Publications by authors named "Takeshi Aiba"

200 Publications

Prevalence and characteristics of the Brugada electrocardiogram pattern in patients with arrhythmogenic right ventricular cardiomyopathy.

J Arrhythm 2021 Oct 30;37(5):1173-1183. Epub 2021 Aug 30.

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

Background: Despite distinct pathophysiology, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Brugada syndrome (BrS) exhibit overlapping phenotypes. We investigated the prevalence and characteristics of the Brugada electrocardiogram (ECG) pattern in ARVC patients.

Methods: A total of 114 ARVC patients fulfilling the revised Task Force Criteria were enrolled. The Brugada ECG pattern was evaluated according to the consensus report on right precordial leads, and 1141 ECGs (median, 1; interquartile range, 1-16 ECGs/patient) were analyzed.

Results: Five patients (4%) showed a Brugada ECG pattern, which disappeared in four patients with ECGs recorded more than 2 years afterward. ARVC patients with the Brugada ECG pattern had a longer PQ interval (220 ± 62 ms vs 180 ± 35 ms,  = .02) and longer QRS duration (138 ± 25 ms vs 102 ± 23 ms,  < .001) than patients without the pattern. During follow-up (median, 11.4; interquartile range, 5.5-17.1 years), 19 ARVC patients experienced cardiac death and 29 experienced heart failure (HF) hospitalization. Kaplan-Meier analysis determined that the Brugada ECG pattern increased the risk of cardiac death and HF hospitalization (log-rank;  < .001,  < .001 respectively). The mean J-point and S-wave amplitudes of the Brugada ECG pattern were 0.29 ± 0.05 mV and 0.34 ± 0.21 mV, respectively, which were significantly lower than those of 26 age-matched BrS patients with a previous ventricular fibrillation episode (0.66 ± 0.33 mV,  < .001 and 0.67 ± 0.39 mV,  = .02 respectively).

Conclusion: The Brugada ECG pattern was infrequently encountered, was transient in ARVC patients, and was associated with a longer PQ interval, longer QRS duration, and cardiac events.
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http://dx.doi.org/10.1002/joa3.12628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485808PMC
October 2021

Retrograde penetration pacing into the conduction system as an alternative approach of his-bundle pacing: Retrograde penetration pacing into the conduction system.

J Cardiol 2021 Sep 10. Epub 2021 Sep 10.

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

Background: The optimal right ventricular (RV) pacing site during pacemaker implantation is still unclear due to left ventricular (LV) dyssynchrony by traditional RV pacing. His-bundle (HIS) pacing has achieved narrow QRS and maintained LV synchrony but high failure rate. RV septal pacing occasionally has QRS waveform with wide and narrow component in the early and late phase, respectively, and maintains LV synchrony, reflecting the normal conduction system. We aimed to define this QRS waveform as retrograde penetration pacing into the conduction system (RPP-CS) and compared its effect on LV synchrony as an alternative approach of HIS pacing.

Methods And Results: We enrolled 42 patients with atrio ventricular block (AVB) or bradycardia atrial fibrillation (AF) requiring pacemaker implantation (RPP-CS, n = 27; no RPP-CS, n = 15). Baseline characteristics were similar between the groups. RPP-CS was observed in 96% and 26% of the RV septum and apex area, respectively. RPP-CS had a significantly shorter QRS width (p < 0.001). The frequency of maintaining LV synchrony was significantly higher in RPP-CS (67% vs. 20%, p = 0.003). The QRS interval's optimal cut-off value during RPP-CS was 132 ms for prediction of LV synchrony (sensitivity 83%, specificity 89%, positive predictive value 94%, and negative predictive value 73%). During RPP-CS, shorter QRS intervals (QRS ≤ 132 ms) had better postoperative LV ejection fraction than longer intervals (p < 0.001).

