LncRNA MALAT1-targeting antisense oligonucleotide ameliorates the AngII-induced vascular smooth muscle cell proliferation and migration via Nrf2/GPX4 antioxidant pathway.

ABSTRACT: The high level of oxidative stress induced by angiotensin II (AngII) is the main pathophysiological process that promotes the proliferation and migration of vascular smooth muscle cells (VSMCs) and induces vascular remodeling. LncRNA Metastasis-related lung adenocarcinoma transcript 1 (MALAT1) has been determined to play an important role in the modulation of oxidative stress and the development of cardiovascular diseases. Nevertheless, the function and underlying mechanism of MALAT1 in restenosis induced by hypertensive angioplasty remain unclear. AngII increased the expression of MALAT1 in VSMCs. We found that anti-sense oligonucleotide lncRNA MALAT1 (ASO-MALAT1) could inhibit AngII induced reactive oxygen species (ROS) production and VSMCs proliferation and migration by inducing the expression of glutathione peroxidase 4 (GPX4), which can be reversed by siRNA-GPX4. And GPX4 overexpression can inhibit the proliferation and migration of VSMCs induced by AngII. In addition, we found that the process by which MALAT1 knockdown induces GPX4 expression involves nuclear factor erythrocyte 2 related factor 2 (Nrf2). Overexpression of Nrf2 can increase the expression of GPX4, and down-regulation of GPX4 by ML385 (Nrf2 inhibitor) blocked the protective effect of ASO-MALAT1 on AngII-induced proliferation and migration of VSMCs. Ferrostatin-1 (Fer-1, ip 5mg/kg per day for 2 weeks), a GPX4 agonist, significantly inhibited neointimal formation in spontaneously hypertensive rat (SHR) by the inhibition of oxidative stress. In conclusion, these data imply that ASO-MALAT1 suppresses the AngII-induced oxidative stress, proliferation and migration of VSMCs by activating Nrf2/GPX4 antioxidant signaling. GPX4 may be a potential target for the therapeutic intervention of hypertensive vascular restenosis.

Comparison of strategies for catheter ablation of left posterior fascicular ventricular tachycardia.

AIMS: Traditional ablation strategies including targeting the earliest Purkinje potential (PP) during left posterior fascicular (LPF) ventricular tachycardia (VT) or linear ablation at the middle segment of LPF during sinus rhythm are commonly used for the treatment of LPF-VT. Catheter ablation for LPF-VT targeting fragmented antegrade Purkinje (FAP) potential during sinus rhythm is a novel approach. We aimed to compare safety and efficacy of different ablation strategies (FAP ablation vs. traditional ablation) for the treatment of LPF-VT. METHODS AND RESULTS: Consecutive patients with electrocardiographically documented LPF-VT referred for catheter ablation received either FAP ablation approach or traditional ablation approach. Electrophysiological characteristics, procedural complications, and long-term clinical outcome were assessed. A total of 189 consecutive patients who underwent catheter ablation for LPF-VT were included. Fragmented antegrade Purkinje ablation was attempted in 95 patients, and traditional ablation was attempted in 94 patients. Acute ablation success with elimination of LPF-VT was achieved in all patients. Left posterior fascicular block occurred in 11 of 95 (11.6%) patients in the FAP group compared with 75 of 94 (79.8%) patients in the traditional group (P < 0.001). Fragmented antegrade Purkinje ablation was associated with significant shorter procedure time (94 ± 26 vs. 117 ± 23 min, P = 0.03) and fewer radiofrequency energy applications (4.1 ± 2.4 vs. 6.3 ± 3.5, P = 0.003) compared with the traditional group. One complete atrioventricular block and one left bundle branch block were seen in the traditional group. Over mean follow-up of 65 months, 89 (93.7%) patients in the FAP group and 81 (86.2%) patients in the traditional group remained free of recurrent VT off antiarrhythmic drugs (P = 0.157). CONCLUSION: Left posterior fascicular-ventricular tachycardia ablation utilizing FAP and traditional ablation approaches resulted in similar acute and long-term procedural outcomes. Serious His-Purkinje injury did occur infrequently during traditional ablation. The use of FAP ablation approach was associated with shorter procedure time and fewer radiofrequency energy applications, especially for non-inducible patients.

