RESUMEN
We present a rare finding on lung ventilation-perfusion (V/Q) scintigraphy for a woman with longstanding dyspnea. CT of the chest showed volume loss on the right side, which raised concern about possible bronchiolitis obliterans or Swyer-James-MacLeod syndrome; however, the right pulmonary artery could not be visualized. A subsequent V/Q scan showed absence of perfusion and decreased ventilation to the entire right lung, consistent with agenesis of the right pulmonary artery. The patient's clinical course and imaging features mimicked Swyer-James-MacLeod syndrome, which usually presents with a matched perfusion defect in a single lung or lobe on V/Q scanning. This case highlights the importance of a multimodality imaging approach to achieve a diagnosis.
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Pulmón , Arteria Pulmonar , Humanos , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/anomalías , Femenino , Pulmón/diagnóstico por imagen , Pulmón/anomalías , Imagen de Perfusión/métodos , Gammagrafía de Ventilacion-Perfusión/métodos , Persona de Mediana EdadRESUMEN
Clinical conditions, including chronic obstructive pulmonary disease or pulmonary arterial hypertension (PAH), can lead to chronic right ventricle pressure overload and progressive right heart failure (RHF). RHF can be identified by right-sided cardiac hypertrophy and dilation associated with abnormal myocardial function affecting the RV and the right atrium (RA). We recently demonstrated that severe RHF is accompanied by an increased risk of atrial inflammation, atrial fibrosis, and atrial fibrillation (AF), the most common type of cardiac arrhythmia (CA). Recent studies have shown that RV and RA inflammation plays an important role in the arrhythmogenesis of CA, including AF. However, the impact of inflammation in the development of CA and AF in RHF is poorly described. Experimental models of RHF are required to better understand the association between right-sided myocardial inflammation and CA. The rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH) is well-established to provoke RHF. However, MCT triggers severe pneumo-toxicity and pulmonary inflammation. Hence, MCT-induced RHF does not help to distinguish whether the subsequent myocardial inflammation originates from the RHF per se or circulating inflammatory signals secreted by the injured lung. In this article, a mechanical method involving pulmonary artery trunk banding (PAB) was used to provoke right-sided cardiac arrhythmogenesis. The PAB consists of performing a permanent suture of the pulmonary artery trunk for 3 weeks. Such an approach generates increased right-sided pressure overload. At D21 post-PAB, the suture results in hypertrophied, dilated, and inflamed RV and RA. The PAB-induced RHF is also accompanied by vulnerability to ventricular and atrial arrhythmias, including AF.
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Arritmias Cardíacas , Modelos Animales de Enfermedad , Arteria Pulmonar , Animales , Ratas , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Remodelación Ventricular/fisiología , Masculino , Hipertensión Pulmonar/fisiopatologíaAsunto(s)
Angiografía por Tomografía Computarizada , Valor Predictivo de las Pruebas , Complicaciones Cardiovasculares del Embarazo , Arteria Pulmonar , Embolia Pulmonar , Humanos , Femenino , Embarazo , Arteria Pulmonar/diagnóstico por imagen , Embolia Pulmonar/diagnóstico por imagen , Complicaciones Cardiovasculares del Embarazo/diagnóstico por imagenRESUMEN
BACKGROUND: The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive. METHODS AND RESULTS: To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats. CONCLUSIONS: Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.
