ABSTRACT Background The subcutaneous implantable cardioverter‐defibrillator (S‐ICD) avoids transvenous leads and is a promising option for sudden cardiac death (SCD) prevention in pediatric patients. However, mid‐term outcomes and post‐shock management strategies remain insufficiently characterized. Methods This multicenter, retrospective observational study included pediatric patients (≤ 18 years) who underwent S‐ICD implantation between February 2016 and July 2021. Clinical characteristics, pre‐implant screening, procedural details, device‐related events, and follow‐up data were analyzed. The incidence and management of appropriate and inappropriate therapies and subsequent recurrence were evaluated. Results Ninety‐six patients (median age 14.5 years) were enrolled and followed for a median of 70 months (29–75.0 months). Sensing vector suitability remained stable despite somatic growth. Appropriate shocks occurred in 32 patients (33.7%), while inappropriate shocks occurred in 27 (28.4%). After appropriate therapy, intensified pharmacological treatment and catheter ablation prevented recurrent device therapy in 45.5% and 50.0% of cases, respectively, although device shock occurred in 50.9% despite intervention. Following inappropriate therapy, device reprogramming and lifestyle guidance prevented recurrence in 71.4% of patients (15/21). Device‐related infection was rare (2 cases), and no lead fractures were observed. Conclusions S‐ICD therapy demonstrated favorable mid‐term safety and efficacy in pediatric patients, with durable sensing performance and a low incidence of device‐related infection. Although inappropriate shocks were not uncommon, appropriate post‐shock management effectively reduced recurrence, supporting S‐ICD as a viable option for selected pediatric patients without pacing requirements.

Background: In Japan, approximately 90,000 individuals die annually from sudden cardiac death (SCD). Predicting SCD using electronic health records (EHRs) from hospitals remains difficult. The growing use of wearable devices enables the continuous collection of personal health records (PHRs) and offers an opportunity to develop robust databases by integrating PHRs with EHRs. Applying artificial intelligence (AI) to these combined datasets may enable the early detection of SCD precursors. Objective: To develop an AI-based predictive model for SCD and related cardiovascular events by integrating PHRs with EHRs. Methods: We are prospectively enrolling high-risk patients—those with prior heart failure (HF), acute coronary syndrome (ACS), or out-of-hospital cardiac arrest—from seven Japanese centers. Participants use wearable devices (e.g., Fitbit, Apple Watch, or VINSTA ring) and home monitors to collect body weight and blood pressure. These data is integrated with EHRs, including clinical outcomes, laboratory tests, electrocardiograms, and echocardiograms. The primary endpoint is SCD, and the secondary endpoints include ACS, lethal arrhythmias, and hospitalization for HF. AI-based analysis was utilized to identify physiological changes preceding cardiovascular events. Results: From April 2024 to October 2025, 212 patients (mean age 58 ± 13 years; 77% male) were enrolled, yielding 167 person-years of follow-up. There were 12 cardiovascular events (3 HF, 3 ACS, 6 lethal arrhythmias) and no SCD. Temporary analysis revealed: 1. In HF, pulse rate increased from baseline 14 days prior, followed by weight gain seven days prior, and increased subjective symptoms three days before hospitalization. (Fig. 1) 2. In ACS, ST-segment depression detected by VINSTA ring appeared two days before the onset and resolved after treatment. (Fig. 2) 3. Event-positive participants showed higher mean pulse rate (81 ± 11 bpm vs. 70 ± 11 bpm; n = 4 vs. 66), greater orthostatic systolic drop (-2.3 ± 14.1 mmHg vs. -0.5 ± 7.2 mmHg; n = 2 vs. 19), and more frequent reports of subjective symptoms (1.9 ± 1.4 items vs. 0.7 ± 1.4 items; n = 4 vs. 57) seven days prior to the events. (Fig.3) Discussion: Integrating PHRs with EHRs enables continuous, personalized monitoring and early detection of cardiovascular deterioration. AI-driven analysis of these multimodal data may substantially enhance SCD risk prediction and support timely interventions to prevent adverse events.

