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1.
Life Sci ; 238: 116974, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639399

RESUMO

AIM: Analyze the effects of voluntary running during the development of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) on the right ventricle (RV) structure, RV myocyte contractility and intracellular Ca2+ transient in rats with MCT-induced PAH. MAIN METHODS: Male Wistar rats were housed sedentary or with free access to a running wheel after MCT or saline injection for until HF or median end-point day of HF in sedentary animals (24 days). Echocardiographic examination and exercise tolerance test were carried out at specific time points of the experimental period. After euthanasia, the heart was dissected, weighed and processed for either histological or single myocyte contractility and intracellular Ca2+ transient analyzes. KEY FINDINGS: Voluntary running delayed the onset of HF (29 days) and the increase in pulmonary artery resistance, and improved exercise tolerance. In the median end-point day of HF, exercise retarded RV adverse remodeling (i.e. increase in extracellular matrix and collagen content). At this stage, exercise also delayed impairments in cell contractile function (i.e. amplitude and times to peak and to half relaxation) and intracellular calcium cycling (i.e. amplitude and times to peak and to half decay) in RV single myocytes. SIGNIFICANCE: Along with HF onset delay and physical effort tolerance enhancement, voluntary running during the development of PAH postpones pulmonary artery resistance increases, RV adverse remodeling and myocyte contractility and intracellular calcium cycling deterioration in rats. Therefore, self-paced intermittent exercise of high intensity may contribute positively to the health and survival of individuals with PAH.


Assuntos
Insuficiência Cardíaca/prevenção & controle , Hipertensão Pulmonar/complicações , Hipertrofia Ventricular Direita/prevenção & controle , Contração Muscular , Miócitos Cardíacos/patologia , Condicionamento Físico Animal , Artéria Pulmonar/patologia , Remodelação Ventricular , Animais , Cálcio , Modelos Animais de Doenças , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Masculino , Ratos , Ratos Wistar , Corrida
2.
Int J Mol Sci ; 20(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909527

RESUMO

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial proliferation and remodeling, resulting in a specific increase in right ventricle systolic pressure (RVSP) and, ultimately right ventricular failure. Recent studies have demonstrated that caffeic acid phenethyl ester (CAPE) exerts a protective role in NF-κB-mediated inflammatory diseases. However, the effect of CAPE on PAH remains to be elucidated. In this study, monocrotaline (MCT) was used to establish PAH in rats. Two weeks after the induction of PAH by MCT, CAPE was administrated by intraperitoneal injection once a day for two weeks. Pulmonary hemodynamic measurements and pulmonary artery morphological assessments were examined. Our results showed that administration of CAPE significantly suppressed MCT-induced vascular remodeling by decreasing the HIF-1α expression and PDGF-BB production, and improved in vivo RV systolic performance in rats. Furthermore, CAPE inhibits hypoxia- and PDGF-BB-induced HIF-1α expression by decreasing the activation of the AKT/ERK pathway, which results in the inhibition of human pulmonary artery smooth muscle cells (hPASMCs) proliferation and prevention of cells resistant to apoptosis. Overall, our data suggest that HIF-1α is regarded as an alternative target for CAPE in addition to NF-κB, and may represent a promising therapeutic agent for the treatment of PAH diseases.


Assuntos
Ácidos Cafeicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Álcool Feniletílico/análogos & derivados , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Expressão Gênica , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Imuno-Histoquímica , Álcool Feniletílico/farmacologia , Fator de Crescimento Derivado de Plaquetas/genética , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos
3.
Redox Biol ; 22: 101161, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30861460

RESUMO

Heart failure (HF) is the single largest cause for increased hospitalization after fine particulate matter (PM2.5) exposure. Patients with left HF often progress to right ventricular (RV) failure even with optimal medical care. An increase of PM2.5 of 10 µg per cubic meter was associated with a 76% increase in the risk of death from cardiovascular disease in 4 years' period. However, the role and mechanism of PM2.5 in HF progression are not known. Here we investigated the role of PM2.5 exposure in mice with existing HF mice produced by transverse aortic constriction (TAC). TAC-induced HF caused lung inflammation, vascular remodeling and RV hypertrophy. We found increased PM2.5 profoundly exacerbated lung oxidative stress in mice with existing left HF. To our surprise, PM2.5 exposure had no effect on LV hypertrophy and function, but profoundly exacerbated lung inflammation, vascular remodeling, and RV hypertrophy in mice with existing left HF. These striking findings demonstrate that PM2.5 and/or air pollution is a critical factor for overall HF progression by regulating lung oxidative stress, inflammation and remodeling as well as RV hypertrophy. Improving air quality may save HF patients from a dismal fate.