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Retardo del Crecimiento Fetal , GTP Fosfohidrolasas , Ratas Sprague-Dawley , Animales , Retardo del Crecimiento Fetal/metabolismo , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Ratas , Femenino , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/patología , Hipertensión Arterial Pulmonar/fisiopatología , Dinámicas Mitocondriales/fisiología , Masculino , Células Cultivadas , Embarazo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Modelos Animales de Enfermedad , Mitocondrias/metabolismo , Mitocondrias/patología , Animales Recién Nacidos , Proteínas MitocondrialesRESUMEN
BACKGROUND: Branch pulmonary artery (PA) stenosis is one of the most common indications for percutaneous interventions in patients with transposition of the great arteries (TGA), tetralogy of Fallot (ToF), and truncus arteriosus (TA). However, the effects of percutaneous branch PA interventions on exercise capacity remains largely unknown. In addition, there is no consensus about the optimal timing of the intervention for asymptomatic patients according to international guidelines. This trial aims to identify the effects of percutaneous interventions for branch PA stenosis on exercise capacity in patients with TGA, ToF, and TA. In addition, it aims to assess the effects on RV function and to define early markers for RV adaptation and RV dysfunction to improve timing of these interventions. METHODS: This is a randomized multicenter interventional trial. TGA, ToF, and TA patients ≥ 8 years with a class IIa indication for percutaneous branch PA intervention according to international guidelines are eligible to participate. Patients will be randomized into the intervention group or the control group (conservative management for 6 months). All patients will undergo transthoracic echocardiography, cardiac magnetic resonance (CMR) imaging, and cardiopulmonary exercise testing at baseline, 6 months, and 2-4 years follow-up. Quality of life (QoL) questionnaires will be obtained at baseline, 2 weeks post intervention or a similar range for the control group, and 6 months follow-up. The primary outcome is exercise capacity expressed as maximum oxygen uptake (peak VO2 as percentage of predicted). A total of 56 patients (intervention group n = 28, control group n = 28) is required to demonstrate a 14% increase in maximum oxygen uptake (peak VO2 as percentage of predicted) in the interventional group compared to the control group (power 80%, overall type 1 error controlled at 5%). Secondary outcomes include various parameters for RV systolic function, RV functionality, RV remodeling, procedural success, complications, lung perfusion, and QoL. DISCUSSION: This trial will investigate the effects of percutaneous branch PA interventions on exercise capacity in patients with TGA, ToF, and TA and will identify early markers for RV adaptation and RV dysfunction to improve timing of the interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05809310. Registered on March 15, 2023.
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Tolerancia al Ejercicio , Cardiopatías Congénitas , Estudios Multicéntricos como Asunto , Arteria Pulmonar , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Arteria Pulmonar/fisiopatología , Cardiopatías Congénitas/fisiopatología , Cardiopatías Congénitas/cirugía , Resultado del Tratamiento , Países Bajos , Estenosis de Arteria Pulmonar/fisiopatología , Estenosis de Arteria Pulmonar/etiología , Estenosis de Arteria Pulmonar/diagnóstico por imagen , Función Ventricular Derecha , Niño , Factores de Tiempo , Prueba de Esfuerzo , Masculino , Recuperación de la Función , Tetralogía de Fallot/cirugía , Tetralogía de Fallot/fisiopatología , FemeninoRESUMEN
OBJECTIVE: This study aims to present the midterm outcomes of surgical correction of the anomalous left coronary artery from the pulmonary artery (ALCAPA). METHODS: This is a retrospective study of patients undergoing anomalous origin of the LCA from the pulmonary artery repair between 2010 and 2019. RESULTS: Forty-nine patients (20 boys and 29 girls) underwent ALCAPA repair. Patients were divided into two groups based on their age at ALCAPA repair: infant (< 1 year of age: n = 24) and non-infant ( ⧠1 year of age: n = 25). Median age at time of repair was 23 months(7-60months). LCA reimplantation was performed in 47 patients, and Takeuchi repair was performed in 2 patients. Hospital mortality in the infant group was 8.2% (4 of 49). Infant group had significantly lower LVEF in pre-operation (p < 0.05), but there was not significantly different between the two groups about LVEF at discharge. The median follow-up duration was 43(18-85)months. The freedom from reoperation was not significantly different between two groups (infants vs. non-infants: 68.8% vs. 87.5% at 10 years; p = 0.096). CONCLUSIONS: Surgical treatment of ALCAPA had an excellent early and midterm outcomes. Left ventricular dysfunction in pre-operation was the main risk of mortality in-hospital. The freedom from reoperation did not differ significantly between infant group and non-infant group.
