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1.
J Cardiovasc Magn Reson ; 22(1): 68, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32938483

RESUMO

BACKGROUND: Cardiovascular magnetic resonance (CMR) phase contrast (PC) flow measurements suffer from phase offset errors. Background subtraction based on stationary phantom measurements can most reliably be used to overcome this inaccuracy. Stationary tissue correction is an alternative and does not require additional phantom scanning. The aim of this study was 1) to compare measurements with and without stationary tissue correction to phantom corrected measurements on different GE Healthcare CMR scanners using different software packages and 2) to evaluate the clinical implications of these methods. METHODS: CMR PC imaging of both the aortic and pulmonary artery flow was performed in patients on three different 1.5 T CMR scanners (GE Healthcare) using identical scan parameters. Uncorrected, first, second and third order stationary tissue corrected flow measurement were compared to phantom corrected flow measurements, our reference method, using Medis QFlow, Circle cvi42 and MASS software. The optimal (optimized) stationary tissue order was determined per scanner and software program. Velocity offsets, net flow, clinically significant difference (deviation > 10% net flow), and regurgitation severity were assessed. RESULTS: Data from 175 patients (28 (17-38) years) were included, of which 84% had congenital heart disease. First, second and third order and optimized stationary tissue correction did not improve the velocity offsets and net flow measurements. Uncorrected measurements resulted in the least clinically significant differences in net flow compared to phantom corrected data. Optimized stationary tissue correction per scanner and software program resulted in net flow differences (> 10%) in 19% (MASS) and 30% (Circle cvi42) of all measurements compared to 18% (MASS) and 23% (Circle cvi42) with no correction. Compared to phantom correction, regurgitation reclassification was the least common using uncorrected data. One CMR scanner performed worse and significant net flow differences of > 10% were present both with and without stationary tissue correction in more than 30% of all measurements. CONCLUSION: Phase offset errors had a significant impact on net flow quantification, regurgitation assessment and varied greatly between CMR scanners. Background phase correction using stationary tissue correction worsened accuracy compared to no correction on three GE Healthcare CMR scanners. Therefore, careful assessment of phase offset errors at each individual scanner is essential to determine whether routine use of phantom correction is necessary. TRIAL REGISTRATION: Observational Study.


Assuntos
Aorta/diagnóstico por imagem , Insuficiência da Valva Aórtica/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Hemodinâmica , Interpretação de Imagem Assistida por Computador , Imagem Cinética por Ressonância Magnética/instrumentação , Artéria Pulmonar/diagnóstico por imagem , Insuficiência da Valva Pulmonar/diagnóstico por imagem , Adolescente , Adulto , Aorta/fisiopatologia , Insuficiência da Valva Aórtica/fisiopatologia , Velocidade do Fluxo Sanguíneo , Criança , Feminino , Cardiopatias Congênitas/fisiopatologia , Humanos , Masculino , Imagens de Fantasmas , Valor Preditivo dos Testes , Artéria Pulmonar/fisiopatologia , Insuficiência da Valva Pulmonar/fisiopatologia , Fluxo Sanguíneo Regional , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto Jovem
2.
Pediatr Clin North Am ; 67(5): 903-921, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32888689

RESUMO

Pulmonary hypertension (PH), the syndrome of increased pressure in the pulmonary arteries, is associated with significant morbidity and mortality for affected children and is associated with a variety of potential underlying causes. Several pulmonary arterial hypertension-targeted therapies have become available to reduce pulmonary artery pressure and improve outcome, but there is still no cure for most patients. This review provides a description of select causes of PH encountered in pediatrics and an update on the most recent data pertaining to evaluation and management of children with PH. Available evidence for specific classes of PH-targeted therapies in pediatrics is discussed.


Assuntos
Diagnóstico por Imagem , Cardiopatias Congênitas/complicações , Hipertensão Arterial Pulmonar , Artéria Pulmonar/fisiopatologia , Pressão Propulsora Pulmonar/fisiologia , Criança , Cardiopatias Congênitas/diagnóstico , Humanos , Prognóstico , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/fisiopatologia
3.
Arterioscler Thromb Vasc Biol ; 40(9): 2293-2309, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32757648

