Pulmonary Arterial Wall Research Articles

CXCL12/CXCR4 pathway as a novel therapeutic target for RNF213-associated pulmonary arterial hypertension

Genetic backgrounds of patients with pulmonary arterial hypertension (PAH) were not fully investigated. A variant of c.14429G > A (p.Arg4810Lys) in the ring finger protein 213 gene (RNF213) was recently identified as a risk allele for poor treatment response and poor clinical prognosis in patients with PAH. However, the molecular mechanisms of the RNF213 p.Arg4810Lys variant in development of PAH are unknown. We investigated the underlying molecular mechanisms of RNF213-associated vasculopathy using an in vivo mouse model. RNF213+/p.Arg4828Lys mice, harboring the heterozygous RNF213 p.Arg4828Lys variant corresponding to the p.Arg4810Lys variant in humans, were created using the CRISPR-Cas9 system to recapitulate the genetic status of PAH patients. RNF213+/p.Arg4828Lys mice had a significant elevation of the right ventricular systolic pressure, hypertrophy of the right ventricle, and increased thickness of the pulmonary arterial medial wall compared with wild-type mice after 3 months of exposure to a hypoxic environment. C-X-C motif chemokine ligand 12 (CXCL12), a C-X-C chemokine receptor type 4 (CXCR4) ligand, was significantly elevated in the lungs of RNF213+/p.Arg4828Lys mice, and PAH was ameliorated by the administration of a CXCR4 antagonist. CXCL12-CXCR4 is an angiogenic chemokine axis, and immunohistochemistry demonstrated an increase in CXCR4 in vimentin-positive spindle-shaped cells in adventitia and interstitial lesions in RNF213+/p.Arg4828Lys mice and lung specimens from severe PAH patients with the RNF213 p.Arg4810Lys variant. We confirmed a cause-and-effect relationship between the RNF213 p.Arg4810Lys variant and PAH via the CXCL12-CXCR4 pathway. The findings in this study suggest that targeting this pathway might be a novel therapeutic strategy for RNF213-associated vasculopathy.

Impact of aortic and pulmonary artery wall histology on radicular dilatation during the Ross procedure

ObjectiveIn our study, we aim to explore the structural differences between the aortic root and the pulmonary artery to better understand the process of pulmonary autograft dilatation during the Ross procedure.Materials and methodsWe studied twenty human fetuses (aged 14–36 weeks of gestation) and four adults (one female and three males, aged 30–45 years, mean age = 37 ± 16 years). Samples of aortic root and pulmonary artery were obtained through dissection. Histological examinations, including hematoxylin–eosin, Masson’s trichrome, and orcein staining, as well as immunohistochemical technique with caldesmon staining, were performed. Microscopic counting was conducted to assess the number of elastic laminae and smooth muscle cells in each arterial wall. Statistical analyses were performed using R software. Means and standard deviations were used to present central tendencies and data dispersion for elastic laminae and smooth muscle.ResultsSignificant histological differences were observed between the aortic root and pulmonary artery in both adults and fetuses. In fetuses, no difference was found between the two vessels in terms of elastic laminae (p = 0.26) and smooth muscle cells (p = 0.69). However, in adults, significant differences were found for elastic laminae (p < 0.001) and smooth muscle cells (p < 0.001) between the aorta and pulmonary artery.ConclusionsThe microscopic vascular structure impacts the mechanical properties of the pulmonary autograft wall and explains its observed dilatation remote from the Ross procedure due to wall stresses related to systemic pressure.

In vivo study of pulmonary artery remodeling and pulsatility in long Fontan patient

