AIM 1: Peripheral Blood Mononuclear Cells (PBMCs): It is our hypothesis that patients with IPAH, PAH secondary to the scleroderma spectrum of diseases (CREST syndrome), and PAH secondary to other causes (PAH associated disease) may have predictive changes in the gene expression of immune cells within their peripheral blood. PBMCs are the immune cells (lymphocytes and monocytes) which compose the peripheral blood. These cells are readily accessible via vein puncture. There is evidence that these cells may participate in an immune response within the pulmonary vasculature contributing to the development of pulmonary hypertension in patients with IPAH and patients with Scleroderma associated PAH. We wish to investigate whether these cells from patients with PAH have an altered genetic expression compared to PBMCs from normal individuals and patients with Scleroderma without pulmonary hypertension. We are looking at gene activity. If we identify genes which are differentially expressed between groups (candidate genes) we will evaluate for the presence of single nucleotide polymorphisms (SNPs) within these genes to explain these differences in expression.
AIM 2: We also believe that circulating mononuclear-fibrogenic cells (CMFCs) have been implicated in inflammation, vascular remodeling and right ventricular dysfunction. We have shown that fibroblasts in PAH patients and in animal models acquire an activated and epigenetically altered phenotype that is capable of generating a microenvironment, which promotes recruitment and activation of circulating mononuclear fibrogenic cells and that these cells contribute directly to tissue fibrosis and cardiac dysfunction. Our proposal will directly examine the mechanisms involved in fibroblast directed recruitment and activation of mononuclear fibrogenic cells and ultimately the role of these cells in driving abnormalities of large and small vessels, RV function and ultimately RV failure.
We wish to draw blood from patients with idiopathic pulmonary arterial hypertension, pulmonary hypertension associated with Scleroderma, pulmonary hypertension associated with other causes (e.g. congenital heart disease, drugs and toxins, thromboembolic disease, paranchymal lung disease), scleroderma patients without pulmonary hypertension, patients with pulmonary fibrosis, and normal controls.
We plan to enroll a total of 2,000 patients with and without pulmonary hypertension from WHO group 1-5 Dana Point Classification Some patients will be asked to donate blood after treatment with medication such as Bosentan and prostacyclin. These patients will be asked to donate 2 other blood samples (for a total of 3 blood draws) each sample at 3 month intervals, to examine the effect of these medications on our findings, (gene expression). Blood samples will be collected at the patient's normal clinic visits. Patients will not be asked to come to the hospital to donate samples outside their normal clinic visits. In addition to the blood samples collected for this study, the subjects will be approached for additional samples of blood that will be stored by Dr. Bull for future research. These samples after deidentification may be shared with other investigators at the University of Colorado or other institutions.