Long-Term Risk of Atherosclerotic CVD in Adults With Familial Hypercholesterolemia

Study Questions:

What is the long-term risk for coronary heart disease (CHD) and total atherosclerotic cardiovascular disease (ASCVD) among US adults with a heterozygous familial hypercholesterolemia (FH) phenotype?


Pooled data from six large epidemiologic cohorts within the Cardiovascular Lifetime Risk Pooling Projection were used for the present analysis. Adults residing in the United States, aged 20-79 years, were stratified by low-density lipoprotein (LDL) cholesterol levels. The FH phenotype was defined by an LDL cholesterol level of ≥190 mg/dl. The referent group was defined by an LDL cholesterol level of <130 mg/dl. The primary outcomes of interest were 30-year hazards for CHD (CHD death or nonfatal myocardial infarction) and total ASCVD (CHD or stroke).


A total of 68,565 adults who completed baseline exams were included, of which 3,850 (5.6%) had the FH phenotype. After adjustment for potential confounders, the FH phenotype was associated with an elevated 30-year risk for CHD (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.1–21.7). Across index ages, CHD risk was accelerated in those with the FH phenotype by 10-20 years in men and 20-30 years in women. Similar associations were observed for total ASCVD risk (HR, 4.1; 95% CI, 1.2–13.4). Alternative FH phenotype definitions incorporating family history, more stringent age based on LDL cholesterol thresholds, or alternative lipid fractions decreased the FH phenotype prevalence to as low as 0.2-0.4% without materially affecting CHD risk estimates.


The investigators concluded that in the general US population, the long-term ASCVD burden related to phenotypic FH, defined by LDL cholesterol ≥190 mg/dl, is likely substantial. The finding of CHD risk acceleration may aid efforts in risk communication.


These data suggest that screening for FH will improve management of elevated LDL and result in reduction of CHD and ASCVD.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Primary Hyperlipidemia

Keywords: Atherosclerosis, Cholesterol, LDL, Coronary Artery Disease, Dyslipidemias, Hypercholesterolemia, Hyperlipoproteinemia Type II, Myocardial Infarction, Phenotype, Primary Prevention, Risk Factors, Stroke

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