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BACKGROUND: Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. METHODS: Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. RESULTS: Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. CONCLUSIONS: Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.
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Quimiocina CCL5 , Hipertensión Pulmonar Primaria Familiar , Células Asesinas Naturales , RNA-Seq , Análisis de la Célula Individual , Linfocitos T , Animales , Humanos , Quimiocina CCL5/metabolismo , Quimiocina CCL5/genética , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/inmunología , Hipertensión Pulmonar Primaria Familiar/genética , Hipertensión Pulmonar Primaria Familiar/patología , Hipertensión Pulmonar Primaria Familiar/metabolismo , Linfocitos T/metabolismo , Linfocitos T/inmunología , Masculino , Comunicación Celular/genética , Ratas Sprague-Dawley , Pulmón/patología , Ratas , Redes Reguladoras de Genes , Monocrotalina , Mapas de Interacción de Proteínas/genética , Biología ComputacionalRESUMEN
Patients with venous thromboembolism (VTE) comorbid renal insufficiency (RI) are at higher risk of bleeding and thrombosis. Recommendations in guidelines on anticoagulation therapy for those patients remain ambiguous. The goal of this study is to compare the efficacy and safety between different anticoagulant regimens in VTE patients comorbid RI at different stages of treatment and prophylaxis. We performed English-language searches of Pubmed, EMBASE, and Web of Science (inception to Nov 2022). RCTs evaluated anticoagulants for VTE treatment at the acute phase, extension phase, and prophylaxis in patients with RI and reported efficacy and safety outcomes were selected. The methodological quality of the studies was assessed at the outcome level using the risk-of-bias assessment tool developed by the Cochrane Bias Methods Group. A meta-analysis of twenty-five RCTs was conducted, comprising data from twenty-three articles, encompassing a total of 9,680 participants with RI. In the acute phase, the risk of bleeding was increased with novel oral anticoagulants (NOACs) compared to LMWH (RR 1.29, 95% CI 1.04-1.60). For the prophylaxis of VTE, NOACs were associated with an elevated risk of bleeding compared with placebo (RR 1.31, 95%CI 1.02-1.68). In comparison to non-RI patients, both NOACs and vitamin K antagonists (VKA) could increase the risk of bleeding among RI patients (RR 1.45, 95%CI 1.14-1.84 and RR 1.53, 95%CI 1.25-1.88, respectively) during acute phase, while NOACs may increase the incidence of VTE in RI population (RR 1.74, 95%CI 1.29-2.34). RI patients who are under routine anticoagulation have a significantly higher risk of adverse outcomes. LMWH is the most effective and safe option for VTE treatment or prophylaxis in patients with RI.
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BACKGROUND: The risk stratification of pulmonary arterial hypertension proposed by the European Society of Cardiology /European Respiratory Society guidelines in 2015 and 2022 included two to three echocardiographic indicators. However, the specific value of echocardiography in risk stratification of pre-capillary pulmonary hypertension (pcPH) has not been efficiently demonstrated. Given the complex geometry of the right ventricular (RV) and influencing factors of echocardiographic parameter, there is no single echocardiographic parameter that reliably informs about PH status. We hypothesize that a multi-parameter comprehensive index can more accurately evaluate the severity of the pcPH. The purpose of this study was to develop and validate an echocardiographic risk score model to better assist clinical identifying high risk of pcPH during initial diagnosis and follow-up. METHODS: We studied 197 consecutive patients with pcPH. A multivariable echocardiographic model was constructed to predict the high risk of pcPH in the training set. Points were assigned to significant risk factors in the final model based on ß-coefficients. We validated the model internally and externally. RESULTS: The echocardiographic score was constructed by multivariable logistic regression, which showed that pericardial effusion, right atrial (RA) area, RV outflow tract proximal diameter (RVOT-Prox), the velocity time integral of the right ventricular outflow tract (TVIRVOT) and S' were predictors of high risk of pcPH. The area under curve (AUC) of the training set of the scoring model was 0.882 (95%CI: 0.809-0.956, p < 0.0001). External validation was tested in a test dataset of 77 patients. The AUC of the external validation set was 0.852. A 10-point score risk score was generated, with scores ranging from 0 to 10 in the training cohort. The estimate risk of high risk of pcPH ranged from 25.1 to 94.6%. CONCLUSIONS: The echocardiographic risk score using five echocardiographic parameters could be comprehensive and useful to predict the high risk of pcPH for initial assessment and follow-up.
