Abstract P336: Early Metabolic Imbalance in Young Adults is a Hidden Risk Factor for Midlife Cardiovascular Disease: CARDIA 35-year Follow Up

Introduction: The U.S. population includes a prevalent group of teens and young adults with early metabolic imbalance or EMI. This insidious condition includes markers of insulin resistance, particularly its interaction with adiposity, as well subclinical inflammation and oxidative stress. High circulating insulin compensates for insulin resistance in tissues, keeping fasting glucose, triglycerides and HDL within normal limits. Thus, individuals with EMI do not meet the criteria for metabolic syndrome or prediabetes. Previously, we reported that compensatory hyperinsulinemia in young adults is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), based on an analysis of 30-year data from CARDIA: Coronary Artery Risk Development in Young Adults. Here, we expand the analysis to include other components of EMI and the latest 35-year follow up data. Hypothesis: In young adults, EMI increases the risk for midlife ASCVD. Methods: This is a retrospective cohort study of CARDIA. The parent study enrolled 5,114 participants, ages 18-30 at baseline. In this retrospective analysis, the baseline exclusion criteria were hyperglycemia, hypertriglyceridemia, low HDL, diabetes, CVD, pregnancy or fasting <8 hours, yielding 3,292 participants without metabolic syndrome or prediabetes. The data were analyzed using Cox proportional hazard regression in Stata 17.0 and JMP 16.2. The primary exposures were markers of insulin resistance, inflammation and oxidative stress at baseline; the covariates were the 2019 ACC/AHA risk factors for ASCVD: increased waist circumference (WC), hypertension, poor fitness, LDL ≥160, nicotine use (serum cotinine), family history of premature ASCVD, race, sex and estimated glomerular filtration rate (eGFR) <60. The primary outcome was time to incident ASCVD (or censor), defined as any fatal or nonfatal MI, coronary revascularization, acute coronary syndrome, CHF, stroke, TIA, carotid or peripheral artery disease. Cox results were reported as hazard ratio (HR) and Harrell’s c-statistic (c). Results: All reported Cox models met the proportional hazards and linearity assumptions. Model 1 includes the ACC/AHA risk factors, yielding a Harrell’s c of 0.714. For WC, the HR for tertile 3 vs. 1 was 2.1, 95% CI 1.4, 3.1, p<0.0001. Cox Model 2 replaces WC with a categorical variable with both WC and HOMA2-IR, a marker of insulin resistance. The HR for both measures in tertile 3 vs. both in tertile 1 was 2.1, 95% CI: 1.3, 2.5, p<0.0001; Harrell’s c increased to 0.728. Cox model 3 adds markers of inflammation and oxidative stress to Model 2, increasing C to 0.735. In models 2 and 3, high WC was a significant risk factor only in combination with high HOMA2-IR, indicative of effect modification. Conclusion: After accounting for canonical risk factors, early metabolic imbalance in otherwise healthy young adults in CARDIA is a hidden risk factor for midlife ASCVD.