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Brugada(ブルガダ)症候群

著者: 清水 渉 日本医科大学大学院医学研究科 循環器内科学分野

監修: 今井靖 自治医科大学 薬理学講座臨床薬理学部門・内科学講座循環器内科学部門

著者校正/監修レビュー済:2020/10/01
参考ガイドライン:
  1. 日本循環器学会:遺伝性不整脈の診療に関するガイドライン(2017年改訂版)
  1. 日本循環器学会/日本不整脈心電学会:不整脈非薬物治療ガイドライン(2018年改訂版)
患者向け説明資料

概要・推奨   

  1. VF・心肺停止既往のあるBrugada症候群患者は再発率が高く、植込み型除細動器のクラスI(絶対)適応である(推奨度1)。
  1. 失神既往例、男性、自然発生Type 1心電図(常にType 1心電図)を認めるBrugada症候群患者は、VF発生のリスクが高く予後不良であり、これらは心事故の独立した予後予測因子である(推奨度1)。
  1. 日本人のBrugada症候群発端者では、VF・心肺停止既往に加えて、45歳未満の突然死の家族歴、後下壁誘導心電図の早期再分極がVF発生の予後予測因子である(推奨度2)。
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  1. 遺伝子確率によりNa+チャネル遺伝子であるSCN5Aに病的変異を認める患者では、変異を認めない患者に比べVF発生リスクが有意に高くなる。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
清水 渉 : 未申告[2021年]
監修:今井靖 : 講演料(第一三共株式会社)[2021年]

改訂のポイント:
  1. 不整脈非薬物治療ガイドライン(2018年改訂版)(日本循環器学会/日本不整脈心電学会合同ガイドライン)に基づき、植込み型除細動器の適応について修正を行った。
  1. また、最近報告されたブルガダ症候群の日本国内多施設前向き登録研究(Yamagata K et al. Circulation 2017)の結果を追記した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. Brugada症候群とは、12誘導心電図のV1またはV2(V3)誘導における特徴的なST上昇と心室細動(VF)を主徴とする、明らかな器質的心疾患を認めない症候群である[1][2][3][4][5][6][7]
 
Brugada症候群(特発性心室細動)

a:12誘導心電図 V2誘導でtype 1心電図(coved型ST上昇)を呈する。
b:心室細動

出典

img1:  著者提供
 
 
 
Brugada症候群の心電図(Wildeの分類)

出典

img1:  Proposed diagnostic criteria for the Brugada syndrome: consensus report.
 
 Circulation. 2002 Nov 5;106(19):2514-9.
 
  1. 男性で頻度が高く(欧米8:1、日本10:1)、VF初発の平均年齢は39~48歳である。
  1. 欧米に比べ、日本を含めたアジア地域で頻度が高いという人種差がある[4][5]
  1. 日本人の中高年男性が夜間に突然死する「ポックリ病」の少なくとも一部は、Brugada症候群に起因すると考えられている。
  1. 本邦の健診ベースの報告で、0.1mV以上のcoved型ST上昇を認める頻度は0.05~0.16%、0.2mV以上のcoved型ST上昇を認めるは0.15%と報告されている。
  1. Brugada症候群では、心房細動の頻度が高く[8]、この場合心房細動に対する薬物治療としてキニジンとベプリコール以外のNaチャネル遮断薬は禁忌である(治療: >詳細情報 薬物治療 参照)。
  1. 一部の患者では遺伝子変異を認めるが、病的遺伝子は、Brugada症候群患者の11~28%で同定されるNaチャネル遺伝子のSCN5Aのみと考えられている。
 
Brugada症候群の原因遺伝子とイオンチャネル機能

 
  1. Brugada症候群では15~40%の患者で遺伝子変異を認め、19個の原因遺伝子が同定されている[9][10][11](S)。
  1. まとめ:Brugada症候群では15~40%の患者で遺伝子変異を認める[9][10]
  1. 代表事例:Kapplingerらは不整脈の遺伝子診断で世界を代表する9カ所の施設におけるBrugada症候群の遺伝子診断率を検討した。Brugada症候群患者2,111例でNa+チャネル遺伝子であるSCN5Aのスクリーニングを施行したところ、遺伝子診断率は11~28%であった。また、L型Ca2+チャネル遺伝子であるCACNA1CCACNB2bや、その他の原因遺伝子の変異の報告はあるが頻度はいずれもまれである。
  1. 結論:Brugada症候群では15~40%の患者で遺伝子変異を認めるが、病的遺伝子はNaチャネル遺伝子のSCN5Aのみと考えられている[12]
 
