Cumulative cardiovascular-kidney-metabolic burden, adverse cardiac remodeling and clinical events: A life-course analysis of MESA and CARDIA

Background Cardiovascular-kidney-metabolic (CKM) syndrome integrates adiposity, metabolic dysfunction, and kidney disease into a continuum of cardiovascular (CV) risk. The implications of cumulative CKM burden over time and across the lifespan remain less explored. Objectives To relate cumulative CKM burden to downstream cardiac remodeling and incident CV events. Methods We studied CARDIA (enrolled at 18–30 years) and MESA (45–84 years, free of clinical CV disease). Cumulative CKM-years were defined as the area under the CKM stage versus time curve from baseline to a landmark visit (Year 25 in CARDIA; Exam 5 in MESA); cumulative body mass index (BMI)-years were derived identically. Exposures were related to downstream echocardiography and incident 3-point major adverse CV events (MACE), adjusting for demographics, risk factors, and baseline exposure. Results Among 2968 CARDIA (age 25±4 years; 56% women) and 4294 MESA participants (age 61±9 years; 53% women), CKM stages 3–4 rose from 0.1% to 28.7% and from 49.7% to 71.1%, respectively. Greater cumulative CKM-years were associated with higher left ventricular (LV) mass index, left atrial volume index, E/e', and worse global longitudinal strain in both cohorts. Over a median 8.9 and 8.7 years, each standard deviation increment was associated with higher MACE risk (CARDIA: HR 2.35 [95% CI: 1.79–3.09]; MESA: 1.71 [1.40–2.09]), including after adjustment for landmark CKM stage. In MESA, structural remodeling was largely explained by concurrent CKM stage. Cumulative BMI-years remained associated with cardiac remodeling beyond baseline BMI in CARDIA, with a significant interaction with baseline BMI in relation to LV mass observed in both cohorts. Conclusions Greater cumulative CKM burden was associated with adverse cardiac remodeling and higher CV event risk across the life course. These findings support longitudinal assessment of CKM burden and cumulative adiposity rather than reliance on single time-point measures.