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After taking an estrogen-containing supplement derived from a tropical plant Pueraria mirifica, a 24-year-old woman presented marked QT prolongation and repetitive torsade de pointes. The patient was found to carry a heterozygous KCNQ1-T587M mutation. This is the first report on Pueraria mirifica-related acquired long QT syndrome.

Background Patients with Brugada syndrome (BrS) are known to have arrhythmic events after alcohol drinking and are recommended to avoid its excessive intake. Mechanisms underlying the alcohol‐induced cardiac events are however unknown. This study aimed to test the hypothesis whether activity of alcohol‐metabolizing enzymes determines fatal arrhythmic events after drinking alcohol. Methods A total of 198 Japanese patients with BrS were enrolled in this study. These patients were classified into symptomatic (n = 90) and asymptomatic (n = 108) groups. The former was divided into an alcohol‐related group (syncope after alcohol drinking, n = 16) and an alcohol‐unrelated group (n = 74). Polymerase chain reaction was performed to determine genetic variants of genes encoding alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2). Results The genotype distribution for ALDH2 was not significantly different between symptomatic and asymptomatic groups and between alcohol‐related and alcohol‐unrelated groups. The genotype distribution for ADH1B was not significantly different between symptomatic and asymptomatic groups, but the genotype ADH1B His/His was significantly more prevalent in the alcohol‐related group than in the alcohol‐unrelated group (81.3% vs 50%, P = .023). In multivariate logistic regression analysis, the genotype of ADH1B His/His was independently associated with syncope after alcohol drinking (odds ratio, 5.746; 95% confidence interval, 1.580‐28.421; P = .007). Conclusions Arrhythmic events after alcohol drinking was associated with enhanced activity of alcohol‐metabolizing enzyme ADH1B in our cohort of BrS. Therefore, the lifestyle change to avoid the excessive alcohol intake deserves attention.

A 10‐month‐old infant experienced cardiac arrest caused by ventricular fibrillation (VF). His electrocardiogram (ECG) at rest was within the normal range. Amiodarone was indispensable due to its refractoriness to defibrillation. After implantable cardioverter defibrillator (ICD) implantation, ICD shock was delivered. ICD recordings documented VF and ventricular tachycardia (VT) triggered by premature ventricular contractions with an extremely short coupling interval (240 ms), which were controlled by verapamil. To the best of our knowledge, our case is the first infant with ScTdP. As the electrical storm with ScTdP occurs unpredictably, it can be a cause of sudden infant death syndrome.

Background Effects of nonparoxysmal atrial fibrillation (non‐PAF) ablation targeting complex fractionated atrial electrogram (CFAE) areas and/or low voltage areas (LVAs) are still controversial. Methods and Results A recently developed online real‐time phase mapping system (ExTRa Mapping) was used to conduct LVA mapping and simultaneous ExTRa and CFAE mapping in 28 non‐PAF patients after pulmonary vein isolation (PVI). Nonpassively activated areas, in the form of meandering rotors and/or multiple wavelets assumed to contain non‐PAF drivers, partly overlapped with CFAE/LVAs but not always coincided with them. Conclusion Real‐time rotor imaging, rather than conventional indirect indicators only, might be very useful for detecting non‐PAF drivers.

Background Phenotypes often differ even within family members carrying the same SCN5A mutation. We aimed to evaluate the genetic modifiers in a family with Brugada syndrome (BrS) and sick sinus syndrome (SSS) with an SCN5A mutation that causes the truncated alpha-subunit of cardiac Na channel protein. Methods To detect the genetic modifiers, we performed targeted panel sequencing of the coding region of 46 genes that are related to primary arrhythmia syndrome, by using a bench-top, next generation sequencer. Phenotype–genotype relationships were evaluated among the family members. Results Index proband was a 13-year old (yo) boy with cardiac conduction defect as well as BrS. Genetic analysis revealed that he and his three asymptomatic family members carried a novel nonsense mutation: SCN5A -Q779X. Both genotype-positive mother and sister exhibited coved type ST elevation and his sister had SSS, whereas his elder brother exhibited saddleback type ST elevation induced by pilsicainide administration. We detected four non-synonymous variants ( DSG2 -R773K, SCN1B -L210P, -S248R, and -R250T) in the proband, his mother and his sister, but not in his brother. Conclusion Phenotypic differences between the proband and his brother carrying the same nonsense SCN5A mutation could be explained by modifiers such as SCN1 B, and DSG2 gene variants.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the leading causes of sudden arrhythmic death in the young. The QT interval in CPVT patients is typically within the normal range. However, those with prolonged QT interval have often been diagnosed with mutation‐negative long QT syndrome (LQTS). We report three CPVT patients with prolonged QT interval. Case 1 and 2 were diagnosed as LQTS at first. Genetic test using next‐generation sequencing (NGS) revealed RyR2 mutations. We should consider genetic test using NGS to identify the genes responsible for CPVT in mutation‐negative LQTS.

