RESUMO
Increasing evidence suggests that patients with pulmonary arterial hypertension (PAH) demonstrate abnormalities in the bone marrow (BM) and hematopoietic progenitor cells. In addition, PAH is associated with myeloproliferative diseases. We have previously demonstrated that low-dose lipopolysaccharide (LPS) is a potent stimulus for the development of PAH in the context of a genetic PAH mouse model of BMPR2 dysfunction. We hypothesized that the hematopoietic progenitor cells might be driving disease in this model. To test this hypothesis, we performed adoptive transfer of BM between wild-type (Ctrl) and heterozygous Bmpr2 null (Mut) mice. Sixteen weeks after BM reconstitution, mice were exposed to low-dose chronic LPS (0.5 mg/kg three times a week for six weeks). Mice underwent right heart catheterization and tissues were removed for histology. After chronic LPS dosing, Ctrl mice in receipt of Mut BM developed PAH, whereas Mut mice receiving Ctrl BM were protected from PAH. BM histology demonstrated an increase in megakaryocytes and there was an increase in circulating platelets in Ctrl mice receiving Mut BM. These findings demonstrate that the hematopoietic stem cell compartment is involved in the susceptibility to PAH in the Mut mouse. The results raise the possibility that hematopoietic stem cell transplantation might be a potential treatment strategy in genetic forms of PAH.
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Levetiracetam is widely regarded as a benign antiepileptic drug, compared to older antiepileptic medication. We report a case of eosinophilic pneumonia due to levetiracetam use in a non-smoking woman aged 59â years with no previous respiratory history. Our patient presented with exertional breathlessness and marked desaturation on exertion. She displayed 'reverse bat-wing' infiltrates on her chest radiograph and peripheral eosinophilia on a complete blood count. Her symptoms, radiology and peripheral eosinophilia resolved completely with cessation of levetiracetam and a course of prednisolone. This is the first report of isolated eosinophilic pneumonia due to levetiracetam. Other reports of levetiracetam-induced eosinophilia describe drug rash, eosinophilia and systemic symptoms (DRESS syndrome). Detection of pulmonary drug reactions requires a careful drug history and high index of suspicion. Identifying and reporting a causative agent is crucially important, as cessation of the drug is essential for resolution of the syndrome.
Assuntos
Piracetam/análogos & derivados , Eosinofilia Pulmonar/diagnóstico , Eosinofilia Pulmonar/tratamento farmacológico , Feminino , Humanos , Levetiracetam , Pessoa de Meia-Idade , Piracetam/efeitos adversos , Prednisolona/uso terapêutico , Eosinofilia Pulmonar/induzido quimicamente , Resultado do TratamentoAssuntos
Fístula Brônquica/diagnóstico por imagem , Broncoscopia/métodos , Doenças Pleurais/diagnóstico por imagem , Intensificação de Imagem Radiográfica/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Meios de Contraste , Fístula/diagnóstico por imagem , Humanos , Iopamidol , MasculinoRESUMO
RATIONALE: Schistosomiasis is a major cause of pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein type-II receptor (BMPR-II) are the commonest genetic cause of PAH. OBJECTIVES: To determine whether Bmpr2(+/-) mice are more susceptible to schistosomiasis-induced pulmonary vascular remodeling. METHODS: Wild-type (WT) and Bmpr2(+/-) mice were infected percutaneously with Schistosoma mansoni. At 17 weeks postinfection, right ventricular systolic pressure and liver and lung egg counts were measured. Serum, lung and liver cytokine, pulmonary vascular remodeling, and liver histology were assessed. MEASUREMENTS AND MAIN RESULTS: By 17 weeks postinfection, there was a significant increase in pulmonary vascular remodeling in infected mice. This was greater in Bmpr2(+/-) mice and was associated with an increase in egg deposition and cytokine expression, which induced pulmonary arterial smooth muscle cell proliferation, in the lungs of these mice. Interestingly, Bmpr2(+/-) mice demonstrated dilatation of the hepatic central vein at baseline and postinfection, compared with WT. Bmpr2(+/-) mice also showed significant dilatation of the liver sinusoids and an increase in inflammatory cells surrounding the central hepatic vein, compared with WT. This is consistent with an increase in the transhepatic passage of eggs. CONCLUSIONS: This study has shown that levels of BMPR-II expression modify the pulmonary vascular response to chronic schistosomiasis. The likely mechanism involves the increased passage of eggs to the lungs, caused by altered diameter of the hepatic veins and sinusoids in Bmpr2(+/-) mice. Genetically determined differences in the remodeling of hepatic vessels may represent a new risk factor for PAH associated with schistosomiasis.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II , Hipertensão Pulmonar/fisiopatologia , Fígado/parasitologia , Artéria Pulmonar/fisiopatologia , Esquistossomose/fisiopatologia , Remodelação Vascular/genética , Animais , Proliferação de Células , Modelos Animais de Doenças , Feminino , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/parasitologia , Camundongos , Artéria Pulmonar/parasitologia , Schistosoma mansoni , Esquistossomose/genética , Transdução de Sinais , Remodelação Vascular/fisiologiaRESUMO