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Valor Predictivo de las Pruebas , Función Ventricular Derecha , Humanos , Masculino , Femenino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Reproducibilidad de los Resultados , Anciano , Estudios Retrospectivos , Pronóstico , Presión Arterial , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Técnicas de Apoyo para la Decisión , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Ecocardiografía Doppler , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/diagnóstico por imagen , Hipertensión Arterial Pulmonar/diagnósticoRESUMEN
INTRODUCTION: Balloon pulmonary angioplasty (BPA) is an effective intervention for patients with chronic thromboembolic pulmonary disease (CTEPD). We aim to identify the patient group with a low success rate or high complication rate of BPA, which is still unclear. METHODS: Both CTEPD patients with or without pulmonary hypertension (CTEPH and NoPH-CTEPD) were included. CTEPH patients were divided into groups with or without pulmonary endarterectomy (PEA-CTEPH and NoPEA-CTEPH). The efficacy and safety of BPA were compared among the groups. RESULTS: There were 450, 66, and 41 sessions in the NoPEA-CTEPH, PEA-CTEPH, and NoPH-CTEPD groups, respectively. The success rate (≥ 1 degree improvement in flow grade) in the PEA-CTEPH group was 94.5%, significantly lower than that in the NoPEA-CTEPH (97.1%) and NoPH-CTEPD (98.4%) groups (P=0.014). The percentage of complete flow recovery in treated vessels was also lower in PEA-CTEPH group. BPA-related complication rate in NoPEA-CTEPH, PEA-CTEPH, and NoPH-CTEPD patients was 6.1%, 6.0%, and 0.0%, respectively (P=0.309). One BPA-related death occurred (solely in NoPEA-CTEPH). Mean pulmonary artery pressure ≥ 41.5 mmHg was a predictor of BPA-related complications. NoPEA-CTEPH patients had more improvement in 6-minute-walk-distance (6MWD, 87±93 m -NoPEA-CTEPH vs 40±43 m -PEA-CTEPH vs 18±20 m -NoPH-CTEPD, P=0.012). CONCLUSIONS: BPA was safe and effective for all CTEPD groups with less improvement for the PEA-CTEPH and NoPH-CTEPD groups. The success rate of BPA was lower in the PEA-CTEPH group and the complication rate was lower in the NoPH-CTEPD group. Pre-BPA treatment to lower pulmonary artery pressure should not be overlooked in CTEPD patients.
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BACKGROUND: Patients with congenital myopathies may experience respiratory involvement, resulting in restrictive ventilatory dysfunction and respiratory failure. Pulmonary hypertension (PH) associated with this condition has never been reported in congenital ryanodine receptor type 1(RYR1)-related myopathy. CASE PRESENTATION: A 47-year-old woman was admitted with progressively exacerbated chest tightness and difficulty in neck flexion. She was born prematurely at week 28. Her bilateral lower extremities were edematous and muscle strength was grade IV-. Arterial blood gas analysis revealed hypoventilation syndrome and type II respiratory failure, while lung function test showed restrictive ventilation dysfunction, which were both worse in the supine position. PH was confirmed by right heart catheterization (RHC), without evidence of left heart disease, congenital heart disease, or pulmonary artery obstruction. Polysomnography indicated nocturnal hypoventilation. The ultrasound revealed reduced mobility of bilateral diaphragm. The level of creatine kinase was mildly elevated. Magnetic resonance imaging showed myositis of bilateral thigh muscle. Muscle biopsy of the left biceps brachii suggested muscle malnutrition and congenital muscle disease. Gene testing revealed a missense mutation in the RYR1 gene (exon33 c.C4816T). Finally, she was diagnosed with RYR1-related myopathy and received long-term non-invasive ventilation (NIV) treatment. Her symptoms and cardiopulmonary function have been greatly improved after 10 months. CONCLUSIONS: We report a case of RYR1-related myopathy exhibiting hypoventilation syndrome, type II respiratory failure and PH associated with restrictive ventilator dysfunction. Pulmonologists should keep congenital myopathies in mind in the differential diagnosis of type II respiratory failure, especially in patients with short stature and muscle weakness.
