Procedural Efficiencies and Clinical Outcomes for Transcatheter Device Closure of Perimembranous Ventricular Septal Defects With Different Waist-Length Occluders.

BACKGROUND: Potential differences in complications and/or long-term outcomes of perimembranous ventricular septal defect (pmVSD) closures with 3-mm waist vs. 4-mm waist double-disk symmetrical occluders are not known.Methods and Results: A total of 395 consecutive pediatric patients with pmVSD recruited between January 2017 and March 2021 underwent successful transcatheter closure using symmetrical pmVSD devices. The final analysis involved 208×3-mm and 172×4-mm cases. The median follow-up was 42 months (range: 12-62 months). A total of 175 post-procedure adverse events (AEs) were observed. Most of these AEs were temporary, and there were only 8 major AEs. Compared to the 3-mm waist group, the incidence of residual shunts was significantly higher in the 4-mm waist group (13.4% vs. 6.7%; P=0.030), whereas other AEs showed similar incidences between the 2 groups. Multivariate Cox regression analysis revealed that larger defect, higher ratio between device size and body surface area, and longer procedure time can cause an increased likelihood of AEs, and smaller defect or left disk placement within aneurysmal tissue may reduce it. CONCLUSIONS: Transcatheter closure of pmVSD using a symmetrical double-disk occluder is safe and effective. Compared with a 3-mm waist symmetrical occluder, transcatheter closure with a 4-mm waist symmetrical occluder correlated with higher incidences of residual shunts.

Predictors and long-term outcomes of heart block after transcatheter device closure of perimembranous ventricular septal defect.

Background: Heart block is the most common and concerning complication associated with transcatheter device closure of perimembranous ventricular septal defect (pmVSD) and its occurrence remains a great challenge for device closure. Methods: Between June 2002 and June 2020, 1076 pediatric patients with pmVSD, who successfully underwent transcatheter device closure in our center, were enrolled in this cohort study, with a median follow-up of 64 months (range: 1 to 19 years). Results: Of 1076 patients, 234 (21.8%) developed postprocedural heart block, with right bundle branch block being the most common (74.8%), followed by left bundle branch block (16.2%), and atrioventricular block (5.6%). Complete atrioventricular block occurred in 5 cases, including 3 cases with permanent pacemaker implantation, 1 case with recovery to normal sinus rhythm, and 1 case with sudden cardiac death. Most patients (97.9%) developed heart block within 1 week of procedure. Finally, 138 cases returned to normal cardiac conduction. Multivariate logistic regression revealed that thin-waist occluders (odds ratio [OR]: 1.759; 95% confidence interval [CI]: 1.023 to 3.022; P = 0.041), and oversized devices (OR: 1.809; 95% CI: 1.322 to 2.476; P < 0.001) were independently associated with occurrence of postprocedural heart block. Moreover, heart block was less likely to occur when the left disk of occluder was placed within the aneurysmal tissue (OR: 0.568; 95% CI: 0.348 to 0.928; P = 0.024). Conclusion: The outcome of postprocedural heart block is favorable in most cases. Oversized devices and thin-waist occluders should be avoided. Placement of the left disk of the device should into the aneurysmal tissue is highly recommended.

Clinical Profile and Risk Factors for Cardiac Death in Pediatric Patients With Primary Dilated Cardiomyopathy at a Tertiary Medical Center in China.

