A new integrative analysis of histopathology and single cell RNA-seq reveals the CCL5 mediated T and NK cell interaction with vascular cells in idiopathic pulmonary arterial hypertension.

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.

Unusual cause of muscle weakness, type II respiratory failure and pulmonary hypertension: a case report of ryanodine receptor type 1(RYR1)-related myopathy.

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.

Clinical characteristics and mortality predictors among very old patients with pulmonary thromboembolism: a multicenter study report.

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.

The management pattern and outcomes of chronic thromboembolic pulmonary hypertension: rationale and design for a Chinese real-world study.

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.

Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population.

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.

Incidence and risk factors of venous thrombotic events in patients with interstitial lung disease during hospitalization.

BACKGROUND: Studies on the incidence of venous thromboembolism (VTE) events in patients with interstitial lung disease (ILD) are limited and the results are inconsistent. The aim of this research was to investigate the incidence and risk factors of VTE in ILD during hospitalization. MATERIALS AND METHODS: In this retrospective, cross-sectional, observational study, a total of 5009 patients diagnosed with ILD from January 2016 to March 2022 in our hospital were retrospectively included. In ILD patients, VTE including pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) were screened from the electronic medical record system. Diagnosis of PTE and DVT were performed by CT pulmonary angiography (CTPA), CTV or ultrasound. And then the incidence and risk factors of VTE in different types of ILD were assessed. RESULTS: Among 5009 patients with ILD, VTE was detected in 129 (2.6%) patients, including 15(0.3%) patients with both PTE and DVT, 34 (0.7%) patients with PTE and 80 (1.6%) patients with DVT. 85.1% of patients with APE were in the intermediate-low risk group. The incidence of VTE in Anti-Neutrophil Cytoplasmic Antibodies -associated vasculitis related ILD (ANCA-AV-ILD), hypersensitivity pneumonitis and idiopathic pulmonary fibrosis (IPF) respectively was 7.9% and 3.6% and 3.5%. In patients with connective tissue disease-associated ILD (CTD-ILD), the incidence of VTE, DVT, PTE, combined PTE and DVT respectively was 3.0%, 2.3%, 0.4% and 0.3%. Among the various risk factors, different ILD categories, age ≥ 80 years (OR 4.178, 95% CI 2.097-8.321, P < 0.001), respiratory failure (OR 2.382, 95% CI 1.533-3.702, P < 0.001) and varicose veins (OR 3.718, 95% CI 1.066-12.964, P = 0.039) were independent risk factors of VTE. The incidence of VTE in patients with ILD increased with the length of time in hospital from 2.2% (< 7 days) to 6.4% (> 21 days). CONCLUSION: The incidence of VTE during hospitalization in ILD patients was 2.6%, with a 1.6% incidence of DVT, higher than the 0.7% incidence of PTE. Advanced age, ILD categories, respiratory failure and varicose veins as independent risk factors for the development of VTE should be closely monitored.

LMWHs dosage and outcomes in acute pulmonary embolism with renal insufficiency, an analysis from a large real-world study.

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 .

Plasminogen activator Inhibitor-2 inhibits pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension via PI3K/Akt and ERK signaling.

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.

The accuracy and influencing factors of Doppler echocardiography in estimating pulmonary artery systolic pressure: comparison with right heart catheterization: a retrospective cross-sectional study.

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.

Prevalence and risk prediction value of tricuspid regurgitation by echocardiography in precapillary pulmonary hypertension.

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.

Trends in risk stratification, in-hospital management and mortality of patients with acute pulmonary embolism: an analysis from the China pUlmonary thromboembolism REgistry Study (CURES).

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.

Gremlin-1 is a key regulator of endothelial-to-mesenchymal transition in human pulmonary artery endothelial cells.

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.

The genetics of venous thromboembolism: a systematic review of thrombophilia families.

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.

Extracellular matrix collagen biomarkers levels in patients with chronic thromboembolic pulmonary hypertension.