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Arteria Pulmonar , Humanos , Masculino , Femenino , Estudios Retrospectivos , Lactante , Arteria Pulmonar/cirugía , Arteria Pulmonar/anomalías , Preescolar , Resultado del Tratamiento , Síndrome de Bland White Garland/cirugía , Vasos Coronarios/cirugía , Mortalidad Hospitalaria , Anomalías de los Vasos Coronarios/cirugía , Factores de TiempoRESUMEN
Pulmonary arterial hypertension (PAH) is a chronic and fatal disease characterized by pulmonary vascular remodeling, similar to the 'Warburg effect' observed in cancer, which is caused by reprogramming of glucose metabolism. Oroxylin A (OA), an active compound derived from Scutellaria baicalensis, which can inhibit glycolytic enzymes [hexokinase 2 (HK2), Lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase 1 (PDK1) by downregulating aerobic glycolysis to achieve the treatment of liver cancer. To the best of our knowledge, however, the impact of OA on PAH has not been addressed. Consequently, the present study aimed to evaluate the potential protective role and mechanism of OA against PAH induced by monocrotaline (MCT; 55 mg/kg). The mean pulmonary artery pressure (mPAP) was measured using the central venous catheter method; HE and Masson staining were used to observe pulmonary artery remodeling. Nontargeted metabolomics was used to analyze the metabolic pathways and pathway metabolites in MCTPAH rats. Western Blot analysis was employed to assess the levels of glucose transporter 1 (Glut1), HK2), pyruvate kinase (PK), isocitrate dehydrogenase 2 (IDH2), pyruvate dehydrogenase kinase 1(PDK1), and lactate dehydrogenase (LDH) protein expression in both lung tissue samples from MCTPAH rats. The results demonstrated that intragastric administration of OA (40 and 80 mg/kg) significantly decreased mPAP from 43.61±1.88 mmHg in PAH model rats to 26.51±1.53 mmHg and relieve pulmonary artery remodeling. Untargeted metabolomic analysis and multivariate analysis indicated abnormal glucose metabolic pattern in PAH model rats, consistent with the Warburg effect. OA administration decreased this effect on the abnormal glucose metabolism. The protein levels of key enzymes involved in glucose metabolism were evaluated by western blotting, which demonstrated that OA could improve aerobic glycolysis and inhibit PAH by decreasing the protein levels of Glut1, HK2, LDH, PDK1 and increasing the protein levels of PK and IDH2. In conclusion, OA decreased MCTinduced PAH in rats by reducing the Warburg effect.
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Flavonoides , Glucólisis , Monocrotalina , Hipertensión Arterial Pulmonar , Animales , Ratas , Masculino , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/metabolismo , Flavonoides/farmacología , Flavonoides/uso terapéutico , Glucólisis/efectos de los fármacos , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Ratas Sprague-Dawley , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Scutellaria baicalensis/química , Modelos Animales de Enfermedad , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Efecto Warburg en Oncología/efectos de los fármacosRESUMEN
Takayasu's arteritis-pulmonary artery involvement (TA-PAI) is a chronic, progressive, inflammatory disease affecting the pulmonary artery and its branches. Patients typically present with non-specific respiratory symptoms, such as fever, dyspnea, and chest pain, leading to a high rate of misdiagnosis. The diagnosis of TA-PAI is currently based on the diagnostic criteria of aortitis and imaging evidence of pulmonary artery involvement. However, pulmonary artery involvement is not typically included in the diagnostic criteria for aortitis, which may lead to a significant underestimation of the diagnostic rate of TA-PAI, particularly in cases where pulmonary artery involvement is the only manifestation. This article reports the case of a 26-year-old female patient who presented with recurrent chest pain and fever. She was initially diagnosed with pneumonia in a foreign hospital but did not show significant improvement after four months of treatment. Eventually, she was diagnosed with pulmonary artery involvement in aortitis and was stabilized with hormones, immunosuppressive drugs, and pulmonary vascular intervention. By analyzing the clinical features and diagnostic and therapeutic approaches of this case, and reviewing the relevant literature, clinicians can improve their understanding of TA-PAI.
