Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-кB Signaling.

Background and Aims: Hepatic fibrosis (HF) is a critical step in the progression of hepatocellular carcinoma (HCC). Gene associated with retinoid-IFN-induced mortality 19 (GRIM19), an essential component of mitochondrial respiratory chain complex I, is frequently attenuated in various human cancers, including HCC. Here, we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis. Methods: GRIM19 expression was evaluated in normal liver tissues, hepatitis, hepatic cirrhosis, and HCC using human liver disease spectrum tissue microarrays. We studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in vivo. We performed flow cytometry, immunofluorescence, immunohistochemistry, western blotting, and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF. Results: Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues, including hepatitis, cirrhosis, and HCC tissues. Hepatocyte-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice. In addition, GRIM19 loss caused chronic liver injury through reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-кB activation via an IKK/IкB partner in hepatocytes. Furthermore, GRIM19 loss activated NLRP3-mediated IL33 signaling via the ROS/NF-кB pathway in hepatocytes. Intraperitoneal administration of the NLRP3 inhibitor MCC950 dramatically alleviated GRIM19 loss-driven HF in vivo. Conclusions: The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-кB signaling, providing potential therapeutic approaches for earlier HF prevention.

Feasibility of the Omaha system for the care of children with dilated cardiomyopathy.

Aim: To explore the feasibility of Omaha system theory in the care of children with dilated cardiomyopathy (DCM), which may provide a practical basis for the continuous nursing of DCM children. Methods: A total of 1,392 records describing symptoms, signs, and nursing interventions were extracted from the medical records of 76 children suffered from DCM. Content analysis method was used to find out existent nursing problems, make precise nursing plans, and take corresponding nursing measurements according to the medical records of DCM children. Cross-mapping method was utilized to compare the conceptual consistency of the medical records and Omaha system (problem classification and intervention subsystems). Results: Of the total 1,392 records, 1,094 (78.59%) were complete consistency, while 245 (17.60%) were partial consistency, and 53 (3.81%) were inconsistency with the Omaha system concepts. The concept matching degree of medical records and Omaha system was approximately 96.19%. Conclusions: The Omaha system may be an effective nursing language for Chinese DCM children, which may be useful to guide nurses in the care of DCM. Further well-design studies need to fully evaluate the feasibility and effectiveness of the Omaha system in nursing children with DCM.

Aortic Regurgitation Requiring Unplanned Surgery following Transcatheter Closure of Ventricular Septal Defect in Children: Incidence and Risk Factors.

INTRODUCTION: Our aim was to investigate the incidence and risk factors for aortic regurgitation (AR) requiring unplanned surgery after transcatheter closure of ventricular septal defect (VSD) in children. METHODS: Medical records of 876 children with VSD who underwent transcatheter closure from July 2009 to September 2018 in our hospital were retrospectively reviewed. Groups with and without new-onset or increasing AR requiring unplanned surgery were compared. Univariate and multivariate analyses were used to identify the possible risk factors. Smoothing plot and threshold effect analysis were carried out to find the relationship between possible factors and risk of new-onset or increasing AR. RESULTS: A total of 29 children (3.3%) underwent unplanned surgery after transcatheter closure owing to new-onset or increasing AR, including 6 children with new-onset AR and 23 children with increasing AR. Multivariate regression analysis revealed that preoperative mild AR (OR: 60.39, 95% CI: 11.53-316.30, p < 0.001), larger ratio between diameter to body surface area (OR: 1.25, 95% CI: 1.01-1.55, p = 0.039), intracristal VSD (OR: 34.09, 95% CI: 4.07-285.65, p < 0.001), and shorter distance from the upper edge of defect to the aortic valve (or the sub-aortic rim) (OR: 0.12, 95% CI: 0.05-0.27, p < 0.001) were risk factors for new-onset or increasing AR requiring unplanned surgery. And, low risk of AR after muscular VSD transcatheter closure was found. An L-shaped nonlinear relationship between the sub-aortic rim and the risk of new-onset or increasing AR was observed, and the risk of new-onset or increasing AR with the sub-aortic rim up to the turning point (2 mm) (adjusted OR: 0.00, 95% CI: 0.00-0.08; p =0.001). With a median time of 7.3 years' follow-up, no new-onset or increasing AR has been found for children who initially did not have unplanned surgery. CONCLUSION: Preoperative mild AR, larger ratio between diameter to body surface area, intracristal VSD, and shorter distance of the sub-aortic rim (especially <2 mm) could increase the risk of new-onset or increasing AR requiring unplanned surgery after transcatheter closure of VSD.

