Natural History Study of Biomarkers in Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival. Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, the "two-hit" hypothesis, appears to play a central role both in the pathogenesis and progression of PAH. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic PAH (IPAH) and patients with disease-associated PAH. However, despite mounting evidence of vascular inflammation in patients with PAH, detailed phenotypic studies are lacking on the temporal evolution of this process and its contribution to right ventricular (RV) and pulmonary vascular remodeling. We hypothesize that a detailed characterization of the temporal evolution of vascular inflammation in PAH and its impact on RV and pulmonary vascular function will add prognostic value to traditional measures of disease severity and suggest novel therapeutic targets for future research. Objectives: Patients with IPAH and disease-associated PAH will be recruited to the NIH and enrolled in this natural history study investigating the ability of circulating markers of vascular inflammation as well as high-resolution cardiac magnetic resonance imaging (MRI) to accurately stage severity of disease and/or predict clinically relevant outcomes. Methods: The total study population will be 150 PAH subjects and approximately 55 age/sex matched healthy control subjects (matched 3:1, stratified by age and sex). PAH subjects will undergo 1) standard clinical examinations including 6-minute walk distance and echocardiography; 2) cardiopulmonary exercise testing; 3) markers of coagulation and fibrotic disease; 4) plasma profiling of inflammatory markers; 5) gene expression profiling of peripheral blood mononuclear cells (PBMCs); 6) high-resolution MRI-based determination of pulmonary vascular and RV structure and function and 7) Cardiac CT scan. Plasma markers of endothelial inflammation, PBMC expression profiles, and high-resolution cardiac MRI will also be studied in age and sex matched controls to define normal ranges and variability for each of these novel assessments. Comparison of these results to PAH subjects at baseline will be used to determine the degree to which these investigative tests distinguish PAH patients from healthy subjects. Likewise, baseline clinical evaluations of PAH subjects will be used to examine whether any novel test (inflammatory markers, or cardiac MRI), accurately classifies patients according to their disease severity. In addition, these tests will be investigated prospectively for their ability to predict PAH disease progression. Disease progression will be defined prospectively as a decrease in the 6-minute walk distance of \> 10% from baseline or clinical worsening requiring an escalation in therapy, hospitalization due to right heart failure, transplantation or death. Additional plasma will be collected from PAH subjects and age/sex matched control subjects. This material will be used to probe for new biomarkers and inflammatory factors using discovery based approaches (i.e. Proteomics and pulmonary artery endothelial cell bioassay).