RATIONALE: Mutations in bone morphogenetic protein receptor type II (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (PAH). However, disease penetrance is only 20-30%, suggesting a requirement for additional triggers. Inflammation is emerging as a key disease-related factor in PAH, but to date there is no clear mechanism linking BMPR-II deficiency and inflammation. OBJECTIVES: To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH. METHODS: We used pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations and compared them with wild-type controls. For the in vivo model, we used mice heterozygous for a null allele in Bmpr2 (Bmpr2(+/-)) and wild-type littermates. MEASUREMENTS AND MAIN RESULTS: Acute exposure to LPS increased lung and circulating IL-6 and KC (IL-8 analog) levels in Bmpr2(+/-) mice to a greater extent than in wild-type controls. Similarly, pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations produced higher levels of IL-6 and KC/IL-8 after lipopolysaccharide stimulation compared with controls. BMPR-II deficiency in mouse and human pulmonary artery smooth muscle cells was associated with increased phospho-STAT3 and loss of extracellular superoxide dismutase. Chronic lipopolysaccharide administration caused pulmonary hypertension in Bmpr2(+/-) mice but not in wild-type littermates. Coadministration of tempol, a superoxide dismutase mimetic, ameliorated the exaggerated inflammatory response and prevented development of PAH. CONCLUSIONS: This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/deficiência , Citocinas/biossíntese , Hipertensão Pulmonar/fisiopatologia , Animais , Antioxidantes/uso terapêutico , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Óxidos N-Cíclicos/uso terapêutico , Fenoterol , Predisposição Genética para Doença , Humanos , Hipertensão Pulmonar/genética , Imuno-Histoquímica , Camundongos Endogâmicos , Marcadores de Spin , Superóxido Dismutase/fisiologiaAssuntos
Malformações Arteriovenosas/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Hipertensão Pulmonar/genética , Mutação , Artéria Pulmonar/anormalidades , Veias Pulmonares/anormalidades , Anti-Hipertensivos/uso terapêutico , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/terapia , Bosentana , Progressão da Doença , Quimioterapia Combinada , Hipertensão Pulmonar Primária Familiar , Seguimentos , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/terapia , Masculino , Pessoa de Meia-Idade , Linhagem , Piperazinas/uso terapêutico , Purinas/uso terapêutico , Citrato de Sildenafila , Sulfonamidas/uso terapêutico , Sulfonas/uso terapêutico , Resultado do Tratamento , Vasodilatadores/uso terapêuticoRESUMO
This study analyzed the relationship between pulmonary vascular resistance (PVR) and pulmonary arterial compliance (Ca) in patients with idiopathic pulmonary arterial hypertension (IPAH) and proximal chronic thromboembolic pulmonary hypertension (CTEPH). It has recently been shown that the time constant of the pulmonary circulation (RC time constant), or PVR × Ca, remains unaltered in various forms and severities of pulmonary hypertension, with the exception of left heart failure. We reasoned that increased wave reflection in proximal CTEPH would be another cause of the decreased RC time constant. We conducted a retrospective analysis of invasive pulmonary hemodynamic measurements in IPAH (n = 78), proximal CTEPH (n = 91) before (pre) and after (post) pulmonary endarterectomy (PEA), and distal CTEPH (n = 53). Proximal CTEPH was defined by a postoperative mean pulmonary artery pressure (PAP) of ≤25 mmHg. Outcome measures were the RC time constant, PVR, Ca, and relationship between systolic and mean PAPs. The RC time constant for pre-PEA CTEPH was 0.49 ± 0.11 s compared with post-PEA-CTEPH (0.37 ± 0.11 s, P < 0.0001), IPAH (0.63 ± 0.14 s, P < 0.001), and distal CTEPH (0.55 ± 0.12 s, P < 0.05). A shorter RC time constant was associated with a disproportionate decrease in systolic PAP with respect to mean PAP. We concluded that the pulmonary RC time constant is decreased in proximal CTEPH compared with IPAH, pre- and post-PEA, which may be explained by increased wave reflection but also, importantly, by persistent structural changes after the removal of proximal obstructions. A reduced RC time constant in CTEPH is in accord with a wider pulse pressure and hence greater right ventricular work for a given mean PAP.