Health-related quality of life in children with congenital heart disease following interventional closure versus minimally invasive closure.

Introduction: The presence of atrial septal defect (ASD) or ventricular septal defect (VSD) significantly affects children's quality of life and, if not treated adequately, can contribute to increased mortality. In this study, we evaluated and compared the health-related quality of life (HRQL) of children who underwent treatment using either minimally invasive closure (MIC) or interventional closure (IC). Materials and methods: In this observational and comparative study 199 children (2 to 4.5 years of age) underwent closure treatment for simple ASD or VSD at the Children's Hospital of Chongqing Medical University between February 2021 and September 2021. Of these, 116 were treated with IC and 83 with MIC. Both preoperative and postoperative HRQL scores were assessed using the PedsQLTM3.0 Cardiac Module and the children were followed up at 3 and 6 months after surgery. Results: The two groups did not differ significantly in terms of demographics, baseline clinical characteristics, or pre-operative data. The duration of anesthesia (45 mins vs. 109 mins), procedures (25 mins vs. 48 mins), and length of postoperative hospital stay (4.32 days vs. 6.87 days) in the IC group were significantly less than in the MIC group (P < 0.001). The incidence of postoperative pneumonia in the VSD patients who underwent MIC was significantly higher than in those who underwent IC treatment (28.9% vs. 0 percent, P < 0.001). The HRQL scores increased significantly in both groups following treatment and follow-up evaluations (P < 0.001). The mean HRQL score of the IC group 3 months after treatment was significantly higher than that of the MIC group (88.9 vs. 85.7, P < 0.001), indicating a significant increase from the baseline score compared with the MIC group (5.4 vs. 2.6, P < 0.001). The IC group also showed higher scores than the MIC group (P < 0.05) in the dimensions of "Heart Problems and Treatment," "Treatment Anxiety," and "Cognitive Problems," with higher scores indicating fewer problems. Conclusion: The health-related quality of life in children with ASD and VSD improved continuously regardless of IC or MIC intervention. However, IC led to better HRQL in the early postoperative stage.

Intranuclear cardiac troponin I plays a functional role in regulating Atp2a2 expression in cardiomyocytes.

In the past studies, it is shown that cardiac troponin I (cTnI, encoded by TNNI3), as a cytoplasmic protein, is an inhibitory subunit in troponin complex, and involves in cardiomyocyte diastolic regulation. Here, we assessed a novel role of cTnI as a nucleoprotein. Firstly, the nuclear translocation of cTnI was found in mouse, human fetuses and rat heart tissues. In addition, there were differences in percentage of intranuclear cTnI in different conditions. Based on weighted gene co-expression network analyses (WGCNA) and verification in cell experiments, a strong expression correlation was found between TNNI3 and Atp2a2, which encodes sarco-endoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a), and involves in ATP hydrolysis and Ca2+ transient. TNNI3 gain and loss caused Atpa2a2 increase/decrease in a dose-dependent manner both in mRNA and protein levels, in vivo and in vitro. By using ChIP-sequence we demonstrated specific binding DNA sequences of cTnI were enriched in ATP2a2 promoter -239∼-889 region and the specific binding sequence motif of cTnI was analyzed by software as "CCAT", which has been reported to be required for YY1 binding to the promoter region of YY1-related genes. Moreover, it was further verified that pcDNA3.1 (-)-TNNI3 could express cTnI proteins and increase the promoter activity of Atp2a2 through luciferase report assay. In the end, we evaluated beat frequencies, total ATP contents, Ca2+ transients in TNNI3-siRNA myocardial cells. These findings indicated, for the first time, cTnI may regulate Atp2a2 in cardiomyocytes as a co-regulatory factor and participate in the regulation of intracellular Ca ions.

Pediatric Diastolic Heart Failure: Clinical Features Description of 421 Cases.

