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Original Article

Williams Syndrome Predisposes to Vascular Stiffness Modified by Antihypertensive Use and Copy Number Changes in NCF1

Beth A. Kozel, Joshua R. Danback, Jessica L. Waxler, Russell H. Knutsen, Lisa de las Fuentes, Gyorgy S. Reusz, Eva Kis, Ami B. Bhatt, Barbara R. Pober
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https://doi.org/10.1161/HYPERTENSIONAHA.113.02087
Hypertension. 2013;HYPERTENSIONAHA.113.02087
Originally published October 14, 2013
Beth A. Kozel
From the Department of Pediatrics (B.A.K., J.R.D.), Department of Cell Biology and Physiology (R.H.K.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Internal Medicine (L.d.l.F.), Washington University School of Medicine, St. Louis, MO; Department of Medical Sciences, Netter School of Medicine, Quinnipiac University, Hamden, CT (B.R.P.); Department of Pediatrics, Massachusetts General Hospital, Boston (J.L.W., B.R.P.); 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary (G.S.R., E.K.); Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (A.B.B.); and Department of Pediatrics, Harvard Medical School, Boston, MA (B.R.P.).
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Joshua R. Danback
From the Department of Pediatrics (B.A.K., J.R.D.), Department of Cell Biology and Physiology (R.H.K.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Internal Medicine (L.d.l.F.), Washington University School of Medicine, St. Louis, MO; Department of Medical Sciences, Netter School of Medicine, Quinnipiac University, Hamden, CT (B.R.P.); Department of Pediatrics, Massachusetts General Hospital, Boston (J.L.W., B.R.P.); 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary (G.S.R., E.K.); Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (A.B.B.); and Department of Pediatrics, Harvard Medical School, Boston, MA (B.R.P.).
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Jessica L. Waxler
From the Department of Pediatrics (B.A.K., J.R.D.), Department of Cell Biology and Physiology (R.H.K.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Internal Medicine (L.d.l.F.), Washington University School of Medicine, St. Louis, MO; Department of Medical Sciences, Netter School of Medicine, Quinnipiac University, Hamden, CT (B.R.P.); Department of Pediatrics, Massachusetts General Hospital, Boston (J.L.W., B.R.P.); 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary (G.S.R., E.K.); Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (A.B.B.); and Department of Pediatrics, Harvard Medical School, Boston, MA (B.R.P.).
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Russell H. Knutsen
From the Department of Pediatrics (B.A.K., J.R.D.), Department of Cell Biology and Physiology (R.H.K.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Internal Medicine (L.d.l.F.), Washington University School of Medicine, St. Louis, MO; Department of Medical Sciences, Netter School of Medicine, Quinnipiac University, Hamden, CT (B.R.P.); Department of Pediatrics, Massachusetts General Hospital, Boston (J.L.W., B.R.P.); 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary (G.S.R., E.K.); Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (A.B.B.); and Department of Pediatrics, Harvard Medical School, Boston, MA (B.R.P.).
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Lisa de las Fuentes
From the Department of Pediatrics (B.A.K., J.R.D.), Department of Cell Biology and Physiology (R.H.K.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Internal Medicine (L.d.l.F.), Washington University School of Medicine, St. Louis, MO; Department of Medical Sciences, Netter School of Medicine, Quinnipiac University, Hamden, CT (B.R.P.); Department of Pediatrics, Massachusetts General Hospital, Boston (J.L.W., B.R.P.); 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary (G.S.R., E.K.); Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (A.B.B.); and Department of Pediatrics, Harvard Medical School, Boston, MA (B.R.P.).
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Gyorgy S. Reusz
From the Department of Pediatrics (B.A.K., J.R.D.), Department of Cell Biology and Physiology (R.H.K.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Internal Medicine (L.d.l.F.), Washington University School of Medicine, St. Louis, MO; Department of Medical Sciences, Netter School of Medicine, Quinnipiac University, Hamden, CT (B.R.P.); Department of Pediatrics, Massachusetts General Hospital, Boston (J.L.W., B.R.P.); 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary (G.S.R., E.K.); Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (A.B.B.); and Department of Pediatrics, Harvard Medical School, Boston, MA (B.R.P.).
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Eva Kis
From the Department of Pediatrics (B.A.K., J.R.D.), Department of Cell Biology and Physiology (R.H.K.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Internal Medicine (L.d.l.F.), Washington University School of Medicine, St. Louis, MO; Department of Medical Sciences, Netter School of Medicine, Quinnipiac University, Hamden, CT (B.R.P.); Department of Pediatrics, Massachusetts General Hospital, Boston (J.L.W., B.R.P.); 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary (G.S.R., E.K.); Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (A.B.B.); and Department of Pediatrics, Harvard Medical School, Boston, MA (B.R.P.).
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Ami B. Bhatt
From the Department of Pediatrics (B.A.K., J.R.D.), Department of Cell Biology and Physiology (R.H.K.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Internal Medicine (L.d.l.F.), Washington University School of Medicine, St. Louis, MO; Department of Medical Sciences, Netter School of Medicine, Quinnipiac University, Hamden, CT (B.R.P.); Department of Pediatrics, Massachusetts General Hospital, Boston (J.L.W., B.R.P.); 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary (G.S.R., E.K.); Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (A.B.B.); and Department of Pediatrics, Harvard Medical School, Boston, MA (B.R.P.).
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Barbara R. Pober
From the Department of Pediatrics (B.A.K., J.R.D.), Department of Cell Biology and Physiology (R.H.K.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Internal Medicine (L.d.l.F.), Washington University School of Medicine, St. Louis, MO; Department of Medical Sciences, Netter School of Medicine, Quinnipiac University, Hamden, CT (B.R.P.); Department of Pediatrics, Massachusetts General Hospital, Boston (J.L.W., B.R.P.); 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary (G.S.R., E.K.); Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (A.B.B.); and Department of Pediatrics, Harvard Medical School, Boston, MA (B.R.P.).
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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.

  • elastin
  • NADPH oxidase
  • pulse wave analysis
  • vascular stiffness
  • Williams syndrome
  • Received July 22, 2013.
  • Revision received August 11, 2013.
  • Accepted September 24, 2013.
  • © 2013 American Heart Association, Inc.
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    Williams Syndrome Predisposes to Vascular Stiffness Modified by Antihypertensive Use and Copy Number Changes in NCF1
    Beth A. Kozel, Joshua R. Danback, Jessica L. Waxler, Russell H. Knutsen, Lisa de las Fuentes, Gyorgy S. Reusz, Eva Kis, Ami B. Bhatt and Barbara R. Pober
    Hypertension. 2013;HYPERTENSIONAHA.113.02087, originally published October 14, 2013
    https://doi.org/10.1161/HYPERTENSIONAHA.113.02087

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    Williams Syndrome Predisposes to Vascular Stiffness Modified by Antihypertensive Use and Copy Number Changes in NCF1
    Beth A. Kozel, Joshua R. Danback, Jessica L. Waxler, Russell H. Knutsen, Lisa de las Fuentes, Gyorgy S. Reusz, Eva Kis, Ami B. Bhatt and Barbara R. Pober
    Hypertension. 2013;HYPERTENSIONAHA.113.02087, originally published October 14, 2013
    https://doi.org/10.1161/HYPERTENSIONAHA.113.02087
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