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1.
Am J Respir Cell Mol Biol ; 62(2): 143-156, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577451

RESUMO

Translational research is essential to the development of reverse-remodeling strategies for the treatment of pulmonary vascular disease, pulmonary hypertension, and heart failure via mechanistic in vivo studies using animal models resembling human pulmonary arterial hypertension (PAH), cardiovascular remodeling, and progressive right heart failure. Since 2007, peroxisome proliferator-activated receptor γ (PPARγ) agonists have emerged as promising novel, antiproliferative, antiinflammatory, insulin-sensitizing, efficient medications for the treatment of PAH. However, early diabetes study results, their subsequent misinterpretations, errors in published review articles, and rumors regarding potential adverse effects in the literature have dampened enthusiasm for considering pharmacological PPARγ activation for the treatment of cardiovascular diseases, including PAH. Most recently, the thiazolidinedione class PPARγ agonist pioglitazone underwent a clinical revival, especially based on the IRIS (Insulin Resistance Intervention After Stroke) study, a randomized controlled trial in 3,876 patients without diabetes status post-transient ischemic attack/ischemic stroke who were clinically followed for 4.8 years. We discuss preclinical basic translational findings and randomized controlled trials related to the beneficial and adverse effects of PPARγ agonists of the thiazolidinedione class, with a particular focus on the last 5 years. The objective is a data-driven approach to set the preclinical and clinical study record straight. The convincing recent clinical trial data on the lack of significant toxicity in high-risk populations justify the timely conduct of clinical studies to achieve "repurposing" or "repositioning" of pioglitazone for the treatment of clinical PAH.


Assuntos
Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , PPAR gama/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Animais , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Tiazolidinedionas/farmacologia
2.
Nat Commun ; 10(1): 5183, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729368

RESUMO

Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.


Assuntos
Anticorpos/administração & dosagem , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Osteoprotegerina/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar Primária Familiar/metabolismo , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Osteoprotegerina/genética , Ligação Proteica , Artéria Pulmonar/citologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Wistar , Remodelação Vascular/efeitos dos fármacos
3.
BMC Pulm Med ; 19(1): 188, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664957

RESUMO

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a fatal illness. Despite many improvements in the treatment of these patients, there is no unique prognostic variable available to track these patients. The aim of this study was to evaluate the association between fractional exhaled nitric oxide (FeNO) levels, as a noninvasive biomarker, with disease severity and treatment outcome. METHODS: Thirty-six patients (29 women and 7 men, mean age 38.4 ± 11.3 years) with IPAH referred to the outpatient's clinic of Masih Daneshvari Hospital, Tehran, Iran, were enrolled into this pilot observational study. Echocardiography, six-minute walking test (6MWT), FeNO, brain natriuretic peptide (BNP) levels and the functional class of patients was assessed before patients started treatment. Assessments were repeated after three months. 30 healthy non-IPAH subjects were recruited as control subjects. RESULTS: There was no significant difference in FeNO levels at baseline between patients with IPAH and subjects in the control group. There was also no significant increase in FeNO levels during the three months of treatment and levels did not correlate with other disease measures. In contrast, other markers of disease severity were correlated with treatment effect over the three months. CONCLUSION: FeNO levels are a poor non-invasive measure of IPAH severity and of treatment response in patients in this pilot study.


Assuntos
Expiração , Hipertensão Pulmonar Primária Familiar/metabolismo , Óxido Nítrico/análise , Adulto , Anti-Hipertensivos/uso terapêutico , Biomarcadores/análise , Estudos de Casos e Controles , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Feminino , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Resultado do Tratamento
4.
Am J Physiol Lung Cell Mol Physiol ; 317(3): L369-L380, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31242023

