Publications by authors named "Nobue Yagihara"

33 Publications

Progressive increase in activation delay during premature stimulation is related to ventricular fibrillation in Brugada syndrome.

J Cardiovasc Electrophysiol 2021 Apr 29. Epub 2021 Apr 29.

Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Introduction: The local conduction delay has been deemed to play an important role in the perpetuation of ventricular fibrillation (VF) in Brugada syndrome (BrS). We evaluated the relationship between the activation delay during programmed stimulation and cardiac events in BrS patients.

Methods: This study included 47 consecutive BrS patients who underwent an electrophysiological study and received implantable cardiac defibrillator therapy. We divided the patients into two groups based on whether they had developed VF (11 patients) or not (36 patients) during the follow-up period of 89 ± 53 months. The activation delay was assessed using the interval between the stimulus and the QRS onset during programmed stimulation. The mean increase in delay (MID) was used to characterize the conduction curves.

Results: The MID at the right ventricular outflow tract (RVOT) was significantly greater in patients with VF (4.5 ± 1.2 ms) than in those without VF (2.2 ± 0.9 ms) (p < .001). A receiver operating characteristics curve analysis indicated that the optimal cut-off point for discriminating VF occurrence was 3.3 with 88.9% sensitivity and 91.3% specificity. Furthermore, patients with an MID at the RVOT ≥ 3.3 ms showed significantly higher rates of VF recurrence than those with an MID at the RVOT < 3.3 ms (p < .001). The clinical characteristics, including the signal-averaged electrocardiogram measurement and VF inducibility were similar between the two groups.

Conclusion: A prolonged MID at the RVOT was associated with VF and maybe an additional electrophysiological risk factor for VF in BrS patients.
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http://dx.doi.org/10.1111/jce.15065DOI Listing
April 2021

J point elevation in high precordial leads associated with risk of ventricular fibrillation.

Ann Noninvasive Electrocardiol 2020 Dec 27:e12820. Epub 2020 Dec 27.

Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicineof Medical and Dental Sciences, Tokyo.

Introduction: The significance of high precordial electrocardiograms in idiopathic ventricular fibrillation (IVF) is unknown.

Method: This study included 50 consecutive patients (48 men; age, 42 ± 18 years) who had spontaneous ventricular fibrillation not linked to structural heart disease and received implantable cardiac defibrillator therapy. IVF was diagnosed in 35 patients and Brugada syndrome was diagnosed in other 15 patients. Electrocardiograms in high intercostal space were compared between 35 patients with IVF and 105 age- and sex-matched healthy controls (patient: control ratio, 1:3).

Results: The frequency of J point elevation ≥ 0.1 mV in the 4th intercostal spaces was similar between patients with IVF (14%) and healthy controls (7%). However, the frequency of J point elevation ≥ 0.1 mV in the 3rd intercostal space was higher in patients with IVF (40%) than controls (11%) (p < .01). J point elevation was present only in the 3rd intercostal space but not in the 4th intercostal space in 30% of patients with IVF but only in 6% of controls (p < .01). During follow-up, the recurrence of ventricular fibrillation was higher in patients with IVF who had J point elevation in the 3rd intercostal space (36%) and Brugada syndrome(40%) than those with IVF who did not have J point elevation in the 3rd intercostal space(11%) (p < .05 for both).

Conclusion: J point elevation in the 3rd intercostal space was associated with IVF and recurrences of ventricular fibrillation. Electrocardiogram recordings in the high intercostal space may be useful to identify risk of sudden death.
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http://dx.doi.org/10.1111/anec.12820DOI Listing
December 2020

Systematic Evaluation of Variant Using ACMG/AMP Guidelines and Risk Stratification in Long QT Syndrome Type 1.

Circ Genom Precis Med 2020 Sep 16. Epub 2020 Sep 16.

Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Suita, Japan.

