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1.
Eur Respir J ; 53(5)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30923185

RESUMO

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5 µm (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined a prioriHigher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11-6.47) per 3 µg·m-3; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44-13.36) per 3 µg·m-3; p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.

2.
Eur Respir J ; 53(3)2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30655285

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-von Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation, ABO groups and ADAMTS13 genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED) (n=35), resolved pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS13-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size.Patients with CTEPH had decreased ADAMTS13 (adjusted ß -23.4%, 95% CI -30.9- -15.1%, p<0.001) and increased VWF levels (ß +75.5%, 95% CI 44.8-113%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identified a genetic variant near the ADAMTS13 gene associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels.The ADAMTS13-VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13-VWF axis in CTEPH pathobiology.

3.
JCI Insight ; 4(1)2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30626738

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS: Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS: PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulin-sensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages. CONCLUSIONS: IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium- and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH. FUNDING: NIH DK096994, HL060906, UL1 RR024975-01, UL1 TR000445-06, DK020593, P01 HL108800-01A1, and UL1 TR002243; American Heart Association 13FTF16070002.

4.
Eur Heart J Cardiovasc Imaging ; 20(6): 668-676, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535300

RESUMO

AIMS: We sought to identify metabolic pathways associated with right ventricular (RV) adaptation to pulmonary hypertension (PH). We evaluated candidate metabolites, previously associated with survival in pulmonary arterial hypertension, and used automated image segmentation and parametric mapping to model their relationship to adverse patterns of remodelling and wall stress. METHODS AND RESULTS: In 312 PH subjects (47.1% female, mean age 60.8 ± 15.9 years), of which 182 (50.5% female, mean age 58.6 ± 16.8 years) had metabolomics, we modelled the relationship between the RV phenotype, haemodynamic state, and metabolite levels. Atlas-based segmentation and co-registration of cardiac magnetic resonance imaging was used to create a quantitative 3D model of RV geometry and function-including maps of regional wall stress. Increasing mean pulmonary artery pressure was associated with hypertrophy of the basal free wall (ß = 0.29) and reduced relative wall thickness (ß = -0.38), indicative of eccentric remodelling. Wall stress was an independent predictor of all-cause mortality (hazard ratio = 1.27, P = 0.04). Six metabolites were significantly associated with elevated wall stress (ß = 0.28-0.34) including increased levels of tRNA-specific modified nucleosides and fatty acid acylcarnitines, and decreased levels (ß = -0.40) of sulfated androgen. CONCLUSION: Using computational image phenotyping, we identify metabolic profiles, reporting on energy metabolism and cellular stress-response, which are associated with adaptive RV mechanisms to PH.

5.
Eur Respir J ; 53(1)2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30545975

RESUMO

Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesis and pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiological studies defining the clinical and demographic characteristics of the condition, a renewed interest in treatment development emerged through collaborations between international experts, industry and regulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of novel therapies that targeted putative pathogenic pathways, leading to the approval of more than 10 novel therapies that have beneficially impacted both the quality and duration of life. However, our understanding of PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifying novel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to better define the efficacy of these new potential treatments and their role in the management scheme. This article, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises the current state of the art, and provides insight into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition.

6.
Circ Res ; 124(1): 52-65, 2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30582444

RESUMO

RATIONALE: Increased expression of CLIC4 (chloride intracellular channel 4) is a feature of endothelial dysfunction in pulmonary arterial hypertension, but its role in disease pathology is not fully understood. OBJECTIVE: To identify CLIC4 effectors and evaluate strategies targeting CLIC4 signaling in pulmonary hypertension. METHODS AND RESULTS: Proteomic analysis of CLIC4-interacting proteins in human pulmonary artery endothelial cells identified regulators of endosomal trafficking, including Arf6 (ADP ribosylation factor 6) GTPase activating proteins and clathrin, while CLIC4 overexpression affected protein regulators of vesicular trafficking, lysosomal function, and inflammation. CLIC4 reduced BMPRII (bone morphogenetic protein receptor II) expression and signaling as a result of Arf6-mediated reduction in gyrating clathrin and increased lysosomal targeting of the receptor. BMPRII expression was restored by Arf6 siRNA, Arf inhibitor Sec7 inhibitor H3 (SecinH3), and inhibitors of clathrin-mediated endocytosis but was unaffected by chloride channel inhibitor, indanyloxyacetic acid 94 or Arf1 siRNA. The effects of CLIC4 on NF-κB (nuclear factor-kappa B), HIF (hypoxia-inducible factor), and angiogenic response were prevented by Arf6 siRNA and SecinH3. Sugen/hypoxia mice and monocrotaline rats showed elevated expression of CLIC4, activation of Arf6 and NF-κB, and reduced expression of BMPRII in the lung. These changes were established early during disease development. Lung endothelium-targeted delivery of CLIC4 siRNA or treatment with SecinH3 attenuated the disease, reduced CLIC4/Arf activation, and restored BMPRII expression in the lung. Endothelial colony-forming cells from idiopathic pulmonary hypertensive patients showed upregulation of CLIC4 expression and Arf6 activity, suggesting potential importance of this pathway in the human condition. CONCLUSIONS: Arf6 is a novel effector of CLIC4 and a new therapeutic target in pulmonary hypertension.