問診・診察のポイント  
  1. 失神、眼前暗黒感、夜間苦悶様呼吸などがあれば、誘因・状況を詳しく聞く。

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文献 

著者: P Brugada, J Brugada
雑誌名: J Am Coll Cardiol. 1992 Nov 15;20(6):1391-6.
Abstract/Text OBJECTIVES: The objectives of this study were to present data on eight patients with recurrent episodes of aborted sudden death unexplainable by currently known diseases whose common clinical and electrocardiographic (ECG) features define them as having a distinct syndrome different from idiopathic ventricular fibrillation.
BACKGROUND: Among patients with ventricular arrhythmias who have no structural heart disease, several subgroups have been defined. The present patients constitute an additional subgroup with these findings.
METHODS: The study group consisted of eight patients, six male and two female, with recurrent episodes of aborted sudden death. Clinical and laboratory data and results of electrocardiography, electrophysiology, echocardiography, angiography, histologic study and exercise testing were available in most cases.
RESULTS: The ECG during sinus rhythm showed right bundle branch block, normal QT interval and persistent ST segment elevation in precordial leads V1 to V2-V3 not explainable by electrolyte disturbances, ischemia or structural heart disease. No histologic abnormalities were found in the four patients in whom ventricular biopsies were performed. The arrhythmia leading to (aborted) sudden death was a rapid polymorphic ventricular tachycardia initiating after a short coupled ventricular extrasystole. A similar arrhythmia was initiated by two to three ventricular extrastimuli in four of the seven patients studied by programmed electrical stimulation. Four patients had a prolonged HV interval during sinus rhythm. One patient receiving amiodarone died suddenly during implantation of a demand ventricular pacemaker. The arrhythmia of two patients was controlled with a beta-adrenergic blocking agent. Four patients received an implantable defibrillator that was subsequently used by one of them, and all four are alive. The remaining patient received a demand ventricular pacemaker and his arrhythmia is controlled with amiodarone and diphenylhydantoin.
CONCLUSIONS: Common clinical and ECG features define a distinct syndrome in this group of patients. Its causes remain unknown.

PMID 1309182  J Am Coll Cardiol. 1992 Nov 15;20(6):1391-6.
著者: Arthur A M Wilde, Charles Antzelevitch, Martin Borggrefe, Josep Brugada, Ramón Brugada, Pedro Brugada, Domenico Corrado, Richard N W Hauer, Robert S Kass, Koonlawee Nademanee, Silvia G Priori, Jeffrey A Towbin, Study Group on the Molecular Basis of Arrhythmias of the European Society of Cardiology
雑誌名: Circulation. 2002 Nov 5;106(19):2514-9.
Abstract/Text
PMID 12417552  Circulation. 2002 Nov 5;106(19):2514-9.
著者: Charles Antzelevitch, Pedro Brugada, Martin Borggrefe, Josep Brugada, Ramon Brugada, Domenico Corrado, Ihor Gussak, Herve LeMarec, Koonlawee Nademanee, Andres Ricardo Perez Riera, Wataru Shimizu, Eric Schulze-Bahr, Hanno Tan, Arthur Wilde
雑誌名: Circulation. 2005 Feb 8;111(5):659-70. doi: 10.1161/01.CIR.0000152479.54298.51. Epub 2005 Jan 17.
Abstract/Text Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a cause of death among young adults in some countries. Electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. Patients with a spontaneously appearing Brugada ECG have a high risk for sudden arrhythmic death secondary to ventricular tachycardia/fibrillation. The ECG manifestations of Brugada syndrome are often dynamic or concealed and may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypo- and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. In recent years, an exponential rise in the number of reported cases and a striking proliferation of articles defining the clinical, genetic, cellular, ionic, and molecular aspects of the disease have occurred. The report of the first consensus conference, published in 2002, focused on diagnostic criteria. The present report, which emanated from the second consensus conference held in September 2003, elaborates further on the diagnostic criteria and examines risk stratification schemes and device and pharmacological approaches to therapy on the basis of the available clinical and basic science data.

PMID 15655131  Circulation. 2005 Feb 8;111(5):659-70. doi: 10.1161/01.・・・
著者: Wataru Shimizu, Takeshi Aiba, Shiro Kamakura
雑誌名: Nat Clin Pract Cardiovasc Med. 2005 Aug;2(8):408-14.
Abstract/Text Brugada syndrome is a clinical entity characterized by ST-segment elevation in the right precordial leads (V1-V3) and an episode of ventricular fibrillation in the absence of structural heart disease. Data regarding genotype-phenotype relationships are limited, since SCN5A, the gene encoding the a subunit of the sodium channel, is as yet the only gene linked to Brugada syndrome. Studies of SCN5A mutations responsible for the Brugada phenotype have shown the presence of functional defects in the sodium-channel current. Experimental studies employing arterially perfused right-ventricular wedge preparations have elucidated cellular mechanisms for this phenotype. Data indicate that an accentuated action-potential notch, mediated by a prominent transient outward current and loss of the action-potential dome in the epicardium (but not in the endocardium) of the right ventricle give rise to a transmural voltage gradient, resulting in ST-segment elevation and the induction of ventricular fibrillation. On the basis of cellular mechanisms, it might be possible to normalize the Brugada phenotype by use of therapeutic agents or interventions that decrease net outward currents by decreasing the transient outward current or outward potassium currents, or increasing the L-type inward calcium current or fast sodium current. Interventions that increase net outward currents through raising the transient outward current or outward potassium currents or decreasing the L-type inward calcium current or fast sodium current might aggravate or unmask the Brugada phenotype, resulting in an acquired form of this syndrome. In this review, we discuss future challenges relating to risk stratification, genetic heterogeneity, sex and ethnic differences in Brugada syndrome.