Reappraisal and New Observations on Idiopathic Ventricular Arrhythmias Ablated From the Noncoronary Aortic Sinus.

BACKGROUND: The electrophysiological characteristics of idiopathic ventricular arrhythmias (VAs) from the noncoronary sinus (NCS) have not been fully described. OBJECTIVES: This study sought to investigate electrophysiological characteristics and catheter ablation in patients with idiopathic NCS-VA. METHODS: This study comprised 11 patients undergoing radiofrequency (RF) catheter ablation for idiopathic NCS-VA. Angiography was performed to confirm the origin in the aortic sinus before RF ablation. RESULTS: Clinical arrhythmias presented left bundle block/inferior axis morphology in all patients. QRS morphology of R' and R/s' pattern was dominantly found in lead III. Mapping in the right ventricle demonstrated the earliest ventricular activation (EVA) site at the His Bundle region, whereas mapping in the NCS demonstrated that the EVA preceded the activation at the His Bundle region by 12.1 ± 7.9 milliseconds. All VAs were successfully ablated in <2.5 seconds within the NCS with 1 RF application. The successful ablation site was at the nadir of NCS in 10 patients, and near the junction of NCS and the right coronary sinus in the remaining one. A discrete potential can be observed at the EVA site within the NCS in 10 patients (91%); however, an excellent pace mapping at the EVA site was obtained in only 2 patients. Junctional beats did not occur during RF application in all 11 patients. There were no complications or clinical recurrence during a mean follow-up of 26.0 ± 9.8 months. CONCLUSIONS: NCS-VA presents a peculiar electrocardiogram. A discrete potential can be mapped within the NCS during VA and sinus rhythm, and can be used in guiding ablation.

Electrophysiological characteristics and long-term outcome of substrate-based catheter ablation for left posterior fascicular ventricular tachycardia targeting fragmented antegrade Purkinje potentials during sinus rhythm.

AIMS: The aim of this study was to investigate the electrophysiological characteristics and long-term outcome of patients undergoing substrate-based ablation of left posterior fascicular ventricular tachycardia (LPF-VT) guided by targeting of fragmented antegrade Purkinje potentials (FAPs) during sinus rhythm. METHODS AND RESULTS: This study retrospectively analysed 50 consecutive patients referred for ablation. Substrate mapping during sinus rhythm was performed to identify the FAP that was targeted by ablation. FAPs were recorded in 48 of 50 (96%) patients during sinus rhythm. The distribution of FAPs was located at the proximal segment of posterior septal left ventricle (LV) in two (4.2%) patients, middle segment in 33 (68.8%) patients, and distal segment in 13 (27.1%) patients. In 32 of 48 (66.7%) patients, the FAP displayed a continuous multicomponent fragmented electrogram, while a fragmented, split, and uncoupled electrogram was recorded in 16 (33.3%) patients. Entrainment attempts at FAP region were performed successfully in seven patients, demonstrating concealed fusion and the critical isthmus of LPF-VT. Catheter ablation targeting at the FAPs successfully terminated the LPF-VT in all 48 patients in whom they were seen. Left posterior fascicular (LPF) block occurred in four (8%) patients after ablation. During a median follow-up period of 61.2 ± 16.8 months, 47 of 50 (94%) patients remained free from recurrent LPF-VT. CONCLUSION: Ablation of LPF-VT targeting FAP during sinus rhythm results in excellent long-term clinical outcome. FAPs were commonly located at the middle segment of posterior septal LV. Region with FAPs during sinus rhythm was predictive of critical site for re-entry.

Administration of Adenosine Triphosphate Provides Additional Value Over Programmed Electrophysiologic Study in Confirmation of Successful Ablation of Atrioventricular Accessory Pathways.

