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Congres Report
 

Symposium 5

 
New Findings of Mechanism and Therapeutic Strategies of Idiopathic Ventricular Fibrillation
 
Brugada Syndrome and Diverse Phenotypes of Cardiac Sodium Channelopathies
Takeru Makiyama
Kyoto University
Kyoto, Japan
ICD Therapy for Idiopathic Ventricular Fibrillation in Japan. The ICD-WEB Registry administered by the Japanese Heart Rhythm Society
Akihiko Shimizu
Osaka City University Graduate School of Medicine
Yamaguchi, Japan
Clinical and Electrophysiological Differentiation of Symptomatic and Asymptomatic Patients with Brugada Syndrome. The Japan Idiopathic Ventricular Fibrillation Study (J-IVFS).
Masahiko Takagi
Osaka City University Graduate School of Medicine
Osaka, Japan
 
Brugada Syndrome and Diverse Phenotypes of Cardiac Sodium Channelopathies
Takeru Makiyama
Kyoto University
Kyoto, Japan
 

Mutations in the SCN5A gene, which encodes the pore-forming alpha-subunit of cardiac sodium channels, can lead to a number of cardiac phenotypes: long-QT syndrome (LQT) type 3, Brugada syndrome, cardiac conduction disease, sick sinus syndrome (SSS), and atrial fibrillation (AF) with or without dilated cardiomyopathy.

The prevalence of SCN5A mutations and the genotype-phenotype relationships in 445 patients with hereditary arrhythmias was investigated by Makiyama and colleagues at Kyoto University. Key findings were:

  • LQTS: 16 mutations in 21 of 232 patients (9%).
  • Brugada Syndrome: 12 mutations in 13 of the 105 patients (11%).
  • Familial SSS: 6 mutations in 6 of the 15 patients (40%).
  • Familial atrial fibrillation: 1 mutation in the 1 patient.

The mutations in the LQTS tend to aggregate in the intracellular region of the cardiac sodium channel. Some of the mutations found in Brugada syndrome and familial SSS can be classified as a missense, which are commonly found in the pore-forming regions. These forms produce non-functioning sodium channels.

 

Case Reviews

Figure 1. A 2-day old infant with long QT syndrome with a 2:1 AV block and a QTc of 720 ms.
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Figure 2. Late sodium currents and action potential duration prolongation were identified in the 2-day-old infant with long QT syndrome.
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Figure 3. A 33-year-old man with Brugada syndrome and familial sick sinus syndrome, who experienced syncope from ventricular fibrillation when febrile.
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Figure 4. A novel gain-of-function SCN5A phenotype was indentified in the setting of familial atrial fibrillation.
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A 2-day old infant with LQTS with a 2:1 AV block and a QTc of 720 ms was found to have a heterozygous SCN5A mutation (N17740) (Figure 1). Late sodium currents resulted in gain-of-function and action potential duration prolongation (Figure 2).

A 33-year-old man with Brugada syndrome and familial SSS experienced syncope from ventricular fibrillation when he was febrile (Figure 3). His mother had SSS and an implanted pacemaker. An SCN5A mutation (T187I) was found in the patient and his mother. A non-functional channel was revealed on functional analysis.

Patients with Brugada syndrome and an SCN5A mutation are at high risk for a bradyarrhythmia; 5 of the 13 Brugada patients identified with an SCN5A mutation had an underlying bradyarrhythmia that produced non-functional channels.

A 53-year old man with SSS had a pacemaker implanted because of a prolonged sinus pause. His mother had atrial standstill and an implanted pacemaker. A heterozygous SCN5A gene missense mutation (K1859E) was identified in both. A loss-of-function modulation was determined as a result of a 40% reduction in sodium channel density in the mutant channels compared to the wild-type channels and a negative shift of 9.2 mV in the INa/peak INa.

In Japanese patients with familial SSS, SCN5A mutations are common as shown by the 40% prevalence. Interestingly, 4 of the 6 patients with SCN5A-linked SSS had an additional overlapping sodium channelopathy, Brugada syndrome and Long QTS.

A novel gain-of-function SCN5A phenotype that manifested as familial AF was identified in this study (Figure 4). The 8 affected family members had a similar clinical course. In their teens, PACs began that later progressed to AF. No structural heart disease or ECG abnormalities were found. The novel M1875T mutation perfectly matched the clinical phenotypes of family members. On functional assay, their inward channels showed slower inactivation compared to wild-type channels. A significantly larger peak sodium channel density was also found in the mutant channels. A marked depolarized shift of 16.4 mV of fast inactivation in the mutant channels was observed. Increased automaticity and irritability in the right atrium was identified with radiofrequency ablation in the probands.

In closing, Makiyama stated that SCN5A mutations were identified in a substantial portion of patients with various inherited arrhythmias, suggesting the diversity and complexity of cardiac sodium channelopathies.

 
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ICD Therapy for Idiopathic Ventricular Fibrillation in Japan. The ICD-WEB Registry administered by the Japanese Heart Rhythm Society
Akihiko Shimizu
Osaka City University Graduate School of Medicine
Yamaguchi, Japan
 

The ICD Committee of the Japanese Heart Rhythm Society analyzed data from their ICD-WEB Registry to understand the characteristics of Japanese patients with idiopathic ventricular fibrillation (IVF) and implantable cardioverter-defibrillators (ICDs).