Background and Aim: Heart failure in children differs substantially from the adult population. Clinical characteristics of pediatric diastolic heart failure has rarely been reported. In this study, we aimed to summary the causes, clinical features, lab tests, and treatment effect of pediatric diastolic heart failure. Methods: This study was a single center, retrospective study conducted in Children's Hospital of Chongqing Medical University. Children who were diagnosed with diastolic heart failure (DHF) without systolic heart failure (SHF) between 2006 and 2014 were included. Meanwhile, SHF (without DHF) cases were also collected from 2013 to 2014. Results: A total of 421 DHF and 42 SHF cases were included. The average age of pediatric DHF was 1.89 ± 3.29 years old, significant younger than that of SHF (4.65 ± 4.90). The top three cardiovascular causes of DHF were complex congenital heart malformations (53.4%), simple congenital heart defect (15.7%), and cardiomyopathy (7.4%). Alternatively, number of cardiomyopathy cases (57.1%) ranked first in SHF group. Simple congenital heart diseases (CHDs) rarely caused SHF. The most common symptom and sign were tachypnea and hepatomegaly in pediatric HF. Symptoms like cyanosis, feeding difficulty, be fidgety, pale, fatigue, and edema were valuable in differential diagnosis of DHF and SHF in children. B-type natriuretic peptide (BNP) increase was found in 36.9% of DHF children, and 60% in SHF patients. Sensitivity of BNP greater than 100 pg/ml in diagnosis of DHF was 0.37, and specificity of it was 0.86. Diastolic function indicators, such as E/A (early wave/late wave) ratio, IVRT (isovolumic relaxation time) were significant recovered after treatment in DHF patients. Less therapeutic benefits were achieved in children with cardiomyopathy induced DHF, in compared with non-cardiomyopathy patients. Conclusion: Pediatric DHF and SHF were largely different in primary causes, clinical symptoms and signs and short-term prognosis. There was a limit diagnostic value of BNP with 100 pg/ml as cut-off value in pediatric DHF. Larger, multicenter studies of pediatric DHF are required in the future.

Outcomes of percutaneous balloon pulmonary valvuloplasty in congenital pulmonary valve stenosis.

Percutaneous balloon pulmonary valvuloplasty (PBPV) is the primary treatment for pulmonary valve stenosis (PVS). The study consisted of 228 children with PVS who underwent PBPV from January 2004 to October 2019 at a single center. The risk factors for ≥moderate pulmonary regurgitation (PR), residual stenosis, and restenosis were analyzed based on the baseline patient characteristics and measured value of corresponding inspection results. Among 228 patients, follow-up results were obtained in 193 patients. The univariate analysis demonstrated that young age, low weight, small pulmonary annulus diameter, higher initial RV-PA PSEG, increased RV/systemic pressure ratio, and severe PVS were associated with ≥moderate PR. The multivariate analysis demonstrated that higher initial RV-PA PSEG and low weight were independently associated with ≥moderate PR, while higher initial RV-PA PSEG was independently associated with residual stenosis and restenosis. PBPV is a preferred tre atment in PVS children with a higher success rate. Higher initial RV-PA PSEG was a significant factor for ≥moderate PR, residual stenosis, and restenosis.

Oxidative Phosphorylation-Mediated E-Selectin Upregulation Is Associated With Endothelia-Monocyte Adhesion in Human Coronary Artery Endothelial Cells Treated With Sera From Patients With Kawasaki Disease.

Background and aims: E-selectin is a cell adhesion molecule of the vascular endothelium that mediates leukocyte rolling in the early inflammatory responses in many diseases including Kawasaki disease (KD). Previous studies have demonstrated that the expression levels of E-selectin was significantly increased in the sera of KD patients and in endothelial cells of KD patient's autopsy. In this study, we aimed to examine E-selectin levels in endothelial cells treated with sera from KD patients and explore the underlying mechanisms. Methods: Human coronary artery endothelial cells (HCAECs) were randomly incubated with sera from either healthy children [healthy control (HC group)] or pediatric KD patients [assigned as KD with coronary artery lesion (KD-CAL+ group) and KD without coronary artery lesion (KD-CAL- group)]. E-selectin levels were determined by RT-qPCR, Western blotting, and immunofluorescence. Cell adhesion assay was performed to quantify the role of E-selectin in intercellular adhesion. High-throughput cell RNA sequencing followed by functional validation was performed to explore the underlying mechanism. Results: E-selectin levels were significantly increased in KD-CAL+ group vs. HC group and KD-CAL- group. Compared with the KD-CAL- group, endothelia-monocyte adhesion was increased in the KD-CAL+ group, while E-selectin-specific siRNA could significantly rescue it. High-throughput cell RNA sequencing analysis also found a significant difference in oxidative phosphorylation (OXPHOS) levels between KD-CAL+ group and KD-CAL- group. Functional validation results further confirmed that the OXPHOS was upregulated in the KD-CAL+ group and KD-CAL- group compared to that in the HC group, while the KD-CAL+ group exhibited a higher OXPHOS than the KD-CAL- group. We also found that the E-selectin levels and endothelia-monocyte adhesion were significantly decreased by OXPHOS inhibitor oligomycin in the KD-CAL+ group and KD-CAL- group, respectively. Conclusion: Sera from KD patients stimulate OXPHOS levels and enhance E-selectin expression in HCAECs, which may contribute to the development of CAL in KD patients.