Abstract Background Pulmonary vasculopathy associated with Fontan circulation is a relatively unexplored entity that could have clinical and therapeutic implications. Purpose Our aim was to evaluate the physiology of the pulmonary artery in patients with Fontan circulation using conventional right heart catheterization (RHC) and intravascular ultrasound (IVUS). Methods From December 2022 to January 2024, data from all consecutive Fontan patients undergoing RHC were prospectively collected at a tertiary referral center for adult congenital heart disease. Pressures and pulmonary artery wall high-definition IVUS recordings (OptiCrossTM, 60 MHz, Boston Scientific) were recorded at rest and during apnea. Pathological Fontan pressure was defined when as exceeding 15 mmHg. IVUS pulsatility index was defined as [(systolic lumen area - diastolic lumen area)/(diastolic lumen area) ×100], Peterson's elastic modulus as (pulmonary pulse pressure/IVUS pulsatility index), and area of wall thickness as [(wall area - lumen area)/(lumen area) x100)]. In the literature, the mean ± standard deviation (SD) normal values of elastic modulus and wall thickness area have been reported as 21 ± 1.7 mmHg and 1.4 ± 1.3%, respectively, in healthy patients without pulmonary hypertension (1: doi: 10.1186/s12931-017-0568-z). We define an alteration in intrinsic pulmonary arterial wall viscoelastic properties as an elastic modulus &amp;gt; 70 mmHg, and we define structural pulmonary wall remodeling as an increase in wall thickness area greater than 5%. Results 13 patients were studied. Median age was 28.1 years interquartile range (IQR) (25.6- 41.4), 7 (53.9%) were female, and 4 (30,8%) were in functional New York Heart Associtation (NYHA) class I. RHC and pulmonary arterial wall IVUS values are presented in Figure 1. 6 (46.2%) had Fontan abnormal pressures at rest. All patients showed minimal pulse pressure in the pulmonary arteries synchronized with heart rate, median pulmonary pulse pressure (IQR) 3 (2-4) mmHg. This pulsatility was detected in the IVUS study in all patients, pulsatility index (median (IQR) 4.8 (3.3-10.1)) and elastic modulus (median (IQR) 51.5 (20.5-101.6) mmHg). All of them had some degree of structural pulmonary wall remodeling (&amp;gt;5% wall thickness area), and 10 (76.9%) of them had marked remodeling (&amp;gt; 10%). The median (IQR) of wall thickness area was 13.6 (10.5-18.3) % (Figure 2). We think that the pseudo-normality of the elastic modulus is due to a low pulmonary pulse pressure, however, structural remodeling could be secondary to the endothelial dysfunction present and described in arteries with very low pulsatility. Conclusions The IVUS evaluation of the pulmonary artery in Fontan patients may be useful for revealing significant information regarding pulmonary physiology. Pulmonary wall thickening has been observed, providing insight into altered structural remodeling of the pulmonary arteries in this population.

Long-acting CRF2 receptor agonist COR-1389 improves cardiopulmonary function parameters in monocrotaline-induced pulmonary hypertension and right heart failure rat model

Abstract Background Pulmonary hypertension (PH) associated with right heart failure (RHF) poses a significant therapeutic challenge. Short term studies have shown that urocortin-2 (UCN-2) administration, either intravenously or subcutaneously, can ameliorate cardiac and/or pulmonary parameters in human heart failure (HF) and in animal models of PH and RHF. Purpose This study aimed to evaluate the potential benefits of COR-1389, a long-acting CRF2 receptor agonist, on cardiopulmonary function and adverse remodeling in a rat model of monocrotaline (MCT)-induced PH and RHF. Method Monocrotaline (40 mg/kg) was administered subcutaneously in rats on Day-0 to induce PH and RHF, while the control group received vehicle. After 14 days, MCT-injected rats were evenly allocated into two groups based on echocardiography parameters of accelerated time/ejection time ratio and tricuspid annular plane systolic excursion (TAPSE), before receiving either COR-1389 (100 ug/kg) or its vehicle subcutaneously every 4 days for 14 days. On Day-28, echocardiography was repeated in all groups, followed by right heart catheterization to directly measure pulmonary hemodynamics. Heart and lung samples were prepared for histological analysis. Results By Day-28, MCT-treated rats exhibited significantly elevated mean pulmonary arterial pressure (mPAP) and right ventricular (RV) mass (Fulton Index/BW), along with decreased RV function (increased TAPSE) and reduced cardiac output (CO) compared to control rats. These changes were accompanied by severe tissue remodeling, including increased vascular muscularization (alpha-smooth muscle actin content) and pulmonary arterial wall thickening, RV fibrosis, and cardiomyocyte hypertrophy. Following 14 days of curative treatment, MCT+COR-1389 compared to MCT, significantly decreased mPAP and RV mass (Fulton Index/BW), while RV function improved (reduced TAPSE) and CO was increased. Moreover, COR-1389 attenuated adverse pulmonary vascular remodeling (reduced muscularization and arterial wall thickening), RV fibrosis, and cardiomyocyte hypertrophy, consistent with its hemodynamic effects. Conclusions Chronic CRF2 agonism with COR-1389 improved dysregulated cardiac and pulmonary function and structure in the MCT rat model, suggesting its potential for the treatment of PH and RHF.

G6pdN126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker-Induced Pulmonary Vascular Disease.

G6PD (glucose-6-phosphate-dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension-associated vascular remodeling. Here, we investigated the role of an X-linked G6pd mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub-Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer. CRISPR-Cas9 genome editing was used to generate the G6pd variant (N126D; G6pdN126D) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen-5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into G6pdN126D rats and their wild-type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PDN126D+SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca2+ were increased in the lungs of G6PDN126D+SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PDN126D+SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor-1, thrombin-antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C-C motif] ligand), CCL5, and CCL7. Our results suggest G6PDN126D increases inositol triphosphate-Ca2+ signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU-treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker-induced pulmonary hypertension in those carrying this G6PD variant.

