title: Williams syndrome predisposes to vascular stiffness modified by antihypertensive use and copy number changes in NCF1.
abstract: Williams syndrome is caused by the deletion of 26 to 28 genes, including elastin, on human chromosome 7. Elastin insufficiency leads to the cardiovascular hallmarks of this condition, namely focal stenosis and hypertension. Extrapolation from the Eln(+/-) mouse suggests that affected people may also have stiff vasculature, a risk factor for stroke, myocardial infarction, and cardiac death. NCF1, one of the variably deleted Williams genes, is a component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex and is involved in the generation of oxidative stress, making it an interesting candidate modifier for vascular stiffness. Using a case-control design, vascular stiffness was evaluated by pulse wave velocity in 77 Williams cases and matched controls. Cases had stiffer conducting vessels than controls (P<0.001), with increased stiffness observed in even the youngest children with Williams syndrome. Pulse wave velocity increased with age at comparable rates in cases and controls, and although the degree of vascular stiffness varied, it was seen in both hypertensive and normotensive Williams participants. Use of antihypertensive medication and extension of the Williams deletion to include NCF1 were associated with protection from vascular stiffness. These findings demonstrate that vascular stiffness is a primary vascular phenotype in Williams syndrome and that treatment with antihypertensives or agents inhibiting oxidative stress may be important in managing patients with this condition, potentially even those who are not overtly hypertensive.
authors.affiliation: Washington University School of Medicine, 660 S Euclid, Campus Box 8208, St. Louis, MO 63110. Kozel_b@kids.wustl.edu.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Kozel
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Danback
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Waxler
authors.forename: Russell H
authors.initials: RH
authors.lastname: Knutsen
authors.forename: Lisa
authors.initials: L
authors.lastname: de las Fuentes
authors.forename: Gyorgy S
authors.initials: GS
authors.lastname: Reusz
authors.forename: Eva
authors.initials: E
authors.lastname: Kis
authors.forename: Ami B
authors.initials: AB
authors.lastname: Bhatt
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Pober
mesh_terms: D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D002648:Child; D018628:Gene Dosage; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics*; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D010641:Phenotype; D063177:Pulse Wave Analysis; D059289:Vascular Stiffness / Q000235:genetics*; D018980:Williams Syndrome / Q000235:genetics*; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
keywords: NADPH oxidase; Williams syndrome; elastin; pulse wave analysis; vascular stiffness