Aim: We sought to identify the clinical characteristics and risk factors for cardiac mortality in pediatric patients with primary dilated cardiomyopathy (DCM) in China. Methods: A total of 138 pediatric patients who were consecutively diagnosed with primary DCM from January 2011 to December 2020 were included. We assessed patients' clinical symptoms and performed laboratory examinations, electrocardiography, and echocardiography. Results: Of these patients, 79 (57%) had severe systolic dysfunction (left ventricular ejection fraction of < 30%), 79 (57.2%) developed DCM before 12 months of age, 62 (45%) were male, 121 (87.7%) presented with advanced heart failure (cardiac functional class III/IV), and 54 (39.1%) presented with arrhythmia. At a median follow-up of 12 months, the overall cardiac mortality rate was 33%, and 40 of 46 deaths occurred within 6 months following DCM diagnosis. A multivariate Cox regression analysis identified several independent cardiac death predictors, including an age of 12 months to 5 years [hazard ratio (HR) 2.799; 95% confidence interval (CI) 1.160-6.758; P = 0.022] or 10-15 years (HR 3.617; 95% CI 1.336-9.788; P = 0.011) at diagnosis, an elevated serum alanine aminotransferase (ALT) concentration (≥ 51.5 U/L) (HR 2.219; 95% CI 1.06-4.574; P = 0.031), and use of mechanical ventilation (HR 4.223; 95% CI 1.763-10.114; P = 0.001). Conclusion: The mortality rate of primary DCM without transplantation is high. Age, an elevated serum ALT concentration, and the need for mechanical ventilation predict mortality in patients with primary DCM, providing new insights into DCM risk stratification.

Electrocardiographic Characteristics and Catheter Ablation of Ventricular Arrhythmias Originating From the Moderator Band in Children.

AIMS: To investigate the electrocardiographic (ECG) characteristics and catheter ablation of ventricular arrhythmias (VAs) originating from the moderator band (MB) in children. METHODS: A total of six children who had VAs originating from the MB-as confirmed by electrophysiological study-and who underwent catheter ablation between January 2016 and December 2020 were retrospectively reviewed. During the procedure, a three-dimensional electroanatomic mapping system was used to facilitate three-dimensional anatomical reconstruction, mapping and ablation. Patients' clinical characteristics, ECG features and procedural data were collected and analyzed. RESULTS: The mean age was 8.4 ± 2.6 years (range: 5.3-11 years) and mean weight was 27.7 ± 11.4 kg (range: 17-47 kg). Four patients presented with frequent premature ventricular contraction (PVC), one patient presented with frequent PVC and non-sustained ventricular tachycardia, and one patient presented with sustained monomorphic ventricular tachycardia. The QRS duration averaged 126.3 ± 4.6 ms. In all patients, the VAs had left bundle branch block QRS with left superior frontal plane axes, rapid downstrokes of the QRS in the precordial leads, and late precordial transitions (>V4). During the same period, 10 cases of VAs originated from the posterior-lateral wall of the tricuspid annulus, with a mean QRS duration of 152.8 ± 6.4 ms. Compared to that, VAs of MB origin have narrower QRS widths, downstroke slopes in the inferior lead, sharper downstroke slopes in the precordial lead, and smaller R-wave amplitudes in the V6 lead. All patients experienced immediate ablation success with activations earlier than QRS by 26.0 ± 3.5 ms, and no procedural complications occurring. Only one case had recurrent PVC during a follow-up period ranging from 6 to 36 months. CONCLUSION: MB VAs in children have distinctive ECG morphology and electrophysiological characteristics. Catheter ablation using a three-dimensional electroanatomic mapping system is safe and effective in these patients.

Next-Generation Sequencing Reveals Novel Genetic Variants for Dilated Cardiomyopathy in Pediatric Chinese Patients.

Dilated cardiomyopathy (DCM) is a myocardial disease characterized by bilateral or left ventricular cardiac dilation and systolic dysfunction that can lead to heart failure and sudden cardiac death in children. Many studies have focused on genetic variation in DCM-related genes in adult populations; however, the mutational landscape in pediatric DCM patients remains undetermined, especially in the Chinese population. We applied next-generation sequencing (NGS) technology to genetically analyze 46 pediatric DCM patients to reveal genotype-phenotype correlations. Our results indicated DCM-associated pathogenic mutations in 10 genes related to the structure or function of the sarcomere, desmosome, and cytoskeleton. We also identified 6 pathogenic mutations (5 novel) in the Titin (TTN) gene that resulted in truncated TTN variants in 6 (13%) out of 46 patients. Correlations between TTN mutations and clinical outcomes were assessed. Our data indicate that one-third of pediatric DCM cases are caused by genetic mutations. The role of TTN variants should not be underestimated in pediatric DCM and age-dependent pathogenic penetrance of these mutations should be considered for familial DCM cases. We argue that genetic testing of DCM cases is valuable for predicting disease severity, prognosis, and recurrence risk, and for screening first-degree relatives.