7.
Thorax ; 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478197

RESUMO

BACKGROUND: Aberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive. OBJECTIVE: To investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH. METHODS: Using nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation. RESULTS: Plasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein-kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL-4 subfraction was confirmed. CONCLUSION: Reduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH.

8.
Circ Genom Precis Med ; 11(10): e002087, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30354297

RESUMO

BACKGROUND: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target. METHODS: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. RESULTS: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)-a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. CONCLUSIONS: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.

9.
Circ Cardiovasc Imaging ; 11(8): e007402, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30354494

RESUMO

BACKGROUND: Pulmonary vascular cell hyperproliferation is characteristic of pulmonary vascular remodeling in pulmonary arterial hypertension. A noninvasive imaging biomarker is needed to track the pathology and assess the response to novel treatments targeted at resolving the structural changes. Here, we evaluated the application of radioligand 3'-deoxy-3'-[18F]-fluorothymidine (18FLT) using positron emission tomography. METHODS AND RESULTS: We performed dynamic 18FLT positron emission tomography in 8 patients with idiopathic pulmonary arterial hypertension (IPAH) and applied in-depth kinetic analysis with a reversible 2-compartment 4k model. Our results show significantly increased lung 18FLT phosphorylation (k3) in patients with IPAH compared with nonpulmonary arterial hypertension controls (0.086±0.034 versus 0.054±0.009 min-1; P<0.05). There was heterogeneity in the lung 18FLT signal both between patients with IPAH and within the lungs of each patient, compatible with histopathologic reports of lungs from patients with IPAH. Consistent with 18FLT positron emission tomographic data, TK1 (thymidine kinase 1) expression was evident in the remodeled vessels in IPAH patient lung. In addition, hyperproliferative pulmonary vascular fibroblasts isolated from patients with IPAH exhibited upregulated expression of TK1 and the thymidine transporter, ENT1 (equilibrative nucleoside transporter 1). In the monocrotaline and SuHx (Sugen hypoxia) rat pulmonary arterial hypertension models, increased lung 18FLT uptake was strongly associated with peripheral pulmonary vascular muscularization and the proliferation marker, Ki-67 score, together with prominent TK1 expression in remodeled vessels. Importantly, lung 18FLT uptake was attenuated by 2 antiproliferative treatments: dichloroacetate and the tyrosine kinase inhibitor, imatinib. CONCLUSIONS: Dynamic 18FLT positron emission tomography imaging can be used to report hyperproliferation in pulmonary hypertension and merits further study to evaluate response to treatment in patients with IPAH.

10.
F1000Res ; 72018.
Artigo em Inglês | MEDLINE | ID: mdl-30079232

RESUMO

Pulmonary arterial hypertension (PAH) is a rare disorder with a high mortality rate. Treatment options have improved in the last 20 years, but patients still die prematurely of right heart failure. Though rare, it is heterogeneous at the genetic and molecular level, and understanding and exploiting this is key to the development of more effective treatments. BMPR2, encoding bone morphogenetic receptor type 2, is the most commonly affected gene in both familial and non-familial PAH, but rare mutations have been identified in other genes. Transcriptomic, proteomic, and metabolomic studies looking for endophenotypes are under way. There is no shortage of candidate new drug targets for PAH, but the selection and prioritisation of these are challenges for the research community.