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Hipertensión Pulmonar , Debilidad Muscular , Insuficiencia Respiratoria , Canal Liberador de Calcio Receptor de Rianodina , Humanos , Femenino , Canal Liberador de Calcio Receptor de Rianodina/genética , Persona de Mediana Edad , Debilidad Muscular/etiología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/genética , Insuficiencia Respiratoria/etiología , Mutación Missense , Imagen por Resonancia Magnética , Enfermedades Musculares/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/complicacionesRESUMEN
BACKGROUND: Hemoptysis resulting from rupture of the pulmonary artery pseudoaneurysm (PAP) is massive and fatal, while factor contributing to the rupture of pseudoaneurysm remains elusive. This study aimed to elucidate the clinical and radiological features of PAP and identify the risk factors associated with rupture. METHODS: Patients who developed hemoptysis with PAP were collected from January 2019 to December 2022 retrospectively. Clinical data of the demographic characteristics, radiological findings, treatment strategies, and prognosis were collected. A comparative analysis was performed on the characteristics in the ruptured and non-ruptured cases. RESULTS: A total of 58 PAPs were identified in the 50 patients. The most common causes were infection (86%) and cancer (8%). The PAPs were located predominantly in the upper lobes of both lungs, and 57 (99.3%) were distributed in the segmental or subsegmental pulmonary arteries. The median diameter was 6.1(4.3-8.7) mm. A total of 29 PAPs were identified adjacent to pulmonary cavitations, with the median diameter of the cavity being 18.9 (12.4-34.8) mm. Rupture of pseudoaneurysm occurred in 21 cases (42%). Compared to unruptured group, the ruptured group had a significantly higher proportion of massive hemoptysis (57.1% vs. 6.9%, p < 0.001), larger pseudoaneurysm diameter (8.1 ± 3.2 mm vs. 6.0 ± 2.3 mm, p = 0.012), higher incidence of pulmonary cavitation (76.2% vs. 44.8%, p = 0.027), and larger cavitation diameters (32.9 ± 18.8 mm vs. 15.7 ± 8.4 mm, p = 0.005). The mean pulmonary artery pressure (mPAP) in the ruptured group was also significantly higher than that in the unruptured group [23.9 ± 7.4 mmHg vs. 19.2 ± 5.0 mmHg, p = 0.011]. Endovascular treatment was successfully performed in all 21 patients with ruptured PAP, of which the clinical success rate was 96.0%. Five patients experienced recurrent hemoptysis within one year. CONCLUSIONS: Massive hemoptysis, pseudoaneurysm diameter, pulmonary cavitation, and elevated mPAP were the risk factors for rupture of pseudoaneurysm. Our findings facilitate early identification and timely intervention of PAP at high risk of rupture.
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Aneurisma Falso , Hemoptisis , Arteria Pulmonar , Humanos , Aneurisma Falso/diagnóstico por imagen , Estudios Retrospectivos , Masculino , Femenino , Arteria Pulmonar/diagnóstico por imagen , Hemoptisis/etiología , Persona de Mediana Edad , Anciano , Factores de Riesgo , Adulto , Aneurisma Roto/complicaciones , Aneurisma Roto/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Clinical characteristics of patients with pulmonary thromboembolism have been described in previous studies. Although very old patients with pulmonary thromboembolism are a special group based on comorbidities and age, they do not receive special attention. OBJECTIVE: This study aims to explore the clinical characteristics and mortality predictors among very old patients with pulmonary thromboembolism in a relatively large population. DESIGN AND PARTICIPANTS: The study included a total of 7438 patients from a national, multicenter, registry study, the China pUlmonary thromboembolism REgistry Study (CURES). Consecutive patients with acute pulmonary thromboembolism were enrolled and were divided into three groups. Comparisons were performed between these three groups in terms of clinical characteristics, comorbidities and in-hospital prognosis. Mortality predictors were analyzed in very old patients with pulmonary embolism. KEY RESULTS: In 7,438 patients with acute pulmonary thromboembolism, 609 patients aged equal to or greater than 80 years (male 354 (58.1%)). There were 2743 patients aged between 65 and 79 years (male 1313 (48%)) and 4095 patients aged younger than 65 years (male 2272 (55.5%)). Patients with advanced age had significantly more comorbidities and worse condition, however, some predisposing factors were more obvious in younger patients with pulmonary thromboembolism. PaO2 < 60 mmHg, eGFR < 60 mL/min/1.73m2, malignancy, anticoagulation as first therapy were mortality predictors for all-cause death in very old patients with pulmonary thromboembolism. The analysis found that younger patients were more likely to have chest pain, hemoptysis (the difference was statistically significant) and dyspnea triad. CONCLUSION: In very old population diagnosed with pulmonary thromboembolism, worse laboratory results, atypical symptoms and physical signs were common. Mortality was very high and comorbid conditions were their features compared to younger patients. PaO2 < 60 mmHg, eGFR < 60 mL/min/1.73m2 and malignancy were positive mortality predictors for all-cause death in very old patients with pulmonary thromboembolism while anticoagulation as first therapy was negative mortality predictors.