Safety Window for Effective Lesion Crossing in Patients With Chronic Thromboembolic Pulmonary Hypertension

BackgroundBalloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension (CTEPH) is limited by a lack of safe and effective tools for crossing these lesions. We aim to identify a safety window for an intraluminal crossing device in this vascular bed by studying the piercing properties of pulmonary arterial vessel walls and intraluminal CTEPH lesion specimens. As a secondary objective, we also describe the histopathologic features of CTEPH lesions. MethodsSpecimens were procured from 9 patients undergoing pulmonary endarterectomy. The specimens were subsampled and identified grossly as arterial wall or intraluminal CTEPH lesions. The force needed for tissue penetration was measured using a 0.38-mm (0.015-in) diameter probe in an ex vivo experimental model developed in our lab. Concurrent histology was also performed. ResultsThe mean force needed to penetrate the arterial wall and intraluminal CTEPH lesions was 1.75 ± 0.10 N (n = 121) and 0.30 ± 0.04 N (n = 56), respectively (P < .001). Histology confirmed the presence of intimal hyperplasia with calcium and hemosiderin deposition in the arterial wall as well as an old, organized thrombus in the lumen. ConclusionsThe pulmonary arterial wall is friable and prone to perforation during instrumentation with workhorse coronary guide wires. However, the results of this study demonstrate that a much lower force is needed for the 0.38-mm (0.015-in) probe to penetrate an intraluminal CTEPH lesion compared to pulmonary arterial intima. This finding suggests the existence of a safety window for lesion-crossing devices, enabling effective balloon pulmonary angioplasty.

A comprehensive map of proteoglycan expression and deposition in the pulmonary arterial wall in health and pulmonary hypertension.

Changes in the extracellular matrix of pulmonary arteries (PAs) are a key aspect of vascular remodeling in pulmonary hypertension (PH). Yet, our understanding of the alterations affecting the proteoglycan (PG) family remains limited. We sought to investigate the expression and spatial distribution of major vascular PGs in PAs from healthy individuals and various PH groups (chronic obstructive pulmonary disease: PH-COPD, pulmonary fibrosis: PH-PF, idiopathic: IPAH). PG regulation, deposition, and synthesis were notably heightened in IPAH, followed by PH-PF, with minor alterations in PH-COPD. Single-cell analysis unveiled cell-type and disease-specific PG regulation. Agrin expression, a basement membrane PG, was increased in IPAH, with PA endothelial cells (PAECs) identified as a major source. PA smooth muscle cells (PASMCs) mainly produced large-PGs, aggrecan and versican, and small-leucine-like proteoglycan (SLRP) biglycan, whereas the major PGs produced by adventitial fibroblasts were SLRP decorin and lumican. In IPAH and PF-PH, the neointima-forming PASMC population increased the expression of all investigated large-PGs and SLRPs, except fibroblast-predominant decorin (DCN). Expression of lumican, versican, and biglycan also positively correlated with collagen 1α1/1α2 expression in PASMCs in patients with IPAH and PH-PF. We demonstrated that transforming growth factor-beta (TGF-β) regulates versican and biglycan expression, indicating their contribution to vessel fibrosis in IPAH and PF-PH. We furthermore show that certain circulating PG levels display a disease-dependent pattern, with increased decorin and lumican across all patient groups, while versican was elevated in PH-COPD and IPAH and biglycan reduced in IPAH. These findings suggest unique compartment-specific PG regulation in different forms of PH, indicating distinct pathological processes.NEW & NOTEWORTHY Idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries (PAs) displayed the greatest proteoglycan (PG) changes, with PH associated with pulmonary fibrosis (PH-PF) and PH associated with chronic obstructive pulmonary disease (PH-COPD) following. Agrin, an endothelial cell-specific PG, was solely upregulated in IPAH. Among all cells, neo-intima-forming smooth muscle cells (SMCs) displayed the most significant PG increase. Increased levels of circulating decorin, lumican, and versican, mainly derived from SMCs, and adventitial fibroblasts, may serve as systemic indicators of pulmonary remodeling, reflecting perivascular fibrosis and neointima formation.

Hypoxic perfusion of pulmonary arterial vasa vasorum increases pulmonary arterial pressure.