Conclusions: RPP-CS, especially with short QRS intervals (≤132 ms), had a high frequency of LV synchrony, maintained postoperative cardiac function, and may be an adequate first-line RV pacing site strategy for AVB or bradycardia AF as an alternative approach of HIS pacing.
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http://dx.doi.org/10.1016/j.jjcc.2021.08.020DOI Listing
September 2021

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 Oct 31;14(5):e003222. 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
October 2021

Ischemia-induced premature ventricular complexes: Is it still complex?

Authors:
Takeshi Aiba

Heart Rhythm 2021 Aug 21. Epub 2021 Aug 21.

Department of Clinical Laboratory Medicine and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan; Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2021.08.020DOI Listing
August 2021

Long term prognosis in patients with pulmonary hypertension undergoing catheter ablation for supraventricular tachycardia.

Sci Rep 2021 08 10;11(1):16176. Epub 2021 Aug 10.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 6-1 Kishibe Shin-machi, Suita, Osaka, 564-8565, Japan.

Various forms of supraventricular tachycardia (SVT) occur in patients with severe pulmonary hypertension (PH). Despite the high efficacy of radiofrequency catheter ablation (RFCA) for SVT, insufficient data exist regarding patients with PH. Thirty SVTs in 23 PH patients (age 47 [35-60] years; mean pulmonary artery pressure 44 [32-50] mmHg) were analyzed. Procedural success rate, short- and long-term clinical outcomes, were evaluated during a median follow-up of 5.1 years. Single-procedure success rate was 83%; 94% (17/18) in typical atrial flutter, 73% (8/11) in atrial tachycardia (AT), and 100% (1/1) in atrioventricular nodal reentrant tachycardia. Antiarrhythmic drugs, serum brain natriuretic peptide levels and number of hospitalizations significantly decreased after RFCA than that before (p = 0.002, 0.04, and 0.002, respectively). Four patients had several procedures. After last RFCA, 12 patients had SVT and 8 patients died. Kaplan-Meier curves showed that patients with SVT after the last RFCA had a lower survival rate compared to those without (p = 0.0297). Multivariate analysis identified any SVT after the last RFCA as significant risk factor of mortality (hazard ratio: 9.31; p = 0.016). RFCA for SVT in patients with PH is feasible and effective in the short-term, but SVT is common during long-term follow-up and associated with lower survival.
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http://dx.doi.org/10.1038/s41598-021-95508-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355112PMC
August 2021

Estimating the Posttest Probability of Long QT Syndrome Diagnosis for Rare Variants.

Circ Genom Precis Med 2021 Aug 26;14(4):e003289. Epub 2021 Jul 26.

Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Departments of Medicine & Pharmacology (K.K., Y.W., C.E., M.J.O., A.M.G., J.D.M., D.M.R., B.C.K., B.M.K.), Vanderbilt University Medical Center, Nashville, TN.

Background: The proliferation of genetic profiling has revealed many associations between genetic variations and disease. However, large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in genes associated with disease both in healthy individuals and those under suspicion of disease. This raises the question of whether these variants can be useful predictors of disease. To answer this question, we assessed the degree to which the presence of a variant in the cardiac potassium channel gene was diagnostically predictive for the autosomal dominant long QT syndrome.

Methods: We estimated the probability of a long QT diagnosis given the presence of each variant using Bayesian methods that incorporated variant features such as changes in variant function, protein structure, and in silico predictions. We call this estimate the posttest probability of disease. Our method was applied to over 4000 individuals heterozygous for 871 missense or in-frame insertion/deletion variants in and validated against a separate international cohort of 933 individuals heterozygous for 266 missense or in-frame insertion/deletion variants.

Results: Our method was well-calibrated for the observed fraction of heterozygotes diagnosed with long QT syndrome. Heuristically, we found that the innate diagnostic information one learns about a variant from 3-dimensional variant location, in vitro functional data, and in silico predictors is equivalent to the diagnostic information one learns about that same variant by clinically phenotyping 10 heterozygotes. Most importantly, these data can be obtained in the absence of any clinical observations.

