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1.
Chest ; 157(1): 89-98, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31351047

RESUMO

BACKGROUND: Patients with interstitial lung disease (ILD) may develop pulmonary hypertension (PH), often disproportionate to the severity of the ILD. The right ventricular to left ventricular diameter (RV:LV) ratio measured at CT pulmonary angiogram (CTPA) has been shown to provide valuable information in patients with pulmonary arterial hypertension and to predict death or deterioration in acute pulmonary embolism. METHODS: Demographic characteristics, ILD subtype, echocardiography, and detailed CTPA measurements were collected in consecutive patients undergoing both CTPA and right heart catheterization at the Royal Brompton Hospital between 2005 and 2015. Fibrosis severity was formally scored according to CT criteria. The RV:LV ratio at CTPA was evaluated by using three different methods. Cox proportional hazards analysis was used to assess the relation of CTPA-derived parameters to predict death or lung transplantation. RESULTS: A total of 92 patients were included (64% male; mean age 65 ± 11 years) with an FVC 57 ± 20% predicted, corrected transfer factor of the lung for carbon monoxide 22 ± 8% predicted, and corrected transfer coefficient of the lung for carbon monoxide 51 ± 17% predicted. PH was confirmed at right heart catheterization in 78%. Of all the CTPA-derived measures, an RV:LV ratio ≥ 1.0 strongly predicted mortality or transplantation at univariate analysis (hazard ratio, 3.26; 95% CI, 1.49-7.13; P = .003), whereas invasive hemodynamic data did not. The RV:LV ratio remained an independent predictor at multivariate analysis (hazard ratio, 3.19; 95% CI, 1.44-7.10; P = .004), adjusting for an ILD diagnosis of idiopathic pulmonary fibrosis and CT imaging-derived ILD severity. CONCLUSIONS: An increased RV:LV ratio measured at CTPA provides a simple, noninvasive method of risk stratification in patients with suspected ILD-PH. This should prompt closer follow-up, more aggressive treatment, and consideration of lung transplantation.

2.
Pulm Circ ; 9(2): 2045894019859474, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31246163

RESUMO

A 36-year-old woman presented with recurrent pulmonary emboli (PE) despite oral anticoagulation. She was a type I diabetic with severe gastroparesis requiring insertion of multiple long-term peripherally inserted central catheters (PICC) over a 10-year period. Imaging at presentation demonstrated a PICC-associated mobile mass in the right atrium and signs of pulmonary hypertension (PH). She was thrombolyzed and fully anticoagulated, and diabetic management without PICC strongly recommended. PH persisted, however, and she developed chronic thromboembolic pulmonary hypertension (CTEPH), for which successful pulmonary endarterectomy (PEA) surgery led to symptomatic and hemodynamic improvement. This was the first case of CTEPH reported related to long-term PICC use outside the setting of malignant disease, and a novel observation that the PEA specimen contained multiple plastic fragments. Long-term PICC placement increases the risk of CTEPH, a life-threatening, albeit treatable, complication.

3.
Pulm Circ ; 9(2): 2045894019845615, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30945593

RESUMO

Early diagnosis of pulmonary artery hypertension (PAH) is diagnostically challenging given the extent of pulmonary vascular remodeling required to bring about clinical signs and symptoms. Exercise testing can be invaluable in this setting, as stressing the cardiopulmonary system may unmask early disease. This report describes a young patient with a positive family history of PAH in whom contemporaneous invasive cardiopulmonary exercise testing and surgical lung biopsy reveal the novel association between exercise pulmonary hypertension (ePH) and early histological changes of PAH. Exercise PH currently carries no pathological correlates which means the hemodynamic effects of early pulmonary vascular remodeling remain unknown. Following the recent proceedings from the World Symposium in Pulmonary Hypertension 2018, which broaden the hemodynamic definition of PAH, this report suggests an important association between ePH and early pulmonary vascular remodeling supporting a role for exercise hemodynamic evaluation in patients at increased familial risk of PAH.