- Mutation/variant-site specific risk stratification in long-QT syndrome type 1 (LQT1) has been well investigated, but it is still challenging to adapt current enormous genomic information to clinical aspects caused by each mutation/variant. We assessed a novel variant-specific risk stratification in LQT1 patients. - We classified a pathogenicity of 141 variants among 927 LQT1 patients (536 probands) based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines and evaluated whether the ACMG/AMP-based classification was associated with arrhythmic risk in LQT1 patients. - Among 141 variants, 61 (43.3%), 55 (39.0%), and 25 (17.7%) variants were classified into pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS), respectively. Multivariable analysis showed that proband (HR = 2.53; 95%CI = 1.94-3.32; p <0.0001), longer QTc (≥500ms) (HR = 1.44; 95%CI = 1.13-1.83; p = 0.004), variants at membrane spanning (MS) (vs. those at N/C terminus) (HR = 1.42; 95%CI = 1.08-1.88; p = 0.01), C-loop (vs. N/C terminus) (HR = 1.52; 95%CI = 1.06-2.16; p = 0.02), and P variants [(vs. LP) (HR = 1.72; 95%CI = 1.32-2.26; p <0.0001), (vs. VUS) (HR = 1.81; 95%CI = 1.15-2.99; p = 0.009)] were significantly associated with syncopal events. The ACMG/AMP-based evaluation was useful for risk stratification not only in family members but also in probands. A clinical score (0~4) based on proband, QTc (≥500ms), variant location (MS or C-loop) and P variant by ACMG/AMP guidelines allowed identification of patients more likely to have arrhythmic events. - Comprehensive evaluation of clinical findings and pathogenicity of variants based on the ACMG/AMP-based evaluation may stratify arrhythmic risk of congenital long-QT syndrome type 1.
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http://dx.doi.org/10.1161/CIRCGEN.120.002926DOI Listing
September 2020

Suppression of cardiac memory-related severe form of torsades de pointes by landiolol in a patient with congenital long QT syndrome type 2.

HeartRhythm Case Rep 2020 Jul 6;6(7):407-410. Epub 2020 Apr 6.

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

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http://dx.doi.org/10.1016/j.hrcr.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360983PMC
July 2020

Replacement of an Implantable Cardioverter-Defibrillator (ICD) with a New Standard Subcutaneous ICD System in a Patient with Jervell and Lange-Nielsen Syndrome.

Int Heart J 2019 Sep 4;60(5):1206-1210. Epub 2019 Sep 4.

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences.

A 7-year-old female suffering from syncope attacks and deafness was genetically diagnosed with Jervell and Lange-Nielsen syndrome (JLNS). A transvenous-designed shock lead and implantable cardioverter-defibrillator (ICD) were atypically implanted subcutaneously, because the patient's body was small. Six years after implantation, we confirmed the patient's eligibility for a subcutaneous ICD (S-ICD) based on electrocardiogram screening. The implanted ICD system was replaced with a new standard S-ICD system. Implantation of the S-ICD may be considered a reliable and safe option in young patients with JLNS, even if their electrocardiograms show remarkable prolongation of the QT interval and T-wave alternans.
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http://dx.doi.org/10.1536/ihj.19-076DOI Listing
September 2019

Early repolarization and risk of lone atrial fibrillation.

J Cardiovasc Electrophysiol 2019 04 25;30(4):565-568. Epub 2019 Jan 25.

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Introduction: Early repolarization syndrome is a recently proposed condition characterized by an early repolarization pattern in the electrocardiogram (ECG) and ventricular fibrillation in the absence of structural heart abnormalities. Although some studies have suggested that early repolarization is associated with frequency of atrial fibrillation, the association of early repolarization with atrial fibrillation is not well known.

Hypothesis: Early repolarization indicates the substrate for atrial fibrillation in addition to that for ventricular fibrillation.

Method: This study included 79 patients (57 men [72%]; age, 45 ± 12 years) aged less than 60 years who had paroxysmal lone atrial fibrillation and 395 age- and sex-matched healthy controls (patient:control ratio, 1:5). Patients who had structural heart disease, hypertension, diabetes, hyperthyroidism, history of successful resuscitation, or the Brugada type ECG were excluded. ECGs recorded during sinus rhythm were compared between patients with atrial fibrillation and healthy controls.

Results: Early repolarization in the inferior and/or lateral leads was more common in patients with atrial fibrillation (25%) than controls (10%; P = 0.001). The location and magnitude of early repolarization were similar between the two groups. Other electrocardiographic measurements were not different between the two groups. Among patients with atrial fibrillation, there was no difference in clinical characteristics including age at atrial fibrillation development, sex, and body mass index between patients with early repolarization and those without early repolarization. Electrocardiographic measurements were not different between patients with early repolarization and those without early repolarization.

