Characteristics, treatments and survival of pulmonary arterial hypertension associated with congenital heart disease in China: Insights from a national multicenter prospective registry.

BACKGROUND: The purpose of this registry was to provide insights into the characteristics, treatments and survival of patients with PAH-CHD in China. METHODS: Patients diagnosed with PAH-CHD were enrolled in this national multicenter prospective registry. Baseline and follow-up data on clinical characteristics, PAH-targeted treatments and survival were collected. RESULTS: A total of 1060 PAH-CHD patients (mean age 31 years; 67.9% females) were included, with Eisenmenger syndrome (51.5%) being the most common form and atrial septal defects (37.3%) comprising the most frequent underlying defect. Approximately 33.0% of the patients were in World Health Organization functional class III to IV. The overall mean pulmonary arterial pressure and pulmonary vascular resistance were 67.1 (20.1) mm Hg and 1112.4 (705.9) dyn/s/cm5, respectively. PAH-targeted therapy was utilized in 826 patients (77.9%), and 203 patients (19.1%) received combination therapy. The estimated 1-, 3-, 5-, and 10-year survival rates of the overall cohort were 96.9%, 92.9%, 87.6% and 73.0%, respectively. Patients received combination therapy had significantly better survival than those with monotherapy (p = 0.016). NT-proBNP >1400 pg/ml, SvO2 ≤ 65% and Borg dyspnea index ≥ 3 and PAH-targeted therapy were independent predictors of mortality. Hemoglobin > 160g/L was a unique predictor for mortality in Eisenmenger syndrome. CONCLUSIONS: Chinese PAH-CHD patients predominantly exhibit Eisenmenger syndrome and have significantly impaired exercise tolerance and right ventricular function at diagnosis, which are closely associated with long-term survival. PAH-targeted therapy including combination therapy showed a favorable effect on survival in PAH-CHD. The long-term survival of Chinese CHD-PAH patients remains to be improved.

Iatrogenic or predetermined aortic dysplasia?

Coarctation of aorta post-transcatheter occlusion of patent ductus arteriosus is rare. We report a special case of infant with patent ductus arteriosus complicated by bicuspid aortic valve, who presented severe coarctation of aorta and aortic valve dysfunction post-patent ductus arteriosus occlusion during follow-up, eventually receiving surgical operations. A genetic rather than iatrogenic predisposition towards post-procedural complications has been discussed.

Characteristics, Long-term Survival, and Risk Assessment of Pediatric Pulmonary Arterial Hypertension in China: Insights From a National Multicenter Prospective Registry.

BACKGROUND: Registry-based studies of pediatric pulmonary arterial hypertension (PPAH) are scarce in developing countries, including China. The PPAH risk assessment tool needs further evaluation and improvement. RESEARCH QUESTION: What are the characteristics and long-term survival of PPAH in China and what is the performance of the PPAH risk model in Chinese patients? STUDY DESIGN AND METHODS: Patients with PAH were enrolled in the national prospective multicenter registry from August 2009 through December 2019. Children 3 months to 18 years of age at the time of PAH diagnosis were analyzed. RESULTS: A total of 247 children with PAH were enrolled. The median patient age was 14.8 years, and 58.3% of patients were female. Most patients had a diagnosis of PAH associated with congenital heart disease (CHD; 61.5%) and idiopathic or heritable PAH (37.7%). The median time from symptom onset to PAH diagnosis was 24 months. The mean pulmonary artery pressure and pulmonary vascular resistance index were 70.78 ± 19.80 mm Hg and 21.82 ± 11.18 Wood Units·m2, respectively. Patients with CHD-associated PAH experienced a longer diagnostic delay and demonstrated higher pulmonary artery pressure, but better cardiac performance, than those with idiopathic or heritable PAH. An increased number of patients received targeted therapy at the last follow-up compared with baseline. The 5- and 10-year survival rates of the entire cohort were 74.9% and 55.7%, respectively, with better survival in patients with CHD-associated PAH than in those with idiopathic or heritable PAH. Patients with low risk had better survival than those with high risk according to the simplified noninvasive risk score model with weight, function class, and echocardiographic right ventricular size, both at baseline and follow-up. INTERPRETATION: Patients with PPAH in China showed severely compromised hemodynamics with marked diagnostic delay. The long-term survival of PPAH is poor despite the increased usefulness of targeted drugs. The simplified noninvasive risk model demonstrated good performance for predicting survival in Chinese children with PAH. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01417338; URL: www. CLINICALTRIALS: gov.