Limited data exist on changes in the extracellular matrix (ECM) collagen biomarkers levels during chronic thromboembolic pulmonary hypertension (CTEPH) development. This study aimed to investigate ECM collagen biomarkers levels in stable patients with CTEPH. Patients with CTEPH and healthy persons were enrolled. Serum levels of procollagen III N-terminal peptide (PIIINP), carboxyterminal propeptide of type I procollagen (PICP), matrix metalloproteinases (MMP2), MMP9, and tissue inhibitor of metalloproteinases 1(TIMP1) were measured by ELISA. Clinical data coincident with samples were collected. The pulmonary endarterectomy (PEA) and control pulmonary artery tissue samples were analyzed for genetic and immunohistochemical differences. The serum concentrations of PIIINP, PICP, MMP2, and MMP9 decreased significantly in CTEPH patients compared to healthy controls (P < 0.001 for each). CTEPH patients had higher serum concentrations of TIMP1 (median, 111.97 [interquartile range, 84.35-139.93]) compared to healthy controls (74.97 [44.03-108.45] ng/mL, P < 0.001). The MMP2 to TIMP1 ratio was lower in patients than in the controls (P < 0.001). After adjusting for the body mass index (BMI), the MMP2 to TIMP1 ratio correlated negatively with pulmonary vascular resistance (PVR) (r = - 0.327, P = 0.025). Increased TIMP1 (P = 0.04) gene expression was identified in tissues of CTEPH patients. Immunohistochemistry results of vascular walls substantiated qRT-PCR results. This study indicates that ECM collagen biomarkers levels were significantly different in stable patients with CTEPH and healthy controls with significantly increased TIMP1 and decreased MMP2 and MMP9. Differences in TIMP1 expression should be expected not only among healthy controls and patients serum, but also across pathological tissue regions. These findings suggest that the state of vascular remodeling in pulmonary vascular bed in stable patients may be represented by ECM collagen biomarkers levels. We conclude that TIMP1 may play an important role in pulmonary vascular reconstruction in stable CTEPH patients.

AKT2 regulates endothelial-mediated coagulation homeostasis and promotes intrathrombotic recanalization and thrombus resolution in a mouse model of venous thrombosis.

Venous thromboembolism (VTE) carries a high risk of morbidity and mortality. Understanding the mechanisms of venous thrombus formation and resolution is critical for improving VTE management. AKT2 kinase is essential for platelet activation and arterial thrombosis. In this study, we examined the role of AKT2 in venous thrombosis in a mouse model of venous thrombosis induced by inferior vena cava (IVC) ligation. We observed an induction of AKT2 expression in the ligated IVC of wild-type (WT) mice. Interestingly, although the initial thrombus size of the ligated IVC was similar between Akt2-/- mice and WT mice, thrombus resolution was delayed in the ligated IVC of Akt2-/- mice. Compared with the ligated IVC of WT mice, the ligated IVC of Akt2-/- mice displayed decreased levels of thrombomodulin (TM) and increased levels of tissue factor (TF), apoptosis, and necroptosis. In addition, intrathrombotic endothelial cells in the ligated IVC of Akt2-/- mice failed to form small vessels, resulting in impaired recanalization and thrombus resolution. TGF-ß signaling activation and fibrotic remodeling were increased in the thrombus and vein wall of the ligated IVC of Akt2-/- mice. We further investigated the AKT2-mediated regulation of coagulation factors in endothelial cells and found that forkhead box protein O1 (FOXO1), a target of AKT, enhanced TF and inhibited TM expression. By inhibiting FOXO1, AKT2 suppressed TF expression while increasing TM expression. Our findings indicate that AKT2 may protect endothelial cells against cell death, regulate endothelial-mediated coagulation homeostasis, and promote intrathrombotic recanalization and thrombus resolution in venous thrombosis. These observations suggest dynamic roles of AKT2 in venous thrombus formation and resolution.

Regional right ventricular longitudinal systolic strain for detection of severely impaired right ventricular performance in pulmonary hypertension.