Conclusion: Early repolarization was associated with lone atrial fibrillation. Early repolarization may indicate increased susceptibility to atrial fibrillation.
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http://dx.doi.org/10.1111/jce.13848DOI Listing
April 2019

A Steam Pop Detected by Intracardiac Echocardiography During Catheter Ablation of the Left Ventricular Papillary Muscle.

Int Heart J 2019 Jan 20;60(1):199-203. Epub 2018 Nov 20.

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences.

A 60-year-old female with premature ventricular contractions (PVCs) originating from the bottom of the posteromedial papillary muscle of the left ventricle underwent radiofrequency catheter ablation (RFCA) using an irrigated-tip catheter. During ablation of the PVCs, a loud steam pop was observed. Intracardiac echocardiography (ICE) revealed a growing, hyperechogenic intramyocardial microbubble formation around the catheter tip. The formation disappeared slowly and completely, leaving an endocardial laceration without pericardial effusion. ICE imaging is valuable during a difficult RFCA procedure, because ICE reveals the exact anatomical position of the catheter and thus allows rapid evaluation of the occurrence of steam popping and any possible subsequent complication.
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http://dx.doi.org/10.1536/ihj.18-136DOI Listing
January 2019

Clinical Manifestations and Long-Term Mortality in Lamin A/C Mutation Carriers From a Japanese Multicenter Registry.

Circ J 2018 10 4;82(11):2707-2714. Epub 2018 Aug 4.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center.

Background: Mutation in the lamin A/C gene (LMNA) is associated with several cardiac phenotypes, such as cardiac conduction disorders (CCD), atrial arrhythmia (AA), malignant ventricular arrhythmia (MVA) and left ventricular dysfunction (LVD), leading to sudden cardiac death (SCD) and/or end-stage heart failure. We investigated how these phenotypes are associated with each other and which of them are most important for total mortality. Methods and Results: A multicenter registry included 110 LMNA mutation carriers (age, 43±15 years, male: 62%) from 60 families. After genetic diagnosis of LMNA mutation (missense: 27%, non-missense: 73%), patients or subjects were followed to evaluate the manifestations of their phenotypes and the risk of total mortality; 90 patients could be followed (median: 5 [0-35] years). Prevalence of the 4 clinical phenotypes was significantly increased during follow-up. Among these phenotypes, AA was significantly associated with MVA. CCD was significantly associated with LVD. LVD, meanwhile, was significantly associated with CCD and MVA. Male sex was significantly associated with MVA. Furthermore, during follow-up, 17 patients died: 12 end-stage heart failure, 4 SCD and 1 stroke. LVD was the only independent predictor for all-cause death (OR: 41.7, 95% CI: 4.1-422.3; P=0.0016).

Conclusions: Several cardiac phenotypes were age-dependently increased in LMNA mutation carriers, suggesting that ICD or CRT-D could suppress SCD after middle age; however, LVD leading to end-stage heart failure was the only independent predictor for total mortality.
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http://dx.doi.org/10.1253/circj.CJ-18-0339DOI Listing
October 2018

Gene-Based Risk Stratification for Cardiac Disorders in Mutation Carriers.

Circ Cardiovasc Genet 2017 Dec;10(6)

Background: Mutations in (), which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance, atrial fibrillation, and malignant ventricular arrhythmias. Although the type of mutations have been reported to be associated with susceptibility to malignant ventricular arrhythmias, the gene-based risk stratification for cardiac complications remains unexplored.

Methods And Results: The multicenter cohort included 77 mutation carriers from 45 families; cardiac disorders were retrospectively analyzed. The mean age of patients when they underwent genetic testing was 45±17, and they were followed for a median 49 months. Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction disturbance (81%), low left ventricular ejection fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular arrhythmias (26%). During the follow-up period, 9 (12%) died, either from end-stage heart failure (n=7) or suddenly (n=2). Genetic analysis showed truncation mutations in 58 patients from 31 families and missense mutations in 19 patients from 14 families. The onset of cardiac disorders indicated that subjects with truncation mutations had an earlier occurrence of cardiac conduction disturbance and low left ventricular ejection fraction, than those with missense mutations. In addition, the truncation mutation was found to be a risk factor for the early onset of cardiac conduction disturbance and the occurrence of atrial arrhythmias and low left ventricular ejection fraction, as estimated using multivariable analyses.