RESUMO

The ß-adrenergic receptor (ßAR) exists in an equilibrium of inactive and active conformational states, which shifts in response to different ligands and results in downstream signaling. In addition to cAMP, ßAR signals to hypoxia-inducible factor 1 (HIF-1). We hypothesized that a ßAR-active conformation (R**) that leads to HIF-1 is separable from the cAMP-activating conformation (R*) and that pulmonary arterial hypertension (PAH) patients with HIF-biased conformations would not respond to a cAMP agonist. We compared two cAMP agonists, isoproterenol and salbutamol, in vitro. Isoproterenol increased cAMP and HIF-1 activity, while salbutamol increased cAMP and reduced HIF-1. Hypoxia blunted agonist-stimulated cAMP, consistent with receptor equilibrium shifting toward HIF-activating conformations. Similarly, isoproterenol increased HIF-1 and erythropoiesis in mice, while salbutamol decreased erythropoiesis. ßAR overexpression in cells increased glycolysis, which was blunted by HIF-1 inhibitors, suggesting increased ßAR leads to increased hypoxia-metabolic effects. Because PAH is also characterized by HIF-related glycolytic shift, we dichotomized PAH patients in the Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure trial (NCT01586156) based on right ventricular (RV) glucose uptake to evaluate ßAR ligands. Patients with high glucose uptake had more severe disease than those with low uptake. cAMP increased in response to isoproterenol in mononuclear cells from low-uptake patients but not in high-uptake patients' cells. When patients were treated with carvedilol for 1 wk, the low-uptake group decreased RV systolic pressures and pulmonary vascular resistance, but high-uptake patients had no physiologic responses. The findings expand the paradigm of ßAR activation and uncover a novel PAH subtype that might benefit from ß-blockers.


Assuntos
Hipertensão Pulmonar Primária Familiar/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Hipertensão Arterial Pulmonar/fisiopatologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Hipóxia/tratamento farmacológico , Isoproterenol/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Hipertensão Arterial Pulmonar/tratamento farmacológico , Receptores Adrenérgicos beta/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
Nat Commun ; 10(1): 2204, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101827

RESUMO

Pulmonary arterial hypertension (PAH) is a devastating disease with poor prognosis and limited therapeutic options. We screened for pathways that may be responsible for the abnormal phenotype of pulmonary arterial smooth muscle cells (PASMCs), a major contributor of PAH pathobiology, and identified cyclin-dependent kinases (CDKs) as overactivated kinases in specimens derived from patients with idiopathic PAH. This increased CDK activity is confirmed at the level of mRNA and protein expression in human and experimental PAH, respectively. Specific CDK inhibition by dinaciclib and palbociclib decreases PASMC proliferation via cell cycle arrest and interference with the downstream CDK-Rb (retinoblastoma protein)-E2F signaling pathway. In two experimental models of PAH (i.e., monocrotaline and Su5416/hypoxia treated rats) palbociclib reverses the elevated right ventricular systolic pressure, reduces right heart hypertrophy, restores the cardiac index, and reduces pulmonary vascular remodeling. These results demonstrate that inhibition of CDKs by palbociclib may be a therapeutic strategy in PAH.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Linhagem Celular , Quinases Ciclina-Dependentes/metabolismo , Modelos Animais de Doenças , Hipertensão Pulmonar Primária Familiar/induzido quimicamente , Hipertensão Pulmonar Primária Familiar/patologia , Hipertensão Pulmonar Primária Familiar/cirurgia , Humanos , Indóis/toxicidade , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monocrotalina/toxicidade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Piridinas/uso terapêutico , Pirróis/toxicidade , Ratos , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Resultado do Tratamento
6.
Clin Sci (Lond) ; 133(9): 1085-1096, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31040165

