Clinical Translational Research Program in Pulmonary Arterial Hypertension (PAH): Disease Mechanisms, Biomarkers, and Novel Therapeutic Targets

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Pulmonary hypertension (PH) due to direct pulmonary vascular injury is collectively referred to as pulmonary arterial hypertension (PAH), and is distinct from other causes of PH such as left sided heart failure, parenchymal lung disease with hypoxemia and chronic thromboembolic disease. Idiopathic PAH (IPAH) is an unexplained form of PAH where the triggering insult to the endothelium is unclear. Several diseases may manifest PAH that is identical in histopathology to IPAH. Diseases resulting in PAH (referred to as disease-associated PAH) include autoimmune disorders (i.e. limited systemic sclerosis, mixed connective tissue disease, and systemic lupus erythematosus), HIV infection, congenital heart disease, and liver disease with portal hypertension. Contemporary paradigms of PAH pathobiology include endothelial damage/disruption, genetic and epigenetic contributions, metabolic derangements with a hyper-proliferative, anti-apoptotic cellular phenotype, and both systemically and locally dysregulated inflammation. In the absence of PAH-specific surrogate markers for assessing disease severity and prognosis, risk prediction continues to rely on subjective functional assessments and invasive hemodynamic measurements. There is continued interest in the discovery of novel, biologically relevant, non-invasive biomarkers that may simplify PAH risk stratification and serve as markers of ongoing disease progression and, ideally, response to therapy. In PAH, inflammation appears to drive the dysfunctional endothelial phenotype, propagating cycles of injury and repair. However, detailed phenotypic studies are lacking on the temporal evolution of this process and its contribution to RV and pulmonary vascular remodeling. At the NIH Clinical Center patients with WHO group 1 PAH are being enrolled in a natural history study (13-CC-0012) assessing patients at baseline, biannually in the 1st year and then annually to: 1) Characterize the contribution of inflammation to disease progression and long-term outcomes in PAH and 2) Identify non-invasive markers of vascular inflammation that add prognostic value to traditional measures of disease severity and suggest novel therapeutic targets for future research. In addition, to standard clinical testing, patients undergo serial assessments using innovative imaging techniques, flow cytometric analyses of endothelial and bone marrow progenitor cells, genome-wide blood transcriptomic profiles and circulating biomarkers such as cfDNA. The collective data will be used to investigate the ability of blood markers of vascular inflammation and/or high-resolution cardiac CT and MRI to stage disease severity and predict clinically relevant outcomes. The study has enrolled 67 individuals (54 patients and 13 healthy volunteers). Total study population will be 150 adult PAH subjects and 50 age and gender matched controls (i.e. healthy volunteer matched to 3 PAH patients). Inflammation is recognized as a feature of the abnormal pulmonary arteries in PAH patients, and it has been hypothesized, but remains unknown as to whether drugs that block inflammation could be beneficial in patients with PAH. Mineralocorticoid receptor (MR) antagonists, like spironolactone, have been widely used in patients with left sided heart failure or LV dysfunction post-myocardial infarction. Evidence suggests spironolactone improves endothelial function and reduces inflammation. Patients with WHO group 1 PAH are being enrolled in the Spironolactone Interventional Trial (SPIRIT-PAH, 12-CC-0211); a phase 1-2 randomized, double blinded, placebo-controlled 6-month study of spironolactone treatment in PAH. The trial examines the safety and tolerability of spironolactone and its efficacy as assessed by effects on exercise capacity and clinical worsening. We seek to determine if spironolactone provides benefits in PAH through anti-inflammatory effects and improvements in endothelial function. The study has enrolled 31 individuals and per statistical assessment plan at least 50. Our original PAH protocol (05-CC-0041: n = 31) assessed whether circulating endothelial cells (CECs) and/or PBMC may serve as PAH biomarkers. The project used flow cytometry to develop a methodology for isolating relevant numbers of viable CECs from healthy and PAH subjects. CECs and PBMCs were obtained from peripheral blood (PB) specimens. A subset of subjects had a right heart catheterization to assess pulmonary pressures and obtain pulmonary blood specimens. Available data suggested no trend towards CEC enrichment in pulmonary vein blood compared to PB for healthy (4.4 vs 4.8 CEC/ml) and PAH (2.4 vs 3.0 CEC/ml) subjects. There was a trend towards CEC enrichment in pulmonary artery blood compared to PB for healthy (13.8 vs 4.8 CEC/ml) and PAH (3.3 vs 3.0 CEC/ml) subjects. In addition, during the current reporting period we published a manuscript (Am J Physiol Lung Cell Mol Physiol, 318(1): L98-L111, 2019) containing our PBMC data as part of a larger meta-analysis. The meta-analysis defined a robust and generalizable transcriptomic signature in the blood of PAH patients that can help inform the identification of biomarkers and therapeutic targets. This protocol (1 of 3) is closed to enrollment and open for data analysis. Remaining bio-specimens include RNA, plasma, serum, circulating endothelial cells and T-Cells. 2019 -20 preliminary results: Plasma Cell-free DNA as a Novel Marker of Disease Severity in PAH. American College of Cardiology 68thAnnual Scientific Session, J Am Coll Cardiol, 73(9, S1): S1897, 2019: In PAH patients, plasma cfDNA was found to be elevated compared to controls (n = 7) and correlated with disease severity (mild PAH n = 7, severe PAH n = 8). cfDNA may add prognostic power to current PAH risk calculators and may help guide management decisions. Based on preliminary results, we entered into an MTA with PAH programs at Allegheny General Hospital and Tufts Medical Center. We received over 200 plasma samples with clinical data. Coronary Artery Plaque Burden in Patients with PAH. American Thoracic Society 115th International Conference Am J Respir Crit Care Med, 199:A6795, 2019: Compared to controls (n = 7) matched for traditional risk factors of coronary artery disease, PAH subjects (n = 7) tended to have a higher burden of coronary artery plaque as determined by CT angiography. These findings and their relevance to symptoms and functional capacity, need to be further investigated in a larger PAH cohort. PAH Patients Display Normal Kinetics of Clot Formation. American Heart Association Scientific Sessions, 140:A10714, 2019: PAH patients on stable medical therapy do not demonstrate abnormal clotting kinetics or fibrinolysis by thrombelastography (TEG). Additionally, these patients do not demonstrate abnormal levels of hematologic markers associated with thrombosis and fibrosis. These results need to be further investigated in a larger PAH cohort.