[AF-FORUM] 130E Brugada综合征中房颤的治疗－Perez Riera医师
AF Symposium
information在af-symposium.org
星期四 四月 26 22:55:44 ART 2007
尊敬的来自中国香港九龙玛利亚医院内科及老年病科
心血管组的Isaac Mok医生，我是来自巴西圣保罗的Andrés
Ricardo Pérez Riera医生。关于您提出的问题我来作出回
答。首先我想向您在Brugada综合征领域获得的研究成
果表示祝贺，我阅读过您在这一领域的所有文章：
1) Mok NS, Chan NY, Wong TY, Lau ST, Choi YC. Brugada syndrome in two
local Chinese men. J HK Coll Cardiol 2000;8:15-21;
2) Mok NS, Choi YC. Brugada syndrome masquerading as acute myocardial
infarction in a patient presenting with ventricular fibrillation.
Chin Med J (Engl) 2002;115:458-60.
3) Mok N, Chan N, Choi Y. Late implantation of an implantable
cardioverter-defibrillator in a patient with Brugada syndrome
prevented sudden arrhythmic death. Int J Cardiol 2003;87:269-271.
4) Mok NS, Priori SG, Napolitano C, Chan NY, Chahine M, Baroudi G. A
newly characterized SCN5A mutation underlying Brugada syndrome
unmasked by hyperthermia. J Cardiovasc Electrophysiol 2003;14:407-411.
5) Mok NS, Priori SG, Napolitano C, Chan KK, Bloise R, Chan HW, Fung
WH, Chan YS, Chan WK, Lam C, Chan NY, Tsang HH.Clinical profile and
genetic basis of Brugada syndrome in the Chinese population. Hong
Kong Med J. 2004;10:32-37.
6) Mok NS, Chan NY, Chi-Suen Chiu A. Successful Use of Quinidine in
Treatment of Electrical Storm in Brugada Syndrome.Pacing Clin
Electrophysiol. 2004 Jun;27(6P1):821-823.
7) Mok NS, Chan NY. Brugada syndrome presenting with sustained
monomorphic ventricular tachycardia. Int J Cardiol. 2004 Nov; 97(2):
307-309.
8) Mok NS, Chan NY. Supraventricular Tachycardia with a Baseline ECG
Pattern of Brugada Syndrome. Pacing Clin Electrophysiol. 2005 Jun; 28
(6):602-603
在上述最后一篇文章中您写到过Brugada综合征中的房
颤。关于阵发性房颤及室速发作的电生理基础可能是
心房及心室壁组织由动作电位及不应期缩短不均一所
致的显著透壁复极不同步(1)。心室组织透壁电压的产
生是心外膜、M细胞复极时程差异及心内膜细胞动作
电位时程差异的结果，M细胞平台电位的出现有助于
解释异常ST段、T波、U波。上述不均一性增大则导致ST
段、T波、U波、QT间期异常，向Brugada综合征、长QT综
合征、短QT综合征发展(2)。
Brugada兄弟（1992）的早期研究发现，Brugada综合征中窦
性节律是正常的；然而，此类病人患房颤的比例异常
增高，达到10～25％，其致心律失常的基础并非仅局
限于心室(3)。Brugada综合征中出现阵发性房颤的现
象，来自巴西及日本的研究者都曾提到(5)。后者还提
到阵发性房颤的发病率可到30％。Eckardt L（6）等曾发
表文章指出Brugada综合征中室上速的发病率达29％。这
些作者都提到了折返引起的室上速发作。我们查到证
实A型WPW综合征与Brugada综合征有关的文章(7-8)。Brugada
综合征出现自发性房颤者有更进一步的疾病过程，而
且室性心律失常的可诱导性与房颤病史明显相关。心
电图表现为自发性Brugada综合征者与氟卡尼诱发者比
较其房颤的发病率为26% vs 10%。Brugada综合征具备安装
ICD指征者较不具备者其房颤的发病率为27% vs 13%。14% 的
ICD植入患者发生房颤导致的不当放电，而只有10.5%ICD
植入患者伴恰当放电。对Brugada综合征预防性置入ICD
治疗者进行长期随访发现不当放电相对频繁的继发于
窦性心动过速、新发的房性心律失常、噪音。多变量
Cox回归分析发现，新发房颤和年龄小于50岁为缩短不
