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1.
Am J Physiol Heart Circ Physiol ; 320(3): H1021-H1036, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481696

RESUMO

Pulmonary hypertension (PH) causes cardiac hypertrophy in the right ventricle (RV) and eventually leads to RV failure due to persistently elevated ventricular afterload. We hypothesized that the mechanical stress on the RV associated with increased afterload impairs vasodilator function of the right coronary artery (RCA) in PH. Coronary vascular response was assessed using microangiography with synchrotron radiation (SR) in two well-established PH rat models, monocrotaline injection or the combined exposure to chronic hypoxia and vascular endothelial growth factor receptor blockade with Su5416 (SuHx model). In the SuHx model, the effect of the treatment with the nonselective endothelin-1 receptor antagonist (ERA), macitentan, was also examined. Myocardial viability was determined in SuHx model rats, using 18F-FDG Positron emission tomography (PET) and magnetic resonance imaging (MRI). Endothelium-dependent and endothelium-independent vasodilator responses were significantly attenuated in the medium and small arteries of severe PH rats. ERA treatment significantly improved RCA vascular function compared with the untreated group. ERA treatment improved both the decrease in ejection fraction and the increased glucose uptake, and reduced RV remodeling. In addition, the upregulation of inflammatory genes in the RV was almost suppressed by ERA treatment. We found impairment of vasodilator responses in the RCA of severe PH rat models. Endothelin-1 activation in the RCA plays a major role in impaired vascular function in PH rats and is partially restored by ERA treatment. Treatment of PH with ERA may improve RV function in part by indirectly attenuating right heart afterload and in part by associated improvements in right coronary endothelial function.NEW & NOTEWORTHY We demonstrated for the first time the impairment of vascular responses in the right coronary artery (RCA) of the dysfunctional right heart in pulmonary hypertensive rats in vivo. Treatment with an endothelin-1 receptor antagonist ameliorated vascular dysfunction in the RCA, enabled tissue remodeling of the right heart, and improved cardiac function. Our results suggest that impaired RCA function might also contribute to the early progression to heart failure in patients with severe pulmonary arterial hypertension (PAH). The endothelium of the coronary vasculature might be considered as a potential target in treatments to prevent heart failure in severe patients with PAH.


Assuntos
Angiografia Coronária , Vasos Coronários/diagnóstico por imagem , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Síncrotrons , Vasodilatação , Disfunção Ventricular Direita/diagnóstico por imagem , Animais , Anti-Hipertensivos/farmacologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/genética , Endotelina-1/metabolismo , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Hipóxia/complicações , Indóis , Monocrotalina , Valor Preditivo dos Testes , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Pirimidinas/farmacologia , Pirróis , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Sulfonamidas/farmacologia , Vasodilatação/efeitos dos fármacos , Disfunção Ventricular Direita/tratamento farmacológico , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita , Remodelação Ventricular
2.
BMJ Case Rep ; 14(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431524

RESUMO

A 34-year-old woman was seen in the emergency department for shortness of breath and chest pain. During a pandemic, it is easy to 'think horses and not zebras', and with a patient presenting with the classic coronavirus symptoms it would have been easy to jump to that as her diagnosis. After a careful history and examination, it became clear that there was another underlying diagnosis. Chest X-ray, echocardiogram and CT scan revealed marked right ventricular dilatation and pulmonary hypertension, alongside a persistent left superior vena cava (PLSVC). Further investigation with cardiac MRI and coronary angiography at a tertiary centre demonstrated that she not only have a PLSVC but also a partial anomalous pulmonary venous drainage and sinus venosus atrial septal defect. This case highlights the importance of considering all differentials and approaching investigations in a logical manner.


Assuntos
/diagnóstico , Dor no Peito/fisiopatologia , Dispneia/fisiopatologia , Comunicação Interatrial/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Hipertrofia Ventricular Direita/diagnóstico por imagem , Síndrome de Cimitarra/diagnóstico por imagem , Adulto , Cateterismo Cardíaco , Dor no Peito/etiologia , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Diagnóstico Diferencial , Dilatação Patológica/complicações , Dilatação Patológica/diagnóstico por imagem , Dilatação Patológica/fisiopatologia , Dispneia/etiologia , Ecocardiografia , Eletrocardiografia , Feminino , Comunicação Interatrial/complicações , Comunicação Interatrial/fisiopatologia , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/complicações , Hipertrofia Ventricular Direita/fisiopatologia , Imagem por Ressonância Magnética , /fisiopatologia , Síndrome de Cimitarra/complicações , Síndrome de Cimitarra/fisiopatologia , Tomografia Computadorizada por Raios X , Pressão Ventricular
3.
ASAIO J ; 67(1): e44-e48, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33346995

RESUMO

Pulmonary hypertension (PH) is a progressive disease that leads to cardiopulmonary dysfunction and right heart failure from pressure and volume overloading of the right ventricle (RV). Mechanical cardiopulmonary support has theoretical promise as a bridge to organ transplant or destination therapy for these patients. Solving the challenges of mechanical cardiopulmonary support for PH and RV failure requires its testing in a physiologically relevant animal model. Previous PH models in large animals have used pulmonary bead embolization, which elicits unpredictable inflammatory responses and has a high mortality rate. We describe a step-by-step guide for inducing pulmonary hypertension and right ventricular hypertrophy (PH-RVH) in sheep by left pulmonary artery (LPA) ligation combined with progressive main pulmonary artery (MPA) banding. This approach provides a controlled method to regulate RV afterload as tolerated by the animal to achieve PH-RVH, while reducing acute mortality. This animal model can facilitate evaluation of mechanical support devices for PH and RV failure.