11.
Radiology ; 288(2): 386-395, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29869959

RESUMO

Purpose To measure right ventricular (RV) trabecular complexity by its fractal dimension (FD) in healthy subjects and patients with pulmonary hypertension (PH) and to assess its relationship with hemodynamic and functional parameters and future cardiovascular events. Materials and Methods This retrospective study used data acquired from May 2004 to October 2013 in 256 patients with newly diagnosed PH who underwent cardiac MRI, right-sided heart catheterization, and 6-minute walk distance testing, with median follow-up of 4.0 years. A total of 256 healthy control subjects underwent cardiac MRI only. Biventricular FD, volumes, and function were assessed on short-axis cine images. Reproducibility was assessed with the intraclass correlation coefficient, correlation between variables was assessed with the Pearson correlation test, and mortality prediction was compared by using uni- and multivariable Cox regression analyses. Results RV FD reproducibility had an intraclass correlation coefficient of 0.97 (95% confidence interval [CI]: 0.96, 0.98). RV FD was higher in patients with PH (median, 1.310; interquartile range [IQR], 1.281-1.341) than in healthy subjects (median, 1.264; IQR, 1.242-1.295; P < .001), with the greatest difference near the apex. RV FD was associated with pulmonary vascular resistance (r = 0.30, P < .001). At univariable Cox regression analysis, RV FD was a significant predictor of death (hazard ratio [HR], 1.256; 95% CI: 1.011, 1.560; P = .04); however, at multivariable analysis, RV FD did not enable prediction of survival independently of conventional parameters of RV remodeling (HR, 1.179; 95% CI: 0.871, 1.596; P = .29). Conclusion Fractal analysis of RV trabecular complexity is a highly reproducible measure of remodeling in patients with PH that is associated with afterload, although the gain in survival prediction over traditional markers is not significant. Published under a CC BY 4.0 license. Online supplemental material is available for this article.


Assuntos
Fractais , Hipertensão Pulmonar/fisiopatologia , Imagem por Ressonância Magnética/métodos , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/fisiopatologia , Idoso , Feminino , Ventrículos do Coração/diagnóstico por imagem , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Resistência Vascular/fisiologia
12.
JACC Basic Transl Sci ; 3(2): 176-186, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29876530

RESUMO

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr1)apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr1)apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170).

14.
Eur Respir J ; 51(4)2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29545281

RESUMO

The European Respiratory Society (ERS) Research Seminar entitled "Pulmonary vascular endothelium: orchestra conductor in respiratory diseases - highlights from basic research to therapy" brought together international experts in dysfunctional pulmonary endothelium, from basic science to translational medicine, to discuss several important aspects in acute and chronic lung diseases. This review will briefly sum up the different topics of discussion from this meeting which was held in Paris, France on October 27-28, 2016. It is important to consider that this paper does not address all aspects of endothelial dysfunction but focuses on specific themes such as: 1) the complex role of the pulmonary endothelium in orchestrating the host response in both health and disease (acute lung injury, chronic obstructive pulmonary disease, high-altitude pulmonary oedema and pulmonary hypertension); and 2) the potential value of dysfunctional pulmonary endothelium as a target for innovative therapies.

16.
Sci Transl Med ; 9(413)2017 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-29070699

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.


Assuntos
Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Hipertensão Pulmonar Primária Familiar/enzimologia , Hipertensão Pulmonar Primária Familiar/genética , Predisposição Genética para Doença , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Biomarcadores/metabolismo , Ácido Dicloroacético/administração & dosagem , Ácido Dicloroacético/sangue , Ácido Dicloroacético/farmacologia , Ácido Dicloroacético/uso terapêutico , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Perfusão , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Sirtuína 3/metabolismo , Proteína Desacopladora 2/metabolismo , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
17.
Circulation ; 136(21): 2022-2033, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-28972005

RESUMO

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.


Assuntos
Pressão Arterial/genética , Hipertensão Pulmonar/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Artéria Pulmonar/fisiopatologia , Adulto , Idoso , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Análise Mutacional de DNA , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Hereditariedade , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X , Adulto Jovem
18.
Lancet Respir Med ; 5(9): 717-726, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28624389