RESUMO

Nuclear receptor binding SET domain 2 (NSD2)-mediated metabolic reprogramming has been demonstrated to regulate oncogenesis via catalyzing the methylation of histones. The present study aimed to investigate the role of NSD2-mediated metabolic abnormality in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH rat model was established and infected with adeno-associated virus carrying short hairpin RNA (shRNA) targeting NSD2. Hemodynamic parameters, ventricular function, and pathology were evaluated by microcatheter, echocardiography, and histological analysis. Metabolomics changes in lung tissue were analyzed by LC-MS. The results showed that silencing of NSD2 effectively ameliorated MCT-induced PAH and right ventricle dysfunction, and partially reversed pathological remodeling of pulmonary artery and right ventricular hypertrophy. In addition, the silencing of NSD2 markedly reduced the di-methylation level of H3K36 (H3K36me2 level) and inhibited autophagy in pulmonary artery. Non-targeted LC-MS based metabolomics analysis indicated that trehalose showed the most significant change in lung tissue. NSD2-regulated trehalose mainly affected ABC transporters, mineral absorption, protein digestion and absorption, metabolic pathways, and aminoacyl-tRNA biosynthesis. In conclusion, we reveal a new role of NSD2 in the pathogenesis of PAH related to the regulation of trehalose metabolism and autophagy via increasing the H3K36me2 level. NSD2 is a promising target for PAH therapy.


Assuntos
Autofagia/fisiologia , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Histona-Lisina N-Metiltransferase/genética , Hipertrofia Ventricular Direita/metabolismo , Hipertensão Arterial Pulmonar/genética , Animais , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Hipertrofia Ventricular Direita/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Monocrotalina/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos
7.
BMC Pulm Med ; 19(1): 80, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30991994

RESUMO

BACKGROUND: Systemic artery to pulmonary artery fistulas (SA-PAFs), are extremely rare in people without congenital heart disease. In this group of patients pulmonary arterial hypertension was reported in the single case. Then, we describe a case of multiple SA-PAFs, which were the cause of severe nonreversible arterial pulmonary hypertension in a patient who had a right-sided pneumothorax 35 years earlier. CASE PRESENTATION: 52-year-old male Caucasian patient with echocardiographically confirmed pulmonary hypertension (PH) was admitted to cardiology department due to exertional dyspnea and signs of right ventricle failure. Routine screening for causes of secondary PH was negative. Right heart catheterization (RHC) confirmed a high degree arterial PH [mean pulmonary artery pressure (mPAP); 50,6 mmHg, pulmonary wedge pressure (PWP); 11,3 mmHg, pulmonary vascular resistance (PVR); 11,9 Wood's units (WU)] irreversible in the test with inhaled nitric oxide. Oxygen saturation (SaO2) of blood samples obtained during the first RHC ranged from 69.3 to 73.2%. Idiopathic pulmonary arterial hypertension was diagnosed. Treatment with inhaled iloprost and sildenafil was initiated. Control RHC, performed 5 months later showed values of mPAP (59,7 mmHg) and PVR (13,4 WU) higher in comparison to the initial measurement, SaO2 of blood obtained during RHC from upper lobe artery of the right lung was elevated and amounted 89.7%. Then, pulmonary arteriography was performed. Lack of contrast in the right upper lobe artery with the evidence of retrograde blood flow visible as a negative contrast in the right pulmonary artery was found. Afterwards, right subclavian artery arteriography detected a huge vascular malformation communicating with right upper lobe artery. Following computed tomography angiogram (angio-CT) additionally revealed the enlargement of bronchial arteries originated fistulas to pulmonary artery of right upper lobe. In spite of intensive pharmacological treatment, including the therapy of pulmonary hypertension and percutaneous embolisation of the fistulas, the patient's condition continued to deteriorate further. He died three months after embolisation due to severe heart failure complicated by pneumonia. CONCLUSION: Non-congenital SA-PAFs are extremely rare, however, they should be excluded in patients with pulmonary arterial hypertension and history of inflammatory or infectious disease of the lung and pleura, pneumothorax, cancer or Takayashu's disease and after chest trauma.


