title: Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHL(R200W) mutation (Chuvash polycythemia).
abstract: BACKGROUND
  Patients with Chuvash polycythemia, (homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL)), have elevated levels of hypoxia inducible factors HIF-1 and HIF-2, often become iron-deficient secondary to phlebotomy, and have elevated estimated pulmonary artery pressure by echocardiography. The objectives of this study were to provide a comprehensive echocardiographic assessment of cardiovascular physiology and to identify clinical, hematologic and cardiovascular risk factors for elevation of tricuspid regurgitation velocity in children and adults with Chuvash polycythemia.
  
  
  METHODS
  This cross-sectional observational study of 120 adult and pediatric VHL(R200W) homozygotes and 31 controls at outpatient facilities in Chuvashia, Russian Federation included echocardiography assessment of pulmonary artery pressure (tricuspid regurgitation velocity), cardiac volume, and systolic and diastolic function, as well as hematologic and clinical parameters. We determined the prevalence and risk factors for elevation of tricuspid regurgitation velocity in this population and its relationship to phlebotomy.
  
  
  RESULTS
  The age-adjusted mean ± SE tricuspid regurgitation velocity was higher in VHL(R200W) homozygotes than controls with normal VHL alleles (2.5±0.03 vs. 2.3±0.05 m/sec, P=0.005). The age-adjusted left ventricular diastolic diameter (4.8±0.05 vs. 4.5±0.09 cm, P=0.005) and left atrial diameter (3.4±0.04 vs. 3.2±0.08 cm, P=0.011) were also greater in the VHL(R200W) homozygotes, consistent with increased blood volume, but the elevation in tricuspid regurgitation velocity persisted after adjustment for these variables. Among VHL(R200W) homozygotes, phlebotomy therapy was associated with lower serum ferritin concentration, and low ferritin independently predicted higher tricuspid regurgitation velocity (standardized beta=0.29; P=0.009).
  
  
  CONCLUSIONS
  Children and adults with Chuvash polycythemia have higher estimated right ventricular systolic pressure, even after adjustment for echocardiography estimates of blood volume. Lower ferritin concentration, which is associated with phlebotomy, independently predicts higher tricuspid regurgitation velocity (www.clinicaltrials.gov identifier NCT00495638).
authors: Division of Cardiology, Children’s National Medical Center, Washington, DC, USA. csable@cnmc.org
authors: Craig A
authors: CA
authors: Sable
authors: Zakari Y
authors: ZY
authors: Aliyu
authors: Niti
authors: N
authors: Dham
authors: Mehdi
authors: M
authors: Nouraie
authors: Vandana
authors: V
authors: Sachdev
authors: Stanislav
authors: S
authors: Sidenko
authors: Galina Y
authors: GY
authors: Miasnikova
authors: Lydia A
authors: LA
authors: Polyakova
authors: Adelina I
authors: AI
authors: Sergueeva
authors: Daniel J
authors: DJ
authors: Okhotin
authors: Vladimir
authors: V
authors: Bushuev
authors: Alan T
authors: AT
authors: Remaley
authors: Xiaomei
authors: X
authors: Niu
authors: Oswaldo L
authors: OL
authors: Castro
authors: Mark T
authors: MT
authors: Gladwin
authors: Gregory J
authors: GJ
authors: Kato
authors: Josef T
authors: JT
authors: Prchal
authors: Victor R
authors: VR
authors: Gordeuk
mesh_terms: D000293:Adolescent; D000328:Adult; D018798:Anemia, Iron-Deficiency / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D006720:Homozygote; D006801:Humans; D000860:Hypoxia / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011086:Polycythemia / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D011669:Pulmonary Wedge Pressure / Q000502:physiology*; D012426:Russia / Q000453:epidemiology; D014262:Tricuspid Valve Insufficiency / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human