Abstract WE423: Intersection between Cardiovascular-Kidney-Metabolic (CKM) Syndrome and Inflammation in Incident Cardiovascular Disease (CVD) and All-cause Mortality: MESA and CARDIA

Background: Limited data exists on the longitudinal joint associations of CKM syndrome and systemic inflammation with incident CVD events. Hypothesis: Systemic inflammation modifies the association between preclinical CKM syndrome stages and incident CVD events. Methods: The AHA classifies CKM syndrome into five stages, spanning optimal cardiovascular health to clinical CVD. We included 9,069 CVD-free participants (median age 54) from the MESA (exam 1, 2000–2002) and CARDIA (exam 7, 2005–2006) studies. We reclassified preclinical CKM syndrome by combining Stages 0 and 1, and subdividing Stage 2 at the median number of Stage 2 components. Baseline interleukin-6 (IL-6), a marker of systemic inflammation, was analyzed both categorically and continuously. Multivariable-adjusted Cox regression models were used to assess the specific associations of preclinical CKM syndrome and IL-6, with risks of incident CVD and all-cause mortality. Models were adjusted for age, sex, race/ethnicity, smoking status, and physical activity. Effect modification was evaluated, and specific estimates were made. Results: Over a median follow-up of 18.2 years, 1,439 atherosclerotic CVD events, 475 heart failure (HF), and 2,115 deaths were recorded. Incidence rates for both atherosclerotic CVD and HF increased with advancing CKM stages, regardless of IL-6 elevation. Notably, the incidence rate of all-cause mortality was higher among participants at CKM Stage 2a with elevated IL-6 levels compared to those at Stage 2b with low IL-6 (178 v.s. 158 per 10,000 py). Elevated IL-6 was independently associated with increased risk of atherosclerotic CVD [HR 95% CI: 1.33 (1.19, 1.49)], HF [1.37 (1.13, 1.66)], and all-cause mortality [1.42 (1.29, 1.56)]. Furthermore, within each CKM stage, the strength of association between IL-6 and CVD outcomes was consistent between individuals with high and low IL-6 levels ( Table ). Effect modification by IL-6 was tested and found to be non-significant. Additionally, individuals at Stage 2b with elevated IL-6 exhibited the highest risk across all outcomes compared to those at Stage 0,1 with low IL-6: atherosclerotic CVD [3.57 (2.83, 4.50)], HF [3.84 (2.52, 5.85)], and all-cause mortality [1.98 (1.66, 2.37)]. Conclusions: IL-6 does not act as an effect modifier. Rather, it is independently associated with CVD events, with a consistent magnitude of association observed across CKM stages. Higher IL-6 coupled with CKM stage 2b is a powerful predictor of future events.