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Neoplasias , Embolia Pulmonar , Anciano , Humanos , Masculino , Anticoagulantes/uso terapéutico , Análisis de los Gases de la Sangre , Oxígeno , Embolia Pulmonar/epidemiología , FemeninoRESUMEN
BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. METHODS AND DESIGN: The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. CONCLUSIONS: As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. REGISTRATION NUMBER IN CLINICALTRIALS.GOV: NCT05311072.
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Angioplastia de Balón , Endarterectomía , Hipertensión Pulmonar , Embolia Pulmonar , Humanos , Hipertensión Pulmonar/terapia , China , Embolia Pulmonar/complicaciones , Embolia Pulmonar/terapia , Enfermedad Crónica , Calidad de Vida , Resultado del Tratamiento , Femenino , Terapia Combinada , Masculino , Pueblos del Este de AsiaRESUMEN
BACKGROUND: A large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese. METHODS: We conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated. RESULTS: After meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 (p-value = 3.81 × 10-14), ABO rs582094 (p-value = 1.16 × 10-10) and newly reported locus FABP2 rs1799883 (p-value = 7.59 × 10-17). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G(rs1799883) promoted the transcription and protein expression of FABP2. Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population. CONCLUSIONS: We identified FABP2, related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.
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Pueblos del Este de Asia , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Embolia Pulmonar , Humanos , China/epidemiología , Pueblos del Este de Asia/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Polimorfismo de Nucleótido Simple/genética , Embolia Pulmonar/epidemiología , Embolia Pulmonar/etnología , Embolia Pulmonar/genética , Factores de RiesgoRESUMEN
Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.
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Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Proteoma/genética , Estudio de Asociación del Genoma Completo/métodos , Análisis de la Aleatorización Mendeliana , Teorema de Bayes , Serpina E2/genética , Proteínas Sanguíneas/genética , Polimorfismo de Nucleótido Simple , Proteínas de la Matriz Extracelular/genéticaRESUMEN
BACKGROUND: According to several studies, ROS1 rearrangement is associated with thrombotic risk in non-small cell lung cancer (NSCLC). However, there is no clear understanding of the predictors and prognostic impact of thromboembolic events (TEEs) in patients with advanced ROS1 rearrangement NSCLC. METHODS: A total of 47 newly diagnosed advanced NSCLC patients with ROS1 rearrangement from four Chinese hospitals were retrospectively included and were evaluated for TEEs incidence, characteristics, predictors, as well as response to therapies and overall survival (OS). RESULTS: Of the 47 enrolled patients, 23.4% (n = 11) patients developed TEEs. Among them, 7 of 11 patients (64%) developed pulmonary embolism (PE), and 5 patients (45%) experienced recurrent TEEs. In multivariate analysis, D-dimer was associated with the occurrence of TEEs in ROS1 rearranged NSCLC (HR 1.16, 95% CI 1.08-1.23, P < 0.001). Median progression-free survival (PFS) after first-line ROS1 tyrosine kinase inhibitors (TKIs) therapy was significantly longer in patients without TEEs than in those developing TEEs (26 months vs. 12 months, P = 0.0383). Furthermore, patients with TEEs had a shorter OS period than those without TEEs (29.8 months vs. not estimable, P = 0.0647). CONCLUSION: The results of this multicenter study indicated that advanced NSCLC patients with ROS1 rearrangement were more likely to experience PE and TEEs recurrence. And patients with TEEs tended to have a worse prognosis. Furthermore, an elevated D-dimer level suggested a hypercoagulable state in NSCLC patients with ROS1 rearrangement.