Conclusions: The truncation mutations were associated with manifestation of cardiac phenotypes in -related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001603DOI Listing
December 2017

Quantitative analysis of PKP2 and neighbouring genes in a patient with arrhythmogenic right ventricular cardiomyopathy caused by heterozygous PKP2 deletion.

Europace 2017 Apr;19(4):644-650

Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Tsukiwa-cho, Seta, Otsu 520-2192, Japan.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease mainly caused by desmosome gene mutations. The genetic culprit, however, remains elusive in ∼50% of ARVC patients. One of the reasons for missing genetic abnormalities is the difficulty in detecting large deletions/duplications, which are called as copy number variation (CNV) by the Sanger sequencing method. This study aimed to identify CNVs in PKP2 and a part of other desmosome genes in ARVC patients.

Methods And Results: The study cohort consisted of 71 ARVC probands who were diagnosed as definite or borderline cases based on 2010 Task Force Criteria. Among them, 32 (45%) carried at least one mutation in desmosome genes detected by the Sanger method. Using the multiplex ligation-dependent probe amplification method, we identified a male proband (1.4%) with a complete deletion of all PKP2 coding exons. He was 31 years old and showed exercise-induced sustained ventricular tachycardia with superior axis and left bundle-branch block pattern. His cardiac magnetic resonance imaging and computed tomography showed right ventricular dilatation and reduced ejection fraction. His 12-lead electrocardiogram showed T-wave inversion in V1-V3, and late potentials were positive, indicating definite ARVC. To confirm the precise location of the deletion, we performed relative quantitative PCR. We found complete deletion of both SYT10 and ALG10 located in 3' of PKP2; the total deletion size was at least 1.23 Mb.

Conclusion: Screening for CNVs in desmosome genes is useful to identify the genetic basis of disease in clinically suspected ARVC patients.
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http://dx.doi.org/10.1093/europace/euw038DOI Listing
April 2017

Arrhythmia risk and β-blocker therapy in pregnant women with long QT syndrome.

Heart 2017 09 14;103(17):1374-1379. Epub 2017 Mar 14.

Department of Perinatal and Pediatric Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan.

Background: Pregnancy is one of the biggest concerns for women with long QT syndrome (LQTS).

Objectives: This study investigated pregnancy-related arrhythmic risk and the efficacy and safety of β-blocker therapy for lethal ventricular arrhythmias in pregnant women with LQTS (LQT-P) and their babies.

Methods: 136 pregnancies in 76 LQT-P (29±5 years old; 22 LQT1, 36 LQT2, one LQT3, and 17 genotype-unknown) were enrolled. We retrospectively analysed their clinical and electrophysiological characteristics and pregnancy outcomes in the presence (BB group: n=42) or absence of β-blocker therapy (non-BB group: n=94).

Results: All of the BB group had been diagnosed with LQTS with previous events, whereas 65% of the non-BB group had not been diagnosed at pregnancy. Pregnancy increased heart rate in the non-BB group; however, no significant difference was observed in QT and T-T intervals between the two groups. In the BB group, only two events occurred at postpartum, whereas 12 events occurred in the non-BB group during pregnancy (n=6) or postpartum period (n=6). The frequency of spontaneous abortion did not differ between the two groups. Fetal growth rate and proportion of infants with congenital malformation were similar between the two groups, but premature delivery and low birthweight infants were more common in those taking BB (OR 4.79, 95% CI 1.51 to 15.21 and OR 3.25, 95% CI 1.17 to 9.09, respectively).

Conclusions: Early diagnosis and β-blocker therapy for high-risk patients with LQTS are important for prevention of cardiac events during pregnancy and the postpartum period, and β-blocker therapy may be tolerated for babies in LQT-P cases.
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http://dx.doi.org/10.1136/heartjnl-2016-310617DOI Listing
September 2017

The effects of pure potassium channel blocker nifekalant and sodium channel blocker mexiletine on malignant ventricular tachyarrhythmias.

J Electrocardiol 2017 May - Jun;50(3):277-281. Epub 2016 Sep 8.

Department of Cardiovascular Biology and Medicine, Niigata University School of Medical and Dental Sciences, Niigata, Japan.

