Publications by authors named "Kengo F Kusano"

79 Publications

Genotype-Phenotype Correlation of Genotype in Patients With Brugada Syndrome and Arrhythmic Events: Insights From the SABRUS in 392 Probands.

Circ Genom Precis Med 2021 Aug 31:CIRCGEN120003222. Epub 2021 Aug 31.

Division of Cardiology, Hospital of Peschiera del Garda, Veneto, Italy (G.A., P.D.).

Background: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to genotype in a large cohort of BrS probands with first arrhythmic event.

Methods: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed.

Results: The study group comprised 392 probands: 92 (23.5%) (44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with (11.4% versus 3%, =0.023). The proportion of females was higher among patients with P/LP compared with - (18.2% versus 6.3%, =0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with - (41.9% versus 16.8%, <0.001). A higher proportion of patients with P/LP were White compared with (87.5% versus 47%, <0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], <0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], =0.009) were independent variables associated with P/LP genotype following logistic regression.

Conclusions: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with . In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.
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http://dx.doi.org/10.1161/CIRCGEN.120.003222DOI Listing
August 2021

The association between late-phase early recurrence within the blanking period after atrial fibrillation catheter ablation and long-term recurrence: Insights from a large-scale multicenter study.

Int J Cardiol 2021 Oct 31;341:39-45. Epub 2021 Jul 31.

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo 113-8603, Japan.

Background: The relationship between the timing of the first early recurrence and late recurrence after a single catheter ablation procedure for atrial fibrillation is controversial.

Methods: The Efficacy of Short-Term Use of Antiarrhythmic Drugs After Catheter Ablation for Atrial Fibrillation trial followed 2038 patients who underwent radiofrequency catheter ablation for atrial fibrillation.

Results: Of the patients, 907 (45%) had early recurrences within 90 days after the initial ablation. We divided these patients into two groups according to the timing of the first early recurrence episode, namely the ER group (early recurrence during the early phase; 0-30 days, n = 814) and ER group (early recurrence during the late phase; 31-90 days, n = 93). Three years after ablation, patients with early recurrences had a significantly lower event-free rate from late recurrences after a 90-day blanking period than patients without early recurrences (36.2% and 74.2%, respectively; log-rank, P < 0.0001). Three years after ablation, the event-free rate was significantly higher in the ER than the ER group (38.3% and 17.1%, respectively; log-rank, P < 0.0001). Moreover, the event-free rate at 3 years in the ER group was extremely low (5.6%) in patient with non-paroxysmal atrial fibrillation.

Conclusion: Early recurrences were strongly associated with late recurrences, especially in patients with the first recurrence episode at >1 month within the blanking period after a single ablation procedure. Therefore, these patients should undergo close observation during follow-up, when they had especially with non-paroxysmal atrial fibrillation.
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http://dx.doi.org/10.1016/j.ijcard.2021.07.053DOI Listing
October 2021

Extracardiac Mass After Pericardiectomy: Mediastinal Fat Replacement Secondary to Progressive Constrictive Pericarditis.

JACC Case Rep 2021 Feb 30;3(2):339-344. Epub 2020 Sep 30.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.

We describe an extracardiac mass in a 72-year-old man with a history of pericardiectomy for constrictive pericarditis. Imaging studies revealed that progressive shrinkage of the residual pericardium compressed mitral valve anteriority, and fat replacement of the secondarily enlarged posterior space of the atrioventricular groove appeared as a space-occupying lesion. ().
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http://dx.doi.org/10.1016/j.jaccas.2020.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310937PMC
February 2021

Echocardiographic predictors of cardioembolic stroke due to underlying atrial fibrillation: Reliable left atrial remodeling signs in acute stroke.

J Neurol Sci 2021 08 1;427:117514. Epub 2021 Jun 1.

Department of Neurology, National Cerebral and Cardiovascular Center, Japan.

Introduction: Atrial remodeling due to high-burden atrial fibrillation (AF) is associated with cardioembolic stroke (CES). As not all CESs is caused by AF, we analyzed the diagnostic values of each echocardiographic parameter to distinguish likely AF-related CES in acute stroke patients while in non-AF rhythm.

Methods: The data of consecutive patients with acute ischemic stroke in sinus rhythm between 2012 and 2015 were obtained. The echocardiographic parameters of patients with CES due to underlying AF (n = 61) and control patients (n = 319) with either large artery atherosclerosis or small-vessel occlusion were compared using receiver operating characteristic curves and logistic regression analyses. Each parameter was reassessed in acute stroke patients through a validation study using the same database with different periods of generalization.

Results: CES patients with underlying AF showed a significantly larger left atrial volume index (LAVi), higher mitral inflow E wave (E), and lower A wave (A) than the controls. The area under the curve (AUC) (95% confidence interval) for diagnosing CES due to underlying AF was significantly higher for LAVi/A than for LAVi (0.785 versus 0.696, P < 0.01). Among patients aged >60 years, the E/A ratio had the highest AUC (0.857) of the parameters. The cut-off values were ≥ 0.70 (sensitivity, 55.7%; specificity, 90.9%) and ≥ 0.82 (sensitivity, 71.4%; specificity, 84.1%) for LAVi/A and the E/A ratio, respectively, in patients >60 years. The cut-off values of all parameters showed similar trends in a validation study.

Conclusion: LAVi/A is a useful indicator for distinguishing CES patients with underlying AF regardless of age, and the E/A ratio is reliable among patients aged >60 years in evaluation during acute stroke admission.
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http://dx.doi.org/10.1016/j.jns.2021.117514DOI Listing
August 2021

An anatomical approach to determine the location of the sinoatrial node during catheter ablation.

J Cardiovasc Electrophysiol 2021 05 4;32(5):1320-1327. Epub 2021 Mar 4.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Introduction: The sinoatrial node (SAN) should be identified before superior vena cava (SVC) isolation to avoid SAN injury. However, its location cannot be identified without restoring sinus rhythm. This study evaluated the usefulness of the anatomically defined SAN by comparing it with the electrically confirmed SAN (e-SAN) to predict the top-most position of e-SAN and thus establish a safe and more efficient anatomical reference for SVC isolation than the previously reported reference of the right superior pulmonary vein (RSPV) roof.

Methods And Results: The e-SAN was identified as the earliest activation site in the electroanatomical map obtained during sinus rhythm. The anatomically defined SAN, the cranial edge of the crista terminalis (CT) visualized with intracardiac echocardiography (CT top), and the RSPV roof, which was obtained from the overlaid electroanatomical image of SVC and RSPV, were tagged on one map. The distance from the e-SAN to each reference was measured. Among 77 patients, the height of the e-SAN from the CT top was a median (interquartile range) of -2.0 (-8.0 to 4.0) mm. The e-SAN existed from 10 mm above the CT top or lower in 74 (96%) patients and from the RSPV roof or below in 73 (95%) patients. The reference of 10 mm above the CT top is more proximal to the right atrium than the RSPV roof and can provide longer isolatable SVC sleeves (30.0 [20.0-35.0] vs. 24.0 [18.0-30.0] mm, p < .001). The e-SAN tended to be found above the CT top when the heart rate during mapping was faster (adjusted odds ratio [95% confidence interval] per 10-bpm increase: 1.71 [1.20-2.43], p < .01).

