Hémodynamique à l'exercice et tolérance à l'effort dans l'hypertension artérielle pulmonaire

L'hypertension artérielle pulmonaire est caractérisée par l'augmentation des résistances vasculaires pulmonaires, conduisant à l'insuffisance cardiaque et à la diminution de tolérance à l'effort. Les tests d'effort permettent d'évaluer la sévérité de l'hypertension artérielle pulmonaire et la réponse aux traitements. Cependant, la réponse hémodynamique à l'exercice et les facteurs influençant la capacité à l'exercice demeurent mal définis. Nous avons documenté une corrélation linéaire insoupçonnée entre la pression de l'artère pulmonaire et la fréquence cardiaque à l'exercice. Ceci était indépendant du volume d'éjection et des résistances vasculaires pulmonaires. L'augmentation du débit cardiaque était principalement liée à l'augmentation de la fréquence cardiaque. Au moment du diagnostic, le volume d'éjection de repos et la réponse en fréquence cardiaque à l'exercice étaient les seules variables indépendamment liées à la capacité à l'exercice. Sous traitement, les changements de tolérance à l'effort observés étaient principalement liés aux changements hémodynamiques à l'exercice, incluant la réponse en fréquence cardiaque.La réponse hémodynamique à l'exercice est largement impliquée dans la physiopathologie de l'intolérance à l'effort dans l'hypertension artérielle pulmonaire. La réponse chronotrope est une composante importante de cette capacité d'adaptation hémodynamique

BET Signaling:A Novel Therapeutic Target for Pulmonary Hypertension? Reply

Therapeutic cell differentiatio

More Insights into the Association between RVX-208 and Pulmonary Arterial Hypertension Reply

Therapeutic cell differentiatio

Pim-1 : a new biomarker in pulmonary arterial hypertension

Provirus integration site for Moloney murine leukemia virus (Pim-1) is an oncoprotein overexpressed in lungs from pulmonary arterial hypertension (PAH) patients and involved in cell proliferation via the activation of the NFAT/STAT3 signaling pathway. We hypothesized that Pim-1 plasma levels would predict the presence of PAH and correlate with disease severity. Pim-1 plasma levels were measured at the time of catheterization in 49 PAH patients, including nonvasoreactive (n = 19) and vasoreactive idiopathic PAH (n = 5), and PAH related to connective tissue disease (n = 16) and congenital heart disease (n = 9). Fifty controls were also recruited. The capacity of Pim-1 to discriminate PAH from controls and its association with disease severity were assessed. Pim-1 plasma levels were higher in PAH than in controls (9.6 ± 4.0 vs. 7.2 ± 2.4 ng/mL, P < 0.01). Pim-1 appropriately discriminated proliferative PAH from controls (AUC = 0.78 to 0.94 using ROC curves). Among PAH patients, Pim-1 correlated with traditional markers of PAH severity. The 1-year survival was 97% and 47% for PAH patients with baseline Pim-1 levels lower and higher than 11.1 ng/mL, respectively (HR 11.4 (3.3–39.7); P <0.01). After adjustment for hemodynamic and biochemical variables, Pim-1 levels remained an independent predictor of mortality (P < 0.01). Pim-1 is a promising new biomarker in PAH

Pulmonary hypertension and chronic lung disease: where are we headed?

Pulmonary hypertension related to chronic lung disease, mainly represented by COPD and idiopathic pulmonary fibrosis, is associated with a worse outcome when compared with patients only affected by parenchymal lung disease. At present, no therapies are available to reverse or slow down the pathological process of this condition and most of the clinical trials conducted to date have had no clinically significant impact. Nevertheless, the importance of chronic lung diseases is always more widely recognised and, along with its increasing incidence, associated pulmonary hypertension is also expected to be growing in frequency and as a health burden worldwide. Therefore, it is desirable to develop useful and reliable tools to obtain an early diagnosis and to monitor and follow-up this condition, while new insights in the therapeutic approach are explored

Impact of the new definition for pulmonary hypertension in patients with lung disease: an analysis of the United Network for Organ Sharing database

The implications of the recent change in the definition of pulmonary hypertension on epidemiology and outcomes are not known. We sought to determine the percentage of patients with the two most common lung diseases that would be reclassified regarding the presence/absence of pulmonary hypertension with the revised definition. A query of the United Network for Organ Sharing database was performed. The percentage of patients meeting the current and previous definition of pulmonary hypertension was described. Outcomes of patients stratified by the current and previous definitions were compared. There were 15,563 patients with right heart catheterization data analyzed. Pulmonary hypertension was more prevalent in both chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis under the new definition at 52.4% versus 82.4%, and 47.6% versus 73.6%, respectively. 'Pre-capillary' pulmonary hypertension by the new definition was lower at 28.1% for chronic obstructive pulmonary disease and 36.8% for idiopathic pulmonary fibrosis. Of the patients with pulmonary hypertension by the old definition, 23.9% of chronic obstructive pulmonary disease patients and 18.7% of idiopathic pulmonary fibrosis patients were not classified as pulmonary hypertension by the new definition. Conversely, 15.9% of chronic obstructive pulmonary disease patients and 15.1% of idiopathic pulmonary fibrosis patients who did not meet diagnostic criteria for pulmonary hypertension by the old definition did have pulmonary hypertension by the new definition. Patients in both disease categories had shorter transplant-free waitlist survival in the presence of pulmonary hypertension by both the new and old definitions. There was a trend toward the new definition of pre-capillary pulmonary hypertension better discerning outcomes compared to the old definition of pulmonary hypertension in idiopathic pulmonary fibrosis patients. Most patients with advanced lung disease who are listed for lung transplantation have pulmonary hypertension, but fewer have pre-capillary pulmonary hypertension than pulmonary hypertension by the old definition. Both the old and new definition of precapillary pulmonary hypertension appear to discern outcomes among the two groups of lung disease analyzed, with some evidence to suggest that the new definition performs slightly better in the idiopathic pulmonary fibrosis population