Assuntos
Exposição Ambiental , Insuficiência Cardíaca/etiologia , Hipertrofia Ventricular Direita/etiologia , Material Particulado , Pneumonia/etiologia , Remodelação Vascular , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fibrose , Insuficiência Cardíaca/patologia , Testes de Função Cardíaca , Humanos , Hipertrofia Ventricular Direita/patologia , Masculino , Camundongos , Estresse Oxidativo , Pneumonia/patologia , Testes de Função Respiratória , Fatores de Tempo , Molécula 1 de Adesão de Célula Vascular/metabolismo
4.
Int Heart J ; 60(2): 451-456, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30799373

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) develops as a consequence of unresolved pulmonary embolism or clots in the pulmonary arteries. The obstruction not only reduces the area of the pulmonary vascular bed, but also elicits high pressure and high shear stress in the spared unobstructed arteries. Subsequent overflow of the small pulmonary arteries induces vascular remodeling, termed as overflow vasculopathy (OV). While the development of OV significantly contributes to the occurrence of pulmonary hypertension, its precise molecular mechanisms are yet to be determined.We established a novel murine pulmonary artery OV (PAOV) model, in which we resected left lung and induced redistribution of the cardiac output to the remaining pulmonary artery of the right lung. At 21 days after operation, mice showed an increase in the vascular media area, indicating the development of pulmonary arterial remodeling. In addition, right ventricular hypertrophy was detected in the PAOV model. Intriguingly, marked accumulation of F4/80-positive monocytes/macrophages was visualized in high-flow arteries, implying the role of an inflammatory process in the pathogenesis of overflow-induced vascular remodeling.


Assuntos
Hipertensão Pulmonar , Pulmão , Macrófagos/imunologia , Monócitos/imunologia , Remodelação Vascular/imunologia , Animais , Movimento Celular/imunologia , Modelos Animais de Doenças , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar/fisiologia , Embolia Pulmonar/complicações
5.
Circulation ; 139(2): 269-285, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30615500

RESUMO

The role of right ventricular (RV) fibrosis in pulmonary hypertension (PH) remains a subject of ongoing discussion. Alterations of the collagen network of the extracellular matrix may help prevent ventricular dilatation in the pressure-overloaded RV. At the same time, fibrosis impairs cardiac function, and a growing body of experimental data suggests that fibrosis plays a crucial role in the development of RV failure. In idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, the RV is exposed to a ≈5 times increased afterload, which makes these conditions excellent models for studying the impact of pressure overload on RV structure. With this review, we present clinical evidence of RV fibrosis in idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, explore the correlation between fibrosis and RV function, and discuss the clinical relevance of RV fibrosis in patients with PH. We postulate that RV fibrosis has a dual role in patients with pressure-overloaded RVs of idiopathic pulmonary arterial hypertension and chronic thromboembolic PH: as part of an adaptive response to prevent cardiomyocyte overstretch and to maintain RV shape for optimal function, and as part of a maladaptive response that increases diastolic stiffness, perturbs cardiomyocyte excitation-contraction coupling, and disrupts the coordination of myocardial contraction. Finally, we discuss potential novel therapeutic strategies and describe more sensitive techniques to quantify RV fibrosis, which may be used to clarify the causal relation between RV fibrosis and RV function in future research.


Assuntos
Insuficiência Cardíaca/etiologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/complicações , Hipertrofia Ventricular Direita/etiologia , Artéria Pulmonar/fisiopatologia , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita , Remodelação Ventricular , Adaptação Fisiológica , Animais , Pressão Arterial , Matriz Extracelular/patologia , Fibrose , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Ventrículos do Coração/patologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/terapia , Miocárdio/patologia , Prognóstico , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/terapia
6.
Acta Cardiol ; 74(3): 238-244, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30348056

RESUMO

Aim: Particulate matter 2.5 (PM2.5) exposure is high risk to cardiovascular diseases. We investigated the influence of PM2.5 exposure on pulmonary arterial hypertension (PAH) murine model induced by left ventricular (LV) failure. Methods: Thirty 10 weeks old C57BL/6 mice were randomised to four groups: sham group, sham + PM2.5 group, TAC group, and TAC + PM2.5 group. Eight weeks post TAC surgery, right ventricular (RV) and lung remodelling (Sirius Red staining and WGA Staining), heart and lung function (EF and RVSBP), and fibrotic genes (TGF-ti mRNA expression and collagen III protein level in lung tissue were measured. Results: Exposure to PM2.5 augments TAC induced PAH as evidenced by decreased EF value and increased RVSBP, RV cardiomyocytes size, RV and lung fibrosis, and upregulated expression of collagen III and TGF-a in comparison to TAC group in lung tissues. Even the LV EF value was deceased from 79.3 ± 3.4% to 63.4 ± 2.1% when sham group exposed to PM2.5, PM2.5 exposure had no effect on RVSBP, RV cardiomyocytes' size, RV weight/tibia length, RV and lung fibrosis, and expression of collagen III and TGF-a in sham surgery mice. Conclusions: Exposure to PM2.5 aggravates deterioration of LV failure induced PAH.


Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Pressão Arterial , Insuficiência Cardíaca/complicações , Material Particulado/toxicidade , Artéria Pulmonar/fisiopatologia , Disfunção Ventricular Esquerda/complicações , Função Ventricular Esquerda , Animais , Colágeno Tipo III/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Exposição por Inalação , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
7.
Int J Cardiovasc Imaging ; 35(1): 143-151, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30094564

RESUMO

Cardiac tachyarrhythmias are the leading cause of morbidity and mortality in patients with repaired tetralogy of Fallot (TOF). We evaluated risk factors for sustained ventricular tachyarrhythmia (VT) and atrial tachyarrhythmia (ATA) in these patients. Patients (n = 319) who underwent cardiac magnetic resonance (CMR) imaging at two tertiary centers between 2007 and 2016 were assessed. Potential risk markers, based on history, cardiac magnetic resonance imaging (CMR), electrocardiography (ECG) and echocardiography, were analyzed for prediction of the primary endpoint of VT, and the secondary endpoint of ATA. During a follow-up of 3.5 (0.9-6.1) years, 20 (6.3%) patients reached the primary endpoint, and 30 (9.4%) the secondary endpoint. Multivariable cox hazards regression identified right ventricular (RV) end-diastolic volume (Hazard ratio [HR] 2.03, per 10 ml/m2 increase; p = 0.02), RV end-systolic volume (HR 3.04, per 10 ml/m2 increase; p = 0.04), RV mass (HR 1.88, per 10 g/m2 increase; p = 0.02), and RV ejection fraction (HR 6.06, per 10% decrease; p = 0.02) derived from CMR to be independent risk factors of VT. In addition, QRS-duration (HR 1.70, per 10 ms increase; p = 0.001) and body mass index (BMI: HR 1.8, per 5 kg/m2 increase; p = 0.02) were independent markers of VT. Older age at TOF repair (HR 1.33, per 2 months increase; p = 0.03) and BMI (HR 1.76, per 5 kg/m2 increase; p < 0.001) independently predicted ATA. RV systolic dysfunction, hypertrophy and dilatation on CMR, together with QRS prolongation, and obesity are predictive of VT in TOF patients. Older age at TOF repair and obesity were associated with the occurrence of ATA.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Imagem Cinética por Ressonância Magnética , Taquicardia Supraventricular/diagnóstico por imagem , Taquicardia Ventricular/diagnóstico por imagem , Tetralogia de Fallot/cirurgia , Adolescente , Adulto , Fatores Etários , Índice de Massa Corporal , Feminino , Frequência Cardíaca , Humanos , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Países Baixos , Obesidade/complicações , Obesidade/fisiopatologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taquicardia Supraventricular/etiologia , Taquicardia Supraventricular/fisiopatologia , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologia , Tetralogia de Fallot/complicações , Tetralogia de Fallot/diagnóstico por imagem , Tetralogia de Fallot/fisiopatologia , Resultado do Tratamento , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita , Adulto Jovem
8.
Medicine (Baltimore) ; 97(48): e13307, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30508919

RESUMO

The prognosis of right heart enlargement varies according to different etiologies. The purpose of this study was to investigate the characteristics of echocardiogram, surgical treatment, chromosome and prognosis for fetal right heart enlargement.The foetal echocardiogram was performed on 3987 pregnant women, and then 88 fetuses with right heart enlargement were identified. The data about prenatal and postnatal echocardiograms, postnatal cardiac surgical treatment, karyotype analysis and autopsy after induced labor were analyzed in the 88 fetuses.Except the 1111 cases that had loss of follow-up, 2876 cases had complete data. Among the 2876 cases, right heart enlargement was identified in 88 fetuses. Of the 88 fetuses, 15 had total atrioventricular septal defect (unbalanced type: right ventricular dominance), 15 Ebstein's anomaly, 18 fallot tetrad, 14 double outlet right ventricle, 13 total anomalous pulmonary venous drainage, and 13 premature closure of ductus arteriosus. Chromosomal abnormality was found in 12 cases.There are many etiological factors causing right heart enlargement. The prognosis is better in the fetuses with single heart malformation than in the fetuses who have extracardiac malformation or/and chromosomal abnormality besides heart malformation. Fetal echocardiography combined with karyotype analysis can provide important bases for evaluating the prognosis of fetuses with right heart enlargement.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Ecocardiografia , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/genética , Ultrassonografia Pré-Natal , Adolescente , Adulto , Aberrações Cromossômicas , Feminino , Seguimentos , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/cirurgia , Humanos , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/cirurgia , Cariótipo , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
9.
PLoS One ; 13(11): e0206856, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30475826