Conclusion: The CT top is useful for predicting the upper limit of the e-SAN and can provide a better reference for SVC isolation than the RSPV roof.
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http://dx.doi.org/10.1111/jce.14961DOI Listing
May 2021

A Pooled Analysis of the Prognostic Significance of Brugada Syndrome with Atrial Fibrillation.

Curr Pharm Des 2020 ;26(1):129-137

Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.

Background: Guidelines have previously suggested that atrial fibrillation (AF) is associated with an increased risk of arrhythmic death in Brugada syndrome (BrS) patients. However, only two articles consisting of 17 AF patients with BrS supported these views. The risk stratification of BrS patients with AF remains controversial. Thus, a meta-analysis is used to estimate the risk stratification of BrS patients with AF.

Methods: We searched for relevant studies published from 2000 to December 30, 2018. A total of 1712 patients with BrS from five studies were included: 200 patients (12%) were reported with AF, among whom 37 patients (19%) had arrhythmic events.

Results: BrS patients with AF in all studies (OR 1.92, 95% CI:0.91to 4.04, P =0.09; Heterogeneity: P = 0.03, I2=61%) and some European studies (OR 1.12, 95% CI: 0.18 to 6.94, P=0.91; Heterogeneity: P = 0.006, I2=80%) did not display a higher risk of arrhythmic events than those without AF, but BrS patients with AF in Japanese studies (OR 2.32, 95% CI: 1.37 to 3.93, P=0.002; Heterogeneity: P = 0.40, I2=0%) had a higher risk of arrhythmic events than those without AF. The proportion of BrS patients with AF was greater in Japanese studies than in some European studies (16% vs. 9%, P<0.001).

Conclusion: On the whole, BrS patients with AF showed no higher risk of arrhythmic events than those without AF, but BrS patients with AF in Japan had a higher risk of arrhythmic events than those without AF.
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http://dx.doi.org/10.2174/1381612826666200114112029DOI Listing
November 2020

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome.

Heart Rhythm 2019 10 5;16(10):1468-1474. Epub 2019 Jul 5.

Quebec Heart and Lung Institute, Quebec City, Quebec, Canada.

Background: There is limited information on ethnic differences between patients with Brugada syndrome (BrS) and arrhythmic events (AEs).

Objective: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between white and Asian patients with BrS and AEs.

Methods: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter survey from Western and Asian countries, gathering 678 patients with BrS and first documented AE. After excluding patients with other (n = 14 [2.1%]) or unknown (n = 30 [4.4%]) ethnicity, 364 (53.7%) whites and 270 (39.8%) Asians comprised the study group.

Results: There was no difference in AE age onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians; P = .285). Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites; P < .001) and frequently presented with aborted cardiac arrest (71.1% vs 56%; P < .001). Asians tended to display more spontaneous type 1 BrS-ECG pattern (71.5% vs 64.3%; P = .068). A family history of sudden cardiac death was noted more in whites (29.1% vs 11.5%; P < .001), with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians; P < .001), as well as more fever-related AEs (8.5% vs 2.9%; P = .011). No difference was observed between the 2 groups regarding history of syncope and ventricular arrhythmia inducibility.

Conclusion: There are important differences between Asian and white patients with BrS. Asian patients present almost exclusively as male adults, more often with aborted cardiac arrest and spontaneous type 1 BrS-ECG. However, they have less family history of sudden cardiac death and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.
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http://dx.doi.org/10.1016/j.hrthm.2019.07.003DOI Listing
October 2019

Characterization and Management of Arrhythmic Events in Young Patients With Brugada Syndrome.

J Am Coll Cardiol 2019 04;73(14):1756-1765

Quebec Heart and Lung Institute, Quebec City, Quebec, Canada.

Background: Information on young patients with Brugada syndrome (BrS) and arrhythmic events (AEs) is limited.

Objectives: The purpose of this study was to describe their characteristics and management as well as risk factors for AE recurrence.

Methods: A total of 57 patients (age ≤20 years), all with BrS and AEs, were divided into pediatric (age ≤12 years; n = 26) and adolescents (age 13 to 20 years; n = 31).

Results: Patients' median age at time of first AE was 14 years, with a majority of males (74%), Caucasians (70%), and probands (79%) who presented as aborted cardiac arrest (84%). A significant proportion of patients (28%) exhibited fever-related AE. Family history of sudden cardiac death (SCD), prior syncope, spontaneous type 1 Brugada electrocardiogram (ECG), inducible ventricular fibrillation at electrophysiological study, and SCN5A mutations were present in 26%, 49%, 65%, 28%, and 58% of patients, respectively. The pediatric group differed from the adolescents, with a greater proportion of females, Caucasians, fever-related AEs, and spontaneous type-1 ECG. During follow-up, 68% of pediatric and 64% of adolescents had recurrent AE, with median time of 9.9 and 27.0 months, respectively. Approximately one-third of recurrent AEs occurred on quinidine therapy, and among the pediatric group, 60% of recurrent AEs were fever-related. Risk factors for recurrent AE included sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, or large S-wave on ECG lead I in the pediatric group and the presence of SCN5A mutation among adolescents.

Conclusions: Young BrS patients with AE represent a very arrhythmogenic group. Current management after first arrhythmia episode is associated with high recurrence rate. Alternative therapies, besides defibrillator implantation, should be considered.
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http://dx.doi.org/10.1016/j.jacc.2019.01.048DOI Listing
April 2019

Meta-Analysis of Risk Stratification of SCN5A With Brugada Syndrome: Is SCN5A Always a Marker of Low Risk?

Front Physiol 2019 19;10:103. Epub 2019 Feb 19.

Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, China.

with Brugada syndrome (BrS) is not commonly considered as an independent risk marker for subsequent cardiac events. However, the risk of combined with other clinical characteristics has not been fully investigated. The aim of this study is to investigate and evaluate risk stratification and related risk factors of in BrS. The databases of PubMed, EMBASE, Cochrane Library, MEDLINE, Chinese National Knowledge Infrastructure (CNKI) and Wanfang Data were searched for related studies published from January 2002 to May 2018 followed by meta-analysis. The BrS patients who underwent gene tests were included. The prognosis and risk stratification of combined with symptoms and asymptoms diagnosis in BrS, electrophysiology study (EPS) were then investigated and evaluated. Outcomes were defined as ventricular tachycardia/fibrillation (VT/VF), sudden cardiac death (SCD). Eleven suitable studies involving 1892 BrS patients who underwent gene tests were identified. (+) was not considered to be a significant predictor of future cardiac events (95% CI: 0.89-2.11; = 0.15; = 0%). However, (+) patients with symptoms at diagnosis revealed a higher prevalence of future VT/VF, SCD compared to (-) patients with symptoms at diagnosis. (95% CI: 1.06-3.70; = 0.03 = 0%) Among asymptomatic patients, the risk did not significantly differ between (+) patients and (-) patients. (95% CI: 0.51-4.72; = 0.45 = 0 %). In an investigation involving patients in EPS (-) BrS electrocardiogram (ECG), the risk of (+) is higher than that of (-) ( < 0.001). In BrS patients with symptoms at diagnosis or EPS (-), the meta-analysis suggests that (+) are at a higher risk of arrhythmic events than (-).
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http://dx.doi.org/10.3389/fphys.2019.00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389868PMC
February 2019

Pooled Analysis of Risk Stratification of Spontaneous Type 1 Brugada ECG: Focus on the Influence of Gender and EPS.

Front Physiol 2018 31;9:1951. Epub 2019 Jan 31.

Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, China.

Risk stratification of patients with Brugada syndrome (BrS) is vital for accurate prognosis and therapeutic decisions. Spontaneous Type 1 ST segment elevation is generally considered to be an independent risk factor for arrhythmic events. Other risk factors include gender, syncope, sudden cardiac arrest (SCA), and positive electrophysiological study (EPS). However, the further risk stratification of spontaneous type 1 combined with the other risk factors remains unclear. The present study pooled data from 4 large trials aiming to systematically evaluate the risk of spontaneous Type-1 ECG when combined with one or more of these other recognized risk factors. We searched for related studies published from November 2, 2002 to February 10, 2018 in PubMed, EMBASE, Cochrane Library, MEDLINE, Chinese National Knowledge Infrastructure (CNKI), and Wanfang Databases. The pooled data were evaluated combining each risk factor with the presence of a spontaneous Type-1 ECG. All analyses were performed using Review Manager, version 5.0.12. Four eligible studies involving 1,338 patients (85% males, mean age: 48.1 ± 18.1 years) were enrolled. Spontaneous Type-1 ECG was associated with higher risk for ventricular tachycardia/fibrillation (VT/VF) than cases with non-Type 1 ECG in males (odds ratio: 95% CI: 1.84-5.17; < 0.0001), but not in females ( = 0.29). Among spontaneous Type-1 cases with syncope or with positive EPS, the difference was not statistically significant ( = 0.06 and 0.07, respectively). Patients with Type-1 ECGs and positive EPS were at higher risk than those with negative EPS (95% CI: 1.10-5.04; = 0.03). Pooled analysis showed an association of Spontaneous Type-1 ECG, Type-1 ECGs combined with male, and Type-1 ECGs combined with positive EPS between increased risk of arrhythmic events. Our results indicate that in BrS patients, a spontaneous Type-1 ECG is an independent risk factor for SCD in males, but not in females. A spontaneous Type-1 BrS is associated with a worse prognosis when combined with positive EPS.
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http://dx.doi.org/10.3389/fphys.2018.01951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365464PMC
January 2019

Multicenter Study of the Validity of Additional Freeze Cycles for Cryoballoon Ablation in Patients With Paroxysmal Atrial Fibrillation: The AD-Balloon Study.

Circ Arrhythm Electrophysiol 2019 01;12(1):e006989

Department of Cardiovascular Medicine (K.M., T.M., K.N., N.K., T.K., M.W., K.Y., K.I., Y.Y.I., S.N., T.N., T.A., C.I., T.N., S.Y., K.F.K.), National Cerebral and Cardiovascular Center, Suita, Japan.

Background: Pulmonary vein isolation (PVI) is a cornerstone of catheter ablation in patients with paroxysmal atrial fibrillation, and balloon-based ablation has been recently performed worldwide. The second-generation cryoballoon (CB2) ablation has proven to be highly effective in achieving freedom from paroxysmal atrial fibrillation. However, there are some debatable questions, including the ideal number of freeze cycles.

Methods: The AD-Balloon study (Multicenter Study of the Validity of Additional Freeze Cycles for Cryoballoon Ablation) was designed as a prospective, multicenter, and randomized clinical trial for investigation of the optimal strategy of freeze cycles for the CB2 ablation. One hundred and ten consecutive patients (aged 64±11 years) were randomly assigned to 2 groups after achieving a PVI by the CB2 ablation: 3-minute freeze cycles were added to each pulmonary vein (AD group: n=55) or not (non-AD group: n=55). Delayed-enhancement magnetic resonance imaging was also performed 1 to 2 months after the PVI to assess the ablation lesions.

Results: The patient characteristics did not differ between the 2 groups. A complete PVI was achieved in all patients. The total number of freeze cycles and durations for all pulmonary veins were significantly shorter in the non-AD group than in the AD group (5.7±1.6 versus 9.1±1.6 cycles, P<0.0001, and 932±244 versus 1483±252 seconds, P<0.0001). The cumulative freedom from any atrial tachyarrhythmia at 1 year was 87.3% in the AD group and 89.1% in the non-AD group (log-rank test P=0.78). There was no significant difference in the frequency of gaps on the PVI lines in the delayed-enhancement magnetic resonance imaging (46% in the AD group versus 36% in the non-AD group; P=0.38).

Conclusions: No benefit was found in the patients receiving additional 3-minute freeze cycles after the complete PVI with the CB2 ablation, suggesting that an insurance freeze after achieving a PVI with the CB2 may be unnecessary and time consuming.
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http://dx.doi.org/10.1161/CIRCEP.118.006989DOI Listing
January 2019

Time-to-first appropriate shock in patients implanted prophylactically with an implantable cardioverter-defibrillator: data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

Europace 2019 May;21(5):796-802

Lankenau Medical Center, Wynnewood, PA, USA.

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce.

Methods And Results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P < 0.05), those with syncope (P = 0.001), and those with Class IIa indication for ICD (P = 0.001). A longer time was associated with a positive family history of sudden cardiac death (P < 0.05). Multivariate Cox regression revealed shorter time-to-ICD therapy in patients with syncope [odds ratio (OR) 1.65, P = 0.001]. In 193 patients (76.6%), therapy was delivered during the first 5 years. Factors associated with this time were syncope (OR 0.36, P = 0.001), spontaneous Type 1 Brugada electrocardiogram (ECG) (OR 0.5, P < 0.05), and Class IIa indication (OR 0.38, P < 0.01) as opposed to Class IIb (OR 2.41, P < 0.01). A near-significant trend for female gender was also noted (OR 0.13, P = 0.052). Two score models for prediction of <5 years to shock were built.

Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy.
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http://dx.doi.org/10.1093/europace/euy301DOI Listing
May 2019

Gender Differences in Prognosis and Risk Stratification of Brugada Syndrome: A Pooled Analysis of 4,140 Patients From 24 Clinical Trials.

Front Physiol 2018 22;9:1127. Epub 2018 Aug 22.

Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, China.

Male gender has been consistently shown to be a risk factor for a greater number of arrhythmic events in patients with Brugada Syndrome (BrS). However, there have been no large-scale comprehensive pooled analyses to statistically and systematically verify this association. Therefore, we conducted a pooled analysis on gender differences in prognosis and risk stratification of BrS with a largest sample capacity at present. We searched PubMed, Embase, Medline, Cochrane Library databases, Chinese National Knowledge Infrastructure, and Wanfang Data for relevant studies published from 2002 to 2017. The prognosis and risk stratification of BrS and risk factors were then investigated and evaluated according to gender. Twenty-four eligible studies involving 4,140 patients were included in the analysis. Male patients (78.1%) had a higher risk of arrhythmic events than female patients (95% confidence interval: 1.46-2.91, < 0.0001). Among the male population, there were statistical differences between symptomatic patients and asymptomatic patients (95% CI: 2.63-7.86, < 0.00001), but in the female population, no statistical differences were found. In the female subgroup, electrophysiological study (EPS) positive patients had a tendency toward a higher risk of arrhythmic events than EPS-negative patients (95% CI: 0.93-29.77, = 0.06). Male patients are at a higher risk of arrhythmic events than female patients. Within the male population, symptomatic patients have a significantly higher risk profile compared to asymptomatic patients, but no such differences are evident within the female population. Consequently, in the female population, the risk of asymptomatic patterns cannot be underestimated.
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http://dx.doi.org/10.3389/fphys.2018.01127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113678PMC
August 2018

Development of Heart Failure From Transient Atrial Fibrillation Attacks in Responders to Cardiac Resynchronization Therapy.

JACC Clin Electrophysiol 2018 09 25;4(9):1227-1234. Epub 2018 Jul 25.

Division of Cardiology, National Cerebral and Cardiovascular Center Japan, Suita Osaka, Japan.

Objectives: This study aimed to clarify the clinical impact of transient atrial fibrillation (AF) attacks themselves and the efficacy of cardiac resynchronization therapy (CRT) in patients with intermittent AF.

Background: The benefit of CRT in patients with intermittent AF, especially the effect of the AF attacks themselves, remains unclear.

Methods: Among our cohort of 269 consecutive CRT patients, we compared the percent of biventricular pacing (BIVP%) and other clinical characteristics between patients with intermittent AF and those with sinus rhythm (SR).

Results: During a median follow-up of 942 days (interquartile range: 379 to 1,464 days) a total of 22 patients, including 59% of CRT responders, developed heart failure (HF) due to a transient AF attack itself, and that accounted for 21% of all HF events. The BIVP% during the AF attacks was significantly lower than that during SR (p < 0.05). When compared to the SR groups, patients with intermittent AF had a significantly higher risk of developing HF or death (hazard ratio: 2.2; 95% confidence interval: 1.3 to 3.8). However, the patients who received a BIVP% of ≥90% during AF attacks were comparable to those with SR (hazard ratio: 1.2; 95% confidence interval: 0.4 to 3.0).

Conclusions: A substantial number of patients developed HF due to transient AF attacks themselves even in the CRT responders, and the reason was mainly due to the loss of the BIVP%.
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http://dx.doi.org/10.1016/j.jacep.2018.06.010DOI Listing
September 2018

Gender differences in patients with Brugada syndrome and arrhythmic events: Data from a survey on arrhythmic events in 678 patients.

Heart Rhythm 2018 10 13;15(10):1457-1465. Epub 2018 Jun 13.

Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs).

Objective: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between males and females in patients with BrS with their first AE.

Methods: The multicenter Survey on Arrhythmic Events in BRUgada Syndrome collected data on the first AE in 678 patients with BrS including 619 males (91.3%) and 59 females (8.7%) aged 0.27-84 years (mean age 42.5 ± 14.1 years) at the time of AE occurrence.

Results: After excluding pediatric patients, it was found that females were older than males (49.5 ± 14.4 years vs 43 ± 12.7 years, respectively; P = .001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, the male to female ratio for AEs was ≈9-fold higher than that in White. Spontaneous type 1 BrS ECG was associated with an earlier onset of AEs in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS ECG was present in males and females above the age of 60 years. Females less frequently showed spontaneous type 1 BrS ECG (41% vs 69%; P < .001) or arrhythmia inducibility at electrophysiology study (36% vs 66%; P < .001). An SCN5A mutation was more frequently found in females (48% vs 28% in males; P = .007).

Conclusion: This study confirms that female patients with BrS are much rarer, display less type 1 Brugada ECG, and exhibit lower inducibility rates than do males. It shows for the first time that female patients with BrS with AE have higher SCN5A mutation rates as well as the relationship between gender vs age at the onset of AEs and ethnicity.
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http://dx.doi.org/10.1016/j.hrthm.2018.06.019DOI Listing
October 2018

Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada Syndrome.

Heart Rhythm 2018 09 9;15(9):1394-1401. Epub 2018 Apr 9.

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart); Service de Cardiologie et CNMR Maladies Cardiaques Héréditaires Rares, Hôpital Bichat, Paris, France, and Université Paris Diderot, Paris, France.

Background: The literature on fever-related arrhythmic events (AEs) in Brugada syndrome (BrS) is currently limited to few case reports and small series.

Objective: The present study aimed to describe the characteristics of fever-related AE in a large cohort of patients with BrS.

Methods: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter study on 678 patients with BrS with first AE documented at the time of aborted cardiac arrest (n = 426) or after prophylactic implantable cardioverter-defibrillator implantation (n = 252).

Results: In 35 of 588 patients (6%) with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%), and proband (70%). The mean age at the time of AE was 29 ± 24 years (range 0.3-76 years). Most patients (80%) presented with aborted cardiac arrest and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope, and spontaneous type 1 Brugada electrocardiogram were noted in 17%, 40%, and 71% of patients, respectively. Ventricular fibrillation was induced at electrophysiology study in 9 of 19 patients (47%). An SCN5A mutation was found in 14 of 28 patients (50%). The highest proportion of fever-related AE was observed in the pediatric population (age <16 years), with a disproportionally higher event rate in the very young (age 0-5 years) (65%). Males were involved in all age groups and females only in the pediatric and elderly groups. Fever-related AE affected 17 Caucasians aged <24 years, but no Asians aged <24 years.

Conclusion: The risk of fever-related AE in BrS markedly varies according to age group, sex, and ethnicity. Taking these factors into account could help the clinical management of patients with BrS with fever.
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http://dx.doi.org/10.1016/j.hrthm.2018.04.007DOI Listing
September 2018

HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia.