Background: Patients with repetitive ventricular tachyarrhythmias - so-called electrical storm - frequently require antiarrhythmic drugs. Amiodarone is widely used for the treatment of electrical storm but is ineffective in some patients. Therefore, we investigated the efficacy of stepwise administration of nifekalant, a pure potassium channel blocker, and mexiletine for electrical storm.

Methods: This study included 44 patients with repetitive ventricular tachyarrhythmias who received stepwise therapy with nifekalant and mexiletine for electrical storm. Nifekalant was initially administered, and mexiletine was subsequently added if nifekalant failed to control ventricular tachyarrhythmias.

Results: Nifekalant completely suppressed recurrences of ventricular arrhythmias in 28 patients (64%), including 6 patients in whom oral amiodarone failed to control arrhythmias. In 9 of 16 patients in whom nifekalant was partially effective but failed to suppress ventricular arrhythmias, mexiletine was added. The addition of mexiletine prevented recurrences of ventricular tachyarrhythmias in 5 of these 9 patients (56%). There was no death associated with electrical storm. In total, the stepwise treatment with nifekalant and mexiletine was effective in preventing ventricular tachyarrhythmias in 33 of 44 patients (75%). There was no difference in cycle length of the ventricular tachycardia, QRS interval, QT interval, or left ventricular ejection fraction between patients who responded to antiarrhythmic drugs and those who did not. During follow-up, 8 patients had repetitive ventricular tachyarrhythmia recurrences, and the stepwise treatment was effective in 6 of these 8 patients (75%).

Conclusions: The stepwise treatment with nifekalant and mexiletine was highly effective in the suppression of electrical storm.
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http://dx.doi.org/10.1016/j.jelectrocard.2016.09.005DOI Listing
February 2018

Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.

J Am Heart Assoc 2016 09 13;5(9). Epub 2016 Sep 13.

Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias.

Methods And Results: We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild-type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity.

Conclusions: Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.
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http://dx.doi.org/10.1161/JAHA.116.003644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079027PMC
September 2016

Frequency characteristics and associations with the defibrillation threshold of ventricular fibrillation in patients with implantable cardioverter defibrillators.

Intern Med 2015 15;54(10):1175-82. Epub 2015 May 15.

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Japan.

Objective: The dominant frequency (DF) in frequency analyses is considered to represent the objective cycle length and complexity of activation under conditions of ventricular fibrillation (VF). However, knowledge regarding the mechanisms determining the DF in human VF is limited. We studied the characteristics of the DF of human VF and relationship between DF and the defibrillation threshold.

Methods: Seventy-two implantable cardioverter-defibrillator patients and 211 VF were studied. Using defibrillation tests, we performed a frequency analysis with fast Fourier transformation. The correlations between DF and clinical characteristics, including the defibrillation threshold, were assessed.

Results: The mean DF of all induced VFs was 5.2±0.8 Hz. The patients were divided into two groups according to DF: the low-DF (DF <5.2 Hz, n=32) and high-DF (DF ≥5.2 Hz, n=40) groups. The frequency of structural heart disease was significantly higher in the low-DF group. In addition, the QRS duration, QT interval and effective refractory period of the right ventricle (RV-ERP) were significantly longer in the low-DF group. A multivariate analysis showed RV-ERP to be the only independent predictor of DF. Excluding patients receiving group III anti-arrhythmic drugs, which are known to have potent defibrillation threshold effects, the defibrillation threshold was significantly lower in the low-DF group (p=0.026).

Conclusion: We found that the DF of human VF is associated with underlying heart disease, the cardiac function, cardiac conduction, ventricular refractoriness and defibrillation threshold. Our findings may be useful for identifying and managing patients with a high defibrillation threshold.
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http://dx.doi.org/10.2169/internalmedicine.54.3113DOI Listing
October 2015

Novel calmodulin mutations associated with congenital arrhythmia susceptibility.

Circ Cardiovasc Genet 2014 Aug 10;7(4):466-74. Epub 2014 Jun 10.

Background: Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations.

Methods And Results: We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.

Conclusions: CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140998PMC
August 2014

The time course of paroxysmal atrial fibrillation and its implications: an analysis from a snapshot.

Int J Cardiol 2013 Oct 28;168(3):2867-8. Epub 2013 Apr 28.

Niigata University Graduate School of Medical and Dental Science, Niigata, Japan; Tachikawa Medical Center, Nagaoka, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2013.03.146DOI Listing
October 2013

An appropriate defibrillation threshold obtained by the combined connection between two shock leads and ICD generator.

