stages 2 and 3 were associated with reduced HF-free survival (−0.40 years [95 % CI: −0.69, −0.01], and −0.87 years [95 % CI: −1.18, −0.55], respectively). Conversely, participants with lower IL-6 levels showed a significant reduction in HF-free survival only at the CKM stage 3 level (−0.36 years: 95 % CI: −0.57, −0.14). hsCRP stratification yielded comparable results but without significant interactions for either cardiovascular outcome. Conclusions: These findings suggest that systemic inflammation, as measured by IL-6, may modify the risk of ASCVD and HF associated with CKM syndrome. Therefore, IL-6 measurement could potentially refine risk stratification and prognosis of CKM syndrome stages. However, further studies are needed to assess the clinical relevance of this approach.