PMID 16119703  Nat Clin Pract Cardiovasc Med. 2005 Aug;2(8):408-14.
著者: Wataru Shimizu
雑誌名: Circ J. 2013;77(12):2867-72. Epub 2013 Nov 7.
Abstract/Text Over the past 2 decades, a number of inherited cardiac arrhythmias, including congenital long QT syndrome (LQTS) and Brugada syndrome (BrS), have been shown to have a link to mutations in genes encoding for ion channels or other membrane components. The recent HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited arrhythmia syndromes has updated the clinical diagnosis of congenital LQTS and BrS. Genetic studies have identified 13 forms of congenital LQTS in 50-80% of clinically affected patients. Genotype-phenotype correlations have been investigated in the 3 major genotypes, LQT1, LQT2 and LQT3 syndromes, resulting in genotype-specific management and therapy. More detailed analyses of each genotype have suggested mutation location-, type-, or function-specific differences in clinical phenotype among the LQT1, LQT2, and possibly LQT3 genotypes. In BrS, only one-third of affected patients can be genotyped, mainly in the sodium channel gene, SCN5A; therefore, clinical studies of genotype-phenotype relationships have been limited. More recently, a genome-wide association study using a gene array explored the role of common genetic variants (polymorphisms) as the susceptible or modifier gene in both congenital LQTS and BrS.

PMID 24200848  Circ J. 2013;77(12):2867-72. Epub 2013 Nov 7.
著者: Silvia G Priori, Arthur A Wilde, Minoru Horie, Yongkeun Cho, Elijah R Behr, Charles Berul, Nico Blom, Josep Brugada, Chern-En Chiang, Heikki Huikuri, Prince Kannankeril, Andrew Krahn, Antoine Leenhardt, Arthur Moss, Peter J Schwartz, Wataru Shimizu, Gordon Tomaselli, Cynthia Tracy
雑誌名: Heart Rhythm. 2013 Dec;10(12):1932-63. doi: 10.1016/j.hrthm.2013.05.014. Epub 2013 Aug 30.
Abstract/Text
PMID 24011539  Heart Rhythm. 2013 Dec;10(12):1932-63. doi: 10.1016/j.h・・・
著者:
雑誌名: 2008 Mar 25;51(12):1169-75.
Abstract/Text
PMID 18355654  2008 Mar 25;51(12):1169-75.
著者: Jamie D Kapplinger, David J Tester, Marielle Alders, Begoña Benito, Myriam Berthet, Josep Brugada, Pedro Brugada, Véronique Fressart, Alejandra Guerchicoff, Carole Harris-Kerr, Shiro Kamakura, Florence Kyndt, Tamara T Koopmann, Yoshihiro Miyamoto, Ryan Pfeiffer, Guido D Pollevick, Vincent Probst, Sven Zumhagen, Matteo Vatta, Jeffrey A Towbin, Wataru Shimizu, Eric Schulze-Bahr, Charles Antzelevitch, Benjamin A Salisbury, Pascale Guicheney, Arthur A M Wilde, Ramon Brugada, Jean-Jacques Schott, Michael J Ackerman
雑誌名: Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm.2009.09.069. Epub 2009 Oct 8.
Abstract/Text BACKGROUND: Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.
OBJECTIVE: This study sought to perform a retrospective analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.
METHODS: Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.
RESULTS: A total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions.
CONCLUSION: This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.

PMID 20129283  Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm・・・
著者: Charles Antzelevitch, Guido D Pollevick, Jonathan M Cordeiro, Oscar Casis, Michael C Sanguinetti, Yoshiyasu Aizawa, Alejandra Guerchicoff, Ryan Pfeiffer, Antonio Oliva, Bernd Wollnik, Philip Gelber, Elias P Bonaros, Elena Burashnikov, Yuesheng Wu, John D Sargent, Stefan Schickel, Ralf Oberheiden, Atul Bhatia, Li-Fern Hsu, Michel Haïssaguerre, Rainer Schimpf, Martin Borggrefe, Christian Wolpert
雑誌名: Circulation. 2007 Jan 30;115(4):442-9. doi: 10.1161/CIRCULATIONAHA.106.668392. Epub 2007 Jan 15.
Abstract/Text BACKGROUND: Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death.
METHODS AND RESULTS: Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca(v beta2b)), CACNA2D1 (Ca(v alpha2delta1)), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca(v)1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals < or = 360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the alpha1- and beta2b-subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca(v)1.2 channels but normal trafficking of channels containing G490R Ca(v)1.2 or S481L Ca(v beta2b)-subunits.
CONCLUSIONS: This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.