恰当放电自由生存的独立预测因素(P值分别为P = 0.04 和
P = 0.036) (9)。
植入单腔起搏器为ICD不当放电的独立预测指标；我们
建议对单腔ICD进行仔细程控以避免其在Brugada综合征
病人中的不当放电(10)。Boveda等(11)发现在一46岁的
Brugada综合征患者中心房来源的心律失常是唯一的自
发性病理节律。这引起我们在文献中及Boveda的个人经
验中对Brugada综合征者出现这一现象的发生率作出重
新考虑。低血钾增加Brugada综合征患者发生室上性及
室性心律失常的危险。曾有报道Brugada综合征伴低血
钾者出现有症状的房颤发作，血钾正常后未出现再次
发作（12）。窦房结功能不全不止是Brugada综合征的一
个并发症，二者可能有基因的相关性。窦房结功能不
全与房颤有关（13）。Brugada综合征是无心脏结构病变
的离子通道病。使用射频导管消融房颤离子通道只有
一个依据：ABCC9基因缺失突变(Thr1547Ile)所致K(ATP)离子
通道疾病是起源于Marshall静脉的肾上腺素能性阵发性
房颤发生的遗传学缺陷背景，并可通过药物治疗的活
性及不应期分析得知。使用射频导管消融破坏Marshall
静脉致心律失常基因环境的治疗是有效的。这是迄今
为止，唯一一篇提及使用射频导管消融破坏房颤离子
通道的参考文献(14)。房颤已定位于9个染色体，4个基
因已得到确认(15)。
结论：我选择的治疗房颤的药物是奎尼丁。此药阻断
心房、心室多个离子通道：快Na+电流、Ito1通道或短
暂外向电流、IK1内向整流、延迟整流: IKS, IKR 和 IKUR, I
KATP或ATP敏感性钾通道、IK-Ach, alpha 1 和 alpha 2 肾上腺
素能受体。在Brugada综合征中利用其阻断Ito离子通道
的性质，重获心房、心室壁心肌的电均一性，消除2
相折返抗心律失常。奎尼丁因其可阻断I(to)通道被作
为置入ICD后的辅助治疗。而且此药有阻断M2受体的有
益性迷走神经松弛作用。M2受体在心房中起重要作
用。此药在心房有效不应期时作用增强。
References
1) Schimpf R, Wolpert C, Gaita F, Short QT syndrome. Cardiovasc Res.
2005; 67: 357-366.
2) Antzelevitch C. Cellular basis for the repolarization waves of the
ECG. Ann N Y Acad Sci. 2006; 1080: 268-281.
3) Brugada P, Brugada J. Right bundle branch block, persistent ST
segment elevation and sudden cardiac death: A distinct clinical and
electrocardiographic syndrome. J Am Coll Cardiol 1992, 20: 1391-1396.
4) Villacorta H, Faig Torres RA, Simões de Castro IR, Lambert H. de
Araujo Gonzáles Alonso R.: Morte súbita em paciente com bloqueio de
ramo direito e elevação persistente do segmento ST. Arq Bras
Cardiol. 1996; 66: 229-231.
5)Itoh H, Shimizu M, Ino H, et al. Hokuriku Brugada Study Group.
Arrhythmias in-patients with Brugada-type electrocardiograph
findings. Jpn Circ J 2001; 65:483-466.
6)Eckardt L, Kirchhof P, Loh P, et al. Brugada Syndrome and
Supraventricular Tachyarrhythmias: A Novel Association? J Cardiovasc
Electrophysiol 2001; 12:680-68
7)Eckardt L, Kirchhof P, Johna R, Haverkamp W, Breithardt G,
Borggrefe M. : Wolff-Parkinson-White syndrome associated with
Brugada syndrome. Pacing Clin Electrophysiol 2001; 24:1423-1424.
8)Bodegas AI, Arana JI, Vitoria Y, Arriandiaga JR, Barrenetxea JI.
Brugada syndrome in a patient with accessory pathway. Europace
2002; 4:87-89
9)Sarkozy A, Boussy T, Kourgiannides G, et al. Long-term follow-up
of primary prophylactic implantable cardioverter- defibrillator
therapy in Brugada syndrome. Eur Heart J. 2007;28:334-344.
