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Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH., Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured., Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival., Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation., (© 2017 The Authors.)

Background: Right ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation., Methods: We measured RV end-systolic and end-diastolic volumes (ESV and EDV) using cardiac magnetic resonance imaging and RV pressures during right heart catheterization in 140 incident PAH patients and 22 controls. A maximum RV pressure (Pmax) was calculated from the nonlinear extrapolations of early and late systolic portions of the RV pressure curve. The gold standard measure of RV function adaptation to afterload, or RV-arterial coupling (Ees/Ea) was estimated by the stroke volume (SV)/ESV ratio (volume method) or as Pmax/mean pulmonary artery pressure (mPAP) minus 1 (pressure method) (n=84). RV function was also assessed by ejection fraction (EF), right atrial pressure (RAP) and SV., Results: Higher Ea and RAP, and lower compliance, SV and EF predicted outcome at univariate analysis. Ees/Ea estimated by the pressure method did not predict outcome but Ees/Ea estimated by the volume method (SV/ESV) did. At multivariate analysis, only SV/ESV and EF were independent predictors of outcome. Survival was poorer in patients with a fall in EF or SV/ESV during follow-up (n=44, p=0.008)., Conclusion: RV function to predict outcome in PAH is best evaluated by imaging derived SV/ESV or EF. In this study, there was no added value of invasive measurements or simplified pressure-derived estimates of RV-arterial coupling., Competing Interests: Dr Bellofiore, Dr Vanderpool, Dr Chesler and Professor Naeije report no relationships that could be construed as a conflict of interest., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease., (Copyright © 2015 the American Physiological Society.)

Hypoxia can be defined as a reduction in available oxygen, whether in a whole organism or in a tissue or cell. It is a real life cause of pulmonary hypertension in humans both in terms of patients with chronic hypoxic lung disease and people living at high altitude. The effect of hypoxia on the pulmonary vasculature can be described in two ways; Hypoxic pulmonary vasoconstriction (HPV) (resulting from smooth muscle cell contraction) and pulmonary vascular remodelling (PVR) (resulting from pulmonary vascular cell proliferation). The pulmonary artery is made up of three resident cell types, the endothelial (intima), smooth muscle (media) and fibroblast (adventitia) cells. This review will examine the effects of hypoxia on the cells of the pulmonary vasculature and give an insight into the possible underlying mechanisms.

Hypoxia-induced endothelial dysfunction plays a crucial role in the pathogenesis of hypoxic pulmonary hypertension. p38 MAPK expression is increased in the pulmonary artery following hypoxic exposure. Recent evidence suggests that increased p38 MAPK activity is associated with endothelial dysfunction. However, the role of p38 MAPK activation in pulmonary artery endothelial dysfunction is not known. Sprague-Dawley rats were exposed to 2 wk hypobaric hypoxia, which resulted in the development of pulmonary hypertension and vascular remodeling. Endothelium-dependent relaxation of intrapulmonary vessels from hypoxic animals was impaired due to a reduced nitric oxide (NO) generation. This was despite increased endothelial NO synthase immunostaining and protein expression. Hypoxia exposure increased superoxide generation and p38 MAPK expression. The inhibition of p38 MAPK restored endothelium-dependent relaxation, increased bioavailable NO, and reduced superoxide production. In conclusion, the pharmacological inhibition of p38 MAPK was effective in increasing NO generation, reducing superoxide burden, and restoring hypoxia-induced endothelial dysfunction in rats with hypoxia-induced pulmonary hypertension. p38 MAPK may be a novel target for the treatment of pulmonary hypertension.

In the Framingham studies, systemic arterial pulse pressure correlated linearly with morbidity and mortality. Right ventricular (RV) systolic dysfunction and pulmonary circulation stiffening result in abnormalities of pulmonary arterial (PA) pulse pressure in PA hypertension (PAH). We investigated the prognostic potential of PA pulse pressure in 67 patients with PAH diagnosed between January 1996 and March 2004 (33 idiopathic PAH, 34 PAH-connective tissue disease). The population was arbitrarily divided into tertiles of PA pulse pressure (= systolic-diastolic PA pressure) and 5-year mortality was assessed using the Kaplan-Meier method. The extent of RV systolic dysfunction and pulmonary circulation stiffening within each tertile was assessed by comparing the mean cardiac index and alpha (a recently described measure of pulmonary circulation distensibility) in each. Independent predictors of mortality were identified by Cox regression. Five-year mortality rates in patients with low, intermediate and high pulse pressures were 40%, 91% and 54%, respectively. Pulse pressure did not independently predict mortality, but cardiac index, 6-min walk test distance and mixed venous oxygen saturation did. Pulse pressure correlated with circulation stiffening (alpha) but did not correlate with cardiac index which tended to be lower in patients with intermediate pulse pressure and high mortality. PA pulse pressure correlated with pulmonary circulation stiffening but did not predict mortality in this study. RV dysfunction provided better prognostic information and probably explains the higher mortality seen in patients with intermediate pulse pressure.