RESUMO

OBJECTIVE: Extracellular vesicles (EVs) have the potential to act as intercellular communicators. The aims were to characterize circulating EVs in patients with pulmonary arterial hypertension (PAH) and to explore whether these EVs contribute to endothelial activation and angiogenesis. Approach and Results: Patients with PAH (n=70) and healthy controls (HC; n=20) were included in this cross-sectional study. EVs were characterized and human pulmonary endothelial cells (hPAECs) were incubated with purified EVs. Endothelial cell activity and proangiogenic markers were analyzed. Tube formation analysis was performed for hPAECs, and the involvement of PSGL-1 (P-selectin glycoprotein ligand 1) was evaluated. The numbers of CD62P+, CD144+, and CD235a EVs were higher in blood from PAH compared with HC. Thirteen proteins were differently expressed in PAH and HC EVs, where complement fragment C1q was the most significantly elevated protein (P=0.0009) in PAH EVs. Upon EVs-internalization in hPAECs, more PAH compared with HC EVs evaded lysosomes (P<0.01). As oppose to HC, PAH EVs stimulated hPAEC activation and induced transcription and translation of VEGF-A (vascular endothelial growth factor A; P<0.05) and FGF (fibroblast growth factor; P<0.005) which were released in the cell supernatant. These proangiogenic proteins were higher in patient with PAH plasma compered with HC. PAH EVs induced a complex network of angiotubes in vitro, which was abolished by inhibitory PSGL-1antibody. Anti-PSGL-1 also inhibited EV-induced endothelial cell activation and PAH EV dependent increase of VEGF-A. CONCLUSIONS: Patients with PAH have higher levels of EVs harboring increased amounts of angiogenic proteins, which induce activation of hPAECs and in vitro angiogenesis. These effects were partly because of platelet-derived EVs evasion of lysosomes upon internalization within hPAEC and through possible involvement of P-selectin-PSGL-1 pathway.


Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Vesículas Extracelulares/metabolismo , Neovascularização Fisiológica , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar/metabolismo , Idoso , Estudos de Casos e Controles , Células Cultivadas , Estudos Transversais , Células Endoteliais/ultraestrutura , Endotélio Vascular/fisiopatologia , Endotélio Vascular/ultraestrutura , Vesículas Extracelulares/ultraestrutura , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Selectina-P/metabolismo , Hipertensão Arterial Pulmonar/patologia , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/ultraestrutura , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
J Cardiovasc Magn Reson ; 22(1): 50, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32698897

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) associated with pulmonary hypertension (PH) is a significant source of morbidity and mortality in premature infants. Recent advances have allowed the use of cardiovascular magnetic resonance (CMR) in the assessment of respiratory and cardiac disease in infants with BPD. In adults and older pediatric patients, decreased CMR interventricular septal curvature correlates with increased mean pulmonary artery pressure and pulmonary vascular resistance. The current study sought to determine the relationship of CMR derived septal curvature in neonates with BPD and BPD-PH with a need for PH therapy. METHODS: Forty moderate or severe BPD and 12 mild BPD or control infants were imaged without contrast between 38 and 47 weeks post-menstrual age on a neonatal-sized, neonatal intensive care unit-sited 1.5 T CMR scanner. CMR indices including eccentricity index (CMR-EI) and septal curvature were measured and compared to BPD severity and clinical outcomes including hospital length of stay (LOS), duration of respiratory support, respiratory support level at discharge and PH therapy. RESULTS: CMR-EI was directly associated and septal curvature was inversely associated with BPD severity. In a univariate analysis, CMR-EI and septal curvature were associated with increased hospital LOS, duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy. In multivariable analysis CMR-EI was associated with hospital LOS and duration of respiratory support and septal curvature was associated with respiratory support at hospital discharge. Septal curvature was the only clinical or CMR variable associated with need for PH therapy (R2 = 0.66, p = 0.0014) in multivariable analysis demonstrating improved discrimination beyond CMR-EI. CONCLUSIONS: CMR derived septal curvature correlates significantly with clinical outcomes including hospital LOS, duration of respiratory support, respiratory support level at hospital discharge, and PH therapy in neonates with BPD and BPD-PH. Further, CMR derived septal curvature demonstrated improved discrimination of need for PH therapy and respiratory support at discharge compared to clinical variables and other CMR indices, supporting septal curvature as a non-invasive marker of PH in this population with potential to guide management strategies.


