Although patients with sickle cell disease (SCD) share a common hemoglobin (Hb) mutation; their clinical presentation is quite variable suggesting a role for extra-erythrocytic genetic and environmental factors in the modulation of the disease process. Chronic pulmonary disease characterized by pulmonary hypertension (PH) and right-sided congestive heart failure (cor pulmonale) is an under-appreciated complication. Although it may be present in up to 40%, it is often asymptomatic. Determination of etiological factors responsible for the development of PH in SCD is important as PH represents an independent risk factor for death in this population. Our laboratory has determined that nitric oxide (NO) metabolism is altered in the acute chest syndrome (ACS) of SCD, with the preferential formation of powerful oxidative metabolites such as peroxynitrite and resultant decreased NO bioavailability. As recurrent episodes of ACS may be a risk factor for the development of PH in SCD patients, similarities in pathogenesis may exist. We hypothesize that extra-erythrocytic genetic polymorphisms are an important pre-disposing risk factor for the development of PH in SCD patients and that these polymorphisms are associated with decreases in NO bioavailability. Reductions in functional NO act within the endothelium to produce a pro-constrictive, pro-adhesive phenotype which likely plays an important role in the development of PH of SCD. To investigate these hypotheses, we will: 1) Determine the prevalence and clinical outcome of PH in a clinic population of SCD patients; 2) Determine the role of altered nitric oxide bioavailability in the development of PH of SCD; and 3) Correlate the presence of single nucleotide polymorphisms in endothelial cell-expressed genes in the NO pathway with the presence of PH of SCD. The goal of this application is to establish a cohort of patients with PH related to SCD so that they may be studied biochemically and genetically to gain great insight into the pathogenesis of pulmonary vascular disease in these patients.