10) Bordachar P, Reuter S, Garrigue S, Cai X, Hocini M, Jais P,
Haissaguerre M, Clementy J. Incidence, clinical implications and
prognosis of atrial arrhythmias in brugada syndrome.Eur Heart J.
2004;25:879-884.
11) Boveda S, Combes N, Albenque JP, et al. Brugada syndrome and
supraventricular arrhythmiasArch Mal Coeur Vaiss. 2004; 97: 688-692.
12) Notarstefano P, Pratola C, Toselli T, et al.Atrial fibrillation
and recurrent ventricular fibrillation during hypokalemia in Brugada
syndrome.Pacing Clin Electrophysiol. 2005; 28:1350-1353.
13)Sumiyoshi M, Nakazato Y, Tokano T, Sinus node dysfunction
concomitant with Brugada syndrome. Circ J. 2005; 69:946-950.
14)Olson TM, Alekseev AE, Moreau C. KATP channel mutation confers
risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin
Pract Cardiovasc Med. 2007; 4:110-116.
15)Roberts R,Genomics and cardiac arrhythmias.J Am Coll Cardiol.
2006;47:9-21.
16)Pérez Riera AR, Zhang L, Uchida AH, et al. The management of
Brugada syndrome patients 2007;14:97-106 www.cardiologyjournal.org
All the best for all
Andrés Ricardo Pérez Riera MD
Chief of Electro-Vectocardiology Sector of the Discipline of
Cardiology,ABC Faculty of Medicine (FMABC), Foundation of ABC
(FUABC) – Santo André São Paulo - Brazil.
riera在uol.com.br
--
Dr. Sergio Dubner
科委会主席
Dr. Edgardo Schapachnik
组委会主席
张欣 译
130E Treatment of AF in Brugada syndrome. Dr. Perez Riera
Dear Dr Isaac Mok: from Department of Medicine and
Geriatrics.Cardiology Team, Department of Medicine & Geriatrics,
Princess Margaret Hospital, Lai Chi Kok, Kowloon, Hong Kong, China.
Here Andrés Ricardo Pérez Riera from São Paolo Brazil answering.
First I want congratulate you for the important contributions in
Brugada syndrome field research. I read all your about this entity.
See below:
1) Mok NS, Chan NY, Wong TY, Lau ST, Choi YC. Brugada syndrome in two
local Chinese men. J HK Coll Cardiol 2000;8:15-21;
2) Mok NS, Choi YC. Brugada syndrome masquerading as acute myocardial
infarction in a patient presenting with ventricular fibrillation.
Chin Med J (Engl) 2002;115:458-60.
3) Mok N, Chan N, Choi Y. Late implantation of an implantable
cardioverter-defibrillator in a patient with Brugada syndrome
prevented sudden arrhythmic death. Int J Cardiol 2003;87:269-271.
4) Mok NS, Priori SG, Napolitano C, Chan NY, Chahine M, Baroudi G. A
newly characterized SCN5A mutation underlying Brugada syndrome
unmasked by hyperthermia. J Cardiovasc Electrophysiol 2003;14:407-411.
5) Mok NS, Priori SG, Napolitano C, Chan KK, Bloise R, Chan HW, Fung
WH, Chan YS, Chan WK, Lam C, Chan NY, Tsang HH.Clinical profile and
genetic basis of Brugada syndrome in the Chinese population. Hong
Kong Med J. 2004;10:32-37.
6) Mok NS, Chan NY, Chi-Suen Chiu A. Successful Use of Quinidine in
Treatment of Electrical Storm in Brugada Syndrome.Pacing Clin
Electrophysiol. 2004 Jun;27(6P1):821-823.
7) Mok NS, Chan NY. Brugada syndrome presenting with sustained
monomorphic ventricular tachycardia. Int J Cardiol. 2004 Nov; 97(2):
307-309.