Objectives: To study the benefit of adenosine triphosphate (ATP) in evaluating ablation endpoints of accessory pathways (AP) and subsequent long-term prognosis. Methods: We reviewed consecutive patients with supraventricular tachycardias due to APs that underwent radiofrequency catheter ablation (RFCA) from January 2016 to September 2018 in our center. The patients were divided into two groups: the ATP group (who had passed both the ATP test and PES after ablation as the endpoint) and the non-ATP group (who had passed PES only after ablation as the endpoint). We reviewed the patients' intra-cardiac electrograms and analyzed their long-term outcomes. Results: In total, 1,343 patients underwent successful RFCA. There were 215 patients in the ATP group with one lost to follow-up. There were 1,128 patients in the non-ATP group with 39 lost to follow-up. Twenty-three patients in the ATP group demonstrated additional electrophysiological entities due to ATP administration, including reappearance of the ablated APs in 16 patients, discovery of PES-undetected APs in 5, induction of atrial fibrillation in 5, premature atrial contractions in 1, and premature ventricular contractions in another. During the 7 to 39 months (average 24.4 ± 9.5 months) follow-up, the recurrence rate was 8.41% (18/214) in the ATP group and 6.80% (74/1,084) in the non-ATP group. In subjects with recurrence, 14 patients (14/18 = 77.8%) in the ATP group and 50 patients (50/74 = 67.6%) in the non-ATP group accepted redo ablations. Among the ATP-group, all the 14 redo APs were the old ones as before. Among the non-ATP-group, redo ablations confirmed that 39 APs were the old ones, while 20 APs were newly detected ones which had been missed previously. The difference in recurrent AP locations confirmed by redo procedures between the two groups was significant (p = 0.008). In the non-ATP group, 20 (40%) of redo cases were proven to have multiple APs, while 33 (3.3%) cases who did not suffer from recurrence had multiple APs. Existences of multiple APs in recurred cases were significantly higher than that in non-recurred ones in the non-ATP group (p < 0.001), while there was no such difference in the ATP group (p = 0.114). Conclusions: The existence of multiple APs was more common in recurrent cases if ATP was not used for confirmation of ablation endpoints. ATP probably has additional value over PES alone by detecting weak AP conductions. ATP can evoke atrial and ventricular arrhythmias.

Feasibility and Safety of Permanent Left Bundle Branch Pacing in Patients With Conduction Disorders Following Prosthetic Cardiac Valves.

Background: The feasibility and safety of left bundle branch pacing (LBBP) in patients with conduction diseases following prosthetic valves (PVs) have not been well described. Methods: Permanent LBBP was attempted in patients with PVs. Procedural success and intracardiac electrical measurements were recorded at implant. Pacing threshold, complications, and echocardiographic data were assessed at implant and follow-up visit. Results: Twenty-two consecutive patients with atrioventricular (AV) conduction disturbances (10 with AV nodal block and 12 with infranodal block) underwent LBBP. The PVs included aortic valve replacement (AVR) in six patients, mitral valve repair or replacement (MVR) with tricuspid valve ring (TVR) in four patients, AVR with TVR in one patient, AVR with MVR plus TVR in three patients, transcatheter aortic valve replacement (TAVR) in five patients, and MVR alone in three patients. LBBP succeeded in 20 of 22 (90.9%) patients. LBB potential was observed in 15 of 22 (68.2%) patients, including 10 of 15 (66.7%) patients with AVR/TAVR and five of seven (71.4%) patients without AVR/TAVR. AVR and TVR served as good anatomic landmarks for facilitating the LBBP. The final sites of LBBP were 17.9 ± 1.4 mm inferior to the AVR and 23.0 ± 3.2 mm distal and septal to the TVR. The paced QRS duration was 124.5 ± 13.8 ms, while the baseline QRS duration was 120.0 ± 32.5 ms (P = 0.346). Pacing threshold and R-wave amplitude at implant were 0.60 ± 0.16 V at 0.5 ms and 11.9 ± 5.5 mV and remained stable at the mean follow-up of 16.1 ± 10.8 months. No significant exacerbation of tricuspid valve regurgitation was observed compared to baseline. Conclusion: Permanent LBBP could be feasibly and safely obtained in the majority of patients with PVs. The location of the PV might serve as a landmark for guiding the final site of the LBBP. Stable pacing parameters were observed during the follow-up.