Efficacy of Human Embryonic Stem Cells Compared to Adipose Tissue-Derived Human Mesenchymal Stem/Stromal Cells for Repair of Murine Post-Stenotic Kidneys.

Clinical translation of mesenchymal stem/stromal cell (MSC) therapy has been impeded by the heterogenous nature and limited replicative potential of adult-derived MSCs. Human embryonic stem cell-derived MSCs (hESC-MSCs) that differentiate from immortal cell lines are phenotypically uniform and have shown promise in-vitro and in many disease models. Similarly, adipose tissue-derived MSCs (MSC(AT)) possess potent reparative properties. How these two cell types compare in efficacy, however, remains unknown. We randomly assigned mice to six groups (n = 7-8 each) that underwent unilateral RAS or a sham procedure (3 groups each). Two weeks post-operation, each mouse was administered either vehicle, MSC(AT)s, or hESC-MSCs (5 × 105 cells) into the aorta. Mice were scanned with micro-MRI to determine renal hemodynamics two weeks later and kidneys then harvested. hESC-MSCs and MSC(AT)s were similarly effective at lowering systolic blood pressure. However, MSC(AT)s more robustly increased renal perfusion, oxygenation, and glomerular filtration rate in the post-stenotic kidney, and more effectively mitigated tubular injury, fibrosis, and vascular remodeling. These observations suggest that MSC(AT) are more effective than hESC-MSC in ameliorating kidney dysfunction and tissue injury distal to RAS. Our findings highlight the importance of tissue source in selection of MSCs for therapeutic purposes and underscore the utility of cell-based therapy for kidney disease.

A newly designed disk-lobe occluder with isogenous barbs for left atrial appendage closure: Initial multicenter experience.

Background: Although the implant success rate of left atrial appendage closure (LAAC) has increased and complications have decreased over time, there are still anatomically and technically complicated cases where novel LAA occluders may simplify the procedure and thus might potentially improve the clinical outcome. Objectives: This study aimed to assess the safety and efficacy of the newly designed device with isogenous barbs in LAAC. Methods: Eight centers in China participated in this prospective study from July 2016 to April 2018. Peri- and post-procedural safety and efficacy were evaluated through scheduled follow-ups and transesophageal echocardiography (TEE). Results: A total of 175 patients with a mean age of 68.4 ± 9.2 years old, a mean CHA2DS2-VASc score of 4.7 ± 1.8, and a mean HAS-BLED score of 3.2 ± 1.3, were included. The device was successfully implanted in 173 patients (98.9%). The device size ranged from 18 to 34 mm. Clinically relevant pericardial effusion (PEF) in the perioperative period, occurred in 3 patients (1.7%). TEE follow-up was available in 167 (96.5%) patients at 12-month. During follow-up, 9 patients suffered serious adverse event: 4 death (2.3%), 1 ischemic stroke (0.6%), and 2 gastro-intestinal bleeding (1.2%) and 2 device-related thrombus (DRT) (1.2%). Estimated annual thromboembolism rate reduced by 90% and estimated annual major bleeding rate reduced by 81% after LAAC with the newly designed device. Conclusion: The newly designed device with isogenous barbs for LAAC could be performed effectively with a low incidence of adverse events and a high incidence of anatomic closure.

Characteristics, goal-oriented treatments and survival of pulmonary arterial hypertension in China: Insights from a national multicentre prospective registry.

