Mutation of the von Hippel-Lindau Gene Alters Human Cardiopulmonary Physiology

Smith, Thomas G.; Brooks, Jt T.; Balanos, George M.; Lappin, Tr R.; Layton, D. M.; Leedham, D L; Liu, C.; Maxwell, PH; McMullin, Mary Frances; McNamara, C J; Percy, MJ; Pugh, Christopher W.; Ratcliffe, Peter J.; Talbot, NP; Treacy, M.; Robbins, Peter A.

doi:10.1007/978-0-387-73693-8_9

Cited by 18 publications

(22 citation statements)

References 7 publications

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“…The pathophysiological phenotype is characterized by augmented hypoxia sensing and a clinical manifestation of erythrocytosis ( 1 ). In addition, basal ventilation and pulmonary vascular tone is elevated, and ventilation, pulmonary vasoconstriction, and heart rate responses to acute hypoxia are considerably increased ( 12 ). Moreover, features observed in patients with Chuvash polycythemia are similar to those associated with acclimatization by low-altitude inhabitants to high-altitude hypoxia ( 2 , 4 ).…”

mentioning

confidence: 83%

Two Hypoxia Sensor Genes and Their Association with Symptoms of Acute Mountain Sickness in Sherpas

Droma¹,

Ôta²,

Hanaoka³

et al. 2008

aviat space environ med

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mentioning

confidence: 83%

Two Hypoxia Sensor Genes and Their Association with Symptoms of Acute Mountain Sickness in Sherpas

Droma¹,

Ôta²,

Hanaoka³

et al. 2008

aviat space environ med

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“…3 Other investigators have documented elevated pulmonary artery pressure and other changes in pulmonary vascular physiology in 3 individuals with Chuvash polycythemia. 11 Iron is needed for the activity of proly hydroxylase domain proteins (PHDs), the principal negative regulators of HIF-α subunit levels. [12][13] Therefore, iron deficiency could exacerbate the hypoxic response and its effects.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHLR200W mutation (Chuvash polycythemia)

et al. 2011

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BackgroundPatients 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. Design and MethodsThis 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. ResultsThe 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 ageadjusted 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). ConclusionsChildren 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).Key words: pulmonary hypertension, tricuspid regurgitation velocity, ferritin, VHL, hypoxia inducible factor.Citation: Sable CA, Aliyu ZY, Dham N, Nouraie M, Sachdev V, Sidenko S, Miasnikova GY, Polyakova LA, Sergueeva AI, Okhotin DJ, Bushuev V, Remaley AT, Niu X, Castro OL, Gladwin MT, Kato GJ, Prchal10 JT, and Gordeuk VR. Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHLR200W mutation (Chuvash polycythemia). Haematologica 2012;97(2):193-200. doi:10.3324/haematol.2011

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“…Other mRNAs, protein expression levels, and enzyme activities studied did not differ from controls. These physiological studies show that although the Chuvash polycythemia is a relatively subtle defect, it has a major effect on the overall metabolism as soon as the metabolism is stressed [Smith et al 2008;Formenti et al 2010].…”

Section: Physiological Studies Of Chuvash Polycythemiamentioning

confidence: 97%

Diagnosis and management of congenital and idiopathic erythrocytosis

McMullin

2012

Therapeutic Advances in Hematology

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An erythrocytosis occurs when there is an increased red-cell mass. The causes of erythrocytosis are divided into primary, when there is an intrinsic defect in the erythroid cell, and secondary, when the cause is extrinsic to the erythroid cell. An idiopathic erythrocytosis occurs when the increased red-cell mass has no identifiable cause. Primary and secondary defects can be further classified as either congenital or acquired causes. The diagnostic pathway starts with a careful history and examination followed by measurement of the erythropoietin (EPO) levels. This allows a division of those patients with a low EPO level, who can then be investigated for primary causes of erythrocytosis, and those with a normal or high EPO level, where the oxygen-sensing pathway needs to be explored further. Physiological studies in those with congenital defects in the oxygen-sensing pathway show many changes in the downstream metabolism adapting to the defect, which has a bearing on the management of the disorders. Low-dose aspirin and venesection to an achievable target are the main therapeutic options that can be considered in the management of erythrocytosis. Specific guidance on venesection options should be considered with certain causes such as high oxygen-affinity hemoglobins.

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Mutation of the von Hippel-Lindau Gene Alters Human Cardiopulmonary Physiology

Cited by 18 publications

References 7 publications

Two Hypoxia Sensor Genes and Their Association with Symptoms of Acute Mountain Sickness in Sherpas

Two Hypoxia Sensor Genes and Their Association with Symptoms of Acute Mountain Sickness in Sherpas

Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHLR200W mutation (Chuvash polycythemia)

Diagnosis and management of congenital and idiopathic erythrocytosis

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