Int Heart J 2018 May 6;59(3):601-606. Epub 2018 May 6.

Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences.

A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 10 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.
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http://dx.doi.org/10.1536/ihj.17-241DOI Listing
May 2018

Profile of patients with Brugada syndrome presenting with their first documented arrhythmic event: Data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

Heart Rhythm 2018 05 8;15(5):716-724. Epub 2018 Jan 8.

Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark; Department of Medicine and Surgery, University of Copenhagen, Copenhagen, Denmark.

Background: Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their first arrhythmic event (AE) after prophylactic implantation of an implantable cardioverter-defibrillator (ICD) is limited.

Objectives: The objectives of this study were (1) to compare clinical, electrocardiographic, electrophysiologic, and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (group A) with profiles of those in whom the AE was documented after prophylactic ICD implantation (group B) and (2) to characterize group B patients' profile using the class II indications for ICD implantation established by HRS/EHRA/APHRS expert consensus statement in 2013.

Methods: A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 patients with BrS who exhibited their AE (group A, n = 426; group B, n = 252).

Results: The first AE occurred in group B patients 6.7 years later than in group A (mean age 46.1 ± 13.3 years vs 39.4 ± 15.1 years; P < .001). Group B patients had a higher incidence of family history of sudden cardiac death and SCN5A mutations. Of the 252 group B patients, 189 (75%) complied with the HRS/EHRA/APHRS indications whereas the remaining 63 (25%) did not.

Conclusion: Patients with BrS with the first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of sudden cardiac death and SCN5A mutations as compared with those presenting with aborted cardiac arrest. Only 75% of patients who exhibited an AE after receiving a prophylactic ICD complied with the 2013 class II indications, suggesting that efforts are still required for improving risk stratification.
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http://dx.doi.org/10.1016/j.hrthm.2018.01.014DOI Listing
May 2018

Age of First Arrhythmic Event in Brugada Syndrome: Data From the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 Patients.

Circ Arrhythm Electrophysiol 2017 Dec 18;10(12). Epub 2017 Dec 18.

From the Department of Cardiology, Tel Aviv Medical Center, Tel Aviv University, Israel (A.M., E.L., M.R., Y.M., B.B.); Service de Cardiologie, L'institut du Thorax, CHU de Nantes, France (A.A., J.-B.G., V.P.); INSERM 1045, LIRYC Institute, Bordeaux University Hospital, France (F.S.); Division of Cardiology and Vascular Disease, Rennes University Health Centre, France (P.M.); Division of Cardiology, Department of Internal Medicine, College of Medicine, Catholic University of Korea, Seoul (S.-H.K.); Heart Rhythm Center, Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Japan (S.M., Y.T., K.H.); Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (T.K., T.A., K.F.K.); Heart Rhythm Management Centre, UZ-VUB (Universitair Ziekenhuis Brussel-Vrije Universiteit Brussel), Belgium (G.C., P.B.); Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei (J.J.M.J.); Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA (E.L.); Arrhythmia Services, Cardiology Division, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (M.R.); Department of Internal Medicine J, Tel Aviv Medical Center, Israel (A.H.); Department of Clinical and Experimental Cardiology, Heart Centre AMC (Academisch Medisch Centrum), University of Amsterdam, The Netherlands (Y.M., P.G.P., A.A.M.W.); Hospital Clínic Pediatric Arrhythmia Unit, Cardiovascular Institute, Pediatric Arrhythmias, Electrophysiology and Sudden Death Unit, Cardiology Department, Hospital Sant Joan de Déu, University of Barcelona, Spain (E.A., J.B.); Department of Cardiology, First Affiliated Hospital of Xiamen University, Fujian, China (Z.H.); Service de Cardiologie et CNMR Maladies Cardiaques Héréditaires Rares, Hôpital Bichat, Paris, France (I.D., A.L.); Université Paris Diderot, Sorbonne, Paris, France (I.D., A.L.); Division of Cardiology, Department of Medical Sciences, Città della Salute e della Scienza Hospital, University of Torino, Italy (C.G., F.G.); Cardiovascular Sciences, St George's, University of London, United Kingdom (Y.D.W., E.R.B.); Cardiology Clinical Academic Group, St George's University Hospitals NHS Foundation Trust, London, United Kingdom (Y.D.W., E.R.B.); Department of Molecular Cardiology, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (C.N., S.G.P.); Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona-IdIBGi, Spain (R.B.); Department of Cardiology, Erasme University Hospital, Université Libre de Bruxelles, Belgium (R.C.-A.); Department of Cardiology, Quebec Heart and Lung Institute, Canada (J.C.); Division of Cardiology, Policlinico Casilino, Roma, Italy (L.C.); Department of Cardiology, Pediatric Arrhythmias, Electrophysiology, and Sudden Death Unit, Hospital Sant Joan de Déu Barcelona, Universitat de Barcelona, Spain (G.S.-B.); Department of Cardiology, Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark (J.T.-H.); Department of Medicine and Surgery, University of Copenhagen, Denmark (J.T.-H.); Department of Molecular Medicine, University of Pavia, Italy (S.G.P.); Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Japan (M.T.); Division of Rhythmology and Electrophysiology, Department of Cardiology, Hannover Medical School, Germany (C.V.); Division of Cardiology, Hospital of Peschiera del Garda, Veneto, Italy (P.D.); Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova, Italy (D.C.); Lankenau Medical Center, Wynnewood, PA (G.-X.Y.); and Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (G.-B.N.).

Background: Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE.

Methods And Results: A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter-defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (<16 years) and elderly patients (>70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27-84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±15.0 years; <0.001). In adult patients (≥16 years), women experienced AE 6.5 years later than men (=0.003). Whites and Asians exhibited their AE at the same median age (43 years).

Conclusions: SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE.
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http://dx.doi.org/10.1161/CIRCEP.117.005222DOI Listing
December 2017

Impact of premature activation of the right ventricle with programmed stimulation in Brugada syndrome.

J Cardiovasc Electrophysiol 2018 01 26;29(1):71-78. Epub 2017 Sep 26.

Okayama City General Medical Center, Okayama, Japan.

Background: In Brugada syndrome (BrS), it has been reported that delayed activation in the RV is related to the development of type-1 ECG, which is more critical than type-2. On the other hand, the coexistence of complete right bundle-branch block (CRBBB), which also causes delayed activation in the RV, sometimes makes typical BrS ECG misleading. We hypothesized that premature stimulation of the RV can unmask the influence of delayed activation in the RV and convert the morphology of ECG in BrS patients.