Experimental Findings and Clinical-Pathologic Correlation of Radiofrequency Catheter Ablation at the Left Ventricle Para-Hisian Region.

BACKGROUND: Catheter ablation target at the site with large His activation in the left ventricle poses a high risk of atrioventricular (AV) block. We aimed to identify far-field (FF) and near-field (NF) His activation at left upper septum (LUS). METHODS: Three-D mapping of the aortic root and left ventricle was performed in 12 dogs. Two sites located at either the base or apex of the triangle interposed between the hinges of the the noncornary coronary cusp (NCC) - right coronary cusp (RCC) were chosen for a single radiofrequency (RF) application. Bipolar and unipolar pacing with different outputs at both sites was attempted to discern NF and FF His activation. RESULTS: The sites chosen for NF and FF ablation were located at the base and apex of the triangle, which were 8.03 ± 1.18 mm (group 1) and 3.42 ± 0.61 mm (group 2) away from the RCC-NCC junction. Lower A/V ratios were found in group 1. Pacing could not differentiate NF from FF His activation. In group 1, ablation resulted in III degree AV block in all 6 dogs, whereas neither PR prolongation nor AV block occurred in group 2. Pathologic examination of group 1 showed complete/partial necrosis of the His bundle (HB) and left bundle branch in all 6 dogs. In group 2, no necrosis of the HB was seen in the 6/6 dogs. CONCLUSION: Anatomical localization in the triangle of RCC-NCC junction can help differentiate NF from FF His activation.

Association between elevated blood glucose level and non-valvular atrial fibrillation: a report from the Guangzhou heart study.

BACKGROUND: To estimate the prevalence of elevated blood glucose level (EBG, including type 2 diabetes mellitus and impaired fasting glucose), and its association with non-valvular atrial fibrillation (NVAF) in Guangzhou, China. METHODS: The population-based follow-up Guangzhou Heart Study collected baseline data from July 2015 to August 2017 among 12,013 permanent residents aged > 35 from 4 Guangzhou districts. Two streets (Dadong and Baiyun) in the Yuexiu District, and one street (Xiaoguwei) and two towns (Xinzao and Nancun) in the Panyu District were chosen as representative of urban and rural areas, respectively. Each participant completed a comprehensive questionnaire, and underwent physical examination, blood sample collection for laboratory testing, electrocardiography, and other evaluations. Multivariable logistic regression analyses were used to estimate the independent association between hyperglycemia and NVAF prevalence. RESULTS: The prevalence of EBG in overall study population was 29.9%. Compared with residents without EBG, the odds ratio (OR) for AF among residents with EBG was significantly higher (1.94, 95% confidence interval [CI]: 1.40-2.70, P <  0.001), even after multivariate adjustment for metabolic abnormalities (OR = 1.60, 95% CI: 1.14-2.25, P = 0.007), and driven by women (OR = 1.80, 95% CI: 1.12-2.91, P = 0.016). CONCLUSIONS: In Guangzhou, China, prevalence of EBG is high among residents aged > 35 years and associated with a multivariate adjusted increase in prevalence of NVAF overall and in women.

Catheter Ablation of Ventricular Arrhythmias Originating From the Pulmonary Sinus Cusp in Pediatric Patients: A Single-Center Retrospective Study.