RESUMO

Electrocardiogram (ECG) has been widely used for assessment of right ventricular (RV) hypertrophy (RVH) in patients with pulmonary hypertension (PH). However, it still remains unclear which ECG criteria of RVH are useful to predict for the severity of PH. The aim of our study was to examine the utility of ECG findings of RVH in assessment of PH. A total of 53 patients (42 women, mean age; 57.6 ± 16.4 years) with pre-capillary PH, who were diagnosed by right heart catheterization, underwent blood sampling, ECG, and cardiac magnetic resonance within a week before the right heart catheterization. We assessed the traditional ECG criteria of RVH in PH patients, and compared to age- and gender-matched control subjects without PH confirmed by 2-dimensional echocardiography (n = 42, mean age 55.3 ± 15.9 years). We also analyzed the clinical variables associated with ECG findings in patients with PH. Mean pulmonary arterial pressure (mPAP), cardiac index, and pulmonary vascular resistance (PVR) in PH patients were 35.3 ± 11.9 mmHg, 2.82 (2.09-3.45) L/min/m2, and 576 ± 376 dyne·sec·cm-5, respectively. The prevalence of right axis deviation (43.4%), R:S ratio V1 > 1 (32.1%), and RV1+SV5/6 > 10.5 mm (69.8%) in PH patients was greater than those in control subjects (p < 0.001). In univariate analysis, mPAP, PVR, RV wall thickness, RV mass index, RV volume, and RV ejection fraction (EF) (inversely) were significantly correlated with the amplitude of RV1+SV5/6. Multiple regression analysis revealed that mPAP and RVEF (inversely) were independently associated with the amplitude of RV1+SV5/6 (R2 = 0.282). Also, we performed the survival analysis among pre-capillary PH patients. During a mean follow-up of 3.7 years, patients with ≥ 16.4 mm of RV1+SV5/6 had worse prognosis than those with < 16.4 mm (Log rank p = 0.015). In conclusion, the amplitude of SV1+RV5/6 could be the most useful factor reflected for RV remodeling, hemodynamics and survival in patients with pre-capillary PH.


Assuntos
Ecocardiografia/métodos , Eletrocardiografia/métodos , Hipertensão Pulmonar/complicações , Hipertrofia Ventricular Direita/diagnóstico , Adulto , Idoso , Cateterismo Cardíaco , Estudos de Casos e Controles , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/mortalidade , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Índice de Gravidade de Doença , Análise de Sobrevida , Resistência Vascular/fisiologia , Função Ventricular Direita/fisiologia , Remodelação Ventricular/fisiologia
10.
J Card Fail ; 24(9): 583-593, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30195828

RESUMO

BACKGROUND: Involvement of right-sided heart chambers (RSHCs) in patients infected with human immunodeficiency virus (HIV) is common and is usually attributed to pulmonary arterial or venous hypertension (PH). However, myocardial involvement in patients with HIV is also common and might affect RSHCs even in the absence of overt PH. Our aim was to define morphologic and functional alterations in RSHC in patients with HIV and without PH. METHODS AND RESULTS: A total of 50 asymptomatic patients with HIV and 25 control subjects without clinical or echocardiographic signs for PH were included in the study. Transthoracic echocardiography was used to obtain measurements. Patients with HIV had significantly increased right ventricular end-diastolic diameter (RVEDD) and right ventricular free wall thickness (RVFWT), as well as increased right atrial area and pulmonary arterial diameter, compared with control subjects. After adjustment for age, sex, and body surface area, RVFWT (average 1.81 mm, 95% confidence interval [CI] 0.35-3.26 mm) and RVEDD (average 6.82 mm, 95% CI 2.40-11.24 mm) were significantly higher in subjects infected with HIV. More patients with right ventricular hypertrophy were on antiretroviral treatment, and RVFWT was on average 1.3 mm higher (95% CI 0.24-2.37 mm) in patients on antiretroviral treatment after adjustment for confounders. CONCLUSIONS: These findings suggest that alterations in RSHCs were present in patients with HIV without PH.