Assuntos
Pressão Arterial , Displasia Broncopulmonar/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Artéria Pulmonar/fisiopatologia , Resistência Vascular , Septo Interventricular/diagnóstico por imagem , Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/fisiopatologia , Displasia Broncopulmonar/terapia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Recém-Nascido , Tempo de Internação , Masculino , Valor Preditivo dos Testes , Artéria Pulmonar/efeitos dos fármacos , Terapia Respiratória , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos , Septo Interventricular/efeitos dos fármacos , Septo Interventricular/fisiopatologia
5.
Rev Cardiovasc Med ; 21(2): 163-179, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32706206

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive and fatal lung disease of multifactorial etiology. Most of the available drugs and FDA-approved therapies for treating pulmonary hypertension attempt to overcome the imbalance between vasoactive and vasodilator mediators, and restore the endothelial cell function. Traditional medications for treating PAH include the prostacyclin analogs and receptor agonists, phosphodiesterase 5 inhibitors, endothelin-receptor antagonists, and cGMP activators. While the current FDA-approved drugs showed improvements in quality of life and hemodynamic parameters, they have shown only very limited beneficial effects on survival and disease progression. None of them offers a cure against PAH, and the median survival rate remains less than three years from diagnosis. Extensive research efforts have led to the emergence of innovative therapeutic approaches in the area of PAH. In this review, we provide an overview of the current FDA-approved therapies in PAH and discuss the associated clinical trials and reported-side effects. As recent studies have led to the emergence of innovative therapeutic approaches in the area of PAH, we also focus on the latest promising therapies in preclinical studies such as stem cell-based therapies, gene transfer, and epigenetic therapies.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Hipertensão Arterial Pulmonar/terapia , Artéria Pulmonar/efeitos dos fármacos , Animais , Terapia Genética , Humanos , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/mortalidade , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Transplante de Células-Tronco , Resultado do Tratamento
7.
J Vis Exp ; (159)2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32478718

RESUMO

Right ventricular (RV) function and failure are major determinants of outcome in acquired and congenital heart diseases, including pulmonary hypertension. Assessment of RV function and morphology is complex, partly due to the complex shape of the RV. Currently, cardiac magnetic resonance (CMR) imaging is the golden standard for noninvasive assessment of RV function and morphology. The current protocol describes CMR imaging in a mouse model of RV pressure load induced by pulmonary artery banding (PAB). PAB is performed by placing a 6-0 suture around the pulmonary artery over a 23 G needle. The PAB gradient is determined using echocardiography at 2 and 6 weeks. At 6 weeks, the right and left ventricular morphology and function is assessed by measuring both end-systolic and end-diastolic volumes and mass by ten to eleven cine slices 1 mm thick using a 9.4 T magnetic resonance imaging scanner equipped with a 1,500 mT/m gradient. Representative results show that PAB induces a significant increase in RV pressure load, with significant effects on biventricular morphology and RV function. It is also shown that at 6 weeks of RV pressure load, cardiac output is maintained. Presented here is a reproducible protocol for the quantification of biventricular morphology and function in a mouse model of RV pressure load and may serve as a method for experiments exploring determinants of RV remodeling and dysfunction.


Assuntos
Imagem por Ressonância Magnética , Miocárdio/patologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Animais , Modelos Animais de Doenças , Ecocardiografia , Feminino , Processamento de Imagem Assistida por Computador , Masculino , Camundongos Endogâmicos C57BL , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/cirurgia
8.
J Vis Exp ; (160)2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32568218

RESUMO

Pulmonary Hypertension (PH) is a pathophysiological condition, defined by a mean pulmonary arterial pressure exceeding 25 mm Hg at rest, as assessed by right heart catheterization. A broad spectrum of diseases can lead to PH, differing in their etiology, histopathology, clinical presentation, prognosis, and response to treatment. Despite significant progress in the last years, PH remains an uncured disease. Understanding the underlying mechanisms can pave the way for the development of new therapies. Animal models are important research tools to achieve this goal. Currently, there are several models available for recapitulating PH. This protocol describes a two-hit mouse PH model. The stimuli for PH development are hypoxia and the injection of SU5416, a vascular endothelial growth factor (VEGF) receptor antagonist. Three weeks after initiation of Hypoxia/SU5416, animals develop pulmonary vascular remodeling imitating the histopathological changes observed in human PH (predominantly Group 1). Vascular remodeling in the pulmonary circulation results in the remodeling of the right ventricle (RV). The procedures for measuring RV pressures (using the open chest method), the morphometrical analyses of the RV (by dissecting and weighing both cardiac ventricles) and the histological assessments of the remodeling (both pulmonary by assessing vascular remodeling and cardiac by assessing RV cardiomyocyte hypertrophy and fibrosis) are described in detail. The advantages of this protocol are the possibility of the application both in wild type and in genetically modified mice, the relatively easy and low-cost implementation, and the quick development of the disease of interest (3 weeks). Limitations of this method are that mice do not develop a severe phenotype and PH is reversible upon return to normoxia. Prevention, as well as therapy studies, can easily be implemented in this model, without the necessity of advanced skills (as opposed to surgical rodent models).


