scholarly journals Incremental Experience in In Vitro Primary Culture of Human Pulmonary Arterial Endothelial Cells Harvested from Swan-Ganz Pulmonary Arterial Catheters

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3229
Author(s):  
Birger Tielemans ◽  
Leanda Stoian ◽  
Allard Wagenaar ◽  
Mathias Leys ◽  
Catharina Belge ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Diseases ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Endothelial Phenotype ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells ◽  
Pulmonary Vascular Diseases

Pulmonary arterial hypertension (PAH) is a devastating condition affecting the pulmonary microvascular wall and endothelium, resulting in their partial or total obstruction. Despite a combination of expensive vasodilatory therapies, mortality remains high. Personalized therapeutic approaches, based on access to patient material to unravel patient specificities, could move the field forward. An innovative technique involving harvesting pulmonary arterial endothelial cells (PAECs) at the time of diagnosis was recently described. The aim of the present study was to fine-tune the initial technique and to phenotype the evolution of PAECs in vitro subcultures. PAECs were harvested from Swan-Ganz pulmonary arterial catheters during routine diagnostic or follow up right heart catheterization. Collected PAECs were phenotyped by flow cytometry and immunofluorescence focusing on endothelial-specific markers. We highlight the ability to harvest patients’ PAECs and to maintain them for up to 7–12 subcultures. By tracking the endothelial phenotype, we observed that PAECs could maintain an endothelial phenotype for several weeks in culture. The present study highlights the unique opportunity to obtain homogeneous subcultures of primary PAECs from patients at diagnosis and follow-up. In addition, it opens promising perspectives regarding tailored precision medicine for patients suffering from rare pulmonary vascular diseases.

scholarly journals Plasma exosomal miR-596: a novel biomarker predicts survival in patients with idiopathic pulmonary artery hypertension

2021 ◽  
Vol 49 (3) ◽  
pp. 030006052110023
Author(s):  
Yang Huang ◽  
Zuo-Gang Wang ◽  
Liang Tang ◽  
Su-Gang Gong ◽  
Yuan-Yuan Sun ◽  
...  
Keyword(s):  
Right Heart Catheterization ◽  
Pulmonary Artery Hypertension ◽  
Right Atrial ◽  
Heart Catheterization ◽  
Distribution Analysis ◽  
Poor Overall Survival ◽  
Transmission Electron ◽  
Exosomal Mirnas ◽  
Pulmonary Arterial

Objective To determine if plasma exosomal microRNAs (miRNAs) can predict survival in patients with idiopathic pulmonary arterial hypertension (IPAH). Methods The study enrolled patients with IPAH that underwent right heart catheterization. Plasma was collected and exosomal miRNAs were extracted. Exosomes were evaluated using transmission electron microscopy, Western blot analysis and particle size distribution analysis. MiRNAs were evaluated using a miRNA microarray and validated using real-time polymerase chain reaction. Results This study included 12 patients with IPAH in the study group and 48 patients with IPAH in the validation group. The mean ± SD follow-up duration was 60.3 ± 35.4 months in the overall cohort. The levels of miR-596 were higher in the nonsurvivors compared with the survivors. The levels of miR-596 significantly correlated with survival time, mean right atrial pressure, pulmonary vascular resistance (PVR) and cardiac index. High levels of miR-596 and PVR were significantly associated with poor overall survival. Multivariate analysis demonstrated that exosomal miR-596 (hazard ratio [HR] = 2.119; 95% confidence interval [CI] 1.402, 3.203) and PVR (HR = 1.146; 95% CI 1.010, 1.300) were independent predictors of survival. Conclusions High levels of plasma exosomal miR-596 were significantly associated with disease severity and poor prognosis of patients with IPAH.