Assuntos
Cardiomiopatia Dilatada/etiologia , Ecocardiografia/métodos , Infecções por HIV/complicações , HIV , Hipertensão Pulmonar/diagnóstico , Hipertrofia Ventricular Direita/etiologia , Remodelação Ventricular/fisiologia , Adulto , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/fisiopatologia , Estudos Transversais , Feminino , Seguimentos , Humanos , Hipertrofia Ventricular Direita/diagnóstico , Hipertrofia Ventricular Direita/fisiopatologia , Masculino
11.
Am J Physiol Lung Cell Mol Physiol ; 315(5): L742-L751, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30091380

RESUMO

Deficient nitric oxide (NO) signaling plays a critical role in the pathogenesis of chronic neonatal pulmonary hypertension (PHT). Physiological NO signaling is regulated by S-nitrosothiols (SNOs), which act both as a reservoir for NO and as a reversible modulator of protein function. We have previously reported that therapy with inhaled NO (iNO) increased peroxynitrite-mediated nitration in the juvenile rat lung, although having minimal reversing effects on vascular remodeling. We hypothesized that sodium nitrite (NaNO2) would be superior to iNO in enhancing lung SNOs, thereby contributing to reversal of chronic hypoxic PHT. Rat pups were exposed to air or hypoxia (13% O2) from postnatal days 1 to 21. Dose-response prevention studies were conducted from days 1-21 to determine the optimal dose of NaNO2. Animals then received rescue therapy with daily subcutaneous NaNO2 (20 mg/kg), vehicle, or were continuously exposed to iNO (20 ppm) from days 14-21. Chronic PHT secondary to hypoxia was both prevented and reversed by treatment with NaNO2. Rescue NaNO2 increased lung NO and SNO contents to a greater extent than iNO, without causing nitration. Seven lung SNO proteins upregulated by treatment with NaNO2 were identified by multiplex tandem mass tag spectrometry, one of which was leukotriene A4 hydrolase (LTA4H). Rescue therapy with a LTA4H inhibitor, SC57461A (10 mg·kg-1·day-1 sc), partially reversed chronic hypoxic PHT. We conclude that NaNO2 was superior to iNO in increasing tissue NO and SNO generation and reversing chronic PHT, in part via upregulated SNO-LTA4H.


Assuntos
Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/prevenção & controle , Hipóxia/complicações , Indicadores e Reagentes/administração & dosagem , Nitrito de Sódio/administração & dosagem , Remodelação Vascular/efeitos dos fármacos , Administração por Inalação , Animais , Animais Recém-Nascidos , Doença Crônica , Feminino , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Masculino , Óxido Nítrico/metabolismo , Ácido Peroxinitroso/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
12.
Int J Mol Sci ; 19(8)2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30061518

RESUMO

Pulmonary hypertension is a co-morbidity, which strongly participates in morbi-mortality in patients with chronic obstructive pulmonary disease (COPD). Recent findings showed that bromodomain-containing proteins, in charge of reading histone acetylation, could be involved in pulmonary arterial hypertension. Our aim was to study the effect of I-BET151, an inhibitor of bromodomain and extra-terminal domain (BET), on the right ventricle hypertrophy and pulmonary hypertension, induced by a combination of chronic hypoxia and pulmonary inflammation, as the two main stimuli encountered in COPD. Adult Wistar male rats, exposed to chronic hypoxia plus pulmonary inflammation (CHPI), showed a significant right ventricle hypertrophy (+57%, p < 0.001), an increase in systolic pressure (+46%, p < 0.001) and in contraction speed (+36%, p < 0.001), when compared to control animals. I-BET151 treated animals (CHPI-iB) showed restored hemodynamic parameters to levels similar to control animals, despite chronic hypoxia plus exposure to pulmonary inflammation. They displayed lower right ventricle hypertrophy and hematocrit compared to the CHPI group (respectively -16%, p < 0.001; and -9%, p < 0.05). Our descriptive study shows a valuable effect of the inhibition of bromodomain and extra-terminal domain proteins on hemodynamic parameters, despite the presence of chronic hypoxia and pulmonary inflammation. This suggests that such inhibition could be of potential interest for COPD patients with pulmonary hypertension. Further studies are needed to unravel the underlying mechanisms involved and the net benefits of inhibiting adaptations to chronic hypoxia.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/etiologia , Hipóxia/complicações , Pneumonia/complicações , Fatores de Transcrição/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipóxia/patologia , Hipóxia/fisiopatologia , Masculino , Pneumonia/patologia , Pneumonia/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ratos Wistar
13.
Toxicol Lett ; 295: 296-306, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29990562