Journal Article Sex-specific clinical course of young patients with Brugada syndrome Get access Tomohiko Imamura, Tomohiko Imamura Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JapanDepartment of Pediatric Cardiology, Saitama Medical University International Medical Center, Hidaka, JapanDepartment of Preventive Services, Kyoto University School of Public Health, Kyoto, Japan https://orcid.org/0000-0003-0197-0597 Search for other works by this author on: Oxford Academic PubMed Google Scholar Takeru Makiyama, Takeru Makiyama Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JapanDepartment of Community Medicine Supporting System, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan Corresponding author. Tel: +81 75 751 3196, Fax: +81 75 751 3299, Email: [email protected] https://orcid.org/0000-0002-9471-5335 Search for other works by this author on: Oxford Academic PubMed Google Scholar Junichi Ozawa, Junichi Ozawa Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan https://orcid.org/0000-0002-6149-2649 Search for other works by this author on: Oxford Academic PubMed Google Scholar Keiko Sonoda, Keiko Sonoda Medical Genome Center, National Cerebral and Cardiovascular Center, Suita, Japan https://orcid.org/0000-0002-7015-5839 Search for other works by this author on: Oxford Academic PubMed Google Scholar Koichi Kato, Koichi Kato Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan https://orcid.org/0000-0002-6125-0789 Search for other works by this author on: Oxford Academic PubMed Google Scholar Takanori Aizawa, Takanori Aizawa Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JapanResearch Unit on Cardiovascular and Metabolic Diseases, Sorbonne Université, Paris, France https://orcid.org/0000-0001-5192-3962 Search for other works by this author on: Oxford Academic PubMed Google Scholar Asami Kashiwa, Asami Kashiwa Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JapanDepartment of Cardiology, Niigata City Hospital, Niigata, Japan https://orcid.org/0000-0001-9562-8981 Search for other works by this author on: Oxford Academic PubMed Google Scholar Jingshan Gao, Jingshan Gao Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JapanStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA https://orcid.org/0000-0003-1599-7803 Search for other works by this author on: Oxford Academic PubMed Google Scholar Hai Huang, Hai Huang Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan https://orcid.org/0000-0003-2693-6993 Search for other works by this author on: Oxford Academic PubMed Google Scholar Yuta Yamamoto, Yuta Yamamoto Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA https://orcid.org/0000-0001-6129-9745 Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Hirohiko Kohjitani, Hirohiko Kohjitani Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JapanDepartment of Biomedical Data Intelligence, Kyoto University Graduate School of Medicine, Kyoto, Japan https://orcid.org/0000-0002-8281-8396 Search for other works by this author on: Oxford Academic PubMed Google Scholar Hisaaki Aoki, Hisaaki Aoki Department of Pediatric Cardiology, Osaka Women's and Children's Hospital, Izumi, Japan https://orcid.org/0000-0002-3083-4597 Search for other works by this author on: Oxford Academic PubMed Google Scholar Seiichi Watanabe, Seiichi Watanabe Department of Pediatrics, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Shota Muraji, Shota Muraji Department of Pediatric Cardiology, Saitama Medical University International Medical Center, Hidaka, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Takuro Kojima, Takuro Kojima Department of Pediatric Cardiology, Saitama Medical University International Medical Center, Hidaka, Japan https://orcid.org/0000-0003-0110-2562 Search for other works by this author on: Oxford Academic PubMed Google Scholar Masao Yoshinaga, Masao Yoshinaga Department of Pediatrics, Kagoshima Medical Center, Kagoshima, Japan https://orcid.org/0000-0002-5054-6074 Search for other works by this author on: Oxford Academic PubMed Google Scholar Seiko Ohno, Seiko Ohno Medical Genome Center, National Cerebral and Cardiovascular Center, Suita, Japan https://orcid.org/0000-0003-1209-8896 Search for other works by this author on: Oxford Academic PubMed Google Scholar Hiroshi Suzuki, Hiroshi Suzuki Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan https://orcid.org/0000-0002-0694-6193 Search for other works by this author on: Oxford Academic PubMed Google Scholar Naokata Sumitomo, Naokata Sumitomo Department of Pediatric Cardiology, Saitama Medical University International Medical Center, Hidaka, Japan https://orcid.org/0000-0001-7094-6772 Search for other works by this author on: Oxford Academic PubMed Google Scholar Yoshihisa Nakagawa, Yoshihisa Nakagawa Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan https://orcid.org/0000-0002-9411-9314 Search for other works by this author on: Oxford Academic PubMed Google Scholar Koh Ono, Koh Ono Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan https://orcid.org/0000-0002-4163-980X Search for other works by this author on: Oxford Academic PubMed Google Scholar Minoru Horie, Minoru Horie Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan https://orcid.org/0000-0002-9029-2339 Search for other works by this author on: Oxford Academic PubMed Google Scholar Takeshi Kimura Takeshi Kimura Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JapanDepartment of Cardiology, Hirakata Kohsai Hospital, Hirakata, Japan https://orcid.org/0000-0002-5665-4076 Search for other works by this author on: Oxford Academic PubMed Google Scholar European Heart Journal, ehae739, https://doi.org/10.1093/eurheartj/ehae739 Published: 05 February 2025 Article history Received: 31 August 2024 Revision received: 28 September 2024 Accepted: 10 October 2024 Published: 05 February 2025

