Current guidelines for the treatment of patients with idiopathic pulmonary arterial hypertension (IPAH) recommend basing therapeutic decision-making on haemodynamic, functional and biochemical variables. Most of these parameters have been evaluated as risk predictors at the time of diagnosis. The aim of the present study was to assess the prognostic impact of changes in these parameters after initiation of targeted therapy.A cohort of 109 patients with IPAH who had undergone haemodynamic, functional and biochemical assessments at baseline and 3-12 months after initiation of pulmonary arterial hypertension (PAH)-targeted therapy, were followed for a median 38 months in order to determine predictors of mortality at baseline and during the course of their disease.Within the observation period, 53 (48.6%) patients died and four (3.7%) underwent lung transplantation. Kaplan-Meier estimates for transplantation-free survival were 92%, 67%, and 51% at 1, 3, and 5 yrs, respectively. Among baseline variables, 6-min walk distance, right atrial pressure, cardiac index, mixed-venous oxygen saturation (Sv,O 2 ) and N-terminal-pro brain natriuretic peptide (NT-proBNP) were independent predictors of survival. During follow-up, changes in World Health Organization functional class, cardiac index, Sv,O 2 and NT-proBNP proved significant predictors of outcome. When assigned to prognostic groups, improvements as well as deteriorations in these parameters after initiation of PAH-targeted therapy had a strong impact on survival. Measurements obtained at follow-up had a higher predictive value than variables obtained at baseline.Changes in established predictors of outcome during the course of the disease provide important prognostic information in patients with IPAH.

Rationale: Pulmonary arterial hypertension (PAH) is a progressive condition with a poor prognosis. Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in its pathobiology. Objectives: To assess safety, tolerability, and efficacy of the PDGFR inhibitor imatinib in patients with PAH. Methods: Patients with PAH in functional classes II-IV were enrolled in a 24-week randomized, double-blind, placebo-controlled pilot study. Patients received imatinib (an inhibitor of PDGFR activity) 200 mg orally once daily (or placebo), which was increased to 400 mg if the initial dose was well tolerated. The primary endpoints were safety and change from baseline in the 6-minute-walk distance (6MWD). Secondary endpoints included hemodynamics and functional classification. Measurements and Main Results: Fifty-nine patients enrolled (imatinib [n 5 28]; placebo [n 5 31]); 42 completed the study. Dropouts were equally matched between the two groups. In the intention-to-treat (ITT) population there was no significant change in the 6MWD (mean 6 SD) in the imatinib versus placebo group (122 6 63 versus 21.0 6 53 m). There was a significant decrease in pulmonary vascular resistance (imatinib 2300 6 347 versus placebo -78 6 269 dynes Á s Á cm 25 , P , 0.01) and increase in cardiac output (imatinib 10.6 6 1.2 versus placebo 20.1 6 0.9 L/min, P 5 0.02). Serious adverse events occurred in 11 imatinib recipients (39%) and 7 placebo recipients (23%). Three deaths occurred in each group. Post hoc subgroup analyses suggest that patients with greater hemodynamic impairment may respond better than patients with less impairment. Conclusions: These data from a Phase II study are consistent with imatinib being well tolerated in patients with PAH, and provide proof of concept for further studies evaluating its safety, tolerability, and efficacy in PAH. Clinical trial registered with www.clinicaltrials.gov (NCT00477269).

PPARgamma is a member of a family of nuclear receptors/ligand-dependent transcription factors, which bind to hormone response elements on target gene promoters. An antiproliferative and proapoptotic action profile of PPARgamma has been described and PPARgamma may function as a tumor suppressor gene, but little is known about the role of PPARgamma in vascular remodeling. One group of human diseases that shows impressive vascular remodeling exclusively in the lungs is the group of severe pulmonary hypertensive disorders, which is characterized by complex, endothelial cell-proliferative lesions of lung precapillary arterioles composed of clusters of phenotypically altered endothelial cells that occlude the vessel lumen and contribute to the elevation of the pulmonary arterial pressure and reduce local lung tissue blood flow. In the present study, we report the ubiquitous PPARgamma expression in normal lungs, and in contrast, a reduced lung tissue PPARgamma gene and protein expression in the lungs from patients with severe PH and loss of PPARgamma expression in their complex vascular lesions. We show that fluid shear stress reduces PPARgamma expression in ECV304 endothelial cells, that ECV304 cells that stably express dominant-negative PPARgamma (DN-PPARgamma ECV304) form sprouts when placed in matrigel and that DN-PPARgamma ECV304 cells, after tail vein injection in nude mice, form lumen-obliterating lung vascular lesions. We conclude that fluid shear stress decreases the expression of PPARgamma in endothelial cells and that loss of PPARgamma expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype.

Primary pulmonary hypertension (PPH) is a frequently fatal disease whose pathobiology is poorly understood. Monoclonal endothelial cell growth is present within plexiform lesions of patients with PPH but not secondary PH because of congenital heart malformations. We hypothesized that endothelial cells within PPH plexiform lesions harbor mutations permissive for clonal cell growth. We found that endothelial cells in PPH plexiform lesions demonstrated microsatellite instability within the human MutS Homolog 2 gene (10 of 20 lesions) and displayed microsatellite site mutations and reduced protein expression of transforming growth factor-beta receptor type II (6 of 19 lesions) and Bax (4 of 19 lesions). These results suggest that, in PPH, proliferated endothelial cells have genetic alterations associated with microsatellite instability and concomitant perturbation of growth and apoptosis gene expression akin to neoplasia. The full text of this article is available at http://www.circresaha.org.