BACKGROUND AND OBJECTIVE: Nationally representative reports on the characteristics and long-term survival of pulmonary arterial hypertension (PAH) from developing countries are scarce. The applicability of the current main risk stratifications and the longitudinal changes in goal-oriented treatments have yet to be elucidated in real-world settings. Therefore, we aimed to provide insights into the characteristics, goal-oriented treatments and survival of PAH in China and to explore the applicability of the main risk stratifications in our independent cohort. METHODS: PAH patients were consecutively enrolled from a national prospective multicentre registry. Data on baseline, follow-up re-evaluation and therapeutic changes were collected. RESULTS: A total of 2031 patients were enrolled, with congenital heart disease (CHD)-PAH (45.2%) being the most common aetiology. The mean age was 35 ± 12 years, and 76.2% were females. At baseline, approximately 20% of the patients with intermediate or high risk received combination treatment. At follow-up, approximately half of the re-evaluated patients did not achieve low-risk profiles, and even among patients who received combination therapy at baseline, 4% of them still worsened. The rate of combination therapy increased significantly from 6.7% before 2015 to 35.5% thereafter. The main risk assessment tools demonstrated good performance for predicting survival both at baseline and at follow-up. CONCLUSION: Chinese PAH patients show both similar and distinct features compared to other countries. Current main risk stratifications can significantly discriminate patients at different risk levels. There were still many patients not achieving low-risk profiles at follow-up, indicating more aggressive treatment should be implemented to optimize the goal-oriented treatment strategy.

Risk prediction in pulmonary hypertension due to chronic heart failure: incremental prognostic value of pulmonary hemodynamics.

BACKGROUND: There is no generally accepted comprehensive risk prediction model cooperating risk factors associated with heart failure and pulmonary hemodynamics for patients with pulmonary hypertension due to left heart disease (PH-LHD). We aimed to explore outcome correlates and evaluate incremental prognostic value of pulmonary hemodynamics for risk prediction in PH-LHD. METHODS: Consecutive patients with chronic heart failure undergoing right heart catheterization were prospectively enrolled. The primary endpoint was all-cause mortality. Individual variable selection was performed by machine learning methods. Cox proportional hazards models were conducted to identify the association between variables and mortality. Incremental value of hemodynamics was evaluated based on the Seattle heart failure model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) scores. RESULTS: A total of 276 PH-LHD patients were enrolled, with a median follow-up time of 34.7 months. By L1-penalized regression model and random forest approach, diastolic pressure gradient (DPG) and mixed venous oxygen saturation (SvO2) were the hemodynamic predictors most strongly associated with mortality (coefficient: 0.0255 and -0.0176, respectively), with consistent significance after adjusted for SHFM [DPG: HR 1.067, 95% CI 1.024-1.113, P = 0.022; SvO2: HR 0.969, 95% CI 0.953-0.985, P = 0.002] or MAGGIC (DPG: HR 1.069, 95% CI 1.026-1.114, P = 0.011; SvO2: HR 0.970, 95% CI 0.954-0.986, P = 0.004) scores. The inclusion of DPG and SvO2 improved risk prediction compared with using SHFM [net classification improvement (NRI): 0.468 (0.161-0.752); integrated discriminatory index (IDI): 0.092 (0.035-0.171); likelihood ratio test: P < 0.001] or MAGGIC [NRI: 0.298 (0.106-0.615); IDI: 0.084 (0.033-0.151); likelihood ratio: P < 0.001] scores alone. CONCLUSION: In PH-LHD, pulmonary hemodynamics can provide incremental prognostic value for risk prediction. CLINICAL TRIAL REGISTRATION: NCT02164526 at https://clinicaltrials.gov .

Meta-Analyses of Multiple Gene Expression Profiles to Screen Hub Genes Related to Osteoarthritis.

BACKGROUND: This study aimed to screen and validate the crucial genes involved in osteoarthritis (OA) and explore its potential molecular mechanisms. METHODS: Four expression profile datasets related to OA were downloaded from the Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) from 4 microarray patterns were identified by the meta-analysis method. The weighted gene co-expression network analysis (WGCNA) method was used to investigate stable modules most related to OA. In addition, a protein-protein interaction (PPI) network was built to explore hub genes in OA. Moreover, OA-related genes and pathways were retrieved from Comparative Toxicogenomics Database (CTD). RESULTS: A total of 1,136 DEGs were identified from 4 datasets. Based on these DEGs, WGCNA further explored 370 genes included in the 3 OA-related stable modules. A total of 10 hub genes were identified in the PPI network, including AKT1, CDC42, HLA-DQA2, TUBB, TWISTNB, GSK3B, FZD2, KLC1, GUSB, and RHOG. Besides, 5 pathways including "Lysosome," "Pathways in cancer," "Wnt signaling pathway," "ECM-receptor interaction" and "Focal adhesion" in CTD and enrichment analysis and 5 OA-related hub genes (including GSK3B, CDC42, AKT1, FZD2, and GUSB) were identified. CONCLUSION: In this study, the meta-analysis was used to screen the central genes associated with OA in a variety of gene expression profiles. Three OA-related modules (green, turquoise, and yellow) containing 370 genes were identified through WGCNA. It was discovered through the gene-pathway network that GSK3B, CDC42, AKT1, FZD2, and GUSB may be key genes related to the progress of OA and may become promising therapeutic targets.