4.
Eur Respir Rev ; 28(151)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30728162

RESUMO

Tumoral pulmonary hypertension (PH) comprises a variety of subtypes in patients with a current or previous malignancy. Tumoral PH principally includes the tumour-related pulmonary microvascular conditions pulmonary tumour microembolism and pulmonary tumour thrombotic microangiopathy. These inter-related conditions are frequently found in post mortem specimens but are notoriously difficult to diagnose ante mortem The outlook for patients remains extremely poor although there is some emerging evidence that pulmonary vasodilators and anti-inflammatory approaches may improve survival. Tumoral PH also includes pulmonary macroembolism and tumours that involve the proximal pulmonary vasculature, such as angiosarcoma; both may mimic pulmonary embolism and chronic thromboembolic PH. Finally, tumoral PH may develop in response to treatments of an underlying malignancy. There is increasing interest in pulmonary arterial hypertension induced by tyrosine kinase inhibitors, such as dasatanib. In addition, radiotherapy and chemotherapeutic agents such as mitomycin-C can cause pulmonary veno-occlusive disease. Tumoral PH should be considered in any patient presenting with unexplained PH, especially if it is poorly responsive to standard approaches or there is a history of malignancy. This article will describe subtypes of tumoral PH, their pathophysiology, investigation and management options in turn.


Assuntos
Hipertensão Pulmonar/patologia , Neoplasias/patologia , Células Neoplásicas Circulantes/patologia , Artéria Pulmonar/patologia , Animais , Antineoplásicos/efeitos adversos , Pressão Arterial , Humanos , Concentração de Íons de Hidrogênio , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/fisiopatologia , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Células Neoplásicas Circulantes/efeitos dos fármacos , Prognóstico , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Medição de Risco , Fatores de Risco , Microambiente Tumoral
5.
Sci Rep ; 8(1): 12972, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30154413

RESUMO

Studies were undertaken to examine any role for the hepcidin/ferroportin axis in proliferative responses of human pulmonary artery smooth muscle cells (hPASMCs). Entirely novel findings have demonstrated the presence of ferroportin in hPASMCs. Hepcidin treatment caused increased proliferation of these cells most likely by binding ferroportin resulting in internalisation and cellular iron retention. Cellular iron content increased with hepcidin treatment. Stabilisation of ferroportin expression and activity via intervention with the therapeutic monoclonal antibody LY2928057 reversed proliferation and cellular iron accumulation. Additionally, IL-6 treatment was found to enhance proliferation and iron accumulation in hPASMCs; intervention with LY2928057 prevented this response. IL-6 was also found to increase hepcidin transcription and release from hPASMCs suggesting a potential autocrine response. Hepcidin or IL-6 mediated iron accumulation contributes to proliferation in hPASMCs; ferroportin mediated cellular iron excretion limits proliferation. Haemoglobin also caused proliferation of hPASMCs; in other novel findings, CD163, the haemoglobin/haptoglobin receptor, was found on these cells and offers a means for cellular uptake of iron via haemoglobin. Il-6 was also found to modulate CD163 on these cells. These data contribute to a better understanding of how disrupted iron homeostasis may induce vascular remodelling, such as in pulmonary arterial hypertension.


Assuntos
Proteínas de Transporte de Cátions/biossíntese , Proliferação de Células , Hepcidinas/biossíntese , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Anticorpos Monoclonais/farmacologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/fisiologia , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Interleucina-6/metabolismo , Ferro/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Artéria Pulmonar/citologia , Receptores de Superfície Celular/metabolismo , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/fisiologia
6.
Respirology ; 23(7): 687-694, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29327393