Matrix Stiffening Induces a Pathogenic QKI-miR-7-SRSF1 Signaling Axis in Pulmonary Arterial Endothelial Cells

2021 ◽  
Author(s):  
Chen-Shan Chen Woodcock ◽  
Neha Hafeez ◽  
Adam Handen ◽  
Ying Tang ◽  
Lloyd D Harvey ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Rna Binding ◽  
Vascular Diseases ◽  
Vascular Stiffness ◽  
Artery Stiffness ◽  
Signaling Axis ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells ◽  
Splicing Factor 1

Pulmonary arterial hypertension (PAH) refers to a set of heterogeneous vascular diseases defined by elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), leading to right ventricular (RV) remodeling and often death. Early increases in pulmonary artery stiffness in PAH drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling. Dysregulation of microRNAs can drive PAEC dysfunction. However, the role of vascular stiffness in regulating pathogenic microRNAs in PAH is incompletely understood. Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs. The RNA binding protein Quaking (QKI) has been implicated in the biogenesis of miR-7. Correspondingly, we found that ECM stiffness up-regulated QKI, and QKI knockdown led to increased miR-7. Downstream of the QKI-miR-7 axis, the serine and arginine rich splicing factor 1 (SRSF1) was identified as a direct target of miR-7. Correspondingly, SRSF1 was reciprocally up-regulated in PAECs exposed to stiff ECM and was negatively correlated with miR-7. Decreased miR-7 and increased QKI and SRSF1 were observed in lungs from PAH patients and PAH rats exposed to SU5416/hypoxia. Lastly, miR-7 upregulation inhibited human PAEC migration, while forced SRSF1 expression reversed this phenotype, proving that miR-7 depended upon SRSF1 to control migration. In aggregate, these results define the QKI-miR-7-SRSF1 axis as a mechanosensitive mechanism linking pulmonary arterial vascular stiffness to pathogenic endothelial function. These findings emphasize implications relevant to PAH and suggest the potential benefit of developing therapies that target this miRNA-dependent axis in PAH.

Diagnosis and clinical investigation of patients presenting with pulmonary hypertension

ESC CardioMed ◽  
2018 ◽  
pp. 2507-2511 ◽  
Author(s):  
Daniela Calderaro ◽  
Luis Felipe Prada ◽  
Rogério Souza
Keyword(s):  
Pulmonary Hypertension ◽  
Clinical Investigation ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Right Heart ◽  
Reference Centre ◽  
Mean Pulmonary Arterial Pressure ◽  
Invasive Test ◽  
Pulmonary Arterial

The diagnosis of pulmonary hypertension (PH) relies on the haemodynamic criterion of mean pulmonary arterial pressure greater than or equal to 25 mmHg, assessed by right heart catheterization. The scope of this chapter is to discuss the key elements of clinical assessment of PH patients and the decision process to indicate right heart catheterization. Investigation must get through all the possible causes of PH according to their probability and frequency in the population. Echocardiography is the most important non-invasive test as an indicator for further diagnostic evaluation. Patients who are eligible for right heart catheterization should always be referred to PH centres, where technical skills and standardized procedures will enable maximal reliability of haemodynamic measurement. In the reference centre, a multidisciplinary team will discuss clinical and haemodynamic data, to propose the best therapeutic and follow-up schedule.

scholarly journals Impact of Three Different Algorithms for the Screening of SSc-PAH and Comparison with the Decisions of a Multidisciplinary Team

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1738
Author(s):  
Valentin Coirier ◽  
Céline Chabanne ◽  
Stéphane Jouneau ◽  
Nicolas Belhomme ◽  
Alice Ballerie ◽  
...  
Keyword(s):  
Multidisciplinary Team ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Right Heart ◽  
Tertiary Center ◽  
Previous Definition ◽  
Pulmonary Arterial ◽  
Definition Of ◽  
The Impact

Background: to compare three existing screening algorithms of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) with the results of a multidisciplinary team (MDT) meeting from a tertiary center. Methods: we conducted a monocentric longitudinal study from 2015 to 2018. All patients with SSc according to LeRoy’s classification were eligible. Patients were excluded in the case of missing data required by any of the three screening algorithms. The algorithms were applied for each patient at inclusion. Right heart catheterization (RHC) was performed based on the MDT decision. MDT members were all blinded from the results of the three algorithms regarding RHC recommendations. The RHC recommendations of each algorithm were compared with the MDT decision, and the impact on diagnosis and management was evaluated. Results: 117 SSc patients were consecutively included in the study, and 99 had follow-up data over the three-year duration of the study (10 deaths). Among the 117 patients, the MDT suggested RHC for 16 patients (14%), DETECT algorithm for 28 (24%), ASIG for 48 (41%) and ESC/ERS 2015 for 20 (17%). Among the 16 patients who had RHC, SSc-PAH was diagnosed in seven. Among patients with an initial recommendation of RHC based on at least one algorithm but not according to the MDT meeting, no SSc-PAH was diagnosed during the three-year follow-up. Results were unchanged when the new 2018 definition of PAH was applied instead of the previous definition. Conclusion: a MDT approach appears interesting for the screening of SSc-PAH, with a significant reduction of RHC performed in comparison with dedicated algorithms. The specific relevance of a MDT for the management and follow-up of patients with RHC recommended by existing algorithms but with no PAH warrants further studies.