The pathophysiology of pulmonary hypertension (PH) is not fully understood. Here, we tested the hypothesis that hypoxic perfusion of the vasa vasorum of the pulmonary arterial (PA) wall causes PH. Young adult pig lungs were explanted and placed into a modified ex vivo lung perfusion unit (organ care system, OCS) allowing the separate adjustment of parameters for mechanical ventilation, as well as PA perfusion and bronchial arterial (BA) perfusion. The PA vasa vasorum are branches of the BA. The lungs were used either as the control group (n = 3) or the intervention group (n = 8). The protocol for the intervention group was as follows: normoxic ventilation and perfusion (steady state), hypoxic BA perfusion, steady state, and hypoxic BA perfusion. During hypoxic BA perfusion, ventilation and PA perfusion maintained normal. Control lungs were kept under steady-state conditions for 105 min. During the experiments, PA pressure (PAP) and blood gas analysis were frequently monitored. Hypoxic perfusion of the BA resulted in an increase in systolic and mean PAP, a reaction that was reversible upon normoxic BA perfusion. The PAP increase was reproducible during the second hypoxic BA perfusion. Under control conditions, the PAP stayed constant until about 80 min of the experiment. In conclusion, the results of the current study prove that hypoxic perfusion of the vasa vasorum of the PA directly increases PAP in an ex situ lung perfusion setup, suggesting that PA vasa vasorum function and wall ischemia may contribute to the development of PH.NEW & NOTEWORTHY Hypoxic perfusion of the vasa vasorum of the pulmonary artery directly increased pulmonary arterial pressure in an ex vivo lung perfusion setup. This suggests that the function of pulmonary arterial vasa vasorum and wall ischemia may contribute to the development of pulmonary hypertension.

(18)F-fluorodeoxyglucose uptake by positron emission tomography in patients with IPAH and CTEPH.

Pulmonary arterial hypertension (PAH) is driven by pathologies associated with increased metabolism such as pulmonary revascularization, vasoconstriction and smooth muscle cell proliferation in pulmonary artery wall. 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) is an imaging technique sensitive to glucose metabolism and might be considered as a non-invasive method for diagnosis due to significant role of inflammation in idiopathic pulmonary artery hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The present study aimed to investigate the role of PET/CT imaging of patients with IPAH and CTEPH as an alternative diagnosis method. Demographic characteristics, FDG uptake in lungs, pulmonary artery and right ventricle (RV) of 17 patients (10 IPAH, 7 CTEPH), and 30 controls were evaluated. PET scanning, 6-min walk test, pro-BNP level, right heart catheterization of patients were performed both at the onsert and after 6-month PAH specific treatment. IPAH and CTEPH patients had significantly higher left lung FDG (p = 0.006), right lung FDG (p = 0.004), right atrial (RA) FDG (p < 0.001) and RV FDG (p < 0.001) uptakes than controls. Positive correlation was detected between the RV FDG uptake and the mean pulmonary artery pressure (mPAP) (r = 0.7, p = 0.012) and between the RA FDG uptake and the right atrial pressure (RAP) (r = 0.5, p = 0.02). Increased RV FDG and RA FDG uptakes predicts the presence of pulmonary hypertension and correlates with mPAP and RAP, respectively, which are important indicators in the prognosis of PAH. Further studies are required whether FDG PET imaging can be used to diagnose or predict the prognosis of pulmonary hypertension.

Resveratrol as an adjuvant prebiotic therapy in the management of pulmonary thromboembolism.

Pulmonary thromboembolism (PTE) presents a grave threat to patient lives, often marked by arterial occlusion in the pulmonary vasculature, frequently stemming from deep vein thrombosis (DVT). While current anticoagulant therapies offer temporary relief, they fall short of addressing the long-term management of PTE. Notably, PTE-associated mortality rates continue to rise annually, positioning it as a crucial concern within the cardiovascular landscape. An intriguing suspect underlying compromised prognoses is the intricate interplay between the gut microbiome and PTE outcomes. The gut-derived metabolite, trimethylamine N-oxide (TMAO), has emerged as a direct contributor to accelerated thrombogenesis, thereby heightening PTE susceptibility. In pursuit of remedies, research has delved into diverse prebiotic and probiotic interventions, with Resveratrol (RSV) emerging as a promising candidate. This paper explores the potential of RSV, a polyphenolic compound, as an adjuvant prebiotic therapy. The proposed therapeutic approach not only augments anticoagulant potency through strategic pharmacokinetic interactions but also introduces a novel avenue for attenuating future PTE incidents through deliberate gut microbiome modulation. RSV's multifaceted attributes extend beyond its role in PTE prevention. Recognized for its anti-inflammatory, antioxidant, and cardioprotective properties, RSV stands as a versatile therapeutic candidate. It exhibits the ability to curtail platelet aggregation, augment warfarin bioavailability, and mitigate pulmonary arterial wall thickening - an ensemble of effects that substantiate its potential as an adjunct prebiotic for PTE patients. This literature review weaves together the latest insights, culminating in a compelling proposition: RSV is an instrumental player in the trajectory of PTE management.

Acute Pulmonary Embolism and Immunity in Animal Models.