Assuntos
Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/patologia , Indóis/farmacologia , Pirróis/farmacologia , Animais , Hipóxia Celular/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Concentração de Íons de Hidrogênio , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/complicações , Masculino , Camundongos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
9.
Int J Cardiovasc Imaging ; 36(10): 2051-2059, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32506286

RESUMO

To compare intravenous contrast material (CM) injection protocols for dual-energy CT pulmonary angiography (CTPA) in patients with suspected acute pulmonary embolism with regard to image quality and pulmonary perfused blood volume (PBV) values. A total of 198 studies performed with four CM injection protocols varying in CM volume and iodine delivery rates (IDR) were retrospectively included: (A) 60 ml at 5 ml/s (IDR = 1.75gI/s), (B) 50 ml at 5 ml/s (IDR = 1.75gI/s), (C) 50 ml at 4 ml/s (IDR = 1.40gI/s), (D) 40 ml at 3 ml/s (IDR = 1.05gI/s). Image quality and PBV values at different resolution settings were compared. Pulmonary arterial tract attenuation was highest for protocol A (397 ± 110 HU; p vs. B = 0.13; vs. C = 0.02; vs. D < 0.001). CTPA image quality of protocol A was rated superior compared to protocols B and D by reader 1 (p = 0.01; < 0.001), and superior to protocols B, C and D by reader 2 (p < 0.001; 0.02; < 0.001). Otherwise, there were no significant differences in CTPA quality ratings. Subjective iodine map ratings did not vary significantly between protocols A, B, and C. Both readers rated protocol D inferior to all other protocols (p < 0.05). PBV values did not vary significantly between protocols A and B at resolution settings of 1, 4 and 10 (p = 0.10; 0.10; 0.09), while otherwise PBV values displayed a decreasing trend from protocol A to D (p < 0.05). Higher CM volume and IDR are associated with superior CTPA and iodine map quality and higher absolute PBV values.


Assuntos
Angiografia por Tomografia Computadorizada , Meios de Contraste/administração & dosagem , Iopamidol/análogos & derivados , Artéria Pulmonar/diagnóstico por imagem , Embolia Pulmonar/diagnóstico por imagem , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Iopamidol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Artéria Pulmonar/fisiopatologia , Embolia Pulmonar/fisiopatologia , Reprodutibilidade dos Testes , Estudos Retrospectivos
10.
Int J Cardiovasc Imaging ; 36(10): 1917-1929, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32500398

RESUMO

PURPOSE: In echocardiography the severity of aortic stenosis (AS) is defined by effective orifice area (EOA), mean pressure gradient (mPGAV) and transvalvular flow velocity (maxVAV). The hypothesis of the present study was to confirm the pathophysiological presence of combined left ventricular hypertrophy (LVH), diastolic dysfunction (DD) and pulmonary artery hypertension (PAH) in patients with "pure" severe AS. METHODS AND RESULTS: Patients (n = 306) with asymptomatic (n = 133) and symptomatic (n = 173) "pure" severe AS (mean age 78 ± 9.5 years) defined by indexed EOA < 0.6 cm2 were enrolled between 2014 and 2016. AS patients were divided into 4 subgroups according to mPGAV and indexed left ventricular stroke volume: low flow (LF) low gradient (LG)-AS (n = 133), normal flow (NF) LG-AS (n = 91), LF high gradient (HG)-AS (n = 21) and NFHG-AS (n = 61). Patients with "pure" severe AS showed mean mPGAV of 31.7 ± 9.1 mmHg and mean maxVAV of 3.8 ± 0.6 m/s. Only 131 of 306 patients (43%) exhibited mPGAV > 40 mmHg and maxVAV > 4 m/s documenting incongruencies of the AS severity assessment by Doppler echocardiography. LVH was documented in 81%, DD in 76% and PAH in 80% of AS patients. 54% of "pure" AS patients exhibited all three alterations. Ranges of mPGAV and maxVAV were higher in patients with all three alterations compared to patients with less than three. 224 (73%) patients presented LG-conditions and 82 (27%) HG-conditions. LVH was predominant in NF-AS (p = 0.014) and PAH in LFHG-AS (p = 0.014). Patients' treatment was retrospectively assessed (surgery: n = 100, TAVI: n = 48, optimal medical treatment: n = 156). CONCLUSION: In patients with "pure" AS according to current guidelines the presence of combined LVH, DD and PAH as accepted pathophysiological sequelae of severe AS cannot be confirmed. Probably, the detection of these secondary cardiac alterations might improve the diagnostic algorithm to avoid overestimation of AS severity.