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Neumonía , Arteria Pulmonar , Arteritis de Takayasu , Humanos , Femenino , Adulto , Arteritis de Takayasu/diagnóstico , Neumonía/diagnóstico , Arteria Pulmonar/patología , Arteria Pulmonar/diagnóstico por imagen , Dolor en el Pecho/etiologíaRESUMEN
Vascular smooth muscle cells (SMCs) can transition between a quiescent contractile or "differentiated" phenotype and a "proliferative-dedifferentiated" phenotype in response to environmental cues, similar to what in occurs in the wound healing process observed in fibroblasts. When dysregulated, these processes contribute to the development of various lung and cardiovascular diseases such as Chronic Obstructive Pulmonary Disease (COPD). Long non-coding RNAs (lncRNAs) have emerged as key modulators of SMC differentiation and phenotypic changes. In this study, we examined the expression of lncRNAs in primary human pulmonary artery SMCs (hPASMCs) during cell-to-cell contact-induced SMC differentiation. We discovered a novel lncRNA, which we named Differentiation And Growth Arrest-Related lncRNA (DAGAR) that was significantly upregulated in the quiescent phenotype with respect to proliferative SMCs and in cell-cycle-arrested MRC5 lung fibroblasts. We demonstrated that DAGAR expression is essential for SMC quiescence and its knockdown hinders SMC differentiation. The treatment of quiescent SMCs with the pro-inflammatory cytokine Tumor Necrosis Factor (TNF), a known inducer of SMC dedifferentiation and proliferation, elicited DAGAR downregulation. Consistent with this, we observed diminished DAGAR expression in pulmonary arteries from COPD patients compared to non-smoker controls. Through pulldown experiments followed by mass spectrometry analysis, we identified several proteins that interact with DAGAR that are related to cell differentiation, the cell cycle, cytoskeleton organization, iron metabolism, and the N-6-Methyladenosine (m6A) machinery. In conclusion, our findings highlight DAGAR as a novel lncRNA that plays a crucial role in the regulation of cell proliferation and SMC differentiation. This paper underscores the potential significance of DAGAR in SMC and fibroblast physiology in health and disease.
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Diferenciación Celular , Proliferación Celular , Fibroblastos , Miocitos del Músculo Liso , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Fibroblastos/metabolismo , Diferenciación Celular/genética , Miocitos del Músculo Liso/metabolismo , Proliferación Celular/genética , Arteria Pulmonar/metabolismo , Arteria Pulmonar/citología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/citología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/patología , Células CultivadasRESUMEN
Introduction: Pulmonary thromboembolism (PTE) has a wide range of clinical presentations. With the advances in computed tomography (CT) technology and easier access to CT, the incidence of incidentally diagnosed cases of PTE has increased. The main aim of our study was to determine the frequency of patients incidentally diagnosed with PTE and whether these patients differ from patients with symptomatic PTE in terms of case characteristics. Materials and Methods: We retrospectively analysed the charts of 148 patients with PTE diagnosed and treated in 2022. Demographic characteristics, thrombus localisation, risk factors, and treatment modalities were compared between symptomatic patients with clinically suspected PTE and patients with incidentally diagnosed PTE by imaging methods performed for other purposes without clinically suspected PTE. Result: Out of 148 patients with PTE, 42 (28.3%) were diagnosed incidentally. The rate of concomitant malignancy was significantly higher in patients with incidental PTE (54.8%) than in patients with symptomatic PTE (28.3%) (p < 0.01). There was no significant difference between symptomatic and incidental PTE patients in terms of the pulmonary artery segment in which the thrombus was located (p > 0.05). Conclusions: In our patient group, approximately one out of four patients diagnosed with PTE were incidentally diagnosed. Patients with malignancies may not have symptoms suspicious for PTE or their symptoms may go unrecognized.
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Hallazgos Incidentales , Embolia Pulmonar , Tomografía Computarizada por Rayos X , Humanos , Embolia Pulmonar/epidemiología , Embolia Pulmonar/diagnóstico por imagen , Embolia Pulmonar/diagnóstico , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Factores de Riesgo , Adulto , Neoplasias/complicaciones , Anciano de 80 o más Años , Turquía/epidemiología , Arteria Pulmonar/diagnóstico por imagenRESUMEN
The pulmonary veins normally drain into the left atrium, with the superior pulmonary veins typically situated anterior and inferior to the right pulmonary arteries. However, anomalies can happen. We encountered an exceedingly rare pulmonary vascular anomaly for a patient presenting with atypical chest pain, where the right superior pulmonary vein aberrantly ran posterior to the right pulmonary artery (RPA) and became compressed between the RPA and the right main bronchus. Coronary computed tomography angiography identified this specific pulmonary vein anomaly but revealed unremarkable coronary arteries.