Assuntos
Hemodinâmica , Hipertensão Pulmonar/etiologia , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar , Embolia Pulmonar/complicações , Adulto , Idoso , Análise de Variância , Pressão Arterial , Cateterismo Cardíaco , Doença Crônica , Complacência (Medida de Distensibilidade) , Endarterectomia das Carótidas , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/cirurgia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/cirurgia , Embolia Pulmonar/fisiopatologia , Embolia Pulmonar/cirurgia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Resistência Vascular , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular DireitaRESUMO
BACKGROUND: Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described. METHODS AND RESULTS: Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1ß, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-ß, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-γ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling. CONCLUSIONS: Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease.
Assuntos
Hipertensão Pulmonar/imunologia , Células Matadoras Naturais/imunologia , Adulto , Idoso , Animais , Antígeno CD56/análise , Quimiocina CCL4/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Proteínas Ligadas por GPI/análise , Genótipo , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/genética , Imunofenotipagem , Células Matadoras Naturais/química , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/patologia , Masculino , Metaloproteinase 9 da Matriz/análise , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptor 1 Desencadeador da Citotoxicidade Natural , Embolia Pulmonar/complicações , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de IgG/análise , Receptores KIR2DL1/biossíntese , Receptores KIR2DL1/genética , Receptores KIR3DL1/biossíntese , Receptores KIR3DL1/genética , Receptores KIR3DS1/biossíntese , Receptores KIR3DS1/genética , Fator de Crescimento Transformador beta/farmacologiaRESUMO
We previously reported that osteoprotegerin (OPG) is regulated by pathways associated with pulmonary arterial hypertension (PAH), and is present at elevated levels within pulmonary vascular lesions and sera from patients with idiopathic PAH (IPAH). Since OPG is a naturally secreted protein, we investigated the relationship between serum OPG and disease severity and outcome in patients with IPAH and animal models. OPG mRNA expression was measured in pulmonary artery smooth muscle cells (PASMC) from pulmonary arteries of patients with and without IPAH. Serum concentrations of OPG were measured in a retrospective and prospective group of patients. OPG levels were compared with phenotypic data and other putative PAH biomarkers. Prognostic significance was assessed and levels compared with healthy controls. Correlation of OPG and pulmonary vascular remodeling was also performed in rodent models of PAH. OPG mRNA was significantly increased 2-fold in PASMC isolated from explanted PAH lungs compared with control. Serum OPG concentrations were markedly elevated in IPAH compared with controls. In Cohort 1 OPG levels significantly correlated with mean right atrial pressure and cardiac index, while in Cohort 2 significant correlations existed between age-adjusted OPG levels and gas transfer. In both cohorts an OPG concentration above a ROC-derived threshold of 4728 pg/ml predicted poorer survival. In two rodent models, OPG correlated with the degree of pulmonary vascular remodeling. OPG levels are significantly elevated in patients with idiopathic PAH and are of prognostic significance. The role of OPG as a potential biomarker and therapeutic target merits further investigation.
