Background Elevated total cholesterol ( TC ), low-density lipoprotein cholesterol ( LDL -C), triglycerides, and non-high-density lipoprotein cholesterol (non- HDL -C) and low high-density lipoprotein cholesterol ( HDL -C) concentrations correlate with atherosclerotic cardiovascular disease ( ASCVD ) and mortality. Therefore, understanding how lipid trajectories throughout adulthood impact ASCVD and mortality risk is essential. Methods and Results We investigated 3875 Framingham Offspring participants (54% women, mean age 48 years) attending ≥1 examination between 1979 and 2014. We evaluated longitudinal correlates of each lipid subtype using mixed-effects models. Next, we clustered individuals into trajectories through group-based modeling. Thereafter, we assessed the prospective association of lipid trajectories with ASCVD and mortality. Male sex, greater body mass index, and smoking correlated with higher TC , LDL -C, triglycerides, non- HDL -C, and lower HDL -C concentrations. We identified 5 TC , HDL -C, and LDL -C trajectories, and 4 triglycerides and non- HDL -C trajectories. Upon follow-up (median 8.2 years; 199 ASCVD events; 256 deaths), elevated TC (>240 mg/ dL ), LDL -C (>155 mg/ dL ), or non- HDL -C (>180 mg/ dL ) concentrations conferred >2.25-fold ASCVD and mortality risk compared with concentrations <165 mg/ dL , <90 mg/ dL , and <115 mg/ dL , respectively ([ TC hazard ratio ( HR )_ASCVD=4.17, 95% CI 1.94-8.99; TC HR _death=2.47, 95% CI 1.28-4.76] [ LDL -C HR_ASCVD=5.09, 95% CI 1.54-16.85; LDL -C HR _death=4.04, 95% CI 1.84-8.89] [non- HDL -C HR_ASCVD=4.60, 95% CI 1.98-10.70; LDL -C HR _death=3.74, 95% CI 2.03-6.88]). Consistent HDL -C concentrations <40 mg/ dL were associated with greater ASCVD and mortality risk than concentrations >70 mg/ dL (HR_ASCVD=3.81, 95% CI 2.04-7.15; HR _death=2.88, 95% CI 1.70-4.89). Triglycerides trajectories were unassociated with outcomes. Conclusions Using a longitudinal modeling technique, we demonstrated that unfavorable lipid trajectories over 35 years confer higher ASCVD and mortality risk later in life.

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