Assuntos
Estenose da Valva Aórtica/diagnóstico por imagem , Valva Aórtica/diagnóstico por imagem , Ecocardiografia Doppler , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/fisiopatologia , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/terapia , Pressão Arterial , Doenças Assintomáticas , Fármacos Cardiovasculares/uso terapêutico , Estudos Transversais , Feminino , Implante de Prótese de Valva Cardíaca , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , Substituição da Valva Aórtica Transcateter , Resultado do Tratamento , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Remodelação Ventricular
11.
Am J Physiol Heart Circ Physiol ; 319(2): H377-H391, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32559140

RESUMO

Pulmonary arterial hypertension (PAH) is a fatal progressive disease characterized by an increased blood pressure in the pulmonary arteries. RhoA/Rho-kinase (RhoA/ROCK) signaling activation is often associated with PAH. The purpose of this study is to investigate the role and mechanisms of long noncoding RNA (lncRNA) smooth muscle-induced lncRNA (SMILR) to activate the RhoA/ROCK pathway in PAH. SMILR, microRNA-141 (miR-141), and RhoA were identified by qRT-PCR in PAH patients' serum. 3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), wound-healing assay, cell counting kit-8 (CCK-8) assay, and flow cytometry were performed to determine cell viability, migration, proliferation, and cell cycle in human pulmonary arterial smooth muscle cells (hPASMCs) and primary PASMCs from PAH patients. We also performed bioinformatical prediction, luciferase reporter assay, and RNA-binding protein immunoprecipitation (RIP) to assess the interaction among SMILR, miR-141, and RhoA. The RhoA/ROCK pathway and proliferation-related proteins were measured by Western blotting. Finally, we introduced the small hairpin (sh)SMILR to monocrotaline-induced PAH rat model and used the hemodynamic measurement, qRT-PCR, and immunohistochemistry to examine the therapeutic effects of shSMILR. SMILR and RhoA expression were upregulated, while miR-141 expression was downregulated in PAH patients. SMILR directly interacted with miR-141 and negatively regulated its expression. Knockdown of SMILR suppressed PASMC proliferation and migration induced by hypoxia. Furthermore, overexpression of miR-141 could inhibit the RhoA/ROCK pathway by binding to RhoA, thereby repressing cell proliferation-related signals. Knockdown of SMILR significantly inhibited the Rho/ROCK activation and vascular remodeling in monocrotaline-induced rats. Knockdown of SMILR effectively elevated miR-141 expression and in turn inhibited the RhoA/ROCK pathway to regulate vascular remodeling and reduce blood pressure in PAH.NEW & NOTEWORTHY Smooth muscle enriched long noncoding RNA (SMILR), as a long noncoding RNA (lncRNA), was increased in pulmonary arterial hypertension (PAH) patients and in vitro and in vivo models. SMILR activated RhoA/ROCK signaling by targeting miR-141 to disinhibit its downstream target RhoA. SMILR knockdown or miR-141 overexpression inhibited hypoxia-induced cell proliferation and migration via repressing RhoA/ROCK signaling in pulmonary arterial smooth muscle cells (PASMCs), which was confirmed in vivo experiments that knockdown of SMILR inhibited vascular remodeling and alleviated PAH in rats. SMILR may be a promising and novel therapeutic target for the treatment and drug development of PAH.