AIMS:The variant in SCN5A with the loss of function (LOF) effect in the cardiac Na+ channel (Nav1.5) is the definitive cause for Brugada syndrome (BrS), and the functional analysis data revealed that LOF variants are associated with poor prognosis. However, which variant types (e.g. missense or non-missense) affect the prognoses of those variant carriers remain unelucidated. METHODS AND RESULTS:We defined SCN5A LOF variants as all non-missense and missense variants that produce peak INa < 65% of wild-type previously confirmed by patch-clamp studies. The study population consisted of 76 Japanese BrS patients (74% patients were male and the median age [IQR] at diagnosis was 28 [14-45] years) with LOF type of SCN5A variants: 40 with missense and 36 with non-missense variants. Non-missense variant carriers presented significantly more severe cardiac conduction disorder compared to the missense variant carriers. During follow-up periods of 9.0 [5.0-14.0] years, compared to missense variants, non-missense variants were significant risk factors of lifetime lethal arrhythmia events (LAEs) (P = 0.023). When focusing only on the missense variants that produce no peak INa, these missense variant carriers exhibited the same clinical outcomes as those with non-missense (log-rank P = 0.325). After diagnosis, however, both variant types were comparable in risk of LAEs (P = 0.155). CONCLUSION:We identified, for the first time, that SCN5A non-missense variants were associated with higher probability of LAE than missense variants in BrS patients though it did not change significantly after diagnosis.

Brugada症候群(BrS)と不整脈原性右室心筋症(ARVC)は,特異的な心電図所見と致死性不整脈を呈する遺伝性心疾患である.BrSの約15~20%にSCN5A遺伝子の機能喪失型変異が検出され,右室流出路の貫壁性活動電位勾配をもとにした再分極障害と,右室流出路心外膜側の線維化とGap結合の異常による脱分極障害がcoved型ST上昇や不整脈基質の原因となる.中年期の発症が多く,頻度は男性で8~10倍多い.この性差にはテストステロンが関与するが,女性ではエストラジオールが保護的に作用する可能性がある.ARVCは,主にデスモソーム関連遺伝子の異常により発症し,細胞間接着の不安定化とWnt/β-catenin経路の異常により心筋細胞が線維脂肪変性する.これに伴い,右側胸部誘導のε波や陰性T波が現れる.右室病変主体のARVCはrevised Task Force criteriaを用いて診断し,左室や両心室に病変を認める症例はPadua criteriaで診断する.小児のBrSやARVCは稀だが,致死性不整脈の頻度は成人より高い.小児症例のエビデンス蓄積が期待される.