Assuntos
Modelos Animais de Doenças , Hipertensão Pulmonar , Hipertrofia Ventricular Direita , Disfunção Ventricular Direita , Animais , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/fisiopatologia , Ligadura , Masculino , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/cirurgia , Ovinos , Disfunção Ventricular Direita/fisiopatologia
4.
Biomed Pharmacother ; 133: 111081, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378977

RESUMO

OBJECTIVE: A growing evidence demonstrates that inflammation is a major contributor to the pathogenesis of pulmonary arterial hypertension (PAH). However, blocking inflammation has only been shown to be of minor clinical benefit due to a lack of understanding of the precise inflammation present in PAH. Thus, the present study aimed to investigate characteristics of inflammatory process in PAH induced by monocrotaline (MCT) in rats. METHODS: Adult male Sprague-Dawley rats received a single dose of MCT (50 mg/kg, ip), and the occurrence of PAH and inflammation biomarkers were measured at 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30 days after MCT injection. RESULTS: From the 6th day after the injection of MCT, the mean pulmonary artery pressure gradually increased and doubled on the 30th day, accompanied by right ventricular hypertrophy and pulmonary arterial remodeling in a time-dependent manner. In the first 6 days after MCT treatment, only pro-inflammatory cytokines TNF-α, IL-1ß increased, which was defined as acute inflammatory phase, after that, both pro-inflammatory factors TNF-α, IL-1ß, IL-6, IL-12 and anti-inflammatory factors Arg1, IL-10, TGF-ß increased, which was defined as chronic inflammatory phase. The M1/M2 macrophage ratios in lung and alveolar lavage fluid were elevated on the 6th and 30th day, moreover, which were higher on the 6th than 30th day, and the PI3K/Akt signaling pathway increased along with the progression of PAH and correlated with pro-inflammatory proteins, which revealed also to some extent the characteristics of inflammation of PAH induced by MCT. CONCLUSION: The course of PAH induced by MCT injection is progressive with persistent inflammation, which is defined as acute inflammatory phase within 6 days after MCT treatment, after that, is defined as chronic inflammatory phase.


Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar/metabolismo , Remodelação Vascular , Animais , Pressão Arterial , Citocinas/genética , Modelos Animais de Doenças , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/patologia , Inflamação/fisiopatologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Monocrotalina , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/patologia , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Ratos Sprague-Dawley , Transdução de Sinais , Fatores de Tempo
5.
PLoS One ; 15(8): e0236988, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764771

RESUMO

Exposure to secondhand cigarette smoke is associated with the development of diverse diseases. Resistance training has been considered one of the most useful tools for patients with pulmonary disease, improving their quality of life. This study aimed to evaluate the effect of resistance training (RT) on the prevention of thickening of the right ventricle wall of rats exposed to secondhand cigarette smoke. Thirty-two Wistar rats were divided into four groups: Control (C), Smoker (S), Exercised (E) and Exercised Smoker (ES). The smoker groups were exposed to the smoke of four cigarettes for 30 min, twice daily, five days a week, for 16 weeks. The exercised groups climbed on a vertical ladder with progressive load, once a day, five days a week, for 16 weeks. The heart, trachea, lung, liver and gastrocnemius muscle were removed for histopathological analysis. Pulmonary emphysema (S and ES vs C and E, P < 0.0001) and pulmonary artery thickness enlargement (S vs C and E, P = 0.003, ES vs C, P = 0.003) were detected in the smoking groups. There was an increase in the right ventricle thickness in the S group compared with all other groups (P < 0.0001). An increase in resident macrophages in the liver was detected in both smoking groups compared with the C group (P = 0.002). Additionally, a relevant reduction of the diameter of the muscle fibers was detected only in ES compared with the C, S and E groups (P = 0.0002), impairing, at least in part, the muscle mass in exercised smoking rats. Therefore, it was concluded that resistance training prevented the increase of thickness of the right ventricle in rats exposed to secondhand cigarette smoke, but it may be not so beneficial for the skeletal muscle of smoking rats.


Assuntos
Fumar Cigarros/efeitos adversos , Hipertrofia Ventricular Direita/prevenção & controle , Condicionamento Físico Animal/métodos , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Fumar Cigarros/patologia , Fumar Cigarros/fisiopatologia , Modelos Animais de Doenças , Humanos , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Músculo Esquelético/patologia , Artéria Pulmonar/fisiologia , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/patologia , Enfisema Pulmonar/fisiopatologia , Ratos , Ratos Wistar , Treinamento de Resistência
6.
Life Sci ; 256: 117848, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585243

RESUMO

AIM: Pulmonary arterial hypertension (PAH) identified by progressive increase in pulmonary vascular resistance and pressure, ultimately leading to right ventricular failure and sudden death. Oxidation resistance 1 (OXR1) and its downstream target genes has a pivotal role for defense against oxidative stress. But its molecular function is unknown in respiratory system disorders. This study designed to determine whether PAH associated with oxidative stress and OXR1 signaling pathway modulation. Also, Crocin co-treatment evaluated to determine the possible role and mechanism in pulmonary arterial hypertension. MAIN METHOD: The PAH model was induced by a single dose of MCT. It was given intraperitoneal administration of Crocin or saline for 21 consecutive days the other groups in this study. In the last day of experiment, hemodynamic parameter and right ventricular hypertrophy was evaluated as PAH index. The expression levels of OXR1, P21 and Nrf2 genes were detected through RT-PCR. Moreover, oxidative stress index and antioxidant capacity were measured and histological examination were used to determine the lung tissue injuries. KEY FINDINGS: Results of the current study demonstrated that the OXR1 and P21 gene expression significantly decrease in PAH which is associated with increase of lipid peroxidation and decrease antioxidant capacity in lung tissue. Crocin co-treatment significantly improved the hemodynamic, oxidative stress biomarkers and histological data of the PAH rats, which associated with increase of OXR1 and its downstream target genes. SIGNIFICANCE: This report reveals the critical role of OXR1 in pathogenesis of oxidative stress-related pulmonary disease. Current experiment also provides evidence that Crocin has a protective effect against MCT-induced pulmonary arterial hypertension by modulation of OXR1 signaling pathway in rats.


Assuntos
Carotenoides/farmacologia , Hipertrofia Ventricular Direita/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Hipertensão Arterial Pulmonar/prevenção & controle , Animais , Antioxidantes/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Peroxidação de Lipídeos/fisiologia , Masculino , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Monocrotalina/toxicidade , Estresse Oxidativo/fisiologia , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Arch Cardiovasc Dis ; 113(1): 70-84, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31924541

RESUMO

Pulmonary arterial hypertension is a progressive and lethal cardiopulmonary disease. The rise in right ventricular afterload leads to right ventricular hypertrophy and failure. Right ventricular failure is the most important prognostic factor for morbidity and mortality in pulmonary arterial hypertension or pulmonary hypertension caused by left heart diseases. Surprisingly, the right ventricle is not targeted by pulmonary arterial hypertension-specific therapies. The current profound lack of basic understanding of pulmonary arterial hypertension-related right ventricular remodelling can explain, at least in part, this paradox. The physiology and haemodynamic function of the right ventricle in the normal state differ considerably from those of the left ventricle, and the known mechanisms of left ventricular dysfunction cannot be generalized to right ventricular dysfunction. Ion channel activities and calcium homeostasis tightly regulate cardiac function, and their dysfunction contributes to the pathogenesis of cardiac diseases. This review focuses on the ion channels (potassium, calcium) and intracellular calcium handling remodelling involved in right ventricular hypertrophy and dysfunction caused by pulmonary arterial hypertension.


Assuntos
Acoplamento Excitação-Contração , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Contração Miocárdica , Hipertensão Arterial Pulmonar/complicações , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita , Remodelação Ventricular , Potenciais de Ação , Animais , Pressão Arterial , Cálcio/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca , Ventrículos do Coração/metabolismo , Humanos , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Potássio/metabolismo , Prognóstico , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Fatores de Risco , Pesquisa Médica Translacional , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologia
8.
Int J Cardiovasc Imaging ; 36(4): 691-700, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31907684

RESUMO

Aortopathy is a recognized comorbidity of Tetralogy of Fallot (TOF). Aortic flow in children with repaired TOF is abnormal despite normal aortic valve anatomy and early surgical repair that results in aortic size normalization. The purpose of this study was to investigate the flow hemodynamics inside the left ventricle (LV) of children with repaired TOF using 4D-Flow MRI derived vorticity. Vorticity is the spatial derivative of flow velocity and is sensitive to anatomic and geometric variations. Vorticity was calculated inside the LV of children with repaired TOF having normal aortic size (n = 14) and normal controls (n = 10) during systolic ejection phase. All subjects underwent comprehensive biventricular analysis including the MRI based feature-tracking based LV strain analysis and mechanical dyssynchrony. Right ventricular (RV) volumetric indices along with LV mechanical indices were correlated with LV vorticity. All TOF patients had supraphysiologic helical flow in the ascending aorta. The generated peak systolic vorticity integrated over the LV volume was elevated in TOF group compared to control (median: 1344 vs. 858 s-1, P < 0.001). TOF patients had increased LV mechanical dyssynchrony (47 ± 11 vs. 32 ± 7 ms, P < 0.001) and reduced LV global circumferential strain (19 ± 2 vs. 21 ± 2%, P = 0.020). In the TOF group, LV systolic vorticity was independent of RV size and LV mechanical indices. Pathologic aortic flow in children with repaired TOF is associated with abnormal ejection flow patterns inside the LV. Increased systolic vorticity was not associated with LV mechanical dyssynchrony and RV dilation, suggesting that systolic flow inside the LV is independent of impaired LV contractile mechanics and inter-ventricular interactions.