Objective: There are few reports of ventricular arrhythmias (VAs) originating from the pulmonary sinus cusp (PSC) in pediatric patients. Thus, we investigated the ablation of PSC-VAs in pediatric patients. Study Design: Clinical, echocardiographic, and ablation data were reviewed in 10 consecutive symptomatic children who underwent successful ablation of VAs of PSC origin at our center between March 2014 and June 2018. Results: The 10 patients' weights ranged from 29 to 63.5 kg, and all had structurally normal hearts and VAs with left bundle branch block (LBBB) morphologies and inferior axes. The initial ablation was performed in the right ventricular outflow tract (RVOT) or the aortic sinus cusp, which failed to terminate the VAs in nine patients. The successful ablation site was in the right cusp (RC) in seven patients, the anterior cusp in two patients, and the left cusp (LC) in one patient. The earliest potential recorded at the PSC ablation site preceded the onset of the QRS complex during VAs by 29.4 ± 4.9 ms. Conclusions: VAs with a LBBB morphologies and inferior axes may originate within the PSC of children. Ablation was effective and safe for the eradication of VAs originating from the PSCs in children. Due to the particularity of ablations in pediatric patients, mapping of PSCs should be considered when ablation fails in the RVOT.

Catheter ablation of right-sided para-Hisian ventricular arrhythmias using a simple pacing strategy.

BACKGROUND: Ablation of para-Hisian ventricular arrhythmias (PH-VAs) is challenging because of the close relationship of the origin site and His bundle. Using pacing techniques to differentiate the near-field from far-field His activations, thereby avoiding atrioventricular block, has been reported in patients with para-Hisian accessory pathways. OBJECTIVES: We applied the same pacing technique and 3-dimensional mapping to guide radiofrequency (RF) ablation in patients with right-sided PH-VAs and investigated the clinical outcome of such cases. METHODS: Fourteen patients with right-sided PH-VAs were included in this study. The earliest activation sites were confirmed in the right ventricle on the 3-dimensional map. Pacing with different outputs was performed at the largest His potential site (P1) and the earliest activation site (P2). If the minimum His bundle-right bundle branch-captured output at P2 was higher than that at P1, RF ablation was performed at the site. RESULTS: All the patients in this study had monomorphic premature ventricular contractions (PVCs) with a mean QRS duration of 118.3 ± 8.1 ms. A His-right bundle branch potential with an amplitude of 0.05 ± 0.02 mV was recorded at P2, with a mean distance of 5.97 ± 1.84 mm away from P1. PVCs were successfully eliminated in 13 of 14 patients (92.9%). One patient exhibited persistent right bundle branch block after ablation, and 1 recurrence of ablated PVCs occurred during a median follow-up period of 15 months. CONCLUSION: Using a simple pacing technique to evaluate the safety of RF energy application led to a high success rate of RF catheter ablation of right-sided PH-VAs without atrioventricular block.

Epidemiological Characteristics of Atrial Fibrillation in Southern China: Results from the Guangzhou Heart Study.

Precise prevalence of atrial fibrillation (AF) and the associated risk factors in southern China are rarely reported. This large population-based follow-up study, the Guangzhou Heart Study, was conducted from 2015 to 2017 to fill up this gap. Permanent residents aged 35 years and above in Guangzhou city were enrolled and demographic factors of participants were collected by a structured questionnaire. Examinations of physical, electrocardiographic and biochemical indicators were performed following a standard operation procedure designed prior to the field investigation. Descriptive statistics were used to evaluate basic characteristics of the study participants, and multivariate logistic regression model was performed to assess the AF prevalence-related factors. The detailed study design, the baseline characteristics and the prevalence of AF were reported here. In total, 12,013 residents were enrolled, and the percentage of participants from rural and urban areas was 53.92% and 46.08%, respectively. In total, 90.57% participants aged 40-79 years old and the proportion of women was more than men (64.98% vs. 35.02%). Overall, the prevalence of AF among the participants was 1.46%. Increasing age, male sex and widowed marital status were associated with higher AF prevalence (P-value < 0.05). The prevalence of AF increased with age and climbed to approximately 5% in residents aged 80 years and over. Residents with abnormal higher blood level of total cholesterol tended to have a lower AF prevalence but a higher prevalence of AF was observed in female participants with lower level of high density lipoprotein cholesterol land higher level uric acid (all P-value < 0.05). Personal illness such as hypertension, diabetes mellitus, dyslipidemia, myocardial infarction, heart failure, stroke and transient ischemic were significantly linked to the attack of AF (all P-value < 0.05). This study will be rich resource for investigating environmental exposure and individual genetic diathesis of AF and other common cardiovascular diseases in Chinese population.