A Retrospective Study from 2 Centers in China on the Effects of Continued Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Patients with Hypertension and COVID-19.

BACKGROUND Use of renin-angiotensin-aldosterone system inhibitors in coronavirus disease 2019 (COVID-19) patients lacks evidence and is still controversial. This study was designed to investigate effects of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on clinical outcomes of COVID-19 patients and to assess the safety of ACEIs/ARBs medication. MATERIAL AND METHODS COVID-19 patients with hypertension from 2 hospitals in Wuhan, China, from 17 Feb to 18 Mar 2020 were retrospectively screened and grouped according to in-hospital medication. We performed 1: 1 propensity score matching (PSM) analysis to adjust for confounding factors. RESULTS We included 210 patients and allocated them to ACEIs/ARBs (n=81; 46.91% males) or non-ACEIs/ARBs (n=129; 48.06% males) groups. The median age was 68 [interquartile range (IQR) 61.5-76] and 66 (IQR 59-72.5) years, respectively. General comparison showed mortality in the ACEIs/ARBs group was higher (8.64% vs. 3.88%) but the difference was not significant (P=0.148). ACEIs/ARBs was associated with significantly more cases 7-categorical ordinal scale >2 at discharge, more cases requiring Intensive Care Unit (ICU) stay, and increased values and ratio of days that blood pressure (BP) was above normal range (P<0.05). PSM analysis showed no significant difference in mortality, cumulative survival rate, or other clinical outcomes such as length of in-hospital/ICU stay, BP fluctuations, or ratio of adverse events between groups after adjustment for confounding parameters on admission. CONCLUSIONS We found no association between ACEIs/ARBs and clinical outcomes or adverse events, thus indicating no evidence for discontinuing use of ACEIs/ARBs in the COVID-19 pandemic.

BKCa compensates impaired coronary vasoreactivity through RhoA/ROCK pathway in hind-limb unweighted rats.

Previous studies have demonstrated cardiac and vascular remodeling induced by microgravity exposure. Yet, as the most important branch of vasculatures circulating the heart, the coronary artery has been seldomly studied about its adaptations under microgravity conditions. Large-conductance Ca2+-activated potassium channel (BKCa) and the Ras homolog family member A (RhoA)/Rho kinase (ROCK) pathway play key roles in control of vascular tone and mediation of microgravity-induced vascular adjustments. Therefore, we investigated the adaptation of coronary vasoreactivity to simulated microgravity and the role of BKCa and the RhoA/ROCK pathway in it. Four-week-old hind-limb unweighted (HU) rats were adopted to simulate effects of microgravity. Right coronary artery (RCA) constriction was measured by isometric force recording. The activity and expression of BKCa and the RhoA/ROCK pathway were examined by Western blot, patch-clamp recordings, and immunoprecipitation. We found HU significantly decreased RCA vasoconstriction to KCl, serotonin, and U-46619, but increased protein expression and current densities of BKCa, inhibition of which by iberiotoxin (IBTX) further decreased RCA vasoconstriction (P < 0.05). Expression of RhoA and ROCK as well as active RhoA and phosphorylation of myosin light chain (MLC) at Ser19 and MLC phosphatase target-1 at Thr696 were significantly increased by HU, and ROCK inhibitor Y-27632 exerted greater suppressing effect on HU RCA vasoconstriction than that of control (P < 0.05). BKCa opener NS1619 increased HU RCA vasoconstriction, which was blocked by both RhoA and ROCK inhibitor, similar to the effect of IBTX. These results indicate that HU impairs coronary vasoconstriction but enhances BKCa activity acting as a protective mechanism avoiding excessive decrease of coronary vasoreactivity through activation of the RhoA/ROCK pathway.-Wu, Y., Yue, Z., Wang, Q., Lv, Q., Liu, H., Bai, Y., Li, S., Xie, M., Bao, J., Ma, J., Zhu, X., Wang, Z. BKCa compensates impaired coronary vasoreactivity through RhoA/ROCK pathway in hind-limb unweighted rats.