RESUMO

BACKGROUND AND OBJECTIVE: In interstitial lung disease (ILD), pulmonary hypertension (PH) is a major adverse prognostic determinant. Transthoracic echocardiography (TTE) is the most widely used tool when screening for PH, although discordance between TTE and right heart catheter (RHC) measured pulmonary haemodynamics is increasingly recognized. We evaluated the predictive utility of the updated European Society of Cardiology/European Respiratory Society (ESC/ERS) TTE screening recommendations against RHC testing in a large, well-characterized ILD cohort. METHODS: Two hundred and sixty-five consecutive patients with ILD and suspected PH underwent comprehensive assessment, including RHC, between 2006 and 2012. ESC/ERS recommended tricuspid regurgitation (TR) velocity thresholds for assigning high (>3.4 m/s), intermediate (2.9-3.4 m/s) and low (<2.8 m/s) probabilities of PH were evaluated against RHC testing. RESULTS: RHC testing confirmed PH in 86% of subjects with a peak TR velocity >3.4 m/s, and excluded PH in 60% of ILD subjects with a TR velocity <2.8 m/s. Thus, the ESC/ERS guidelines misclassified 40% of subjects as 'low probability' of PH, when PH was confirmed on subsequent RHC. Evaluating alternative TR velocity thresholds for assigning a low probability of PH did not significantly improve the ability of TR velocity to exclude a diagnosis of PH. CONCLUSION: In patients with ILD and suspected PH, currently recommended ESC/ERS TR velocity screening thresholds were associated with a high positive predictive value (86%) for confirming PH, but were of limited value in excluding PH, with 40% of patients misclassified as low probability when PH was confirmed at subsequent RHC.


Assuntos
Cateterismo Cardíaco , Ecocardiografia , Hipertensão Pulmonar/diagnóstico por imagem , Doenças Pulmonares Intersticiais/complicações , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Idoso , Estudos de Coortes , Erros de Diagnóstico , Feminino , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Pressão Propulsora Pulmonar , Insuficiência da Valva Tricúspide/complicações
8.
Respirology ; 22(1): 157-164, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27539364

RESUMO

BACKGROUND AND OBJECTIVE: Nuclear factor kappa B (NF-kB)-mediated inflammatory gene expression and vascular endothelial cell proliferation/remodelling are implicated in the pathophysiology of the fatal disease, pulmonary arterial hypertension (PAH). Bromodomain and extra-terminal (BET) proteins are essential for the expression of a subset of NF-kB-induced inflammatory genes. BET mimics including JQ1+ prevent binding of BETs to acetylated histones and down-regulate the expression of selected genes. METHODS: The effects of JQ1+ on the proliferation of primary human pulmonary microvascular endothelial cells (HPMECs) from healthy subjects were measured by bromodeoxyuridine (BrdU) incorporation. Cell cycle progression was assessed by flow cytometry; mRNA and protein levels of cyclin-dependent kinases (CDKs), inhibitors and cytokines were determined by reverse transcription-quantitative PCR (RT-qPCR), Western blotting or ELISA. Histone acetyltransferase (HAT) and deacetylase (HDAC) activities were determined in nuclear extracts from whole lung of PAH and control patients. RESULTS: JQ1+ significantly inhibited IL6 and IL8 (IL6 and CXCL8) mRNA and protein in HPMECs compared with its inactive enantiomer JQ1-. JQ1+ decreased NF-kB p65 recruitment to native IL6 and IL8 promoters. JQ1+ showed a concentration-dependent decrease in HPMEC proliferation compared with JQ1--treated cells. JQ1+ induced G1 cell cycle arrest by increasing the expression of the CDK inhibitors (CDKN) 1A (p21cip ) and CDKN2D (p19INK4D ) and decreasing that of CDK2, CDK4 and CDK6. JQ1+ also inhibited serum-stimulated migration of HPMECs. Finally, HAT activity was significantly increased in the lung of PAH patients. CONCLUSION: Inhibition of BETs in primary HPMECs decreases inflammation and remodelling. BET proteins could be a target for future therapies for PAH.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Endoteliais , Hipertensão Pulmonar , NF-kappa B/metabolismo , Proteínas/metabolismo , Remodelação Vascular/efeitos dos fármacos , Azepinas/farmacologia , Técnicas de Cultura de Células , Regulação para Baixo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Inflamação/metabolismo , Interleucina-8/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Circulação Pulmonar , Triazóis/farmacologia
9.
Circulation ; 135(5): 460-475, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-27881557

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. METHODS: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis. RESULTS: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects. CONCLUSIONS: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.


