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.

Clinical Topics: Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and Heart Failure, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Interventions, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Lipid Metabolism, Nonstatins, Primary Hyperlipidemia, Acute Heart Failure, Interventions and Vascular Medicine, Hypertension, Smoking

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

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