PMID 17224476  Circulation. 2007 Jan 30;115(4):442-9. doi: 10.1161/CIR・・・
著者: Wataru Shimizu
雑誌名: J Am Coll Cardiol. 2014 Jul 8;64(1):80-2. doi: 10.1016/j.jacc.2014.04.023.
Abstract/Text
PMID 24998132  J Am Coll Cardiol. 2014 Jul 8;64(1):80-2. doi: 10.1016/・・・
著者: Kenichiro Yamagata, Minoru Horie, Takeshi Aiba, Satoshi Ogawa, Yoshifusa Aizawa, Tohru Ohe, Masakazu Yamagishi, Naomasa Makita, Harumizu Sakurada, Toshihiro Tanaka, Akihiko Shimizu, Nobuhisa Hagiwara, Ryoji Kishi, Yukiko Nakano, Masahiko Takagi, Takeru Makiyama, Seiko Ohno, Keiichi Fukuda, Hiroshi Watanabe, Hiroshi Morita, Kenshi Hayashi, Kengo Kusano, Shiro Kamakura, Satoshi Yasuda, Hisao Ogawa, Yoshihiro Miyamoto, Jamie D Kapplinger, Michael J Ackerman, Wataru Shimizu
雑誌名: Circulation. 2017 Jun 6;135(23):2255-2270. doi: 10.1161/CIRCULATIONAHA.117.027983. Epub 2017 Mar 24.
Abstract/Text BACKGROUND: The genotype-phenotype correlation of SCN5A mutations as a predictor of cardiac events in Brugada syndrome remains controversial. We aimed to establish a registry limited to probands, with a long follow-up period, so that the genotype-phenotype correlation of SCN5A mutations in Brugada syndrome can be examined without patient selection bias.
METHODS: This multicenter registry enrolled 415 probands (n=403; men, 97%; age, 46±14 years) diagnosed with Brugada syndrome whose SCN5A gene was analyzed for mutations.
RESULTS: During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5%/y. In comparison with probands without mutations (SCN5A (-), n=355), probands with SCN5A mutations (SCN5A (+), n=60) experienced their first cardiac event at a younger age (34 versus 42 years, P=0.013), had a higher positive rate of late potentials (89% versus 73%, P=0.016), exhibited longer P-wave, PQ, and QRS durations, and had a higher rate of cardiac events (P=0.017 by log-rank). Multivariate analysis indicated that only SCN5A mutation and history of aborted cardiac arrest were significant predictors of cardiac events (SCN5A (+) versus SCN5A (-): hazard ratio, 2.0 and P=0.045; history of aborted cardiac arrest versus no such history: hazard ratio, 6.5 and P<0.001).
CONCLUSIONS: Brugada syndrome patients with SCN5A mutations exhibit more conduction abnormalities on ECG and have higher risk for cardiac events.

© 2017 American Heart Association, Inc.
PMID 28341781  Circulation. 2017 Jun 6;135(23):2255-2270. doi: 10.1161・・・
著者: Josep Brugada, Ramon Brugada, Charles Antzelevitch, Jeffrey Towbin, Koonlawee Nademanee, Pedro Brugada
雑誌名: Circulation. 2002 Jan 1;105(1):73-8.
Abstract/Text BACKGROUND: The electrocardiographic pattern of right bundle-branch block with ST-segment elevation in leads V1 to V3 is increasingly recognized among patients who have aborted sudden cardiac death, but also in asymptomatic individuals, raising questions about its prognostic significance.
METHODS AND RESULTS: The clinical, electrophysiological, and follow-up data of 334 patients with the Brugada phenotype were analyzed. A total of 79 women and 255 men with a mean age at diagnosis of 42+/-16 years were studied. The abnormal ECG was recognized after a resuscitated cardiac arrest in 71 patients (group A), after a syncopal episode in 73 patients (group B), and in 190 asymptomatic individuals (group C). Sustained ventricular arrhythmias were inducible in 83%, 63%, and 33% of patients in group A, group B, and group C, respectively. During 54+/-54 and 26+/-36 months of follow-up, respectively, 62% of patients in group A and 19% of group B patients had a new arrhythmic event. Inducibility of ventricular arrhythmias was the only predictor of arrhythmia occurrence in both groups. During a mean follow-up of 27+/-29 months, 8% of group C individuals had a first arrhythmic event. In these individuals, inducibility of ventricular arrhythmias and a basal abnormal ECG were predictors of arrhythmia occurrence.
CONCLUSIONS: An ECG showing right bundle-branch block and ST-segment elevation in the right precordial leads is a marker of malignant ventricular arrhythmias and sudden death. Recurrence of malignant arrhythmias is high after the occurrence of symptoms. Among asymptomatic individuals, those with a spontaneously abnormal ECG and inducible to ventricular arrhythmias have the poorer prognosis.

