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Nature Communications Nov 2023Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA...
Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm). Gene expression analysis of EC-Atm and EC-Bmpr2 lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2 mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.
Topics: Mice; Humans; Animals; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension; Pulmonary Artery; DNA Damage; Bone Morphogenetic Protein Receptors, Type II; Forkhead Transcription Factors
PubMed: 37989727
DOI: 10.1038/s41467-023-43039-y -
European Respiratory Review : An... Dec 2023Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and potentially life-threatening complication of acute pulmonary embolism. It is characterised by...
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and potentially life-threatening complication of acute pulmonary embolism. It is characterised by persistent fibro-thrombotic pulmonary vascular obstructions and elevated pulmonary artery pressure leading to right heart failure. The diagnosis is based on two steps, as follows: 1) suspicion based on symptoms, echocardiography and ventilation/perfusion scan and 2) confirmation with right heart catheterisation, computed tomography pulmonary angiography and, in most cases, digital subtraction angiography. The management of CTEPH requires a multimodal approach, involving medical therapy, interventional procedures and surgical intervention. This clinical-radiological-pathological correlation paper illustrates the diagnostic and therapeutic management of two patients. The first had chronic thromboembolic pulmonary disease without pulmonary hypertension at rest but with significant physical limitation and was successfully treated with pulmonary endarterectomy. The second patient had CTEPH associated with splenectomy and was considered unsuitable for surgery because of exclusive subsegmental lesions combined with severe pulmonary hypertension. The patient benefited from multimodal treatment involving medical therapy followed by multiple sessions of balloon pulmonary angioplasty. Both patients had normalised functional capacity and pulmonary haemodynamics 3-6 months after the interventional treatment. These two examples show that chronic thromboembolic pulmonary diseases are curable if diagnosed promptly and referred to CTEPH centres for specialist treatment.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Embolism; Angioplasty, Balloon; Angiography; Tomography, X-Ray Computed; Chronic Disease; Endarterectomy; Pulmonary Artery
PubMed: 38123236
DOI: 10.1183/16000617.0149-2023 -
Clinical and Experimental Hypertension... Dec 2023To explore the correlation between pulmonary vascular performance and hemodynamics in patients with pulmonary arterial hypertension (PAH), using right heart...
OBJECTIVE
To explore the correlation between pulmonary vascular performance and hemodynamics in patients with pulmonary arterial hypertension (PAH), using right heart catheterization (RHC) and intravascular ultrasound (IVUS).
METHOD
A total of 60 patients underwent RHC and IVUS examinations. Of these, 27 patients were diagnosed with PAH associated with connective tissue diseases (PAH-CTD group), 18 patients were diagnosed with other types of PAH (other-types-PAH group), and 15 patients were without PAH (control group). The hemodynamics and morphological parameters of pulmonary vessels in PAH patients were assessed using RHC and IVUS.
RESULTS
There were statistically significant differences in right atrial pressure (RAP), pulmonary artery systolic pressure (sPAP), pulmonary artery diastolic pressure (dPAP), mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) values between the PAH-CTD group, other-types-PAH group, and the control group (P < .05). No statistically significant difference was noticed in pulmonary artery wedge pressure (PAWP) and cardiac output (CO) values between these three groups (P > .05). The mean wall thickness (MWT), wall thickness percentage (WTP), pulmonary vascular compliance, dilation, elasticity modulus, stiffness index β, and other indicators were significantly different between these three groups (P < .05). Pairwise comparison showed that the average levels of pulmonary vascular compliance and dilation in PAH-CTD group and other-types-PAH group were lower than those in control group, while the average levels of elastic modulus and stiffness index β were higher than those in control group.
CONCLUSION
Pulmonary vascular performance deteriorates in PAH patients, and the performance is better in PAH-CTD patients than in other types of PAH.
Topics: Humans; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hemodynamics; Pulmonary Artery; Lung
PubMed: 36906960
DOI: 10.1080/10641963.2023.2185253 -
Immunology Letters Nov 2023The role of inflammation in pulmonary hypertension is gradually gaining increasing research attention. However, no previous study has evaluated the characteristics of...
The role of inflammation in pulmonary hypertension is gradually gaining increasing research attention. However, no previous study has evaluated the characteristics of inflammation during chronic hypoxia-induced pulmonary hypertension. Therefore, the aim of this study was to investigate the characteristics of the inflammatory process involved in hypoxia-induced pulmonary hypertension in mice. The current study evaluated from day 4 to day 28 of hypoxia, the PAAT and PAAT/PET decreased, accompanied by pulmonary vascular remodeling and right ventricular hypertrophy, as well as increased numbers of CD68 macrophages. The expression of the pro-inflammatory factors IL-1β and IL-33 increased, but decreased on day 28. The expression of IL-12 increased from day 4 to day 28, whereas that of the anti-inflammatory factor IL-10 in lung tissue decreased. Furthermore, the expression of the IL-33/ST2 signaling pathway also increased over time under hypoxic conditions. In conclusion, pulmonary artery remodeling in HPH mice worsens progressively in a time-dependent manner, with inflammatory cell infiltration predominating in the early stage and pulmonary vascular remodeling occurring in the later stage.