RESUMO

Although iron excess is toxic to the vasculature and even that pulmonary hypertension has been reported in this scenario, the role of iron overload per se remains to be clarified. This study aimed to test the effects of chronic iron-overload in rats on the morphophysiology of resistance pulmonary arteries (RPA) and right ventricle (RV) remodeling. Rats were injected with saline or iron-dextran (10, 100 and 200 mg/kg/day i.p.) for 28 days. Our results indicated increased circulating iron with significant lung deposits. Moreover, rats treated with the highest dose exhibited RV dysfunction and hypertrophy; inward remodeling and increased vasoconstriction of the RPA. Vascular hyperreactivity was accompanied by reduced nitric oxide (NO), and was reversed by incubation with Dimethylsulfoxide, Catalase and Tempol. The NADPH oxidase subunit gp91phox was increased due to iron-overload, and incubation with angiotensin II type-1 receptor (AT1) antagonist losartan not only reduced oxidative stress but also restored vascular function. Thus, we concluded that AT1 pathway plays a role in pulmonary vascular dysfunction by increasing oxidative stress and reducing NO bioavailability, thereby contributing to vascular remodeling and pulmonary hypertension of iron-overload. This finding should instigate future studies on the beneficial impacts of in vivo blockade of AT1 receptor under iron overload.


Assuntos
Hemodinâmica , Hipertensão Pulmonar/etiologia , Hipertrofia Ventricular Direita/etiologia , Sobrecarga de Ferro/complicações , Artéria Pulmonar/fisiopatologia , Remodelação Vascular , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita , Remodelação Ventricular , Animais , Doença Crônica , Modelos Animais de Doenças , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Sobrecarga de Ferro/induzido quimicamente , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/fisiopatologia , Complexo Ferro-Dextran , Masculino , NADPH Oxidase 2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo , Artéria Pulmonar/metabolismo , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resistência Vascular , Vasoconstrição , Vasodilatação , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologia
14.
Rev Chil Pediatr ; 89(3): 361-367, 2018 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-29999142

RESUMO

INTRODUCTION: Tetralogy of Fallot (TOF) is the most frequent cyanotic congenital heart disease. Pulmonary regurgitation (PR) and right ventricle (RV) enlargement and dysfunction are the most common long-term complications. Cardiac magnetic resonance (CMR) is the gold standard for RV evaluation. OBJECTIVE: To analyze CMR results in the follow-up of TOF patients. PATIENTS AND METHOD: All CMR performed between 2007 and 2012 in TOF patients with transannular patch (TAP) repair or infundibular widening, and without pulmonary valve replacement (PVR) were included. Pulmonary regurgitant fraction (PRF), ventricular end-diastolic (EDV) and end-systolic volume (ESV), and ejection fraction (EF) were examined. RESULTS: 122 CMR were performed in 114 patients. Average age at CMR was 15.4±7.4 years. 53.3% of them presented severe PR (> 40%). RVEDV was 157.3 ± 38.6 ml/m2, RVESV was 85.3 ± 27 ml/m2 and RVEF was 46.4 ± 7.1%. RVEDV was > 150 ml/ m2 in 48.4% and > 170 ml/m2 in 32.8% of patients. Patients with TAP showed larger RV volumes compared with those with infundibular widening. RVEDV > 170 ml/m2 showed worse RVEF that those with lower RVEDV (47.9 ± 7% vs 43.2 ± 6.4%, p < 0.01). CONCLUSION: Almost half of the pa tients showed significant RV enlargement, demonstrating that the indication of CMR is late in their follow-up. TAP was associated with higher RVEDV and RVESV, but no worse RVEF.


Assuntos
Hipertrofia Ventricular Direita/diagnóstico por imagem , Imagem por Ressonância Magnética , Complicações Pós-Operatórias/diagnóstico por imagem , Tetralogia de Fallot/cirurgia , Disfunção Ventricular Direita/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hipertrofia Ventricular Direita/etiologia , Lactente , Masculino , Estudos Retrospectivos , Tetralogia de Fallot/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia
15.
Circulation ; 138(19): 2106-2115, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30030416