The efficacy of catheter ablation versus ICD for prevention of ventricular tachycardia in patients with ischemic heart disease: a systematic review and meta-analysis.

PURPOSE: Although implantable cardioverter defibrillator (ICD) could prevent the sudden death of ventricular tachycardia (VT) in patients with ischemic heart disease, it could not effectively prevent the recurrence of ventricular tachycardia. Several studies have suggested that catheter ablation may effectively decrease the incidence of ICD events, but relevant dates from randomized controlled trials were limited. METHODS: A systematic review and meta-analysis of randomized controlled trials were performed to evaluate the effect of catheter ablation for the prevention of VT in patients with ischemic heart disease. Random-effects model with inverse-variance weighting method was used to pool odds ratios. Egger method was performed to evaluate whether there was public bias in each outcome. RESULTS: Four studies enrolling a total of 605 patients were included in the present meta-analysis. Compared with the control group (ICD ± AAD), catheter ablation could significantly reduce the incidence of ICD therapy (OR, 0.49; 95% CI, 0.28 ~ 0.87), ICD shock (OR, 0.50; 95% CI, 0.28 ~ 0.87), VT storm (OR, 0.60; 95% CI, 0.40 ~ 0.90), and cardiovascular-related hospitalization (OR, 0.66; 95% CI, 0.45 ~ 0.9). But there was no significant difference among the risk of all-cause mortality (OR, 0.89; 95% CI, 0.59 ~ 1.34), cardiovascular mortality (OR, 0.76; 95% CI, 0.44 ~ 1.30), and complication (OR, 0.89; 95% CI, 0.30 ~ 2.67). CONCLUSION: These results showed that catheter ablation combined with ICD could reduce ICD therapy, ICD shock, and VT storm in patients with ischemic heart disease, but there was no improvement in all-cause mortality. Meanwhile, it also provided a basic guidance for the design of larger clinical randomized trials with longer follow-up in the future.

Clinical Analysis of Thrombocytopenia following Transcatheter Occlusion of a Patent Ductus Arteriosus.

BACKGROUND: Our aim is to analyze the correlation between severe thrombocytopenia and the diameter of patent ductus arteriosus (PDA) and residual shunt after PDA closure. METHODS: The patients with severe thrombocytopenia (platelet count <50 × 109/L) following transcatheter occlusion of a PDA from January 2010 to December 2018 in the Children's Hospital of Chongqing Medical University were collected. And the high-risk factors, diagnosis, treatment, and prognosis of severe thrombocytopenia were analyzed. RESULTS: A total of 1,581 children with transcatheter occlusion of a PDA were collected; 22 (1.39%) of the enrolled patients had severe thrombocytopenia. Further data analysis showed that the median diameter of PDA (6.7 [IQR: 1.63]) mm in children with severe thrombocytopenia was significantly larger than that in children without severe thrombocytopenia (3.6 ± 1.7 mm, p < 0.001). Furthermore, the incidence of thrombocytopenia in children with residual shunt after operation (10.9%) was significantly higher than that in children without residual shunt (0.2%, p < 0.001). The mean time of thrombocytopenia was found to be 2.4 ± 1.3 days after intervention. All patients with thrombocytopenia were treated by methylprednisolone with or without platelet transfusion and recovered without major organ hemorrhage. CONCLUSIONS: Severe thrombocytopenia following transcatheter occlusion of a PDA may be related to the larger diameter of PDA and residual shunt. If early detection of severe thrombocytopenia is obtained, our study supports a good prognosis if appropriate measures are implemented.

Comparison for the efficacy and safety of time-to-isolation protocol and conventional protocol of cryoballoon in the treatment of atrial fibrillation: a meta-analysis and systematic review.