Assuntos
Hipertensão Pulmonar/genética , Metabolômica/métodos , RNA de Transferência/metabolismo , Adulto , Idoso , Metabolismo Energético , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Adulto Jovem
12.
Pulm Circ ; 5(3): 498-505, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26401250

RESUMO

In a subgroup of patients with systemic sclerosis (SSc), vasospasm affecting the pulmonary circulation may contribute to worsening respiratory symptoms, including dyspnea. Noninvasive assessment of pulmonary blood flow (PBF), utilizing inert-gas rebreathing (IGR) and dual-energy computed-tomography pulmonary angiography (DE-CTPA), may be useful for identifying pulmonary vasospasm. Thirty-one participants (22 SSc patients and 9 healthy volunteers) underwent PBF assessment with IGR and DE-CTPA at baseline and after provocation with a cold-air inhalation challenge (CACh). Before the study investigations, participants were assigned to subgroups: group A included SSc patients who reported increased breathlessness after exposure to cold air (n = 11), group B included SSc patients without cold-air sensitivity (n = 11), and group C patients included the healthy volunteers. Median change in PBF from baseline was compared between groups A, B, and C after CACh. Compared with groups B and C, in group A there was a significant decline in median PBF from baseline at 10 minutes (-10%; range: -52.2% to 4.0%; P < 0.01), 20 minutes (-17.4%; -27.9% to 0.0%; P < 0.01), and 30 minutes (-8.5%; -34.4% to 2.0%; P < 0.01) after CACh. There was no significant difference in median PBF change between groups B or C at any time point and no change in pulmonary perfusion on DE-CTPA. Reduction in pulmonary blood flow following CACh suggests that pulmonary vasospasm may be present in a subgroup of patients with SSc and may contribute to worsening dyspnea on exposure to cold.

14.
Thorax ; 69(12): 1120-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25223582

RESUMO

INTRODUCTION: The burden of chronic heart failure (HF) is rising owing to an increased survivorship after myocardial infarction (MI). Pulmonary structural remodelling in patients with HF may protect against oedema while causing dyspnoea, the predominant symptom associated with HF. The cellular and molecular mechanisms underlying these processes in HF are poorly understood. We hypothesised that pulmonary venous hypertension (PVH) following MI provides a mechanical stimulus for structural remodelling of the lung via monocyte chemoattractant protein-1 (MCP-1). METHODS: Human lung microvascular endothelial cells (HLMVEC) and Ea.Hy 926 cells exposed to cyclic mechanical strain (CMS) in vitro were analysed for MCP-1 expression and activation of signalling intermediates. HF was induced in Sprague-Dawley rats 16 weeks after MI; a cohort was rescued with AAV9.SERCA2a gene therapy to reduce PVH. RESULTS: HLMVEC and Ea.Hy 926 cells exposed to CMS upregulated MCP-1 gene expression and protein release in an extracellular-signal-regulated kinase (ERK) 1/2 dependent manner. Supernatants from these experiments stimulated fibroblast (human fetal lung fibroblast -1) and pulmonary artery smooth muscle cell proliferation and differentiation. Total lung collagen, a marker of structural remodelling, and MCP-1 gene expression were increased in the lungs of rats with post-MI HF. SERCA2a gene therapy that attenuated PVH after MI was associated with lower levels of lung collagen and MCP-1 gene expression in the lung. CONCLUSIONS: Mechanical strain associated with PVH may stimulate pulmonary structural remodelling through ERK 1/2 dependent induction of MCP-1. These findings provide insights into the pathophysiology of lung remodelling in HF and highlight novel, potential therapeutic targets.