Assuntos
Fístula Artério-Arterial/complicações , Cateterismo Cardíaco , Hipertensão Pulmonar Primária Familiar/diagnóstico , Pneumotórax/complicações , Angiografia por Tomografia Computadorizada , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Evolução Fatal , Insuficiência Cardíaca/fisiopatologia , Humanos , Iloprosta/uso terapêutico , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/patologia , Pressão Propulsora Pulmonar , Citrato de Sildenafila/uso terapêutico , Resistência Vascular
8.
Pediatr Pulmonol ; 54(1): 66-72, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30485728

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) results from pulmonary vascular disease and may eventually lead to right heart failure and death. Vasodilator therapy has greatly improved PAH prognosis. Circulating microvesicles are considered as surrogate markers of endothelial and hematopoietic cell activation. AIM: Thus, our purpose was to determine if MVs are upregulated in pediatric PAH such as reported in adult patients, and to analyze the impact of vasodilator therapies on MV count and function. PATIENTS: Population study consisted of 26 patients of median age 6.09 years, with Congenital Heart Disease (CHD) and elevated pulmonary vascular resistance (CHD-PAH) or idiopathic PAH (iPAH). RESULTS: Compared to healthy controls, all circulating MV subpopulations were found higher in untreated PAH patients. No significant differences of annexin-V+ total MV, endothelial, or leukocyte derived-MV counts were found between untreated patients and those receiving oral vasodilator therapies. Conversely, platelet MVs were significantly lower in the group treated with SC-treprostinil compared with both untreated PAH and oral therapy groups (P = 0.01), and exhibited a significant decrease of phospholipid procoagulant activity. Control samples treated in vitro with treprostinil at therapeutic concentrations showed as expected a significant decrease of platelet aggregation but also a reduced spontaneous MV generation. CONCLUSION: Our results suggest that treprostinil, besides vasodilation, might exert its beneficial effect through an inhibition of platelet activation, resulting in a decreased number and procoagulant activity of circulating MVs.


Assuntos
Anti-Hipertensivos/administração & dosagem , Epoprostenol/análogos & derivados , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Hipertensão Pulmonar/tratamento farmacológico , Adolescente , Adulto , Micropartículas Derivadas de Células/efeitos dos fármacos , Criança , Pré-Escolar , Coagulantes/química , Epoprostenol/administração & dosagem , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/tratamento farmacológico , Humanos , Lactente , Pulmão/fisiopatologia , Masculino , Hipertensão Arterial Pulmonar/complicações , Hipertensão Arterial Pulmonar/tratamento farmacológico , Circulação Pulmonar/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Adulto Jovem
9.
PLoS One ; 13(11): e0205195, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30383775

RESUMO

Treprostinil is applied for pulmonary arterial hypertension (PAH) therapy. However, the mechanism by which the drug achieves its beneficial effects in PAH vessels is not fully understood. This study investigated the effects of treprostinil on PDGF-BB induced remodelling parameters in isolated human pulmonary arterial smooth muscle cells (PASMC) of four PAH patients. The production of TGF-ß1, CTGF, collagen type-I and -IV, and of fibronectin were determined by ELISA and PCR. The role of cAMP was determined by ELISA and di-deoxyadenosine treatment. Proliferation was determined by direct cell count. Treprostinil increased cAMP levels dose and time dependently, which was not affected by PDGF-BB. Treprostinil significantly reduced PDGF-BB induced secretion of TGF-ß1 and CTGF, both was counteracted when cAMP generation was blocked. Similarly, the PDGF-BB induced proliferation of PASMC was dose dependently reduced by treprostinil through signalling via cAMP-C/EBP-α p42 -p21(WAf1/Cip1). In regards to extracellular matrix remodelling, treprostinil significantly reduced PDGF-BB-TGF-ß1-CTGF induced synthesis and deposition of collagen type I and fibronectin, in a cAMP sensitive manner. In contrast, the deposition of collagen IV was not affected. The data suggest that this action of treprostinil in vessel wall remodelling may benefit patients with PAH and may reduce arterial wall remodelling.


Assuntos
Becaplermina/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Epoprostenol/análogos & derivados , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Fator de Crescimento Transformador beta1/genética , Adulto , Becaplermina/sangue , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo IV/genética , Fator de Crescimento do Tecido Conjuntivo/sangue , AMP Cíclico/biossíntese , Epoprostenol/administração & dosagem , Matriz Extracelular/efeitos dos fármacos , Hipertensão Pulmonar Primária Familiar/sangue , Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar Primária Familiar/patologia , Feminino , Fibronectinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/genética , Miócitos de Músculo Liso/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/sangue , Remodelação Vascular/efeitos dos fármacos
10.
Circ Genom Precis Med ; 11(10): e002087, 2018 10.
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.