Venous thromboembolism, encompassing acute pulmonary embolism (APE) and deep vein thrombosis (DVT), is a potentially fatal disease with complex pathophysiology. Traditionally, the Virchow triad provided a framework for understanding the pathogenic contributors to thrombus formation, which include endothelial dysfunction, alterations in blood flow and blood hypercoagulability. In the last years, it has become apparent that immunity plays a central role in thrombosis, interacting with classical prothrombotic mechanisms, oxidative stress and vascular factors. Thrombosis amplifies inflammation, and exaggerated inflammatory processes can trigger thrombosis mainly due to the activation of leukocytes, platelets, and endothelial cells. APE-related endothelium injury is a major trigger for immune system activation. Endothelium is also a key component mediating inflammatory reaction and it is relevant to maintain vascular permeability. Exaggerated right ventricular wall stress and overload, with coexisting systemic hypotension and hypoxemia, result in myocardial injury and necrosis. Hypoxia, tissue factor activation and cytokine storm are engaged in the thrombo-inflammatory processes. Thrombus development is characterized by inflammatory state vascular wall caused mainly by an early extravasation of leukocytes and intense selectins and cytokines production. Nevertheless, immunity of DVT is well described, little is known about potential chemokine and cellular differences between thrombus that develops in the vein and thrombus that detaches and lodges in the pulmonary circulation being a cause of APE. There is a paucity of data considering inflammatory state in the pulmonary artery wall during an acute episode of pulmonary embolism. The main aim of this review is to summarize the knowledge of immunity in acute phase of pulmonary embolism in experimental models.

Hidden enemy of pulmonary arteries: COVID-19

It has been reported that COVID-19 may cause severe endothelial damage. Pulmonary Artery Stiffness (PAS) is a strong predictor of right ventricular function. PAS can reveal important information about the endothelial functions of the pulmonary bed. In this study, we aimed to elucidate the possible effect of COVID-19 on PAS. The study was performed by measuring PAS values with transthoracic echocardiography in 130 patients, 60 of whom had COVID-19 and 70 were controls. COVID-19 patients with positive polymerase chain reaction (PCR) test results were included in the study 3-6 months after their positivity. When the Maximal frequency shift (MFS) (Hz) results were examined, no significant difference was observed between the patient and control groups (2764±279.24 and 2664.8±673.91 p=0.340, respectively). There was a significant difference between the patient and control groups in favor of the patient group in pulmonary acceleration time (PAT) (msec) results (93.18±14.99 and 126.1±17.58, respectively, p&lt;0.001). There was a significant difference between the patient and control groups in favor of the patient group in PAS (Hz/msec) results (30.28±5.07 and 21.57±7.04, respectively, p&lt;0.001). It is possible that COVID-19 may have adverse effects on the pulmonary artery wall and bed. As a result of endothelial damage due to COVID-19, an increase in PAS values can be observed.

Comparison of CT-Determined Pulmonary Artery Diameter among Smokers and Non-smokers: A Cross-sectional Study

Introduction: Tobacco smoking is a common addiction in our society. The toxic chemical compounds present in tobacco smoke cause epithelial damage and inflammation of the airways. Chronic smoking results in the thickening of the pulmonary arterial wall and vasoconstriction, leading to the development of pulmonary arterial hypertension. Hence, measurement of pulmonary artery diameter using Contrast Enhanced Computed Tomography (CECT) may be helpful in the early detection of pulmonary arterial hypertension. Aim: To compare the diameters of the Main Pulmonary Artery (MPA), Right Pulmonary Artery (RPA), and Left Pulmonary Artery (LPA) using CECT thorax in smokers and non-smokers. Materials and Methods: A cross-sectional study was conducted from April 2021 to March 2022 in the department of radiodiagnosis, KS Hegde Hospital, Karnataka, India, consisting of 100 patients referred for CECT thorax in the age group of 18-85 years. They were divided into two groups: smokers and non-smokers, with 50 patients in each group. They were further categorised into three age groups: &lt; 50 years, 50-60 years, and &gt;60 years. The widest diameters of the MPA were measured at the level of bifurcation of the artery and perpendicular to the long axis of the artery. At this level, RPA and LPA diameters were measured at the widest portion on 1.25 mm axial images of the arterial phase. Variation in the pulmonary artery diameter was compared between smokers and non-smokers with respect to age and analysed by unpaired t-test and Pearson correlation. Results: Diameters of MPA, RPA, and LPA were statistically significant (p&lt;0.05) in smokers compared to non-smokers. In smokers, MPA and RPA diameters correlated with age, which was statistically significant (p&lt;0.05). No significant correlation (p&gt;0.05) was shown between age and MPA, RPA, and LPA diameter in non-smokers. The mean MPA diameter showed a significant difference (p&lt;0.05) in all three age groups. Conclusion: The diameter of the pulmonary artery is statistically significant in smokers compared to non-smokers. Hence, assessment of pulmonary artery diameters among smokers using CECT thorax will help to diagnose Pulmonary Hypertension (PH) at an early stage.