Conclusions: We show how variant-specific features can inform a prior probability of disease for rare variants even in the absence of clinically phenotyped heterozygotes.
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http://dx.doi.org/10.1161/CIRCGEN.120.003289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373797PMC
August 2021

Atrioventricular nodal reentrant tachycardia in a nonagenarian-Triple traps of AV block.

HeartRhythm Case Rep 2021 Jul 8;7(7):442-445. Epub 2021 Apr 8.

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

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http://dx.doi.org/10.1016/j.hrcr.2021.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283418PMC
July 2021

Pulmonary Vein Isolation and Pacemaker Implantation in a Patient with Dextrocardia Situs Inversus.

Int Heart J 2021 Jul 17;62(4):927-931. Epub 2021 Jul 17.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center.

A 70-year-old female with dextrocardia with situs inversus (DSI) totalis and inferior vena cava occlusion underwent radiofrequency catheter ablation because she had symptomatic paroxysmal atrial fibrillation (AF). Careful preoperative examination made successful pulmonary vein isolation through the left jugular vein approach. One-year later, however, AF recurred, and symptomatic sinus bradycardia or junctional bradycardia often occurred. Then, the pacemaker was implanted. We here reported a rare case of congenital abnormality, DSI with inferior vena cava occlusion who had undergone successful pulmonary vein isolation and pacemaker implantation without any complications.
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http://dx.doi.org/10.1536/ihj.20-804DOI Listing
July 2021

Differential diagnosis between LQT1 and LQT2 by QT/RR relationships using 24-hour Holter monitoring: A multicenter cross-sectional study.

Ann Noninvasive Electrocardiol 2021 Sep 10;26(5):e12878. Epub 2021 Jul 10.

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: The clinical course and therapeutic strategies in the congenital long QT syndrome (LQTS) are genotype-specific. However, accurate estimation of LQTS genotype is often difficult from the standard 12-lead ECG.

Objectives: This study aims to evaluate the utility of QT/RR slope analysis by the 24-hour Holter monitoring for differential diagnosis of LQTS genotype between LQT1 and LQT2.

Methods: This cross-sectional study enrolled 54 genetically identified LQTS patients (29 LQT1 and 25 LQT2) recruited from three medical institutions. The QT-apex (QTa) interval and the QT-end (QTe) interval at each 15-second were plotted against the RR intervals, and the linear regression (QTa/RR and QTe/RR slopes, respectively) was calculated from the entire 24-hour and separately during the day or night-time periods of the Holter recordings.

Results: The QTe/RR and QTa/RR slopes at the entire 24-hour were significantly steeper in LQT2 compared to those in LQT1 patients (0.262 ± 0.063 vs. 0.204 ± 0.055, p = .0007; 0.233 ± 0.052 vs. 0.181 ± 0.040, p = .0002, respectively). The QTe interval was significantly longer, and QTe/RR and QTa/RR slopes at daytime were significantly steeper in LQT2 than in LQT1 patients. The receiver operating curve analysis revealed that the QTa/RR slope of 0.211 at the entire 24-hour Holter was the best cutoff value for differential diagnosis between LQT1 and LQT2 (sensitivity: 80.0%, specificity: 75.0%, and area under curve: 0.804 [95%CI = 0.68-0.93]).

Conclusion: The continuous 24-hour QT/RR analysis using the Holter monitoring may be useful to predict the genotype of congenital LQTS, particularly for LQT1 and LQT2.
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http://dx.doi.org/10.1111/anec.12878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411756PMC
September 2021

Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.

Eur Heart J 2021 07;42(29):2854-2863

Omics Research Center, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita 5648565, Japan.

Aims: The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability.

Methods And Results: Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves.

Conclusion: In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.
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http://dx.doi.org/10.1093/eurheartj/ehab254DOI Listing
July 2021

Complications Associated With Catheter Ablation in Patients With Atrial Fibrillation: A Report From the JROAD-DPC Study.