Clinical outcomes of percutaneous or surgical closure of ruptured sinus of Valsalva aneurysm.

OBJECTIVE: To evaluate the clinical efficacy, safety, and long-term outcomes of percutaneous closure (PC) and surgical repair of ruptured sinus of Valsalva aneurysm (RSVA). METHODS: Eighty-five consecutive patients with RSVA were included in this study. Patients were considered candidates for PC if they met the criterion, surgical repair was performed on patients who were unsuitable or failed PC. Of them, 30 patients underwent PC, while the other 55 patients had surgical repair. RESULTS: RSVA was successfully occluded in 29 of 30 patients who were treated by PC. The mean narrowest diameter at the ruptured site was 6.45 ± 1.60 mm measured by aortography. One patient developed serious occluder-related aortic regurgitation and underwent surgery. The success rate of the interventional approach was 96.7%. In the surgical group, 23 patients underwent repair of combined RSVA and ventricular septal defect. The hospital mortality rate of the surgical approach was 3.57%. During a median follow-up of 83 months (8-152 months), the improvement in NYHA functional class in the PC group was significantly greater than those in the surgical group (P < .01). One patient died of infective endocarditis in the surgical group. There were no further serious complications. CONCLUSIONS: PC is a safe alternative to surgical repair for patients with isolated RSVA. Surgical repair is more suitable for those who have multiple cardiac lesions requiring surgical treatment or failed PC.

Simultaneous transcatheter intervention for atrial septal defect complicated with patent ductus arteriosus: A 13-year single institutional retrospective study.

Purpose: The feasibility and validity of simultaneous transcatheter interventions for patients with atrial septal defect (ASD) complicated with patent ductus arteriosus (PDA) has not been systematically evaluated. Materials and Methods: A retrospective analysis was conducted in patients who received transcatheter procedures for ASD complicated with PDA concurrently. The indications and treatment protocols were in accordance with the current guidelines. The sequence of therapy for ASD complicated with PDA was determined by clinical experience. Patients were followed up for at least 6 months after therapy Results: Overall, 22 patients received simultaneous transcatheter interventional therapy, and the success rate was a 100%. No severe complications transpired during the procedure or follow-up stage. Conclusion: Simultaneous transcatheter intervention is feasible and effective for patients who have concurrent complications for both ASD and PDA.

Simultaneous transcatheter therapy for perimembranous ventricular septal defect combined with patent ductus arteriosus.

OBJECTIVE: This study aims to assess the clinical efficiency and safety of simultaneous transcatheter interventional treatment for perimembranous ventricular septal defect (pmVSD) combined with patent ductus arteriosus (PDA). METHODS: Twenty-five patients with pmVSD and PDA treated with simultaneous transcatheter interventions from April 2004 to December 2015 were included in this study. The mean age was 9.80 ± 8.14 years and the mean weight was 29.76 ± 14.82 Kg. Transthoracic echocardiography (TTE) and angiography were performed immediately after the procedure. Patients were re-examined by electrocardiogram, X-ray, and TTE at 2 days, 1 month, 3 months, and 6 months postoperatively. RESULTS: The interventional procedure was successfully performed in all 25 patients. No intraoperative complication was noted. TTE examination of the VSD and PDA immediately after the procedure showed no residual shunt and the occluder was well positioned. Among these patients, four patients showed electrocardiogram changes after the procedure that resolved after drug therapy. The cardiothoracic ratio, left atrial diameter, left ventricular end-systolic diameter, and left ventricular end-diastolic diameter recovered to normal in most patients at 6 months postoperatively. CONCLUSIONS: Simultaneously transcatheter interventional therapy is a safe and effective method for pmVSD combined with PDA.

Effectiveness and Safety of Transcatheter Closure of Perimembranous Ventricular Septal Defects in Adults.