In 1992, the Brugada syndrome (BrS) was recognized as a disease responsible for sudden cardiac death, characterized by a right bundle-branch block with ST segment elevation in the leads V1 and V2. This syndrome is highly associated with sudden cardiac death, especially in young males. BrS is currently diagnosed in patients with ST-segment elevation showing type 1 morphology ≥2 mm in ≥1 leads among the right precordial leads V1 or V2 positioned in the 2nd, 3rd, or 4th intercostal space, and occurring either spontaneously or after a provocative drug test by the intravenous administration of Class I antiarrhythmic drugs. With accumulated findings, the BrS inheritance model is believed to be an autosomal dominant inheritable model with incomplete penetrance, although most patients with BrS were sporadic cases. SCN5A, which was identified as the first BrS-associated gene in 1998, has emerged as the most common gene associated with BrS, and more than 10 BrS-associated genes have been identified thereafter. Mutation-specific genetic testing is recommended for the family members and appropriate relatives following the identification of BrS-causative mutations in an index patient. In addition, comprehensive or BrS1 (SCN5A) targeted genetic testing could be useful for patients in whom a cardiologist has established a clinical index of suspicion for BrS based on the patient׳s clinical history, family history, and the expressed electrocardiographic (resting 12-lead ECGs and/or provocative drug challenge testing) phenotype.Over the past 20 years, extensive research in this field has allowed better understanding of the pathophysiology, genetic background, and management of BrS even though controversies still exist. In this review article, a background of genetics, the genetic background of BrS, the genotype and phenotype relationship, the role of genetic screening in clinical practice, and the interpretation of the identified genetic variants have been addressed based on this understanding.

Background: Landiolol effectively controls rapid heart rate in atrial fibrillation or flutter (AF/AFL) patients with left ventricular (LV) dysfunction. However, predicting landiolol Responders and Non-Responders and patients who will experience adverse effects remains a challenge. The aim of this study was to clarify the potential applicability of landiolol for rapid AF/AFL and refractory ventricular tachyarrhythmias (VTs) in patients with heart failure. Methods: A total of 39 patients with AF/AFL with ventricular response ≥120 bpm and 12 VTs were retrospectively enrolled. Landiolol Responders for rapid AF/AFL were defined as patients whose ventricular response was suppressed to less than 110 bpm or decreased by ≥20% from the initial heart rate after administration of landiolol. Responders for VTs were defined as patients with no recurrent VTs during the 24 h after the initiation of landiolol. Results: For AF/AFL, 29 patients (74%) were Responders. In nine patients (31%), AF was spontaneously terminated after starting landiolol. Eight Non-Responders (80%) needed to have AF terminated by cardioversion. Left ventricular ejection fraction (LVEF) at baseline was significantly associated with landiolol efficacy. For VTs, seven patients (58%) were Responders, and smaller LV diastolic and systolic diameters were associated with landiolol efficacy. Hypotension after landiolol treatment occurred in 5 of 51 patients, and lower LV systolic function was associated with the development of adverse events. Conclusions: Landiolol is effective in patients with heart failure not only due to rapid AF/AFL but also due to VTs. However, preserved LVEF is important for efficacy and safety in landiolol treatment.