The earliest structural change in hypoxia-induced pulmonary hypertension is increased proliferation of adventitial fibroblasts. This fibroproliferative response occurs in acute and chronic hypoxic models, is dependent on p38 mitogen-activated protein (MAP) kinase activation, is selective for the pulmonary circulation, and would seem an important therapeutic target. Simvastatin attenuates pulmonary vascular remodeling in animal models, but additional information regarding mechanisms of action, differential antiproliferative effects and dose responses of available statins is required for appropriate clinical trial design. Our objectives were to determine the effects of statins on acute hypoxia-induced proliferation and p38 MAP kinase activation in pulmonary and systemic artery fibroblasts, to assess the effects of cholesterol intermediates, prenyltransferase and related inhibitors, and to determine the statin's mechanism of action. Atorvastatin, fluvastatin, and simvastatin inhibited adventitial fibroblast proliferation. At low doses (1 microM), this effect was selective for hypoxic (versus serum-induced) proliferation and was also selective for pulmonary (versus systemic) fibroblasts. Complete inhibition of hypoxia-induced p38 MAP kinase activity was achieved at this 1-microM dose. The lipophilic statins exhibited similar potency. The statin effect was reversed by geranylgeranyl pyrophosphate and mimicked by geranylgeranyl transferase and Rac1 inhibitors. Hypoxia-induced p38 MAP kinase activation and proliferation in pulmonary adventitial fibroblasts is dependent on a geranylgeranylated signaling protein, probably Rac1. One micromolar of fluvastatin exhibits a circulation- and stimulus-selective antiproliferative effect on pulmonary artery fibroblasts. The pharmacokinetics of fluvastatin would suggest that its antiproliferative effects may be useful in pulmonary hypertension associated with hypoxia.

Pulmonary arterial hypertension (PAH) is a disease that results in thickening of the vascular wall. Some of the most prominent changes are seen in the adventitia as a result of fibroblast proliferation and increased extracellular matrix deposition. Previous work from this laboratory using animal models has shown that pulmonary but not systemic artery fibroblasts proliferate to hypoxic exposure and that this response is dependent on activation of p38 mitogen-activated protein kinase (p38MAPK). In this study, we wished to determine whether human pulmonary artery fibroblasts (HPAFs) behaved similarly under conditions of acute hypoxic exposure (35 mmHg for 24 h). Fibroblast proliferation was assessed by [(3)H]thymidine uptake and protein assays performed using Western blotting techniques. HPAFs proliferated in response to acute hypoxic exposure, human systemic artery fibroblasts did not. This hypoxia-mediated proliferation was p38 MAPK dependent and could be blocked using a specific p38 MAPK inhibitor. Hypoxia-inducible factor-1 (HIF-1) expression was increased in hypoxic pulmonary but not systemic cells and could be partially abrogated with the p38 inhibitor. This work in man confirmed our previous findings in animals that significant differences exist between the pulmonary and systemic circulations in response to hypoxic exposure. This study highlights the importance of p38 MAPK and HIF-1 in hypoxia-mediated proliferation of pulmonary artery adventitial fibroblasts.

Many cardiopulmonary diseases are associated with pulmonary hypertension which adds significant co-morbidity. Pulmonary hypertension is due partly to vasoconstriction but sustained by pulmonary vascular remodelling. If pathological endpoints are to be reversed in patients with pulmonary hypertension, the processes by which vascular remodelling occur need to be determined. Hypoxia provides a good model of pulmonary hypertension. We have previously shown that chronic hypoxia results in increased proliferation of pulmonary artery fibroblasts and stimulation of the mitogen-activated protein kinase (MAPK) family of signalling enzymes. Under the same conditions systemic artery fibroblasts were unaffected. This differential response of pulmonary fibroblasts to hypoxia represents a model to investigate the processes of pulmonary artery remodelling. The current study showed that acute hypoxia was capable of causing enhanced proliferation in pulmonary but not systemic artery fibroblasts and was linked to increased activation of p38 MAP kinase. Second, we have now shown that it is alpha and gamma isoforms of p38 MAP kinase, which are responsible. Third we have shown a link between stimulation of p38 MAP kinase and HIF-1 proportional, variant induction. An increased understanding of the effects of hypoxia on remodelling and proliferation represents a critical step in identifying targets for the treatment of pulmonary hypertension.

