title: Increased Aortic Valve Calcification in Familial Hypercholesterolemia: Prevalence, Extent, and Associated Risk Factors.
abstract: BACKGROUND
  Familial hypercholesterolemia is typically caused by LDL receptor (LDLR) mutations that result in elevated levels of LDL cholesterol (LDL-C). In homozygous FH, the prevalence of aortic valve calcification (AoVC) reaches 100% and is often symptomatic.
  
  
  OBJECTIVE
  The objective of this study was to investigate the prevalence, extent, and risk-modifiers of AoVC in heterozygous FH (he-FH) that are presently unknown.
  
  
  METHODS
  Asymptomatic patients with he-FH and 131 non-familial hypercholesterolemia controls underwent CT computed tomography calcium scoring. AoVC was defined as the presence of calcium at the aortic valve leaflets. The extent of AoVC was expressed in Agatston units, as the AoVC-score. We compared the prevalence and extent of AoVC between cases and controls. In addition, we investigated risk modifiers of AoVC, including the presence of LDLR mutations without residual function (LDLR-negative mutations), maximum untreated LDL-cholesterol (maxLDL), LDL-C, blood pressure, and coronary artery calcification (CAC).
  
  
  RESULTS
  We included 145 asymptomatic patients with he-FH (93 men; mean age 52 ± 8 years) and 131 non-familial hypercholesterolemia controls. The prevalence (%) and AoVC-score (median, IQR) were higher in he-FH patients than in controls: 41%, 51 (9-117); and 21%, 21 (3-49) (p < 0.001 and p = 0.007). Age, untreated maxLDL, CAC, and diastolic blood pressure were independently associated with AoVC. LDLR-negative mutational he-FH was the strongest predictor of the AoVC-score (OR: 4.81; 95% CI: 2.22 to 10.40; p = <0.001).
  
  
  CONCLUSIONS
  Compared to controls, he-FH is associated with a high prevalence and a large extent of subclinical AoVC, especially in patients with LDLR-negative mutations, highlighting the critical role of LDL-C metabolism in AoVC etiology.
authors.affiliation: Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Interuniversitair Cardiologisch Instituut Nederland, Utrecht, the Netherlands; Department of Cardiology, Thorax Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Gert-Jan R
authors.initials: GR
authors.lastname: Ten Kate
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Sven
authors.initials: S
authors.lastname: Bos
authors.affiliation: Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Interuniversitair Cardiologisch Instituut Nederland, Utrecht, the Netherlands; Department of Cardiology, Thorax Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Admir
authors.initials: A
authors.lastname: Dedic
authors.affiliation: Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Interuniversitair Cardiologisch Instituut Nederland, Utrecht, the Netherlands; Department of Cardiology, Thorax Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Lisan A
authors.initials: LA
authors.lastname: Neefjes
authors.affiliation: Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Akira
authors.initials: A
authors.lastname: Kurata
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Janneke G
authors.initials: JG
authors.lastname: Langendonk
authors.affiliation: Department of Cardiology, Sint Franciscus Gasthuis, Rotterdam, the Netherlands.
authors.forename: Anho
authors.initials: A
authors.lastname: Liem
authors.affiliation: Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Adriaan
authors.initials: A
authors.lastname: Moelker
authors.affiliation: Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Gabriel P
authors.initials: GP
authors.lastname: Krestin
authors.affiliation: Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Department of Cardiology, Thorax Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Pim J
authors.initials: PJ
authors.lastname: de Feyter
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, the Netherlands. Electronic address: j.roetersvanlennep@erasmusmc.nl.
authors.forename: Jeanine E
authors.initials: JE
authors.lastname: Roeters van Lennep
authors.affiliation: Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Department of Cardiology, Thorax Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Koen
authors.initials: K
authors.lastname: Nieman
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sijbrands
mesh_terms: D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology*; D002114:Calcinosis / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology*; D002118:Calcium / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004452:Echocardiography; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications* / Q000235:genetics; D008074:Lipoproteins / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D014057:Tomography, X-Ray Computed
chemical_list: D008074:Lipoproteins; D004247:DNA; D002118:Calcium
keywords: LDLR-negative mutation; aortic valve calcification; calcific aortic stenosis; coronary artery calcification; familial hypercholesterolemia; low-density lipoprotein receptor