RESUMO
Flow-directed pulmonary artery occlusion is posited to enable partitioning of vascular resistance into small and large vessels. As such it may have a role in assessment for pulmonary endarterectomy. To test if the occlusion technique distinguished small from large vessel disease we studied 59 subjects with chronic thromboembolic pulmonary hypertension (CTEPH), idiopathic pulmonary arterial hypertension (IPAH), and connective tissue disease (CTD)-associated PAH. At right heart catheterisation, occlusion pressures were recorded. With fitting of the pressure decay curve, pulmonary vascular resistance was partitioned into downstream (small vessels) and upstream (large vessels, Rup). 47 patients completed the study; 14 operable CTEPH, 15 inoperable CTEPH, 13 idiopathic or CTD-PAH and five post-operative CTEPH. There was a significant difference in mean Rup in the proximal operable CTEPH group 87.3 (95% CI 84.1-90.5); inoperable CTEPH mean 75.8 (95% CI 66.76-84.73), p=0.048; and IPAH/CTD, mean 77.1 (95% CI 71.86-82.33), p=0.003. Receiver operating characteristic curves to distinguish operable from inoperable CTEPH demonstrated an area under the curve of 0.75, p=0.0001. A cut-off of 79.3 gave 100% sensitivity (95% CI 73.5-100%) but 57.1% specificity (95% CI 28.9-82.3%). In a subgroup analysis of multiple lobar sampling there was demonstrable heterogeneity. Rup is significantly increased in operable proximal CTEPH compared with non-operable distal CTEPH and IPAH/CTD-PAH. Rup variability in patients with CTEPH and PAH is suggestive of pathophysiological heterogeneity.
Assuntos
Hipertensão Pulmonar/fisiopatologia , Embolia Pulmonar/fisiopatologia , Resistência Vascular/fisiologia , Adulto , Idoso , Cateterismo Cardíaco , Doença Crônica , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/fisiopatologia , Endarterectomia , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/cirurgia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/cirurgia , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/cirurgia , Curva ROCRESUMO
N-terminal pro B-type natriuretic peptide (NT-proBNP) is a product of cleavage of the cardiac prohormone pro B-type natriuretic peptide into its active form. It has proven to be a useful biomarker in left heart failure. However, studies examining the utility of serial measurements of NT-proBNP in pulmonary arterial hypertension (PAH) patients have shown mixed results. We compared three methods of predicting adverse clinical outcomes in PAH patients: the change in 6 minute walk distance (6MWD), the change in absolute levels of NT-proBNP and the change in log-transformed levels of NT-proBNP. All PAH patients presenting from March-June 2007 were screened. Patients who were clinically unstable, had abnormal renal function or hemoglobin levels or lacked a prior NT-proBNP were excluded. 63 patients were followed up for adverse clinical outcomes (defined as death, transplantation, hospitalisation for right heart failure, or need for increased therapy). Three methods were used to predict adverse events, i.e.: (a) comparing a 6MWD performed in March-June 2007 and a previous 6MWD. A decrease in 6MWD of ≥30m was used to predict clinical deterioration; (b) comparing a NT-proBNP value measured in March-June 2007 and a previous NT-proBNP. An increase in NT-proBNP of ≥250pg/ml was used to predict clinical deterioration (250pg/ml represented approximately 30% change from the baseline median value of NT-proBNP for this cohort); and (c) comparing the loge equivalents of two consecutive NT-proBNP values. We used the formula: loge(current NT-proBNP) - loge(previous NT-proBNP)=x. A value of x≥+0.26 was used to predict adverse events. This is equivalent to a 30% change from baseline, and hence is comparable to the chosen cut-off for absolute levels of NT-proBNP. A loge difference of ≥+0.26 identifies patients at risk of adverse events with a specificity of 98%, a sensitivity of 60%, a positive predictive value of 89%, and a negative predictive value of 90%. A drop in 6MWD of ≥30m has a specificity of 29%, a sensitivity of 73%, a positive predictive value of 24% and a negative predictive value of 24%. It seems possible to risk-stratify apparently stable PAH patients by following the changes in their serial log-transformed NT-proBNP values. In this small pilot study, this method was better than relying on changes in the actual levels of NT-proBNP or changes in 6MWD. This needs to be validated prospectively in a larger cohort.