Abstract 1636: Adverse Effect of Estrogen on Bone Morphogenetic Protein Receptor Signal Pathway in Pulmonary Arterial Endothelial Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hiroaki Ichimori ◽  
Shigetoyo Kogaki ◽  
Hidekazu Ishida ◽  
Jun Narita ◽  
Toshiki Uchikawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Estrogen Receptor ◽  
Bone Morphogenetic Protein ◽  
Signal Pathway ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells

Gender differences in the development of Pulmonary Artery Hypertension (PAH) have been documented in both human and animal studies. In human, idiopathic PAH is predominantly a disease of young women in their child-bearing years, which suggests a role of female sex hormones in the pathogenesis of PAH. However, the effect of sex hormones on pulmonary vasculatures and the development of PAH has not been fully understood. Recent researches have revealed genetic predisposition such as BMPR (Bone Morphogenetic Protein Receptor). The aim of the present study is to investigate the effect of β-estradiol (E2) and oxygen concentration upon BMPR signal pathway in pulmonary arterial endothelial cells (PAEC) in vitro. Human and rat PAEC were cultured and we examined the expression of BMPR2, BMP-regulated Smads, and Id1 under 21% or 1% O 2 with BMP2 stimulation. Then, we investigate changes in the expression of these molecules in the presence of E2 with or without estrogen receptor antagonist (ICI 182.780.). First, we confirmed that estrogen receptor α and β were expressed in both PAECs. Second, we demonstrated that the expression of mRNA transcripts for BMPR2 and Id1 in PAEC was reduced after exposure to 24 hours’ hypoxia. In addition, E2 decreased the expression of phosphorylated Smad (p-Smad)1/5/8 in a dose-dependent manner (10 −10 M-10 −7 M) and p-Smad1/5/8 expression were decreased about 80% by 10 −7 M of E2. These attenuation of p-Smad1/5/8 expression were rescued by ICI182.780. Third, under normoxic condition with cobalt chloride or deferoxamine to prevent the degradation of HIF (hypoxia-inducible factor)-1α, the presence of E2 decreased the expression of p-Smad1/5/8 like under hypoxia. Conversely, administration of HIF-1α inhibitor (YC-1) canceled the reduced expression of p-Smad1/5/8 like under normoxia. Under hypoxia, the presence of E2 attenuates the BMPR signal pathway in PAEC in vitro. Our data indicated that the advance effect of E2 on BMPR signal pathway was associated with HIF-1α and estrogen receptor. Our observations provide the first evidence that female sex hormone affects on BMPR signal pathway, which can offer new strategies for the treatment of PAH.

Abstract 16770: The Epigenetic Modifier EP300: A New Corner Stone in the Regulation of Both Vascular Remodeling and Right Ventricle Failure in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Alice Bourgeois ◽  
Sarah-Eve Lemay ◽  
Yann Grobs ◽  
Charlotte romanet ◽  
Junichi Omura ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Annexin V ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Pulmonary Arterial

