Pulmonary Hypertension and the Hypoxic Response in SCD

Summary

Principal Investigator: V R Gordeuk
Abstract: The proposed research is designed to determine the prevalence and risk factors of pulmonary hypertension (PHTN) in children and adolescents with sickle cell disease (SCD), and to determine the role of the hypoxic response in its pathogenesis. The present proposal is based on 3 postulates. First, the problem of SCD-associated PHTN may begin during childhood and adolescence. Second, the pathogenesis of SCD-associated PHTN may include not only the effects of nitric oxide scavenging in a chronic hemolytic disorder, but also the consequences of chronic hypoxia related to severe anemia and to repeated vaso-occlusive episodes. PHTN is a complication of conditions marked by chronic hypoxia, and also a complication of Chuvash polycythemia (CP), a congenital disorder of oxygen sensing in which the hypoxic response is constitutively up regulated in the absence of hypoxia. Third, we postulate that the pathophysiology of SCD-associated PHTN may be elucidated by comparing proliferative vascular responses mediated by HIF and by nitric oxide scavenging in patients with SCD and CP according to the presence or absence of pulmonary hypertension. Based on a comparison of the clinical and pathophysiologic features of SCD and CP, we hypothesize that, in addition to increased nitric oxide-scavenging, altered expression of a gene or genes regulated by hypoxia inducible factor (HIF) is central to the pathophysiology of PHTN in both SCD and CP. Aim 1. Determine the prevalence, risk factors and clinical consequences of pulmonary hypertension (PHTN) in children and adolescents with sickle cell disease (SCD). Aim 2. Elucidate the pathophysiology of PHTN in SCD by comparing proliferative vascular responses mediated by i) HIF-regulated pathways and ii) nitric oxide-scavenging from the clinical to cellular level in patients with SCD and patients with Chuvash polycythemia (CP). Aim 3. Using micro array analysis and high throughput genotyping, examine patterns of gene expression and candidate gene polymorphisms of the HIF-mediated hypoxic response in SCD and CP patients with and without PHTN.
Funding Period: 2005-08-01 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. pmc Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency
    Victor R Gordeuk
    Center for Sickle Cell Disease, Howard University, Washington, District of Columbia 20060, USA
    Am J Hematol 83:15-8. 2008
  2. pmc Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression
    Victor R Gordeuk
    Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, DC 20060, USA
    Blood 118:5278-82. 2011
  3. pmc Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia
    Deepika S Darbari
    Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
    J Pediatr 160:286-90. 2012
  4. pmc Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom
    Vandana Sachdev
    Cardiovascular and Pulmonary Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
    Circulation 124:1452-60. 2011
  5. pmc Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHL(R200W) mutation (Chuvash polycythemia)
    Craig A Sable
    Division of Cardiology, Children s National Medical Center, Washington, DC, USA
    Haematologica 97:193-200. 2012
  6. pmc Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in U.S. hospital discharge records: a cross-sectional study
    Mehdi Nouraie
    Center for Sickle Cell Disease, Howard University, Washington, DC, USA
    Sex Transm Infect 88:528-33. 2012
  7. pmc A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease
    Ankit A Desai
    Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
    Am J Respir Crit Care Med 186:359-68. 2012
  8. pmc Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin
    Sergei Nekhai
    Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, DC, USA
    Haematologica 98:455-63. 2013
  9. pmc The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W)
    Nikica Ljubas Tomasic
    Division of Neonatology, University Hospital Merkur, Zagreb, Croatia
    Haematologica 98:560-7. 2013
  10. pmc Genetic determinants of haemolysis in sickle cell anaemia
    Jacqueline N Milton
    Biostatistics, Boston University School of Medicine, 72 E Concord St, Boston, MA 02118, USA
    Br J Haematol 161:270-8. 2013