RESUMO
RATIONALE: Schistosomiasis is the most common worldwide cause of pulmonary arterial hypertension. The anti-schistosome drug praziquantel has been shown to reverse the liver fibrosis associated with Schistosoma mansoni in mice. OBJECTIVES: We sought to determine whether praziquantel reverses established pulmonary vascular remodeling and pulmonary hypertension in a mouse model of S. mansoni. METHODS: Mice were infected percutaneously with S. mansoni. At 17 weeks after infection mice were either killed or received two doses of praziquantel or vehicle by oral gavage. Treated mice were studied at 25 weeks after infection. MEASUREMENTS AND MAIN RESULTS: Vehicle-treated mice demonstrated significant increases in right ventricular systolic pressures (RVSP) and right ventricular hypertrophy (RVH) at 25 weeks, accompanied by pulmonary vascular remodeling. The degree of vascular remodeling correlated with proximity to granulomas. The elevation of RVSP and RVH at 25 weeks was dependent on the presence of eggs in the lung. Praziquantel eliminated the production of eggs in feces and led to clearance of eggs from the lung and to a lesser extent from liver. Praziquantel prevented the rise in RVSP and RVH seen in vehicle-treated mice and reversed established pulmonary vascular remodeling. Praziquantel significantly reduced lung mRNA expression of IL-13, IL-8, and IL-4, but did not reduce serum cytokine levels. CONCLUSIONS: The development of pulmonary hypertension associated with S. mansoni infection can be prevented by praziquantel, and established vascular remodeling can be reversed. The mechanism involves clearance of lung eggs and reduced local expression of lung cytokines.
Assuntos
Anti-Helmínticos/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Hipertensão Pulmonar/fisiopatologia , Pulmão/irrigação sanguínea , Praziquantel/farmacologia , Esquistossomose mansoni/complicações , Esquistossomose mansoni/fisiopatologia , Animais , Pressão Sanguínea , Citocinas/metabolismo , Regulação para Baixo , Feminino , Granuloma/parasitologia , Granuloma/patologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/parasitologia , Hipertrofia Ventricular Direita/parasitologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/prevenção & controle , Mediadores da Inflamação/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-8/metabolismo , Fígado/parasitologia , Pulmão/metabolismo , Pulmão/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Óvulo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/patologiaAssuntos
Amiodarona/efeitos adversos , Hipertensão Pulmonar/tratamento farmacológico , Hipertireoidismo/induzido quimicamente , Hipertireoidismo/mortalidade , Vasodilatadores/efeitos adversos , Adulto , Idoso , Amiodarona/uso terapêutico , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertireoidismo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Valores de Referência , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Testes de Função Tireóidea , Resultado do Tratamento , Vasodilatadores/uso terapêuticoRESUMO
BACKGROUND: Anaemia is common in left heart failure and is associated with a poorer outcome. Many patients with pulmonary arterial hypertension (PAH) are anaemic or iron-deficient. This study was performed to investigate the prevalence of iron deficiency in PAH and to identify possible causes. METHODS: All patients with idiopathic or heritable PAH diagnosed in 1995-2008 were identified. Controls were selected from patients with chronic thromboembolic pulmonary hypertension (CTEPH). Full blood counts were examined and any abnormality was investigated. Patients were excluded if they had a cause for iron deficiency. The prevalence study was based on 85 patients with idiopathic PAH and 120 with CTEPH. A separate group of 20 patients with idiopathic PAH and 24 with CTEPH with matching haemodynamics were prospectively investigated for serum factors affecting iron metabolism. RESULTS: The prevalence study identified a point prevalence of unexplained iron deficiency of 50% in premenopausal women with idiopathic PAH compared with 8% in premenopausal women with CTEPH (p=0.002); 14% in postmenopausal women with idiopathic PAH compared with 6% in postmenopausal women with CTEPH (p=0.16); 28% in men with idiopathic PAH men compared with 2% in men with CTEPH (p=0.002); and 60% in patients with heritable PAH. The serum study showed that patients with idiopathic PAH had lower serum iron and transferrin saturations than those with CTEPH. Interleukin-6 levels correlated with iron levels (r=-0.6, p=0.006) and transferrin saturations (r=-0.68, p=0.001) in idiopathic PAH but not in CTEPH. CONCLUSIONS: The prevalence of unexplained iron deficiency is significantly higher in idiopathic PAH than in CTEPH. This may be linked to interleukin-6.