Expression profiles and functional analysis of plasma tRNA-derived small RNAs in children with fulminant myocarditis.

Aim: Fulminant myocarditis (FM) has neither validated biomarkers nor well-established therapy. Roles of tRNA-derived small RNAs (tsRNAs) in FM remain unknown. Materials & methods: Small RNA sequencing was conducted in plasma from children with FM during acute and convalescent phase and matched healthy volunteers. Data were validated by quantitative real-time PCR in larger sample-sized groups and in vitro. Functional analysis was performed to explore the roles. Results: tiRNA-Gln-TTG-001 was overexpressed in children with FM during acute phase, and the generation and extracellular release of tiRNA-Gln-TTG-001 were higher after myocarditis-mimicked activity in vitro. Several pathways might participate in the pathogenesis of FM. Conclusion: tsRNAs may play an important role in FM, and tiRNA-Gln-TTG-001 might represent a novel and promising biomarker and therapeutic target.

The Efficacy and Medium to Long-Term Follow-Up of Transcatheter Retrograde Closure of Perimembranous Ventricular Septal Defects via the Femoral Artery With Amplatzer Duct Occluder II in Children.

Objective: The aim of this study was to assess the efficacy and safety of transcatheter retrograde closure of perimembranous ventricular septal defect (pmVSD) via the femoral artery with an Amplatzer Duct Occluder II (ADO II) in children. Methods: The clinical and follow-up data of 102 children who had successfully undergone transcatheter retrograde closure of pmVSD via the femoral artery with Amplatzer Duct Occluder II (ADO II) from February 2012 to June 2019 in our center were retrospectively reviewed. Results: In 102 of 103 patients, the defects were successfully closed (99.0%). The average age was 4.03 ± 1.84 years and the mean weight was 17.50 ± 5.58 kg. The mean diameter of the defects was 2.58 ± 0.63 mm. Hundred of the occluders had a waist length of 4 mm. The complete closure rate was 89.2% 24 h after the procedure and 98% at the last follow-up. The follow-up period ranged from 6 to 92 months, with a median of 36 months. One child developed new mild aortic regurgitation (AR), and 9 patients developed new mild tricuspid regurgitation (TR). During follow-up, TR disappeared in 5 patients and decreased in 4 patients, and AR relieved in one patient. One patient developed intermittent complete left bundle branch block 4 days after the procedure and recovered sinus rhythm 2 days later. No serious complications occurred. Conclusion: Transcatheter retrograde closure of pmVSD via the femoral artery with ADO II in children is safe, feasible, and effective in selected patients.

Transcatheter Device Closure of Perimembranous and Intracristal Ventricular Septal Defects in Children: Medium- and Long-Term Results.

Background In children, the practice of transcatheter closure of intracristal ventricular septal defect (icVSD) has been limited. Currently, there is a lack of comparison between device closure of perimembranous ventricular septal defect (pmVSD) and icVSD, and long-term clinical outcomes are rare. Methods and Results This study included a total of 633 children (39 with icVSD and 594 with pmVSD), aged 18 months to 16 years, who underwent transcatheter closure of ventricular septal defect between January 2014 and December 2018. All patients were followed up until September 2020, with a median follow-up of 46 months in the pmVSD group and 52 months in the icVSD group. The procedural success rate was 96.3% and 84.6% in pmVSD and icVSD groups, respectively (P=0.002). The median of age, weight, procedure time, fluoroscopic time, and radiation dose were greater in the icVSD group compared with the pmVSD group. More eccentric ventricular septal defect occluders were used in the icVSD group. Most adverse events were minor without any intervention, with cardiac rhythm/conduction abnormalities being the most common. In the pmVSD group, 2 patients experienced complete atrioventricular block, with one implanting a permanent pacemaker and the other dying of cardiac arrest secondary to reversible complete atrioventricular block 40 days postprocedure. Complete left bundle-branch block occurred in 14 patients, and 12 cases were transient. In the icVSD group, no complete atrioventricular block or death occurred, and one patient developed transient complete left bundle-branch block. Conclusions In selected patients, transcatheter device closure of pmVSD and icVSD can be performed safely and successfully, with excellent medium- and long-term results in children.

