Physicians' Academy for Cardiovascular Education

Mutation-carrying relatives of patients with FH are at increased long-term CV risk

Long‐Term Cardiovascular Risk in Heterozygous Familial Hypercholesterolemia Relatives Identified by Cascade Screening

Kjærgaard KA, Christiansen MK, Schmidt M, et al. - J Am Heart Assoc. 2017;6:e005435


The risk of premature CAD among patients with clinically diagnosed heterozygous Familial Hypercholesterolemia (HeFH) is still high, despite statin therapy [1-3]. Moreover, the screening of their family members is often incomplete, and their CV risk is not known [4,5]. In this study, the long-term CV risk of mutation-carrying HeFH relatives was compared with non-mutation-carrying HeFH relatives, as well as with the general population.

For this purpose, relatives of patients with prevalent clinical FH and an LDLR mutation were identified and underwent cascade screening. Each LDLR mutation consistent with a diagnosis of HeFH was followed as far as possible in the respective family pedigrees, thereby identifying mutation-carrying and noncarrying HeFH relatives. All diagnoses of HeFH were genetically verified. Lipid-lowering therapy with statins was recommended to all mutation-carrying HeFH participants. A population-based comparison cohort was matched (10:1) to the family members. 220 relatives from 32 families and 2199 controls from the general population were followed-up for a median duration of 21 years (IQR: 18–22 years), and the total person-time at risk was 46 178 years.

The primary endpoint was a composite of all-cause death and major adverse CV events including first events of acuut myocardinfarct (AMI), ischemic stroke, TIA, PAD, PCI and CABG. The individual components of the primary endpoint were the secondary endpoints of the study.

Main results


HeFH relatives with LDLR mutations had an increased long-term risk of adverse CV events compared with non-mutation-carrying relatives and the general population cohort. These results support the importance of cascade screening and aggressive lipid-lowering therapy in families with familial hypercholesterolemia.


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