OBJECTIVES: Right ventricular (RV) function is identified as a key determinant of the outcome in patients with pulmonary hypertension (PH). Several studies have assessed the role of peak global longitudinal RV strain in PH patients; however, less emphasis was given to the RV regional longitudinal strain. The aim of this study was to evaluate the regional RV systolic strain in PH patients and investigate the relationship of these parameters with the severity of PH. METHODS: RV regional longitudinal peak systolic strain (LPSS) and strain rate (LPSSR) were measured using speckle tracking echocardiography on 100 patients with PH who underwent right heart catheterization, and 29 control subjects. Severe PH was identified by a decreased cardiac index (CI) (<2.0 L/min/m2 ). RESULTS: LPSS and LPSSR of the RV free wall were significantly lower in PH patients than control subjects, especially when comparing the basal and mid regions (P < .001). When comparing severe PH and nonsevere PH, basal and mid LPSS and LPSSR were significantly lower (P < .001). RV free wall mid LPSSR correlated with CI (r = -.703, P < .001). In the multiple logistic regression analysis, mid LPSSR was identified as an independent predictor of severe PH (odds ratio 1.82; 95% confidential interval 1.39-2.40; P < .001). In the receiver operating characteristics curve analysis, a cutoff value of mid LPSSR of -0.92 s-1 predicted severe PH, with a sensitivity and specificity of 75.0% and 93.7%, respectively (AUC = 0.889, P < .001). CONCLUSIONS: RV free wall mid longitudinal peak systolic strain rate may be useful for the detection of severely impaired RV performance in PH.

Awareness and management of pulmonary embolism among physicians in China: a nationwide cross-sectional study.

Pulmonary embolism (PE) is a leading cause of cardiovascular mortality. We intended to evaluate the awareness and management status of PE among Chinese physicians and provide the basis for establishing Chinese clinical guidelines on PE. We designed a nationwide survey to collect data on physicians' awareness of diagnosis, treatment and follow-up on PE. The questionnaires were distributed to physicians during offline academic meetings and by the online platforms from August 2016 to October 2016. Also, results were sub-grouped by age, hospital grades, departments and trained or not. A total of 2954 valid questionnaires were collected. We observed that there were several defects in the management of PE among Chinese physicians. First, a considerable proportion of physicians chose the incorrect clinical prediction rules for acute PE. Second, a considerable percentage of hospitals could not carry out computed tomographic pulmonary angiography (22.4%) or ventilation-perfusion scintigraphy (65.2%). Third, only a few physicians knew the use of new oral anticoagulants clearly (33.4%). Fourth, only 49% of physicians achieved follow-up management in over half of their patients. Additionally, physicians in the tertiary hospitals, aged > 35 years, trained and from respiratory department have a better knowledge of the management of PE. In conclusion, our survey demonstrates the enhancement of PE-related trainings, especially for physicians in lower-level hospitals, aged ≤ 35 years and from non-respiratory department, can help to improve the management of PE in Chinese physicians. And our study also highlights the need for the establishment of national guidelines for the management of PE in China.

NLRP3 (Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3)-Caspase-1 Inflammasome Degrades Contractile Proteins: Implications for Aortic Biomechanical Dysfunction and Aneurysm and Dissection Formation.

OBJECTIVE: Increasing evidence suggests that contractile dysfunction in smooth muscle cells (SMCs) plays a critical role in aortic biomechanical dysfunction and aortic aneurysm and dissection (AAD) development. However, the mechanisms underlying SMC contractile dysfunction in sporadic AAD are poorly understood. In this study, we examined the role of the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3)-caspase-1 inflammasome, a key inflammatory cascade, in SMC contractile dysfunction in AAD. APPROACH AND RESULTS: We observed significant SMC contractile protein degradation in aortas from patients with sporadic thoracic AAD. The contractile protein degradation was associated with activation of the NLRP3-caspase-1 inflammasome cascade. In SMCs, caspase-1 bound and directly cleaved and degraded contractile proteins, leading to contractile dysfunction. Furthermore, Nlrp3 or caspase-1 deficiency in mice significantly reduced angiotensin II-induced contractile protein degradation, biomechanical dysfunction, and AAD formation in both thoracic and abdominal aortas. Finally, blocking this cascade with the inflammasome inhibitor, glyburide (an antidiabetic medication), reduced angiotensin II-induced AAD formation. CONCLUSIONS: Inflammasome-caspase-1-mediated degradation of SMC contractile proteins may contribute to aortic biomechanical dysfunction and AAD development. This cascade may be a therapeutic target in AAD formation. In addition, glyburide may have protective effects against AAD development.