Introduction: Pulmonary Arterial Hypertension (PAH) is characterized by excessive proliferation and resistance to apoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs), leading to progressive increases in pulmonary vascular resistance, and ultimately right ventricular (RV) failure and death. Thanks to omics technologies, we made tremendous progress in understanding gene misregulation during disease processes and identified the epigenetic factor EP300 as a critical player in pathological processes like proliferation/apoptosis and hypertrophy/fibrosis all of which are critical features of both PA remodeling and RV failure in PAH. We hypothesized that EP300 is upregulated in PAH and contributes to both PA remodeling and RV failure. Methods and Results: By Western blot (WB) and immunofluorescence (IF), we found that EP300 is up-regulated in isolated PASMCs and distal PAs from PAH patients (n=11-14) compared to controls (n=8-10) (p<0.01). Similar results were observed in 3 PAH animal models, namely the monocrotaline (MCT), the Sugen/Hypoxia (Su/Hx) and the Fawn-Hooded rat (FHR) (p<0.05). In vitro, pharmacological inhibition of EP300 using CCS-1477 reduces PAH-PASMC proliferation (Ki67 labeling & WB PCNA; p<0.05) and resistance to apoptosis (Annexin V assay & WB Survivin; p<0.05). These effects were confirmed at the molecular level by RNA-Seq analysis. In addition, increased EP300 expression was observed in hypertrophied and failed RV from PAH patients, as well as in rats injected with MCT or subjected to pulmonary artery banding (WB, p<0.05). In animal models, EP300 negatively correlates with CO and positively correlates with RVEDP, cardiomyocyte surface area and fibrosis. Finally, we demonstrated that inhibition of EP300 using CCS-1477 or SGC-CBP30 significantly improved established PAH (right heart catheterization) in two animal models (MCT and FHR). Conclusion: EP300 upregulation contributes to both pulmonary vascular remodeling and RV dysfunction seen in PAH and its inhibition represents a promising therapeutic avenue.

scholarly journals Right ventricular dimension index by cardiac magnetic resonance for prognostication in connective tissue diseases and pulmonary hypertension

Rheumatology ◽  
2019 ◽  
Author(s):  
Nobuya Abe ◽  
Masaru Kato ◽  
Michihito Kono ◽  
Yuichiro Fujieda ◽  
Hiroshi Ohira ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Right Heart ◽  
Pulmonary Arterial ◽  
Dimension Index

Abstract Objectives Pulmonary hypertension (PH) in patients with CTD is a heterogeneous condition affected by left heart disease, chronic lung disease and thromboembolism as well as pulmonary vascular disease. Recent studies using cardiac magnetic resonance (CMR) have shown that right ventricular dysfunction is predictive for mortality in patients with PH, but limited to pulmonary arterial hypertension. This study aimed to analyse prognostic factors in PH-CTD. Methods This retrospective analysis comprised 84 CTD patients, including SSc, who underwent both CMR and right heart catheterization from 2008 to 2018. Demographics, laboratory findings, and haemodynamic and morphological parameters were extracted. The prognostic value of each parameter was evaluated by multivariate analysis using covariables derived from propensity score to control confounding factors. Results Of 84 patients, 65 had right heart catheterization-confirmed PH (54 pulmonary arterial hypertension, 11 non-pulmonary arterial hypertension). Nine out of these PH patients died during a median follow-up period of 25 months. In 65 patients with PH, right ventricular end-diastolic dimension index (RVEDDI) evaluated by CMR was independently associated with mortality (hazard ratio 1.24; 95% CI: 1.08–1.46; P = 0.003). In a receiver operating characteristic analysis, RVEDDI highly predicted mortality, with area under the curve of 0.87. The 0.5–2-year follow-up data revealed that RVEDDI in both survivors and non-survivors did not significantly change over the clinical course, leading to the possibility that an early determination of RVEDDI could predict the prognosis. Conclusion RVEDDI simply evaluated by CMR could serve as a significant predictor of mortality in PH-CTD. A further validation cohort study is needed to confirm its usability.

scholarly journals Seizures in Idiopathic Pulmonary Arterial Hypertension

2018 ◽  
Vol 05 (02) ◽  
pp. 107-109
Author(s):  
Jamir Pitton Rissardo ◽  
Ana Letícia Fornari Caprara
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Supplemental Oxygen ◽  
Right Heart Catheterization ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Heart Catheterization ◽  
Right Heart ◽  
Systemic Disorder ◽  
Pulmonary Arterial

AbstractPulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy. A 29-year-old female patient presenting with dyspnea and syncope within 6 hours of onset was admitted to our hospital. The patient stated that she looked for a neurologist months ago because she experienced abrupt shaking limbs occurring during physical activity. She was diagnosed with focal seizure, and carbamazepine (CBZ) was started. On admission, she reported that the dyspnea had started in the last week and recurrent episodes of syncope in the last few hours. A right heart catheterization was diagnostic of PAH. She was started on spironolactone, furosemide, sildenafil, warfarin, and supplemental oxygen. On 10th admission day, the patient was seizure free and the dose of CBZ was tapered. In the follow-up, the patient remained seizure free. An investigation to search for a chronic lung disease or hypoxemia, systemic disorder, hematological disorder, and metabolic disorder was negative.