A Novel High-Intensity Focused Ultrasound-Treated Herpes Simplex Virus 2 Vaccine Induces Long-Term Protective Immunity against Lethal Challenge in Mice.

High-intensity focused ultrasound (HIFU), a noninvasive ablation therapy that has been widely used clinically in ablation of solid tumors, induces immune sensitization. We therefore in this study investigated whether HIFU treatment could enhance the efficacy of a herpes simplex virus 2 (HSV-2) vaccine. First, we observed that in HSV-2-positive cervical intraepithelial neoplasia (CIN) II patients, HIFU treatment induced significantly higher anti-HSV-2 neutralization response than surgical removal. Next, we tested the efficacy of HIFU-treated, UV-inactivated HSV-2-infected cells as a proof-of-concept vaccine in mice. Our data showed that HIFU-treated formulation significantly enhanced HSV-2 antibody titers and neutralization titers, compared to UV-, microwave (MW)-, or freeze-thaw (FT)-treated formulations. HIFU treatment also promoted the Th1/2 cell-mediated response. A long-term full protection was observed in mice that received the HIFU-treated formulation, and no weight loss was detected. Our findings indicate that the novel application of HIFU in vaccine production may represent a rational way to improve vaccine efficacy.IMPORTANCE High-intensity focused ultrasound (HIFU) is mainly used in tumor ablation and tumor vaccinology study. It has been shown to induce immune sensitization and enhance tumor responsiveness to other therapies. Our study has shown enhanced anti-HSV-2 response in HIFU-treated CIN II patients. Furthermore, in a murine model, we have demonstrated that HIFU-treated HSV-2 vaccine induced long-term protective immunity against lethal challenge. Our findings indicate that the novel application of HIFU in vaccine production may represent a rational way to improve vaccine efficacy.

The Clinical Features of Children With Acute Fulminant Myocarditis and the Diagnostic and Follow-Up Value of Cardiovascular Magnetic Resonance.

Objective: To investigate the clinical features and the diagnostic and follow-up value of acute fulminant myocarditis (AFM) in children. Methods: A total of 20 children diagnosed with AFM admitted to our department were reviewed, and the clinical manifestations; pathogenic examination results; myocardial injury biomarkers; and electrocardiography, echocardiogram, and cardiovascular magnetic resonance (CMR) results were analyzed. Results: Twenty children with AFM, including 12 males and 8 females, aged 3-16 years, were analyzed. The initial symptoms were abdominal pain, vomiting, fatigue, syncope, and convulsions. All children had significantly increased hs-cTnT and NT-pro BNP. In addition to nonspecific ST-T changes, there were 10 cases of complete atrioventricular block, 2 cases of advanced atrioventricular block, and 1 case of ventricular tachycardia. Echocardiography showed an increase in the cardiac chamber sizes in 15 patients and a decrease in left ventricular ejection fraction (LVEF) in 17 patients. There were 16 patients with abnormal CMR findings, including 13 cases of high T2-weighted image (T2WI) signal and 14 cases of late gadolinium enhancement (LGE). In the patients who underwent CMR within 14 days of onset, the sensitivity of T2WI and LGE and the positive diagnosis rate were higher than in those who underwent CMR after 14 days, but the difference was not statistically significant. CMR was followed up in 10 patients: 7 patients returned to normal, 2 patients still had mild LGE, and 1 patient developed inflammatory dilated cardiomyopathy. All patients were treated with high-dose immunoglobulin, 11 of whom received high-dose immunoglobulin combined with glucocorticoids. Eight patients received temporary pacemakers, and 1 patient received ECMO. None of the patients died. The peak of hs-cTnT was significantly higher in the glucocorticoid group than in the unused glucocorticoid group (2853.4 ± 2217.2 and 1124.7 ± 527.3 pg/ml, respectively). Conclusion: Children with AFM have unique clinical features. Early identification and effective treatment can reduce the mortality rate and improve the prognosis. CMR is highly sensitive in the diagnosis of ARM, especially within 14 days of onset, and is a useful noninvasive imaging technique for the early identification of AFM in children. The dynamic observation and follow-up of children with AFM through CMR can guide clinical decision-making and prognosis assessment.