Assuntos
Exoma , Hipertensão Pulmonar Primária Familiar/genética , Mutação de Sentido Incorreto , Receptores Sulfonilureia/genética , Adulto , Substituição de Aminoácidos , Criança , Análise Mutacional de DNA , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Feminino , Humanos , Masculino
11.
Lung ; 196(6): 745-753, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30182153

RESUMO

PURPOSE: To evaluate the influence of riociguat on World Health Organization functional class (WHO FC), 6-min walk distance (6MWD), right heart remodeling, and right ventricular-pulmonary arterial (RV-PA) coupling in patients with idiopathic pulmonary arterial hypertension (IPAH) who are treatment-naïve or who have failed to achieve treatment goals with sildenafil therapy. METHODS: Twenty patients with IPAH were enrolled: 12 had not previously received PAH-targeted therapy (treatment-naïve subgroup) and 8 had been receiving sildenafil therapy but failed to achieve treatment goals; on entering this pilot study these 8 patients were switched from sildenafil to riociguat therapy (treatment-switch subgroup). Patients received riociguat individually dose-adjusted up to a maximum of 2.5 mg three times daily. After 12 weeks, patients were assessed for WHO FC, 6MWD, right heart remodeling, and RV-PA coupling. RESULTS: Riociguat significantly improved WHO FC in treatment-naïve patients (from 0/4/8/0 patients in WHO I/II/III/IV at baseline to 1/6/5/0 at week 12) and in treatment-switch patients (from 0/4/4/0 patients in WHO I/II/III/IV at baseline to 1/4/3/0 at week 12). Additionally, treatment-naïve and treatment-switch patients showed significant improvements at week 12 versus baseline in 6MWD (increases of + 76.8 m and + 71.6 m, respectively), RV systolic function, and RV-PA coupling. CONCLUSION: These results support the proven efficacy of riociguat in patients with IPAH, including treatment-naïve patients and those switching to riociguat following failure to achieve treatment goals with sildenafil, and suggest that it may be possible to delay disease progression in this patient group.


Assuntos
Ativadores de Enzimas/uso terapêutico , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Átrios do Coração/fisiopatologia , Ventrículos do Coração/fisiopatologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Remodelamento Atrial , Substituição de Medicamentos , Ecocardiografia , Ativadores de Enzimas/efeitos adversos , Hipertensão Pulmonar Primária Familiar/diagnóstico por imagem , Feminino , Átrios do Coração/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Artéria Pulmonar/fisiopatologia , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Citrato de Sildenafila/uso terapêutico , Remodelação Ventricular , Teste de Caminhada
12.
Am J Emerg Med ; 36(11): 2130.e3-2130.e5, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30033134

RESUMO

Chest pain and shortness of breath are chief complaints frequently evaluated in the emergency department. ACS, pulmonary embolism, and disorders involving the lung parenchyma are some of the disease processes commonly screened for. Occasionally, patients presenting with histories and clinical exams consistent with these common illnesses may end up having more rare pathology. We present the case of a young patient who presented with chest pain and dyspnea with ECG changes and history concerning for pulmonary embolism who was ultimately diagnosed with idiopathic primary pulmonary hypertension. The importance of a prompt diagnosis of this condition along with emergency department management of complications related to the disease is discussed in this report.


Assuntos
Dispneia/etiologia , Hipertensão Pulmonar Primária Familiar/complicações , Hipertensão Pulmonar Primária Familiar/diagnóstico , Adulto , Dor no Peito/etiologia , Angiografia por Tomografia Computadorizada , Diagnóstico Diferencial , Eletrocardiografia , Serviço Hospitalar de Emergência , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Furosemida/uso terapêutico , Humanos , Masculino , Citrato de Sildenafila/uso terapêutico , Espironolactona/uso terapêutico
15.
J Control Release ; 280: 113-123, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29723610

RESUMO

Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ±â€¯6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH.