Figure 2. Characteristics of electrophysiological testing in this analysis.
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Figure 2. Characteristics of electrophysiological testing in this analysis.
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A total of 2,426 subjects with an implanted ICD or CRT-D enrolled between August 4, 2006 to March 13, 2008 were included in this analysis, and their clinical characteristics are shown in Figure 1. The IVF group comprised 16% of the subjects, while the balance were in the organic heart disease (OHD) group. The ratio of men to women was 5.6 in the IVF group, whose mean age was 49 years and 3.2 in the OHD group, with a mean age of 64 years. Left ventricular ejection fraction was significantly better in the IVF group compared to the OHD group. In the IVF group, 60% had Brugada syndrome, 31% non-Brugada syndrome, and 10% Long QT syndrome.

ICD implantation was for primary prevention in 50% of the Brugada syndrome subjects, 7% of the non-Brugada syndrome, and 6% of the Long QT syndrome subjects. In the OHD group, 34% of patients had implantation for primary prevention. In these patients, an electrophysiological study (EPS) was performed in 91% of the Brugada subjects, 63% of the non-Brugada, and 42% of the OHD subjects (Figure 2).  Further, ventricular tachyarrhythmias were inducible in 91% of Brugada subjects, 80% of non-Brugada subjects, and 86% of OHD subjects.

This registry data show that in Japan, Brugada syndrome comprises 60% of subjects with IVF and an implanted ICD, and for half of these patients the ICD was for primary prevention, much higher than the other forms of IVF.

Data from Aihara and published in Heart View in 2007 show that asymptomatic patients with Brugada syndrome appear to be at low risk for arrhythmic events, with an event rate of 1% at 2 years. In patients with a history of syncope, the even rate was only 4% in the Brugada patients.

Shimizu stated that further examination to identify the high-risk persons with Brugada syndrome is required, because of the apparent low risk in asymptomatic patients for arrhythmic events.

 
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Clinical and Electrophysiological Differentiation of Symptomatic and Asymptomatic Patients with Brugada Syndrome. The Japan Idiopathic Ventricular Fibrillation Study (J-IVFS).
Masahiko Takagi
Osaka City University Graduate School of Medicine
Osaka, Japan
 

The Japan Idiopathic Ventricular Fibrillation Study sought to identify a new marker for distinguishing low-risk and high-risk persons with Brugada syndrome. Risk stratification of symptomatic and asymptomatic persons with Brugada is unsettled, and while Japan has a relatively high incidence of Brugada syndrome, there is no consensus on risk stratification.

Figure 1. The ECG parameters measured in the J-IVFS study.
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Figure 2. The r-J interval was significantly longer in the symptomatic groups compared to asymptomatic group in the J-IVFS study.
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Figure 3. The QRS duration was significantly longer in the symptomatic groups compared to asymptomatic group in the J-IVFS study.
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This analysis comprised 241 persons with Brugada syndrome diagnosed using the Wilde criteria (mean age 52 years, 14 women) enrolled from 47 institutions across Japan between February 2002 and January 2007. The asymptomatic group included 129 persons, syncope group 67 persons, and the ventricular fibrillation (VF) group 45 persons; age and sex were similar across the three groups. Clinical characteristics and symptoms were assessed, along with electrocardiographic findings and clinical outcome of sudden cardiac death and VF.

A lower family history of sudden cardiac death (16%) was found in the J-IVFS compared to the European data, and was similar across the three groups. A significantly higher family history of atrial fibrillation (AF) was found in the symptomatic groups (22% to 27%) compared to the asymptomatic group (11%).

The ECG parameters measured in this study are illustrated in Figure 1. Twenty-three ECGs were excluded because of AF or other abnormalities. The r-J interval was significantly longer in the symptomatic groups (97 ms syncope group, 104 ms VF group compared to the asymptomatic group (94 ms), while the other measured parameters did not differ across the groups (Figure 2). The QRS duration was significantly longer in the symptomatic groups (98 ms syncope group, 102 ms VF group) versus the asymptomatic group (95 ms), but there were no differences in the other parameters (Figure 3).

Positive late potential was found in 72% and inducible VF by EP in 78% of patients. No differences across groups was found.

A significantly higher incidence (42%) of cardiac events was found in the VF group over the mean 40-months follow-up, compared to 10% in the syncope group and no cardiac events in the asymptomatic group.

 

Predictors of cardiac events in J-IVFS

A longer r-J interval in V2 (≥ 90 ms, versus < 90 ms) and a family history of AF were associated with a significantly higher incidence of cardiac events in this study. A family history of sudden cardiac death and inducible VF were not predictors of cardiac events, with no difference in the incidence of events.

 

Sex differences in Japanese patients

Only 6% of the study patients were women, compared to 22-55% in European data. In J-IVFS, women had a significantly lower incidence of symptoms than men (21% vs 48%, respectively) and had a significantly higher incidence of family history of SCD compared to men (36% vs 15%, respectively). No difference in positive late potential and inducible VF was found between women and men. No cardiac events occurred in women during the follow-up period.

 

Closing

  • Symptomatic, versus asymptomatic, patients exhibited prolonged ventricular depolarization.
  • Cardiac events recurred only in symptomatic patients.  
  • The markers of depolarization (r-J interval ≥ 90 ms in V2) may distinguish low-risk and high-risk patients.
  • Positive late potentials and VF induciblity by EPS are not proven as predictive markers for cardiac events.
 
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