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Angiografía por Tomografía Computarizada , Angiografía Coronaria , Venas Pulmonares , Humanos , Venas Pulmonares/anomalías , Venas Pulmonares/diagnóstico por imagen , Venas Pulmonares/fisiopatología , Arteria Pulmonar/anomalías , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Masculino , Malformaciones Vasculares/diagnóstico por imagen , Malformaciones Vasculares/fisiopatología , Malformaciones Vasculares/complicaciones , Persona de Mediana Edad , Flebografía , FemeninoAsunto(s)
Antihipertensivos , Hipertensión Pulmonar , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/metabolismo , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Terapia Molecular Dirigida , Transducción de Señal/efectos de los fármacos , Presión Arterial/efectos de los fármacosRESUMEN
BACKGROUND: A coronary artery fistula is an abnormal connection between one or more coronary arteries and a cardiac chamber or great vessel, often discovered incidentally through cardiac imaging. Although coronary artery fistulas are typically asymptomatic during the first two decades of life, particularly when small, they can become clinically significant over time. CASE PRESENTATION: We present the case of a 71-year-old female patient with a history of exertional dyspnea. Diagnostic coronary angiography revealed a significant coronary artery fistula originating from the proximal right coronary artery and draining into the pulmonary artery trunk. Given the patient's symptoms and the anatomical features of the fistula, she was successfully treated with transcutaneous closure using a liquid embolic agent (Onyx). CONCLUSION: Although surgical intervention has historically been the primary treatment for CAF, minimally invasive techniques such as transcutaneous closure are proving to be effective alternatives.
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Fístula Arterio-Arterial , Arteria Pulmonar , Humanos , Femenino , Anciano , Fístula Arterio-Arterial/cirugía , Fístula Arterio-Arterial/diagnóstico por imagen , Arteria Pulmonar/anomalías , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/cirugía , Angiografía Coronaria , Embolización Terapéutica/métodosRESUMEN
Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious pulmonary vascular disease characterized by residual thrombi in the pulmonary arteries and distal pulmonary microvascular remodeling. The pathogenesis of CTEPH remains unclear, but many factors such as inflammation, immunity, coagulation and angiogenesis may be involved. Monocytes are important immune cells that can differentiate into macrophages and dendritic cells and play an important role in thrombus formation. However, the distribution, gene expression profile and differentiation trajectory of monocyte subsets in CTEPH patients have not been systematically studied. This study aims to reveal the characteristics and functions of monocytes in CTEPH patients using single-cell sequencing technology, and to provide new insights for the diagnosis and treatment of CTEPH. Methods: Single-cell RNA sequencing (scRNA-seq) were performed to analyze the transcriptomic features of peripheral blood mononuclear cells (PBMCs) from healthy controls, CTEPH patients and the tissues from CTEPH patients after the pulmonary endarterectomy (PEA). We established a CTEPH rat model with chronic pulmonary embolism caused by repeated injection of autologous thrombi through a central venous catheter, and used flow cytometry to detect the proportion changes of monocyte subsets in CTEPH patients and CTEPH rat model. We also observed the infiltration degree of macrophage subsets in thrombus tissue and their differentiation relationship with peripheral blood monocyte subsets by immunofluorescence staining. Results: The results showed that the monocyte subsets in peripheral blood of CTEPH patients changed significantly, especially the proportion of CD16+ monocyte subset increased. This monocyte subset had unique functional features at the transcriptomic level, involving processes such as cell adhesion, T cell activation, coagulation response and platelet activation, which may play an important role in pulmonary artery thrombus formation and pulmonary artery intimal remodeling. In addition, we also found that the macrophage subsets in pulmonary endarterectomy tissue of CTEPH patients showed pro-inflammatory and lipid metabolism reprogramming features, which may be related to the persistence and insolubility of pulmonary artery thrombi and the development of pulmonary hypertension. Finally, we also observed that CD16+ monocyte subset in peripheral blood of CTEPH patients may be recruited to pulmonary artery intimal tissue and differentiate into macrophage subset with high expression of IL-1ß, participating in disease progression. Conclusion: CD16+ monocytes subset had significant gene expression changes in CTEPH patients, related to platelet activation, coagulation response and inflammatory response. And we also found that these cells could migrate to the thrombus and differentiate into macrophages with high expression of IL-1ß involved in CTEPH disease progression. We believe that CD16+ monocytes are important participants in CTEPH and potential therapeutic targets.