J Am Heart Assoc 2021 06 27;10(11):e019701. Epub 2021 May 27.

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

Background Aging is one of the major concerns and determinants of the indications for catheter ablation (CA) for atrial fibrillation. This study aimed to assess the safety of CA in older patients with atrial fibrillation undergoing CA. Methods and Results The JROAD-DPC (Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination) is a nationwide claims database using data from the Japanese Diagnosis Procedure Combination/Per Diem Payment System. Among 6 632 484 records found between April 2012 and March 2018 from 1058 hospitals, 135 299 patients with atrial fibrillation (aged 65±10 years, 38 952 women) who underwent CA in 456 hospitals were studied and divided into the following age groups: <60, 60 to 64, 65 to 69, 70 to 74, 75 to 79, 80 to 84, and ≥85 years. The overall in-hospital complication rate was 3.4% (cardiac tamponade 1.2%), and in-hospital mortality was 0.04%. Older patients had a higher prevalence of women, lower body mass index, and a higher burden of comorbidities such as hypertension, and all of those characteristics were predictors for complications in multivariate analysis. A multivariate adjusted odds ratio revealed that increased age was independently and significantly associated with overall complications (60-64 years, 1.19; 65-69 years, 1.29; 70-74 years, 1.57; 75-79 years, 1.63; 80-84 years, 1.90; and ≥85 years, 2.86; the reference was <60 years). Conclusions The nationwide JROAD-DPC database demonstrated that the frequency of complications following CA in patients with atrial fibrillation increased according to age.
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http://dx.doi.org/10.1161/JAHA.120.019701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483553PMC
June 2021

Narrow QRS complex tachycardia with a 2:1 atrioventricular block: What is the mechanism.

Pacing Clin Electrophysiol 2021 Jul 1;44(7):1224-1226. Epub 2021 Jun 1.

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

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http://dx.doi.org/10.1111/pace.14279DOI Listing
July 2021

Relationship between electrical gaps after Maze procedure and atrial tachyarrhythmias and ablation outcomes after cardiac surgery and concomitant Maze procedure.

Heart Vessels 2021 May 13;36(5):675-685. Epub 2021 Feb 13.

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

Atrial tachycardia (AT) and atrial fibrillation (AF) commonly occur after cardiac surgeries (CSs). This study investigated the mechanisms and long-term outcomes of AT and AF ablation after various Maze procedures, particularly whether atrial tachyarrhythmias after the Maze procedure occur due to gaps in the Maze lines. We analyzed 37 consecutive cases with atrial tachyarrhythmias after the Maze procedures and concomitant CSs between 2007 and 2019. Fifty-nine atrial tachyarrhythmias were induced in 37 consecutive cases, and 49 of those atrial tachyarrhythmias were mappable ATs. Forty ATs were related to the Maze procedures in the 49 mappable ATs (81.6%). All 37 consecutive cases had residual electrical conductions (gaps) in the Maze lines (88 gaps; 2.4 ± 1.2 gaps/patient). Forty of 88 gaps (45.5%) were associated with gap-related ATs. The common ATs in this study were 1. peri-mitral atrial flutter due to gaps at pulmonary vein isolation (PVI) line to mitral valve annulus (MVA) (20 cases), and 2. peri-tricuspid atrial flutter due to gaps at right atrial incision to the tricuspid valve annulus (TVA) (10 cases). Forty-seven of 49 ATs (95.9%) were successfully ablated at the first session, and there were no complications. The mean follow-up period after ablation was 3.6 ± 3.2 (median, 2.1; interquartile range, 0.89-6.84) years. The Kaplan-Meier analysis of freedom from recurrent atrial tachyarrhythmias after Maze procedure was 82.7% at 1-year follow-up and 75.5% at 4-year follow-up after a single procedure. Reentry was the main mechanism of ATs after Maze procedures and concomitant CSs, and ATs were largely related to the gaps on the Maze lines between the PVI line and the MVA or those on the lines between right atrial incision to the TVA. Long-term follow-up data suggest that catheter ablation of atrial tachyarrhythmias after various Maze procedures is effective and safe.
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http://dx.doi.org/10.1007/s00380-020-01737-3DOI Listing
May 2021

High-risk atrioventricular block in Brugada syndrome patients with a history of syncope.