Abstract Background Pituitary homeobox 2 (PITX2) encoded by PITX2, is one of the transcription factors and plays an important role in establishing the left-right axis during development. In the heart, PITX2 inhibits the development of the sinoatrial node (SAN) in the left atrium, whereas the absence of PITX2 allows the development of SAN in the right atrium. In a multicenter study, we recently identified a sizeable intergenic deletion between PITX2 and ANK2 on chromosome 4q25 in familial sinus node dysfunction (SND). The deletion contains a CTCF-binding motif (19 bps) which forms a topologically associating domain (TAD) involved in PITX2, and putatively disrupts the TAD. In order to investigate how the intergenic deletion causes SND, we analyzed iPS cells (iPSCs) by specifically differentiating them into SAN cardiomyocytes. Methods and results We identified an intergenic heterozygous deletion of 30k bps in a Japanese family with SND by whole genome sequencing. In the SND family, all 11 genetically affected patients developed SND since childhood, and seven of them underwent pacemaker implantation (the mean age was 26). To elucidate the pathology, we utilized 3 iPSC lines: an iPSC line from a patient, a homozygous CTCF-binding motif knockout line by gene editing, and a control line from a healthy volunteer. We modified the previously reported SAN differentiation protocol1 and generated SAN-like iPSC-derived cardiomyocytes (SANLCMs). SANLCMs showed a higher beating rate than ventricular-like cardiomyocytes (VLCMs), and exhibited SAN-like action potential morphology recorded using a patch-clamp technique. SANLCMs contained lesser NKX2-5 positive cells than VLCMs by immunostaining analysis and their gene expression patterns were compatible with SAN cardiomyocytes: higher expression levels of SHOX2, TBX18, TBX3, and HCN4, and lower expression levels of PITX2, NKX2-5, and MYL2 compared with VLCMs. Then, we analyzed the gene expression profiles during the SAN differentiation. SANLCMs from CTCF-binding motif knockout iPSC lines showed lower beating rates than controls. We also found that the levels of PITX2 expression in SANLCMs from patient-derived and CTCF-binding motif knockout iPSC lines were significantly higher compared to those from the control. Conclusion Our findings suggest that the lack of CTCF-binding motif involved in a large intergenic deletion on chromosome 4q25 might be associated with a hypoplasia of SAN via PITX2 overexpression during cardiac development.

AIMS More than one-third of type 2 long QT syndrome (LQT2) patients carry KCNH2 non-missense variants that can result in haploinsufficiency (HI), leading to mechanistic loss-of-function. However, their clinical phenotypes have not been fully investigated. The remaining two-thirds of patients harbour missense variants, and past studies uncovered that most of these variants cause trafficking deficiency, resulting in different functional changes: either HI or dominant-negative (DN) effects. In this study, we examined the impact of altered molecular mechanisms on clinical outcomes in LQT2 patients. METHODS AND RESULTS We included 429 LQT2 patients (234 probands) carrying a rare KCNH2 variant from our patient cohort undergoing genetic testing. Non-missense variants showed shorter corrected QT (QTc) and less arrhythmic events (AEs) than missense variants. We found that 40% of missense variants in this study were previously reported as HI or DN. Non-missense and HI-groups had similar phenotypes, while both exhibited shorter QTc and less AEs than the DN-group. Based on previous work, we predicted the functional change of the unreported variants-whether they cause HI or DN via altered functional domains-and stratified them as predicted HI (pHI)- or pDN-group. The pHI-group including non-missense variants exhibited milder phenotypes compared to the pDN-group. Multivariable Cox model showed that the functional change was an independent risk of AEs (P = 0.005). CONCLUSION Stratification based on molecular biological studies enables us to better predict clinical outcomes in the patients with LQT2.

Background: In adult patients, subcutaneous implantable cardioverter defibrillators (S-ICDs) have been reported to be non-inferior to transvenous ICDs with respect to the incidence of device-related complications and inap-propriate shocks. Only a few reports have investigated the efficacy of S-ICDs in the pediatric field. This study aimed to investigate the utility and safety of S-ICDs in patients <= 18 years old.Methods: This study was a multicenter, observational, retrospective study on S-ICD implantations. Patients <18 years old who underwent S-ICD implantations were enrolled. The detailed data on the device implantations and eligibility tests, incidence of appropriate-and inappropriate shocks, and follow-up data were assessed.Results: A total of 62 patients were enrolled from 30 centers. The patients ranged in age from 3 to 18 (median 14 years old [IQR 11.0-16.0 years]). During a median follow up of 27 months (13.3-35.8), a total of 16 patients (26.2%) received appropriate shocks and 13 (21.3%) received inappropriate shocks. The common causes of the inappropriate shocks were sinus tachycardia (n = 4, 30.8%) and T-wave oversensing (n = 4, 30.8%). In spite of the physical growth, the number of suitable sensing vectors did not change during the follow up. No one had any lead fractures or device infections in the chronic phase.Conclusions: Our study suggested that S-ICDs can prevent sudden cardiac death in the pediatric population with a low incidence of lead complications or device infections. The number of suitable sensing vectors did not change during the patients' growth.