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Hipertensión Pulmonar , Monocitos , Embolia Pulmonar , Receptores de IgG , Análisis de la Célula Individual , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/inmunología , Hipertensión Pulmonar/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Receptores de IgG/metabolismo , Embolia Pulmonar/inmunología , Embolia Pulmonar/metabolismo , Animales , Masculino , Enfermedad Crónica , Ratas , Femenino , Persona de Mediana Edad , Proteínas Ligadas a GPI/metabolismo , Modelos Animales de Enfermedad , Transcriptoma , Anciano , Arteria Pulmonar/metabolismo , Arteria Pulmonar/inmunología , Arteria Pulmonar/patologíaRESUMEN
Induction of resistin-like molecule ß (Relm-ß) and mitofusin 2 (MFN2) mediated aberrant mitochondrial fission have been found to be involved in the pathogenesis of pulmonary arterial hypertension (PAH). However, the molecular mechanisms underlying Relm-ß regulation of MFN2 therefore mitochondrial fission remain unclear. This study aims to address these issues. Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. The results showed that Relm-ß promoted cells proliferation in PASMCs, this was accompanied with the upregulation of USP18, Twist1 and miR-214, and downregulation of MFN2. We found that Relm-ß increased USP18 expression which in turn raised Twist1 by suppressing its proteasome degradation. Elevation of Twist1 increased miR-214 expression and then reduced MFN2 expression and mitochondrial fragmentation leading to PASMCs proliferation. In vivo study, we confirmed that Relm-ß was elevated in MCT-induced PAH rat model, and USP18/Twist1/miR-214/MFN2 axis was altered similar as in vitro. Targeting this cascade by Relm-ß receptor inhibitor Calhex231, proteasome inhibitor MG-132, Twist1 inhibitor Harmine or miR-214 antagomiR prevented the development of pulmonary vascular remodeling and therefore PAH in MCT-treated rats. In conclusion, we demonstrate that Relm-ß promotes PASMCs proliferation and vascular remodeling by activating USP18/Twist1/miR-214 dependent MFN2 reduction and mitochondrial fission, suggesting that this signaling pathway might be a promising target for management of PAH.
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Proliferación Celular , GTP Fosfohidrolasas , MicroARNs , Mitocondrias , Ratas Sprague-Dawley , Transducción de Señal , Proteína 1 Relacionada con Twist , Ubiquitina Tiolesterasa , Animales , Masculino , Ratas , Proliferación Celular/efectos de los fármacos , GTP Fosfohidrolasas/metabolismo , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales , Monocrotalina/toxicidad , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/patología , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Arteria Pulmonar/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 Relacionada con Twist/metabolismo , Proteína 1 Relacionada con Twist/genética , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genéticaRESUMEN
BACKGROUND Pulmonary artery sling (PAS) is an anatomical vascular anomaly due to the origin of the left pulmonary artery from the right pulmonary artery, which runs posteriorly between the esophagus and trachea, resulting in compression of adjacent structures. Accurate evaluation for malformation of the pulmonary artery and severity of airway obstruction is essential to surgical strategy. This report presents the diagnosis and surgical management of pulmonary artery sling in a 12-year-old boy. CASE REPORT A 12-year-old boy had chest tightness and wheezing after exercise for 6 years. He was diagnosed with PSA based on findings from imaging tests, demonstrating the left pulmonary artery originated from the middle of the right pulmonary artery and the tracheal carina was located at the site of the T6 thoracic vertebra. The main bronchus and esophagus were compressed by the left pulmonary artery due to its ectopic origin. Then, after comprehensive preoperative assessment, the patient underwent surgical repair of PAS. CONCLUSIONS This report highlights the importance of pulmonary artery sling diagnosis, imaging, and surgical planning, and the role of a multidisciplinary team in preoperative and postoperative patient management. An individualized strategy based on the preoperative assessment, intraoperative coordination among cardiologists, surgeons, and perfusionists, and careful postoperative management are the core elements for successful PAS repair.