This study was designed to determine the long-term safety and efficacy of using modified double-disk occluders for perimembranous ventricular septal defect (pmVSD) closure in adults. From January 2004 to December 2014, 337 adults with pmVSDs were treated through transcatheter intervention using 2 types of double-disk occluders; 302 patients received a symmetrical concentric pmVSD occluder, and 35 patients received an asymmetrical concentric pmVSD occluder. All patients were followed up through electrocardiography and transthoracic echocardiography until June 2015. The success rate was 100% for both procedures. During the median 71-month follow-up period, no cases of infective endocarditis, cerebrovascular accidents, heart failure, or death occurred. Two major adverse events (0.6%) were recorded: complete atrioventricular block requiring surgical treatment in one patient and severe tricuspid valvular regurgitation requiring surgical repair in another patient. Cardiac conduction block was the most common minor adverse event. The mean left ventricular (LV) end-diastolic volume decreased from 96.6 ± 23.2 ml before intervention to 86.0 ± 22.0 ml (p <0.05) at the 6-month follow-up visit. Previously enlarged LV chambers decreased to normal sizes during the follow-up period. In conclusion, transcatheter closure of pmVSDs using modified double-disk occluders was both safe and effective and yielded excellent long-term results in adults. The potential benefits of this intervention included remodeling of the heart, a reduced incidence of infective endocarditis and prevention of LV volume overload.

Clinical Application of Superior Vena Cava Spectra in Evaluation of Pulmonary Hypertension: A Comparative Echocardiography and Catheterization Study.

This study was designed to assess whether superior vena cava (SVC) Doppler flow velocities are associated with invasive measures of pulmonary arterial pressure. Eighty patients with unrepaired congenital heart disease who underwent cardiac catheterization were included (31 men, 49 women; mean age: 37.3 ± 14.7 y). Compared with the non-pulmonary hypertension group, the moderate and severe pulmonary hypertension groups had decreased SVC ventricular reserve flow velocity and a significantly increased ratio of atrial reverse flow to systolic flow (AR/S). AR/S correlated significantly with invasive pulmonary arterial systolic pressure (r = 0.426, p < 0.0001). A cutoff of 0.45 had a sensitivity and specificity of 74% and 80%, respectively, for prediction of pulmonary hypertension. Good correlation also existed between SVC AR/S and pulmonary arterial systolic pressure in cases without tricuspid regurgitation (r = 0.706, p = 0.034). These results indicate that SVC AR/S may be an alternative method for assessing pulmonary hypertension.

Early- and intermediate-term results of surgical correction in 122 patients with total anomalous pulmonary venous connection and biventricular physiology.

BACKGROUND: We retrospectively reported our 26-year experience with operative repair of total anomalous pulmonary venous connection (TAPVC) with biventricular physiology. METHODS: Between December 1982 and December 2008, 122 TAPVC patients with biventricular heart underwent surgical repair in our department. Moderate or deep hypothermia was induced at the time of cardiopulmonary bypass (CPB). Follow-up was conducted for 5 postoperative years. Surgical outcomes of early and intermediate deaths after TAPVC repair were retrospectively analyzed. RESULTS: Six deaths occurred operatively; and three deaths, during follow-up. The 5-year survival rates after TAPVC repair was 92.6 %, without gradient across the anastomosis. The survival rate of the patients who were younger was 78.8 %, significantly lower than those older than 1 year. It was also lower in those who were less than 6 kg in weight. Three patients died during follow-up. Three patients died of ventricular arrhythmia, right heart failure, and pneumonia, respectively, during follow-up. If the left atrium pressure was higher than 15 mm Hg, the snare of the vertical vein was loosened after CPB ceased in the patients with supracardiac connection. It decreased from 21 ± 5 to 13 ± 3 mm Hg. The vertical vein was ligated in 57 cases and left open in 20 cases. A patient with an intact vertical vein had a large shunt and was cured by intervention afterward. Supraventricular arrhythmia occurred in 19 patients with the supercardiac type repaired through a biatrial incision. One patient died of ventricular arrhythmia, and none of the remaining patients had arrhythmias. CONCLUSION: Surgical treatment of TAPVC carried a low operative risk and had satisfactory immediate and intermediate results. Age younger than 1 year and weight less than 6 kg were risk factors. It was a good choice to leave the vertical vein open in the patients with a left atrial pressure higher than 15 mm Hg.

Tetrandrine inhibits migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes through down-regulating the expressions of Rac1, Cdc42, and RhoA GTPases and activation of the PI3K/Akt and JNK signaling pathways.

Tetrandrine (Tet), the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet (0.3, 1 µmol·L(-1)) was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC (against PI3K, Akt, JNK, ERK, p38 MAPK and NF-κB-p65, respectively) were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Rac1, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK.