[SCD-FORUM] EXPERTS ASK, EXPERTS ANSWER

[SCD Symposium]

Dr. Merino 问：
心动过缓在猝死机制中的真正作用是什么？他是相当 
一部分猝死患者的主要病因吗？或者象电机械分离或 
休克等仅仅是其他心脏状态的表象？



Dr. Perez Riera 答：
     房室传导阻滞或病态窦房结综合征的患者（SSS） 
经常出现由于心搏停止或严重的心动过缓所导致的眩 
晕、黑朦、晕厥、呼吸中断以及心衰。
     缓慢型心律失常导致晕厥在不同的患者人群中占 
3-10%。窦房结功能的损伤或高度的房室传导阻滞以及 
颈动脉窦综合征和病理性血管压力反射均可导致明显 
的心动过缓或心搏停止。根据标准的心电图，高度房 
室传导阻滞的出现可以诊断心动过缓性晕厥。窦房结 
功能的减退是晕厥最常见的原因之一，特别是不适当 
的持久性窦性心动过缓，窦性停搏或者窦房传导阻滞 
以及阵发性房性心动过速与房性心动过缓交替出现。 
对可疑性房性心律失常可以选择动态心电图监测，但 
是有时会由于缺少症状发作时的记录从而妨碍诊断。 
有时仅仅使用无创的方法，例如详细询问病史、动态 
心电图和运动试验等不能发现大于3秒的窦性停搏或 
者高度房室传导阻滞这些导致晕厥的确切证据。在这 
种情况下，这些患者应不应该从事电生理检查呢？几 
项研究显示，对静息时病理性心电图（一度房室传导 
阻滞、束支阻滞和不适当的窦性心动过缓）和心脏疾 
病患者，通过电生理检查证实晕厥的原因超过30%。
进展性心脏传导缺陷（PCCD）总称为原发性传导系统 
疾病（Lev-Lenègre）。Lenègre 病（常称为原发性 
PCCD），和继发于机械损伤（导致骨架硬化或Lev氏 
病）经常导致左束支阻滞或右束支阻滞，并经常与分 
支阻滞相关。有时，他们进展成高度的传导阻滞，并 
由于完全的房室传导阻滞而产生潜在的心脏性猝死， 
一定程度上他们代表第一世界国家起搏器植入的最重 
要的原因，每年千分之0.15。（在南美Chagas病是主要 
原因）

SCN5A基因错义突变既能导致Brugada综合症又能导致 
PCCD。修饰基因可能影响  SCN5A基因突变的表型结果。在 
4372位置的G突变为T被直接排序确认，并预期可以使Na 
+通道蛋白在DIII-S5 和 DIII-S6区域间的精氨酸变为甘氨 
酸。最近的研究报道在Brugada综合症发现2个新的等位 
基因突变，位于Na+通道SCN5基因的亚组，在临床上翻 
译表现成房室阻滞。他们是丝氨酸(G298S)在I S5-S6区域 
被甘氨酸替代的结果，以及天冬氨酸在IV的 S3 (D1595N)  
被门冬氨酸替代的结果。既减少钠通道密度防止快速 
失活的突变又强调失活的慢成分。这种结合导致传导 
速度的降低和房室阻滞及猝死倾向。

Kyndt等认为快Na+通道蛋白的半胱氨酸被甘氨酸替代导 
致室内传导异常。几乎50%的Brugada综合症病例PR间期和 
HV电图延长。HV电图延长约达正常高限的两倍。

初步观察：LEV氏病不应继续被归类于特发性进展性希 
氏束系统的疾病。他应该被称作进展性的心脏传导缺 
陷或者PCCD。他已经被认为是快Na+通道的疾病或者由 
SCN5A基因突变所致的通道病变，作为Brugada综合症不同 
表现型的等位基因，相似于遗传性家族性长QT综合症的 
LQT3变异。SCN5A基因相同的错义突变能产生两个表型： 
Brugada综合症和LEV氏病







Dr. Merino ask:


What is the true role of bradyarrhtymia in the mechanisms of sudden  
death?

Do they represent the responsible cause for sudden death in a  
significant proportion of patients or are they mere epiphenomena of  
other cardiac situations, such as electromechanical dissociation or  
shock?

Dr. Perez Riera  Answer


Dear José Luis Merino fromSpain   here your friend Andrés Ricardo  
Pérez Riera form São Paulo Brazil. You ask: What is the true role of  
bradyarrhtymia in the mechanisms of sudden death?  Do they represent  
the responsible cause for sudden death in a significant proportion of  
patients or are they mere epiphenomena of other cardiac situations,  
such as electromechanical dissociation or shock?