8) Mok NS, Chan NY. Supraventricular Tachycardia with a Baseline ECG
Pattern of Brugada Syndrome. Pacing Clin Electrophysiol. 2005 Jun; 28
(6):602-603
In the last one you wrote about atrial arrhythmias in BrS. The
possible electrophysiological substrate for the development of
paroxysmal AF and VT may be a significant transmural dispersion of
the repolarization due to a heterogeneous abbreviation of the action
potential duration (APd) and refractory period in both atrial and
ventricular wall (1). In ventricles, transmural voltage gradients
developing as a result of difference in the time course of
repolarization of the epicardial, M,
and endocardium cell APs, and the more positive plateau potential of
the M cell contribute to inscription of the ST segment, T and U
waves. Amplification of these heterogeneities can results in
abnormalities of the ST segment (J wave), T wave, U wave and QT
interval leading to the development of the Brugada, long QT, and
short QT syndromes (2).
In BrS sinus rhythm is the usual; however, BrS patients exhibit an
abnormally high proportion of atrial arrhythmias that are found in
10 to 25% of cases since the arrhythmogenic substrate is not limited to
the ventricles. In the original discovery by the Brugada brothers
(1992) (3). Temporary AF was mentioned, as well as by authors from
Brazil (4) and from Japan (5). The latter mentioned that the
paroxysmal form of AF is observed in a 30% of cases. A publication by
Eckardt L et al (6) indicates a frequency for Supraventricular
arrhythmias of 29%. These authors described episodes of AV
Supraventricular tachycardia with reentry.
There are references of Wolff-Parkinson-White syndrome A type
associated to BrS (7-8) There is a more advanced disease process in
BS patients with spontaneous atrial arrhythmias and ventricular
inducibility was significantly related to a history of atrial
arrhythmias;The incidence of atrial arrhythmias in patients with a
spontaneous electrocardiogram of BrS was 26% vs 10% in patients with
a flecainide- induced ECG;In patients with an indication of ICD, the
incidence of atrial arrhythmias reached 27% vs 13% in patients with
BrS but without ICD indication. Inappropriate shocks due to atrial
arrhythmias episodes were observed in 14% of ICD patient's vs 10.5%
of appropriate shocks. In patients Long-term follow-up of primary
prophylactic ICD therapy in BrS inappropriate shocks are relatively
frequent consequence of sinus tachycardia; new onset atrial
arrhythmias; and noise over sensing. In multivariable Cox-regression
analysis, new onset atrial AF and less than 50 years of age were
independent predictors of significantly shorter inappropriate shocks -
free survival (P = 0.04 and P = 0.036, respectively) (9).
The implantation of a single-chamber device is as an independent
predictive factor of inappropriate ICD discharges; Careful
programming of single-chamber ICD should be recommended to avoid
inappropriate discharges in patients with BrS (10).Arrhythmia of
atrial origin was the only spontaneous pathologic rhythmic observed
in a 46 years old man patient with BrS by Boveda et al (11).
Consequently it led to reconsider its prevalence in patients
presenting this syndrome both in the literature and according
Boveda's time personal experience. Hypokalemia
increases the risk of both supraventricular and ventricular
arrhythmic events in BrS. Episode of symptomatic AF were described in
patients with BrS associated with hypokalemia. No further episodes
occurred after normalization of serum levels of potassium (12).
Sinus node dysfunction (SND) is not a rare concomitant disorder in
BrS and there is a possible genetic connection. SND is associated
with AF (13) BrS is a channelopathy without apparently structural
heart disease. The use of Radiofrequency Catheter Ablation in AF
channelopathies have only one reference: K(ATP) channelopathy caused
by missense mutation (Thr1547Ile) of the ABCC9 gene conferring
predisposition to adrenergic paroxysmal AF originating from the vein
of Marshall and precipitated by activity and refractory to medical
therapy. Disruption of arrhythmogenic gene-environment substrate at
the vein of Marshall by RFCA was effective. This is the single
reference of literature until to day about treatment of AF with RFCA
in channelopathies (14). AF is mapped to nine chromosomal loci and
four genes are identified (15).
