Abstract 4366227: Cumulative LDL-C Exposure and Presence of CAC at Midlife: A Combined Predictor of Long-Term Cardiovascular Risk

Background: Emerging evidence suggests that cumulative exposure to low-density lipoprotein cholesterol (LDL-C), rather than a single measurement, may be a stronger determinant of future ASCVD. The presence of coronary artery calcium (CAC) at midlife offers a subclinical marker of atherosclerotic burden. Herein, we aim to assess the interplay of early-life LDL-C exposure and CAC in young adults for predicting long-term ASCVD risk. Methods: We included 2159 participants free of clinical ASCVD from the CARDIA (Coronary Artery Risk Development in Young Adults) study who had longitudinal LDL-C measurements from early adulthood, underwent CAC scanning and were ≥40 years old at exam 15 (mean age: 42.7; 57.3% female; 41.4% Black). LDL-C exposure was quantified as area under the curve (AUC) from age 18-40 and categorized into tertiles. CAC was assessed at exam 15 (CAC=0 or CAC>0). Participants were followed for 18 years for MACE, defined as nonfatal CHD, myocardial infarction, ischemic stroke, acute coronary syndrome, revascularization, transient ischemic attack, peripheral artery disease, death, and CHF. Results: The overall prevalence of CAC>0 at exam 15 increased across LDL-C exposure tertiles (6.5-20%). Compared to tertile 1, adjusted odds of CAC>0 were (OR: 1.47; 95% CI: 0.99-2.17; p=0.051) in tertile 2 and (OR: 2.96; 95% CI: 2.07-4.28; p<0.001) in tertile 3. Over a mean follow-up of 18 years, 238 (11%) MACE events were observed with an annualized event rate of 0.61%. Both higher cumulative LDL exposure and presence of CAC at midlife were associated with higher risk of MACE ( Table 1 ). Among those with CAC=0, MACE rates ranged from 0.43%-0.60% across LDL exposure as compared to those with CAC>0 whose rates ranged from 1.25%-1.92%. In multivariable Cox models adjusting for age, race, sex, SBP, BMI, HDL-C, eGFR, and triglycerides, both higher LDL-C AUC (HR: 1.47; 95% CI: 1.05-2.17; p=0.026) and CAC>0 (HR:2.31; 95% CI: 1.69-3.16; p<0.001) were independently associated with increased risk of MACE. Conclusion: In this young adult cohort, cumulative LDL-C exposure and presence of CAC were independently associated with future ASCVD events. While higher lifetime LDL-C was linked to increased odds of CAC>0 at midlife, individuals with CAC=0 had low long-term event rates, whereas those with both CAC>0 and elevated LDL-C had the highest absolute risk, highlighting the heterogeneity of risk conferred by LDL-C exposure and the additive prognostic value of CAC in midlife.