Abstract Body (Do not enter title and authors here): Background: In 2023, the American Heart Association defined Cardiovascular-Kidney-Metabolic (CKM) Syndrome, reflecting the connections among cardiovascular, kidney, and metabolic risk, and outlined a staging system for CKM Syndrome. The associations of CKM Stages with cardiovascular disease (CVD) subtypes have not yet been quantified.

Methods: We categorized ARIC Visit 4 (1996-98) participants by CKM Stages: 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); Stage 3, ≥20% predicted CVD risk per PREVENT calculator or very high-risk CKD; and Stage 4, clinical CVD. We used Cox regression to estimate relative risk associations of CKM stages with atherosclerotic CVD (ASCVD), heart failure (HF), total CVD (ASCVD + HF), and CVD mortality over 10 years and through 12/30/2021. We calculated population attributable fractions (PAFs) to estimate how much of CVD risk is attributable to CKM Syndrome for each CVD subtype. We further assessed time to CVD events and mortality across stages.

Results: Among 8,937 participants (mean age 63 years, 55% female, 18% Black), 3.8% were at Stage 0, 12.8% at Stage 1, 57% at Stage 2, 5.7% at Stage 3, and 20.6% at Stage 4 of CKM Syndrome. There was a stepwise increase in CVD risk with higher CKM stages (Table), with CKM stage 3 vs 0 associated with HRs of 4.1 for ASCVD, 11.2 for HF and 4.8 for total CVD, and CKM stage 4 vs 0 with a HR of 5.9 for CVD mortality. At 10 years, the PAFs associated with CKM Syndrome were 55% for ASCVD, 80% for HF, 62% for total CVD, and 62% for CVD mortality. Patterns were similar but attenuated over the full follow-up. Over the full study period, CVD events occurred 6-7 years earlier in CKM stage 3 vs 0, and CVD mortality 7 years earlier in CKM stage 4 vs 0.

Conclusion: Higher CKM syndrome stages are associated with greater risk of and earlier onset of CVD events, with CKM syndrome contributing the highest attributable risk for HF among CVD subtypes. These findings highlight the role of CKM staging for facilitating the prevention of CVD, especially HF, in the general population.