Background: CaM (calmodulin) is a ubiquitously expressed, multifunctional Ca 2+ sensor protein that regulates numerous proteins. Recently, CaM missense variants have been identified in patients with malignant inherited arrhythmias, such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the exact mechanism of CaM-related CPVT in human cardiomyocytes remains unclear. In this study, we sought to investigate the arrhythmogenic mechanism of CPVT caused by a novel variant using human induced pluripotent stem cell (iPSC) models and biochemical assays. Methods: We generated iPSCs from a patient with CPVT bearing CALM2 p.E46K. As comparisons, we used 2 control lines including an isogenic line, and another iPSC line from a patient with long QT syndrome bearing CALM2 p.N98S (also reported in CPVT). Electrophysiological properties were investigated using iPSC-cardiomyocytes. We further examined the RyR2 (ryanodine receptor 2) and Ca 2+ affinities of CaM using recombinant proteins. Results: We identified a novel de novo heterozygous variant, CALM2 p.E46K, in 2 unrelated patients with CPVT accompanied by neurodevelopmental disorders. The E46K-cardiomyocytes exhibited more frequent abnormal electrical excitations and Ca 2+ waves than the other lines in association with increased Ca 2+ leakage from the sarcoplasmic reticulum via RyR2. Furthermore, the [ 3 H]ryanodine binding assay revealed that E46K-CaM facilitated RyR2 function especially by activating at low [Ca 2+ ] levels. The real-time CaM-RyR2 binding analysis demonstrated that E46K-CaM had a 10-fold increased RyR2 binding affinity compared with wild-type CaM which may account for the dominant effect of the mutant CaM. Additionally, the E46K-CaM did not affect CaM-Ca 2+ binding or L-type calcium channel function. Finally, antiarrhythmic agents, nadolol and flecainide, suppressed abnormal Ca 2+ waves in E46K-cardiomyocytes. Conclusions: We, for the first time, established a CaM-related CPVT iPSC-CM model which recapitulated severe arrhythmogenic features resulting from E46K-CaM dominantly binding and facilitating RyR2. In addition, the findings in iPSC-based drug testing will contribute to precision medicine.

BACKGROUND A missense mutation in the alpha 1c subunit of voltage-gated L-type Ca2+ channel-coding CACNA1C-E1115K, located in the Ca2+ selectivity site, causes a variety of arrhythmogenic phenotypes. OBJECTIVE We aimed to investigate the electrophysiological features and pathophysiological mechanisms of CACNA1C-E1115K in patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). METHODS We generated iPSCs from a patient carrying heterozygous CACNA1C-E1115K with overlapping phenotypes of long QT syndrome, Brugada syndrome, and mild cardiac dysfunction. Electrophysiological properties were investigated using iPSC-CMs. We used iPSCs from a healthy individual and an isogenic iPSC line corrected using CRISPR-Cas9-mediated gene editing as controls. A mathematical E1115K-CM model was developed using a human ventricular cell model. RESULTS Patch-clamp analysis revealed that E1115K-iPSC-CMs exhibited reduced peak Ca2+ current density and impaired Ca2+ selectivity with an increased permeability to monovalent cations. Consequently, E1115K-iPSC-CMs showed decreased action potential plateau amplitude, longer action potential duration (APD), and a higher frequency of early afterdepolarization compared with controls. In optical recordings examining the antiarrhythmic drug effect, late Na+ channel current (I-NaL) inhibitors (mexiletine and GS-458967) shortened APDs specifically in E1115K-iPSC-CMs. The AP-clamp using a voltage command obtained from E1115K-iPSC-CMs with lower action potential plateau amplitude and longer APD confirmed the upregulation of I-NaL. An in silico study recapitulated the in vitro electrophysiological properties. CONCLUSION Our iPSC-based analysis in CACNA1C-E1115K with disrupted Ca(V)1.2 selectivity demonstrated that the aberrant currents through the mutant channels carried by monovalent cations resulted in specific action potential changes, which increased endogenous I-NaL, thereby synergistically contributing to the arrhythmogenic phenotype.

Brugada syndrome (BrS) is an inherited arrhythmia that is characterized by male predominance and life-threatening arrhythmic events (LAEs) mainly in middle age. Children with BrS are rare, therefore, the clinical features and sex differences remain unclear.