Assuntos
MicroRNAs/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Hipertensão Arterial Pulmonar/enzimologia , RNA Longo não Codificante/metabolismo , Remodelação Vascular , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/patologia , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/patologia , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , RNA Longo não Codificante/genética , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/genética
13.
PLoS One ; 15(5): e0232544, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32396557

RESUMO

This study examined the impact of septal flattening on left ventricular (LV) torsion in patients with precapillary pulmonary hypertension (PH). Fifty-two patients with proven precapillary PH and 13 healthy controls were included. Ventricular function was assessed including 4D-measurements, tissue velocity imaging, and speckle tracking analysis. Increased eccentricity index (1.39 vs. 1.08, p<0.001), systolic pulmonary artery pressure (64 vs. 29mmHg, p<0.001) and right ventricular Tei index (0.55 vs. 0.28, p = 0.007), and reduced tricuspid annular plane systolic excursion (19.0 vs. 26.5mm, p<0.001) were detected in PH patients as compared to controls. With increasing eccentricity of left ventricle, LV torsion was both decreased and delayed. Torsion rate paralleled this pattern of change during systole, but not during diastole. In conclusion, right ventricular pressure overload directly affects LV torsion mechanics. The echocardiographic methodology applied provides novel insights in the interrelation of right- and left ventricular function.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Direita/fisiologia , Pressão Ventricular/fisiologia , Adulto , Idoso , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Ecocardiografia , Humanos , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Torção Mecânica , Disfunção Ventricular Esquerda/etiologia
14.
PLoS One ; 15(5): e0233176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421724

RESUMO

INTRODUCTION: Levosimendan is approved for acute heart failure. Within this context, pulmonary hypertension represents a frequent co-morbidity. Hence, the effects of levosimendan on segmental pulmonary vascular resistance (PVR) are relevant. So far, this issue has been not studied. Beyond that the relaxant effects of levosimendan in human pulmonary vessel are unknown. We addressed these topics in rats' isolated perfused lungs (IPL) and human precision-cut lung slices (PCLS). MATERIAL AND METHODS: In IPL, levosimendan (10 µM) was perfused in untreated and endothelin-1 pre-contracted lungs. The pulmonary arterial pressure (PPA) was continuously recorded and the capillary pressure (Pcap) was determined by the double-occlusion method. Thereafter, segmental PVR, expressed as precapillary (Rpre) and postcapillary resistance (Rpost) and PVR were calculated. Human PCLS were prepared from patients undergoing lobectomy. Levosimendan-induced relaxation was studied in naïve and endothelin-1 pre-contracted PAs and PVs. In endothelin-1 pre-contracted PAs, the role of K+-channels was studied by inhibition of KATP-channels (glibenclamide), BKCa2+-channels (iberiotoxin) and Kv-channels (4-aminopyridine). All changes of the vascular tone were measured by videomicroscopy. In addition, the increase of cAMP/GMP due to levosimendan was measured by ELISA. RESULTS: Levosimendan did not relax untreated lungs or naïve PAs and PVs. In IPL, levosimendan attenuated the endothelin-1 induced increase of PPA, PVR, Rpre and Rpost. In human PCLS, levosimendan relaxed pre-contracted PAs or PVs to 137% or 127%, respectively. In pre-contracted PAs, the relaxant effect of levosimendan was reduced, if KATP- and Kv-channels were inhibited. Further, levosimendan increased cGMP in PAs/PVs, but cAMP only in PVs. DISCUSSION: Levosimendan reduces rats' segmental PVR and relaxes human PAs or PVs, if the pulmonary vascular tone is enhanced by endothelin-1. Regarding levosimendan-induced relaxation, the activation of KATP- and Kv-channels is of impact, as well as the formation of cAMP and cGMP. In conclusion, our results suggest that levosimendan improves pulmonary haemodynamics, if PVR is increased as it is the case in pulmonary hypertension.


Assuntos
Hipertensão Pulmonar , Pulmão , Artéria Pulmonar , Veias Pulmonares , Simendana/farmacologia , Resistência Vascular/efeitos dos fármacos , Animais , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Perfusão , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Veias Pulmonares/metabolismo , Veias Pulmonares/fisiopatologia , Ratos , Ratos Wistar
15.
J Cardiovasc Magn Reson ; 22(1): 28, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32354373

