Time Course of LDL-C Exposure and CVD Event Risk

Quick Takes

  • The risk of atherosclerotic cardiovascular disease depends on the cumulative exposure to LDL-C (mg/dl x years) based on the CARDIA study of young healthy persons and Mendelian randomization studies in persons with familial hypercholesterolemia associated with very high LDL-C from birth.
  • This study also suggests that earlier optimization of LDL-C level may be more beneficial than later intervention, and late LDL-C intervention may not overcome accumulated risk.
  • Future trials of maintaining very low LDL-C at a young age may support this strategy to reduce the prevalence of coronary heart disease.

Study Questions:

Does the risk of cardiovascular disease attributable to low-density lipoprotein cholesterol (LDL-C) differ for the same area under the exposure curve (mg/dl x years) at different ages?


The authors used the CARDIA (Coronary Artery Risk Development in Young Adults) study data to assess the relationship of area under LDL-C versus age curve with incident cardiovascular event risk and modulation of risk by time course of area accumulation. CARDIA was a multisite prospective study of 5,115 participants ages 18-30 years enrolled from 1985-1986 to assess known cardiovascular disease (CVD) risk factors and were scheduled for nine follow-up visits at up to 30 years. A total of 4,958 were observed for CV events from age 40-66 years. The outcome was a composite of nonfatal coronary heart disease (CHD), stroke, transient ischemic attack, heart failure hospitalization, coronary revascularization, peripheral arterial disease intervention, or cardiovascular death.


At baseline, mean age was 25 years; at age 40 years, mean LDL-C was 111 mg/dl, blood pressure was 112/73 mm Hg (27% had hypertension), glucose was 92 mg/dl (diabetes 4%), mean body mass index was 28 kg/m2, family history of CHD was 25%, ever-smoker was 50%, 55% were women, and 51% were Black. During a median 16-year follow-up after age 40 years, 275 participants had an incident CVD event. The first CVD events occurred at a median age of 49.4 years (range 40-60 years), and the CVD event rate was 3.1% at age 50 years and 7.8% at age 60 years. Average yearly exposure of LDL-C was 115 mg/dl with a minimal mean change over the 22 years (slope of LDL-C time course was 0.10 ± 0.53 mg/dl/year, with a range of -2.75 to +3.36 mg/dl/year). After adjustment for sex, race, and traditional risk factors, both area under LDL-C versus age curve and time course of area accumulation (slope of LDL-C curve) were significantly associated with CVD event risk (hazard ratio, 1.053; p < 0.0001 per 100 mg/dl x years; hazard ratio, 0.797 per mg/dl/year; p = 0.045, respectively). Event rate at 55 years in the upper quartile was 8.6% and lower 2.6% (p < 0.0001).


Incident CVD event risk depends on cumulative prior exposure to LDL-C and, independently, time course of area accumulation. The same area accumulated at a younger age, compared with older age, resulted in a greater risk increase, emphasizing the importance of optimal LDL-C control starting early in life.


The rationale for this type of analysis and importance comes from studies showing the CV event rate in heterozygous familial hypercholesterolemia is four-fold higher at any level of LDL-C from 130-190 mg/dl and 20-fold higher at an LDL-C of 190 mg/dl compared to 130 mg/dl (risk increases with LDL-C over time (mg/dl x years). Individuals with the same cumulative LDL-C exposure at age 40 years (area under the LDL-C vs. age curve) but with a greater fraction of that exposure occurring earlier in life had a greater risk of incident CVD event risk subsequent to age 40 years. That is, area under LDL-C versus age curve accumulated early was associated with greater risk compared with when the same area was accumulated later in life.

Keywords: Atherosclerosis, Cardiovascular Diseases, Cholesterol, LDL, Coronary Disease, Heart Failure, Hyperlipoproteinemia Type II, Hypertension, Ischemic Attack, Transient, Metabolic Syndrome, Myocardial Revascularization, Peripheral Arterial Disease, Primary Prevention, Risk Factors, Smoking, Young Adult

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