Pulmonary Hypertension and the Hypoxic Response in SCD
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
- Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiencyVictor 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...
- Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expressionVictor 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...
- Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemiaDeepika 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....
- 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 KingdomVandana Sachdev
Cardiovascular and Pulmonary Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
Circulation 124:1452-60. 2011....
- 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....
- Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in U.S. hospital discharge records: a cross-sectional studyMehdi 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...
- A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell diseaseAnkit 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)...
- Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidinSergei Nekhai
Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, DC, USA
Haematologica 98:455-63. 2013..ClinicalTrials.gov Identifier:NCT00011648)...
- 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...
- Genetic determinants of haemolysis in sickle cell anaemiaJacqueline 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...
- Clinical correlates of acute pulmonary events in children and adolescents with sickle cell diseaseRabindra Paul
Howard University, Washington, DC, USA
Eur J Haematol 91:62-8. 2013We 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.
- Iron deficiency modifies gene expression variation induced by augmented hypoxia sensingXu 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. ..
- Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemiaManuel 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...
- Differences in the clinical and genotypic presentation of sickle cell disease around the worldSantosh 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. ..
- The heterozygote advantage of the Chuvash polycythemia VHLR200W mutation may be protection against anemiaGalina 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...
- Predictors of osteoclast activity in patients with sickle cell diseaseMehdi 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...
- Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemiaVictor 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...
- Elevated homocysteine, glutathione and cysteinylglycine concentrations in patients homozygous for the Chuvash polycythemia VHL mutationAdelina 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...
- Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertensionLiliana 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...
- Prevalence and risk factors for pulmonary artery systolic hypertension among sickle cell disease patients in NigeriaZakari 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...
- Severe vaso-occlusive episodes associated with use of systemic corticosteroids in patients with sickle cell diseaseDeepika 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...
- Altered cytokine profiles in patients with Chuvash polycythemiaXiaomei 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...
- Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturationCaterina P Minniti
Children s National Medical Center, Washington, DC, USA
Haematologica 94:340-7. 2009....
- Echocardiographic findings in patients with sickle cell diseaseShahla 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...
- Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patientsAndrew 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...
- Prospective echocardiography assessment of pulmonary hypertension and its potential etiologies in children with sickle cell diseaseNiti 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...
- Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell diseaseVictor 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...
- Angiogenic and inflammatory markers of cardiopulmonary changes in children and adolescents with sickle cell diseaseXiaomei 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...
- Increased size of solid organs in patients with Chuvash polycythemia and in mice with altered expression of HIF-1alpha and HIF-2alphaDonghoon 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...
- NT-proBNP as a marker of cardiopulmonary status in sickle cell anaemia in AfricaZakari 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...
- Association of G6PD with lower haemoglobin concentration but not increased haemolysis in patients with sickle cell anaemiaMehdi 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...
- Prediction of fetal hemoglobin in sickle cell anemia using an ensemble of genetic risk prediction modelsJacqueline 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...