RESUMO

BACKGROUND: Pulmonary hypertension (PH) conveys a worse prognosis in heart failure (HF), in particular when right ventricular (RV) dysfunction ensues. Cardiovascular magnetic resonance (CMR) non-invasively estimates pulmonary vascular resistance (PVR), which has shown prognostic value in HF. Importantly, RV to pulmonary artery (PA) coupling is altered early in HF, before significant rise in PV resistance occurs. The aim of this study was to assess the prognostic value of mean velocity at the pulmonary artery (mvPA), a novel non-invasive parameter determined by CMR, in HF with reduced ejection fraction (HFrEF) with and without associated PH. METHODS: Prospective inclusion of 238 patients admitted for new-onset HFrEF. MvPA was measured with CMR during index admission. The primary endpoint was defined as a composite of HF readmissions and all-cause mortality. RESULTS: During a median follow-up of 25 months, 91 patients presented with the primary endpoint. Optimal cut-off value of mvPA calculated by the receiver operator curve for the prediction of the primary endpoint was 9 cm/s. The primary endpoint occurred more frequently in patients with mvPA≤9 cm/s, as indicated by Kaplan-Meier survival curves; Log Rank 16.0, p <  0.001. Importantly, mvPA maintained its prognostic value regardless of RV function and also when considering mortality and HF readmissions separately. On Cox proportional hazard analysis, reduced mvPA≤9 cm/s emerged as an independent prognostic marker, together with NYHA III-IV/IV class, stage 3-4 renal failure and ischemic cardiomyopathy. CONCLUSIONS: In our HFrEF cohort, mvPA emerged as an independent prognostic indicator independent of RV function, allowing identification of a higher-risk population before structural damage onset. Moreover, mvPA emerged as a surrogate marker of the RV-PA unit coupling status.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Artéria Pulmonar/diagnóstico por imagem , Volume Sistólico , Função Ventricular Esquerda , Idoso , Velocidade do Fluxo Sanguíneo , Progressão da Doença , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Artéria Pulmonar/fisiopatologia , Fatores de Risco , Fatores de Tempo , Função Ventricular Direita
16.
Int J Cardiovasc Imaging ; 36(8): 1497-1505, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32350704

RESUMO

Pulmonary hypertension (PH) is a well-recognised complication of sarcoidosis. Non-invasive diagnosis is challenging due to limited accuracy of echocardiography in interstitial lung disease. This study evaluates the value of echocardiographic PH probability for diagnosing PH in pulmonary sarcoidosis. All consecutive patients between August 2015 and November 2018 were prospectively screened for PH, and classified as low, intermediate or high PH probability. Patients with intermediate or high PH probability were referred for right heart catheterisation. PH was defined as a mean pulmonary artery pressure of ≥ 25 mm Hg. Additional data on pulmonary function and chest-CT was collected. Of all 479 patients, PH was present in 17 and absent in 19 patients. Six patients refused right heart catheterisation. PH was present in 33% and 75% of patients with intermediate and high PH probability respectively (n = 36). TRV max was measurable in 46% of all patients. Measurability did not correlate with FVC% predicted or presence of significant fibrosis. In intermediate and high PH probability, TRV max < 2.9 m/s successfully ruled out PH whereas a TRV max > 3.4 confirmed PH in all patients. If TRV max was absent or in between 2.9 and 3.4, secondary echocardiographic signs were not able to improve the diagnostic accuracy. PH is unlikely in patients with a TRV max < 2.9 m/s on echocardiography, whereas PH is highly suspected in a TRV max > 3.4 m/s. Discrimination is challenging if the TRV max is between 2.9-3.4 m/s or absent. Additional secondary signs do not improve discrimination. Decision making for further investigations should be made by an expert team.


Assuntos
Ecocardiografia , Hipertensão Pulmonar/diagnóstico por imagem , Sarcoidose Pulmonar/diagnóstico por imagem , Adulto , Idoso , Pressão Arterial , Função do Átrio Direito , Progressão da Doença , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Fatores de Risco , Sarcoidose Pulmonar/complicações , Sarcoidose Pulmonar/fisiopatologia , Função Ventricular Direita
17.
Am J Respir Cell Mol Biol ; 63(3): 279-292, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32453969

RESUMO

In this review, we explore the main themes from the 62nd Annual Aspen Lung Conference (hypoxia, cellular metabolism, inflammatory pathways, aberrant proliferation, and personalized medicine) and highlight challenges and opportunities in the coming decade of pulmonary vascular disease.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/tratamento farmacológico , Miócitos de Músculo Liso/metabolismo , Medicina de Precisão , Artéria Pulmonar/fisiopatologia , Animais , Humanos , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Músculo Liso Vascular/metabolismo
18.
Int J Cardiovasc Imaging ; 36(10): 1831-1843, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32462450