RESUMO

BACKGROUND: Risk factors for adverse clinical outcomes have been identified in patients with repaired tetralogy of Fallot before pulmonary valve replacement (PVR). However, pre-PVR predictors for post-PVR sustained ventricular tachycardia and death have not been identified. METHODS: Patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort (International Multicenter TOF Registry), a 4-center international cohort study, who had a comprehensive preoperative evaluation and subsequently underwent PVR were included. Preprocedural clinical, ECG, cardiovascular magnetic resonance, and postoperative outcome data were analyzed. Cox proportional hazards multivariable regression analysis was used to evaluate factors associated with time from pre-PVR cardiovascular magnetic resonance until the primary outcome: death, aborted sudden cardiac death, or sustained ventricular tachycardia. RESULTS: Of the 452 eligible patients (median age at PVR, 25.8 years), 36 (8%) reached the primary outcome (27 deaths, 2 resuscitated death, and 7 sustained ventricular tachycardia) at a median time after PVR of 6.5 years. Cox proportional hazards regression identified pre-PVR right ventricular ejection fraction <40% (hazard ratio, 2.39; 95% CI, 1.18-4.85; P=0.02), right ventricular mass-to-volume ratio ≥0.45 g/mL (hazard ratio, 4.08; 95% CI, 1.57-10.6; P=0.004), and age at PVR ≥28 years (hazard ratio, 3.10; 95% CI, 1.42-6.78; P=0.005) as outcome predictors. In a subgroup analysis of 230 patients with Doppler data, predicted right ventricular systolic pressure ≥40 mm Hg was associated with the primary outcome (hazard ratio, 3.42; 95% CI, 1.09-10.7; P=0.04). Preoperative predictors of a composite secondary outcome, postoperative arrhythmias and heart failure, included older age at PVR, pre-PVR atrial tachyarrhythmias, and a higher left ventricular end-systolic volume index. CONCLUSIONS: In this observational investigation of patients with repaired tetralogy of Fallot, an older age at PVR and pre-PVR right ventricular hypertrophy and dysfunction were predictive of a shorter time to postoperative death and sustained ventricular tachycardia. These findings may inform the timing of PVR if confirmed by prospective clinical trials.


Assuntos
Procedimentos Cirúrgicos Cardíacos/mortalidade , Implante de Prótese de Valva Cardíaca/mortalidade , Estenose da Valva Pulmonar/cirurgia , Valva Pulmonar/cirurgia , Taquicardia Ventricular/mortalidade , Tetralogia de Fallot/cirurgia , Adolescente , Adulto , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ecocardiografia Doppler , Eletrocardiografia , Feminino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Hemodinâmica , Humanos , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/mortalidade , Hipertrofia Ventricular Direita/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valva Pulmonar/diagnóstico por imagem , Valva Pulmonar/fisiopatologia , Estenose da Valva Pulmonar/etiologia , Estenose da Valva Pulmonar/mortalidade , Estenose da Valva Pulmonar/fisiopatologia , Sistema de Registros , Medição de Risco , Fatores de Risco , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologia , Tetralogia de Fallot/mortalidade , Tetralogia de Fallot/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/mortalidade , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita , Adulto Jovem
16.
Methods Mol Biol ; 1816: 233-241, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29987824

RESUMO

Pulmonary arterial hypertension (PAH) is a syndrome characterized by pulmonary vascular remodeling and vasoconstriction, leading to increased pulmonary vascular resistance, right ventricular pressure overload and, eventually, to right ventricular failure and premature death. Animal models have been an essential tool for understanding pulmonary hypertension pathophysiology and for the discovery and development of novel therapies.MCT-induced PAH in rats leads to a significant increase in RV pressure and pulmonary vascular remodeling, as well as greater RV hypertrophy. In this chapter, we describe protocols for inducing and assessing the monocrotaline (MCT) rat model, the most classical and widely used in vivo model of PAH. Using this protocol, rats reproducibly develop pulmonary hypertension with a mean pulmonary pressure of ~40 mmHg approximately 4 weeks after single MCT administration.


Assuntos
Modelos Animais de Doenças , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/fisiopatologia , Monocrotalina , Artéria Pulmonar/fisiopatologia , Ratos , Animais , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/patologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Artéria Pulmonar/patologia , Ratos/fisiologia , Ratos Sprague-Dawley , Remodelação Vascular , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia
17.
Molecules ; 23(6)2018 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-29861433

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. Several studies have demonstrated that betaine possesses outstanding anti-inflammatory effects. However, whether betaine exerts protective effects on PAH by inhibiting inflammatory responses in the lungs needs to be explored. To test our hypothesis, we aimed to investigate the effects of betaine on monocrotaline-induced PAH in rats and attempted to further clarify the possible mechanisms. METHODS: PAH was induced by monocrotaline (50 mg/kg) and oral administration of betaine (100, 200, and 400 mg/kg/day). The mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricle hypertrophy index were used to evaluate the development of PAH. Hematoxylin and eosin staining and Masson staining were performed to measure the extents of vascular remodeling and proliferation in fibrous tissue. Monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were also detected by immunohistochemical staining. Nuclear factor-κB (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1ß (IL-1ß) were assessed by Western blot. RESULTS: This study showed that betaine improved the abnormalities in right ventricular systolic pressure, mean pulmonary arterial pressure, right ventricle hypertrophy index, and pulmonary arterial remodeling induced by monocrotaline compared with the PAH group. The levels of MCP-1 and ET-1 also decreased. Western blot indicated that the protein expression levels of NF-κB, TNF-α, and IL-1ß significantly decreased (p < 0.01). CONCLUSION: Our study demonstrated that betaine attenuated PAH through its anti-inflammatory effects. Hence, the present data may offer novel targets and promising pharmacological perspectives for treating monocrotaline-induced PAH.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Betaína/farmacologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Monocrotalina/efeitos adversos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Animais , Biomarcadores , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Endotelina-1/metabolismo , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Ratos
18.
Int J Cardiovasc Imaging ; 34(10): 1595-1605, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29850969