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Arteria Pulmonar , Humanos , Arteria Pulmonar/anomalías , Arteria Pulmonar/cirugía , Arteria Pulmonar/diagnóstico por imagen , Masculino , Niño , Malformaciones Vasculares/cirugía , Malformaciones Vasculares/diagnósticoRESUMEN
ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by persistently elevated pulmonary artery pressure and vascular resistance. Sympathetic overactivity in hypertension participates in pulmonary vascular remodeling and heart failure. The present study aims to explore the efficacy of highly selective thoracic sympathectomy (HSTS) on lowering pulmonary artery pressure, reversing pulmonary vascular remodeling, and improving right ventricular function in rats. A total of 24 Sprague-Dawley rats were randomly assigned into the control group ( n = 8) and experimental group ( n = 16). Rats in the control group were intraperitoneally injected with 0.9% normal saline, and those in the experimental group were similarly administered with received monocrotaline (MCT) injections at 60 mg/kg. Two weeks later, rats in the experimental group were further subdivided randomly into the MCT-HSTS group ( n = 8) and MCT-sham group ( n = 8), and they were surgically treated with HSTS and sham operation, respectively. Two weeks later, significantly lowered mean pulmonary artery pressure (mPAP), pulmonary artery systolic pressure (sPAP), and the ratio of sPAP to femoral artery systolic pressure (sFAP) were detected in the MCT-HSTS group than those of the MCT-sham group. In addition, rats in the MCT-HSTS group presented a significantly lower ratio of vascular wall area to the total vascular area (WT%), right ventricular hypertrophy index, and degrees of right ventricular fibrosis and lung fibrosis in comparison to those of the MCT-sham group. HSTS significantly downregulated protein levels of inflammasomes in pulmonary artery smooth muscle cells (PASMCs). Collectively, HSTS effectively reduces pulmonary artery pressure, pulmonary arteriolar media hypertrophy, and right ventricular hypertrophy in MCT-induced PAH rats. It also exerts an anti-inflammatory effect on PASMCs in PAH rats by suppressing inflammasomes and the subsequent release of inflammatory cytokines.
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Monocrotalina , Hipertensión Arterial Pulmonar , Ratas Sprague-Dawley , Simpatectomía , Animales , Simpatectomía/métodos , Masculino , Ratas , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/patología , Remodelación Vascular , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Progresión de la Enfermedad , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/patologíaRESUMEN
Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by increased pulmonary vascular resistance because of vascular remodeling and vasoconstriction. Subsequently, PAH leads to right ventricular hypertrophy and heart failure. Cell death mechanisms play a significant role in development and tissue homeostasis, and regulate the balance between cell proliferation and differentiation. Several basic and clinical studies have demonstrated that multiple mechanisms of cell death, including pyroptosis, apoptosis, autophagy, ferroptosis, anoikis, parthanatos, and senescence, are closely linked with the pathogenesis of PAH. This review summarizes different cell death mechanisms involved in the death of pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs), the primary target cells in PAH. This review summarizes the role of these cell death mechanisms, associated signaling pathways, unique effector molecules, and various pro-survival or reprogramming mechanisms. The aim of this review is to summarize the currently known molecular mechanisms underlying PAH. Further investigations of the cell death mechanisms may unravel new avenues for the prevention and treatment of PAH.
Asunto(s)
Células Endoteliales , Miocitos del Músculo Liso , Hipertensión Arterial Pulmonar , Arteria Pulmonar , Transducción de Señal , Humanos , Células Endoteliales/patología , Miocitos del Músculo Liso/patología , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Muerte Celular , Animales , Apoptosis , Autofagia/fisiología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatologíaRESUMEN
Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.