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BACKGROUND: Renal function is associated with prognoses for acute pulmonary embolism (PE). OBJECTIVE: To investigate the application of anticoagulants and dosage of LMWH among patients with renal insufficiency (RI), and the association between LWMH dosage and the patients' in-hospital outcomes. METHODS: Adult patients diagnosed with non-high risk acute PE from 2009 to 2015, with available data of creatinine clearance (CCr) were enrolled from a multicenter registry in China. Renal insufficiency (RI) was defined as CCr < 60 ml/min. LMWH dosage was converted into IU/kg daily dose and presented as adjusted dose (≤ 100 IU/kg/day) and conventional dose (> 100 IU/kg/day). All-cause death, PE-related death and bleeding events during hospitalization were analyzed as endpoints. RESULTS: Among the enrolled 5870 patients, RI occurred in 1311 (22.3%). 30 ≤ CCr < 60 ml/min was associated with higher rate of bleeding events and CCr < 30 ml/min was associated with all-cause death, PE-related death and major bleeding. Adjusted-dose LMWH was applied in 26.1% of patients with 30 ≤ CCr < 60 ml/min and in 26.2% of CCr < 30 ml/min patients. Among patients with RI, in-hospital bleeding occurred more frequently in those who were administered conventional dose of LMWH, compared with adjusted dose (9.2% vs 5.0%, p = 0.047). Adjusted dose of LMWH presented as protective factor for in-hospital bleeding (OR 0.62, 95%CI 0.27-1.00, p = 0.0496) and the risk of bleeding increased as length of hospital stay prolonged (OR 1.03, 95%CI 1.01-1.06, p = 0.0014). CONCLUSIONS: The proportion of adjusted usage of LMWH was low. The application of adjusted-dose LMWH was associated with lower risk of in-hospital bleeding for RI patients, in real-world setting of PE treatment. Anticoagulation strategy for RI patients should be paid more attention and requires evidence of high quality. TRIAL REGISTRATION: The CURES was registered in ClinicalTrias.gov, identifier number: NCT02943343 .
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BACKGROUND: The proliferation of pulmonary arterial smooth muscle cells (PASMCs) and subsequent pulmonary vascular remodeling leads to pulmonary arterial hypertension (PAH). Understanding the underlying mechanisms and identifying molecules that can suppress PASMCs proliferation is critical for developing effective pharmacological treatment. We previously showed that plasminogen activator inhibitor-2 (PAI-2) inhibited human PASMC (hPASMCs) proliferation in vitro. However, its inhibitory effect on PAH remains to be determined, and the mechanism remains to be illustrated. METHODS: We compared serum PAI-2 levels between PAH patients and healthy controls, and examined the correlation between PAI-2 level and disease severity. In monocrotaline-induced PAH rats, we examined the effects of exogenous PAI-2 administration on pulmonary vascular remodeling and PAH development. The effect of PAI-2 and potential mechanisms was further examined in cultured hPASMCs. RESULTS: The serum PAI-2 was decreased in PAH patients compared with controls. PAI-2 level was negatively correlated with mean pulmonary arterial pressure and estimated systolic pulmonary arterial pressure in ultrasonic cardiogram, while positively correlated with 6-min walking distance. In rats, administration of exogenous PAI-2 significantly reversed monocrotaline-induced PAH, as indicated by the decrease in right ventricle systolic pressure, right ventricular hypertrophy index and percent media thickness of pulmonary arterioles. Further mechanistic investigation in hPASMCs showed that PAI-2 inhibited cell proliferation by preventing the activation of PI3K/Akt and ERK pathways. CONCLUSION: PAI-2 is downregulated in PAH patients. PAI-2 attenuates PAH development by suppressing hPASMCs proliferation via the inhibition of PI3K/Akt and ERK pathways. PAI-2 may serve as a potential biomarker and therapeutic target for PAH.