Methods And Results: In 35 BrS patients with type-1 ECG including 8 patients with concomitant CRBBB and 6 control subjects with CRBBB, progressively premature single stimulations were delivered from the RV apex on electrophysiological study. Then we evaluated QRS morphology of fusion beats created by single premature stimulation in each patient. In 29 (83%) of 35 of the BrS patients, conversion from type-1 to type-2 ECG was observed during the process of single premature stimulation. Additionally, in all 8 BrS patients with concomitant CRBBB, type-1 or type-2 BrS ECG was revealed by premature stimulation with relief of CRBBB. These findings were not observed in any of the control subjects with CRBBB.

Conclusion: Single premature stimulation of the RV converts ECG from type-1 to type-2 in most BrS cases and unmasks type-1 ECG in all BrS cases with CRBBB. Our results could suggest that type-1 ECG is associated with delayed activation of the RV compared with type-2 ECG.
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http://dx.doi.org/10.1111/jce.13336DOI Listing
January 2018

Persistent increase in cardiac troponin T at hospital discharge predicts repeat hospitalization in patients with acute decompensated heart failure.

PLoS One 2017 5;12(4):e0173336. Epub 2017 Apr 5.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.

Background: High-sensitive cardiac troponin T (hsTnT) is a sensitive biomarker of myocardial damage and predictor of acute decompensated heart failure (ADHF). However, there is little information on changes over time in hsTnT level during ADHF management. The aim of this prospective study was to evaluate changes in hsTnT levels between admission and at discharge in patients with ADHF, and identify factors that determine such levels and their prognostic significance.

Methods And Results: We evaluated 404 ADHF patients with abnormal hsTnT levels (≥0.0135 ng/ml) on admission. The median (interquartile ranges) hsTnT levels on admission, at discharge, and percent changes in hsTnT levels were 0.038 (0.026 to 0.065), 0.032 (0.021 to 0.049) ng/ml, and -12.0 (-39.8 to 7.4) % respectively. The numbers of patients with falling (hsTnT decrease > -15%), stable (hsTnT change between -15 and +15%) and rising (hsTnT increase > +15%) hsTnT level at discharge were 190, 146, and 68, respectively. The percent change in B-type natriuretic peptide (BNP) levels was greater in the falling group, compared to the stable (p<0.001) and rising groups (p<0.001). Changes in hsTnT levels correlated significantly with changes in BNP levels (ρ = 0.22, p<0.001). Multivariate Cox regression analysis identified rising or stable hsTnT at discharge as a significant predictor of heart failure-related rehospitalization (hazard ratio: 1.69; 95% confidence interval: 1.06 to 2.70; p = 0.03).

Conclusions: Persistent increase in hsTnT levels at discharge correlated with inadequate decrease of BNP levels, and was a predictor of poor clinical outcome, with repeat heart failure hospitalizations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173336PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381770PMC
August 2017

Local Left Ventricular Epicardial J Waves and Late Potentials in Brugada Syndrome Patients with Inferolateral Early Repolarization Pattern.

Front Physiol 2017 26;8:14. Epub 2017 Jan 26.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center Osaka, Japan.

Brugada syndrome (BrS) is characterized by J-point or ST-segment elevation on electrocardiograms (ECGs) and increased risk of ventricular fibrillation (VF). In BrS, epicardial depolarization abnormality with delayed potential on the right ventricular outflow tract is reportedly the predominant mechanism underlying VF. Yet VF occurrence is also associated with early repolarization (ER) pattern in the inferolateral ECG leads, which may represent the inferior and/or left lateral ventricular myocardium. The aim of this study was to examine epicardial electrograms recorded directly at the left ventricle (LV) in BrS patients after VF episodes. In 12 BrS patients who had experienced VF episodes and 17 control subjects, a multipolar catheter was introduced into the left lateral coronary vein for unipolar and bipolar electrogram recordings at the LV epicardium. Both inferior and lateral ER patterns on ECG were observed in three BrS patients and six control subjects. In the epicardium, prominent J waves were detected using unipolar recording, and potentials after the QRS complex were detected using bipolar recording in three of the 12 BrS patients. These three patients also showed both inferior and lateral ER patterns on ECG. Neither prominent J waves nor potentials after the QRS complex were recorded at the endocardium of the LV in any of these three patients; nor were they seen at the epicardium in any of the control subjects. These features were accentuated on pilsicainide administration ( = 2) but diminished on constant atrial pacing ( = 3) and isoproterenol administration ( = 1). The J waves observed through unipolar recording coincided with the potentials after QRS complex observed through bipolar recording and with the inferolateral ER patterns on ECG. We recorded prominent J waves in unipolar electrogram and potentials after QRS complex in bipolar electrogram at the LV epicardium in BrS patients with global ER pattern. The prominent J waves coincided with the potentials after QRS complex and the inferolateral ER pattern on ECG. The characteristics of the inferolateral ER pattern on ECG in these patients primarily represent depolarization feature.
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http://dx.doi.org/10.3389/fphys.2017.00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266732PMC
January 2017

Utility of High-Resolution Magnetocardiography to Predict Later Cardiac Events in Nonischemic Cardiomyopathy Patients With Normal QRS Duration.

Circ J 2016 Dec 17;81(1):44-51. Epub 2016 Nov 17.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center.

Background: Nonischemic dilated cardiomyopathy (NIDCM) patients, even those with a narrow QRS, are at increased risk for major adverse cardiac events (MACE). We hypothesized that 64-channel magnetocardiography (MCG) would be useful to detect prognostic left intraventricular disorganized conduction (LiDC) by overcoming the limitations of fragmented QRS (fQRS, qualitative definitions, low specificity) and late potential (abnormality undetectable in earlier QRS).Methods and Results:We evaluated LiDC on MCG, defined as significant deviation from a global clockwise left ventricular (LV) activation pattern, and conventional noninvasive predictors of MACE, including fQRS and late potential, in 51 NIDCM patients with narrow QRS (LV ejection fraction, 22±7%; QRS duration, 99±11 ms). MACE was defined as cardiac death, lethal ventricular arrhythmias, or LV assist device (LVAD) implantation. LiDC was present in 22 patients. Baseline characteristics were comparable between patients with and without LiDC, except for the ratio of positive late potential. During a mean follow-up of 2.9 years, MACE developed in 16 NIDCM patients (3 cardiac deaths, 9 lethal ventricular arrhythmias, and 4 LVAD). MACE was more incident in patients with LiDC (13/22) than in those without (3/29, P<0.001). Multivariate analysis revealed LiDC, but not fQRS or late potential, as the strongest independent predictor of MACE (hazard ratio 4.28, 95% confidence interval 1.30-19.39, P=0.015).

Conclusions: MCG accurately depicts LiDC, a promising noninvasive predictor of MACE in patients with NIDCM and normal QRS.
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http://dx.doi.org/10.1253/circj.CJ-16-0683DOI Listing
December 2016

Potentially Lethal Ventricular Arrhythmias and Heart Failure in Arrhythmogenic Right Ventricular Cardiomyopathy: What Are the Differences Between Men and Women?