Transcatheter closure of congenital perimembranous ventricular septal defect using the Amplatzer duct occluder 2.

OBJECTIVE: The objective of this study was to explore the clinical effect of the transcatheter closure of congenital perimembranous ventricular septal defect using the Amplatzer duct occluder 2. METHODS: Between February 2012 and December 2016, 51 patients were subjected to Amplatzer duct occluder 2 for transcatheter closure of perimembranous ventricular septal defect. A total of 51 patients with perimembranous ventricular septal defect who underwent transcatheter closure by the conventional membranous ventricular septal occluder comprised the control group. The success rate and complications were compared, and indications of Amplatzer duct occluder 2 for perimembranous ventricular septal defect were explored. RESULTS: The success rate of the interventional procedure was 98.0% (50/51) in the group of Amplatzer duct occluder 2 versus 100% in the group of conventional membranous ventricular septal occluder. The mean age of the patients of Amplatzer duct occluder group was 5.0±3.7 years (range: 1.5-25.0), and the mean weight was 19.3±8.1 kg (range: 11.0-52.0). The mean outlet diameter of the defects was 2.8±0.6 mm (range: 1.8-5.1) as measured by transthoracic echocardiography. The device was implanted by a retrograde approach in 40 patients and antegrade approach in 10 patients. No statistical significance was observed in the incidence of complication and hospitalisation duration between the two groups; however, the Amplatzer duct occluder 2 group was cost-effective (p<0.05) and required less fluoroscopy time (p<0.05). Neither deaths nor new onset of aortic and tricuspid insufficiency occurred during the median 26.2 months (range: 3-65) of follow-up. CONCLUSIONS: Amplatzer duct occluder 2 has advantages of simple manipulation and less medical costs compared with conventional device in transcatheter closure of small type perimembranous ventricular septal defect.

Postprocedural Outcomes and Risk Factors for Arrhythmias Following Transcatheter Closure of Congenital Perimembranous Ventricular Septal Defect: A Single-center Retrospective Study.

BACKGROUND: Currently, transcatheter closure of perimembranous ventricular septal defect (pmVSD) is a widely accepted therapeutic modality. However, arrhythmias, especially postprocedural heart blocks, are a concern and outcomes are not very clear. This study explored the outcomes and risk factors of arrhythmias associated with transcatheter device closure of pmVSD. METHODS: A total of 395 patients diagnosed with pmVSD who successfully underwent transcatheter intervention between January 2010 and December 2015 in our center were retrospectively reviewed. Electrocardiographic data before and after the procedure were collected and analyzed. We first evaluated the potential risk factors including gender, age, weight, inlet and outlet diameters of defect, subaortic rim length, occluder size, corrected occluder size into body surface area, fluoroscopy time, presence of aneurysm, and deployment position. We compared the potential risk factors between arrhythmia and nonarrhythmia groups using univariate analysis, followed by logistic analysis for independent risk factors. RESULTS: Various arrhythmias were detected in 95 cases (24.1%) following transcatheter closure procedure. Logistic regression analysis revealed that eccentric (odds ratio [OR] 2.9, 95% confidence interval [CI]: 1.2-7.2) and large occluders (OR 2.0, 95% CI: 1.6-2.5), as well as long fluoroscopy time (OR 1.1, 95% CI: 1.1-1.2), were correlated with postprocedural arrhythmia. During 35.5 months (range: 9-80 months) of follow-up, most of the patients (74 out of 95) reverted to normal heart rhythm. CONCLUSIONS: The mid-term outcome of patients with arrhythmias after transcatheter closure of pmVSD was satisfactory as most of the patients recovered normal rhythm. Eccentric, large device and long fluoroscopy time increase the risk of arrhythmias after transcatheter closure of pmVSD.