Assuntos
Anemia Ferropriva/etiologia , Adulto , Idoso , Anemia Ferropriva/sangue , Métodos Epidemiológicos , Hipertensão Pulmonar Primária Familiar , Feminino , Ferritinas/sangue , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/complicações , Interleucina-6/sangue , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Pré-Menopausa/sangueRESUMO
The past decade has seen increased application of 18-flurodeoxyglucose positron emission tomography ((18)FDG-PET) imaging to help diagnose and monitor disease, particularly in oncology, vasculitis and atherosclerosis. Disordered glycolytic metabolism and infiltration of plexiform lesions by inflammatory cells has been described in idiopathic pulmonary arterial hypertension (IPAH). We hypothesized that increased (18)FDG uptake may be present in the lungs, large pulmonary arteries and right ventricle of patients with pulmonary hypertension, and that this uptake would be related to markers of immune activation. We imaged the thorax of 14 patients with pulmonary hypertension (idiopathic and chronic thromboembolic) and six controls by (18)FDG-PET/computed tomography (CT) and measured uptake in the lung parenchyma, large pulmonary arteries and right ventricle. (18)FDG uptake in the lungs and pulmonary arteries was normalized for venous blood activity to give a target-to-background ratio (TBR). Blood was contemporaneously drawn for high-sensitivity CRP - C-reactive protein (CRP) (hsCRP), N-Terminal Probrain natriuteric peptide (NT-ProBNP) and other inflammatory cytokines. IPAH patients had significantly higher lung parenchymal TBR (P=0.034) and right ventricle FDG uptake (P=0.007) than controls. Uptake in the main pulmonary arteries was similar in chronic thromboembolic pulmonary hypertension, IPAH and controls. There were no correlations between (18)FDG uptake and hsCRP or inflammatory cytokine levels. NT-ProBNP correlated with RV uptake in those with pulmonary hypertension (r=0.55, P=0.04). In this pilot study, we found increased (18)FDG uptake in the lung parenchyma and right ventricle of subjects with IPAH. The lung uptake might be useful as a surrogate marker of increased cellular metabolism and immune activation as underlying mechanisms in this disease. Further evaluation of the impact of targeted therapies in treatment-naïve patients and the significance of right ventricular uptake is suggested.
RESUMO
BACKGROUND: Inflammation is a feature of pulmonary arterial hypertension (PAH), and increased circulating levels of cytokines are reported in patients with PAH. However, to date, no information exists on the significance of elevated cytokines or their potential as biomarkers. We sought to determine the levels of a range of cytokines in PAH and to examine their impact on survival and relationship to hemodynamic indexes. METHODS AND RESULTS: We measured levels of serum cytokines (tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta, -2, -4, -5, -6, -8, -10, -12p70, and -13) using ELISAs in idiopathic and heritable PAH patients (n=60). Concurrent clinical data included hemodynamics, 6-minute walk distance, and survival time from sampling to death or transplantation. Healthy volunteers served as control subjects (n=21). PAH patients had significantly higher levels of interleukin-1beta, -2, -4, -6, -8, -10, and -12p70 and tumor necrosis factor-alpha compared with healthy control subjects. Kaplan-Meier analysis showed that levels of interleukin-6, 8, 10, and 12p70 predicted survival in patients. For example, 5-year survival with interleukin-6 levels of >9 pg/mL was 30% compared with 63% for patients with levels < or = 9 pg/mL (P=0.008). In this PAH cohort, cytokine levels were superior to traditional markers of prognosis such as 6-minute walk distance and hemodynamics. CONCLUSIONS: This study illustrates dysregulation of a broad range of inflammatory mediators in idiopathic and familial PAH and demonstrates that cytokine levels have a previously unrecognized impact on patient survival. They may prove to be useful biomarkers and provide insight into the contribution of inflammation in PAH.