BACKGROUND: Cryoballoon (CB) has been widely utilized in the treatment of drug-refractory atrial fibrillation (AF), but the balance point between efficacy and safety has been unclear. The protocol based on the time-to-isolation (TTI) was expected to provide patients with individualized ablation strategies. METHODS: All studies up to June 2020 comparing the CB of TTI-based protocol (TTIP) and conventional protocol (ConP) in PubMed, Embase, and Cochrane Library databases were searched. The pooled OR or SMD with 95% CIs for each outcome were calculated with inverse-variance random effect model. The Egger method was used to evaluate the publication bias and the subgroup analysis was conducted according to the type of atrial fibrillation. RESULTS: Six studies enrolling a total of 1770 patients with drug-refractory AF were included. The pool real-time recording of pulmonary veins potential was 71% (95% CI: 61 ~ 81%, I2 = 97.9%) and a similar incidence of freedom from ATs after 1 year (OR: 1.12; 95% CI: 0.86 ~ 1.46, I2 = 0.0%, P = 0.481) was observed between two protocols. No difference was observed in complications (OR: 0.67; 95% CI: 0.43 ~ 1.04, I2 = 0.0%, P = 0.717) and phrenic nerve palsy (OR: 0.70; 95% CI: 0.37 ~ 1.35, I2 = 0.0%, P = 0.807). TTIP could significantly decrease the CB freezes per patient (SMD: - 2.44; 95% CI: - 4.46 to approximately - 0.41; I2 = 99.5%, P = 0.00) and shorten the cryotherapy application time (SMD: - 3.04; 95% CI: - 4.18 to approximately - 1.89; I2 = 97.4%, P = 0.00), procedure time (SMD: - 1.51; 95% CI: - 2.08 to approximately - 0.94; I2 = 95.4%, P = 0.00), and fluorescence time (SMD: - 0.70; 95% CI: - 1.25 to approximately - 0.15; I2 = 95.7%, P = 0.00). CONCLUSION: TTIP is safe and effective and it opens a new chapter in the field of individualized protocol of CB for patients with AF.

A New Diagnostic Model to Distinguish Kawasaki Disease From Other Febrile Illnesses in Chongqing: A Retrospective Study on 10,367 Patients.

Objective: Kawasaki disease (KD) is one of the most prevailing vasculitis among infants and young children, and has become the leading cause of acquired heart disease in childhood. Delayed diagnosis of KD can lead to serious cardiovascular complications. We sought to create a diagnostic model to help distinguish children with KD from children with other febrile illnesses [febrile controls (FCs)] to allow prompt treatment. Methods: Significant independent predictors were identified by applying multivariate logistic regression analyses. A new diagnostic model was constructed and compared with that from diagnostic tests created by other scholars. Results: Data from 10,367 patients were collected. Twelve independent predictors were determined: a lower percentage of monocytes (%MON), phosphorus, uric acid (UA), percentage of lymphocyte (%LYM), prealbumin, serum chloride, lactic dehydrogenase (LDH), aspartate aminotransferase: alanine transaminase (AST: ALT) ratio, higher level of globulin, gamma-glutamyl transpeptidase (GGT), platelet count (PLT), and younger age. The AUC, sensitivity, and specificity of the new model for cross-validation of the KD diagnosis was 0.906 ± 0.006, 86.0 ± 0.9%, and 80.5 ± 1.5%, respectively. An equation was presented to assess the risk of KD, which was further validated using KD (n = 5,642) and incomplete KD (n = 809) cohorts. Conclusions: Children with KD could be distinguished effectively from children with other febrile illnesses by documenting the age and measuring the level of %MON, phosphorus, UA, globulin, %LYM, prealbumin, GGT, AST:ALT ratio, serum chloride, LDH, and PLT. This new diagnostic model could be employed for the accurate diagnosis of KD.

Comparison of Pulmonary Artery Pressure Measurement With Doppler Echocardiography or With Right Heart Catheterization in Patients With Congenital Heart Disease.