Assuntos
Aorta/fisiopatologia , Doenças da Aorta/fisiopatologia , Procedimentos Cirúrgicos Cardíacos , Hemodinâmica , Tetralogia de Fallot/cirurgia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Adolescente , Aorta/diagnóstico por imagem , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/etiologia , Velocidade do Fluxo Sanguíneo , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Criança , Feminino , Humanos , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Imagem Cinética por Ressonância Magnética , Masculino , Imagem de Perfusão do Miocárdio/métodos , Estudos Retrospectivos , Fatores de Risco , Sístole , Tetralogia de Fallot/complicações , Tetralogia de Fallot/diagnóstico por imagem , Tetralogia de Fallot/fisiopatologia , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Direita , Remodelação Ventricular
9.
Basic Res Cardiol ; 115(2): 17, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980934

RESUMO

AIMS: The cytoskeletal signaling protein four and-a-half LIM domains 1 (FHL-1) has recently been identified as a novel key player in pulmonary hypertension as well as in left heart diseases. In this regard, FHL-1 has been implicated in dysregulated hypertrophic signaling in pulmonary arterial smooth muscle cells leading to pulmonary hypertension. In mice, FHL-1-deficiency (FHL-1-/-) led to an attenuated hypertrophic signaling associated with a blunted hypertrophic response of the pressure-overloaded left ventricle (LV). However, the role of FHL-1 in right heart hypertrophy has not yet been addressed. METHODS AND RESULTS: We investigated FHL-1 expression in C57Bl/6 mice subjected to chronic biomechanical stress and found it to be enhanced in the right ventricle (RV). Next, we subjected FHL-1-/- and corresponding wild-type mice to pressure overload of the RV by pulmonary arterial banding for various time points. However, in contrast to the previously published study in LV-pressure overload, which was confirmed here, RV hypertrophy and hypertrophic signaling was not diminished in FHL-1-/- mice. In detail, right ventricular pressure overload led to hypertrophy, dilatation and fibrosis of the RV from both FHL-1-/- and wild-type mice. RV remodeling was associated with impaired RV function as evidenced by reduced tricuspid annular plane systolic excursion. Additionally, PAB induced upregulation of natriuretic peptides and slight downregulation of phospholamban and ryanodine receptor 2 in the RV. However, there was no difference between genotypes in the degree of expression change. CONCLUSION: FHL-1 pathway is not involved in the control of adverse remodeling in the pressure overloaded RV.


Assuntos
Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Direita/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Proteínas Musculares/metabolismo , Disfunção Ventricular Direita/metabolismo , Função Ventricular Direita , Remodelação Ventricular , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Fibrose , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Direita/genética , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/deficiência , Proteínas com Domínio LIM/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Peptídeos Natriuréticos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Transdução de Sinais , Disfunção Ventricular Direita/genética , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia
10.
Pediatr Cardiol ; 41(4): 669-676, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31900509

RESUMO

Lung biopsy is the gold standard for evaluating pathological changes in the pulmonary vascular bed. Knowing the distribution characteristics of pulmonary vascular lesions can improve the accuracy of lung biopsy. To investigate the distribution characteristics of pulmonary vascular remodeling, a reliable porcine model of shunt-associated pulmonary arterial hypertension (PAH) was established. Twenty piglets were randomly divided into the experimental group (n = 10) and the control group (n = 10). A modified Blalock-Taussig shunt (MBTS, left innominate artery to main pulmonary artery) was created surgically in the experimental group. Three months later, an invasive catheter was used to obtain hemodynamic parameters, and lung biopsy was performed to assess the remodeling of pulmonary vascular bed. MBTS was successfully implemented in six piglets. There's no significant difference in hemodynamic parameters of the two groups before the shunt. However, these parameters and right ventricular hypertrophy index of the experimental group were significantly increased after three months shunting. Pathological changes in the experimental group, including thickening of pulmonary artery media, intimal fibrosis, and right ventricular hypertrophy, were observed. Furthermore, the percentage of media thickness and medial area of the experimental group were significantly higher than control group. Histopathology showed that vascular remodeling of the lung was inhomogeneous and that the lateral lesion was more severe than other segments. These results indicated that MBTS could be used to establish a reliable porcine model of shunt-associated PAH and that multisite detection with different segments should be applied to assess the severity of pulmonary vascular remodeling.


Assuntos
Hipertensão Arterial Pulmonar/fisiopatologia , Remodelação Vascular , Animais , Modelos Animais de Doenças , Humanos , Hipertrofia Ventricular Direita/fisiopatologia , Pulmão/fisiopatologia , Distribuição Aleatória , Suínos
11.
Cardiovasc J Afr ; 31(4): 75-80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31544202

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a haemodynamic and pathophysiological condition with restricted flow through the pulmonary arterial circulation. In pulmonary hypertension, right ventricular hypertrophy and diastolic dysfunction can lead to an increase in atrial strain, fibrosis and dilation, which cause inhomogeneous atrial conduction. Interlead variation in P-wave duration is called P-wave dispersion (PwD), which is an electrocardiographic parameter that can be used to predict atrial arrhythmias. Our aim was to investigate the relationship between PwD, functional capacity, and invasive and non-invasive haemodynamic parameters of patients diagnosed with PAH. METHODS: Between 2015 and 2017 we enrolled 33 patients admitted to our in-patient clinic and diagnosed with PAH, and 32 healthy individuals for the control group. Details of these patients at the time of diagnosis were analysed, including gender, age, physical examination, electrocardiogram (ECG), echocardiography, six-minute walk test distance (6MWD), haemodynamic parameters and blood tests for biochemical markers that are correlated with clinical severity. Statistical analyses were performed using SPSS version 20.0 (SPSS Inc, Chicago, Illinois, USA). Statistical significance was taken as p < 0.05. RESULTS: In the forward stepwise multiple linear regression analysis, PwD and mean pulmonary artery pressure determined by right heart catheterisation were independently related to the functional capacity tested by the 6MWD (p < 0.02 and p < 0.01, respectively). CONCLUSIONS: PwD can easily be calculated from a surface ECG to indirectly estimate the functional status and prognosis of the patient with PAH.