Background: Anisotropic and slow conduction in the atrium underlie the development of atrial fibrillation (AF). This study aimed to investigate the P wave characteristics associated with the development of AF in patients with a biphasic P wave in the inferior leads. Methods: Digital analysis of retrospectively recorded 12-lead electrocardiograms was performed to select patients with a biphasic P wave (positive/negative) in lead II from a database of 114,334 patients. Characteristics of the P wave in the inferior leads associated with incidence of AF were determined. Receiver operating characteristic curves dichotomized P wave variables were measured in each lead. Results: A total of 141 patients (77 men; mean age, 64±19 years) were enrolled in this study. Twenty-nine (20.6%) patients developed AF (AF group) vs. 112 (79.6%) who did not (non-AF group) during a follow-up period of 50±62 months. The amplitude of the initial P wave portion in lead II was significantly larger in the AF group when compared with the non-AF group (77.3±77.0 µV vs. 51.0±30.1 µV, p=0.003), while the amplitude of the terminal P wave portion in lead III was significantly decreased in the AF group when compared with the non-AF group (−70.6±41.3 µV vs. −89.1±38.1 µV, p=0.024). The duration of the initial P wave portion in lead III was significantly longer in the AF group when compared with the non-AF group (52.7±34.6 ms vs. 35.8±30.4 ms, p=0.011). Multivariate Cox proportional-hazards analysis confirmed that the increased duration of the initial P wave portion in lead III (≥71 ms) was independently associated with AF development (hazard ratio 2.90, 95% confidence interval 1.16–7.11, p=0.02). Conclusion: The analyses of the biphasic P wave in the inferior leads suggest that the development of AF could be attributed to increased atrial slow conduction.

Background: The nature and significance of the frequency characteristics of the surface electrocardiogram (ECG) in patients with persistent atrial fibrillation (AF) undergoing radiofrequency ablation are unclear. Methods: Preablation surface and intracardiac ECGs were obtained using offline fast Fourier transform (FFT) analysis in 40 patients with persistent AF. For the FFT analysis of the surface f-wave, the QRS-T complex was canceled utilizing a template subtraction algorithm. The ablation procedure included isolation of the pulmonary veins (PV) and posterior left atrium and linear ablation of the mitral isthmus and additional lesions using a stepwise approach. Results: The dominant frequency (DF) of all the intracardiac signals, except for the left inferior PV, had a significant correlation with the DFs from the surface electrocardiogram. The strongest correlation was observed between the DFs of the left atrial appendage (LAA) and those on the limb leads (correlation coefficient, 0.802–0.882, P

Background The gene KCNE1 encodes the β-subunit of cardiac voltage-gated K + channels and causes long QT syndrome (LQTS). LQTS is characterized by the prolongation of QT interval and lethal arrhythmias such as torsade de pointes (TdP). A KCNE1 polymorphism, D85N, has been shown to modify the phenotype of LQTS through a loss-of-function effect on both KCNQ1 and KCNH2 channels when co-expressed and reconstituted in a heterologous expression system. Methods A screening for the D85N polymorphism was performed in 355 LQTS families with mutations in KCNQ1 , KCNH2 , or SCN5A . Among the probands who had a heterozygous status with the polymorphism, we focused on a family with a KCNH2 mutation (E58K), a N-terminal missense mutation, and examined the clinical significance of this polymorphism. We also conducted biophysical assays to analyze the effect of the polymorphism in mammalian cells. Results In 355 probands, we found 14 probands (3.9%) who had a heterozygous compound status with the D85N polymorphism. In the family with a KCNE1 -D85N polymorphism and a KCNH2 -E58K mutation, the proband and her daughter carried both the KCNH2 mutation and the KCNE1 -D85N polymorphism. They experienced repetitive syncope and TdP. Two sons of the proband had either KCNH2 -E58K mutation or KCNE1 -D85N, but were asymptomatic. Biophysical assays of KCNE1 -D85N with KCNH2 -E58K variants produced a larger reduction in the reconstituted I Kr currents compared to co-expression with wild-type KCNE1 . Conclusions The KCNE1 -D85N polymorphism modified the clinical features of LQTS patients.

