Predictors of long-term survival in Japanese patients with heart failure with reduced ejection fraction (HFrEF) treated with cardiac resynchronization therapy-defibrillators (CRT-D).

BACKGROUND: Reports on the factors predicting long-term survival of CRT-D cases from Western countries are increasing, however, those from Asia including Japan are still sparse. We aimed to clarify the factors predicting long-term survival of Japanese CRT-D cases. METHODS: We retrospectively analyzed consecutive 133 patients who underwent CRT-D implantation between 2006 and 2021. We compared clinical factors between patients who died within 5 years after implantation (short-survival group: n = 31) and who had survived for more than 5 years (long-survival group: n = 36) after implantation. RESULTS: Major underlying heart diseases were dilated cardiomyopathy (45%) and ischemic heart disease (12%). There was no difference between the short-survival group and the long-survival group in incidence of CLBBB (32% vs. 30%), whereas CRBBB was more common in the short-survival group (26% vs. 0%, p = .004). Mechanical dyssynchrony at implantation was more frequent in the long-survival group (48% vs. 78%, p = .02). The incidence of response to CRT at 1 year after implantation was higher in long-survival group (19% vs. 50%, p = .02). Multiple logistic regression analysis identified NYHA class, mechanical dyssynchrony at implantation, and response at one year as predictors of long-term survival. CONCLUSIONS: In Japanese CRT-D cases, lower NHYA class, preexisting mechanical dyssynchrony, and 1-year response to CRT predict long-term survival.

Clinical impact of nocturnal ventricular tachyarrythmias in electrical storm.

BACKGROUND: The incidence of electrical storm (ES) is significantly higher during the daytime. However, the association between nocturnal ventricular tachyarrythmias during ES and prognosis remains unclear. Therefore, this study aimed to investigate the clinical characteristics and outcomes of ES with midnight ventricular tachyarrythmias. METHODS: We included 48 consecutive patients who had an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator implanted between 2010 and 2020 and those who had experienced the onset of an out-of-hospital ES episode. According to the midnight (0:00 a.m.-6:00 a.m.) occurrence of ventricular arrythmia events consisting of ventricular tachycardia (VT) and ventricular fibrillation (VF), we divided them into two groups (with-midnight group: n = 27, without-midnight group: n = 21). The clinical characteristics and outcomes of the two groups were compared. RESULTS: The patients in the with-midnight group were mostly males, had longer QRS duration, and longer corrected QT-interval than those in the without-midnight group (p < .05). The incidence of all-cause death, especially heart failure death, was higher in the with-midnight group than in the without-midnight group (p < .01). Multivariate analysis showed that the presence of midnight VT/VF during ES was the only independent risk factors for heart failure death (HR = 18.9, 95%CI = 1.98-181, p = .011). CONCLUSIONS: The presence of midnight VT/VF during ES might be associated with the poor prognosis. The loss of a sympathetic circadian pattern of VT/VF distribution during ES might suggest advanced stages of the cardiac disease.

The Risk of Ventricular Tachyarrhythmias in Patients with Antimitochondrial Antibodies-Related Noncardiac Diseases.

Antimitochondrial antibodies (AMA) are serum autoantibodies specific to primary biliary cholangitis and are linked to myopathy and myocardial damage; however, the presence of AMA as a risk factor for ventricular tachyarrhythmias (VTs) has remained unknown. This study aimed to elucidate whether the presence of AMA-related noncardiac diseases indicates VTs risk.This cohort study enrolled 1,613 patients (883 females) who underwent AMA testing to assess noncardiac diseases. The incidence of VTs and supraventricular tachyarrhythmias (SVTs) from a year before the AMA testing to the last visit of the follow-up were retrospectively investigated as primary and secondary objectives. Using propensity score matching, we extracted AMA-negative patients whose covariates were matched to those of 152 AMA-positive patients. In this propensity score-matched cohort, the incidence of VTs and SVTs in the AMA-positive patients were compared with that in AMA-negative patients.The AMA-positive patients had higher estimated cumulative incidence (log-rank, P = 0.013) and prevalence (5.9% versus 0.7%, P = 0.020) of VTs than the AMA-negative patients. The presence of AMA was an independent risk factor for VTs (hazard ratio, 4.02; 95% CI, 1.44-20.01; P = 0.005). Meanwhile, AMA were associated with atrial flutter and atrial tachycardia development. In AMA-positive patients, VTs were associated with male sex, underlying myopathy, high creatine kinase levels, presence of chronic heart failure or ischemic heart disease, left ventricular dysfunction, presence of SVTs, and the electrocardiographic parameters indicating atrial disorders.The presence of AMA-related noncardiac diseases is an independent risk factor for VTs.

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

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.

Efficacy of antitachycardia pacing alert by remote monitoring of implantable cardioverter-defibrillators for out-of-hospital electrical storm.