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Miocitos del Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidor 2 de Activador Plasminogénico/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Arteria Pulmonar/metabolismo , Adulto , Animales , Proliferación Celular , Células Cultivadas , Femenino , Humanos , Inyecciones Intraperitoneales , Sistema de Señalización de MAP Quinasas , Masculino , Persona de Mediana Edad , Miocitos del Músculo Liso/patología , Inhibidor 2 de Activador Plasminogénico/administración & dosificación , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/patología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Noninvasive assessment of pulmonary artery systolic pressure by Doppler echocardiography (sPAPECHO) has been widely adopted to screen for pulmonary hypertension (PH), but there is still a high proportion of overestimation or underestimation of sPAPECHO. We therefore aimed to explore the accuracy and influencing factors of sPAPECHO with right heart catheterization (RHC) as a reference. METHODS: A total of 218 highly suspected PH patients who underwent RHC and echocardiography within 7 days were included. The correlation and consistency between tricuspid regurgitation (TR)-related methods and RHC results were tested by Pearson and Bland-Altman methods. TR-related methods included peak velocity of TR (TR Vmax), TR pressure gradient (TR-PG), TR mean pressure gradient (TR-mPG), estimated mean pulmonary artery pressure (mPAPECHO), and sPAPECHO. With mPAP ≥ 25 mm Hg measured by RHC as the standard diagnostic criterion of PH, the ROC curve was used to compare the diagnostic efficacy of sPAPECHO with other TR-derived parameters. The ratio (sPAPECHO-sPAPRHC)/sPAPRHC was calculated and divided into three groups as follows: patients with an estimation error between - 10% and + 10% were defined as the accurate group; patients with an estimated difference greater than + 10% were classified as the overestimated group; and patients with an estimation error greater than - 10% were classified as the underestimated group. The influencing factors of sPAPECHO were analyzed by ordinal regression analysis. RESULTS: sPAPECHO had the highest correlation coefficient (r = 0.781, P < 0.001), best diagnostic efficiency (AUC = 0.98), and lowest bias (mean bias = 0.07 mm Hg; 95% limits of agreement, - 32.08 to + 32.22 mm Hg) compared with other TR-related methods. Ordinal regression analysis showed that TR signal quality, sPAPRHC level, and pulmonary artery wedge pressure (PAWP) affected the accuracy of sPAPECHO (P < 0.05). Relative to the good signal quality, the OR values of medium and poor signal quality were 0.26 (95% CI: 0.14, 0.48) and 0.23 (95% CI: 0.07, 0.73), respectively. Compared with high sPAPRHC level, the OR values of low and medium sPAPRHC levels were 21.56 (95% CI: 9.57, 48.55) and 5.13 (95% CI: 2.55, 10.32), respectively. The OR value of PAWP was 0.94 (95% CI: 0.89, 0.99). TR severity and right ventricular systolic function had no significant effect on the accuracy of sPAPECHO. CONCLUSIONS: In this study, we found that all TR-related methods, including sPAPECHO, had comparable and good efficiency in PH screening. To make the assessment of sPAPECHO more accurate, attention should be paid to TR signal quality, sPAPRHC level, and PAWP.
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Hipertensión Pulmonar , Insuficiencia de la Válvula Tricúspide , Presión Sanguínea , Cateterismo Cardíaco/métodos , Estudios Transversales , Ecocardiografía Doppler/métodos , Humanos , Hipertensión Pulmonar/diagnóstico por imagen , Arteria Pulmonar/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
BACKGROUND: In precapillary pulmonary hypertension (PH), the incidence of different tricuspid regurgitation (TR) degree is poorly defined. The impact of TR severity on pulmonary artery pressure (PAP) assessment and clinical risk stratification in precapillary PH remains unclear. METHODS: A total of 207 patients diagnosed precapillary PH who underwent right heart catheterization (RHC) and echocardiography within 3 days were included. The severity of TR was graded as trace, mild, moderate and severe. Pearson correlation analysis was performed to evaluate the correlation between systolic PAP by echocardiography (sPAPECHO) and mean PAP by RHC (mPAPRHC) in different TR degree groups. The impact factors on risk stratification of precapillary PH were analyzed by logistic regression analysis. RESULTS: The proportion of None, Trace, Mild, Moderate and Severe TR group was 2.4%, 23.7%, 39.1%, 28.5% and 6.3% respectively. Right atrium (RA) area increased gradually with TR aggravation (p < 0.001). Moderate and Severe TR group had higher N-terminal pro-B-type natriuretic peptide (p < 0.001), right atrial pressure (RAP) (p = 0.018), right ventricular basal diameter (RVD)/left ventricular basal diameter (LVD) ratio (p < 0.001), larger right ventricle (RV) (p < 0.001) and lower tricuspid annular plane systolic excursion (p = 0.006) compared with Trace and Mild group. TR-sPAPECHO in Moderate TR group had the greatest correlation coefficient with mPAPRHC (0.742, p < 0.001) followed by Mild (0.635, p < 0.001) and severe group (0.592, p = 0.033), while there was no correlation in Trace TR group (0.308, p = 0.076). Multivariate logistic regression showed three significant independent echocardiography predictors of high-risk precapillary PH: RVD/LVD ratio (OR = 5.734; 95%CI1.502-21.889, p = 0.011), RA area (OR 1.054; 95% CI 1.004-1.107, p = 0.035) and systolic annular tissue velocity of the lateral tricuspid annulus (S') (OR 0.735, 95% CI 0.569-0.949, p = 0.018). CONCLUSIONS: Precapillary PH was not necessarily accompanied by significant TR. None or Trace TRaccounted for 26% in our population and TR-sPAPECHO was not applicable to estimate PAP in these patients. RVD/LVD ratio, RA area and S' can independently predict the high-risk patients with precapillary PH. TR may play an indirect role in risk stratification by affecting these indicators.