Background: Doppler echocardiography (D-ECHO) is a commonly used imaging tool for both diagnosis and follow-up examination of congenital heart disease (CHD). The goal of this study is to evaluate the accuracy of D-ECHO as used to measure an estimate sPAP in pediatric patients with CHD. Methods: A prospective study in 397 pediatric patients with CHD has been carried out to compare estimate sPAP measured with D-ECHO to that measured with right heart catheterization (RHC). Pearson correlation analyses were used to calculate the correlation coefficients between RHC and D-ECHO. Bland-Altman analyses were carried out to assess the agreement between the two methods. Results: Our data have demonstrated a significant underestimation of sPAP by D-ECHO compared to that by RHC. A strong correlation (r = 0.957, p < 0.01) was found between sPAP (36.1 ± 14.9 mmHg) and RVSP (36.0 ± 14.5 mmHg) measured with RHC. However, a relatively weak correlation (r = 0.219, p < 0.01) was observed between sPAP (36.1 ± 14.9 mmHg) measured during RHC and sPAP (28.7 ± 9.7 mmHg) as estimated using D-ECHO. The Bland-Altman analysis demonstrated that the bias for D-ECHO sPAP estimates was 6.6 mmHg with 95% limits of agreement ranging from -23.6 to 36.8 mmHg. A total of 57.5% of D-ECHO measurements were found to be accurate, with accuracy predefined as 95% of agreement within ±10 mmHg for sPAP estimates. Conclusions: sPAP measured with D-ECHO may be underestimated in pediatric patients with CHD.

A de novo Mutation in the MTUS1 Gene Decreases the Risk of Non-compaction of Ventricular Myocardium via the Rac1/Cdc42 Pathway.

Background: The MTUS1 gene encodes a microtubule-associated protein involved in multiple processes including cell polarity and microtubule balance during myocardial development. Aims: To investigate the association between a de novo c. 2617A->C mutation in MTUS1 (NM_001001924.2) and non-compaction of ventricular myocardium (NVM) and explore the potential mechanisms. Methods: A de novo mutation in MTUS1 was identified for a familial pedigree with NVM. Lentiviral vectors containing MTUS1 wild type or the mutation MTUS1 were constructed and co-infected into HEK-293 cells. MTUS1, Rac1/Cdc42, α-tubulin, α/ß-tubulin, polarity protein (PAR6), and the morphology of daughter cells were measured by real-time PCR, Western blot, and immunofluorescence assays, respectively. Results: The lentiviral vectors were constructed successfully. Immunofluorescence assays revealed the fluorescence intensity of α-tubulin to be decreased and α/ß-tubulin to be increased in the mutation MTUS1 group. The fluorescence intensity of PAR6 was higher and morphology of the daughter cells in the mutation group was different from the wild type group. The phosphorylation of Rac1/Cdc42 in the mutation group was significantly lower than in the wild type group. Conclusions: A de novo mutation in MTUS1 decreased the stability of microtubules and increased cell polarity via the Rac1/Cdc42 pathway, which may partly elucidate the mechanism underlying cellular protection in NVM.

Green tea extract catechin improves cardiac function in pediatric cardiomyopathy patients with diastolic dysfunction.

BACKGROUND: Our previous studies have demonstrated that Ca2+ desensitizing catechin could correct diastolic dysfunction in experimental animals with restrictive cardiomyopathy. In this study, it is aimed to assess the effects of green tea extract catechin on cardiac function and other clinical features in pediatric patients with cardiomyopathies. METHODS: Twelve pediatric cardiomyopathy patients with diastolic dysfunction were enrolled for the study. Echocardiography, ECG, and laboratory tests were performed before and after the catechin administration for 12 months. Comparison has been made in these patients before and after the treatment with catechin. Next Generation Sequencing was conducted to find out the potential causative gene variants in all patients. RESULTS: A significant decrease of isovolumetric relaxation time (115 ± 46 vs 100 ± 42 ms, P = 0.047 at 6 months; 115 ± 46 vs 94 ± 30 ms, P = 0.033 at 12 months), an increase of left ventricle end diastolic volume (40 ± 28 vs 53 ± 28 ml, P = 0.028 at 6 months; 40 ± 28 vs 48 ± 33 ml, P = 0.011 at 12 months) and stroke volume (25 ± 16 vs 32 ± 17 ml, P = 0.022 at 6 months; 25 ± 16 vs 30 ± 17 ml, P = 0.021 at 12 months) were observed with echocardiography in these patients 6-month after the treatment with catechin. Ejection fraction, left ventricular wall thickness, biatrial dimension remained unchanged. No significant side effects were observed in the patients tested. CONCLUSIONS: This study indicates that Ca2+ desensitizing green tea extract catechin, is helpful in correcting the impaired relaxation in pediatric cardiomyopathy patients with diastolic dysfunction.

MicroRNA-7 as a potential therapeutic target for aberrant NF-κB-driven distant metastasis of gastric cancer.

