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Congres Report
 

Symposium 4

 
Inherited Arrhythmias: Diagnosis and Treatment
 
Efficient Diagnostic Method and Alarming Prognosis in Catecholaminergic Polymorphic Ventricular Tachycardia
Meiso Hayashi
Nippon Medical School, Tokyo, Japan
Latent Genetic Backgrounds of Acquired Long QT Syndrome
Hideki Itoh
Shiga University Medical Science, Japan
Clinical Phenotype and Prognosis of Probands with Brugada Syndrome in Relation to SCN5A Mutation
Kenichiro Yamagata
Japanese Brugada Syndrome Multicenter Registry, Japan
Impact of Sodium Channel Dysfunction on Arrhythmogenesis in Brugada Syndrome
Hiroshi Morita, MD
Okayama University Graduate School of Medicine, Okayama, Japan; Indiana University School of Medicine, Indianapolis, IN, USA
 
Efficient Diagnostic Method and Alarming Prognosis in Catecholaminergic Polymorphic Ventricular Tachycardia
Meiso Hayashi
Nippon Medical School, Tokyo, Japan
 

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that is a significant cause of sudden cardiac death (SCD) in the young. Because CPVT is triggered by physical or emotional stress, exercise stress test is considered an appropriate diagnostic tool. While some studies have reported exercise stress test-induced premature ventricular complexes (PVCs) and VT in 80%-100% of CPVT patients, two studies found no arrhythmias in 23% and 35% of genetically affected family members. Diagnosis of CPVT in patients with a negative exercise stress test remains controversial. Dr. Meiso Hayashi, Nippon Medical School, presented a study that evaluated diagnostic methods and long-term outcomes in patients with CPVT.

Figure 1. Cardiac Events During Follow-Up.
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Figure 2. Cardiac Events During Follow-Up: Beta Blockers vs No Beta Blockers.
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Figure 3. Cardiac Events During Follow-Up: Positive vs Negative Exercise Stress Test.
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This retrospective analysis of 55 CPVT probands from European and Japanese patients focused on results of initial exercise stress tests, Holter monitoring, and genetic tests for RyR2 and CASQ2. The investigators also reviewed clinical outcomes of the patients and drugs prescribed during the follow-up period. Positive exercise stress tests and Holter monitoring were defined as VT (≥3 PVCs) or PVCs with bigeminy or couplets. Cardiac events were defined as occurrence of syncope, appropriate implantable cardiac defibrillator (ICD) discharge, or SCD. Follow-up was 9.5 ± 5.6 years.

About half of the patients were males, 40% had a family history of SCD, 93% received beta blocker therapy, and 27% had an ICD. In the initial examinations, exercise stress test was positive in 73% (38/52), 24-hour Holter monitor was positive in 62% (31/52), and genetic analysis was positive in 79% (37/47) of patients. Among the 17 patients with negative exercise stress test, Holter monitor or genetic analysis was positive in 71% (N=12) (8 positive Holter monitor, 9 positive genetic analysis). Five of the 17 had cardiac events during follow-up.

The cardiac event-free survival rate was 89% at 4 years and 65% at 10 years follow-up (Figure 1). Cardiac events were significantly reduced in patients receiving beta blockers (p <0.001) (Figure 2). Cardiac event-free survival was not significantly different in patients with a positive versus a negative exercise stress test (Figure 3). Among 8 patients who experienced SCD or aborted SCD, 5 occurred after 10 years of stable follow-up; of 5 patients who were taking beta blockers, 4 had discontinued the medication.

Dr. Hayashi concluded that Holter monitoring and genetic analysis, in addition to exercise stress tests, are necessary to improve the rate of CPVT diagnosis. Beta-blocker therapy is associated with a reduced event rate but their discontinuation is partially responsible for SCD.

 
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Latent Genetic Backgrounds of Acquired Long QT Syndrome
Hideki Itoh
Shiga University Medical Science, Japan
 

Several gene mutations associated with congenital long QT syndrome (cLQTS) have been identified, including 12 genes encoding cardiac ion channel-composing proteins or a family of membrane adapters. Acquired LQTS (aLQTS) is associated with clinical phenotypes that are similar to cLQTS. aLQTS develops as a result of secondary factors, including antiarrhythmic, antibiotic, and other drugs, severe bradycardia, and electrolyte abnormalities. Some research groups have reported genes associated with aLQTS in case reports. Dr. Hideki Itoh and his group at Shiga University Medical Science carried out genetic testing for LQTS-related genes in cLQTS and aLQTS patients.

