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Arteriosclerosis, Thrombosis, and... Jun 2024Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, which involves aberrant proliferation and...
BACKGROUND
Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, which involves aberrant proliferation and apoptosis resistance of the pulmonary arterial smooth muscle cells (PASMCs), resembling the hallmark characteristics of cancer. In cancer, the HMGB2 (high-mobility group box 2) protein promotes the pro-proliferative/antiapoptotic phenotype. However, the function of HMGB2 in PH remains uninvestigated.
METHODS
Smooth muscle cell (SMC)-specific HMGB2 knockout or HMGB2-OE (HMGB2 overexpression) mice and HMGB2 silenced rats were used to establish hypoxia+Su5416 (HySu)-induced PH mouse and monocrotaline-induced PH rat models, respectively. The effects of HMGB2 and its underlying mechanisms were subsequently elucidated using RNA-sequencing and cellular and molecular biology analyses. Serum HMGB2 levels were measured in the controls and patients with pulmonary arterial (PA) hypertension.
RESULTS
HMGB2 expression was markedly increased in the PAs of patients with PA hypertension and PH rodent models and was predominantly localized in PASMCs. SMC-specific HMGB2 deficiency or silencing attenuated PH development and pulmonary vascular remodeling in hypoxia+Su5416-induced mice and monocrotaline-treated rats. SMC-specific HMGB2 overexpression aggravated hypoxia+Su5416-induced PH. HMGB2 knockdown inhibited PASMC proliferation in vitro in response to PDGF-BB (platelet-derived growth factor-BB). In contrast, HMGB2 protein stimulation caused the hyperproliferation of PASMCs. In addition, HMGB2 promoted PASMC proliferation and the development of PH by RAGE (receptor for advanced glycation end products)/FAK (focal adhesion kinase)-mediated Hippo/YAP (yes-associated protein) signaling suppression. Serum HMGB2 levels were significantly increased in patients with PA hypertension, and they correlated with disease severity, predicting worse survival.
CONCLUSIONS
Our findings indicate that targeting HMGB2 might be a novel therapeutic strategy for treating PH. Serum HMGB2 levels could serve as a novel biomarker for diagnosing PA hypertension and determining its prognosis.
Topics: Animals; HMGB2 Protein; Humans; Vascular Remodeling; Male; Myocytes, Smooth Muscle; Disease Models, Animal; Pulmonary Artery; Mice, Knockout; Muscle, Smooth, Vascular; Rats; Mice, Inbred C57BL; Mice; Cell Proliferation; Severity of Illness Index; Signal Transduction; Pulmonary Arterial Hypertension; Rats, Sprague-Dawley; Female; Cells, Cultured; Middle Aged; Hypertension, Pulmonary
PubMed: 38572649
DOI: 10.1161/ATVBAHA.123.319916 -
Journal of the College of Physicians... Nov 2023To investigate whether pulmonary artery diameters obtained from lung perfusion single-photon emission computed tomography-computed tomography (SPECT-CT) images and... (Observational Study)
Observational Study
OBJECTIVE
To investigate whether pulmonary artery diameters obtained from lung perfusion single-photon emission computed tomography-computed tomography (SPECT-CT) images and semiquantitative visual scoring (SVS) could serve as predictors of chronic pulmonary thromboembolic disease (CPTED) in acute pulmonary embolism patients (APE).
STUDY DESIGN
Observational study. Place and Duration of the Study: Department of Nuclear Medicine, Samsun Provincial Health Directorate, Gazi State Hospital, Samsun, Turkey, from January 2016 to March 2021.
METHODOLOGY
A total of 142 patients undergoing lung perfusion SPECT-CT were included in this study. Patients were classified as APE (+) (n=42) and APE (-) (n=100) based on laboratory and radiological findings, clinical diagnosis, and treatment protocol. Non-contrast CT images were used to determine the diameters (mm) of the main (MPA), right (RPA), and left (LPA) pulmonary arteries and the main pulmonary artery/aorta (PA/AO) ratio. All perfusion defects were scored using SVS for the PE (+) group. Seventeen patients with a diagnosis of CPTED were followed up. The scores and arterial diameters of recovered APE and follow-up patients were compared.