BACKGROUND: Dysregulated miR-7 and aberrant NF-κB activation were reported in various human cancers. However, the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in human gastric cancers (GC) metastasis remain largely unknown. This study is to investigate the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in GC and to explore the potential therapeutic effect of miR-7 to GC distant metastasis. METHODS: TCGA STAD and NCBI GEO database were used to investigate the expression profile of miR-7 and NF-κB RelA/p65 and clinical relevance. Lentivirus-mediated gene delivery was applied to explore the therapeutic effect of miR-7 in GC. Real-time PCR, FACS, IHC, IF, reporter gene assay, IP, pre-miRNA-7 processing and binding assays were performed. RESULTS: Low miR-7 correlated with high RelA/p65 in GC with a clinical relevance that low miR-7 and high RelA/p65 as prognostic indicators of poor survival outcome of GC patients. Moreover, an impaired pre-miR-7 processing caused by dysregulated Dicer1 expression is associated with downregulated miR-7 in GC cells. Functionally, delivery of miR-7 displays therapeutic effects to GC lung and liver metastasis by alleviating hemangiogenesis, lymphangiogenesis as well as inflammation cells infiltration. Mechanistically, miR-7 suppresses NF-κB transcriptional activity and its downstream metastasis-related molecules Vimentin, ICAM-1, VCAM-1, MMP-2, MMP-9 and VEGF by reducing p65 and p-p65-ser536 expression. Pharmacologic prevention of NF-κB activator LPS obviously restored miR-7-suppressed NF-κB transcriptional activation and significantly reverted miR-7-inhibited cell migration and invasion. CONCLUSIONS: Our data suggest loss of miR-7 in GC promotes p65-mediated aberrant NF-κB activation, facilitating GC metastasis and ultimately resulting in the worse clinical outcome. Thus, miR-7 may act as novel prognostic biomarker and potential therapeutic target for aberrant NF-κB-driven GC distant metastasis.

Is balloon angioplasty superior to surgery in the treatment of paediatric native coarctation of the aorta: a systematic review and meta-analysis.

A meta-analysis was performed to compare the outcomes between surgery and balloon angioplasty (BA) for native coarctation of the aorta in paediatric patients. Electronic databases, including PubMed, EMbase, Medline and Cochrane Library were searched systematically for literature aimed mainly at comparing the therapeutic effects for native coarctation of the aorta administered by surgery or BA. Corresponding data sets were extracted and 2 reviewers independently assessed the methodological quality. Ten studies meeting the inclusive criteria were identified involving a total of 723 subjects. Eventually, it was observed that compared with BA, surgery was significantly associated with a lower incidence of recoarctation, repeat intervention due to recoarctation and residual transcoarctation gradient in mid- to long-term follow-up. However, BA was significantly associated with a shorter hospitalization time. Incidence of aneurysm formation, perioperative mortality, complications and immediate transcoarctation residual gradient were not statistically different between surgery and BA. The overall level of evidence for our study was low and randomized controlled trials should be designed to evaluate and compare the safety and effectiveness of both approaches for native coarctation of the aorta.

Identification of target genes in cardiomyopathy with fibrosis and cardiac remodeling.

BACKGROUND: Identify genes probably associated with chronic heart failure and predict potential target genes for dilated cardiomyopathy using bioinformatics analyses. METHODS: Gene expression profiles (series number GSE3585 and GSE42955) of cardiomyopathy patients and healthy controls were downloaded from the Expression Omnibus Gene (GEO) database. Differential expression of genes (DEGS) between the two groups of total 14 cardiomyopathy patients and 10 healthy controls were subsequently identified by limma package of R. Database for Annotation, Visualization, and Integrated Discovery (DAVID Tool), which is an analysis of enriched biological processes. Search Tool for the Retrieval Interacting Genes (STRING) was used as well for the analysis of protein-protein interaction network (PPI). Prediction of the potential drugs was suggested based on the preliminarily identified genes using Connectivity Map (CMap). RESULTS: Eighty-nine DEGs were identified (57 up-regulated and 32 down-regulated). The most enrichment Gene Ontology (GO) terms (P < 0.05) contain genes involved in extracellular matrix (ECM) and biological adhesion signal pathways (P < 0.05, ES > 1.5) such as ECM-receptors, focal adhesion and transforming growth factor beta (TGF-ß), etc. Fifty-one differentially expressed genes were found to encode interacting proteins. Eleven key genes along with related transcription factors were identified including CTGF, POSTN, CORIN, FIGF, etc. CONCLUSION: Bioinformatics-based analyses reveal the targeted genes probably associated with cardiomyopathy, which provide clues for pharmacological therapies aiming at the targets.