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Hipertensión Pulmonar , Insuficiencia de la Válvula Tricúspide , Humanos , Insuficiencia de la Válvula Tricúspide/diagnóstico por imagen , Insuficiencia de la Válvula Tricúspide/epidemiología , Insuficiencia de la Válvula Tricúspide/complicaciones , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/complicaciones , Prevalencia , Ecocardiografía Doppler , EcocardiografíaRESUMEN
Transparency Ecosystem for Research and Journals in Medicine (TERM) working group summarized the essential recommendations that should be considered to review and publish a high-quality guideline. These recommendations from editors and reviewers included 10 components of essential requirements: systematic review of existing relevant guidelines, guideline registration, guideline protocol, stakeholders, conflicts of interest, clinical questions, systematic reviews, recommendation consensus, guideline reporting and external review. TERM working group abbreviates them as PAGE (essential requirements for Publishing clinical prActice GuidelinEs), and recommends guideline authors, editors, and peer reviewers to use them for high-quality guidelines.
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Guías de Práctica Clínica como Asunto , HumanosRESUMEN
Similar trends of management and in-hospital mortality of acute pulmonary embolism (PE) have been reported in European and American populations. However, these tendencies are not clear in Asian countries. We retrospectively analysed the trends of risk stratification, management and in-hospital mortality for patients with acute PE through a multicentre registry in China (CURES).Adult patients with acute symptomatic PE were included between 2009 and 2015. Trends in disease diagnosis, treatment and death in hospital were fully analysed. Risk stratification was retrospectively classified by haemodynamic status and the simplified Pulmonary Embolism Severity Index (sPESI) score according to the 2014 European Society of Cardiology/European Respiratory Society guidelines.Among 7438 patients, the proportions with high (haemodynamic instability), intermediate (sPESI≥1) and low (sPESI=0) risk were 4.2%, 67.1% and 28.7%, respectively. Computed tomographic pulmonary angiography was the most widely used diagnostic approach (87.6%) and anticoagulation was the most frequently adopted initial therapy (83.7%). Between 2009 and 2015, a significant decline was observed for all-cause mortality (from 3.1% to 1.3%, adjusted pfor trend=0.0003), with a concomitant reduction in the use of initial systemic thrombolysis (from 14.8% to 5.0%, pfor trend<0.0001). The common predictors for all-cause mortality shared by haemodynamically stable and unstable patients were co-existing cancer, older age and impaired renal function.The considerable reduction of mortality over the years was accompanied by changes in initial treatment. These findings highlight the importance of risk stratification-guided management throughout the nation.