RESULTS
The mean diameters (mm) of MPA, RPA, and LPA and PA/AO ratio were 29.74±5.51, 21.73±4.11, 22.74±4.16, and 0.83±0.16 in the APE (+) group and 26.18±4.99, 19.35±3.84, 19.49±4.15, and 0.77±0.15 in the APE (-) group, respectively (p<0.001). Mean MPA diameter (mm), total defect (TD), right visual defect (RVD), and PA/AO ratio were 31.67±15.65, 29.88±15.59, 17.65±10.51, and 0.91±0.18 in the CPTED group and 28.06±4.59, 18.92±13.30, 10.4±7.41, and 0.78±0.15 in the recovered APE group, respectively (p<0.05).
CONCLUSION
Assessment of pulmonary artery diameter and PA/AO ratio may indicate APE, but TD and RVD scores may be predictive factors for CPTED when included in the assessment along with MPA dilatation and PA/AO ratio.
KEY WORDS
Acute pulmonary embolism, Pulmonary artery diameter, Lung SPECT-CT, Chronic pulmonary thromboembolic disease, Semi-quantitative visual scoring.
Topics: Humans; Animals; Pulmonary Artery; Pulmonary Embolism; Acute Disease; Lung Diseases; Tomography, X-Ray Computed; Tomography, Emission-Computed, Single-Photon; Hominidae; Retrospective Studies
PubMed: 37926872
DOI: 10.29271/jcpsp.2023.11.1229 -
Acta Radiologica (Stockholm, Sweden :... Jul 2023A hemorrhagic aortopulmonary artery sheath (HAPS) is an infrequent and critical complication of aortic dissection (AD), which is caused by a hematoma extending through... (Review)
Review
A hemorrhagic aortopulmonary artery sheath (HAPS) is an infrequent and critical complication of aortic dissection (AD), which is caused by a hematoma extending through the ruptured aortic wall into the aortopulmonary artery sheath. The adventitial hematoma might narrow or even occlude the lumen of the pulmonary arteries and extend into the pulmonary interstitium and alveoli. The prompt and accurate recognition of HAPS on computed tomography (CT) is crucial and might assist in the diagnosis of unidentifiable AD. HAPS was manifested as high attenuation areas surrounded the pulmonary arteries without enhancement on CT; even thickened bronchovascular sheath and ground-glass consolidations surrounded bronchovascular distribution, which might be associated with the prognosis. Aggressive and effective surgical treatment is the primary determinant of short-term survival.
Topics: Humans; Aortic Dissection; Hemorrhage; Aorta; Pulmonary Artery; Hematoma
PubMed: 36683329
DOI: 10.1177/02841851221151148 -
The European Respiratory Journal Dec 2023Pulmonary vascular disease (PVD) affects the majority of preterm neonates with bronchopulmonary dysplasia (BPD) and significantly determines long-term mortality through...
BACKGROUND
Pulmonary vascular disease (PVD) affects the majority of preterm neonates with bronchopulmonary dysplasia (BPD) and significantly determines long-term mortality through undetected progression into pulmonary hypertension. Our objectives were to associate characteristics of pulmonary artery (PA) flow and cardiac function with BPD-associated PVD near term using advanced magnetic resonance imaging (MRI) for improved risk stratification.
METHODS
Preterms <32 weeks postmenstrual age (PMA) with/without BPD were clinically monitored including standard echocardiography and prospectively enrolled for 3 T MRI in spontaneous sleep near term (AIRR (Attention to Infants at Respiratory Risks) study). Semi-manual PA flow quantification (phase-contrast MRI; no BPD n=28, mild BPD n=35 and moderate/severe BPD n=25) was complemented by cardiac function assessment (cine MRI).
