No association between familial hypercholesterolemia or high LDL-c levels and ischemic stroke risk

Relationship of Familial Hypercholesterolemia and High LDL Cholesterol to Ischemic Stroke: The Copenhagen General Population Study

Literature - Beheshti S, Madsen CM, Varbo A, et al. - Circulation 2018; published online ahead of print

Introduction and methods

Patients with familial hypercholesterolemia (FH) are at high risk of ischemic heart disease (IHD), but it is not clear whether they are also at high risk of ischemic stroke (IS), since the available evidence is contradictory [1].

In this study, it was evaluated whether individuals in the general population with FH and/or high levels of LDL-c have higher risk of IS. For this purpose, FH causative mutations were used that are not prone to confounding by other IS risk factors, and 3 clinical FH criteria were applied: Simon Broome [2], Make Early Diagnosis to Prevent Early Death (MEDPED) [3], and Dutch Lipid Clinic Network (DLCN) [4]. Moreover, observational and genetic Mendelian randomization studies were performed to determine if high LDL-c per se has a causal effect on IS risk.

The Copenhagen General Population Study (CGPS) is a prospective cohort study initiated in 2003 that recruited 106,412 individuals aged 20-100 years, who were genotyped for FH causative mutations. 1,649 individuals were excluded due to ischemic or hemorrhagic stroke prior to study attendance, leaving a sample of 104,763 individuals.

The Copenhagen City Heart Study (CCHS) is a prospective study of the general population that recruited individuals as in the CGPS. 10,372 individuals from the 1991-1994 and the 2001-2004 examinations with baseline measurements of LDL-c and information on genetic variants were included as an independent cohort for confirmation of the results of the CGPS, and for the Mendelian randomization analysis.

A diagnosis of IS or myocardial infarction (MI) was confirmed using the national Danish Patient Registry [5], and the national Danish Causes of Death Registry [6]. FH causative mutations were LDLR W23X(rs267607213), W66G(rs121908025), W556S, and APOB R3500Q(rs5742904).

Main results

  • In the CGPS, there was no association between FH and IS risk, with a multivariable-adjusted HR for IS of 0.42 (95%CI: 0.06-3.01) for mutation carriers compared to non-carriers.
  • Using Simon Broome criteria, the HR for IS was 1.03 (95%CI: 0.79-1.34) for possible FH, and when using MEDPED criteria, the HR was 1.31 (95%CI: 0.83-2.07) for probable FH, when compared to individuals unlikely to have FH.
  • Using DLCN criteria, there was an association between clinical FH and increased risk of IS, with a HR of 1.30 (95%CI: 1.08-1.56) for possible FH and 2.50 (95%CI: 1.33-4.69) for definite or probable FH, when compared to individuals unlikely to have FH.
  • When individuals were stratified based only on LDL-c levels and not based on clinical FH criteria, very high concentrations of LDL-c ≥5mmol/L were associated with increased IS risk in individuals with IHD before baseline with a HR of 1.81 (95%CI: 1.03-3.18). There was no association in individuals without IHD before baseline.
  • In the CCHS, there was no association between FH mutations and IS risk (P=0.61), but there was a tendency towards increased risk of MI in FH mutation carriers, although not statistically significant (P=0.08).
  • In a Mendelian randomization analysis, combining individuals from the CGPS and CCHS, the observational HR for IS for a 1 mmol/L higher plasma concentration of LDL-c was 1.09 (95%CI: 1.05-1.13), and the genetic causal risk ratio was 1.11 (95%CI: 0.62-2.02) for IS and 1.45 (95%CI: 1.08-1.93) for MI.


There was no association between FH mutations and IS risk in both cohort studies. Observational and Mendelian randomization analyses showed no association of high levels of LDL-c with IS in individuals without IHD, but did in individuals with IHD at baseline.


1. Kaste M and Koivisto P. Risk of brain infarction in familial hypercholesterolemia. Stroke. 1988;19:1097-1100.

2. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ. 1991;303:893-896.

3. Williams RR, Hunt SC, Schumacher MC, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993;72:171-176.

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;34:3478-3490a

5. Lynge E, Sandegaard JL and Rebolj M. The Danish National Patient Register. Scand J Public Health. 2011;39:30-33.

6. Helweg-Larsen K. The Danish Register of Causes of Death. Scand J Public Health. 2011;39:26-29.

Find this article online at Circulation 2018

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