Subject-specific one-dimensional fluid dynamics model of chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) develops due to the accumulation of blood clots in the lung vasculature that obstructs flow and increases pressure. The mechanobiological factors that drive progression of CTEPH are not understood, in part because mechanical and hemodynamic changes in the small pulmonary arteries due to CTEPH are not easily measurable. Using previously published hemodynamic measurements and imaging from a large animal model of CTEPH, we applied a subject-specific one-dimensional (1D) computational fluid dynamic (CFD) approach to investigate the impact of CTEPH on pulmonary artery stiffening, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) in extralobar (main, right, and left) pulmonary arteries and intralobar (distal to the extralobar) arteries. Our results demonstrate that CTEPH increases pulmonary artery wall stiffness and decreases TAWSS in extralobar and intralobar arteries. Moreover, CTEPH increases the percentage of the intralobar arterial network with both low TAWSS and high OSI, quantified by the novel parameter φ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varphi$$\\end{document}, which is related to thrombogenicity. Our analysis reveals a strong positive correlation between increases in mean pulmonary artery pressure (mPAP) and φ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varphi$$\\end{document} from baseline to CTEPH in individual subjects, which supports the suggestion that increased φ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varphi$$\\end{document} drives disease severity. This subject-specific experimental–computational framework shows potential as a predictor of the impact of CTEPH on pulmonary arterial hemodynamics and pulmonary vascular mechanics. By leveraging advanced modeling techniques and calibrated model parameters, we predict spatial distributions of flow and pressure, from which we can compute potential physiomarkers of disease progression. Ultimately, this approach can lead to more spatially targeted interventions that address the needs of individual CTEPH patients.

Abstract 14923: Induced Pluripotent Stem Cell Derived Endothelial Progenitor Cells Attenuate Pulmonary Arterial Hypertension

Introduction: Although transplantation of adult endothelial progenitor cells (EPCs) holds promise in the treatment for pulmonary arterial hypertension (PAH), the low number and weakened functions of human primary EPCs are serious problems for autologous transplantation for patients and limited their therapeutic efficiency. Hypothesis: Te aim of this study is to investigate the efficiency of induced pluripotent stem cell derived EPCs on attenuating PAH. Methods: This study differentiated induced pluripotent stem cells from healthy people into vascular endothelial precursor cells (iPSC-EPC), whose specific protein expressed CD133 accounted for 95.4% and KDR accounted for 75.7%, and further confirmed that iPSC-EPC have the ability to differentiate vascular endothelial cells (iPSC-EC) with similar EC cobblestone morphology, acetylated LDL uptake, and UEA-1 lectin binding. IPSC-EC-specific protein expression CD144 accounts for 99.0% and CD31 accounts for 75.1%. Results: This study explored the efficacy of healthy iPSC-EPC in the treatment of PAH in an animal model. Both prophylactic and therapeutic treatments of iPSC-EPC were effective in rescuing monocrotaline (MCT)-induced right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary artery wall thickening in PAH. Pulmonary artery smooth muscle cells (PASMC) derived from MCT-treated rats (MCT-PASMC) developed more proliferative and pro-migratory phenotypes, which were attenuated by the iPSC-EPC derived culture medium (EPC-CM) treatment. Moreover, the proliferation and migration of MCT-PASMC were reduced by EPC-CM with suppression of PCNA, cyclin D1, MMP-1, and MMP-9. This study also found that iPSC-EPC treatment reduced MCT-PASMC senescence and senescence-associated secretory phenotype (SASP) in MCT-treated rats. Conclusions: This study found that ctrl iPSC-EPC restored miRNA levels in the lung tissue of MCT-treated rats. IPSC-EPC is effective at preventing and reversing pulmonary hypertension by regulating the expression of miRNAs, and reducing pulmonary vascular remodelling.

