Abstract Body (Do not enter title and authors here):
Introduction
Cumulative exposure to LDL-C over time is independently associated with incident atherosclerotic cardiovascular disease (ASCVD), while the absence of coronary artery calcium (CAC) is associated with a low risk of ASCVD events regardless of baseline LDL-C. Whether cumulative LDL-C exposure influences clinical risk stratification in individuals with CAC=0 is unknown.

Objectives
To assess whether cumulative LDL-C exposure in young adults with CAC=0 was associated with incident ASCVD events or future conversion to CAC>0.

Methods
This analysis included Coronary Artery Risk Development in Young Adults (CARDIA) participants who underwent CAC scans at year 15 (Y15) (n=3043) or Y25 (n=3189) with measures of LDL-C from Y0 (baseline), 2, 5, 7, 10, 15, 20, 25, 30, and 35. Of those with CAC measured at Y15 and Y25, 2734 (89.9%) and 2282 (71.6%) had CAC=0, respectively. Cumulative LDL-C exposure was calculated using area under the curve (LDL-AUC) for three different time intervals: Y0-15, Y0-25, and Y15-25. Univariate and multivariate Cox regression models (adjusted for age, sex, race, and traditional ASCVD risk factors) were used to determine the association of LDL-AUC (per 100 mg/dL x years) with incident fatal and non-fatal ASCVD events with mean follow-up time 19.1 years after Y15 and 9.7 years after Y25. Logistic regression was used to measure the association of LDL-AUC with conversion from CAC=0 to CAC>0.

Results
Of those with CAC=0 at Y15 (58% female, mean age 40 years) and Y25 (65% female, mean age 50 years), the event rate was 2.8 and 3.0 per 1000 person-years, respectively. After multivariate adjustment, LDL-AUC_[Y0-15] in individuals with CAC=0 at Y15 was not associated with a significant increase in risk for ASCVD events (HR 1.01, 95% CI: 0.97-1.05). LDL-AUC_[Y0-25] was associated with a significantly increased risk for ASCVD events after multivariate adjustment in those with persistent CAC=0 at Y25 (HR 1.05, 95% CI: 1.01-1.09). There was a significant association between LDL-AUC_[Y15-25] and conversion from CAC=0 at Y15 to CAC>0 at Y25 (OR 1.10, 95% CI: 1.05-1.14).

Conclusions
In young adults with CAC=0, long-term cumulative exposure to LDL-C remains independently associated with a significant increase in ASCVD events and development of future CAC. While the risk of cardiovascular events is low for those with CAC=0, risk is detectable over longer exposure to greater cumulative LDL-C, confirming the continued importance of long-term LDL-C control.