J Cardiovasc Electrophysiol 2021 03 19;32(3):772-781. Epub 2021 Jan 19.

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

Background: Determining the etiology of syncope is challenging in Brugada syndrome (BrS) patients. Implantable cardioverter defibrillator placement is recommended in BrS patients who are presumed to have arrhythmic syncope. However, arrhythmic syncope in BrS patients can occur in the setting of atrioventricular block (AVB), which should be managed by cardiac pacing. The clinical characteristics of BrS patients with high-risk AVB remain unknown.

Methods: This study included 223 BrS patients with a history of syncope from two centers. The clinical characteristics of patients with high-risk AVB (Mobitz type II second-degree AVB, high-degree AVB, or third-degree AVB) were investigated.

Results: During the 99 ± 78 months of follow-up, we identified six BrS patients (2.7%) with high-risk AVB. Three of the six patients (50%) with AVB presented with syncope associated with prodromes or specific triggers. Four patients (67%) were found to have paroxysmal third-degree AVB during the initial evaluation for BrS and syncope, while two patients developed third-degree AVB during the follow-up period. The incidence of first-degree AVB was significantly higher in AVB patients than in non-AVB patients (83% vs. 15%; p = .0005). There was no significant difference in the incidence of ventricular fibrillation between AVB and non-AVB patients (AVB [17%], non-AVB [12%]; p = .56).

Conclusion: High-risk AVB can occur in BrS patients with various clinical presentations. Although rare, the incidence is worth considering, especially in BrS patients with first-degree AVB.
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http://dx.doi.org/10.1111/jce.14876DOI Listing
March 2021

Unusual Overlapping Cardiac Sarcoidosis and Long-QT Type 3 Induced Ventricular Fibrillation.

Intern Med 2021 1;60(1):85-89. Epub 2021 Jan 1.

Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan.

A 54-year-old woman had been resuscitated after ventricular fibrillation and her electrocardiogram showed a QT prolongation (QTc=510 ms), and genetic screening revealed a missense variant, R1644C, in the SCN5A gene. She was therefore diagnosed with congenital long-QT syndrome (LQTS) type 3. However, the patient had left ventricular dysfunction, and based on the findings of cardiac magnetic resonance imaging, positron emission tomography and pathological examinations, she was diagnosed with cardiac sarcoidosis. Although both are rare diseases, their overlapping presence in this case may have led to an increased cardiovascular risk compared with either alone. Thus, not only genetic but comprehensive clinical examinations are important for making a correct diagnosis.
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http://dx.doi.org/10.2169/internalmedicine.5018-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835453PMC
April 2021

First episode of ventricular fibrillation in an 84-year-old man with long-QT type 2 syndrome: A case report.

J Cardiol Cases 2020 Dec 17;22(6):257-259. Epub 2020 Aug 17.

Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Congenital long QT syndrome (LQTS) is associated with ventricular arrhythmia and an increased risk of sudden cardiac death in young people. However, it is extremely rare for an elderly man to experience ventricular fibrillation (VF) due to congenital LQTS as a first episode. We describe the case of an 84-year-old man who experienced syncope after urination. He had a medical history of hypertension and asthma, but no history of syncope. Electrocardiographic findings in 2017 showed QT prolongation (corrected QT = 505 ms). No medication that could induce QT prolongation was administered. Blood test results on admission showed no electrolyte abnormalities, and there were no abnormal findings on echocardiography. The second episode of loss of consciousness occurred during hospitalization, and electrocardiography revealed incessant torsade de pointes, caused by R-on-T with short-long-short (SLS) sequences due to bradyarrhythmia. Coronary angiography did not detect myocardial ischemia, and an implantable cardioverter-defibrillator was implanted for secondary prevention. Genetic testing revealed a mutation of the gene, indicating LQTS type 2. In summary, we report a rare case of prolonged QT interval with SLS sequences due to sick sinus syndrome triggering VF as the first attack in an elderly patient with LQTS type 2. < Physicians should be aware of the prolongation of QT as a cause of syncope in elderly patients and should pay attention to QT duration. Furthermore, patients with elderly-onset QT prolongation may have a genetic background associated with congenital long QT syndrome (LQTS); therefore, we should not hesitate to perform genetic testing in cases where LQTS is suspected in elderly patients.>.
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http://dx.doi.org/10.1016/j.jccase.2020.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718543PMC
December 2020

Incorporating Latent Variables Using Nonnegative Matrix Factorization Improves Risk Stratification in Brugada Syndrome.

J Am Heart Assoc 2020 11 10;9(22):e012714. Epub 2020 Nov 10.

Second Department of Cardiology Laboratory of Cardiac Electrophysiology Evangelismos General Hospital of Athens Athens Greece.

Background A combination of clinical and electrocardiographic risk factors is used for risk stratification in Brugada syndrome. In this study, we tested the hypothesis that the incorporation of latent variables between variables using nonnegative matrix factorization can improve risk stratification compared with logistic regression. Methods and Results This was a retrospective cohort study of patients presented with Brugada electrocardiographic patterns between 2000 and 2016 from Hong Kong, China. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation. The external validation cohort included patients from 3 countries. A total of 149 patients with Brugada syndrome (84% males, median age of presentation 50 [38-61] years) were included. Compared with the nonarrhythmic group (n=117, 79%), the spontaneous ventricular tachycardia/ ventricular fibrillation group (n=32, 21%) were more likely to suffer from syncope (69% versus 37%, =0.001) and atrial fibrillation (16% versus 4%, =0.023) as well as displayed longer QTc intervals (424 [399-449] versus 408 [386-425]; =0.020). No difference in QRS interval was observed (108 [98-114] versus 102 [95-110], =0.104). Logistic regression found that syncope (odds ratio, 3.79; 95% CI, 1.64-8.74; =0.002), atrial fibrillation (odds ratio, 4.15; 95% CI, 1.12-15.36; =0.033), QRS duration (odds ratio, 1.03; 95% CI, 1.002-1.06; =0.037) and QTc interval (odds ratio, 1.02; 95% CI, 1.01-1.03; =0.009) were significant predictors of spontaneous ventricular tachycardia/ventricular fibrillation. Increasing the number of latent variables of these electrocardiographic indices incorporated from n=0 (logistic regression) to n=6 by nonnegative matrix factorization improved the area under the curve of the receiving operating characteristics curve from 0.71 to 0.80. The model improves area under the curve of external validation cohort (n=227) from 0.64 to 0.71. Conclusions Nonnegative matrix factorization improves the predictive performance of arrhythmic outcomes by extracting latent features between different variables.
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http://dx.doi.org/10.1161/JAHA.119.012714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763720PMC
November 2020

Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in Families.

Circ Genom Precis Med 2020 12 9;13(6):e002911. Epub 2020 Nov 9.

National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.).

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- is the most common mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and mutation type on BrS phenotype in BrS families with mutations.

Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles).

Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; =0.0078). Among -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; =0.0846). In -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; =0.0146). Among E1784K- positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; =0.0011).

Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a mutation and severity of loss of function.
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http://dx.doi.org/10.1161/CIRCGEN.120.002911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748043PMC
December 2020

Novel Non-Invasive Index for Prediction of Responders in Cardiac Resynchronization Therapy Using High-Resolution Magnetocardiography.

Circ J 2020 11 7;84(12):2166-2174. Epub 2020 Nov 7.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center.