To date, randomized controlled clinical trials performed in pulmonary arterial hypertension (PAH) have been relatively short-term studies involving mainly patients with advanced disease. The primary end points in these trials have addressed exercise capacity, usually by using the 6-min walk test. Although this approach is still warranted in future trials assessing new treatments, it is likely that the focus will shift toward trials of longer duration, involving patients with less advanced disease, and that different drugs and drug-combination regimens will be compared. In such trials, it is possible that a composite of markers indicating clinical deterioration (e.g., hospitalization for right heart failure, the requirement for the introduction of an alternative treatment, and predefined indicators of worsening exercise tolerance) may be more useful as primary end points. Quality of life will become a very important issue; however, appropriate quality-of-life questionnaires for PAH have yet to be developed. In addition, hemodynamics will likely remain valuable as secondary end points, but future clinical trials should include hemodynamics obtained both during exercise and at rest. Finally, cardiopulmonary exercise testing, echocardiographic studies, and biochemical parameters, such as brain natriuretic peptide or troponin T, may also prove useful as secondary end points in the future.

BackgroundRight ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation.MethodsWe measured RV end-systolic and end-diastolic volumes (ESV and EDV) using cardiac magnetic resonance imaging and RV pressures during right heart catheterization in 140 incident PAH patients and 22 controls. A maximum RV pressure (Pmax) was calculated from the nonlinear extrapolations of early and late systolic portions of the RV pressure curve. The gold standard measure of RV function adaptation to afterload, or RV-arterial coupling (Ees/Ea) was estimated by the stroke volume (SV)/ESV ratio (volume method) or as Pmax/mean pulmonary artery pressure (mPAP) minus 1 (pressure method) (n=84). RV function was also assessed by ejection fraction (EF), right atrial pressure (RAP) and SV.ResultsHigher Ea and RAP, and lower compliance, SV and EF predicted outcome at univariate analysis. Ees/Ea estimated by the pressure method did not predict outcome but Ees/Ea estimated by the volume method (SV/ESV) did. At multivariate analysis, only SV/ESV and EF were independent predictors of outcome. Survival was poorer in patients with a fall in EF or SV/ESV during follow-up (n=44, p=0.008).ConclusionRV function to predict outcome in PAH is best evaluated by imaging derived SV/ESV or EF. In this study, there was no added value of invasive measurements or simplified pressure-derived estimates of RV-arterial coupling.

Pulmonary hypertension is a life-threatening chronic disorder of the pulmonary circulation. Elevated pressure and resistance in the pulmonary vessels lead to progressive right heart failure which results in functional limitations and ultimately the death of most patients. Thus, the monitoring of right ventricular (RV) function is of great importance. Cardiac magnetic resonance imaging (cardiac MRI) has several advantages over other imaging methods. The use of cine acquisition techniques allows precise description of characteristic volumetric and functional variables, such as right ventricular volumes, muscle mass, stroke volume, ejection fraction, or cardiac output. Impaired right ventricular contractility and function have also been assessed using measures like ventricular septal bowing and pressure-volume loops. MRI investigations have been performed to monitor medical treatment, and the improvement in well-established prognostic factors, such as the 6-min walk, were correlated with measures of right ventricular function. Flow-derived parameters of the pulmonary arteries (such as peak velocity, acceleration time and volume, or pulmonary flow profile) are available using velocity-encoded imaging, and may detect early signs of remodelling. Additionally, magnetic resonance angiography is a promising new tool to visualise pulmonary perfusion and to diagnose chronic thromboembolic pulmonary hypertension. The purpose of this review is to summarise recent advances of cardiovascular magnetic resonance imaging, which will play an increasing role in the comprehensive diagnostic work-up of patients with pulmonary hypertension as a tool to monitor the course of the disease and to evaluate new therapeutic approaches. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article reports on a study that evaluated the significance of the robust correlations among diastolic pulmonary artery pressure (DPAP), systolic PAP (SPAP), and mean PAP (MPAP) in patients at rest with those exercising and those who just received vasodilation therapy. The results revealed a strong correlation between MPAP, SPAP and DPAP and this was preserved under different conditions.