Intern Med 2011 15;50(22):2815-8. Epub 2011 Nov 15.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Japan.

A 60-year-old man with arrhythmogenic right ventricular cardiomyopathy was readmitted for the battery exchange of his implantable cardioverter-defibrillator (ICD). Since (i) he had been treated with a dual-coil shock lead (Sprint Fidelis, Medtronic) and (ii) pre-operative venography showed mild collateral flow to the left subclavian vein, a single-coil lead was additionally implanted. However, the single-coil defibrillation system was unable to terminate the induced ventricular fibrillation (VF), thus dual defibrillation shock pathways were created using the connection to the superior vena cava coil of the Fidelis lead. The combined connections of the two shock leads provided an appropriate margin of the defibrillation threshold.
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http://dx.doi.org/10.2169/internalmedicine.50.5792DOI Listing
March 2012

Analysis of J waves during myocardial ischaemia.

Europace 2012 May 28;14(5):715-23. Epub 2011 Oct 28.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, 1-754 Asahimachi-dori, Chuo-Ku, Niigata-City, Niigata 951-8510, Japan.

Aims: The aim of this study was to investigate the relationship between J-wave dynamics and arrhythmias during myocardial ischaemia in patients with vasospastic angina (VSA).

Methods And Results: Sixty-seven consecutive patients diagnosed with VSA by a provocation test for coronary spasm were grouped according to whether they had a J wave in the baseline electrocardiograms or not (VSA-JW group, n = 14; VSA-non-JW group: n = 53). We retrospectively studied the associations between J-wave and ST-segment dynamics and induced ventricular fibrillations (VFs) during coronary spasm.  In the VSA-JW group, 7 of the 14 patients showed changes in J-wave morphology and/or gains in J-wave voltage, followed by VF in 4 patients. Compared with patients without VF, the four patients with VF showed similar maximal voltage in the baseline J waves but a higher voltage during induced coronary spasms (0.57 ± 0.49 vs. 0.30 ± 0.11 mV; P = 0.011). In three patients with VF, J waves progressively increased and were accompanied by the characteristic coved-type or lambda-shaped ST-segment elevations. In the VSA-non-JW group, only four patients showed new appearances of J waves during coronary spasms and another patient without a distinct J wave developed VF. Ventricular fibrillations were induced more frequently in the VSA-JW group than in the VSA-non-JW group [4/14 (29%) vs. 1/53 (2%); P = 0.012].

Conclusion: J-wave augmentations were caused by myocardial ischaemia during coronary spasms. The presence and augmentation of J waves, especially prominent J waves with the characteristic ST-elevation patterns, were associated with VF.
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http://dx.doi.org/10.1093/europace/eur323DOI Listing
May 2012

Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization.

Circ Arrhythm Electrophysiol 2011 Dec 25;4(6):874-81. Epub 2011 Oct 25.

Division of Cardiology, Niigata University School of Medicine, Niigata, Japan.

Background: Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear.

Methods And Results: This study included 50 patients (44 men; age, 45 ± 17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels.

Conclusions: We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.
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http://dx.doi.org/10.1161/CIRCEP.111.963983DOI Listing
December 2011

Association between lipid profile and risk of atrial fibrillation.

Circ J 2011 14;75(12):2767-74. Epub 2011 Sep 14.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Dyslipidemia, an important risk factor for cardiovascular disease, may be associated with atrial fibrillation (AF). Cross-sectional studies that have examined this association, however, have produced controversial results, and few longitudinal studies have been conducted.

Methods And Results: Using annual health examinations in Japan, the association between lipid profile and the risk of new-onset AF was investigated in the general population. A total of 28,449 individuals who did not have AF at baseline were included in the study. During a follow-up of 4.5±2.7 years, 265 individuals (0.9%) developed AF. In multivariate models, low high-density lipoprotein (HDL) cholesterol was associated with the development of AF in women (hazard ratio [HR], 2.86; 95% confidence interval [CI]: 1.49-5.50) but not in men (HR, 1.35; 95%CI: 0.77-2.38). Women had a 28% higher risk of AF with each 10% decrease in HDL cholesterol. Neither triglycerides nor lipid ratios were associated with AF. After excluding individuals with risk factors for AF, including those who were taking anti-hypertensive drugs, had diabetes, and structural heart disease, the association between low HDL cholesterol and AF remained significant in women.