Assuntos
Potenciais de Ação , Função do Átrio Direito , Remodelamento Atrial , Eletrocardiografia , Frequência Cardíaca , Hipertrofia Ventricular Direita/diagnóstico , Hipertensão Arterial Pulmonar/diagnóstico , Disfunção Ventricular Direita/diagnóstico , Adulto , Idoso , Pressão Arterial , Cateterismo Cardíaco , Estudos de Casos e Controles , Ecocardiografia , Tolerância ao Exercício , Feminino , Humanos , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Hipertensão Arterial Pulmonar/complicações , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Fatores de Tempo , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita , Teste de Caminhada , Adulto Jovem
12.
Cardiovasc Res ; 116(1): 171-182, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753422

RESUMO

AIMS: Heart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory, and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model. METHODS AND RESULTS: HFrEF was induced after myocardial infarction (MI) in rats. Two weeks later, sham-operated and MI groups received PBI-4050 (200 mg/kg/day by gavage) or saline for 3 weeks. Animals were analysed according to infarct size as large (≥30% left ventricle) or medium MI (<30%). Large MI caused PH and RV hypertrophy (RVH) with a restrictive lung syndrome. PBI-4050 did not adversely affect left ventricular (LV) function but markedly reduced PH and RVH and improved RV dysfunction. PBI-4050 reduced lung remodelling and improved respiratory compliance with decreased lung fibrosis, alveolar wall cellular proliferation and α-smooth muscle actin expression. The increased expression of endothelin-1 (ET-1), transforming growth factor beta (TGF-ß), interleukin-6 (IL-6) and of tissue inhibitor of metalloprotease-1 in the lungs from HFrEF were reduced with PBI-4050 therapy. Activation of isolated human lung fibroblasts (HLFs) to a myofibroblastic pro-fibrogenic phenotype was markedly reduced by PBI-4050. The fatty acid receptor GPR84 was increased in HFrEF lungs and in activated HLFs, and reduced by PBI-4050. GPR84 agonists activated fibrogenesis in HLFs and finally, PBI-4050 reduced ERK1/2 phosphorylation. CONCLUSIONS: PBI-4050 reduces PH and RVH in HFrEF by decreasing lung fibrosis and remodelling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function. A contributing mechanism involves reducing the activation of lung fibroblasts by IL-6, TGF-ß, and ET-1 by antagonism of GPR84 and reduced ERK1/2 phosphorylation. PBI-4050 is a novel promising therapy for targeting lung remodelling in group II PH.


Assuntos
Acetatos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Ventrículos do Coração/efeitos dos fármacos , Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/prevenção & controle , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Células Cultivadas , Modelos Animais de Doenças , Endotelina-1/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Interleucina-6/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Fosforilação , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/fisiopatologia , Ratos Wistar , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologia
13.
Cardiovasc Res ; 116(2): 406-415, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31020333

RESUMO

AIMS: In patients with pulmonary hypertension, right ventricular hypertrophy (RVH) is a detrimental condition that ultimately results in right heart failure and death. The ubiquitin proteasome system has been identified as a major protein degradation system to regulate cardiac remodelling in the left heart. Its role in right heart hypertrophy, however, is still ambiguous. METHODS AND RESULTS: RVH was induced in mice by pulmonary artery banding (PAB). Both, expression and activity of the proteasome was found to be up-regulated in the hypertrophied right ventricle (RV) compared to healthy controls. Catalytic inhibition of the proteasome by the two proteasome inhibitors Bortezomib (BTZ) and ONX-0912 partially improved RVH both in preventive and therapeutic applications. Native gel analysis revealed that specifically the 26S proteasome complexes were activated in experimental RVH. Increased assembly of 26S proteasomes was accompanied by elevated expression of Rpn6, a rate-limiting subunit of 26S proteasome assembly, in hypertrophied cardiomyocytes of the right heart. Intriguingly, patients with RVH also showed increased expression of Rpn6 in hypertrophied cardiomyocytes of the RV as identified by immunohistochemical staining. CONCLUSION: Our data demonstrate that alterations in expression and activity of proteasomal subunits play a critical role in the development of RVH. Moreover, this study provides an improved understanding on the selective activation of the 26S proteasome in RVH that might be driven by the rate-limiting subunit Rpn6. In RVH, Rpn6 therefore represents a more specific target to interfere with proteasome function than the commonly used catalytic proteasome inhibitors.