Diabetes mellitus is associated with increased bleeding in pulmonary embolism receiving conventional anticoagulant therapy: findings from a "real-world" study.

Bleeding refers to the most important complication during anticoagulation therapy in patients with pulmonary embolism (PE). However, the incidence and risk factors of bleeding in Chinese population with anticoagulant therapy remains unknown. Although diabetes mellitus (DM) has been demonstrated to increase the risk of PE, little information of its influence on anticoagulation-associated bleeding risk can be available. In our study, 563 acute PE patients, who fulfilled the including criteria were enrolled from a single center and received conventional anticoagulant therapy. And there were 539 patients completed the 3 months following-up. The cumulative incidences of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) were 3.0% (95% CI 1.01-3.05) and 14.0% (95% CI 1.47-5.21), respectively. Besides, anemia (OR 3.52, 95% CI 1.12-11.41) and recent history of MB (OR 8.14, 95% CI 1.41-31.95) were independently associated with MB. Age >65 year (OR 1.51, 95% CI 1.12-3.11), cancer (OR 2.01, 95% CI 1.12-4.01) and therapeutic range (TTR) during 3 months (OR 0.93, 95% CI 0.91-0.98) were independently associated with CRNMB. Additionally, DM was an independent risk factor for both MB (OR 2.11, 95% CI 1.10-4.12) and CRNMB (OR 2.11, 95% CI 1.10-4.12). Notably, the incidence of MB or CRNMB was significantly higher in DM patients than non-DM patients. At the end of 3-month follow-up, the HbA1C in CRNMB group was 8.3%, yet it was 7.0% in non-CRNMB group among diabetic patients (p = 0.04). In conclusions, the bleeding rates are high in patients with acute PE who receive anticoagulant therapy. In addition to the already known bleeding risk factors, DM can also increase the bleeding risk significantly. Thus, good glycemic control may be essential after prescription of anticoagulant therapy.

Pleural effusions as a predictive parameter for poor prognosis for patients with acute pulmonary thromboembolism.

The incidence, characteristics of pleural effusions due to pulmonary thromboembolism (PTE) have been reported previously. However, the impact of pleural effusions on the prognosis of acute PTE patients and the involved influencing factors remain unclear. A total of 518 consecutive PTE patients were enrolled in Beijing Chao-Yang Hospital from January 2009 to April 2014. The diagnosis was confirmed with Spiral computer tomography pulmonary angiography or/and high-probability ventilation and perfusion scans. All patients finished one-year clinical follow-up. Among 518 patients with acute PTE, pleural effusions were found in 120 patients (23.2 %). No strictly tight association between side of pleural effusions and location of thrombus was observed. The diagnosis time between patients of PTE with pleural effusions and without pleural effusions had no statistically significant difference. During the 3-month follow-up, the all-cause mortality of PTE patients with pleural effusions was significantly higher than those without pleural effusions [10/120 (8.3 %) vs. 8/398 (2.0 %)]. During the 1-year follow-up, analysis of survival also showed that all-cause mortality was significantly higher in PTE patients with pleural effusions than those without pleural effusions. In both univariate Cox-regression analysis [P < 0.001, HR 3.044, 95 % CI (1.647, 5.625)] and multivariate Cox-regression analysis [P < 0.05, HR 2.040, 95 % CI (1.038, 4.009)] pleural effusions showed to be risk factor of poor prognosis. Pleural effusions in patients with acute PTE were significantly correlated with higher mortality. Pleural effusions in acute PTE patients might be used as a predictive parameter for prognosis.