Background: Approximately one-third of patients with advanced heart failure (HF) do not respond to cardiac resynchronization therapy (CRT). We investigated whether the left ventricular (LV) conduction pattern on magnetocardiography (MCG) can predict CRT responders.Methods and Results:This retrospective study enrolled 56 patients with advanced HF (mean [±SD] LV ejection fraction [LVEF] 23±8%; QRS duration 145±19 ms) and MCG recorded before CRT. MCG-QRS current arrow maps were classified as multidirectional (MDC; n=28) or unidirectional (UDC; n=28) conduction based on a change of either ≥35° or <35°, respectively, in the direction of the maximal current arrow after the QRS peak. Baseline New York Heart Association functional class and LVEF were comparable between the 2 groups, but QRS duration was longer and the presence of complete left bundle branch block and LV dyssynchrony was higher in the UDC than MDC group. Six months after CRT, 30 patients were defined as responders, with significantly more in the UDC than MDC group (89% vs. 14%, respectively; P<0.001). Over a 5-year follow-up, Kaplan-Meyer analysis showed that adverse cardiac events (death or implantation of an LV assist device) were less frequently observed in the UDC than MDC group (6/28 vs. 15/28, respectively; P=0.027). Multivariate analysis revealed that UDC on MCG was the most significant predictor of CRT response (odds ratio 69.8; 95% confidence interval 13.14-669.32; P<0.001).

Conclusions: Preoperative non-invasive MCG may predict the CRT response and long-term outcome after CRT.
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http://dx.doi.org/10.1253/circj.CJ-20-0325DOI Listing
November 2020

Subcutaneous and transvenous implantable cardioverter defibrillator in high-risk long-QT syndrome type 3 associated with Val411Met mutation in SCN5A.

J Cardiol Cases 2020 Nov 11;22(5):238-241. Epub 2020 Aug 11.

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

Congenital long-QT syndrome type 3 (LQT3) with -V411M mutation has been reported as a malignant case of LQT3 with highest risk for sudden cardiac death (SCD). Here, we present two cases of LQT3 with -V411M who had been implanted with subcutaneous (S-) or transvenous (TV-) implantable cardioverter defibrillators (ICD). Case 1, a 2-year-old boy, although he had no symptoms, was diagnosed as having LQT3 (V411M-) due to family history. The QTc interval was still longer than 500 ms during follow-up even under oral mexiletine. Case 2 (his aunt) diagnosed as LQT3 suffered from syncope caused by ventricular fibrillation at 35-years-old despite taking mexiletine. Furthermore, case 1's father and half-brother, both had the V411M mutation with LQT3, had suddenly died. Thus, case 1 was recommended S-ICD when he was 15-years-old for primary prevention of SCD but not necessary for pacing therapy, while, case 2 had been implanted TV-ICD for secondary prevention of SCD. They had no event after ICD implantation, however, case 2 had to have added an extra ICD-lead due to lead failure when she was 44-years-old. The S-ICD may be a potent therapeutic option for high-risk LQTS when patients are younger and do not need pacing therapy. < In congenital long-QT syndrome (LQTS) type 3, some of the first events are lethal, particularly, LQT3 with V411M- mutation is the highest risk for sudden cardiac death (SCD). Which implantable cardioverter defibrillator (ICD), transvenous (TV-ICD) or subcutaneous (S-ICD) is better for primary prevention of SCD in LQTS is still controversial. The S-ICD rather than TV-ICD may have a potent benefit for high-risk LQTS when patients are younger and do not need pacing therapy.>.
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http://dx.doi.org/10.1016/j.jccase.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588482PMC
November 2020

Improved Risk Stratification of Patients With Brugada Syndrome by the New Japanese Circulation Society Guideline - A Multicenter Validation Study.

Circ J 2020 11 17;84(12):2158-2165. Epub 2020 Oct 17.

Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center.