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Embolia Pulmonar , Adulto , Anciano , Hospitales , Humanos , Pronóstico , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/terapia , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To evaluate pulmonary function and clinical symptoms in coronavirus disease 2019 (COVID-19) survivors within 3â months after hospital discharge, and to identify risk factors associated with impaired lung function. METHODS AND MATERIAL: COVID-19 patients were prospectively followed-up with pulmonary function tests and clinical characteristics for 3â months following discharge from a hospital in Wuhan, China between January and February 2020. RESULTS: 647 patients were included. 87 (13%) patients presented with weakness, 63 (10%) with palpitations and 56 (9%) with dyspnoea. The prevalence of each of the three symptoms were markedly higher in severe patients than nonsevere patients (19% versus 10% for weakness, p=0.003; 14% versus 7% for palpitations, p=0.007; 12% versus 7% for dyspnoea, p=0.014). Results of multivariable regression showed increased odds of ongoing symptoms among severe patients (OR 1.7, 95% CI 1.1-2.6; p=0.026) or patients with longer hospital stays (OR 1.03, 95% CI 1.00-1.05; p=0.041). Pulmonary function test results were available for 81 patients, including 41 nonsevere and 40 severe patients. In this subgroup, 44 (54%) patients manifested abnormal diffusing capacity of the lung for carbon monoxide (D LCO) (68% severe versus 42% nonsevere patients, p=0.019). Chest computed tomography (CT) total severity score >10.5 (OR 10.4, 95% CI 2.5-44.1; p=0.001) on admission and acute respiratory distress syndrome (ARDS) (OR 4.6, 95% CI 1.4-15.5; p=0.014) were significantly associated with impaired D LCO. Pulmonary interstitial damage may be associated with abnormal D LCO. CONCLUSION: Pulmonary function, particularly D LCO, declined in COVID-19 survivors. This decrease was associated with total severity score of chest CT >10.5 and ARDS occurrence. Pulmonary interstitial damage might contribute to the imparied D LCO.
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COVID-19 , Monóxido de Carbono , China , Estudios de Seguimiento , Humanos , Pulmón/diagnóstico por imagen , SARS-CoV-2RESUMEN
BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). Gremlin-1 promotes vascular remodeling of PAH and mediates epithelial-mesenchymal transition, which is similar to EndMT. In the present study we investigated the potential role of gremlin-1 plays in EndMT of pulmonary artery endothelial cells (PAECs). METHODS: Immunofluorescence staining was performed to detect the expression of alpha smooth muscle actin (α-SMA) and von Willebrand factor (VWF). Migration and angiogenic responses of PAECs were determined by transwell assay and tube formation assay, respectively. Protein expression levels were determined by western blotting. RESULTS: Gremlin-1 induced EndMT of PAECs in a phospho-smad2/3-dependent manner. This was characterized by the loss of platelet endothelial cell adhesion molecule 1 and an increase in protein levels of a-SMA, nerve-cadherin, and matrix metalloproteinase 2. It was also determined that gremlin-1 facilitated the migration and angiogenic responses of PAECs in a dose-dependent manner. Bone morphogenetic protein 7 (BMP-7) was found to attenuate gremlin-1-mediated EndMT, migration and angiogenesis of PAECs by inducing phosphorylation of Smad1/5/8 and suppressing phosphorylation of Smad2/3. CONCLUSION: Gremlin-1 mediates EndMT in PAECs, and BMP-7 reverses gremlin-1-induced EndMT by an induction of p-Smad1/5/8 and suppression of p-Smad2/3.
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Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Transición Epitelial-Mesenquimal , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Actinas/genética , Actinas/metabolismo , Proteína Morfogenética Ósea 7/genética , Proteína Morfogenética Ósea 7/metabolismo , Movimiento Celular , Células Cultivadas , Células Endoteliales/fisiología , Endotelio Vascular/citología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Arteria Pulmonar/citología , Proteínas Smad/genética , Proteínas Smad/metabolismoRESUMEN
Genetic risk factors are important for the occurrence and prognosis of venous thromboembolism (VTE). The studies of thrombophilia families are important for dissecting the genetic background of the thrombotic disease. We conducted the systematic review of all published family-based studies on VTE genetics across all racial groups through PubMed and Embase prior to 13th April 2020. This systematic review of 287 families (including 225 Caucasian families, 52 East Asian families, and families of other ethnicities) revealed a total of 21 different genes; the five most reported mutated genes were F5 (88/287, 30.7%), SERPINC1 (67/287, 23.3%), PROC (65/287, 22.6%), F2 (40/287, 13.9%) and PROS1 (48/287, 16.7%). For Caucasian families, F5 mutations were most frequently reported at 37.8% (85/225), while PROS1 mutations were most frequently reported, at 40.4% (21/52), for East Asian families (Chinese, Japanese and Korean). Factor V Leiden was reported more frequently in Caucasians than in East Asians. Missense mutations were reported frequently in the SERPINC1, PROC and PROS1 genes. In conclusion, our study found the most likely mutated genes associated with VTE among different ethnic groups and provided indications for VTE genetic testing and research in the future.