Comparison of clinical outcomes between open and thoracoscopic repair for esophageal atresia with tracheoesophageal fistula: a systematic review and meta-analysis.

OBJECTIVE: A meta-analysis was performed for a comparison of outcomes between open repair (OR) and thoracoscopic repair (TR) for esophageal atresia with tracheoesophageal fistula (EA with TEF). METHODS: Electronic databases, including PubMed, Cochrane Library, and Medline, were searched systematically for the literatures aimed mainly at comparing the therapeutic effects for EA with TEF administrated by OR and TR. Corresponding data sets were extracted and two reviewers independently assessed the methodological quality. Meta-analysis was performed with Stata 12.0. RESULTS: Ten studies meeting the inclusion criteria were included, involving 447 subjects in total. It was observed that OR entailed a shorter operative time with significant statistical differences (SMD 0.604; 95% CI 0.344-0.864, P = 0). While TR was superior in two aspects: shorter length of hospital stay (SMD 0.584; 95% CI 0.214-0.953; P = 0.002) and shorter first oral feeding time (SMD 0.652; 95% CI 0.27-1.035; P = 0.001). However, meta-analyses of occurrence rate of leaks (OR, 1.747; 95% CI 0.817-3.737; P = 0.15), strictures (OR, 0.937; 95% CI 0.5-1.757; P = 0.839), pulmonary complications (OR, 1.08; 95% CI 0.21-5.44; P = 0.897), fundoplication rate of Gastroesophageal Reflux Disease (GERD) (OR, 1.642; 95% CI 0.855-3.153; P = 0.601), and blood loss (SMD 0.048; 95% CI -1.292 to 1.388; P = 0.944) showed no significant differences between OR and TR. Meta-analysis of ventilation time showed similar outcome between OR and TR (SMD 0.474; 95% CI 0.02-0.968; P = 0.06), but the result remained controversial due to estimated result changing after sensitivity analysis (SMD 0.61; 95% CI 0.16-1.07; P = 0). CONCLUSIONS: Compared with OR, a longer operative time was associated within TR group, although the TR procedure could possibly reduce the length of hospital stay and first oral feeding time. Meanwhile, the occurrence rate for leaks, strictures, pulmonary complications, and the fundoplication rate of GERD, and blood loss were similar between the OR and TR groups. Estimated result of ventilation time between the two groups remained ambiguous.

Differentiation of mesenchymal stem cells into cardiomyocytes is regulated by miRNA-1-2 via WNT signaling pathway.

BACKGROUND: Bone marrow derived stem cells (BMSCs) have the potential to differentiate into cardiomyocytes, but the rate of differentiation is low and the mechanism of differentiation is unclear completely. Here, we aimed to investigate the role of miR1-2 in differentiation of mouse BMSCs into cardiomyocyte-like cells and reveal the involved signaling pathways in the procedure. METHODS: Mouse BMSCs were treated with miR1-2 and 5-azacytine (5-aza). The expression of cardiac cell markers: NKx2.5, cTnI and GATA4 in BMSCs were examined by qPCR. The apoptosis rate was detected by flow cytometry and the activity of the Wnt/ß-catenin signaling pathway was evaluated by measuring the upstream protein of this signaling pathway. RESULTS: After over-expression of miR1-2 in mouse BMSCs, the apoptosis rate was significantly lower than the 5-aza group, while the expressions of cardiac-specific genes: such as Nkx2.5, cTnI and GATA4 were significantly increased compared to the control group and the 5-aza group. Meanwhile, over-expression of miR1-2 in mouse BMSCs enhanced the expression of wnt11, JNK, ß-catenin and TCF in the Wnt/ß-catenin signaling pathway. Use of LGK-974, an inhibitor of Wnt/ß-catenin signaling pathway, significantly reduced the expression of cardiac-specific genes and partially blocked the role of the miR1-2. CONCLUSION: Over-expression of miR1-2 in mouse BMSCs can induce them toward promoted cardiomyocyte differentiation via the activation of the Wnt/ß-catenin signaling pathway. Compared to 5-aza, miR1-2 can induce differentiation of BMSCs into cardiomyocytes more effectively with a less cytotoxicity.