Assuntos
Remodelação das Vias Aéreas/fisiologia , Quimiocina CCL2/biossíntese , Insuficiência Cardíaca/fisiopatologia , Hipertensão Pulmonar/metabolismo , Mecanotransdução Celular/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/fisiologia , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Células Endoteliais/fisiologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Terapia Genética/métodos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Infarto do Miocárdio/complicações , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Estresse Mecânico , Regulação para Cima/fisiologia
15.
Sarcoidosis Vasc Diffuse Lung Dis ; 31(2): 82-90, 2014 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-25078636

RESUMO

BACKGROUND: Pulmonary hypertension (PH), an increasingly recognised complication of pulmonary sarcoidosis, is associated with increased morbidity and mortality Evidence of benefit with targeted therapies in sarcoidosis associated pulmonary hypertension (SAPH) is limited. METHODS: We conducted a retrospective review of patients with sarcoidosis and right heart catheter proven PH who received treatment with targeted therapies (phosphodiesterase-5 inhibitors, endothelin receptor antagonists, or combination) at our hospital. Six minute walk test (6MWT), World Health Organisation (WHO) functional class, echocardiography, pulmonary function test (PFT) and serum brain natriuretic peptide (BNP) data were collected at baseline and during follow-up. RESULTS: Thirty-three patients (16 men) with a mean age of 55.5 ± 10.7 years and mean pulmonary artery pressure of 44.0 ± 8.6 mm Hg received treatment with targeted PH therapies (sildenafil=29, bosentan=4). At six months, median six minute walk distance improved from 227 (88-526) meters to 240 (140-380) metres (p=0.04), median serum BNP levels improved from 35 (2-424) pmol/L to 26 (4-255) pmol/L (p<0.01), and at echocardiography, median tricuspid annular plane systolic excursion (TAPSE) improved from 17.5 (8.0-27.0) mm to 20.0 (15.0-27.0) mm (p=0.03). WHO functional class improved in 14 patients. Two patients developed side-effects attributed to sildenafil (n=1) or bosentan (n=1), requiring conversion to alternative PH therapies. Ten patients died, and one patient underwent lung transplantation, a median of 13.5 (3-37) months after commencing targeted therapies. CONCLUSIONS: Our results suggest that targeted therapies are safe in patients with SAPH. Controlled trials are warranted before therapeutic recommendations can be made.


Assuntos
Anti-Hipertensivos/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Sarcoidose Pulmonar/complicações , Vasodilatadores/uso terapêutico , Idoso , Anti-Hipertensivos/efeitos adversos , Pressão Arterial/efeitos dos fármacos , Biomarcadores/sangue , Antagonistas dos Receptores de Endotelina/efeitos adversos , Teste de Esforço , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Londres , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Peptídeo Natriurético Encefálico/sangue , Inibidores da Fosfodiesterase 5/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/mortalidade , Sarcoidose Pulmonar/terapia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Vasodilatadores/efeitos adversos
19.
PLoS One ; 8(10): e75415, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24124488