RESUMO

Pulmonary embolism onset is frequently neglected due to the non-specific character of its symptoms. Pocket-size imaging devices (PSID) present an opportunity to implement imaging diagnostics into conventional physical examination. The aim of this study was to test the hypothesis that supplementation of the initial bedside assessment of patients with suspected pulmonary embolism (PE) with four-point compression venous ultrasonography (CUS) and right ventricular size assessment with the use of PSID equipped with dual probe could positively influence the accuracy of clinical predictions. A single-centre, prospective analysis was conducted on 100 patients (47 men, mean age 68 ± 13 years) with suspected PE. Clinical assessment on the basis of Wells and revised Geneva score and physical examination were supplemented with CUS and RV measurements by PSID. The mean time of PSID scanning was 4.9 ± 0.8 min and was universally accepted by the patients. Fifteen patients had deep venous thrombosis and RV enlargement was observed in 59 patients. PE was confirmed in 24 patients. If the both CUS was positive and RV enlarged, the specificity was 100% and sensitivity 54%, ROC AUC 0.771 [95% CI 0.68-0.85]. The Wells rule within our study population had the specificity of 86% and sensitivity of 67%, ROC AUC 0.776 (95% CI 0.681-0.853, p < 0.0001). Similar values calculated for the revised Geneva score were as follows: specificity 58% and sensitivity 63%, ROC AUC 0.664 (95% CI 0.563-0.756, p = 0.0104). Supplementing the revised Geneva score with additional criteria of CUS result and RV measurement resulted in significant improvement of diagnostic accuracy. The difference between ROC AUCs was 0.199 (95% Cl 0.0893-0.308, p = 0.0004). Similar modification of Wells score increased ROC AUC by 0.133 (95% CI 0.0443-0.223, p = 0.0034). Despite the well-acknowledged role of the PE clinical risk assessment scores the diagnostic process may benefit from the addition of basic bedside ultrasonographic techniques.


Assuntos
Técnicas de Diagnóstico Cardiovascular/instrumentação , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Direita/diagnóstico por imagem , Embolia Pulmonar/diagnóstico , Ultrassonografia/instrumentação , Trombose Venosa/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Técnicas de Imagem Cardíaca/instrumentação , Computadores de Mão , Técnicas de Apoio para a Decisão , Feminino , Humanos , Hipertrofia Ventricular Direita/etiologia , Masculino , Pessoa de Meia-Idade , Testes Imediatos , Estudos Prospectivos , Embolia Pulmonar/etiologia , Trombose Venosa/complicações
20.
Int J Cardiovasc Imaging ; 34(9): 1439-1449, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29605901

RESUMO

To characterize the morphological change in the right ventricle (RV) of patients with pulmonary artery hypertension (PAH) and further explore the correlation between septomarginal trabeculation (SMT) and right ventricular (RV) function, myocardial fibrosis, and exercise capacity in patients with PAH. Sixty untreated PAH patients were prospectively included from May 2016 to April 2017. All patients underwent comprehensive clinical evaluation and cardiac magnetic resonance (CMR). The area and diameter of the basal segment of SMT, and the mass of SMT were measured on cine SSFP images. Relationship between parameters of SMT and RV ejection fraction (RVEF), 6 min walking distance (6MWD), myocardial fibrosis and pulmonary vascular resistance (PVR) were evaluated by Pearson's correlation and logistic regression. Predictive performance of SMT parameters for reduced RVEF or impaired 6MWD was evaluated by receiver operating characteristics (ROC) analysis. Compared with SMT diameter index and mass index, SMT area index (SMT Ai) in basal segment was the best parameter to show correlation with RVEF (r = - 0.496, P < 0.001), 6MWD (r = - 0.619, P < 0.001), and inferior insertion point (I IP) extracelluar volume (ECV) (r = 0.365, P = 0.008). ROC showed that SMT Ai had the strongest predictive value for reduced RVEF (AUC = 0.756), and impaired 6MWD (AUC = 0.813). SMT parameters were closely correlated with RV systolic function and 6MWD in patients with PAH. SMT Ai is a simple imaging indicator for the severity of PAH.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Adulto , Feminino , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/diagnóstico por imagem , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/etiologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Volume Sistólico , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia , Adulto Jovem
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