PMID 11772879  Circulation. 2002 Jan 1;105(1):73-8.
著者: Silvia G Priori, Carlo Napolitano, Maurizio Gasparini, Carlo Pappone, Paolo Della Bella, Umberto Giordano, Raffaella Bloise, Carla Giustetto, Roberto De Nardis, Massimiliano Grillo, Elena Ronchetti, Giovanna Faggiano, Janni Nastoli
雑誌名: Circulation. 2002 Mar 19;105(11):1342-7.
Abstract/Text BACKGROUND: Treatment of patients with Brugada syndrome is complicated by the incomplete information on the natural history of the disease related to the small number of cases reported. Furthermore, the value of programmed electrical stimulation (PES) for risk stratification is highly debated. The objective of this study was to search for novel parameters to identify patients at risk of sudden death.
METHODS AND RESULTS: Clinical data were collected for 200 patients (152 men, 48 women; age, 41+/-18 years) and stored in a dedicated database. Genetic analysis was performed, and mutations on the SCN5A gene were identified in 28 of 130 probands and in 56 of 121 family members. The life-table method of Kaplan-Meier used to define the cardiac arrest-free interval in patients undergoing PES failed to demonstrate an association between PES inducibility and spontaneous occurrence of ventricular fibrillation. Multivariate Cox regression analysis showed that after adjusting for sex, family history of sudden death, and SCN5A mutations, the combined presence of a spontaneous ST-segment elevation in leads V1 through V3 and the history of syncope identifies subjects at risk of cardiac arrest (HR, 6.4; 95% CI, 1.9 to 21; P<0.002).
CONCLUSIONS: The information on the natural history of patients obtained in this study allowed elaboration of a risk-stratification scheme to quantify the risk for sudden cardiac death and to target the use of the implantable cardioverter-defibrillator.

PMID 11901046  Circulation. 2002 Mar 19;105(11):1342-7.
著者: Shiro Kamakura, Tohru Ohe, Kiyoshi Nakazawa, Yoshifusa Aizawa, Akihiko Shimizu, Minoru Horie, Satoshi Ogawa, Ken Okumura, Kazufumi Tsuchihashi, Kaoru Sugi, Naomasa Makita, Nobuhisa Hagiwara, Hiroshi Inoue, Hirotsugu Atarashi, Naohiko Aihara, Wataru Shimizu, Takashi Kurita, Kazuhiro Suyama, Takashi Noda, Kazuhiro Satomi, Hideo Okamura, Hitonobu Tomoike, Brugada Syndrome Investigators in Japan
雑誌名: Circ Arrhythm Electrophysiol. 2009 Oct;2(5):495-503. doi: 10.1161/CIRCEP.108.816892. Epub 2009 Aug 2.
Abstract/Text BACKGROUND: The prognosis of patients with saddleback or noncoved type (non-type 1) ST-elevation in Brugada syndrome is unknown. The purpose of this study was to clarify the long-term prognosis of probands with non-type 1 ECG and those with coved (type 1) Brugada-pattern ECG.
METHODS AND RESULTS: A total of 330 (123 symptomatic, 207 asymptomatic) probands with a coved or saddleback ST-elevation > or = 1 mm in leads V(1)-V(3) were divided into 2 ECG groups-type 1 (245 probands) and non-type 1 (85 probands)-and were prospectively followed for 48.7+/-15.0 months. The absence of type 1 ECG was confirmed by drug provocation test and multiple recordings. The ratio of individuals with a family history of sudden cardiac death (14%) was lower than previous studies. Clinical profiles and outcomes were not notably different between the 2 groups (annual arrhythmic event rate of probands with ventricular fibrillation; type 1: 10.2%, non-type 1: 10.6%, probands with syncope; type 1: 0.6%, non-type 1: 1.2%, and asymptomatic probands; type 1: 0.5%, non-type 1: 0%). Family history of sudden cardiac death at age <45 years and coexistence of inferolateral early repolarization with Brugada-pattern ECG were independent predictors of fatal arrhythmic events (hazard ratio, 3.28; 95% confidence interval, 1.42 to 7.60; P=0.005; hazard ratio, 2.66; 95% confidence interval, 1.06 to 6.71; P=0.03, respectively, by multivariate analysis), although spontaneous type 1 ECG and ventricular fibrillation inducibility by electrophysiological study were not reliable parameters.
CONCLUSIONS: The long-term prognosis of probands in non-type 1 group was similar to that of type 1 group. Family history of sudden cardiac death and the presence of early repolarization were predictors of poor outcome in this study, which included only probands with Brugada-pattern ST-elevation.

