Pulmonary Hypertension and the Hypoxic Response in Sickle Cell Disease

Principal Investigator: Victor R. Gordeuk, MD

The aim of this multi-centered research endeavor is to determine the prevalence and risk factors of pulmonary hypertension in children and adolescents with sickle cell disease, and the role of hypoxic responses in pulmonary hypertension pathogenesis. The proposal demonstrates innovation and novelty in proposing to compare SCD disease mechanisms with those mediating disease in Chuvash polycythemia; a congenital disorder of the oxygen sensing mechanism in which the hypoxic response is constitutively up regulated. The investigative team is unique, and the resources for conducting the research are available in all 3 centers. The preliminary data is exciting. The application directly links mechanisms of pulmonary vascular disease with genetic aspects of altered HIF1 signaling pathways. The strengths include an outstanding group of investigators, a novel and supported hypothesis, and a unique study population. The hypothesis that there is a defect in the oxygen sensing mechanism associated with HIF1 is novel. One weakness of the application is that it assumes that the genes important in progression of the disease will be evolutionarily conserved, thereby identifiable in a mouse model. While notable, the latter was considered to be a minor issue.

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 three 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.

Specific Aims

  1. Determine the prevalence, risk factors and clinical consequences of pulmonary hypertension (PHTN) in children and adolescents with sickle cell disease (SCD).
  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).
  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.