Effect of ambient oxygen on cultured endothelial cells from different vascular beds

1987 ◽  
Vol 253 (4) ◽  
pp. H878-H883 ◽  
Author(s):  
H. W. Farber ◽  
D. M. Center ◽  
S. Rounds
Keyword(s):  
Endothelial Cells ◽  
Tissue Injury ◽  
Umbilical Vein ◽  
Human Umbilical Vein ◽  
Ambient Oxygen ◽  
Pulmonary Arterial ◽  
Vascular Beds ◽  
Umbilical Vein Endothelial Cells ◽  
Arterial Endothelial Cells

By the use of production of neutrophil chemoattractant activity as a marker, we investigated the responsiveness of endothelial cells of four different anatomic origins to altered ambient oxygen tension to determine whether genetic or conditioned variation existed. The ability of bovine aortic, bovine pulmonary arterial, bovine coronary arterial, and human umbilical vein endothelial cells incubated in decreased oxygen concentrations to release neutrophil chemoattractant activity was assessed. Bovine aortic, human umbilical vein, and bovine coronary arterial endothelial cells produce neutrophil chemoattractant activity in response to 10 or 3% ambient oxygen in vitro. In contrast, 0% ambient oxygen is required for appearance of neutrophil chemoattractant activity from pulmonary artery endothelial cells. These studies suggest that there may be genetic or conditioned variations in the response of endothelium from different vascular beds to decreased oxygen tensions. Furthermore, endothelial cells may play a role in neutrophil-mediated tissue injury during ischemia.

scholarly journals Pulmonary hypertension in systemic sclerosis: diagnosis by systematic screening and prognosis after three years follow-up

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Verônica Silva Vilela ◽  
Marcio Macri Dias ◽  
Ângelo Antunes Salgado ◽  
Bruno Rangel Antunes da Silva ◽  
Agnaldo José Lopes ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Systemic Sclerosis ◽  
Right Heart Catheterization ◽  
Diagnostic Tools ◽  
Heart Catheterization ◽  
Systematic Screening ◽  
Mean Pulmonary Arterial Pressure ◽  
Common Group ◽  
Pulmonary Arterial

Abstract Background Systemic sclerosis (SSc) is a rare disease, and the presence of pulmonary hypertension can be a determining factor in prognosis. The aim of this study was to evaluate the diagnosis, profile, and prognosis of systemic sclerosis pulmonary hypertension (SSc-PH) diagnosed by systematic screening in a Brazilian population. Methods A cohort of SSc patients underwent systematic screening for SSc-PH. Patients were referred for right heart catheterization (RHC) according to transthoracic echocardiogram or a combination of diagnostic tools. The clinical, immunological, and hemodynamic features and prognosis after 3 years were evaluated. Results Twenty patients underwent RHC. SSc pulmonary arterial hypertension (SSc-PAH) was the most common group of SSc-PH. These patients had long disease duration, high urate levels and highly elevated mean pulmonary arterial pressure (mPAP) and peripheral vascular resistance (PVR) on hemodynamics. Patients with mPAP > 20– < 25 mmHg had hemodynamic features of intermediate disease. Patients with SSc-PH associated to interstitial lung disease (SSc-ILD-PH) had signs of vasculopathy on hemodynamics. In patients with no-SSc-PH, the survival at 1, 2, and 3 years was 96%, 92% and 92%, respectively and in patients with SSc-PH it was 86.7%, 60% and 53.3%, respectively. Conclusions Patients identified with SSc-PAH and SSc-ILD-PH in our screening had severe clinical and hemodynamic features. Mortality remains high in SSc-PH but was more related to Bo-PAH and SSc-ILD-PH, while in SSc-PAH, the prognosis was better. Trial registration: Current Controlled Trials ISRCTN 72968188, July 8th, 2021. Retrospectively registered.

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