Figure 1. Results of Mutation Analysis.
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Figure 2. The Rates of Positive Mutations with or without Cardiac Symptoms.
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Figure 3. KCNQ1 Mutation in Bradycardia Induced TdP.
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Figure 4. Simulated Action Potential Durations.
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A total of 413 cLQTS probands and 82 aLQTS probands were analyzed. Gene mutations were found in 235 cLQTS probands (57%) and 20 aLQTS probands (24%) (Figure 1). Among symptomatic patients with aLQTS, 34% were positive for mutations versus 0% among asymptomatic aLQTS patients (p <0.005) (Figure 2). There was no significant difference in the percent of positive mutations in symptomatic cLQTS (59%) versus asymptomatic cLQTS (49%) patients.

KCNQ1 loss of function mutations were associated with drug-induced aLQTS. In the functional analysis, KCNQ1 and KCNH2 mutant channels that were reconstituted in Chinese Hamster Ovary (CHO) cells showed complex gating defects and varying degrees of mildly decreased current density.

Figure 3 shows a case of bradycardia-induced aLQTS with QT prolongation. Complete AV block developed, resulting in Torsades de Pointes (TdP). DNA analysis showed a G272V/KCNQ1 missense mutation. This mutant channel showed a loss of function in IKs. In the heterozygous mutation, current density decreased by 70%. The activation curve shifted to the depolarized state. Other KCNQ1 mutants also show a loss of function with a dominant negative effect in contrast to drug-induced aLQTS.

In a Luo-Rudy simulation model of action potential durations (APD), APD of cLQTS was severely prolonged compared to the WT (Figure 4). The APD of drug-induced aLQTS was mildly prolonged, while the APD of bradycardia-induced aLQTS was similar to that observed in cLQTS.

In summary, the positive mutation rate in aLQTS was significantly lower than in cLQTS. In the aLQTS group, the incidence of mutations in symptomatic patients was significantly higher than in asymptomatic patients. The functional analysis demonstrated complex gating defects and decreased current density in mutant channels. The simulation study showed that APD of drug-induced aLQTS was mildly prolonged, while APD of bradycardia-induced aLQTS was severely prolonged, similar to cLQTS.

This molecular genetic study contributes to the understanding of the pathogenesis of aLGTS. There is a strong need to consider latent genetic backgrounds related to aLQTS in patients who experience unexpected aborted SCD. Dysfunctions associated with mutations in aLQTS may depend on the aLQTS subtypes associated with arrhythmic triggers.

 
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Clinical Phenotype and Prognosis of Probands with Brugada Syndrome in Relation to SCN5A Mutation
Kenichiro Yamagata
Japanese Brugada Syndrome Multicenter Registry, Japan
 

Mutations of the SCN5A gene are present in 10% to 30% of patients with clinically diagnosed Brugada syndrome. Dr. Kenichiro Yamagata, Japanese Brugada Syndrome Multicenter Registry, reported on a study that investigated electrocardiographic (ECG) characteristics associated with the presence of the SCN5A mutation in Japanese probands with Brugada syndrome. The study also assessed risk factors for predicting cardiac events during the study follow-up period.

Figure 1. ECG Parameters (1)
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Figure 2. ECG Parameters (2).
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Figure 3. ECG Parameters (3).
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Figure 4. Kaplan Meier Cumulative Curve (for VF/ACA history).
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Figure 5. Kaplan Meier Cumulative Curve (for SCN5A mutation)
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A total of 335 (325 males) probands with Brugada syndrome were screened for the SCN5A gene. Brugada syndrome was diagnosed on the basis of a type 1 ECG observed in more than one of the right precordial leads at baseline or after a sodium channel blocker test. SCN5A mutations were identified in 54 (16%) of the probands. Clinical characteristics and ECG parameters before and after the sodium channel blocker challenge were compared between the Brugada probands with and without SCN5A mutations. Prognosis during the follow-up period (60±40 months) also was compared.

Most baseline characteristics were similar between the two groups. The SCN5A-positive group had more frequent late potentials (90%) than the SCN5A-negative group (71%) (p=0.001). The depolarization parameters at baseline and after the drug challenge test, including P wave duration, PQ interval, QRS duration (lead V2, V5), and S wave duration (lead II, V5) were significantly longer in Brugada probands with the SCN5A mutation (Figures 1 and 2). S wave amplitudes (lead II, V5) were deeper in SCN5A mutation probands (Figure 3). After the sodium channel blocker test, P wave duration, QRS duration, and S wave duration were significantly more prolonged in the SCN5A mutation probands (Figures 1, 2, 3).