Detail Information

Publications33

  1. pmc Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency
    Victor R Gordeuk
    Center for Sickle Cell Disease, Howard University, Washington, District of Columbia 20060, USA
    Am J Hematol 83:15-8. 2008
    ..Whether antihypertensive and/or nitric oxide donor therapy in sickle cell disease patients with relative hypertension prevents these and other complications should be determined by clinical trials...
  2. pmc Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression
    Victor R Gordeuk
    Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, DC 20060, USA
    Blood 118:5278-82. 2011
    ..In conclusion, up-regulation of the hypoxic response leads to decreased expression of hepcidin that may be independent of increased erythropoietin levels and increased RBC counts...
  3. pmc Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia
    Deepika S Darbari
    Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
    J Pediatr 160:286-90. 2012
    ....
  4. pmc Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom
    Vandana Sachdev
    Cardiovascular and Pulmonary Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
    Circulation 124:1452-60. 2011
    ....
  5. pmc Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHL(R200W) mutation (Chuvash polycythemia)
    Craig A Sable
    Division of Cardiology, Children s National Medical Center, Washington, DC, USA
    Haematologica 97:193-200. 2012
    ....
  6. pmc Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in U.S. hospital discharge records: a cross-sectional study
    Mehdi Nouraie
    Center for Sickle Cell Disease, Howard University, Washington, DC, USA
    Sex Transm Infect 88:528-33. 2012
    ..Some studies suggest that HIV infection progresses slowly in patients with sickle cell disease (SCD). The authors aimed to determine the relationships between SCD and HIV infection...
  7. pmc A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease
    Ankit A Desai
    Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
    Am J Respir Crit Care Med 186:359-68. 2012
    ..An increased tricuspid regurgitation jet velocity (TRV > 2.5 m/s) and pulmonary hypertension defined by right heart catheterization both independently confer increased mortality in sickle cell disease (SCD)...
  8. pmc Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin
    Sergei Nekhai
    Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, DC, USA
    Haematologica 98:455-63. 2013
    ..ClinicalTrials.gov Identifier:NCT00011648)...
  9. pmc The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W)
    Nikica Ljubas Tomasic
    Division of Neonatology, University Hospital Merkur, Zagreb, Croatia
    Haematologica 98:560-7. 2013
    ..In conclusion, our studies further define the hematologic phenotype of VHL H191D and provide additional evidence for phenotypic heterogeneity associated with the positional effects of VHL mutations...
  10. pmc Genetic determinants of haemolysis in sickle cell anaemia
    Jacqueline N Milton
    Biostatistics, Boston University School of Medicine, 72 E Concord St, Boston, MA 02118, USA
    Br J Haematol 161:270-8. 2013
    ..Perhaps by independently down-regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia...
  11. pmc Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease
    Rabindra Paul
    Howard University, Washington, DC, USA
    Eur J Haematol 91:62-8. 2013
    We aimed to identify risk factors for acute pulmonary events in children and adolescents in the Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study.
  12. pmc Iron deficiency modifies gene expression variation induced by augmented hypoxia sensing
    Xu Zhang
    Comprehensive Sickle Cell Center, Section of Hematology Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
    Blood Cells Mol Dis 52:35-45. 2014
    ..This pattern is consistent with potentiation of HIF-1α protein stability by iron deficiency but a trend for down-regulation of HIF-2α translation by iron deficiency overriding an increase in HIF-2α protein stability. ..
  13. ncbi Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia
    Manuel Arteta
    Department of Medicine, University of Michigan, Ann Arbor, MI Center for Sickle Cell Disease, Howard University Department of Pediatrics, Children s National Medical Center, Washington, DC Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD Department of Medicine, University of Pittsburgh, Pittsburgh, PA Sickle Cell Center, University of Illinois, Chicago, IL
    J Pediatr Hematol Oncol 36:185-9. 2014
    ..Full pulmonary function testing should be performed in children with hemoglobin SS or Sβ(0)-thalassemia, especially with history of asthma or wheezing and accentuated elevations in hemolytic markers...
  14. pmc Differences in the clinical and genotypic presentation of sickle cell disease around the world
    Santosh L Saraf
    Comprehensive Sickle Cell Center, Section of Hematology Oncology, University of Illinois Hospital and Health Sciences System, Chicago, IL Electronic address
    Paediatr Respir Rev 15:4-12. 2014
    ..Identification of additional genetic modifiers will improve prediction of cardiopulmonary complications in SCD. ..
  15. pmc The heterozygote advantage of the Chuvash polycythemia VHLR200W mutation may be protection against anemia
    Galina Y Miasnikova
    Chuvash Republic Clinical Hospital No 1, Cheboksary, Russia
    Haematologica 96:1371-4. 2011
    ..4-22.7; P=0.017). In conclusion, heterozygosity for VHL(R200W) may provide protection from anemia; such protection could explain the persistence of this mutation...
  16. pmc Predictors of osteoclast activity in patients with sickle cell disease
    Mehdi Nouraie
    Center for Sickle Cell Disease and Department of Medicine, Howard University, 1840 7th Street NW, Washington, DC 20001, USA
    Haematologica 96:1092-8. 2011
    ..In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease...
  17. pmc Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia
    Victor R Gordeuk
    Center for Sickle Cell Disease, Howard University, Washington, DC 20060, USA
    Haematologica 96:33-40. 2011
    ..The role of intravascular hemolysis in the development of this complication is controversial...