RESUMO

BACKGROUND: Idiopathic and heritable pulmonary arterial hypertension form a rare but molecularly heterogeneous disease group. We aimed to measure and validate differences in plasma concentrations of proteins that are associated with survival in patients with idiopathic or heritable pulmonary arterial hypertension to improve risk stratification. METHODS: In this observational cohort study, we enrolled patients with idiopathic or heritable pulmonary arterial hypertension from London (UK; cohorts 1 and 2), Giessen (Germany; cohort 3), and Paris (France; cohort 4). Blood samples were collected at routine clinical appointment visits, clinical data were collected within 30 days of blood sampling, and biochemical data were collected within 7 days of blood sampling. We used an aptamer-based assay of 1129 plasma proteins, and patient clinical details were concealed to the technicians. We identified a panel of prognostic proteins, confirmed with alternative targeted assays, which we evaluated against the established prognostic risk equation for pulmonary arterial hypertension derived from the REVEAL registry. All-cause mortality was the primary endpoint. FINDINGS: 20 proteins differentiated survivors and non-survivors in 143 consecutive patients with idiopathic or heritable pulmonary arterial hypertension with 2 years' follow-up (cohort 1) and in a further 75 patients with 2·5 years' follow-up (cohort 2). Nine proteins were both prognostic independent of plasma NT-proBNP concentrations and confirmed by targeted assays. The functions of these proteins relate to myocardial stress, inflammation, pulmonary vascular cellular dysfunction and structural dysregulation, iron status, and coagulation. A cutoff-based score using the panel of nine proteins provided prognostic information independent of the REVEAL equation, improving the C statistic from area under the curve 0·83 (for REVEAL risk score, 95% CI 0·77-0·89; p<0·0001) to 0·91 (for panel and REVEAL 0·87-0·96; p<0·0001) and improving reclassification indices without detriment to calibration. Poor survival was preceded by an adverse change in panel score in paired samples from 43 incident patients with pulmonary arterial hypertension in cohort 3 (p=0·0133). The protein panel was validated in 93 patients with idiopathic or heritable pulmonary arterial hypertension in cohort 4, with 4·4 years' follow-up and improved risk estimates, providing complementary information to the clinical risk equation. INTERPRETATION: A combination of nine circulating proteins identifies patients with pulmonary arterial hypertension with a high risk of mortality, independent of existing clinical assessments, and might have a use in clinical management and the evaluation of new therapies. FUNDING: National Institute for Health Research, Wellcome Trust, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, Inserm, Université Paris-Sud, and Agence Nationale de la Recherche.


Assuntos
Proteínas Sanguíneas/análise , Hipertensão Pulmonar Primária Familiar/sangue , Hipertensão/sangue , Proteoma/análise , Adulto , Idoso , Pressão Arterial , Biomarcadores/sangue , Estudos de Coortes , Hipertensão Pulmonar Primária Familiar/mortalidade , Feminino , Humanos , Hipertensão/mortalidade , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco
19.
Cardiovasc Res ; 113(3): 276-287, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28395021

RESUMO

Aims: RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect. Methods and results: The analysis of lung tissues from rodent models and pulmonary hypertensive patients showed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerization and increased eNOS expression in vitro and in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB), and tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator. Unlike simvastatin, tipifarnib did not increase the expression levels of Rho proteins. Conclusions: Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Hipertensão Pulmonar/prevenção & controle , Hipóxia/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Quinolonas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Farnesiltranstransferase/metabolismo , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Hipóxia/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Prenilação de Proteína , Proteômica/métodos , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Fatores de Tempo , Transfecção , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Proteína rhoB de Ligação ao GTP/genética , Proteína rhoB de Ligação ao GTP/metabolismo
20.
Radiology ; 283(2): 381-390, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28092203

RESUMO

Purpose To determine if patient survival and mechanisms of right ventricular failure in pulmonary hypertension could be predicted by using supervised machine learning of three-dimensional patterns of systolic cardiac motion. Materials and Methods The study was approved by a research ethics committee, and participants gave written informed consent. Two hundred fifty-six patients (143 women; mean age ± standard deviation, 63 years ± 17) with newly diagnosed pulmonary hypertension underwent cardiac magnetic resonance (MR) imaging, right-sided heart catheterization, and 6-minute walk testing with a median follow-up of 4.0 years. Semiautomated segmentation of short-axis cine images was used to create a three-dimensional model of right ventricular motion. Supervised principal components analysis was used to identify patterns of systolic motion that were most strongly predictive of survival. Survival prediction was assessed by using difference in median survival time and area under the curve with time-dependent receiver operating characteristic analysis for 1-year survival. Results At the end of follow-up, 36% of patients (93 of 256) died, and one underwent lung transplantation. Poor outcome was predicted by a loss of effective contraction in the septum and free wall, coupled with reduced basal longitudinal motion. When added to conventional imaging and hemodynamic, functional, and clinical markers, three-dimensional cardiac motion improved survival prediction (area under the receiver operating characteristic curve, 0.73 vs 0.60, respectively; P < .001) and provided greater differentiation according to difference in median survival time between high- and low-risk groups (13.8 vs 10.7 years, respectively; P < .001). Conclusion A machine-learning survival model that uses three-dimensional cardiac motion predicts outcome independent of conventional risk factors in patients with newly diagnosed pulmonary hypertension. Online supplemental material is available for this article.


Assuntos
Hipertensão Pulmonar/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imagem Tridimensional/métodos , Imagem Cinética por Ressonância Magnética/métodos , Volume Sistólico , Disfunção Ventricular Direita/etiologia , Idoso , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão Pulmonar/complicações , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Reconhecimento Automatizado de Padrão/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Disfunção Ventricular Direita/complicações
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