RESULTS
We identified abnormalities in PA flow and cardiac function, increased net forward volume right/left ratio, decreased mean relative area change and pathological right end-diastolic volume, to sensitively detect BPD-associated PVD while correcting for PMA (leave-one-out area under the curve 0.88, sensitivity 0.80 and specificity 0.81). We linked these changes to increased right ventricular (RV) afterload (RV-arterial coupling (p=0.02), PA mid-systolic notching (t2; p=0.015) and cardiac index (p=1.67×10)) and correlated echocardiographic findings. Identified in moderate/severe BPD, we successfully applied the PA flow model in heterogeneous mild BPD cases, demonstrating strong correlation of PVD probability with indicators of BPD severity, duration of mechanical ventilation (r=0.63, p=2.20×10) and oxygen supplementation (r=0.60, p=6.00×10).
CONCLUSIONS
Abnormalities in MRI PA flow and cardiac function exhibit significant, synergistic potential to detect BPD-associated PVD, advancing the possibilities of risk-adapted monitoring.
Topics: Infant, Newborn; Infant; Humans; Pulmonary Artery; Lung; Bronchopulmonary Dysplasia; Hypertension, Pulmonary; Magnetic Resonance Imaging; Vascular Diseases
PubMed: 37678954
DOI: 10.1183/13993003.02445-2022 -
Scientific Reports Dec 2023Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene...
Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This "cell biopsy" method may provide insight into patient and lung EC heterogeneity to advance precision medicine approaches in PAH.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Artery; Endothelial Cells; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Vascular Diseases; Wnt Signaling Pathway
PubMed: 38110438
DOI: 10.1038/s41598-023-48077-6 -
Cells May 2024Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing... (Review)
Review
Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing and remodeling extracellular matrixes and organizing functional tissue networks, which are essential for tissue homeostasis and various human diseases. Pulmonary hypertension (PH) is a devastating syndrome with high mortality, characterized by remodeling of the pulmonary vasculature and significant cellular and structural changes within the intima, media, and adventitia layers. Most research on PH has focused on alterations in the intima (endothelial cells) and media (smooth muscle cells). However, research over the past decade has provided strong evidence of the critical role played by pulmonary artery adventitial fibroblasts in PH. These fibroblasts exhibit the earliest, most dramatic, and most sustained proliferative, apoptosis-resistant, and inflammatory responses to vascular stress. This review examines the aberrant phenotypes of PH fibroblasts and their role in the pathogenesis of PH, discusses potential molecular signaling pathways underlying these activated phenotypes, and highlights areas of research that merit further study to identify promising targets for the prevention and treatment of PH.
Topics: Humans; Hypertension, Pulmonary; Fibroblasts; Animals; Signal Transduction; Pulmonary Artery
PubMed: 38891046
DOI: 10.3390/cells13110914 -
Journal of the American College of... Nov 2023
Topics: Humans; Echocardiography, Stress; Exercise Test; Hypertension, Pulmonary; Ventricular Function, Right; Ventricular Dysfunction, Right; Heart Ventricles; Pulmonary Artery
PubMed: 37968016
DOI: 10.1016/j.jacc.2023.09.815 -
Circulation Research May 2024The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is...
BACKGROUND
The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is still debatable although it is believed that they predominantly derive from preexisting vascular smooth muscle cells (VSMCs).
METHODS
mice were used to lineage trace GLI1+ (glioma-associated oncogene homolog 1-positive) cells in the context of pulmonary hypertension using 2 independent models of vascular remodeling and reverse remodeling: hypoxia and cigarette smoke exposure. Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3-dimensional reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neomuscularization of the pulmonary vasculature.
