Abstract Body (Do not enter title and authors here): Background: Higher stages of Cardiovascular-Kidney-Metabolic (CKM) Syndrome are associated with greater cardiovascular disease (CVD) risk. However, the rates of CKM stage progression over time and its impact on CVD outcomes are currently unknown.

Methods: We evaluated 8,367 ARIC Visit 4 (1996-98) participants without CVD at Visit 1 (1987-89), with available data to define CKM stage at Visits 1 and 4. We categorized based on CKM Stages at Visits 1 and 4, defined as: Stage 0, no CKM risk factors; Stage 1, excess/dysfunctional adiposity; Stage 2, metabolic risk factors (hypertriglyceridemia, hypertension, metabolic syndrome, or diabetes) and/or moderate- to high-risk chronic kidney disease (CKD, per KDIGO classification); Stage 3, ≥20% predicted CVD risk per PREVENT calculator or very high-risk CKD; and Stage 4, clinical CVD. For those in CKM stages 0-3 at Visit 1, we quantified transitions in CKM stages by Visit 4, as well as incidence rates of atherosclerotic CVD (ASCVD), heart failure (HF), total CVD (ASCVD + HF), and CVD mortality over 10 years according to CKM stage progression. We evaluated rates of first CVD events for those in Stages 0 to 3 by Visit 4, and of first recurrent CVD events for those in Stage 4 by Visit 4.

Results: The mean age was 55 years at Visit 1, with 52% female, and 21% Black adults. Most participants progressed to a higher CKM stage by Visit 4 (~9-year interval): 77% of those in Stage 0 at Visit 1, 73% of Stage 1, 42% of Stage 2, and 75% of Stage 3 (Figure). Within each CKM stage at Visit 1, progression to higher CKM stages by Visit 4 was associated with a higher incidence of CVD events (Table), with higher risk for those at a higher CKM stage at Visit 1. The transition from Stage 2 to 3 was associated with the highest rate (per 1000 person-years) of first CVD events (49.8, versus 20.0 for remaining in stage 2), while the transition from stage 3 to 4 was associated with the highest rate of recurrent CVD events (151.1). Similar patterns were seen for ASCVD, HF and CVD mortality.

Conclusion: Most middle-aged adults transition to a higher stage of CKM Syndrome over a decade, which is linked to greater CVD risk. Preventing the progression of CKM Syndrome may help to mitigate CVD risk.