JACC Clin Electrophysiol 2016 Oct 25;2(5):546-555. Epub 2016 May 25.

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

Objectives: The aim of this study was to assess sex-related differences in sporadic cases of arrhythmogenic right ventricular cardiomyopathy (ARVC).

Background: Previous studies have suggested male predominance in ARVC. However, the impact of sex on the heterogeneous clinical profile and prognosis of ARVC were not fully recognized.

Methods: The study population included 110 patients with ARVC who fulfilled the revised Task Force criteria (median age 48 years [interquartile range (IQR): 36 to 57 years]). All patients were sporadic cases without family history of ARVC. Male patients had a 3:1 predominance (75%). Ninety-seven patients (88%) were considered to have "definite" ARVC based on revised Task Force criteria.

Results: At the initial evaluation, there were no significant sex-related differences in age, 12-lead electrocardiogram findings, late potentials by signal-averaged electrocardiogram, left ventricular ejection fraction, or right ventricular ejection fraction. During a median follow-up of 10.0 years (IQR: 5.2 to 15.6 years), 18 patients died from cardiac causes. Kaplan-Meier analysis, considering patients' lives since birth, revealed that male patients had a significantly higher risk of ventricular tachycardia/ventricular fibrillation than did female patients (56% vs. 90%, p = 0.02), whereas female patients had a significantly higher risk of heart failure (HF) death or heart transplantation (22% vs. 5%, p = 0.002). On multivariate Cox regression analysis, female sex was an independent risk factor for HF death or heart transplantation due to HF (hazard ratio: 6.29, 95% confidence interval: 1.29 to 40.2; p = 0.02).

Conclusions: Among patients with sporadic ARVC, men had a significantly higher risk of ventricular tachycardia/ventricular fibrillation, whereas women had a significantly higher risk of HF death or heart transplantation due to HF.
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http://dx.doi.org/10.1016/j.jacep.2016.02.019DOI Listing
October 2016

Prognostic Value of Prothrombin Time International Normalized Ratio in Acute Decompensated Heart Failure - A Combined Marker of Hepatic Insufficiency and Hemostatic Abnormality.

Circ J 2016 26;80(4):913-23. Epub 2016 Feb 26.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center.

Background: There are limited studies regarding the prognostic value of coagulation abnormalities in heart failure patients. The clinical significance of prothrombin time international normalized ratio (INR), a widely accepted marker assessing coagulation abnormalities, in acute decompensated heart failure (ADHF) remains unclear.

Methods and results: Among 561 consecutive patients admitted for ADHF, INR was assessed in 294 patients without prior anticoagulation therapy, acute coronary syndrome, liver disease, or overt disseminated intravascular coagulation. Increased INR on admission was positively associated with increased levels of thrombin-antithrombin complex, C-reactive protein, total bilirubin, γ-glutamyl transpeptidase, inferior vena cava diameter, tricuspid regurgitation severity, markers of neurohormonal activation, and also negatively associated with decreased albumin, cholinesterase, and total cholesterol. In contrast, there was no significant association with left ventricular ejection fraction, serum sodium or blood urea nitrogen. Multivariate analysis showed that increased INR was independently associated with increased all-cause mortality (hazard ratio 1.89 per 0.1 increase, 95% confidence interval 1.14-3.13, P=0.013) during the median follow up of 284 days. Increased INR also had a higher prognostic value compared to risk score models including the Model for End-Stage Liver Disease (MELD) score or the MELD excluding INR (MELD-XI) score.

Conclusions: Increased INR is an independent predictor of all-cause mortality in ADHF patients without anticoagulation, reflecting coagulation abnormalities and hepatic insufficiency, possibly through systemic inflammation, neurohormonal activation and venous congestion.
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http://dx.doi.org/10.1253/circj.CJ-15-1326DOI Listing
December 2016

Diagnosis and treatment of cardiac sarcoidosis.

Heart 2016 Feb 7;102(3):184-90. Epub 2015 Dec 7.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan Department of Cardiology, Tokyo Medical University Hachioji Medical Center, Hachioji, Japan.

Sarcoidosis is a systemic granulomatous disease of unknown aetiology. The frequency of cardiac involvement (cardiac sarcoidosis (CS)) varies in the different geographical regions, but it has been reported that it is an absolutely important prognostic factor in this disease. Complete atrioventricular block is the most common, and ventricular tachycardia/ventricular fibrillation the second most common arrhythmia in this disease, both of which are associated with cardiac sudden death. Diagnosing CS is sometimes difficult because of the non-specific ECG and echocardiographic findings, and CS is sometimes misdiagnosed as dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy or an idiopathic ventricular aneurysm, and therefore, endomyocardial biopsy is important, but has a low sensitivity. Another problem is the recognition of isolated types of CS. Recently, MRI and (18)F-fluorodeoxyglucose positron emission tomography have been demonstrated to be useful tools for the non-invasive diagnosis of CS as well as therapeutic evaluation tools, but are still unsatisfactory. Treatment of CS is usually done by corticosteroid therapy to control inflammation, prevent fibrosis and protect from any deterioration of the cardiac function, but the long-term outcome is still in debate. Despite the advancement of non-pharmacological approaches for CS (pacing, defibrillators and catheter ablation) to improve the prognosis, there are still many issues remaining to resolve diagnosing and managing CS. Here, we attempt a review of the clinical evidence, with special focus on the current understanding of this disease and showing the current strategies and remaining problems of diagnosing and managing CS.
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http://dx.doi.org/10.1136/heartjnl-2015-307877DOI Listing
February 2016

Incidence and Clinical Significance of Brugada Syndrome Masked by Complete Right Bundle-Branch Block.

Circ J 2015 8;79(12):2568-75. Epub 2015 Oct 8.

Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences.

Background: Brugada syndrome (BrS)-type electrocardiogram (ECG) is concealed by complete right bundle-branch block (CRBBB) in some cases of BrS. Clinical significance of BrS masked by CRBBB is not well known.

Methods and results: We reviewed an ECG database of 326 BrS patients who had type 1 ECG with or without pilsicainide. "BrS masked by CRBBB" was defined on ECG as <2-mm elevation of the J point at the time of CRBBB in the right precordial leads, and BrS-type J-point elevation ≥2 mm at the time of normalized QRS complex on relieved CRBBB. We identified 25 BrS patients (7.7%) with persistent (n=12) or intermittent CRBBB (n=13). Relief of CRBBB by pacing was performed in patients with persistent CRBBB. The prevalence of BrS masked by CRBBB was 3.1% (10/326 patients). Three patients had type 1 ECG, and 7 patients had type 2 or 3 ECG on relief of CRBBB. Two of these 10 patients had lethal arrhythmic events during the follow-up period (mean, 86.4±57.2 months). There was no prognostic difference between BrS masked by CRBBB and other BrS.