This international consensus statement is the collaborative effort of three medical societies representing electrophysiology in North America, Europe, and Asian-Pacific area: the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the Asia Pacific Heart Rhythm Society. The objective of the consensus document is to provide clinical guidance for diagnosis, risk stratification, and management of patients affected by inherited primary arrhythmia syndromes. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the clinical data on patients affected by channelopathies. This document does not address the indications of genetic testing in patients affected by inherited arrhythmias and their family members. Diagnostic, prognostic, and therapeutic implications of the results of genetic testing are also not included in this document because this topic has been covered by a recent publication1 coauthored by some of the contributors of this consensus document, and it remains the reference text on this topic. Guidance for the evaluation of patients with idiopathic ventricular fibrillation, sudden arrhythmic death …

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by episodic ventricular tachycardia induced by adrenergic stress. Although β-blockers are used as first-line therapy, their therapeutic effects are largely incomplete. Flecainide has recently been shown to modify the molecular defects in CPVT. The aim of this study was to investigate the effects of flecainide as an add-on to conventional therapy on exercise-induced ventricular arrhythmia and compare them with those of conventional therapy alone. Methods The study included 5 CPVT patients with a mutation in RYR 2. They experienced episodic arrhythmic events despite conventional β-blocker therapy and were therefore given flecainide in addition. The effects of the addition of flecainide therapy on ventricular arrhythmia during exercise testing were compared with those of conventional therapy alone. Results Both β-blockers alone and with additional flecainide increased the maximal workload attained at the onset of ventricular arrhythmia; however, only flecainide increased the sinus rate at the onset of ventricular arrhythmias. Furthermore, flecainide increased the exercise capacity by preventing exercise-induced arrhythmias. During a follow-up period of 17±2 months, 1 patient experienced recurrent arrhythmic episodes that were associated with noncompliance. All patients reported improvements in their ability to perform the activities of daily living. Conclusion Flecainide effectively reduced ventricular arrhythmias via a mechanism that differs from that of β-blockers in genotype-positive patients with CPVT. The specific effects of flecainide may be critical in the improvement noted in the patients' ability to perform daily activities.

Background J-point elevation has been demonstrated to be associated with ventricular fibrillation (VF) and has been proposed as a cause of the J-wave syndrome (JWS). A mutation of KCNJ8 , S422L, was reported as a culprit gene. This study aimed to determine the prevalence of KCNJ8 mutations in a Japanese population with JWS or idiopathic VF (IVF). Methods A total of 230 probands with JWS and IVF underwent genetic screening of KCNJ8 . To analyze and compare clinical and electrocardiographic characteristics, the probands were divided into 4 groups: Brugada (Br) pattern only, early repolarization (ER) pattern only, Br and ER patterns, and true IVF. Results The results of the genetic analysis revealed no S422L or other KCNJ8 mutations and indicated no significant difference between the groups. Conclusion The KCNJ8 mutation showed no association with JWS or IVF among our Japanese patients.

Brugada syndrome (BrS) is associated with the familial sudden death syndrome, and more than 10 genes have been reported as causative for or modifiers of BrS. All gene mutations are related to functional changes of inward sodium or calcium currents or outward potassium currents. SCN5A was the first gene known to be associated with BrS; it encodes the α-subunit of the cardiac sodium channel. Approximately 20% of BrS patients in genotyped cases were found to carry SCN5A mutations. The frequency for other BrS-associated gene mutations is so low that genotype–phenotype correlations for these genes have not been studied to the same extent as SCN5A -related BrS. In some families with SCN5A mutations, the penetrance of the mutations is low, and pathophysiological changes in the right ventricular outflow tract were reported in patients with SCN5A mutations. Furthermore, the phenotypes of SCN5A -related BrS can overlap with other phenotypes, including long QT and sick sinus syndrome, thereby suggesting that SCN5A mutations might be modifiers for BrS, but they do not direct cause BrS. Here, we summarize the genetic background of BrS, with a particular focus on recent progress in this field.