Conclusions: Low HDL cholesterol was associated with an increased risk of new-onset AF in women, but not in men.
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http://dx.doi.org/10.1253/circj.cj-11-0780DOI Listing
March 2012

The prevalence of early repolarization in Wolff-Parkinson-White syndrome with a special reference to J waves and the effects of catheter ablation.

J Electrocardiol 2012 Jan-Feb;45(1):36-42. Epub 2011 Jun 25.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.

We determined the prevalence of J waves in the electrocardiograms (ECG) of 120 patients with Wolff-Parkinson-White syndrome in comparison with J-wave prevalence in a control group of 1936 men and women with comparable demographic and ECG characteristics and with normal atrioventricular conduction. J waves were present only during manifest preexcitation in 22 of 120 patients (18.3%), disappearing after catheter ablation and suggesting that J waves were associated with the presence of preexcitation. J waves were present in 19 (15.8%) of 120 patients only after ablation, apparently having been masked by early depolarization of the preexcited myocardial region, and in 22 patients (18.3%), J waves were not altered significantly by preexcitation. Thus, the overall J-wave prevalence was 52.5% (63/120) and, excluding those apparently due to preexcitation, 34.8% (41/120), both substantially higher than the prevalence (11.5%) in the control group (P < .001 for both). The patients with J waves appearing only during preexcitation were younger, predominantly females. The presence of J waves after ablation was associated with a history of atrial fibrillation and shorter ventricular effective refractory period. It is concluded that the prevalence of J waves is high in patients with Wolff-Parkinson-White syndrome and is influenced by manifest preexcitation.
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http://dx.doi.org/10.1016/j.jelectrocard.2011.04.006DOI Listing
April 2012

Suppression of storms of ventricular tachycardia by epicardial ablation of isolated delayed potential in noncompaction cardiomyopathy.

Pacing Clin Electrophysiol 2013 Apr 5;36(4):e115-9. Epub 2011 Jan 5.

First Department of Internal Medicine, School of Health Science, Niigata University School of Medicine, Niigata, Japan.

A 65-year-old recipient of an implantable cardioverter defibrillator suffering from ventricular noncompaction developed storms of ventricular tachycardia (VT). Epicardial voltage mapping revealed the presence of a large low-voltage area in the left ventricular apical and inferoposterior wall, and isolated delayed potential was recorded over 1.5 cm in the posterior border between low and normal myocardial voltage. Pacemapping at the delayed potential recording site produced two different QRS depending on pacing output strength, and these two QRS morphologies were similar to clinically documented VTs. During one of the VTs, a mid-diastolic potential was recorded from the site with the delayed potential, and rapid pacing produced concealed entrainment. After epicardial radiofrequency ablation of the isolated delayed potential, VTs were noninducible and the VT storm was suppressed.
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http://dx.doi.org/10.1111/j.1540-8159.2010.02999.xDOI Listing
April 2013

Preexcitation unmasks J waves: 2 cases.

J Electrocardiol 2011 May-Jun;44(3):359-62. Epub 2010 Dec 3.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.

It is not known if J waves of early repolarization can be affected by depolarization or not. We report 2 cases in whom J waves were unmasked by preexcitation. A 59-year-old woman with Wolff-Parkinson-White syndrome who had frequent episodes of tachycardia underwent radiofrequency catheter ablation. The 12-lead electrocardiogram on admission showed delta waves and a notch in leads II, III, and aVF (J waves), which disappeared after the elimination of preexcitation. A 56-year-old man with Wolff-Parkinson-White syndrome was admitted for catheter ablation for supraventricular tachycardia. His electrocardiogram showed delta waves in I, II, aVL, V(2) to V(6), and J waves in the inferior leads and V(3) through V(6) with ST elevation and ST elevation in V(2). After ablation, J waves disappeared and were replaced by S waves. However, ST elevation remained in the precordial leads. The 2 cases suggest that J waves may be affected by the depolarization process: preexcitation.
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http://dx.doi.org/10.1016/j.jelectrocard.2010.09.004DOI Listing
September 2011

Ischemia-induced prominent J waves in a patient with Brugada syndrome.

Intern Med 2010 15;49(18):1979-82. Epub 2010 Sep 15.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Science, Niigata.