Answer: Dizziness, black spell, syncope, short of breathness and HF  
due to cardiac arrest or severe bradycardia are often observed in  
patients with AV block or sick sinus syndrome(SSS).
Bradyarrhythmias, depending on the patient population, are the cause  
of syncope in 3 to 10%. Marked bradycardia or asystole can be due to  
impaired function of the sinus node (SSS) or high-grade AV-conduction  
block as well as carotid sinus syndrome and pathologic vasodepressor  
reactions. In the presence of high-grade AV-block, the diagnosis of  
bradyarrhythmia-induced syncope can frequently be established on the  
basis of a standard ECG. One of the most common causes of syncope is  
functional impairment of the sinus node, in particular, an inadequate  
permanent sinus bradycardia, sinus node arrest or SA-block and  
paroxysmal atrial tachycardia alternating with atrial bradycardia.  
The method of choice for detecting suspected paroxysmal arrthythmias  
is ambulatory ECG monitoring but interpretation may be encumbered by  
the absence of concomitant symptoms during the registration.  
Frequently, the use of non-invasive methods alone, such as detailed  
history, ambulatory ECG and ECG exercise testing, will not render  
confirmatory findings to document the cause of syncope, that is, > 3  
s pause in sinus rhythm or high-grade AV-block. In this situation,  
the question arises which patients should undergo EPS. Several  
studies have shown that in patients with a pathologic resting ECG  
(first degree AV-block, bundle branch block, inadequate sinus  
bradycardia) and cardiac disease, PES   will document a cause of  
syncope in more than 30%.

Progressive Cardiac Conduction Defects (PCCD), are grouped together  
as primary conduction diseases (Lev-Lenègre). Both Lenègre disease— 
known as "primary" PCCD —as well as the secondary mechanic lesion— 
sclerosis of the left "cardiac skeleton" or Lev disease — usually  
cause LBBB or RBBB, frequently associated with divisional blocks.  
Occasionally, they develop into more advanced degrees of block with a  
potential to cause SCD due to total AV block, to the extent that they  
represent the most important cause of   pacemaker implantation in the  
first world: 0.15 per 1,000 inhabitants a year.( Here in South  
America the main cause is Chagas disease).

The same mutation in novel single SCN5A missense mutation can lead  
either to Brugada syndrome or to an PCCD . Modifier gene(s) may  
influence the phenotypic consequences of a SCN5A mutation. A G-to-T  
mutation at position 4372 was identified by direct sequencing and was  
predicted to change a glycine for an arginine (G1406R) between the  
DIII-S5 and DIII-S6 domain of the Na+ channel protein . A recent  
publication has reported the discovery of two new allelic  
heterozygotic mutations with Brugada syndrome, located in the alpha  
subunit of the Na+ channel in the SCN5A gene, what has been  
clinically translated into AV block. They are the result of the  
substitution of the serine amino acid by glycine (G298S) in the  
domain of the I S5-S6 loop, and asparagine by aspartic acid within  
the S3 of the IV domain (D1595N). Both mutations prevent fast  
inactivation, reduce sodium channel density, and accentuate the slow  
component of inactivation. This combination causes a decrease in  
conduction velocity and leads to AV block and SCD tendency .

Kyndt et al identified, which causes intraventricular dromotropic  
disorder secondary to substitution of the cysteine amino acid by  
glycine (G514C) in the Na+ proteic fast channel. In Brugada syndrome,  
the PR interval and the HV of the electrogram are prolonged in nearly  
50% of cases. HV can reach a duration of approximately twice its  
maximal normal limit.

Observation: Lenègre disease should not continue to be classified as  
an idiopathic progressive disease of the His-Purkinje system. It  
should be called a Progressive Cardiac Conduction Defect or PCCD. It  
has been identified as a disease of the Na+ fast channel or  
channelopathy by mutation in the SCN5A gene, and as allele of Brugada  
syndrome with a different phenotypic expression, in a similar fashion  
to the LQT3 variant of the hereditary-familial LQTS. The same  
missense mutation in the SCN5A gene can cause both phenotypes:  
Brugada disease and Lenègre disease.

All the best
  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.
Sebastião Afonso 885 Jardim Miriam SP Brazil
Zip Code: 04417-100
Phone: 5506-5925 Fax: 5506-0398
riera在uol.com.br

--
Dr. Sergio Dubner
President of Scientific Committee

Dr. Edgardo Schapachnik
President of Steering Committee