MicroRNA-138 and microRNA-25 down-regulate mitochondrial calcium uniporter, causing the pulmonary arterial hypertension cancer phenotype

Rationale: Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by excessive pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis resistance. This cancer-like phenotype is promoted by increased cytosolic calcium ([Ca2+]cyto), aerobic glycolysis, and mitochondrial fission. Objectives: To determine how changes in mitochondrial calcium uniporter (MCU) complex (MCUC) function influence mitochondrial dynamics and contribute to PAH’s cancer-like phenotype. Methods: PASMCs were isolated from patients with PAH and healthy control subjects and assessed for expression of MCUC subunits. Manipulation of the pore-forming subunit, MCU, in PASMCs was achieved through small interfering RNA knockdown or MCU plasmid-mediated up-regulation, as well as through modulation of the upstream microRNAs (miRs) miR-138 and miR-25. In vivo, nebulized anti-miRs were administered to rats with monocrotaline-induced PAH. Measurements and Main Results: Impaired MCUC function, resulting from down-regulation of MCU and up-regulation of an inhibitory subunit, mitochondrial calcium uptake protein 1, is central to PAH’s pathogenesis. MCUC dysfunction decreases intramitochondrial calcium ([Ca2+]mito), inhibiting pyruvate dehydrogenase activity and glucose oxidation, while increasing [Ca2+]cyto, promoting proliferation, migration, and fission. In PAH PASMCs, increasing MCU decreases cell migration, proliferation, and apoptosis resistance by lowering [Ca2+]cyto, raising [Ca2+]mito, and inhibiting fission. In normal PASMCs, MCUC inhibition recapitulates the PAH phenotype. In PAH, elevated miRs (notably miR-138) down-regulate MCU directly and also by decreasing MCU’s transcriptional regulator cAMP response element–binding protein 1. Nebulized anti-miRs against miR-25 and miR-138 restore MCU expression, reduce cell proliferation, and regress established PAH in the monocrotaline model. Conclusions: These results highlight miR-mediated MCUC dysfunction as a unifying mechanism in PAH that can be therapeutically targeted

Pulmonary hypertension in chronic lung disease and hypoxia

Pulmonary hypertension (PH) frequently complicates the course of patients with various forms of chronic lung disease (CLD). CLD-associated PH (CLD-PH) is invariably associated with reduced functional ability, impaired quality of life, greater oxygen requirements and an increased risk of mortality. The aetiology of CLD-PH is complex and multifactorial, with differences in the pathogenic sequelae between the diverse forms of CLD. Haemodynamic evaluation of PH severity should be contextualised within the extent of the underlying lung disease, which is best gauged through a combination of physiological and imaging assessment. Who, when, if and how to screen for PH will be addressed in this article, as will the current state of knowledge with regard to the role of treatment with pulmonary vasoactive agents. Although such therapy cannot be endorsed given the current state of findings, future studies in this area are strongly encouraged

Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition.

RATIONALE: Vascular remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of vascular cells. Loss of BMPR-II (bone morphogenetic protein receptor 2) signaling and increased signaling via TGF-β (transforming growth factor β) and its downstream mediators SMAD (small body size [a C. elegans protein] mothers against decapentaplegic [a Drosophila protein family])-2/3 has been proposed to drive lung vascular remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH. OBJECTIVES: We proposed that SMAD3 may be dysregulated in PAH and that loss of SMAD3 may present a pathophysiological master switch by disinhibiting its interaction partner, MRTF (myocardin-related transcription factor), which drives muscle protein expression. METHODS: SMAD3 levels were measured in lungs from PAH patients, rats treated either with Sugen/hypoxia or monocrotaline (MCT), and in mice carrying a BMPR2 mutation. In vitro, effects of SMAD3 or BMPR2 silencing or SMAD3 overexpression on cell proliferation or smooth muscle hypertrophy were assessed. In vivo, the therapeutic and prophylactic potential of CCG1423, an inhibitor of MRTF, was investigated in Sugen/hypoxia rats. MEASUREMENTS AND MAIN RESULTS: SMAD3 was downregulated in lungs of patients with PAH and in pulmonary arteries of three independent PAH animal models. TGF-β treatment replicated the loss of SMAD3 in human pulmonary artery smooth muscle cells (huPASMCs) and human pulmonary artery endothelial cells. SMAD3 silencing increased proliferation and migration in huPASMCs and human pulmonary artery endothelial cells. Coimmunoprecipitation revealed reduced interaction of MRTF with SMAD3 in TGF-β-treated huPASMCs and pulmonary arteries of PAH animal models. In huPASMCs, loss of SMAD3 or BMPR-II increased smooth muscle actin expression, which was attenuated by MRTF inhibition. Conversely, SMAD3 overexpression prevented TGF-β-induced activation of an MRTF reporter and reduced actin stress fibers in BMPR2-silenced huPASMCs. MRTF inhibition attenuated PAH and lung vascular remodeling in Sugen/hypoxia rats. CONCLUSIONS: Loss of SMAD3 presents a novel pathomechanism in PAH that promotes vascular cell proliferation and-via MRTF disinhibition-hypertrophy of huPASMCs, thereby reconciling the parallel induction of a synthetic and contractile huPASMC phenotype