Assuntos
Ventrículos do Coração/enzimologia , Hipertrofia Ventricular Direita/enzimologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Função Ventricular Direita , Remodelação Ventricular , Animais , Modelos Animais de Doenças , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/prevenção & controle , Mediadores da Inflamação/metabolismo , Camundongos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Transdução de Sinais , Ubiquitinação , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
14.
Cardiovasc Res ; 116(3): 686-697, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173066

RESUMO

AIMS: The progressive accumulation of cells in pulmonary vascular walls is a key pathological feature of pulmonary arterial hypertension (PAH) that results in narrowing of the vessel lumen, but treatments targeting this mechanism are lacking. The C-X-C motif chemokine 12 (CXCL12) appears to be crucial in these processes. We investigated the activity of two CXCL12 neutraligands on experimental pulmonary hypertension (PH), using two complementary animal models. METHODS AND RESULTS: Male Wistar rats were injected with monocrotaline (MCT) or were subjected to SU5416 followed by 3-week hypoxia to induce severe PH. After PH establishment, assessed by pulsed-wave Doppler echocardiography, MCT-injected or SU5416 plus chronic hypoxia (SuHx) rats were randomized to receive CXCL12 neutraligands chalcone 4 or LIT-927 (100 mg/kg/day), the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100 (5 mg/kg/day), or vehicle, for 2 or 3 weeks, respectively. At the end of these treatment periods, echocardiographic and haemodynamic measurements were performed and tissue samples were collected for protein expression and histological analysis. Daily treatment of MCT-injected or SuHx rats with established PH with chalcone 4 or LIT-927 partially reversed established PH, reducing total pulmonary vascular resistance, and remodelling of pulmonary arterioles. Consistent with these observations, we found that neutralization of CXCL12 attenuates right ventricular hypertrophy, pulmonary vascular remodelling, and decreases pulmonary artery smooth muscle cell (PA-SMC) proliferation in lungs of MCT-injected rats and SuHx rats. Importantly, CXCL12 neutralization with either chalcone 4 or LIT-927 inhibited the migration of PA-SMCs and pericytes in vitro with a better efficacy than AMD3100. Finally, we found that CXCL12 neutralization decreases vascular pericyte coverage and macrophage infiltration in lungs of both MCT-injected and SuHx rats. CONCLUSION: We report here a greater beneficial effect of CXCL12 neutralization vs. the conventional CXCR4 blockade with AMD3100 in the MCT and SuHx rat models of severe PH, supporting a role for CXCL12 in the progression of vascular complications in PH and opening to new therapeutic options.


Assuntos
Chalconas/farmacologia , Quimiocina CXCL2/antagonistas & inibidores , Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Pirimidinonas/farmacologia , Remodelação Vascular/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL2/metabolismo , Modelos Animais de Doenças , Compostos Heterocíclicos/farmacologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/prevenção & controle , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Pericitos/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Ratos Wistar , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Transdução de Sinais
15.
Circ Heart Fail ; 12(11): e005819, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31707802

RESUMO

BACKGROUND: Angiotensin II has been implicated in maladaptive right ventricular (RV) hypertrophy and fibrosis associated with pulmonary hypertension (PH). Natriuretic peptides decrease RV afterload by promoting pulmonary vasodilation and inhibiting vascular remodeling but are degraded by neprilysin. We hypothesized that angiotensin receptor blocker and neprilysin inhibitor, sacubitril/valsartan (Sac/Val, LCZ696), will attenuate PH and improve RV function by targeting both pulmonary vascular and RV remodeling. METHODS: PH was induced in rats using the SU5416/hypoxia model (Su/Hx), followed by 6-week treatment with placebo, Sac/Val, or Val alone. There were 4 groups: CON-normoxic animals with placebo (n=18); PH-Su/Hx rats+placebo (n=34); PH+Sac/Val (N=24); and PH+Val (n=16). RESULTS: In animals with PH, treatment with Sac/Val but not Val resulted in significant reduction in RV pressure (mm Hg: PH: 62±4, PH+Sac/Val: 46±5), hypertrophy (RV/LV+S: PH: 0.74±0.06, PH+Sac/Val: 0.46±0.06), collagen content (µg/50 µg protein: PH: 8.2±0.3, PH+Sac/Val: 6.4±0.4), pressures and improvement in RVs (mm/s: PH: 31.2±1.8, PH+Sac/Val: 43.1±3.6) compared with placebo. This was associated with reduced pulmonary vascular wall thickness, increased lung levels of ANP (atrial natriuretic peptide), BNP (brain-type natriuretic peptide), and cGMP, and decreased plasma endothelin-1 compared with PH alone. Also, PH+Sac/Val animals had altered expression of PKC isozymes in RV tissue compared with PH alone. CONCLUSIONS: Sac/Val reduces pulmonary pressures, vascular remodeling, as well as RV hypertrophy in a rat model of PH and may be appropriate for treatment of pulmonary hypertension and RV dysfunction.