OBJECTIVES:This study aimed to investigate the clinical characteristics of young patients with Brugada syndrome (BrS) with ventricular septal defect (VSD) and explore their genetic backgrounds. BACKGROUND:VSD is the most frequently occurring congenital heart disease among children. In contrast, BrS is a rare hereditary disease that is responsible for ventricular fibrillation and sudden cardiac death. Owing to their low incidence, the genetic background and clinical characteristics of patients with BrS with VSD have not been elucidated yet. METHODS:This study enrolled 36 individuals who were diagnosed with BrS when they were <20 years of age and performed genetic screening for SCN5A. The functional alteration in mutant Na+ channels was confirmed by patch clamp technique. RESULTS:Among the 36 patients with BrS, 5 had been diagnosed with VSD. This study found 14 heterozygous SCN5A variants in 15 unrelated patients. The 5 patients with VSD carried SCN5A variants, including R367S, R535∗, R893C, W1345C, and G1743R. The 3 missense variants (R893C, W1345C, and G1743R) have been proved to reduce peak Na+ current to <10%. A functional analysis of SCN5A R367S was performed and the variant was found to be nonfunctional. CONCLUSIONS:This study identified 5 loss-of-function SCN5A variants in 5 young patients with BrS with VSD. The study hypothesizes that altered blood flow in the right ventricular outflow tract leads to fibrosis and electrophysiological changes, predisposing the patients to earlier clinical presentation of BrS. In patients with VSD and ST-segment elevation in the right precordial leads, BrS should be considered and appropriate screening should be pursued accordingly.

Restrictive cardiomyopathy (RCM) is a rare myocardial disease with an impaired diastolic function and poor prognosis. Almost all RCM patients are reported to have abnormal P-waves due to atrial overloading. This study aimed to reveal the characteristics of the P-waves in RCM patients and to suggest the diagnostic index of RCM in children with a 12-lead electrocardiogram (ECG). We retrospectively investigated 17 ECGs of children with idiopathic RCM during the initial visit at 15 institutes in Japan between 1979 and 2013. The RCM group was divided into four groups based on the age (elementary school [ES] and junior high school [JHS] students) and inception of the diagnosis (abnormal ECG on school-heart-screening [e-RCM] and some cardiovascular symptoms [s-RCM]), the ES/e-RCM (n = 5), ES/s-RCM (n = 4), JHS/e-RCM (n = 4), and JHS/s-RCM (n = 4) groups. As an aged-match control group, school-heart-screening ECGs of 1st-grade ES students (16,770 students) and 1st-grade JHS students (18,126 students) from Kagoshima in 2016 were adopted. For a comparison between the groups, we used the effect size "Hedge's g" by calculating the mean and standard deviation of the two groups. An effect size of 0.8 (or above) had an overlap of 53% (or less). The effect sizes of the sum of the absolute values of the forward and backward amplitudes in lead V1 (P1 + P2 V1) was the largest, and the ES/e-RCM, ES/s-RCM, JHS/e-RCM, and JHS/s-RCM were 15.8, 22.1, 9.4, and 10.3, respectively. A P1 + P2 V1 > 200 μV was able to rule in all RCM patients, thus, we proposed 200 µV as the cutoff value for screening purposes. In conclusion, the P1 + P2 V1 in the school-heart-screening may be useful for detecting asymptomatic or early-stage RCM in school-age children.

Transcatheter atrial septal defect (ASD) closures using an Amplatzer Septal Occluder (ASO) have been widely performed. Compared to children, we sometimes experience late recovery of exercise performance in adult patients. Our study aimed to evaluate the change in the cardiopulmonary exercise capacity in asymptomatic or mildly symptomatic adult patients after a transcatheter ASD closure using an ASO. The subjects consisted of 29 patients (age 39.5 ± 13.6 years) that underwent cardiopulmonary exercise testing (CPX) before, 3, 6, and 12 months after a transcatheter secundum ASD closure using an ASO. The peak oxygen consumption (peak VO2), anaerobic threshold (AT), and slope of the correlation between the ventilation and carbon dioxide production (VE/VCO2 slope) were evaluated. We also evaluated the left-ventricular end-diastolic diameter (LVEDD), right-ventricular end-diastolic dimension (RVEDD) by echocardiography, and hemodynamic values by cardiac catheterization before the ASO procedure. The peak VO2 did not show any improvement 3 months after the ASO procedure; however, a significant improvement was displayed 6 and 12 months (baseline: 23.4 ± 6.3, 3 months: 23.6 ± 6.4, 6 months: 25.1 ± 5.6, 12 months: 26.4 ± 5.3 mL/kg/min; p < 0.001) after the ASO. The LVEDD (before: 38.1 ± 3.6, 3 months: 43.4 ± 3.4 mm; p < 0.001) and RVEDD (before: 33.6 ± 5.3, 3 months: 26.3 ± 2.6 mm; p < 0.001) on echocardiography quickly improved 3 months after the ASO. Although the LVEDD and RVEDD normalized 3 months after the ASO, the peak VO2 still decreased; however, the peak VO2 improved to almost a normal range 6 months after the ASO.