[Mechanism of conditioned immune response in curing bronchial asthma in mice].

OBJECTIVE: To understand the mechanism of effect of conditioned immune response in curing bronchial asthma. METHODS: An experimental asthma modal was produced on healthy BALB/C mice (female, 4 - 6 weeks old) by sensitization and stimulation with ovalbumin (OV A). Totally 105 mice were divided into 7 groups randomly with 15 in each and treated differently: in group CIR(1), noise was used as conditioned stimulus (CS) and budesonide and salbutamol as unconditioned stimulus (UCS) respectively, a conditioned immune response model of mice with asthma was established by the combination of CS and UCS 7 times (7 days), then the mice were given CS only, and the combination were given once a week for 20 weeks. In group CIR(2) saccharin (SAC) was taken as CS, and the other treatments were the same as the group CIR(1). In the group of conventional therapy, the mice were given inhalation of nebulized budesonide and salbutamol only for 20 weeks. In the group of lower dose conventional therapy, the mice were given nebulized inhalation of budesonide and salbutamol for the first 7 days, then once a week for 20 weeks. In the noise group the mice were given noise only everyday for 20 weeks. In SAC group the mice were treated with SAC only everyday for 20 weeks. In the blank control group the mice were treated with placebo for 20 weeks. The mice in all the groups were stimulated with OVA once a day. The mice in the healthy control group were given PBS inhalation for 20 weeks. After 20 weeks therapy, the bronchoalveolar lavage fluid (BALF) was taken for eosinophils (EOS) counting. The spleens were taken to obtain CD4(+)T lymphocytes and the expression of neuronal acetylcholine receptor alpha 7 (nAChRalpha7), IL-4, IFN-gamma and IL-17 were detected by flow cytometry. RESULTS: (1) The percent of EOS of groups CIR(1), CIR(2), conventional therapy and healthy control was much lower than that of blank control (P < 0.01), and there was no significant difference among groups CIR(1), CIR(2) and conventional therapy (P > 0.05). (2) The expression of nAChRalpha7, IL-4 and IL-17 of groups CIR(1), CIR(2), conventional therapy and healthy control was much lower than that in blank control group, IFN-gamma was much higher (P < 0.01), and no significant difference was found among groups CIR(1), CIR(2) and conventional therapy (P > 0.05). There was a positive correlation between nAChRalpha7 and IL-4 (r = 0.76, P < 0.01), nAChRalpha7 and IL-17 (r = 0.46, P < 0.01). There was a negative correlation between nAChRalpha7 and IFN-gamma (r = 0.69, P < 0.01). (3) In the groups treated with lower dose of conventional therapy, noise, SAC and blank control, the epithelial tissue of airway were much thicker, the lumens were much narrower, and inflammatory cells and collagen fibers were much more than in the healthy control group, and after therapy, the inflammation in groups CIR(1), CIR(2) and conventional therapy was significantly improved. CONCLUSION: The conditioned immune response models established by both noise and SAC as CS and budesonide and salbutamol as UCS can downregulate nAChRalpha7 on CD4(+)T lymphocytes, regulate the function of CD4(+)T lymphocytes, and achieve the same therapeutic efficacy in treatment of asthma.