Topics: Mice; Animals; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Interleukin-33; Vascular Remodeling; Inflammation; Macrophages; Hypoxia
PubMed: 37875238
DOI: 10.1016/j.imlet.2023.10.005 -
Epigenetics Dec 2023Idiopathic pulmonary arterial hypertension (IPAH) is a serious and fatal disease. Recently, m6A has been reported to play an important role in the lungs of IPAH patients...
Idiopathic pulmonary arterial hypertension (IPAH) is a serious and fatal disease. Recently, m6A has been reported to play an important role in the lungs of IPAH patients and experimental pulmonary hypertension models. However, the meaning of m6A mRNAs in the peripheral blood of IPAH patients remains largely unexplored. We aimed to construct a transcriptome-wide map of m6A mRNAs in the peripheral blood of IPAH patients. M6A RNA Methylation Quantification Kit was utilized to measure the total m6A levels in the peripheral blood of IPAH patients. A combination of MeRIP-seq, RNA-seq and bioinformatics analysis was utilized to select m6A-modified hub genes of IPAH. MeRIP-qPCR and RT-qPCR were used to measure the m6A levels and mRNA levels of TP53, RPS27A, SMAD3 and FoxO3 in IPAH patients. Western blot was performed to assess the protein levels of m6A related regulators and m6A related genes in experimental PH animal models, hypoxia-treated and PDGF-BB induced PASMCs. We found that the total m6A levels were increased in peripheral blood of IPAH patients and verified that m6A levels of RPS27A and SMAD3 were significantly elevated and m6A levels of TP53 and FoxO3 were significantly reduced. The mRNA or protein levels of RPS27A, SMAD3, TP53 and FoxO3 were changed in human blood samples, experimental PH animal models and PDGF-BB induced PASMCs. Moreover, METTL3 and YTHDF1 were increased in the hypoxia induced pulmonary hypertension rat model, hypoxia-treated and PDGF-BB induced PASMCs. These finding suggested that m6A may play an important role in IPAH.
Topics: Humans; Rats; Animals; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Becaplermin; Pulmonary Artery; Epigenome; Cell Proliferation; Myocytes, Smooth Muscle; DNA Methylation; RNA, Messenger; Methyltransferases
PubMed: 37537976
DOI: 10.1080/15592294.2023.2242225 -
Journal of Cellular and Molecular... Dec 2023Pulmonary arterial hypertension (PAH) comprises a heterogeneous group of diseases with diverse aetiologies. It is characterized by increased pulmonary arterial pressure...
Pulmonary arterial hypertension (PAH) comprises a heterogeneous group of diseases with diverse aetiologies. It is characterized by increased pulmonary arterial pressure and right ventricular (RV) failure without specific drugs for treatment. Emerging evidence suggests that inflammation and autoimmune disorders are common features across all PAH phenotypes. This provides a novel idea to explore the characteristics of immunological disorders in PAH and identify immune-related genes or biomarkers for specific anti-remodelling regimens. In this study, we integrated three gene expression profiles and performed Gene Ontology (GO) and KEGG pathway analysis. CIBERSORT was utilized to estimate the abundance of tissue-infiltrating immune cells in PAH. The PPI network and machine learning were constructed to identify immune-related hub genes and then evaluate the relationship between hub genes and differential immune cells using ImmucellAI. Additionally, we implemented molecular docking to screen potential small-molecule compounds based on the obtained genes. Our findings demonstrated the density and distribution of infiltrating CD4 T cells in PAH and identified four immune-related genes (ROCK2, ATHL1, HSP90AA1 and ACTR2) as potential targets. We also listed 20 promising molecules, including TDI01953, pemetrexed acid and radotinib, for PAH treatment. These results provide a promising avenue for further research into immunological disorders in PAH and potential novel therapeutic targets.
Topics: Humans; Pulmonary Arterial Hypertension; Molecular Docking Simulation; Familial Primary Pulmonary Hypertension; Heart Failure; Biomarkers
PubMed: 37753829
DOI: 10.1111/jcmm.17962 -
Current Problems in Cardiology Aug 2023Pulmonary hypertension is one of the difficult situations to treat. Complex pathophysiology, association of the multiple comorbidities make clinical scenario... (Review)
Review
Pulmonary hypertension is one of the difficult situations to treat. Complex pathophysiology, association of the multiple comorbidities make clinical scenario challenging. Recently it is being shown that patients who had recovered from coronavirus disease infection, are at risk of developing pulmonary hypertension. Studies on animals have been going on to find out newer treatment options. There are recent advancements in the treatment of pulmonary hypertension. Role of anticoagulation, recombinant fusion proteins, stem cell therapy are emerging as therapeutic options for affected patients. SGLT2 inhibitors have potential to have beneficial effects on pulmonary hypertension. Apart from the medical managements, advanced interventions are also getting popular. In this review article, the authors have discussed pathophysiology, recent advancement of treatments including coronavirus disease patients, and future aspect of managing pulmonary hypertension. We have highlighted treatment options for patients with sleep apnea, interstitial lung disease to discuss the challenges and possible options to manage those patients.