BACKGROUND: Remote monitoring (RM) has been shown to reduce all-cause mortality in patients with implantable cardioverter-defibrillators or cardiac resynchronization therapy defibrillators (ICD/CRT-D). Not all devices transmit an alert for antitachycardia pacing (ATP) therapy, and it is unknown whether differences of RM alert affect the outcomes of electrical storm (ES). METHODS: We enrolled 42 patients with ICD/CRT-D whose out-of-hospital ES were detected by RM between 2013 and 2020. We divided their 54 episodes into two groups (ATP-alert-on; 22, ATP-alert-off; 32), and clinical outcomes were compared between the two groups. RESULTS: In 35 of 54 episodes of ES, ventricular tachycardia (VT) could be terminated within 24 h of ES onset just by ATP (ATP-alert-on: 14, ATP-alert-off: 21); however, many patients subsequently received shock delivery for VT. Among the 35 episodes, only in ATP-alert-on group, seven patients were prompted to visit our hospital without ICD shock through confirmation of ES by ATP-alert. Episodes that led to shock delivery 24 h or longer after the ES onset were significantly less common in the ATP-alert-on group (ATP-alert-on: 1/14, ATP-alert-off: 9/21, p = .03). Although there were no significant differences in the number of shock deliveries between episodes in the two groups, the number of ATP deliveries were significantly fewer in the ATP-alert-on group (12[7-26] vs. 29[16-53] in ATP-alert-off group, p = .03). Multivariate logistic regression analyses showed that the only ATP-alert significantly reduced ATP deliveries (HR = 0.14, 95%CI = 0.04-0.57, p = .003). CONCLUSION: Remote monitoring with an ATP-alert function during electrical storm may reduce appropriate ICD therapy through prompting early review.

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

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.

Early repolarization and risk of lone atrial fibrillation.

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Differences in coagulation responses to vascular injury between uninterrupted dabigatran and apixaban - a clinical prospective randomized study.

BACKGROUND: The coagulation response during vascular injury with uninterrupted administration of direct oral anticoagulants (DOACs) has not been elucidated. OBJECTIVE: Our aim was to evaluate differences in coagulation responses after vascular injury between uninterrupted direct thrombin inhibitor and direct factor Xa inhibitor recipients. METHODS: Patients scheduled for catheter ablation for atrial fibrillation were randomly assigned to receive dabigatran or apixaban in this prospective, randomized, comparative, parallel-group study. Venous blood was collected three times: 180 minutes after taking the anticoagulant on the day before the procedure, before vascular punctures of the ablation procedure, and 10-15 minutes after the start of vascular punctures. RESULTS: Forty-two patients were enrolled. The prothrombin fragment 1+2 (F1+2) level, the primary endpoint, was much larger after vascular puncture in the uninterrupted dabigatran recipients (median: 83 pmol/L; interquartile range: 56-133 pmol/L) than in the uninterrupted apixaban recipients (median: 1 pmol/L; interquartile range: -3-19 pmol/L; P < 0.001). Antithrombin levels decreased after vascular puncture in dabigatran recipients, and both protein C and antithrombin levels decreased after vascular puncture in apixaban recipients. CONCLUSIONS: Unlike uninterrupted apixaban, uninterrupted dabigatran does not inhibit thrombin generation in response to vascular injury.

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

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.

Analysis of J waves during myocardial ischaemia.

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.

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

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.

Clinical impact of ECG changes on oversensing of subcutaneous implantable cardioverter-defibrillators.

BACKGROUND: Inappropriate shocks delivered by subcutaneous implantable cardioverter-defibrillators (S-ICDs) are most frequently caused by cardiac oversensing. However, the predictors for oversensing of S-ICD remain unclear. OBJECTIVE: We aimed to investigate the predictors for oversensing of S-ICD, especially clinical impact of an electrocardiographic (ECG) change. METHODS: We retrospectively enrolled 99 consecutive patients who underwent S-ICD implantation between 2013 and 2021. Oversensing events were defined as inappropriate charge of the capacitors induced by cardiac or noncardiac signals other than tachycardia. RESULTS: During a median follow-up period of 34 months (interquartile range 20-50 months), 11 of 99 patients (11%) experienced 34 oversensing events and 4 patients (4%) received inappropriate shocks during their events. Six patients exhibited ECG changes (bundle branch block, 3; ventricular pacing, 1; inverted T wave, 1; poor R-wave progression, 1) during the follow-up period. Oversensing events were observed in 4 of 6 patients with ECG change (67%), and 3 patients underwent S-ICD removal because of inevitable shock. Contrastingly, of the remaining patients without ECG change, all 7 patients who experienced oversensing events could continue using S-ICD with the reprogramming sensing vector and/or restriction of excessive exercise. Logistic regression analysis showed that lower voltage of Sokolow-Lyon ECG (V1S + V5R) was the predictor of oversensing in patients without ECG change. When the cutoff value was 2.1 mV, the sensitivity, specificity, positive predictive value, and negative predictive value were 85.7%, 62.7%, 15.7%, and 98.1%, respectively. CONCLUSION: Unavoidable oversensing resulting in S-ICD removal is caused by ECG change. Oversensing in patients without ECG change can be managed.

Targeted deep sequencing analyses of long QT syndrome in a Japanese population.

Long QT syndrome (LQTS) is one of the most common inherited arrhythmias and multiple genes have been reported as causative. Presently, genetic diagnosis for LQTS patients is becoming widespread and contributing to implementation of therapies. However, causative genetic mutations cannot be detected in about 20% of patients. To elucidate additional genetic mutations in LQTS, we performed deep-sequencing of previously reported 15 causative and 85 candidate genes for this disorder in 556 Japanese LQTS patients. We performed in-silico filtering of the sequencing data and found 48 novel variants in 33 genes of 53 cases. These variants were predicted to be damaging to coding proteins or to alter the binding affinity of several transcription factors. Notably, we found that most of the LQTS-related variants in the RYR2 gene were in the large cytoplasmic domain of the N-terminus side. They might be useful for screening of LQTS patients who had no known genetic factors. In addition, when the mechanisms of these variants in the development of LQTS are revealed, it will be useful for early diagnosis, risk stratification, and selection of treatment.