Abstract-The availability of new treatments for patients with pulmonary arterial hypertension has increased awareness and interest in the medical community for pulmonary vascular diseases in general. Many uncertainties exist, however, regarding the diagnosis and treatment of patients with pulmonary arterial hypertension that are particularly pertinent for the management of patients with idiopathic pulmonary arterial hypertension and pulmonary hypertension associated with underlying diseases. This review highlights controversial issues around the definition and diagnosis of pulmonary hypertension, the interpretation of hemodynamic variables, and the interpretation of clinical responsiveness to chronic therapies. In addition, we propose guidelines applicable to the conduct of new therapeutic trials in pulmonary arterial hypertension, which aim to provide greater confidence in the efficacy and safety of new treatments currently under development. Key Words: catheterization Ⅲ hypertension, pulmonary Ⅲ hypoxia Ⅲ trials Ⅲ vasoconstriction P ulmonary hypertension from any cause is more prevalent than previously believed. As reported in a Centers for Disease Control study of the prevalence of pulmonary hypertension in the United States, more than 260 000 people were discharged from the hospital with a diagnosis of pulmonary hypertension in 2002. 1 It is likely that the increasing attention being paid to making a diagnosis of pulmonary hypertension is related to the fact that there are now therapies available that were not available a decade ago to treat these patients. 2 Furthermore, the broad availability of Doppler echocardiography has helped with (earlier) detection of pulmonary hypertension.A new classification of clinical pulmonary hypertension, which was revised recently, 3 designated 5 categories that are distinctive because they differ in their clinical presentation, diagnostic findings, and response to treatment (Table 1). 4 As we now know, a treatment that is effective for one cause of pulmonary hypertension can worsen the prognosis for pulmonary hypertension due to a different cause. 5 Equally important is the fact that some treatments for pulmonary hypertension can be lifesaving, and the failure to make a correct diagnosis in a patient who is potentially curable could be catastrophic. 6 It is also important to emphasize that the approved treatments for pulmonary arterial hypertension (PAH; category 1, the only category of pulmonary hypertension for which treatments are approved) have serious side effects, are exceedingly expensive, and have not been shown to be effective in patients with other forms of pulmonary hypertension. When one takes into account the mortality associated with pulmonary hypertension, as well as the risks and benefits of the different treatments, it becomes apparent that an accurate diagnosis of the cause of pulmonary hypertension is as essential as the correct diagnosis of the type of tumor in a patient with cancer. Uncertainties With the Definition of PAHThere appear to be discrepanci...

Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of a disease model representative of the human condition is a key obstacle to the development of new treatments. Here we present a model of PAH, based on a biomimetic pulmonary artery (PA)-on-a-chip, that permits the study of the molecular and functional changes in human pulmonary vascular endothelial and smooth muscle cells in response to triggers of the disease and their response to drugs. We combine natural or induced BMPR2 dysfunction with hypoxia in vascular endothelial cells to trigger smooth muscle activation and proliferation and relate accompanying transcriptomic changes in affected cells to functional effects. Changes in gene expression consistent with observations made in genomic and biochemical studies of the human disease enable insights into underlying disease pathways and mechanisms of drug response. The model offers a novel, promising and more easily accessible approach for researchers to study pulmonary vascular remodelling and advance drug development in PAH.

Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudo-malignant phenotype. We investigated the expression and the role of the receptor tyrosine kinase Axl in experimental (i.e., monocrotaline and Su5416/hypoxia treated rats) and clinical PAH. In vitro Axl inhibition by R428 and Axl knock-down inhibited growth factor-driven proliferation and migration of non-PAH and PAH PASMCs. Conversely, Axl overexpression conferred a growth advantage. Axl declined in PAECs of PAH patients. Axl blockage inhibited BMP9 signaling and increased PAEC apoptosis, while BMP9 induced Axl phosphorylation. Gas6 induced SMAD1/5/8 phosphorylation and ID1/ID2 increase were blunted by BMP signaling obstruction. Axl association with BMPR2 was facilitated by Gas6/BMP9 stimulation and diminished by R428. In vivo R428 aggravated right ventricular hypertrophy and dysfunction, abrogated BMPR2 signaling, elevated pulmonary endothelial cell apoptosis and loss. Together, Axl is a key regulator of endothelial BMPR2 signaling and potential determinant of PAH.

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