Evaluation of Electrophysiological Mechanisms of Post-Surgical Atrial Tachycardias Using an Automated Ultra-High-Density Mapping System.

OBJECTIVES: This study aimed to evaluate the electrophysiological mechanisms of post-surgical atrial tachycardias (ATs) during mapping with an automated high-resolution mapping system (Rhythmia, Boston Scientific, Marlborough, Massachusetts). BACKGROUND: Mapping and ablation of post-operative ATs following previous open-heart surgery is often challenging because the potential mechanisms remain incompletely understood. METHODS: Fifty-one consecutive patients underwent mapping and ablation of post-surgical ATs. RESULTS: A total of 64 ATs were identified, and the mechanism was macro re-entry in 58 of 63 (92.1%) ATs, focal in 4 ATs, localized micro re-entry in 1 AT, and undetermined in 1 AT. Of 11 patients who underwent surgical repair of congenital heart disease, 6 (54.5%) had peri-tricuspid re-entrant AT, 5 had either right atrial (RA) free-wall incisional ATs or figure-8 re-entrant ATs, with an isthmus between the tricuspid annulus and the RA free-wall incision or between the incisions, and none had left atrial (LA) or focal ATs. In 32 patients with valve replacement and 8 who underwent valvuloplasty, peri-tricuspid ATs were observed in 14 (43.4%) and 6 (75%) patients, RA free wall or septal incisions-related ATs were seen in 7 and 2 patients, and LA macro re-entrant ATs were observed in 12 patients and 1 patient, respectively. A macro pseudo re-entry pattern was identified in 8 of 51 patients (15.7%). All these activations could be easily excluded by manually moving the window of interest, except in 2 cases with a figure-8 re-entrant configuration. CONCLUSIONS: RA macro re-entrant ATs predominate, irrespective of the types of initial surgical procedures, but LA ATs occur more frequently in patients with valve replacement. Pseudo re-entry atrial activation is common and easily recognized by adjusting the mapping window.

Whole exome sequencing identified a pathogenic mutation in RYR2 in a Chinese family with unexplained sudden death.

OBJECTIVE: This study aimed to identify the pathogenic mutation in a Chinese family with unexplained sudden death (USD) or occasional syncope. MATERIALS AND METHODS: Whole exome sequencing and target capture sequencing were respectively conducted for two related patients. The genetic data was screened using the 1000 genomes project and SNP database (PubMed), and the identified mutations were assessed for predicted pathogenicity using the SIFT and Polyphen-2 algorithms. RESULTS: We identified a heterozygous mutation in the RYR2 gene at c.490C>T (p.P164S), highly conserved across all species, in three family members of USD, syncope and malignant ventricular tachycardias induced by treadmill exercise test, while another heterozygous de novo mutation in SCN5A at c.5576G>A p.R1859H was detected in one family member. Both variants were verified by Sanger sequencing. Importantly, RYR2 p.P164S is associated with the risk of sudden cardiac death, such as in catecholaminergic polymorphic ventricular tachycardia. CONCLUSIONS: A pathogenic mutation in RYR2 (p.P164S) is the likely cause of USD in a Chinese family associated with malignant ventricular arrhythmias. Whole exome and target capture sequencing can be useful for discovering the genetic causes of USD.

Experimental, Pathologic, and Clinical Findings of Radiofrequency Catheter Ablation of Para-Hisian Region From the Right Ventricle in Dogs and Humans.

