Our studies suggest that secondary pulmonary hypertension is common in adult patients with sickle cell disease, appears to be resistant to hydroxyurea therapy, is linked to hemolysis and is associated with a high mortality. This study evaluated (1) the pathophysiologic processes that are associated with and potentially contribute to secondary pulmonary hypertension in adult patients with sickle cell anemia. (2) the relative acute vasodilatory effects of oxygen, intravenous prostacyclin, and inhaled nitric oxide on pulmonary artery pressures and other hemodynamic parameters in patients with secondary pulmonary hypertension and sickle cell disease. (3) the effects of two months of inhaled nitric oxide on pulmonary artery pressures, other hemodynamic parameters, exercise tolerance and symptoms in this patient population and (4) the effects of three months of exchange transfusion on pulmonary artery pressures, other hemodynamic parameters, exercise tolerance, and symptoms in patients who do not receive or fail to respond to NO therapy. We enrolled 60 subjects in the clinical trial with 50 completing stage I, 16 completing stage II and 7 completing stage III. Due to the availability of FDA approved oral medications, such as Prostacyclin, Bosentan, Sildenafil and L-Arginine, etc, Stage II of this protocol was only offered if the oral medications failed or were not tolerated. There were no adverse events related to the inhalation of nitric oxide and approximately 80% of patients responded with decreases in pulmonary pressures. The efficacy data accrued to date are currently under analysis for publication. Conclusions: The use of six-minute walk distance to evaluate the effects of therapies such as hydroxyurea, transfusion, and selective pulmonary vasodilator and remodeling agents has the potential to accelerate the development of specific therapies for this population. These results suggest that increased pulmonary vascular resistance is poorly tolerated in patients with severe anemia, potentially explaining the increased mortality associated with its development in this population. This protocol is now closed for accrual and is only open for data and sample analysis. We planned to continue analysis for the coming year, which includes: The analysis of Stage I of the protocol consists of descriptive statistics proportions, means, standard deviations, etc. We are comparing these studies to the control group of sickle cell patients that do not have pulmonary hypertension. Protocol hemodynamic, pulmonary function, clinical laboratory and other data are being analyzed in relationship to mortality in preparation for publication. These data are also being analyzed to determine relationships to 1) radiology data obtained during the study, in collaboration with CC Radiology Department collaborators led by D. Daniel Mollura;2) planned analysis of hemodynamic Witt monitor digital files by calculating right ventricular flow-volume loops, a promising way to determine right ventricular function, in collaboration with University of Pittsburgh cardiologist Hunter Champion. The primary endpoint in Stage II of the protocol is response or no response to study medications, with response defined as a decrease of at least 10% in systolic pulmonary artery pressure. The proportion of responders on each medication (i.e NO, prostacyclin, and oxygen) will be estimated (point estimate and 95% confidence intervals). In addition, point estimates and 95% confidence intervals will be determined for differences between proportions responding to different medications, taking the paired nature of the data into account. We are noting the proportions of patients with every possible combination of responses i.e., response to all three medications, response to NO and oxygen but not to prostacyclin, etc. In particular, we are noting the association between response to NO and response to prostacyclin. Mean absolute changes in systolic pulmonary artery pressure are also being compared among the medications. Change in vascular and cardiac pressure and in cardiac output are also being summarized and compared among medications. For Stage III of the protocol we are analyzing mean pulmonary artery pressure (MPAP) in the completed population by a paired t-test, on the change from baseline (i.e., MPAP at eight weeks vs. MPAP at baseline). The statistical null hypothesis tested is that there is either no change or an increase in mean change of MPAP. It is not expected that the assumption of a normal distribution of the changes will be seriously violated. If it is, however, perhaps because of an extremely skewed distribution of the changes, the baseline and eight-week values may be transformed (probably logarithmically) before calculating the change. A manuscript has been prepared and submitted.

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Nguyen, Kim-Lien; Tian, Xin; Alam, Shoaib et al. (2016) Elevated transpulmonary gradient and cardiac magnetic resonance-derived right ventricular remodeling predict poor outcomes in sickle cell disease. Haematologica 101:e40-3
Mehari, Alem; Alam, Shoaib; Tian, Xin et al. (2013) Hemodynamic predictors of mortality in adults with sickle cell disease. Am J Respir Crit Care Med 187:840-7
Mehari, Alem; Gladwin, Mark T; Tian, Xin et al. (2012) Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 307:1254-6