Calmodulin (CaM) is a ubiquitous Ca2+ sensor molecule encoded by three distinct calmodulin genes, CALM1–3, and has an important role for cardiac ion channel function. Recently, heterozygous missense mutations in CALM genes were reported to cause a new category of life-threatening genetic arrhythmias such as long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), which is called as “calmodulinopathy”. The patients with calmodulinopathy show poor prognosis and there is no effective treatment for them. Considering the dominant-negative effect of mutant calmodulin proteins produced by heterozygous missense mutations in CALMs, we aimed to prove the concept of antisense-based therapy to treat calmodulinopathy using human iPS cell-derived cardiomyocyte (hiPSC-CM) model. We designed multiple locked nucleic acid (LNA) gapmer-antisense oligonucleotides (ASOs) targeting CALM2 and analyzed the silencing efficiency and toxicity in cultured cells to select the most potent ASO. Using CMs differentiated from hiPSCs which were generated form a 12-year-old boy with LQTS carrying a heterozygous CALM2-N98S mutation, CALM2 expression and action potentials (APs) were analyzed to evaluate the efficacy of ASOs. We identified several ASOs which reduced CALM2 expression without affecting cell viability in human cultured cells (HepG2) (ASO 50 nM, n=2; Figure 1A). Considering further experiments in vivo mouse model, we investigated the CALM2 silencing activity in mouse cultured cells (3T3-L1) without transfection (free-uptake) (ASO 1 μM, n=2; †ASOs have homologous sequence between human and mouse; Figure B). After free-uptake CALM2 silencing analysis in 3T3-L1 cells, we identified that ASO #2 has the most potent CALM2 silencing activity and low cytotoxicity (Figure 1B). ASO #2 effectively reduced CALM2 expression even in hiPSC-CMs (ASO(−): n=3, lipofection: n=4, free-uptake: n=3; P<0.05; Figure 1C). In action potential recordings, we demonstrated that ASO #2 ameliorated prolonged AP durations (APD90) in N98S-hiPSC-CMs at 0.5 Hz pacing (ASO(−): 666±123 ms (n=7), lipofection: 329±21 ms (n=8), free-uptake: 388±34 ms (n=12); P<0.05; Figure 1D). Our results using patient-derived hiPSC-CM model suggest that ASO-based therapy might be a promising strategy for the treatment of calmodulinopathy. Figure 1 Type of funding source: Private company. Main funding source(s): Nissan Chemical Corporation

Abstract Background A missense mutation, CACNA1C-E1115K, located in the cardiac L-type calcium channel (LTCC), was recently reported to be associated with diverse arrhythmias. Several studies reported in-vivo and in-vitro modeling of this mutation, but actual mechanism and target drug of this disease has not been clarified due to its complex ion-mechanisms. Objective To reveal the mechanism of this diverse arrhythmogenic phenotype using combination of in-vitro and in-silico model. Methods and results Cell-Engineering Phase: We generated human induced pluripotent stem cell (hiPSC) from a patient carrying heterozygous CACNA1C-E1115K and differentiated into cardiomyocytes. Spontaneous APs were recorded from spontaneously beating single cardiomyocytes by using the perforated patch-clamp technique. Mathematical-Modeling Phase: We newly developed ICaL-mutation mathematical model, fitted into experimental data, including its impaired ion selectivity. Furthermore, we installed this mathematical model into hiPSC-CM simulation model. Collaboration Phase: Mutant in-silico model showed APD prolongation and frequent early afterdepolarization (EAD), which are same as in-vitro model. In-silico model revealed this EAD was mostly related to robust late-mode of sodium current occurred by Na+ overload and suggested that mexiletine is capable of reducing arrhythmia. Afterward, we applicated mexiletine onto hiPSC-CMs mutant model and found mexiletine suppress EADs. Conclusions Precise in-silico disease model can elucidate complicated ion currents and contribute predicting result of drug-testing. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists

An 18-year-old male who had a past medical history of an intracardiac total cavopulmonary connection (TCPC) operation was referred to our hospital for radiofrequency catheter ablation (RFCA) of supraventricular tachycardia (SVT). Two types of SVTs were induced, and 3-dimensional (3D) maps were created using an ultra-high-density 3-dimensional mapping system (Rhythmia). The earliest atrial activation site (EAAS) of SVT1 was at the superior part of the conduit, and the EAAS of SVT2 was at the inferior part of the single atrium (SA). The SVTs were terminated by energy deliveries to the EAAS from the conduit in SVT1 and from inside the single atrium in SVT2. Detailed maps of the SVTs were important to understand the mechanisms of the SVTs. The Rhythmia system was useful for the detailed mapping of complex arrhythmias. The use of Rhythmia in patients after a TCPC is difficult, because puncturing the TCPC conduit and proceeding and manipulating the Orion catheter via a narrow puncture hole are difficult. We were the first to succeed in ablating two atrial tachycardias (ATs) originating from the inside and outside of the conduit after a TCPC operation by using an ultra-high-density 3-dimensional mapping system.

BACKGROUND:T-wave inversion (TWI) is not considered useful for diagnosing pediatric arrhythmogenic right ventricular cardiomyopathy (ARVC), because right precordial TWI in ARVC resembles a normal juvenile pattern. OBJECTIVES:The aims of this study were to clarify the electrocardiographic (ECG) characteristics of pediatric ARVC to distinguish those patients from healthy children. METHODS:Between 1979 and 2017, 11 ARVC patients under 18 years old were registered and compared with school screening ECGs from 48,401 healthy children. RESULTS:The mean age at the first arrhythmic event or diagnosis was 13.3 ± 4.7 years. Nine patients were asymptomatic initially and were found by ECG screening, but 6 developed severe symptoms during the follow-up. Healthy children had a normal juvenile pattern, while ARVC children, especially symptomatic patients, had a significant tendency to have inferior and anterior TWI. The phenomenon of T-wave discontinuity (TWD) in which the TWI became deeper from V1 to V3 and suddenly turned positive in V5 was significantly more frequent in ARVC (60%) than healthy children (0.55%). Anterior TWI and TWD were also significantly more frequent in those who developed severe symptoms. The sensitivity and specificity of TWD were 60% (95% CI, 31-83%), and 99% (95% CI, 99-99%) to distinguish ARVC from healthy children, as well as 100% (95% CI, 71-100%) and 80% (95% CI, 51-80%), respectively, to predict severe symptoms in the future. CONCLUSIONS:The ECG is useful to distinguish ARVC children, even in the early phase. Anterior TWI and TWD could detect ARVC children and to predict the possible serious conditions.

Abstract Introduction Brugada syndrome (BrS) is an inherited arrhythmia characterized by a coved-type ST elevation and sudden death, especially in middle-aged males and more common in Asia. Mutations in SCN5A are detected in 15–20% and reported to be associated with poor prognosis. Among children, BrS is rare and the risk factors in pediatric BrS are unknown, especially in Asian population. Purpose The purpose of this study is to elucidate the risk factors for fatal arrhythmic events in Japanese pediatric patients with BrS. Methods We enrolled 52 Japanese children with BrS younger than 20 years, and performed genetic analysis and collected the clinical information. Results The mean age of initial symptoms was 10.7±5.5 years, and the mean follow-up period was 3.9±5.5 years. Ninety percent of patients were probands. No subjective symptom was confirmed in 28 of the patients, but aborted cardiac arrest (ACA) in 4, ventricular tachycardia in 4, ventricular fibrillation in 1, and syncope in 11. We identified mutations in SCN5A in 63%. There was no significant gender difference in ≤10 years, but a significant male predominance appeared in >10 years. And no gender difference was confirmed in the incidence of severe cardiac events in ≤10 years. Conclusion No gender difference was confirmed in ≤10 years in this study about Asian children. And being girls did not reduce the risk in ≤10 years. The frequency of SCN5A mutations was higher than adults, but decreased from childhood (68%) to adolescence (59%). In BrS, genetical and environmental factors may be more effective in childhood and adulthood, respectively. Funding Acknowledgement Type of funding source: None