Pulmonary Hypertension in SCD

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DESCRIPTION (provided by applicant): Pulmonary complications such as pulmonary hypertension (pHTN) have become a major source of both morbidity and mortality. The Duke-UNC Comprehensive Sickle Cell Center offers a large and well characterized patient population with which to study many aspects of pHTN in SCD. The long-term goals of our proposed work are (1) to increase our understanding of both the natural history of pHTN in SCD, as well as the pathophysiologic mechanisms leading to its development; and (2) to identify specific therapeutic interventions that can ameliorate the course of this devastating complication. To these ends, we will accomplish the following three Specific Aims. AIM 1: We will study the natural history and course of disease progression, as well as identify disease markers of SCD and disease-modifying genes associated with pHTN. We will screen 200 additional patients with SCD for pHTN and we will study >100 patients with mild severe pHTN and SCD during follow up periods of no less than two years and up to 4 years. Studies will focus on clinical characteristics (Project 1), as well as disease markers and genetic polymorphisms (Project 2). AIM 2: We will determine the effects of two therapeutic maneuvers-bosentan and transfusion-on pHTN and other parameters of pulmonary and cardiovascular function, as well as biomarkers of SCD activity. We will conduct a randomized trial of bosentan (Project 3) vs. placebo in 60 patients with mild pHTN. In addition, we will study the effects of transfusion on moderate-severe pHTN (Project 4). AIM 3: We will investigate basic pathophysiologic mechanisms involving NO, superoxide and red cell biology (Project 5), as they affect the pulmonary circulation in humans and animals. Achievement of these aims will provide a more in-depth understanding of the development and natural history of pHTN in SCD, help identify those patients at greatest risk for pHTN, elucidate pathogenetic mechanisms in pHTN, and provide guidance toward effective treatment of this life-threatening syndrome. (End of Description)