Assuntos
Aminobutiratos/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Proteases/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Tetrazóis/farmacologia , Animais , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Fibrose , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/prevenção & controle , Masculino , Neprilisina/antagonistas & inibidores , Artéria Pulmonar/fisiopatologia , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular
16.
Vascul Pharmacol ; 122-123: 106599, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31629919

RESUMO

Targeting vascular remodeling in pulmonary arterial hypertension (PAH) remains a challenge given the lack of potent anti-remodeling abilities of the therapeutic drugs. Although sildenafil has been shown to ameliorate cardiopulmonary remodeling, that of tadalafil is questionable. Masitinib, a tyrosine kinase inhibitor appears safer and more potent than imatinib for treatment of malignancies, but its efficacy on PAH is unknown. Therefore, we investigated the anti-remodeling properties of masitinib (5, 15, 50 mg/kg) and tadalafil (5, 10 mg/kg) using a monocrotaline-induced rat model of PAH. The 14-day treatment with masitinib (15, 50 mg/kg) resulted in significantly decreased right ventricular (RV) systolic pressure (RVSP) and hypertrophy (RVH), and pulmonary vascular remodeling, whereas tadalafil showed weaker anti-remodeling properties. Besides, masitinib significantly blocked the mitogen-associated protein kinase (MAPK) pathway, and reduced phosphodiesterase (PDE)-5 mRNA expression in the lungs. By contrast, tadalafil did not significantly inhibit the MAPK pathway. Further, the 28-day treatment extension revealed that masitinib-treated rats (15 mg/kg) had significantly lower RVSP, and higher heart rate and serum cyclic guanosine monophosphate (cGMP) level, whereas those treated with tadalafil (10 mg/kg) showed insignificantly lower RVSP and higher cGMP level. Moreover, the RVH indices, heart rates, body weight gains, and survival rates of rats in both groups were comparable. Collectively, these results suggest that the treatment with a low-dose masitinib was non-inferior than tadalafil. A lower dose of masitinib may represent a novel approach to target both the cardiopulmonary remodeling and the dysregulated vasoconstriction in PAH.


Assuntos
Anti-Hipertensivos/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Tadalafila/farmacologia , Tiazóis/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/prevenção & controle , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , Monocrotalina , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Transdução de Sinais , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
17.
J Am Heart Assoc ; 8(17): e013169, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31450994

RESUMO

Background The right ventricle exposed to chronic pressure overload exhibits hypertrophy and decompensates when exposed to stress. We hypothesize that impaired ability to increase myocardial oxidative flux through pyruvate dehydrogenase leads to hypertrophied right ventricular (RV) dysfunction when exposed to hemodynamic stress, and pyruvate dehydrogenase stimulation can improve RV function. Methods and Results Infant male Yorkshire piglets (13.5±0.6 kg weight, n=19) were used to assess substrate fractional contribution to the citric acid cycle after sustained pulmonary artery banding (PAB). Carbon 13-labeled glucose, lactate, and leucine, oxidative substrate tracers for the citric acid cycle, were infused into the right coronary artery on 7 to 10 days after PAB. RV systolic pressure, RV free wall thickness, and individual cardiomyocyte cell size after PAB were significantly elevated compared with the sham group. Both fractional glucose and lactate oxidations in the PAB group were >2-fold higher than in the sham group. Pigs with overdrive atrial pacing (≈80% increase in heart rate) stress after PAB showed only a 22% increase in rate-pressure product from baseline before atrial pacing and limited carbohydrate oxidation rate in the right ventricle. Intracoronary infusion of dichloroacetate, a pyruvate dehydrogenase agonist, produced higher rate-pressure product (59% increase) in response to increased workload by atrial pacing in association with a marked increase in lactate oxidation. Conclusions The immature hypertrophied right ventricle shows limited ability to increase carbohydrate oxidation in response to tachycardia stress leading to energy supply/utilization imbalance and decreased systolic function. Enhanced pyruvate dehydrogenase activation by dichloroacetate increases energy supply and preserves hypertrophied RV contractile function during hemodynamic stress.


Assuntos
Metabolismo Energético , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Direita/metabolismo , Disfunção Ventricular Direita/metabolismo , Função Ventricular Direita , Remodelação Ventricular , Animais , Animais Recém-Nascidos , Ácido Dicloroacético/administração & dosagem , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática , Ativadores de Enzimas/administração & dosagem , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Ligadura , Masculino , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/cirurgia , Complexo Piruvato Desidrogenase/metabolismo , Sus scrofa , Disfunção Ventricular Direita/tratamento farmacológico , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
18.
Am J Physiol Heart Circ Physiol ; 317(4): H685-H694, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31347913

RESUMO

High-intensity interval training (HIIT) improves physical performance of endurance athletes, although studies examining its cardiovascular effects are sparse. We evaluated the impact of HIIT on blood pressure, heart rate, and cardiac cavities' size and function in endurance-trained adults. Seventeen endurance-trained men underwent 24-h ambulatory blood pressure monitoring and Doppler echocardiography at baseline and after 6 wk of HIIT. Participants were divided into 2 groups [85% maximal aerobic power (HIIT85), n = 8 and 115% maximal aerobic power (HIIT115), n = 9] to compare the impact of different HIIT intensities. Ambulatory blood pressure monitoring and cardiac chambers' size and function were similar between groups at baseline. HIIT reduced heart rate (55 ± 8 vs. 51 ± 7 beats/min; P = 0.003), systolic blood pressure (121 ± 11 vs. 118 ± 9 mmHg; P = 0.01), mean arterial pressure (90 ± 8 vs. 89 ± 6 mmHg; P = 0.03), and pulse pressure (52 ± 6 vs. 49 ± 5 mmHg; P = 0.01) irrespective of training intensity. Left atrium volumes increased after HIIT (maximal: 50 ± 14 vs. 54 ± 14 mL; P = 0.02; minimal: 15 ± 5 vs. 20 ± 8 mL; P = 0.01) in both groups. Right ventricle global longitudinal strain lowered after training in the HIIT85 group only (20 ± 4 vs. 17 ± 3%, P = 0.04). In endurance-trained men, 6 wk of HIIT reduced systolic blood pressure and mean arterial pressure and increased left atrium volumes irrespective of training intensity, whereas submaximal HIIT deteriorated right ventricle systolic function.NEW & NOTEWORTHY The novel findings of this study are that 6 wk of high-intensity interval training increases left atrial volumes irrespective of training intensity (85 or 115% maximal aerobic power), whereas the submaximal training decreases right ventricular systolic function in endurance-trained men. These results may help identify the exercise threshold for potential toxicity of intense exercise training for at-risk individuals and ideal exercise training regimens conferring optimal cardiovascular protection and adapted endurance training for athletes.


