title: Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers.
abstract: BACKGROUND
  Some recently emerged lipid-lowering therapies are currently restricted to patients with homozygous familial hypercholesterolemia (HoFH), and studies are underway to also assess these therapies in patients with 'severe heterozygous FH (HeFH)'. However, no uniform definition of 'severe HeFH' exists, although untreated low-density lipoprotein cholesterol (LDL-C) levels above 8 mmol/L (309 mg/dl) have been historically used to define this phenotype. Our aim was to define severe HeFH, to establish its prevalence and CVD risk, and to study the relative contribution of classical risk factors to CVD risk in HeFH patients.
  
  
  RESULTS
  We analysed a cohort of 14,283 patients with molecularly defined HeFH, identified by the national FH screening programme in the Netherlands. Age and gender specific percentiles of untreated LDL-C were determined. The percentile corresponding to an LDL-C level of 8 mmol/L (309 mg/dL) in men aged 36-40 years (90(th) percentile) was selected as the cut-off value for severe HeFH. By applying this percentile-criterion to the whole cohort, 11% of the HeFH patients could be considered as having severe HeFH. Combined with an estimated HeFH prevalence of 1:300 in the Netherlands, this would translate into a prevalence of approximately 1:3,000 for severe HeFH. CVD risk was significantly increased in severe HeFH patients compared to non-severe HeFH patients (adjusted hazard ratio: 1.25 [95% CI: 1.05-1.51], p = 0.015). In line, male gender, increased age, increased BMI, smoking, hypertension, diabetes, high LDL-C and low high-density lipoprotein cholesterol were independent CVD risk factors in HeFH per se.
  
  
  CONCLUSIONS
  We changed the commonly used static LDL-C level of 8 mmol/L for the identification of severe HeFH into an age and gender corrected percentile. This definition would theoretically result in a prevalence of 1:3,000 for severe HeFH. Patients with severe HeFH are at increased CVD risk compared to non-severe HeFH patients, which underscores the need for more aggressive LDL-C lowering these patients.
authors: Department of Vascular Medicine, Academic Medical Centre, The Netherlands. Electronic address: j.besseling@amc.nl.
authors: Joost
authors: J
authors: Besseling
authors: StOEH, Foundation for Identification of Persons with Inherited Hypercholesterolemia, Amsterdam, The Netherlands.
authors: Iris
authors: I
authors: Kindt
authors: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Michel
authors: M
authors: Hof
authors: Department of Vascular Medicine, Academic Medical Centre, The Netherlands.
authors: John J P
authors: JJ
authors: Kastelein
authors: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Barbara A
authors: BA
authors: Hutten
authors: Department of Vascular Medicine, Academic Medical Centre, The Netherlands.
authors: G Kees
authors: GK
authors: Hovingh
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000209:etiology; D008078:Cholesterol, LDL / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence; D012307:Risk Factors
chemical_list: D008078:Cholesterol, LDL
keywords: Cardiovascular disease; Familial hypercholesterolemia; Prevalence; Severe familial hypercholesterolemia