Assuntos
Reposicionamento de Medicamentos/métodos , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Rosiglitazona/farmacologia , Administração por Inalação , Animais , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Masculino , Modelos Animais , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Porosidade , Artéria Pulmonar/efeitos dos fármacos , Ratos Sprague-Dawley , Rosiglitazona/administração & dosagem , Rosiglitazona/efeitos adversos , Rosiglitazona/uso terapêutico , Resultado do Tratamento
16.
J Cardiothorac Vasc Anesth ; 32(6): 2547-2559, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29525197

RESUMO

OBJECTIVES: The mortality of pregnant women with idiopathic pulmonary arterial hypertension (PAH) is very high. There are limited data on the management of idiopathic PAH during pregnancy. The authors aimed to examine systematically the characteristics of parturient women with idiopathic PAH, to explore the adverse effects of idiopathic PAH on pregnancy outcomes, and to report the multidisciplinary perioperative management strategy from the largest comprehensive cardiac hospital in China. DESIGN: Observational case series study. SETTING: Tertiary referral acute care hospital in Beijing, China. PARTICIPANTS: The cases of 17 consecutive pregnant idiopathic PAH patients undergoing abortion or parturition at Anzhen Hospital were reviewed retrospectively. INTERVENTIONS: Preoperative characteristics, anesthesia method, intensive care management, PAH-specific therapy, and maternal and neonatal outcomes were analyzed in this case series study. MEASURES AND MAIN RESULTS: Maternal and neonatal outcomes were the main measures. The mean ages of the 17 parturient women with idiopathic PAH were 28.3 ± 5.4 years, and the mean systolic pulmonary arterial pressure was 97.9 ± 18.6 mmHg. Fifteen patients (88.2%) received PAH-specific therapy before delivery, including sildenafil, iloprost, and treprostinil. All except 1 parturient received epidural anesthesia for surgery due to an emergency Caesarean section. Three patients experienced pulmonary hypertension crisis that necessitated conversion to general anesthesia. Ten parturients underwent Caesarean delivery at a median gestational age of 31 weeks. Three patients developed acute pulmonary hypertensive crisis intraoperatively. Two patients underwent cardiopulmonary resuscitation and extracorporeal membrane oxygenation support. The maternal mortality was 17.6% (3/17). Of the 10 delivered neonates, 9 (90.0%) survived. CONCLUSIONS: The maternal mortality of the idiopathic PAH parturient was high in this case series from China. The authors applied epidural anesthesia, early management with multidisciplinary approaches, PAH-specific therapy, avoidance of oxytocin, and timely delivery or pregnancy termination to improve maternal and neonatal outcomes.


Assuntos
Anti-Hipertensivos/uso terapêutico , Gerenciamento Clínico , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Assistência Perioperatória/métodos , Complicações Cardiovasculares na Gravidez , Pressão Propulsora Pulmonar/fisiologia , Aborto Terapêutico/métodos , Adulto , Cesárea/métodos , China/epidemiologia , Hipertensão Pulmonar Primária Familiar/mortalidade , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Feminino , Humanos , Mortalidade Materna/tendências , Gravidez , Pressão Propulsora Pulmonar/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
17.
Medicine (Baltimore) ; 97(10): e0075, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29517668