Background: β-blockers offer the first line therapy in congenital long QT syndrome (LQTS), and are more effective to prevent the cardiac event in LQTS type 1 than in type 2 or 3. In contrast, left cardiac sympathetic denervation (LCS D) was shown to be highly effective in patients refractory to β-blockers. Total sympathetic ablation by LCSD indicates the addititional involvement of α-adr enoceptor-mediated pathway. In genotyped LQT2 patients, we therefore hypothesized that blockade of α-adrenoceptor in addition to α-adrenoceptor by carvedilol could reduce cardiac events more efficiently than other types of β-blockers. Methods and Results: The study population consisted of 51 genotyped LQT2 patients (18 males, 23 ± 11years old). They were divided into 2 groups (group 1: 43 patients treated with selective β-blockers, group 2: 8 patients with carvedilol) and retrospectively analyzed the efficacy of the respective β-blocker therapy in suppressing cardiac events. Cardiac events were observed in 11 patients of group 1 (26%) but none in group 2 during a follow-up period of 83 ± 80 months (P = 0.098). Conclusions: Carvedilol may be a potentially beneficial therapy for genotyped LQT2 patients who are refractory to other β selective blockers.

Background: Early repolarization, which was regarded as benign, has recently been associated with malignant arrhythmia. Despite the newly emerged importance of early repolarization, little is known about prevalence and QT interval of early repolarization. Methods: Early repolarization (defined as an elevation at the junction between QRS complex and ST segment ≥ 0.1 mV in at least 2 leads) was assessed in database containing 308,391 ECGs consisting of 102,065 patients (52,779 males and 49,286 females). Results: A total of 1,775 patients (mean age, 49 ± 30 years) with early repolarization were chosen (1.7% of total population). The prevalence of early repolarization was about 11-times higher in male patients (n = 1,623) than in female patients (n = 152). The prevalence of early repolarization was 1.4% at the age of 0-9 years, peaked (5.0%) at the age of 10-19 years, and progressively decreased with advancing age from 20 to 79 years (3.3, 2.1, 1.6, 0.9, 0.5, and 0.3% at the age of 20-29, 30-39, 40-49, 50-59, 60-69, and 70-79 years, respectively). Bazett's QTc interval of patients with early repolarization did not significantly differ among groups of each decade and between genders. Conclusion: The prevalence of early repolarization was both age- and gender-dependent in a hospital-based population. Yet, there was no association between QTc interval and age and between QTc interval and gender.

Arrhythmogenic right venticular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy with a very low penetrance affecting the right ventricle (RV) and presenting palpitation and syncope due to ventricular tachycardia (VT) originating from RV. The VT can degenerate into ventricular fibrillation and sudden cardiac death. The genetic background of ARVD/C has recently been found to be heterogeneous, mainly resulting from cell adhesion abnormalities due to mutations in five different genes encoding members of the desmosome complex. In Asian countries, however, the genetic aspect of the disease has not been fully studied, although the clinical features of Asian ARVD/C patients are different from those in Western countries in the penetrance of phenotypes, relation to Brugada syndrome and link to RV outflow tract ventricular tachycardia. It is of urgent need to have a registry of Asian ARVD/C patients and to conduct a more detailed genetic survey on the candidate genes, including desomosomal ones.

Introduction: Due to the difficulty in performing detailed mapping around the tricuspid annulus and the high occurrence of mechanical trauma during the procedure, the outcome of right-sided accessory pathway (AP) ablation still has a relatively high primary failure and recurrence rate. Methods and Results: Six patients with right free-wall APs underwent electroanatomical mapping. The AP had retrograde unidirectional conduction in 3 patients, anterograde unidirectional conduction in 1 patient, and bidirectional conduction in 2 patients. The right atrial (RA) activation map was constructed during right ventricular (RV) pacing (n = 5), and the RV activation map was constructed during RA pacing (n = 3). During mapping, the AP conduction was interrupted by catheter mechanical trauma in 3 patients. The first RF application successfully eliminated the AP conduction within 2 seconds in 3 patients with concealed pathways. In the remaining 3 patients, rescue RF energy was delivered at the tagged bump site on the map. The mean procedure time was 214 ± 77 minutes, and mean fluoroscopy time 63 ± 23 minutes. No recurrence occurred during 12 ± 3.2 months of followup in any of the patients. Conclusions: With the guidance of an electroanatomical mapping system, right-sided accessory pathways can be satisfactorily eliminated without later recurrence.