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

Literature - 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

  • The risk of the primary end point was higher in mutation-carrying HeFH relatives compared with the general population (adjHR: 1.65, 95%CI: 1.17–2.33). This was not the case in relatives without a mutation (adjHR: 0.85, 95%CI: 0.56–1.29). Accordingly, the risk in mutation-carrying HeFH relatives compared with non-carrying relatives was increased (adjHR: 1.94, 95%CI: 1.14–3.31).
  • Mutation-carrying HeFH relatives showed a higher risk than the general population with regard to AMI (adjHR: 3.14, 95%CI: 1.78–5.55), TIA (adjHR: 4.38, 95%CI: 1.95–9.84), PCI (adjHR: 4.78, 95%CI: 2.49–9.18) and CABG (adjHR: 13.8, 95%CI: 7.14–26.7).
  • There was no difference in any of the secondary outcomes among the non-carrying relatives compared with the general population cohort, except for an elevated risk of coronary events, which was driven by cardiac revascularization procedures but not AMI.
  • When comparing the two groups of relatives, only the risk of coronary events, CV events, and CABG was elevated in carriers. No increased all-cause mortality risk was noted in either group of HeFH relatives compared with the general population cohort.


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.


1. Neil A, Cooper J, Betteridge J, et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J. 2008;29:2625–2633.

2. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008;337:a2423.

3. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group. Atherosclerosis. 1999;142:105–112.

4. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34:3478–3490.

5. Hadfield SG, Horara S, Starr BJ, et al. Are patients with familial hypercholesterolaemia well managed in lipid clinics? An audit of eleven clinics from the Department of Health Familial Hypercholesterolaemia Cascade Testing project. Ann Clin Biochem. 2008;45:199–205.

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