Background: The new guideline (NG) published by the Japanese Circulation Society (JCS) places emphasis on previous arrhythmic syncope and inducibility of ventricular fibrillation (VF) by ≤2 extrastimuli during programmed electrical stimulation (PES) for deciding the indication of an implantable cardioverter-defibrillator in patients with Brugada syndrome (BrS). This study evaluated the usefulness of the NG and compared it with the former guideline (FG) for risk stratification of patients with BrS.Methods and Results:This was a multicenter (7 Japanese hospitals) retrospective study involving 234 patients with BrS who underwent PES at baseline (226 males; mean age at diagnosis: 44.9±13.4 years). At diagnosis, 46 patients (20%) had previous VF, 100 patients (43%) had previous syncope, and 88 patients (37%) were asymptomatic. We evaluated the difference in the incidence of VF in each indication according to the new and FGs. During the follow-up period (mean: 6.9±5.2 years), the incidence of VF was higher in patients with Class IIa indication according to the NG (NG: 16/45 patients [35.6%] vs. FG: 16/104 patients [15.4%]), while the incidence of VF in patients with other than class I or IIa indication was similarly low in both guidelines (NG: 2/143 patients [1.4%] vs. FG: 2/84 patients [2.4%]).

Conclusions: This study validated the usefulness of the NG for risk stratification of BrS patients.
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http://dx.doi.org/10.1253/circj.CJ-19-0910DOI Listing
November 2020

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

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

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

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

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 01 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Cardiac Emerinopathy: A Nonsyndromic Nuclear Envelopathy With Increased Risk of Thromboembolic Stroke Due to Progressive Atrial Standstill and Left Ventricular Noncompaction.

Circ Arrhythm Electrophysiol 2020 10 29;13(10):e008712. Epub 2020 Jul 29.

Omics Research Center (T.I., N.M.), National Cerebral and Cardiovascular Center, Suita, Japan.

Background: Mutations in the nuclear envelope genes encoding and are responsible for Emery-Dreifuss muscular dystrophy. However, mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with mutations.

Methods: Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51).

Results: We identified 3 X-linked recessive mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with has never been reported, we further genetically screened 102 LVNC patients and found a frameshift mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC.

Conclusions: Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.
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http://dx.doi.org/10.1161/CIRCEP.120.008712DOI Listing
October 2020

Prevalence, Determinants, and Prognostic Significance of Hospital Acquired Pneumonia in Patients with Acute Heart Failure.

J Clin Med 2020 Jul 13;9(7). Epub 2020 Jul 13.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan.

The prognostic impact of hospital-acquired pneumonia (HAP) in acute heart failure (AHF) patients have not been fully elucidated. We evaluated 776 consecutive hospitalized AHF patients. The primary in-hospital outcomes were all-cause death and worsening heart failure (WHF), while the outcome following discharge was all-cause death. The clinical diagnosis of HAP was based on clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Patients with HAP had a significantly higher incidence of in-hospital death (12% vs. 1%, < 0.001), WHF during the hospitalization (28% vs. 7%, < 0.001), and longer length of hospital stay ( = 0.003) than those without. Among patients who survived at discharge, during a median follow-up period of 741 (interquartile range 422-1000) days, the incidence of all-cause death was significantly higher in patients with HAP than in those without ( < 0.001). In the multivariable Cox regression, HAP development was independently associated with all-cause death after discharge (HR [hazard ratio] 1.86, 95%CI [confidence interval] 1.08-3.19). Furthermore, older age (OR [odds ratio] 1.04, 95%CI 1.01-1.08), male sex (OR 2.21, 95%CI 1.14-4.28), and higher serum white blood cell count (OR 1.18, 95%CI 1.09-1.29) and serum C-reactive protein (OR 1.08, 95%CI 1.01-1.06) were independently associated with HAP development. In hospitalized patients with AHF, HAP development was associated with worse clinical outcomes, suggesting the importance of prevention and early screening for HAP.
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http://dx.doi.org/10.3390/jcm9072219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408712PMC
July 2020
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