Long-Term Risk of Atherosclerotic Cardiovascular Disease in US Adults With the Familial Hypercholesterolemia Phenotype

Abstract

Background: Heterozygous familial hypercholesterolemia (FH) affects up to 1 in 200 individuals in the United States, but atherosclerotic cardiovascular disease (ASCVD) outcomes of FH in the general US population have not been described. We therefore sought to evaluate long-term coronary heart disease (CHD) and total ASCVD risks in US adults with an FH phenotype.

Methods: Using individual pooled data from 6 large US epidemiological cohorts, we stratified participants by low-density lipoprotein cholesterol level at index ages from 20 to 79 years. For the primary analysis, low-density lipoprotein cholesterol levels ≥190 and <130 mg/dL defined the FH phenotype and referent, respectively. Sensitivity analyses evaluated the effects of varying the FH phenotype definition. We used Cox regression models to assess covariate-adjusted associations of the FH phenotype with 30-year hazards for CHD (CHD death or nonfatal myocardial infarction) and total ASCVD (CHD or stroke).

Results: We included 68 565 baseline person-examinations; 3850 (5.6%) had the FH phenotype by the primary definition. Follow-up across index ages ranged from 78 985 to 308 378 person-years. After covariate adjustment, the FH phenotype was associated with substantially elevated 30-year CHD risk, with hazard ratios up to 5.0 (95% confidence interval, 1.1-21.7). Across index ages, CHD risk was accelerated in those with the FH phenotype by 10 to 20 years in men and 20 to 30 years in women. Similar patterns of results were found for total ASCVD risk, with hazard ratios up to 4.1 (95% confidence interval, 1.2-13.4). Alternative FH phenotype definitions incorporating family history, more stringent age-based low-density lipoprotein cholesterol thresholds, or alternative lipid fractions decreased the FH phenotype prevalence to as low as 0.2% to 0.4% without materially affecting CHD risk estimates (hazard ratios up to 8.0; 95% confidence interval, 1.0-61.6).

Conclusions: In the general US population, the long-term ASCVD burden related to phenotypic FH, defined by low-density lipoprotein cholesterol ≥190 mg/dL, is likely substantial. Our finding of CHD risk acceleration may aid efforts in risk communication.

Keywords: coronary disease; epidemiology; hypercholesterolemia.

Figure 1. Unadjusted rates of coronary heart disease death or nonfatal myocardial infarction per 1000 person-years, and underlying observed event numbers, in (A) men and (B) women

Unadjusted event rates are graphed by index age and LDL-C category; LDL-C ≥190 mg/dL represents the FH phenotype and LDL-C <130 mg/dL represents the referent. For men (A), event rates in the FH phenotype group at any given age are equivalent to those for men in the referent group who are 10 to 20 years older, indicating acceleration of CHD risk by 10 to 20 years. For women (B), CHD risk is accelerated by 20 to 30 years. The tables show observed event numbers for the FH phenotype and referent groups, by sex and index age. LDL-C, low-density lipoprotein cholesterol, FH, familial hypercholesterolemia.

Figure 2. Adjusted* 30-year survival free from coronary heart disease death or nonfatal myocardial infarction for index ages (A) 20–29, (B) 30–39, (C) 40–49, (D) 50–59, (E) 60–69, and (F) 70–79† years

Over 30 years of follow-up, event-free survival is progressively worse for the FH phenotype group (LDL-C ≥190 mg/dL) than for the other two groups. Baseline mean (SD) LDL-C levels (mg/dL) for the LDL-C <130 (referent), 130–189, and ≥190 mg/dL (FH phenotype) groups were respectively: (A) 20–29 years: 96 (20), 148 (15), 213 (38); (B) 30–39 years: 98 (20), 150 (15), 210 (24); (C) 40–49 years: 100 (21), 152 (16), 213 (28); (D) 50–59 years: 100 (26), 154 (16), 214 (25); (E) 60–69 years: 101 (26), 154 (16), 213 (27); and (F) 70–79 years: 100 (25), 153 (16), 213 (22). *Adjusted for: age, sex, race, body mass index, diabetes mellitus, smoking, systolic blood pressure, antihypertensive therapy, high-density lipoprotein cholesterol, cholesterol treatment, and cohort. †Follow-up for index age 70–79-years is truncated at 23 years, due to insufficient sample size thereafter. LDL-C, low-density lipoprotein cholesterol.