RESUMO

BACKGROUND: Oral bosentan has been widely applied in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). A systemic review and meta-analysis was conducted for a therapeutic evaluation of oral bosentan in both adult and pediatric patients with PAH-CHD. The acute responses and a long-term effect were respectively assessed in a comparison with baseline characteristics, and the improvement of exercise tolerance was analyzed. METHODS: PubMed, Medline, Embase, and Cochrane Central Register of clinical controlled trails or observational studies have been searched for a recording of bosentan effects on the PAH-CHD participants. For mortality and rate of adverse events (AEs), it was described in detail. Randomized-effects model or fixed-effects model was used to calculate different effective values with a sensitivity analysis. RESULTS: Seventeen studies were pooled in this review, and 3 studies enrolled the pediatric patients. Among all studies, 456 patients were diagnosed with PAH-CHD, and 91.7% were treated with oral bosentan. With a term less than 6 months of bosentan therapy, there existed a significant improvement in 6-minute walk distance (6MWD) and the World Health Organization functional class (WHO-FC), but no such differences in Borg dyspnea index scores (BDIs) and the resting oxygen saturation (SpO2). Although with a prolonged treatment, not only 6MWD and FC, but also the resting SpO2 and heart rate were changed for a better exercise capability. Additionally, compared with the basic cardiopulmonary hemodynamics, it showed a statistically significant difference in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRi). Although a limitation of pooled studies with comparative outcomes of different terms, outcomes presented a lower WHO-FC which contributes to a success in a prolonged treatment. CONCLUSIONS: Bosentan in PAH-CHD is well established and still requires clinical trials for an identification of its efficiency on CHD patients for an optimized period lessening a serious complication and the common AEs.


Assuntos
Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Cardiopatias Congênitas/complicações , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Bosentana , Criança , Pré-Escolar , Hipertensão Pulmonar Primária Familiar/complicações , Humanos , Lactente , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
18.
Am J Physiol Lung Cell Mol Physiol ; 314(3): L349-L359, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29146573

RESUMO

Prostacyclin agonists that bind the prostacyclin receptor (IP) to stimulate cAMP synthesis are effective vasodilators for the treatment of idiopathic pulmonary arterial hypertension (IPAH), but this signaling may occur through nuclear peroxisome proliferator-activated receptor-γ (PPARγ). There is evidence of scant IP and PPARγ expression but stable prostanoid EP4 receptor (EP4) expression in IPAH patients. Both IP and EP4 functionally couple with stimulatory G protein (Gs), which activates signal transduction. We investigated the effect of an EP4-specific agonist on pulmonary arterial remodeling and its regulatory mechanisms in pulmonary arterial smooth muscle cells (PASMCs). Immunoblotting evealed IP, EP4, and PPARγ expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue. Isolated PASMCs from MCT-induced PAH rats (MCT-PASMCs) were treated with L-902,688, a selective EP4 agonist, to investigate the anti-vascular remodeling effect. Scant expression of IP and PPARγ but stable expression of EP4 was observed in IPAH patient lung tissues and MCT-PASMCs. L-902,688 inhibited IP-insufficient MCT-PASMC proliferation and migration by activating PPARγ in a time- and dose-dependent manner, but these effects were reversed by AH-23848 (an EP4 antagonist) and H-89 [a protein kinase A (PKA) inhibitor], highlighting the crucial role of PPARγ in the activity of this EP4 agonist. L-902,688 attenuated pulmonary arterial remodeling in hypoxic PAH mice and MCT-induced PAH rats; therefore, we conclude that the selective EP4 agonist L-902,688 reverses vascular remodeling by activating PPARγ. This study identified a novel EP4-PKA-PPARγ pathway, and we propose EP4 as a potential therapeutic target for PAH.


Assuntos
Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Músculo Liso Vascular/efeitos dos fármacos , PPAR gama/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Pirrolidinonas/farmacologia , Receptores de Prostaglandina E Subtipo EP4/agonistas , Tetrazóis/farmacologia , Adulto , Animais , Proliferação de Células , Células Cultivadas , Hipertensão Pulmonar Primária Familiar/metabolismo , Hipertensão Pulmonar Primária Familiar/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Adulto Jovem
19.
Heart Lung Circ ; 27(2): 183-189, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28400191