Conclusion: My choose approach for AF in BrS is Quinidine This drugs
block the following channels in both atria and ventricle: Fast Na+
current; Ito1 channel or transient outward current; Inward rectifier
IK1, delayed rectifier: IKS, IKR and IKUR, I KATP or adenosine
triphosphate ATP sensitive potassium channel, IK-Ach, alpha 1 and
alpha 2 adrenergic receptors. In the BrS it is used by its property
to block the Ito channel and thus restorer electrical homogeneity
across atrial and ventricular myocardial wall and in abolishing
arrhythmias by phase 2 reentry.Quinidine, by virtue of its actions to
block I(to), has been proposed as adjunctive therapy, with an ICD as
backup. Additionally the drug has a benefic vagolytic effects occur
through muscarinic (M2) receptor block. This last one are important
in atrium.(16). The drug in atrium Effective Refractory Period is
augmented
References
1) Schimpf R, Wolpert C, Gaita F, Short QT syndrome. Cardiovasc Res.
2005; 67: 357-366.
2) Antzelevitch C. Cellular basis for the repolarization waves of the
ECG. Ann N Y Acad Sci. 2006; 1080: 268-281.
3) Brugada P, Brugada J. Right bundle branch block, persistent ST
segment elevation and sudden cardiac death: A distinct clinical and
electrocardiographic syndrome. J Am Coll Cardiol 1992, 20: 1391-1396.
4) Villacorta H, Faig Torres RA, Simões de Castro IR, Lambert H. de
Araujo Gonzáles Alonso R.: Morte súbita em paciente com bloqueio de
ramo direito e elevação persistente do segmento ST. Arq Bras
Cardiol. 1996; 66: 229-231.
5)Itoh H, Shimizu M, Ino H, et al. Hokuriku Brugada Study Group.
Arrhythmias in-patients with Brugada-type electrocardiograph
findings. Jpn Circ J 2001; 65:483-466.
6)Eckardt L, Kirchhof P, Loh P, et al. Brugada Syndrome and
Supraventricular Tachyarrhythmias: A Novel Association? J Cardiovasc
Electrophysiol 2001; 12:680-68
7)Eckardt L, Kirchhof P, Johna R, Haverkamp W, Breithardt G,
Borggrefe M. : Wolff-Parkinson-White syndrome associated with
Brugada syndrome. Pacing Clin Electrophysiol 2001; 24:1423-1424.
8)Bodegas AI, Arana JI, Vitoria Y, Arriandiaga JR, Barrenetxea JI.
Brugada syndrome in a patient with accessory pathway. Europace
2002; 4:87-89
9)Sarkozy A, Boussy T, Kourgiannides G, et al. Long-term follow-up
of primary prophylactic implantable cardioverter- defibrillator
therapy in Brugada syndrome. Eur Heart J. 2007;28:334-344.
10) Bordachar P, Reuter S, Garrigue S, Cai X, Hocini M, Jais P,
Haissaguerre M, Clementy J. Incidence, clinical implications and
prognosis of atrial arrhythmias in brugada syndrome.Eur Heart J.
2004;25:879-884.
11) Boveda S, Combes N, Albenque JP, et al. Brugada syndrome and
supraventricular arrhythmiasArch Mal Coeur Vaiss. 2004; 97: 688-692.
12) Notarstefano P, Pratola C, Toselli T, et al.Atrial fibrillation
and recurrent ventricular fibrillation during hypokalemia in Brugada
syndrome.Pacing Clin Electrophysiol. 2005; 28:1350-1353.
13)Sumiyoshi M, Nakazato Y, Tokano T, Sinus node dysfunction
concomitant with Brugada syndrome. Circ J. 2005; 69:946-950.
14)Olson TM, Alekseev AE, Moreau C. KATP channel mutation confers
risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin
Pract Cardiovasc Med. 2007; 4:110-116.
15)Roberts R,Genomics and cardiac arrhythmias.J Am Coll Cardiol.
2006;47:9-21.
16)Pérez Riera AR, Zhang L, Uchida AH, et al. The management of
Brugada syndrome patients 2007;14:97-106 www.cardiologyjournal.org
All the best for all
Andrés Ricardo Pérez Riera MD
Chief of Electro-Vectocardiology Sector of the Discipline of
Cardiology,ABC Faculty of Medicine (FMABC), Foundation of ABC
(FUABC) – Santo André São Paulo - Brazil.
riera在uol.com.br
--
Dr. Sergio Dubner
President of Scientific Committee
Dr. Edgardo Schapachnik
President of Steering Committee
--
Dr. Sergio Dubner
President of Scientific Committee
Dr. Edgardo Schapachnik
President of Steering Committee
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