Abstract 19092: Endothelial Caveolin-1 Deficiency Increases Susceptibility to Lethal Heart Failure in Male Mice With Hypoxia-Induced Pulmonary Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is an incurable disease with high mortality. Reduced endothelial cell caveolin-1 (EC Cav1) expression contributes to idiopathic PAH, and in animal models, can be alleviated by inhibiting or deleting endothelial nitric oxide synthase (eNOS). Hypothesis: As females are at greater risk of developing PAH but exhibit a more favorable outcome compared to males, we hypothesized that EC Cav1 deficiency in male mice would contribute to EC Cav1-dependent sex differences following chronic hypoxia exposure. Methods: EC-Cav1 -/- mice ( Cdh5.Cre ERT2 ;mTmG;Cav1 f/f injected with tamoxifen; ECKO) vs. wild-type liter mates injected with oil (ECWT), and Cav1 KO, Cav1-RC, and WT mice (6-8 week old) were exposed to 10% O 2 for up to 8 weeks (hypoxia-induced PH (HPH)). Echocardiography, right ventricular systolic pressure (RVSP) and hypertrophy (RVH), lung histology, Western blot, and survival were used to quantify pulmonary and cardiac function. Data were analyzed by two-way ANOVA and Tukey’s post hoc analysis. Results: After 8-weeks of hypoxia exposure, over 90% of male and 40% of female Cav1 KO became moribund, whereas lethality was less than 10% for WT and Cav1 RC mice (p &lt; 0.01). Cav1 ECKO mice exhibited 30% lethality, whereas all ECWT siblings survived. Both Cav1 KO and ECKO mice exhibited a significant increase in pulmonary artery wall thickness, RVH, and RVSP. Hypoxia also reduced PAT and TAPSE, as well as LV systolic and diastolic function, including IVRT, CO, EF, FS, and global longitudinal strain in Cav1 KO and ECKO as compared to WT, ECWT, and Cav1-RC mice indicating EC Cav1 expression is cardioprotective in the context of HPH. In whole lung lysates, we observed reduced eNOS dimerization and an increase in eNOS pSer1179 indicative of eNOS dysfunction under normoxia which was exaggerated following hypoxia exposure to a greater extent in male Cav1 KO and ECKO as compared to Cav1-RC or WT mice. Conclusions: Chronic hypoxia-induced PH and mortality observed in Cav1 KO and ECKO mice is associated with both RV and LV failure and eNOS dysfunction to a greater extent in male mice, which was largely prevented by EC Cav1 expression.

A repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in NOG mice by intravenous injection

ABSTRACT Background Stem cell-based therapies have demonstrated great potential in several clinical trials. However, safety data on stem cell application remain inadequate. This study evaluated the toxicity of human umbilical cord mesenchymal stem cells (hUC-MSCs) in NOD/Shi-scid/IL-2 Rγnull (NOG) mice. Research design and methods Mice were administered hUC-MSCs intravenously at doses of 3.5 × 106 cells/kg and 3.5 × 107 cells/kg. Toxicity was assessed by clinical observation, behavioral evaluation, pathology, organ weight, and histopathology. We determined the distribution of hUC-MSCs using a validated qPCR method and colonization using immunohistochemistry. Results No significant abnormal effects on clinical responses, body weight, or food intake were observed in the mice, except for two in the high-dose group that died during the last administration. Mouse activity in the high-dose group decreased 6 h after the first administration. Terminal examination revealed dose-dependent changes in hematology. The mice in the high-dose group displayed pulmonary artery wall plaques and mild alveolar wall microthrombi. hUC-MSCs colonized primarily the lung tissues and were largely distributed there 24 h after the final administration. Conclusions The no observed adverse effect level for intravenous administration of hUC-MSCs in NOG mice over a period of 3 w was 3.5 × 106 cells/kg.

Relationship of Main Pulmonary Artery (Truncus Pulmonalis) Diameter With Hospital Stay and Mortality in Pulmonary Hypertension Patients Admitted to the Emergency Department.

Pulmonary hypertension (PH) is a haemodynamic and pathophysiological disease significantly associated with morbidity and mortality. The increase in pulmonary vascular resistance, high pulmonary artery pressure and wall tension that occurs in PH results in dilatation of the main pulmonary artery (truncus pulmonalis), one of the largest and most important vessels in the body. The aim of this study is to investigate the relationship between the diameter of the truncus pulmonalis and hospitalization, length of hospital stay, and mortality in patients diagnosed with PH. Demographic characteristics, number of Emergency Department (ED) admissions, post-admission status, treatment, truncus pulmonalis diameter, and mortality were evaluated statistically through the patient files of 115 PH patients who presented to the ED of Fırat University Faculty of Medicine,Elazığ, Türkiye, between January 2022 and December 2022. Of the 115 PH patients who came to the ED, 70 (60.8%) were women and 45 (39.2%) were men, with a mean age of 78.77±8.72 years. Fifty-one of these patients were discharged from the ED after treatment, and 64 were hospitalized. The mean length of hospital stay was two (min=0, max=38) days. Thoracic CT scans demonstrated that the mean diameter of the truncus pulmonalis of the patients was 34.874±3.288 mm (35.20±3.6509 mm in women, 34.367±2.5836 mm in men; p₌0.351) and there was no statistically significant relationship with mortality (p=0.496), hospitalization (p=0.806), and length of hospital stay (p=0.416). There was a statistically significant relationship between mortality rate and male gender (p=0.02) and comorbidity (p=0.001). It was determined that there was no statistically significant relationship between the truncus pulmonalis diameter and gender, comorbidity, hospitalization, length of hospital stay, and mortality in this study in which single-centre one-year admissions of PH, which differ in aetiology, epidemiology, and demographic features were examined. However, among the patient demographics, a significant relationship was determined between gender and the number of comorbidities and mortality.