RESUMO

OBJECTIVES: To assess activation of the inflammatory transcription factor NF-kappa B (NF-κB) in human idiopathic pulmonary arterial hypertension (PAH). BACKGROUND: Idiopathic PAH is a severe progressive disease characterized by pulmonary vascular remodeling and excessive proliferation of vascular cells. Increasing evidence indicates that inflammation is important in disease pathophysiology. METHODS: NF-κB-p65 and CD68, CD20 and CD45 were measured by immunohistochemistry and confocal microscopy on lung specimens from patients with idiopathic PAH (n = 12) and controls undergoing lung surgery (n = 14). Clinical data were recorded for all patients including invasive pulmonary hemodynamics for the PAH patients. Immunohistochemical images were analyzed by blinded observers to include standard pulmonary vascular morphometry; absolute macrophage counts/mm(2) and p65-positivity (p65+) using composite images and image-analysis software; and cytoplasmic:nuclear p65+ of individual pulmonary arterial endothelial and smooth muscle cells (PASMC) in 10-20 pulmonary arteries or arterioles per subject. The expression of ET-1 and CCL5 (RANTES) in whole lung was determined by RT-qPCR. RESULTS: Macrophage numbers were increased in idiopathic PAH versus controls (49.0±4.5 vs. 7.95±1.9 macrophages/100 mm(2), p<0.0001): these macrophages demonstrated more nuclear p65+ than in macrophages from controls (16.9±2.49 vs. 3.5±1.25%, p<0.001). An increase in p65+ was also seen in perivascular lymphocytes in patients with PAH. Furthermore, NF-κB activation was increased in pulmonary arterial endothelial cells (62.3±2.9 vs. 14.4±3.8, p<0.0001) and PASMC (22.6±2.3 vs. 11.2±2.0, p<0.001) in patients with PAH versus controls, with similar findings in arterioles. Gene expression of both ET-1 mRNA ((0.213±0.069 vs. 1.06±0.23, p<0.01) and CCL5 (RANTES) (0.16±0.045 vs. 0.26±0.039, p<0.05) was increased in whole lung homogenates from patients with PAH. CONCLUSIONS: NF-κB is activated in pulmonary macrophages, lymphocytes, endothelial and PASMC in patients with end-stage idiopathic PAH. Future research should determine whether NF-κB activation is a driver or bystander of pulmonary vascular inflammation and if the former, its potential role as a therapeutic target.


Assuntos
Hipertensão Pulmonar/mortalidade , NF-kappa B/metabolismo , Artéria Pulmonar/metabolismo , Idoso , Hipertensão Pulmonar Primária Familiar , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Pulmão/metabolismo , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Int J Cardiol ; 168(3): 2248-54, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23453874

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is considered primarily a disease of the distal pulmonary arteries whereas little is known on the effect of long-standing pulmonary hypertension on the larger proximal pulmonary arteries. This study aims to investigate the structural changes in the great arteries of adults who developed PAH in association with congenital heart disease (CHD), with severe cases termed Eisenmenger syndrome. METHODS: We performed macroscopic and light microscopy analyses on the great arteries of 10 formalin-fixed human hearts from patients with PAH/CHD and compared them to age-matched healthy controls. A detailed histology grading score was used to assess the severity of medial wall abnormalities. RESULTS: Severe atherosclerotic lesions were found macroscopically in the elastic pulmonary arteries of 4 PAH/CHD specimens and organised thrombi in 3; none were present in the controls. Significant medial wall abnormalities were present in the pulmonary trunk (PT), including fibrosis (80%), and atypical elastic pattern (80%). Cyst-like formations were present in less than one third of patients and were severe in a single case leading to wall rupture. The cumulative PT histology grading score was significantly higher in PAH/CHD cases compared to controls (p<0.0001) and correlated positively with larger PT diameters (ρ=0.812, p<0.0001) and the degree of medial wall hypertrophy (ρ=0.749, p<0.0001). CONCLUSIONS: Chronic PAH in association with CHD results in marked macroscopic and histological abnormalities in the large pulmonary arteries. These abnormalities are likely to affect haemodynamics and contribute to morbidity and mortality in this cohort.


Assuntos
Aorta Torácica/patologia , Complexo de Eisenmenger/complicações , Hipertensão Pulmonar/patologia , Artéria Pulmonar/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo de Eisenmenger/patologia , Feminino , Seguimentos , Humanos , Hipertensão Pulmonar/etiologia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Adulto Jovem
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