Younger Patients With Familial Hypercholesterolemia May Have Greatest Risk for CHD and ASCVD

ASCVD CHD Risk Familial Hypercholesterolemia
ASCVD CHD Risk Familial Hypercholesterolemia
An up to 5-fold increased risk of coronary heart disease hazards was observed in the familial hypercholesterolemia phenotype group for ages 20 to 29.

Patients with undiagnosed or undertreated familial hypercholesterolemia may have higher risks of developing long-term coronary heart disease (CHD) and total atherosclerotic cardiovascular disease (ASCVD), according to new research published in Circulation.

Since the burden of ASCVD in this patient population is generally unknown, Amanda M. Perak, MD, of Northwestern University Feinberg School of Medicine in Chicago, and colleagues sought to evaluate the long-term CHD and ASCVD risks in US adults with a familial hypercholesterolemia phenotype.

They gathered patient data from the Cardiovascular Lifetime Risk Pooling Project, which included the following cohorts: Framingham Heart Study, Framingham Offspring Study, Cardiovascular Health Study, ARIC (Atherosclerosis Risk in Communities), CARDIA (Coronary Artery Risk Development in Young Adults), and NHANES III (National Health and Nutrition Examination Survey III Mortality Study).

Familial hypercholesterolemia phenotype definitions were determined using common criteria to identify possible disease as well as the simplified diagnostic criteria proposed in the recent American Heart Association statement: “LDL-C [low-density lipoprotein cholesterol] ≥190 mg/dL plus a first-degree relative with similar degree of hypercholesterolemia or premature CHD.”

To understand the effects of the familial hypercholesterolemia phenotype on CVD outcomes across the lifespan, researchers looked at 30-year risks from different index ages (baseline): 20 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, and 70 to 79 years. Patients were stratified into 3 person-examination groups according to lipid levels (familial hypercholesterolemia phenotype, referent, and middle group).

A total of 68 565 baseline person-examinations were included in the final analysis with 3850 (5.6%) who had the familial hypercholesterolemia phenotype by the primary definition. After covariate adjustment, the phenotype was associated with a substantially elevated 30-year CHD risk (hazard ratios [HR] up to 5.0; 95% confidence interval [CI]: 1.1-21.7). In men, CHD risk was accelerated in those with the phenotype by 10 to 20 years and in women, by 20 to 30 years. Total ASCVD risk had HRs up to 4.1 (95% CI: 1.2-13.4).

When researchers used “alternative” familial hypercholesterolemia phenotype definitions that incorporated family history, more stringent age-based LDL-C thresholds, or alternative lipid fractions, the phenotype prevalence was decreased to as low as 0.2% to 0.4% without “materially affecting CHD risk estimates” (HRs up to 8.0; 95% CI: 1.0-61.6).

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They pointed out, “unadjusted event rates were similar for men and women with the FH [familial hypercholesterolemia] phenotype for the index age of 20 to 29 years, but for older index ages, the rates in men were almost double those in women. Conversely, age-based acceleration of CHD risk compared with the referent group was great for women than for men.”

There was an up to 5-fold increased risk of CHD hazards in the familial hypercholesterolemia phenotype group for the index age of 20 to 29 years. Conversely, there were relatively lower hazards at older ages, particularly a nonsignificant increase in risk between 70 to 79 years of age. Interestingly, there was also no significant interaction between races (black and nonblack) and LDL-C levels on the hazard ratios.

When they focused on CHD death outcome alone and total ASCVD, researchers found the results approximated those for the primary outcome of CHD death or nonfatal MI. Hazard ratios were similar, and the range of confidence intervals varied with the numbers of observed events.

“In combination with prior work suggesting the vast underdiagnosis of FH, our data indicate that there is likely to be an important long-term burden of ASCVD in phenotypic but unrecognized FH patients in the United States,” researchers concluded.

They added that their findings may also have implications for risk communication. For example, a 25-year-old woman with newly diagnosed familial hypercholesterolemia can now be informed that at her current age, her risk of death from CHD or nonfatal MI is on par with a 55-year-old woman, if her cholesterol is not treated. This knowledge, along with patient counseling, may encourage behavioral and therapeutic changes.


Perak AM, Ning H, de Ferranti SD, Gooding HC, Wilkins JT, Lloyd-Jones DM. Long-term risk of atherosclerotic cardiovascular disease in US adults with familial hypercholesterolemia phenotype. Circulation. 2016;134:9-19. doi: 10.1161/CIRCULATIONAHA.116.022335.