PMID 19843917  Circ Arrhythm Electrophysiol. 2009 Oct;2(5):495-503. do・・・
著者: V Probst, C Veltmann, L Eckardt, P G Meregalli, F Gaita, H L Tan, D Babuty, F Sacher, C Giustetto, E Schulze-Bahr, M Borggrefe, M Haissaguerre, P Mabo, H Le Marec, C Wolpert, A A M Wilde
雑誌名: Circulation. 2010 Feb 9;121(5):635-43. doi: 10.1161/CIRCULATIONAHA.109.887026. Epub 2010 Jan 25.
Abstract/Text BACKGROUND: Brugada syndrome is characterized by ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death (SCD). Fundamental questions remain on the best strategy for assessing the real disease-associated arrhythmic risk, especially in asymptomatic patients. The aim of the present study was to evaluate the prognosis and risk factors of SCD in Brugada syndrome patients in the FINGER (France, Italy, Netherlands, Germany) Brugada syndrome registry.
METHODS AND RESULTS: Patients were recruited in 11 tertiary centers in 4 European countries. Inclusion criteria consisted of a type 1 ECG present either at baseline or after drug challenge, after exclusion of diseases that mimic Brugada syndrome. The registry included 1029 consecutive individuals (745 men; 72%) with a median age of 45 (35 to 55) years. Diagnosis was based on (1) aborted SCD (6%); (2) syncope, otherwise unexplained (30%); and (3) asymptomatic patients (64%). During a median follow-up of 31.9 (14 to 54.4) months, 51 cardiac events (5%) occurred (44 patients experienced appropriate implantable cardioverter-defibrillator shocks, and 7 died suddenly). The cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients. Symptoms and spontaneous type 1 ECG were predictors of arrhythmic events, whereas gender, familial history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation were not predictive of arrhythmic events.
CONCLUSIONS: In the largest series of Brugada syndrome patients thus far, event rates in asymptomatic patients were low. Inducibility of ventricular tachyarrhythmia and family history of SCD were not predictors of cardiac events.

PMID 20100972  Circulation. 2010 Feb 9;121(5):635-43. doi: 10.1161/CIR・・・
著者: Silvia G Priori, Maurizio Gasparini, Carlo Napolitano, Paolo Della Bella, Andrea Ghidini Ottonelli, Biagio Sassone, Umberto Giordano, Carlo Pappone, Giosuè Mascioli, Guido Rossetti, Roberto De Nardis, Mario Colombo
雑誌名: J Am Coll Cardiol. 2012 Jan 3;59(1):37-45. doi: 10.1016/j.jacc.2011.08.064.
Abstract/Text OBJECTIVES: The PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) prospective registry was designed to assess the predictive accuracy of sustained ventricular tachycardia/ventricular fibrillation (VTs/VF) inducibility and to identify additional predictors of arrhythmic events in Brugada syndrome patients without history of VT/VF.
BACKGROUND: Brugada syndrome is a genetic disease associated with increased risk of sudden cardiac death. Even though its value has been questioned, inducibility of VTs/VF is widely used to select candidates to receive a prophylactic implantable defibrillator, and its accuracy has never been addressed in prospective studies with homogeneous enrolling criteria.
METHODS: Patients with a spontaneous or drug-induced type I electrocardiogram (ECG) and without history of cardiac arrest were enrolled. The registry included 308 consecutive individuals (247 men, 80%; median age 44 years, range 18 to 72 years). Programmed electrical stimulation was performed at enrollment, and patients were followed-up every 6 months.
RESULTS: During a median follow-up of 34 months, 14 arrhythmic events (4.5%) occurred (13 appropriate shocks of the implantable defibrillator, and 1 cardiac arrest). Programmed electrical stimulation performed with a uniform and pre-specified protocol induced ventricular tachyarrhythmias in 40% of patients: arrhythmia inducibility was not a predictor of events at follow-up (9 of 14 events occurred in noninducible patients). History of syncope and spontaneous type I ECG (hazard ratio [HR]: 4.20), ventricular refractory period <200 ms (HR: 3.91), and QRS fragmentation (HR: 4.94) were significant predictors of arrhythmias.
CONCLUSIONS: Our data show that VT/VF inducibility is unable to identify high-risk patients, whereas the presence of a spontaneous type I ECG, history of syncope, ventricular effective refractory period <200 ms, and QRS fragmentation seem useful to identify candidates for prophylactic implantable cardioverter defibrillator.

Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PMID 22192666  J Am Coll Cardiol. 2012 Jan 3;59(1):37-45. doi: 10.1016・・・
著者: Takeshi Ohgo, Hideo Okamura, Takashi Noda, Kazuhiro Satomi, Kazuhiro Suyama, Takashi Kurita, Naohiko Aihara, Shiro Kamakura, Tohru Ohe, Wataru Shimizu
雑誌名: Heart Rhythm. 2007 Jun;4(6):695-700. doi: 10.1016/j.hrthm.2007.02.014. Epub 2007 Feb 20.
Abstract/Text BACKGROUND: Some patients with Brugada syndrome experience an electrical storm of ventricular fibrillation (VF).
OBJECTIVE: The purpose of this study was to investigate the clinical, laboratory, electrocardiographic, and electrophysiologic characteristics, acute and subsequent chronic treatment, and follow-up data of patients with Brugada syndrome associated with electrical storm of VF.
METHODS: Sixty-seven patients with Brugada syndrome (65 men and 2 women, age 46 +/- 14 years) were divided into three groups: 7 patients with a history of electrical storm of VF (group I), 39 symptomatic patients with documented VF and/or syncope (group II), and 21 asymptomatic patients (group III). Electrical storm was defined as three or more episodes of VF per day recorded by the memory of an implantable cardioverter-defibrillator.
RESULTS: No significant differences were observed among the three groups with regard to clinical (age at diagnosis, familial history of sudden cardiac death), laboratory (SCN5A mutation and serum potassium level), electrocardiographic and electrophysiologic characteristics, and follow-up duration after diagnosis. However, arrhythmic events during follow-up after diagnosis and number of arrhythmic events per patient were significantly higher in group I compared with groups II and III. Isoproterenol infusion (0.003 +/- 0.003 microg/kg/min for 24 +/- 13 days) completely suppressed electrical storm of VF in all five patients treated and was successfully replaced with oral medications, including denopamine, quinidine, isoproterenol, cilostazol, and bepridil alone or in combination.
CONCLUSION: No specifically clinical, laboratory, electrocardiographic, and electrophysiologic characteristics were recognized in patients with Brugada syndrome associated with electrical storm of VF. Isoproterenol infusion was effective as an acute treatment in suppressing electrical storm of VF and was successfully replaced with chronic oral medications.

PMID 17556186  Heart Rhythm. 2007 Jun;4(6):695-700. doi: 10.1016/j.hrt・・・
著者: W Shimizu, S Kamakura
雑誌名: J Electrocardiol. 2001;34 Suppl:173-5.
Abstract/Text Catecholamines have long been used as a provocative test in some forms of tachyarrhythmias including long QT syndrome (LQTS). In contrast, catecholamines are reported to decrease ST-segment elevation in leads V1-V3 in some patients with Brugada syndrome. Differential effects of catecholamines on QT interval, action potential duration, transmural dispersion of repolarization and Torsade de Pointes between LQT1, LQT2, and LQT3 forms of the LQTS were shown in experimental models of the LQTS by using arterially-perfused wedge preparations as well as in patients with congenital LQTS including children. In our preliminary result of patients with Brugada syndrome including a child, isoproterenol infusion was effective to decrease the ST-segment elevation in leads V1-V2 and to suppress the electrical storm of ventricular fibrillation.

PMID 11781952  J Electrocardiol. 2001;34 Suppl:173-5.
著者: Atsuyuki Watanabe, Kengo Fukushima Kusano, Hiroshi Morita, Daiji Miura, Wakako Sumida, Shigeki Hiramatsu, Kimikazu Banba, Nobuhiro Nishii, Satoshi Nagase, Kazufumi Nakamura, Satoru Sakuragi, Tohru Ohe
雑誌名: Eur Heart J. 2006 Jul;27(13):1579-83. doi: 10.1093/eurheartj/ehl060. Epub 2006 Jun 7.
Abstract/Text AIMS: Arrhythmic storm or repetitive ventricular arrhythmia (VA) has been occasionally observed in Brugada syndrome (BS). A beta-adrenergic stimulator [isoproterenol (ISP)] has been reported to suppress this arrhythmic storm in sporadic cases. Accordingly, we investigated the antiarrhythmic effects of ISP infusion in consecutive BS patients with arrhythmic storm or repetitive VA.
METHODS AND RESULTS: Seven BS patients with arrhythmic storm were studied. Intravenous ISP was administered as a bolus injection (1-2 microg), followed by continuous infusion (0.15 microg/min). Arrhythmic storm or repetitive VA was suppressed immediately after the bolus administration of ISP, which was followed by continuous infusion of low-dose ISP for 1-3 days. In all patients, ST-elevation decreased in right precordial leads. In six of the seven patients, VA subsided after the discontinuance of ISP. RR interval was shortened and ST-elevation in right precordial leads was decreased after ISP bolus injection. ST-elevation in right precordial leads remained decreased during continuous ISP infusion, whereas the RR interval returned to the control level.
CONCLUSION: Continuous administration of low-dose ISP may be effective for the suppression of repetitive VA occurrence in patients with BS.