A 75-year-old man was admitted to our hospital in January 2010 for evaluation of syncope and abnormal ECG. ECG showed type 1 ST elevation in lead V(1) and he was diagnosed as Brugada syndrome. During cardiac catheterization, baseline coronary angiography was normal, but intracoronary ergonovine maleate induced spasms of the right and left coronary arteries concomitant with chest pain and ST elevation on ECG. J waves were accentuated or newly developed. Soon after an intracoronary injection of nitroglycerin, chest pain was relieved and ischemia-induced J wave disappeared and the ST segment returned to the same morphology as baseline. Extrastimuli induced ventricular fibrillation. He received an implantable cardioverter-defibrillator. He was also treated with Ca antagonist and isosorbide dinitrate and has had an uneventful course for 5 months.
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http://dx.doi.org/10.2169/internalmedicine.49.3933DOI Listing
August 2011

Effects of bepridil versus E-4031 on transmural ventricular repolarization and inducibility of ventricular tachyarrhythmias in the dog.

Pacing Clin Electrophysiol 2010 Aug 4;33(8):950-9. Epub 2010 May 4.

First Department of Internal Medicine, Niigata University School of Medicine, Niigata, Japan.

Background: Bepridil (a multiple channel blocker) may markedly prolong the QT interval and induce polymorphic ventricular tachyarrhythmias (VTA). We compared the transmural ventricular repolarization characteristics and inducibility of polymorphic VTA after administration of bepridil versus the pure I(Kr) blocker, E-4031, each administered to five open-chest dogs.

Methods: We used plunge needle electrode to record transmural left ventricular (LV) repolarization and activation-recovery interval (ARI) to estimate local repolarization. The correlation between paced cycle length and ARI was separately examined in the LV endocardium, mid-myocardium (Mid), and epicardium. Attempts to induce VTA were made during bradycardia and sympathetic stimulation.

Results: Bepridil and E-4031 prolonged QT interval and ARI in all LV layers, though the magnitude of prolongation was greatest in Mid, increasing the transmural ARI dispersion, particularly during bradycardia. Compared with E-4031, bepridil caused mild, reverse use-dependent changes in ventricular repolarization, and less ARI dispersion than E-4031 during slow ventricular pacing. Both drugs increased ARI(max) and cycle length at 50% of ARI(max), though the changes were smaller after bepridil than after E-4031 administration. Bradycardia after the administration of each drug induced no VTA; however, sympathetic stimulation induced sustained polymorphic VTA in two of five dogs treated with E-4031 versus no dog treated with bepridil.

Conclusions: Unlike the pure I(kr) blocker, E-4031, bepridil exhibited weak properties of reverse use-dependency and protected against sympathetic stimulation-induced VTA. It may be an effective supplemental treatment for recipients of implantable cardioverter defibrillator.
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http://dx.doi.org/10.1111/j.1540-8159.2010.02768.xDOI Listing
August 2010

Efficacy of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia.

Circ J 2010 May 26;74(5):864-9. Epub 2010 Mar 26.

Division of Cardiology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.

Background: The efficacy of antiarrhythmic drugs in terminating sustained monomorphic ventricular tachycardia (SMVT) was assessed in a retrospective manner to provide a basis for recommending their use.

Methods And Results: The 90 patients were included in this study to evaluate the efficacy to terminate SMVT using procainamide or lidocaine. All patients were alert and responsive. The mean systolic blood pressure was 91+/-25 mmHg (range, 40-150 mmHg). SMVT was diagnosed from ECG recordings and later in an electrophysiologic study. VTs with a cycle length of 329+/-55 and 324+/-61 ms were treated with the mean doses of 358+/-50 mg and 81+/-30 mg of procainamide and lidocaine and were terminated in 53/70 (75.7%) and in 7/20 (35.0%) respectively. The drugs were discontinued if there was no rise in blood pressure after slowing of the tachycardia rate or if there were signs of impending deterioration in consciousness. Though procainamide was effective, blood pressure was often low and DC shock should be available at all times during administration of the drug.

Conclusions: Procainamide, the relatively older drug, was more effective than lidocaine in terminating SMVT associated with structural heart diseases. This is a retrospective analysis but can form the basis for formulating guidelines for initial management of SMVT.
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http://dx.doi.org/10.1253/circj.cj-09-0932DOI Listing
May 2010