Topics: Animals; Humans; Hypertension, Pulmonary; Comorbidity
PubMed: 35500734
DOI: 10.1016/j.cpcardiol.2022.101236 -
Journal of the American College of... Nov 2023Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue...
BACKGROUND
Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear.
OBJECTIVES
The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival.
METHODS
Pulmonary Vascular Disease Phenomics (National Heart, Lung, and Blood Institute) cohort participants (patients with group 1 PAH, comparators, and healthy control participants) with sleep studies were included. Multimodal RV functional measures were examined in association with AHI and percentage of recording time with oxygen saturation <90% (T90) per 10-unit increment. Linear models, adjusted for demographics, oxygen, diffusing capacity of the lungs for carbon monoxide, pulmonary hypertension medications, assessed AHI and T90, and RV measures. Log-rank test/Cox proportional hazards models adjusted for demographics, oxygen, and positive airway pressure were constructed for transplantation-free survival analyses.
RESULTS
Analysis included 186 participants with group 1 PAH with a mean age of 52.6 ± 14.1 years; 71.5% were women, 80.8% were Caucasian, and there were 43 events (transplantation or death). AHI and T90 were associated with decreased RV ejection fraction (on magnetic resonance imaging), by 2.18% (-2.18; 95% CI: -4.00 to -0.36; P = 0.019) and 0.93% (-0.93; 95% CI: -1.47 to -0.40; P < 0.001), respectively. T90 was associated with increased RV systolic pressure (on echocardiography), by 2.52 mm Hg (2.52; 95% CI: 1.61 to 3.43; P < 0.001); increased mean pulmonary artery pressure (on right heart catheterization), by 0.27 mm Hg (0.27; 95% CI: 0.05 to 0.49; P = 0.019); and RV hypertrophy (on electrocardiography), 1.24 mm (1.24; 95% CI: 1.10 to 1.40; P < 0.001). T90, but not AHI, was associated with a 17% increased 5-year risk for transplantation or death (HR: 1.17; 95% CI: 1.07 to 1.28). In non-CTD-associated PAH, T90 was associated with a 21% increased risk for transplantation or death (HR: 1.21; 95% CI: 1.08 to 1.34). In CTD-associated PAH, T90 was associated with RV dysfunction, but not death or transplantation.
CONCLUSIONS
Sleep-related hypoxia was more strongly associated than AHI with measures of RV dysfunction, death, or transplantation overall and in group 1 non-CTD-associated PAH but only with RV dysfunction in CTD-associated PAH. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887).
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Heart Failure; Hypertension, Pulmonary; Hypoxia; Oxygen; Pulmonary Arterial Hypertension; Sleep; Ventricular Dysfunction, Right; Ventricular Function, Right
PubMed: 37968017
DOI: 10.1016/j.jacc.2023.09.806 -
The European Respiratory Journal Jun 2024https://bit.ly/3TMm6bi
https://bit.ly/3TMm6bi
Topics: Humans; Hypertension, Pulmonary; Child; Pediatrics
PubMed: 38575157
DOI: 10.1183/13993003.01518-2023 -
Biomedicine & Pharmacotherapy =... Aug 2023Pulmonary arterial hypertension (PAH) is a chronic obstructive disease characterized by vascular remodeling. Studies have confirmed that ginsenoside Rg1 can improve...
Pulmonary arterial hypertension (PAH) is a chronic obstructive disease characterized by vascular remodeling. Studies have confirmed that ginsenoside Rg1 can improve pulmonary hypertension to a certain extent, but the potential mechanism by which it improves hypoxia-induced PAH remains unclear. The aim of this study was to investigate the therapeutic effect of ginsenoside Rg1 on hypoxia-induced PAH. The results showed that hypoxia promoted inflammation, EndMT, and vascular remodeling, which were accompanied by decreased CCN1 levels and increased p-NFκB p65, TGF-β1, and p-Smad 2/3 levels. Treatment with ginsenoside Rg1, recombinant CCN1, BAY-11-7082, and SB-431542 could prevent hypoxia-induced vascular remodeling, reduce the expression of the hypoxia-induced inflammatory cytokines TNF-α and IL-1β, inhibit the expression of the mesenchymal markers α-SMA and Vimentin and restore the expression of the endothelial markers CD31 and VE-cadherin to improve hypoxia-induced EndMT, which may be associated with the upregulation of CCN1 protein expression and downregulation of p-NFκB p65, TGF-β1, and p-Smad 2/3 in rats and cells. siRNA CCN1 transfection increased the expression of p-NFκB p65, TGF-β1, and p-Smad 2/3 and accelerated the occurrence and development of inflammation and EndMT after hypoxia. In summary, our study indicated that hypoxia-induced EndMT and inflammation play a role in hypoxic pulmonary hypertension (HPH). Ginsenoside Rg1 treatment could reverse hypoxia-induced EndMT and inflammation by regulating CCN1 and has potential value in the prevention and treatment of HPH.
Topics: Rats; Animals; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Transforming Growth Factor beta1; Vascular Remodeling; Inflammation; Hypoxia
PubMed: 37216706
DOI: 10.1016/j.biopha.2023.114920