RESULTS
The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and this lineage contributes to around 50% of newly formed ACTA2+ cells around these normally nonmuscularized vessels. During reverse remodeling, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented vascular remodeling in response to hypoxia and attenuated the increase in right ventricular systolic pressure and right heart hypertrophy. Single-cell RNA sequencing on sorted lineage-labeled GLI1+ cells revealed an fraction of cells with pathways in cancer and MAPK (mitogen-activated protein kinase) signaling as potential players in reprogramming these cells during vascular remodeling. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both group 1 and group 3 pulmonary hypertension and can promote proliferation and myogenic differentiation.
CONCLUSIONS
Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in pulmonary hypertension and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.
Topics: Animals; Zinc Finger Protein GLI1; Mice; Vascular Remodeling; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Mice, Inbred C57BL; Pulmonary Artery; Mice, Transgenic; Male; Humans; Hypoxia
PubMed: 38639105
DOI: 10.1161/CIRCRESAHA.123.323736 -
International Journal of Cardiology Jan 2024Right ventricular-pulmonary artery (RV-PA) coupling indicates efficiency of energy transfer from the right ventricle to the pulmonary circulation. The gold standard... (Review)
Review
Right ventricular-pulmonary artery (RV-PA) coupling indicates efficiency of energy transfer from the right ventricle to the pulmonary circulation. The gold standard measurement, end-systolic elastance/arterial elastance ratio (Ees/Ea), is derived from invasive pressure-volume loop, which is technically demanding, expensive and limited in clinical practice. Recent studies have proposed various non-invasive surrogates of Ees/Ea based on echocardiography assessment, of which TAPSE/PASP ratio is an easily-obtained and validated parameter in severe pulmonary hypertension and rapidly applicated in the diagnosis and risk evaluation of various diseases and cardiac intervention. In this review, we summarized principles and validations of echocardiographic surrogates, and their clinical utilities and also limitations. The goal is to systematically review the research advances of echocardiography assessment of RV-PA coupling and help to guide clinical practice.
Topics: Humans; Pulmonary Artery; Heart Ventricles; Echocardiography; Hypertension, Pulmonary; Pulmonary Circulation; Ventricular Dysfunction, Right; Ventricular Function, Right; Stroke Volume
PubMed: 37704177
DOI: 10.1016/j.ijcard.2023.131358 -
Current Problems in Cardiology Sep 2023Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality. The treatment is based on the type of PH. Prognosis still remains poor despite... (Meta-Analysis)
Meta-Analysis Review
Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality. The treatment is based on the type of PH. Prognosis still remains poor despite the use of different medications. Pulmonary artery denervation (PADN) has been studied as a novel therapeutic option in these patients. PUBMED, EMBASE and COCHRANE databases were searched by 2 investigators until January 2023. Information was analyzed for the following outcomes: 6-minute walk distance (6MWD), mean pulmonary artery pressure, pulmonary vascular resistance and cardiac output. Subgroup analysis comparing pre and post PADN in different PH groups was done. Statistical analysis was performed with the Review Manager version 5.4. This meta- analysis included 6 controlled trials and 6 single-arm prospective studies with a total of 616 patients. Our pooled analysis showed a significant reduction in mean pulmonary artery pressure [WMD -6.51, 95% CI (-9.87, -3.15), p = 0.0001], pulmonary vascular resistance [WMD -3.69, 95% CI (-6.74, -0.64), p = 0.02] and increased cardiac output [WMD -0.37, 95% CI (0.08, 0.65), p = 0.01]. Subgroup analysis pre and post PADN demonstrated a significant improvement in 6MWD in the WHO group 1 [WMD 99.53, 95% CI (19.60, 179.47), p = 0.01], group 2 [WMD: 69.96, 95% CI (36.40, 103.51), p = < 0.0001] and group 4 [WMD: 99.54, 95% CI (21.80, 177.28), p = 0.01]. This meta-analysis supports PADN as a therapeutic option for patients with PH, regardless of group class. Further randomized trials are still needed to evaluate safety and efficacy.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Artery; Prospective Studies; Denervation
PubMed: 37121454
DOI: 10.1016/j.cpcardiol.2023.101776