BACKGROUND: Ablation of para-Hisian accessory pathway (AP) poses high risks of atrioventricular block. We developed a pacing technique to differentiate the near-field (NF) from far-field His activations to avoid the complication. METHODS AND RESULTS: Three-dimensional mapping of the right ventricle was performed in 15 mongrel dogs and 23 patients with para-Hisian AP. Using different pacing outputs, the NF- and far-field His activation was identified on the ventricular aspect. Radiofrequency application was delivered at the NF His site in 8 (group 1) and the far-field His site in 7 dogs (group 2), followed by pathologic examination after 14 days. NF His activation was captured with 5 mA/1 ms in 10 and 10 mA/1 ms in 5 dogs. In group 1, radiofrequency delivery resulted in complete atrioventricular block in 3, right bundle branch block with HV (His-to-ventricular) interval prolongation in 1, and only right bundle branch block in 2 dogs, whereas no changes occurred in group 2. Pathologic examination in group-1 dogs showed complete or partial necrosis of the His bundle in 4 and complete necrosis of the right bundle branch in 5 dogs. In group 2, partial necrosis in the right bundle branch was found only in 1 dog. Using this pacing technique, the APs were 5.7±1.2 mm away from the His bundle located superiorly in 20 or inferiorly in 3 patients. All APs were successfully eliminated with 1 to 3 radiofrequency applications. No complications and recurrence occurred during a follow-up of 11.8±1.4 months. CONCLUSIONS: Differentiating the NF His from far-field His activations led to a high ablation success without atrioventricular block in para-Hisian AP patients.

Whole Genome Sequence Identified a Rare Homozygous Pathogenic Mutation of the DSG2 Gene in a Familial Arrhythmogenic Cardiomyopathy Involving Both Ventricles.

BACKGROUND: This study was designed to identify the pathogenic mutation in a Chinese family with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) using whole genome sequencing (WGS). METHODS AND RESULTS: Probands II:1 and II:2 underwent routine examinations for diagnosis. Genomic DNA was extracted from the peripheral blood of family members and analyzed using WGS. A total of 60,285 single-nucleotide polymorphisms (SNP) and 13,918 insertions/deletions (InDel) occurring in the exonic regions of genes and predisposing to cardiomyopathies and arrhythmias were identified. When filtered using the 1000 Genomes Project (2014 version), NHLBI ESP6500, and ExAC databases, 12 missense SNP and 2 InDel in exonic regions remained, the allele frequencies of which were <0.01 or unknown. The potentially pathogenic mutations that occurred in the genes DSG2, PKP4, PRKAG2, FOXD4, CTTN, and DMD, which were identified by SIFT or PolyPhen-2 software as "damaging," were validated using Sanger sequencing. Probands II:1 and II:2 shared an extremely rare homozygous mutation in the DSG2 (p.F531C) gene, which was also demonstrated using intersection analysis of WGS data from probands II:1 and II:2. Electron microscopy and histological staining of myocardial biopsies showed widened and destroyed intercalated discs, and interrupted, atrophic, and disarranged myocardial fibers, and hyperplastic interstitial fibers, collagen fibers, and adipocytes were infiltrated and invaded. CONCLUSIONS: A homozygous mutation of DSG2 p.F531C was identified as the pathogenic mutation in patients with ARVC/D involving both ventricles, as a result of widened and impaired intercalated discs, interrupted myocardial fibers, and abnormally hyperplastic interstitial fibers, collagen fibers, and adipocytes.

Long-Term Outcomes of Radio-Frequency Catheter Ablation on Ventricular Tachycardias Due to Arrhythmogenic Right Ventricular Cardiomyopathy: A Single Center Experience.