RESUMO

Noninvasive estimation of systolic pulmonary artery pressure (SPAP) during exercise stress echocardiography (ESE) is recommended for pulmonary hemodynamics evaluation but remains flow-dependent. Our aim was to assess the feasibility of pulmonary vascular reserve index (PVRI) estimation during ESE combining SPAP with cardiac output (CO) or exercise-time and compare its value in three group of patients: with invasively confirmed pulmonary hypertension (PH), at risk of PH development (PH risk) mainly with systemic sclerosis and in controls (C) without clinical risk factors for PH, age-matched with PH risk patients. We performed semisupine ESE in 171 subjects: 31 PH, 61 PH at risk and 50 controls as well as in 29 young, healthy normals. Rest and stress assessment included: tricuspid regurgitant flow velocity (TRV), pulmonary acceleration time (ACT), CO (Doppler-estimated). SPAP was calculated from TRV or ACT when TRV was not available. We estimated PVRI based on CO (peak CO/SPAP*0.1) or exercise-time (ESE time/SPAP*0.1). During stress, TRV was measurable in 44% patients ACT in 77%, either one in 95%. PVRI was feasible in 65% subjects with CO and 95% with exercise-time (p < 0.0001). PVRI was lower in PH compared to controls both for CO-based PVRI (group 1 = 1.0 ± 0.95 vs group 3 = 4.28 ± 2.3, p < 0.0001) or time-based PVRI estimation (0.66 ± 0.39 vs 3.95 ± 2.26, p < 0.0001). The proposed criteria for PH detection were for CO-based PVRI ≤ 1.29 and ESE-time based PVRI ≤ 1.0 and for PH risk ≤ 1.9 and ≤ 1.7 respectively. Noninvasive estimation of PVRI can be obtained in near all patients during ESE, without contrast administration, integrating TRV with ACT for SPAP assessment and using exercise time as a proxy of CO. These indices allow for comparison of pulmonary vascular dynamics in patients with varied exercise tolerance and clinical status.


Assuntos
Ecocardiografia Doppler , Ecocardiografia sob Estresse , Teste de Esforço , Hemodinâmica , Hipertensão Pulmonar/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Circulação Pulmonar , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Arterial , Débito Cardíaco , Estudos de Casos e Controles , Europa (Continente) , Tolerância ao Exercício , Estudos de Viabilidade , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Artéria Pulmonar/fisiopatologia , Fatores de Tempo , Adulto Jovem
20.
Br J Radiol ; 93(1110): 20191011, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32160003

RESUMO

OBJECTIVE: Our study was conducted with an attempt to investigate the diagnostic analysis of abnormal increase of fetal pulmonary artery systolic pressure (PASP) in middle and late pregnancy by color Doppler echocardiography. METHODS: From August 2017 to January 2019, 52 fetuses with moderate or greater tricuspid high-speed regurgitation were retrospectively analyzed and selected as Group A. 88 fetuses with full-color blood flow of the two ventricles and symmetrical sizes of the cardiac cavities on both sides harboring tricuspid valve and mild regurgitation or a small amount of regurgitation were selected as Group B. The pulmonary artery blood flow acceleration time (AT) and right ventricular ejection time (ET) was measured, and the PASP was calculated. RESULTS: The tricuspid regurgitation velocity, tricuspid regurgitation pressure difference and PASP in Group A were higher than those in Group B (p < 0.05), and the AT and AT/ET values in Group A were lower than those in Group B (p < 0.05). Gestational age, tricuspid regurgitation velocity and tricuspid regurgitation pressure difference were positively correlated with PASP. However, AT/ET and AT value were negatively correlated with PASP. CONCLUSION: The abnormal increase of pulmonary artery can be assessed by color Doppler echocardiography of fetal tricuspid regurgitation, which is worth popularizing and applying in clinic. ADVANCES IN KNOWLEDGE: It was suggested that the middle- and late-stage fetuses with moderate or greater tricuspid regurgitation and with >20 mmHg regurgitation pressure difference should be followed up in clinic. If PASP was ≥70 mmHg with symptoms of right heart failure, fetuses should be closely observed until 35-36 weeks old to ensure fetal safety and early delivery would be recommended.


Assuntos
Ecocardiografia Doppler em Cores , Doenças Fetais/diagnóstico por imagem , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Adulto , Pressão Arterial/fisiologia , Feminino , Doenças Fetais/fisiopatologia , Idade Gestacional , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologia , Humanos , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Volume Sistólico , Insuficiência da Valva Tricúspide/fisiopatologia
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