RESUMO

BACKGROUND: The clinical impact of pulmonary capillary wedge pressure (PCWP) on long-term mortality among patients with pulmonary arterial hypertension (PAH) has been incompletely reported, particularly in relation to concomitant treprostinil administration. The goal of this study was to assess the impact of PCWP on long-term mortality in PAH patients treated with parenteral treprostinil. METHODS: We studied a cohort of 743 patients with PAH treated with parenteral treprostinil therapy. The long-term all-cause mortality was compared in patients with baseline mean PCWP≤8mmHg, 811mmHg over 4-year follow-up. RESULTS: Of the 743 patients studied, 280 patients (37.7%) had a baseline mean PCWP ≤ 8mmHg, 233 patients (31.4%) had a mean PCWP of >8mmHg and ≤11mmHg, and 230 patients (31.0%) had a mean PCWP >11mmHg. While patients with higher PCWP had higher mean right atrial and PA pressures, no difference was noted in cardiac output and pulmonary vascular resistance (PVR). All-cause mortality was similar between patients with PCWP≤8mmHg, 811mmHg at 1 year (10.4% vs 9.9% vs 10.0%, p=0.980) and 4 years (16.8% vs 21.9% vs 19.2%, p=0.353) respectively. In multivariate analysis, PCWP was not independently predictive of 4-year all-cause mortality [HR 1.00, 95%CI 0.95-1.05, p=0.98 (permmHg)]. Predictors of 4-year mortality included older age [HR 1.02, 95%CI 1.00-1.03, p=0.0091 (per year)], non-​Caucasian race, and higher PVR [HR 1.06, 95% CI 1.04-1.08, p<0.0001 (per Woods Unit)]. CONCLUSIONS: In this study of patients with PAH receiving parenteral treprostinil, PCWP was not associated with long-term all-cause mortality. Further studies examining prognostic indicators in patients with PAH optimised on guideline-based therapies are warranted.


Assuntos
Epoprostenol/análogos & derivados , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Pressão Propulsora Pulmonar/fisiologia , Resistência Vascular/ética , Adulto , Anti-Hipertensivos/administração & dosagem , Causas de Morte/tendências , Relação Dose-Resposta a Droga , Método Duplo-Cego , Epoprostenol/administração & dosagem , Hipertensão Pulmonar Primária Familiar/mortalidade , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Prognóstico , Pressão Propulsora Pulmonar/efeitos dos fármacos , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados Unidos/epidemiologia , Resistência Vascular/efeitos dos fármacos
20.
J Heart Lung Transplant ; 37(3): 365-375, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28912026

RESUMO

BACKGROUND: In idiopathic pulmonary arterial hypertension (IPAH) treatment goals include improving right ventricular (RV) function, hemodynamics and symptoms to move patients to a low-risk category for adverse clinical outcomes. No data are available on the effect of upfront combination therapy on RV improvement as compared with monotherapy. The aim of this study was to evaluate echocardiographic RV morphology and function in patients affected by IPAH and treated with different strategies. METHODS: Sixty-nine consecutive, treatment-naive IPAH patients treated with first-line upfront combination therapy at 10 centers were retrospectively evaluated and compared with 2 matched cohorts treated with monotherapy after short-term follow-up. Evaluation included clinical, hemodynamic and echocardiographic parameters. RESULTS: At 155 ± 65 days after baseline evaluation, patients in the oral+prostanoid group (Group 1) had the most clinical and hemodynamic improvement compared with the double oral group (Group 2), the oral monotherapy group (Group 3) and the prostanoid monotherapy group (Group 4). The more extensive reduction of pulmonary vascular resistance in Groups 1, 2 and 4 was associated with significant improvement in all RV echocardiographic parameters compared with Group 3. Considering the number of patients who reached the target goals suggested by established guidelines, 8 of 27 (29.6%) and 7 of 42 (16.7%) patients in Groups 1 and 2, respectively, achieved low-risk status, as compared with 2 of 69 (2.8%) and 6 of 27 (22.2%) in Groups 3 and 4, respectively. CONCLUSIONS: In advanced treatment-naive IPAH patients, an upfront combination therapy strategy seems to significantly improve hemodynamics and RV morphology and function compared with oral monotherapy. The most significant results seem to be achieved with prostanoids plus oral drug, whereas the use of the double oral combination and prostanoids as monotherapy seem to produce similar results.


Assuntos
Ecocardiografia , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Quimioterapia Combinada , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Feminino , Ventrículos do Coração/patologia , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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