Conclusions: In a small BrS population, CRBBB can completely mask typical BrS-type ECG. BrS masked by CRBBB is associated with the same risk of fatal ventricular tachyarrhythmia as other BrS.
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http://dx.doi.org/10.1253/circj.CJ-15-0618DOI Listing
September 2016

Efficacy of Antiarrhythmic Drugs Short-Term Use After Catheter Ablation for Atrial Fibrillation (EAST-AF) trial.

Eur Heart J 2016 Feb 28;37(7):610-8. Epub 2015 Sep 28.

Department of Cardiovascular Medicine, Okamura Memorial Hospital, Shizuoka, Japan.

Aims: Substantial portion of early arrhythmia recurrence after catheter ablation for atrial fibrillation (AF) is considered to be due to irritability in left atrium (LA) from the ablation procedure. We sought to evaluate whether 90-day use of antiarrhythmic drug (AAD) following AF ablation could reduce the incidence of early arrhythmia recurrence and thereby promote reverse remodelling of LA, leading to improved long-term clinical outcomes.

Methods And Results: A total of 2038 patients who had undergone radiofrequency catheter ablation for paroxysmal, persistent, or long-lasting AF were randomly assigned to either 90-day use of Vaughan Williams class I or III AAD (1016 patients) or control (1022 patients) group. The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of class I or III AAD at 1 year, following the treatment period of 90 days post ablation. Patients assigned to AAD were associated with significantly higher event-free rate from recurrent atrial tachyarrhythmias when compared with the control group during the treatment period of 90 days [59.0 and 52.1%, respectively; adjusted hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.73-0.96; P = 0.01]. However, there was no significant difference in the 1-year event-free rates from the primary endpoint between the groups (69.5 and 67.8%, respectively; adjusted HR 0.93; 95% CI 0.79-1.09; P = 0.38).

Conclusion: Short-term use of AAD for 90 days following AF ablation reduced the incidence of recurrent atrial tachyarrhythmias during the treatment period, but it did not lead to improved clinical outcomes at the later phase.
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http://dx.doi.org/10.1093/eurheartj/ehv501DOI Listing
February 2016

Enhancement of Spontaneous Activity by HCN4 Overexpression in Mouse Embryonic Stem Cell-Derived Cardiomyocytes - A Possible Biological Pacemaker.

PLoS One 2015 18;10(9):e0138193. Epub 2015 Sep 18.

Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.

Background: Establishment of a biological pacemaker is expected to solve the persisting problems of a mechanical pacemaker including the problems of battery life and electromagnetic interference. Enhancement of the funny current (If) flowing through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and attenuation of the inward rectifier K+ current (IK1) flowing through inward rectifier potassium (Kir) channels are essential for generation of a biological pacemaker. Therefore, we generated HCN4-overexpressing mouse embryonic stem cells (mESCs) and induced cardiomyocytes that originally show poor IK1 currents, and we investigated whether the HCN4-overexpressing mESC-derived cardiomyocytes (mESC-CMs) function as a biological pacemaker in vitro.

Methods And Results: The rabbit Hcn4 gene was transfected into mESCs, and stable clones were selected. mESC-CMs were generated via embryoid bodies and purified under serum/glucose-free and lactate-supplemented conditions. Approximately 90% of the purified cells were troponin I-positive by immunostaining. In mESC-CMs, expression level of the Kcnj2 gene encoding Kir2.1, which is essential for generation of IK1 currents that are responsible for stabilizing the resting membrane potential, was lower than that in an adult mouse ventricle. HCN4-overexpressing mESC-CMs expressed about a 3-times higher level of the Hcn4 gene than did non-overexpressing mESC-CMs. Expression of the Cacna1h gene, which encodes T-type calcium channel and generates diastolic depolarization in the sinoatrial node, was also confirmed. Additionally, genes required for impulse conduction including Connexin40, Connexin43, and Connexin45 genes, which encode connexins forming gap junctions, and the Scn5a gene, which encodes sodium channels, are expressed in the cells. HCN4-overexpressing mESC-CMs showed significantly larger If currents and more rapid spontaneous beating than did non-overexpressing mESC-CMs. The beating rate of HCN4-overexpressing mESC-CMs responded to ivabradine, an If inhibitor, and to isoproterenol, a beta-adrenergic receptor agonist. Co-culture of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with aggregates composed of mESC-CMs resulted in synchronized contraction of the cells. The beating rate of hiPSC-CMs co-cultured with aggregates of HCN4-overexpressing mESC-CMs was significantly higher than that of non-treated hiPSC-CMs and that of hiPSC-CMs co-cultured with aggregates of non-overexpressing mESC-CMs.

Conclusions: We generated HCN4-overexpresssing mESC-CMs expressing genes required for impulse conduction, showing rapid spontaneous beating, responding to an If inhibitor and beta-adrenergic receptor agonist, and having pacing ability in an in vitro co-culture system with other excitable cells. The results indicated that these cells could be applied to a biological pacemaker.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138193PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575154PMC
May 2016

Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial.

Eur Heart J 2015 Dec 30;36(46):3276-87. Epub 2015 Aug 30.

Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.

Aims: Most of recurrent atrial tachyarrhythmias after pulmonary vein isolation (PVI) for atrial fibrillation (AF) are due to reconnection of PVs. The aim of the present study was to evaluate whether elimination of adenosine triphosphate (ATP)-induced dormant PV conduction by additional energy applications during the first ablation procedure could reduce the incidence of recurrent atrial tachyarrhythmias.

Methods And Results: We randomly assigned 2113 patients with paroxysmal, persistent, or long-lasting AF to either ATP-guided PVI (1112 patients) or conventional PVI (1001 patients). The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of Vaughan Williams class I or III antiarrhythmic drugs at 1 year with the blanking period of 90 days post ablation. Among patients assigned to ATP-guided PVI, 0.4 mg/kg body weight of ATP provoked dormant PV conduction in 307 patients (27.6%). Additional radiofrequency energy applications successfully eliminated dormant conduction in 302 patients (98.4%). At 1 year, 68.7% of patients in the ATP-guided PVI group and 67.1% of patients in the conventional PVI group were free from the primary endpoint, with no significant difference (adjusted hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.74-1.09; P = 0.25). The results were consistent across all the prespecified subgroups. Also, there was no significant difference in the 1-year event-free rates from repeat ablation for any atrial tachyarrhythmia between the groups (adjusted HR 0.83; 95% CI 0.65-1.08; P = 0.16).

Conclusion: In the catheter ablation for AF, we found no significant reduction in the 1-year incidence of recurrent atrial tachyarrhythmias by ATP-guided PVI compared with conventional PVI.
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http://dx.doi.org/10.1093/eurheartj/ehv457DOI Listing
December 2015
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