Defining high risk in the cardiovascular-kidney-metabolic syndrome and associated cardiovascular disease outcomes

Abstract Background The American Heart Association (AHA) recently developed the cardiovascular-kidney-metabolic (CKM) syndrome construct with stages 0-4 to comprehensively characterize the spectrum of cardiovascular disease (CVD) risk [1]. CKM Stage 3 is defined by subclinical CVD or high (≥20%) estimated 10-year CVD risk according to the newly-derived PREVENT models [2]. However, within CKM Stage 3, the burden of subclinical atherosclerosis equivalent to a ≥20% estimated CVD risk, and long-term CVD outcomes associated with CKM Stage 3, are not known. Purpose To (1) characterize the distribution of subclinical atherosclerosis by coronary artery calcium (CAC) according to PREVENT estimated CVD risk categories, and (2) quantify long-term CVD risk associated with CKM Stage 3, in two international cohorts of adults without prior CVD. Methods In participants of the Multi-Ethnic Study of Atherosclerosis (MESA, age 45-84 years) and the Rotterdam Study (age ≥55 years), the burden of CAC was calculated across estimated 10-year CVD risk (low, 0 to <5%; borderline 5 to <7.5%; intermediate, 7.5 to <20%; high, ≥20%). Participants were categorized into CKM stages according to CVD risk factors (body mass index, waist circumference, glycemic status, blood pressure, lipids, kidney function), estimated 10-year CVD risk (by AHA PREVENT model), and presence of CAC. The association of CKM syndrome stage with fatal or nonfatal CVD outcomes was evaluated with covariate-adjusted proportional hazards regression. Results Among 6,123 MESA participants (52% female, mean age 61.4 years) and 1,691 Rotterdam Study participants (46% female, mean age 67.1 years), the distribution of CAC across absolute 10-year CVD risk categories is shown in Figure 1. In high (≥20%) CVD risk adults, CAC score ≥100 was present in 50% of MESA participants and 48% of Rotterdam Study participants. Most participants were classified as CKM Stage 3 (53% in MESA, 83% in Rotterdam). Over a median follow-up of 17.5 years in MESA, CVD events occurred in 5% of CKM Stage 0, 6% of Stage 1, 9% of Stage 2, and 26% of Stage 3 participants. Over a median follow-up of 10.2 years in the Rotterdam Study, CVD events occurred in 0% of CKM Stage 0 and 1, 8% of Stage 2, and 17% of Stage 3 participants (Figure 2). The risk of total CVD was significantly higher in CKM Stage 3 participants relative to CKM Stage 0-2 (MESA: adjusted HR 2.74, 95% CI 2.32, 3.23; Rotterdam: adjusted HR 2.18, 95% CI 1.34, 3.54). Conclusions In an international, multi-ethnic sample of middle-aged adults, adults with high (≥20%) absolute 10-year CVD risk by PREVENT had substantial burden of CAC. Adults in CKM Stage 3 had approximately 2.2- to 2.7-times higher risk for CVD, compared with adults in lower CKM stages. Accounting for estimated CVD risk and burden of cardiovascular, kidney, and metabolic risk factors informs prevention of subclinical and clinical CVD.