Kaplan-Meier curves showed that probands with ventricular fibrillation or aborted cardiac arrest (ACA) had a significantly higher risk for subsequent cardiac events (p <0.001) (Figure 4), as did the presence of the SCN5A mutation (p=0.003) (Figure 5). Univariate analysis showed that QRS >120 ms (p=0.032) also is a significant risk factor for cardiac events. Multivariate analysis demonstrated that SCN5A mutation (odds ratio [OR]=2.387, 95% CI 1.102-5.169, p=0.027) and history of VF or aborted cardiac arrest (OR=7.788, 95% CI 3.808-15.926, p<0.001) were independent predictors for the occurrence of subsequent cardiac events. QRS >120 ms was not an independent risk factor on multivariate analysis.

Japanese Brugada probands with the SCN5A mutation had more late potentials and severe depolarization abnormalities on ECG. Brugada probands with a history of ventricular fibrillation or aborted cardiac arrest and SCN5A mutations had a poorer prognosis.

 
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Impact of Sodium Channel Dysfunction on Arrhythmogenesis in Brugada Syndrome
Hiroshi Morita, MD
Okayama University Graduate School of Medicine, Okayama, Japan; Indiana University School of Medicine, Indianapolis, IN, USA
 

Brugada syndrome is associated with inherited ion channel abnormalities. Sodium (Na+) channel gene (SCN5A) mutations are found in 20% of patients and calcium ion (Ca2+) channel gene mutations are present in 8% of patients. To date, only a few studies have reported on genotype-phenotype correlations in Brugada syndrome. Hiroshi Morita, MD, Okayama University Graduate School of Medicine, presented results of two studies of genotype-phenotype relationships related to arrhythmogenesis and Brugada syndrome.

Figure 1. ECG Parameters and HV Interval in Patients with and without SCN5A Mutation.
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Figure 2. Fragmented QRS.
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Figure 3. Event Free Survival in Genotyped Patients.
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Figure 4. Methods: Tissue Preparation.
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Figure 5. Electrophysiological Parameters.
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Patients with Brugada spontaneous type 1 ECGs (N=80) were examined; 44 were asymptomatic, 14 had syncope, 22 had documented ventricular fibrillation (VF), and 18 had SCN5A mutations. The patients were assessed with ECG, QRS fragmentation, signal averaged electrogram, and electrophysiologic study (EPS) at 81 ± 38 months follow-up. Event-free survival (EFS) was measured in patients with VF. There were no differences in clinical parameters between the two groups. Patients with SCN5A mutation had longer PQ (p <0.05) and HV (p <0.01) intervals than those without the mutation (Figure 1). Fragmented QRS (f-QRS) was more common in patients with SCN5A mutation (p<0.05) (Figure 2). Patients with the SCN5A mutation had earlier recurrence of VF than patients without the mutation (p=0.0157) (Figure 3).

In the second study, 19 right ventricular (RV) free wall tissues from the canine heart were perfused with Tyrode solution. Action potential duration (APD) and activation time (AT) maps were constructed (Figure 4). A Na+ channel dysfunction model and a Ca2+ channel dysfunction model were induced. There was no action potential (AP) heterogeneity and the J wave was small in controls. The Na+ channel model had a longer epicardial activation time than the Ca2+ channel model. The Na+ channel model had epicardial action potential heterogeneity, resulting in a larger APD dispersion at the epicardium than in the Ca2+ channel model. The Na+ model versus the Ca2+ channel model had frequent premature ventricular contractions (PVC) (>80% vs <5%, p=0.0001) and ventricular tachycardia episodes (>40% vs <5%, p=0.0277). In the Na+ channel dysfunction model, epicardial AP heterogeneity and APD dispersion (repolarization abnormality) initiated the premature activation (phase 2 reentry) and conduction slowing (depolarizatin abnormality) facilitated maintenance of the reentrant circuit (Figure 5).

Dr. Morita concluded that conduction disturbances and AP heterogeneity, present in the patients and the experimental model with Na+ channel dysfunction, were associated with more frequent occurrences of ventricular arrhythmias than in patients and the canine model (Ca2+ channel dysfunction) without conduction disturbances.

 
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