AIMS: To summarize our experience of radiofrequency catheter ablation (RFCA) for recurrent drug-refractory ventricular tachycardias (VTs) due to arrhythmogenic right ventricular cardiomyopathy (ARVC) in our center over the past 11 years and its related factors. METHODS AND RESULTS: We reviewed 48 adults (mean age 39.9 ± 12.9 years, range: 14 to 65) who met the present ARVC diagnostic criteria and accepted RFCA for VTs from December 2004 to April 2016. The patients received a total of 70 procedures using two ablation approaches, the endocardial approach in 52 RFCAs, and the combined epicardial and endocardial approach (the combined approach) in 18 RFCAs. Kaplan-Meier survival analysis showed that the combined approach achieved better acute procedural success (p = 0.003) and better long-term outcomes (p = 0.028) than the endocardial approach. Patients who obtained acute procedural success with non-inducibility had better long-term outcomes (p < 0.001). COX regression of multivariate analysis showed that procedural success was the only factor that benefited long-term outcome, irrespective of the endocardial or the combined approach (p = 0.001). The rate of sudden cardiac death (SCD) in patients without procedural success was significantly higher than that in patients with procedural success (p = 0.005). All patients without implantable cardioverter defibrillator (ICD) implantation who had successful final RFCA survived. CONCLUSIONS: The combined approach resulted in better procedural success and long-term VT-free survival compared with the endocardial approach in ARVC patients with recurrent VTs. Acute procedural success with non-inducibility was strongly related to better long-term VT-free survival and reduced SCD, irrespective of whether this was achieved by the endocardial approach or the combined approach.

Mapping and ablation of anteroseptal atrial tachycardia in patients with congenitally corrected transposition of the great arteries: implication of pulmonary sinus cusps.

AIMS: We sought to investigate focal atrial tachycardias (ATs) in patients with congenitally corrected transposition of the great arteries (ccTGA). METHODS AND RESULTS: We identified three cases of focal ATs with ccTGA from 2007 to 2015. The clinical findings, electrocardiography, electrophysiological features, and ablation were reported. All three cases had {S,L,L}-type ccTGA. The AT P waves shared the following features: narrow in width, positive in leads I and aVL, and negative/positive in lead V1. All ATs had focal activation pattern with early activation at the anteroseptal area, and further mapping demonstrated earliest atrial activation (EAA) inside the pulmonary sinus cusps (PSCs), especially the right PSC. In Cases 1 and 2, double potentials were recorded at the EAA sites. Conduction delay between the two potentials during atrial extrastimulus was observed. After successful ablation, the second potential during sinus rhythm was further delayed in Case 1 and was eliminated in Case 2. However, only one potential was recorded in Case 3. All three cases were successfully managed by ablating the sites with EAA, which preceded the P-wave onset by 60, 80, and 42 ms, respectively. During ablation, no junctional rhythm was observed. Incomplete left bundle branch block was induced during mapping in Case 1, but no other complications occurred. All patients were free from tachycardia during follow-up periods of 36, 7, and 5 months, respectively. CONCLUSION: Anteroseptal AT in patients with ccTGA could be eliminated by ablation inside the PSC.

A new electrophysiologic observation in patients with idiopathic left ventricular tachycardia.

BACKGROUND: In patients with idiopathic left ventricular tachycardia (ILVT), the arrhythmogenic substrate is poorly understood. OBJECTIVE: The purpose of this study was to elucidate the ILVT characteristics and outcome of radiofrequency catheter ablation in patients with ILVT. METHODS: Twenty-four patients with ILVT and 15 patients with left accessory pathways (control) underwent high-density mapping of the left His-Purkinje system during sinus rhythm (SR) using 3-dimensional electroanatomic mapping. RESULTS: Fragmented antegrade Purkinje potential (FAP) was represented at the left ventricular septum slightly inferoposterior to the left posterior fascicle (LPF) in 23 patients with ILVT. In control subjects, no FAPs could be recorded at the same region, FAPs were identified at the proximal portion of the LPF (4 patients) and at the distal LPF (1 patient). The finding of any FAPs in ILVT patients was significantly higher than that in control patients (23/24 vs 5/15, P < .01). Radiofrequency ablation at the area of FAP resulted in successful ablation in 23 patients with ILVT. No ILVT recurred during follow-up of 16.3 ± 7.2 months. CONCLUSION: In patients with ILVT, FAP located at the left ventricular septum slightly inferoposterior to the LPF is a novel finding using 3-dimensional electroanatomic mapping. The FAP may represent an arrhythmogenic substrate in ILVT and may be used for guiding successful ablation.