Quercetin improves pulmonary arterial hypertension in rats by regulating the HMGB1/RAGE/NF-κB pathway

To explore the mechanism through which quercetin improves pulmonary arterial hypertension (PAH). Rat models of hypoxic pulmonary hypertension were established by exposure to hypoxia for 8-10 h each day (6 days a week for 4 weeks), and before each hypoxic exposure, the rats were given intragastric administration of 100 mg/kg quercetin or saline. After the treatments, the right ventricular systolic pressure (RVSP) and pulmonary artery systolic pressure of the rats were recorded. The right ventricular hypertrophy index (RVHI) was measured to evaluate right ventricular hypertrophy. HE staining was used to observe the remodeling of the pulmonary arterioles. The right cardiac function of the rats was evaluated by ultrasound. The protein levels of HMGB1, RAGE, NF-κB, Bax, Bcl-2 and cleaved caspase-3 in the lung tissue of the rats were detected using Western blotting. Compared with the rats maintained in normoxia, the rats with chronic hypoxic exposure showed significantly increased RVHI and RVSP (P<0.01), which were obviously lowered by quercetin treatment (P<0.01). HE staining showed significant pulmonary artery wall thickening with reduced lumen diameter in hypoxia group, and quercetin treatment effectively improved pulmonary vascular remodeling. Ultrasound examination revealed a significantly increased RVFW and a lowered PAT/PET ratio in hypoxia group (P<0.01), and such changes were ameliorated by quercetin treatment (P<0.01). Chronic hypoxia significantly increased the protein expressions of HMGB1 (P<0.01), RAGE, NF-κB and Bcl-2 (P<0.01) and lowered the protein expressions of Bax and cleaved caspase-3 (P<0.01); Quercetin treatment obviously lowered the protein expressions of HMGB1, NF-κB (P<0.05), RAGE (P<0.01) and (P<0.05) and increased the expressions of Bax and cleaved caspase-3 in the rat models (P<0.01). Quercetin improves pulmonary hypertension in rats possibly by promoting apoptosis through the HMGB1/RAGE/NF-κB pathway.

Overexpressed microRNA (miR)-382-3p promoted vascular remodeling via suppressing autophagy-related protein 7 (ATG7) in chronic thromboembolic pulmonary hypertension.

This research has investigated the role of miR-382-3p in chronic thromboembolic pulmonary hypertension (CTEPH). Human pulmonary artery smooth muscle cells (hPASMCs) were treated with PDGF-BB to induce proliferation, and then transfected with miR-382-3p mimic, miR-382-3p inhibitor, ATG7 overexpression plasmid, and siATG7. MiR-382-3p, ATG7, VEGF, PCNA, p62, and LC3-Ⅱ/LC3-I levels were detected by qRT-PCR and Western blotting. Cell viability and migration were tested through CCK-8 and wound healing assays, respectively. Target genes of miR-382-3p were predicted by Targetscan and starBase, and pathway analysis was implemented through WebGestalt. The binding relationship between miR-382-3p and ATG7 was analyzed by the dual-luciferase reporter and RIP assays. A CTEPH model was constructed in rats with the treatment of miR-382-3p antagomir or agomir, and mean pulmonary artery pressure (mPAP) was measured. Lung tissue was observed through the HE staining assay. MiR-382-3p level in hPASMCs was obviously upregulated with the increasing dose of PDGF-BB. MiR-382-3p mimic promoted yet miR-382-3p inhibitor suppressed hPASMC proliferation. MiR-382-3p directly targeted ATG7. ATG7 overexpression repressed hPASMC proliferation and migration, whereas siATG7 exerted the opposite effects. ATG7 overexpression partly neutralized the effects of miR-382-3p mimic on proliferation, migration, and autophagy-related proteins (ATG7, p62, and LC3-Ⅱ/LC3-I) in hPASMCs, whereas siATG7 partly offset the impacts of miR-382-3p inhibitor. MiR-382-3p antagomir reversed CTEPH-induced mPAP elevation, miR-382-3p upregulation, thickening of the pulmonary artery wall, and increased expressions of VEGF, PCNA, and autophagy-related proteins in rats, while miR-382-3p agomir potentiated these effects induced by CTEPH. Overexpressed miR-382-3p promotes vascular remodeling via ATG7 inhibition in CTEPH.