PMID 16760208  Eur Heart J. 2006 Jul;27(13):1579-83. doi: 10.1093/eurh・・・
著者: Jean-Sylvain Hermida, Isabelle Denjoy, Jérôme Clerc, Fabrice Extramiana, Geneviève Jarry, Paul Milliez, Pascale Guicheney, Stefania Di Fusco, Jean-Luc Rey, Bruno Cauchemez, Antoine Leenhardt
雑誌名: J Am Coll Cardiol. 2004 May 19;43(10):1853-60. doi: 10.1016/j.jacc.2003.12.046.
Abstract/Text OBJECTIVES: We sought to assess hydroquinidine (HQ) efficacy in selected patients with Brugada syndrome (BrS).
BACKGROUND: Management of asymptomatic patients with BrS and inducible arrhythmias remains a key issue. Effectiveness of class Ia antiarrhythmic drugs, which inhibit the potassium transient outward current of the action potential, has been suggested in BrS.
METHODS: From a cohort of 106 BrS patients, we studied 35 who received HQ (32 men; mean age 48 +/- 11 years). Patients had asymptomatic BrS and inducible arrhythmia (n = 31) or multiple appropriate shocks from an implantable cardioverter-defibrillator (ICD) (n = 4). Asymptomatic patients with inducible arrhythmia underwent electrophysiologic (EP)-guided therapy. When ventricular tachycardia (VT)/ventricular fibrillation (VF) inducibility was not prevented, or in case of HQ intolerance, an ICD was placed.
RESULTS: Hydroquinidine prevented VT/VF inducibility in 76% of asymptomatic patients who underwent EP-guided therapy. Syncope occurred in two of the 21 patients who received long-term (17 +/- 13 months) HQ therapy (1 syncope associated with QT interval prolongation and 1 unexplained syncope associated with probable noncompliance). In asymptomatic patients who received an ICD (n = 10), one appropriate shock occurred during a follow-up period of 13 +/- 8 months. In patients with multiple ICD shocks, HQ prevented VT/VF recurrence in all cases during a mean follow-up of 14 +/- 8 months.
CONCLUSIONS: Hydroquinidine therapy prevented VT/VF inducibility in 76% of asymptomatic patients with BrS and inducible arrhythmia, as well as VT/VF recurrence in all BrS patients with multiple ICD shocks. These preliminary data suggest that preventive treatment by HQ may be an alternative strategy to ICD placement in asymptomatic patients with BrS and inducible arrhythmia.

PMID 15145111  J Am Coll Cardiol. 2004 May 19;43(10):1853-60. doi: 10.・・・
著者: Bernard Belhassen, Aharon Glick, Sami Viskin
雑誌名: Circulation. 2004 Sep 28;110(13):1731-7. doi: 10.1161/01.CIR.0000143159.30585.90. Epub 2004 Sep 20.
Abstract/Text BACKGROUND: Automatic implantable cardioverter-defibrillator therapy is considered the only effective treatment for high-risk patients with Brugada syndrome. Quinidine depresses I(to) current, which may play an important role in the arrhythmogenesis of this disease.
METHODS AND RESULTS: The effects of quinidine bisulfate (mean dose, 1483+/-240 mg) on the prevention of inducible and spontaneous ventricular fibrillation (VF) were prospectively evaluated in 25 patients (24 men, 1 woman; age, 19 to 80 years) with Brugada syndrome. There were 15 symptomatic patients (including 7 cardiac arrest survivors and 7 patients with unexplained syncope) and 10 asymptomatic patients. All 25 patients had inducible VF at baseline electrophysiological study. Quinidine prevented VF induction in 22 of the 25 patients (88%). After a follow-up period of 6 months to 22.2 years, all patients are alive. Nineteen patients were treated with quinidine for 6 to 219 months (mean+/-SD, 56+/-67 months). None had an arrhythmic event, although 2 had non-arrhythmia-related syncope. Administration of quinidine was associated with a 36% incidence of side effects that resolved after drug discontinuation.
CONCLUSIONS: Quinidine effectively prevents VF induction in patients with Brugada syndrome. Our data suggest that quinidine also suppresses spontaneous arrhythmias and could prove to be a safe alternative to automatic implantable cardioverter-defibrillator therapy for a substantial proportion of patients with Brugada syndrome. Randomized studies comparing these two therapies seem warranted.

PMID 15381640  Circulation. 2004 Sep 28;110(13):1731-7. doi: 10.1161/0・・・
著者: Sami Viskin, Arthur A M Wilde, Hanno L Tan, Charles Antzelevitch, Wataru Shimizu, Bernard Belhassen
雑誌名: Heart Rhythm. 2009 Mar;6(3):401-4. doi: 10.1016/j.hrthm.2008.11.030. Epub 2008 Dec 3.
Abstract/Text
PMID 19251219  Heart Rhythm. 2009 Mar;6(3):401-4. doi: 10.1016/j.hrthm・・・

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