Assuntos
Cardiomegalia Induzida por Exercícios , Treinamento Intervalado de Alta Intensidade , Hipertrofia Ventricular Direita/fisiopatologia , Resistência Física , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita , Remodelação Ventricular , Adulto , Pressão Arterial , Função do Átrio Esquerdo , Remodelamento Atrial , Ecocardiografia Doppler , Frequência Cardíaca , Humanos , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/etiologia , Masculino , Fadiga Muscular , Fatores de Tempo , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia , Função Ventricular Esquerda , Adulto Jovem
19.
Am J Physiol Lung Cell Mol Physiol ; 317(4): L445-L455, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31322432

RESUMO

Pulmonary arterial hypertension (PAH) is a female predominant disease in which progressive vascular remodeling and vasoconstriction result in right ventricular (RV) failure and death. Most PAH patients utilize multiple therapies. In contrast, the majority of preclinical therapeutic studies are performed in male rats with a single novel drug often markedly reversing disease in the model. We sought to differentiate single drug therapy from combination therapy in female rats with severe disease. One week after left pneumonectomy, we induced PH in young female Sprague-Dawley rats with an injection of monocrotaline (45 mg/kg). Female rats were then randomized to receive combination therapy (ambrisentan plus tadalafil), ambrisentan monotherapy, tadalafil monotherapy, or vehicle. We measured RV size and function on two serial echocardiograms during the development of disease. We measured RV systolic pressure (RVSP) invasively at day 28 after monocrotaline before analyzing the vascular volume with microcomputed tomography (microCT) of the right middle lobe. RVSP was significantly lower in female rats treated with combination therapy, and combination therapy resulted in increased small vessel volume density measured by microCT compared with untreated rats. Combination-treated rats had the smallest RV end-diastolic diameter on echocardiogram as compared with the other groups. In summary, we report a female model of pulmonary hypertension that can distinguish between one and two drug therapies; this model may facilitate better preclinical drug testing for novel compounds.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Hipertrofia Ventricular Direita/tratamento farmacológico , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Tadalafila/farmacologia , Disfunção Ventricular Direita/tratamento farmacológico , Animais , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Ecocardiografia , Feminino , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/fisiopatologia , Pulmão/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Monocrotalina/administração & dosagem , Pneumonectomia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Disfunção Ventricular Direita/induzido quimicamente , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/fisiopatologia , Microtomografia por Raio-X
20.
Sci Rep ; 9(1): 8369, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182733

RESUMO

Exposure to chronic hypoxia results in pulmonary hypertension characterized by increased vascular resistance and pulmonary vascular remodeling, changes in functional parameters of the pulmonary vasculature, and right ventricular hypertrophy, which can eventually lead to right heart failure. The underlying mechanisms of hypoxia-induced pulmonary hypertension have still not been fully elucidated while no curative treatment is currently available. Commonly employed pre-clinical analytic methods are largely limited to invasive studies interfering with cardiac tissue or otherwise ex vivo functional studies and histopathology. In this work, we suggest volumetric optoacoustic tomography (VOT) for non-invasive assessment of heart function in response to chronic hypoxia. Mice exposed for 3 consecutive weeks to normoxia or chronic hypoxia were imaged in vivo with heart perfusion tracked by VOT using indocyanide green contrast agent at high temporal (100 Hz) and spatial (200 µm) resolutions in 3D. Unequivocal difference in the pulmonary transit time was revealed between the hypoxic and normoxic conditions concomitant with the presence of pulmonary vascular remodeling within hypoxic models. Furthermore, a beat-to-beat analysis of the volumetric image data enabled identifying and characterizing arrhythmic events in mice exposed to chronic hypoxia. The newly introduced non-invasive methodology for analysis of impaired pulmonary vasculature and heart function under chronic hypoxic exposure provides important inputs into development of early diagnosis and treatment strategies in pulmonary hypertension.


Assuntos
Tomografia Computadorizada de Feixe Cônico , Coração/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Animais , Fenômenos Fisiológicos Cardiovasculares , Modelos Animais de Doenças , Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/fisiopatologia , Hipóxia/diagnóstico por imagem , Hipóxia/fisiopatologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Camundongos , Músculo Liso Vascular/diagnóstico por imagem , Músculo Liso Vascular/fisiopatologia , Técnicas Fotoacústicas , Artéria Pulmonar/patologia , Remodelação Vascular/fisiologia
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