  18. pmc Elevated homocysteine, glutathione and cysteinylglycine concentrations in patients homozygous for the Chuvash polycythemia VHL mutation
    Adelina I Sergueeva
    Cheboksary Children s Hospital, Cheboksary, Russia
    Haematologica 93:279-82. 2008
    ..We conclude that up-regulated hypoxia-sensing may influence multiple steps in thiol metabolism. The effects of the resultant elevated levels of homocysteine and glutathione on systemic blood pressure may largely balance each other out...
  19. pmc Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension
    Liliana Moreno-Vinasco
    Section of Pulmonary and Critical Care Medicine, Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637, USA
    Physiol Genomics 33:278-91. 2008
    ..In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target...
  20. pmc Prevalence and risk factors for pulmonary artery systolic hypertension among sickle cell disease patients in Nigeria
    Zakari Y Aliyu
    Department of Medicine and Center for Sickle Cell Disease, Howard University, Washington, District of Columbia 20060, USA
    Am J Hematol 83:485-90. 2008
    ..The inclusion of African sites in sickle cell pulmonary hypertension clinical trials should be encouraged...
  21. ncbi Severe vaso-occlusive episodes associated with use of systemic corticosteroids in patients with sickle cell disease
    Deepika S Darbari
    Center for Cancer and Blood Disorders, Children s National Medical Center, Washington, DC, USA
    J Natl Med Assoc 100:948-51. 2008
    ..We conclude that corticosteroids should be used with caution in patients with SCD...
  22. pmc Altered cytokine profiles in patients with Chuvash polycythemia
    Xiaomei Niu
    Center for Sickle Cell Disease and Department of Medicine, Howard University, Washington, District of Columbia 20060, USA
    Am J Hematol 84:74-8. 2009
    ..In conclusion, the up-regulated hypoxic response in Chuvash polycythemia is associated with increased plasma products of both the Th1 and Th2 pathways, but the balance between the two pathways seems to be preserved...
  23. pmc Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation
    Caterina P Minniti
    Children s National Medical Center, Washington, DC, USA
    Haematologica 94:340-7. 2009
    ....
  24. ncbi Echocardiographic findings in patients with sickle cell disease
    Shahla G Naoman
    Department of Medicine, Howard University, Washington, DC 20001, USA
    Ann Hematol 89:61-6. 2010
    ..Significant, independent associations were found with both elevated LDH concentration and degree of anemia, suggesting that hemolytic and other mechanisms contribute to pulmonary hypertension in patients with sickle cell disease...
  25. pmc Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patients
    Andrew Campbell
    University of Michigan, Ann Arbor, MI, USA
    Br J Haematol 147:352-9. 2009
    ..022). In conclusion, lower haemoglobin oxygen saturation is independently associated with increasing degrees of anaemia and haemolysis but not pulmonary function abnormalities among children and adolescents with sickle cell disease...
  26. pmc Prospective echocardiography assessment of pulmonary hypertension and its potential etiologies in children with sickle cell disease
    Niti Dham
    Department of Cardiology, Children s National Medical Center, Washington, District of Columbia, USA
    Am J Cardiol 104:713-20. 2009
    ..In conclusion, children with SCD had mildly increased TRV that was correlated with increased cardiac output and left ventricular filling pressures. Hemoglobin-adjusted analysis also suggested a contribution of primary vascular changes...
  27. pmc Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease
    Victor R Gordeuk
    Howard University, Washington, DC 20060, USA
    Blood 114:4639-44. 2009
    ..The hemolysis-lowering and hemoglobin F-augmenting effects of hydroxyurea may exert countervailing influences on pulmonary blood pressure in sickle cell disease...
  28. pmc Angiogenic and inflammatory markers of cardiopulmonary changes in children and adolescents with sickle cell disease
    Xiaomei Niu
    Center for Sickle Cell Disease, Howard University, Washington, DC, United States of America
    PLoS ONE 4:e7956. 2009
    ..Pulmonary hypertension is associated with hemolysis and hypoxia, but other unidentified factors are likely involved in pathogenesis as well...
  29. pmc Increased size of solid organs in patients with Chuvash polycythemia and in mice with altered expression of HIF-1alpha and HIF-2alpha
    Donghoon Yoon
    Department of Medicine, University of Utah, Salt Lake, UT 84132, USA
    J Mol Med (Berl) 88:523-30. 2010
    ..At least in the liver, this phenotype may result from increased HIF-2alpha and decreased p21(Cip1) levels leading to increased hepatocyte proliferation...
  30. pmc NT-proBNP as a marker of cardiopulmonary status in sickle cell anaemia in Africa
    Zakari Y Aliyu
    Taraba State Specialist Hospital, Jalingo, Nigeria
    Br J Haematol 150:102-7. 2010
    ..5-21.0; P = 0.011). In conclusion, NT-proBNP elevation is common and is associated with markers of anaemia, inflammation and iron status and with severe functional impairment among sickle cell anaemia patients in Nigeria...
  31. pmc Association of G6PD with lower haemoglobin concentration but not increased haemolysis in patients with sickle cell anaemia
    Mehdi Nouraie
    Center for Sickle Cell Disease, Howard University, Washington, DC 20060, USA
    Br J Haematol 150:218-25. 2010
    ..007), and increased severe pain episodes (P < 0.001). In conclusion, G6PD(202A,376G) may be associated with lower haemoglobin concentration in sickle cell anaemia by a mechanism other than increased haemolysis...
  32. pmc Prediction of fetal hemoglobin in sickle cell anemia using an ensemble of genetic risk prediction models
    Jacqueline N Milton
    Department of Biostatistics, Boston University School of Public Health, Boston, MA
    Circ Cardiovasc Genet 7:110-5. 2014
    ..Combining SNPs into a genetic risk score can help to explain a larger amount of the variability of HbF level, but the challenge of this approach is to select the optimal number of SNPs to be included in the genetic risk score...