Satoshi Nagase

Fragmented QRS as a Marker of Conduction Abnormality and a Predictor of Prognosis of Brugada Syndrome

Background— Conduction abnormalities serve as a substrate for ventricular fibrillation (VF) in patients with Brugada syndrome (BS). Signal-averaged electrograms can detect late potentials, but the significance of conduction abnormalities within the QRS complex is still unknown. The latter can present as multiple spikes within the QRS complex (fragmented QRS [f-QRS]). We hypothesized that f-QRS could indicate a substrate for VF and might predict a high risk of VF for patients with BS. Methods and Results— In study 1, we analyzed the incidence of f-QRS in 115 patients with BS (13 resuscitated from VF, 28 with syncope, and 74 asymptomatic). f-QRS was observed in 43% of patients, more often in the VF group (incidence of f-QRS: VF 85%, syncope 50%, and asymptomatic 34%, P<0.01). SCN5A mutations occurred more often in patients with f-QRS (33%) than in patients without f-QRS (5%). In patients with syncope or VF, only 6% without f-QRS experienced VF during follow-up (43±25 months), but 58% of patients with f-QRS had recurrent syncope due to VF (P<0.01). In study 2, to investigate the mechanism of f-QRS, we studied in vitro models of BS in canine right ventricular tissues (n=4) and optically mapped multisite action potentials. In the experimental model of BS, ST elevation resulted from a large phase 1 notch of the action potential in the epicardium, and local epicardial activation delay reproduced f-QRS in the transmural ECG. Conclusions— f-QRS appears to be a marker for the substrate for spontaneous VF in BS and predicts patients at high risk of syncope.

Carvedilol decreases elevated oxidative stress in human failing myocardium

Background—Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating &bgr;-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results—Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (P <0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9±4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22±8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (P <0.005) along with amelioration of heart failure. Conclusions—Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.

Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome

OBJECTIVES We sought to study atrial vulnerability in patients with Brugada syndrome. BACKGROUND Atrial fibrillation (AF) often occurs in patients with Brugada syndrome, but atrial vulnerability in Brugada syndrome has not been evaluated. METHODS The patient group consisted of 18 patients with Brugada syndrome. The control group consisted of 12 age- and gender-matched subjects who had neither organic heart disease nor AF episodes. The incidence and clinical characteristics of AF were evaluated in all 18 patients with Brugada syndrome, and an electrophysiologic study was performed in all 12 control subjects and in 14 of the 18 patients with Brugada syndrome. The atrial effective refractory period of the right atrium (RA-ERP), intra-atrial conduction time (conduction time from the stimulus at the right atrium to atrial deflection at the distal portion of the coronary sinus), duration of local atrial potential, and repetitive atrial firing (occurrence of two or more premature atrial complexes after atrial stimulation) were studied. RESULTS Spontaneous AF occurred in 7 of the 18 patients with Brugada syndrome but in none of the control subjects. The RA-ERP was not different between the two groups. The intra-atrial conduction time was increased in the Brugada syndrome group versus the control group (168.4 +/- 17.5 vs. 131.8 +/- 13.0 ms, p < 0.001). The duration of atrial potential at the RA-ERP was prolonged in the Brugada syndrome group versus the control group (80.3 +/- 18.0 vs. 59.3 +/- 9.2 ms, p < 0.001). Repetitive atrial firing was induced in nine patients with Brugada syndrome and in six control subjects. Atrial fibrillation was induced in eight patients with Brugada syndrome but in none of the control subjects. In patients with Brugada syndrome without spontaneous AF, the intra-atrial conduction time and duration of atrial potential were also increased. CONCLUSIONS Atrial vulnerability is increased in patients with Brugada syndrome. Abnormal atrial conduction may be an electrophysiologic basis for induction of AF in patients with Brugada syndrome.

Epicardial electrogram of the right ventricular outflow tract in patients with the brugada syndrome: Using the epicardial lead

OBJECTIVES We tried to record an epicardial electrogram directly, and we examined local electrograms before and after administration of a class IC anti-arrhythmic drug in patients with the Brugada syndrome. BACKGROUND Electrical heterogeneity of the epicardium in the right ventricular outflow tract (RVOT) has been thought to be related to the Brugada syndrome. However, an epicardial abnormality has not been demonstrated in patients with the Brugada syndrome. METHODS In five patients with a Brugada-type electrocardiogram (ECG), local unipolar electrograms were recorded at the epicardium and endocardium of the RVOT. To record the epicardial electrogram directly, we introduced an electrical guidewire into the conus branch (CB) of the right coronary artery. The duration of the local electrogram after termination of the QRS complex (DP) was measured before and after class IC anti-arrhythmic drug administration. The signal-averaged electrocardiogram (SAECG) was also obtained in all patients. RESULTS A definite DP was observed at the epicardium, but not at the endocardium. After administration of a class IC anti-arrhythmic drug, the DP at the epicardium was prolonged from 38 +/- 10 ms to 67 +/- 24 ms. The late potential corresponding to the DP at the epicardium was observed in all patients on the SAECG. CONCLUSIONS An epicardial electrogram can be recorded from the CB. Recording from the CB enables identification of an epicardial abnormality in patients with the Brugada syndrome. These abnormal electrograms may be related to a myocardial abnormality in the epicardium of patients with the Brugada syndrome.

Atrial Fibrillation in Patients With Brugada Syndrome : Relationships of Gene Mutation, Electrophysiology, and Clinical Backgrounds

OBJECTIVES The goal of our work was to examine the relationships of atrial fibrillation (AF) with genetic, clinical, and electrophysiological backgrounds in Brugada syndrome (BrS). BACKGROUND Atrial fibrillation is often observed in patients with BrS and indicates that electrical abnormality might exist in the atrium as well as in the ventricle. SCN5A, a gene encoding the cardiac sodium channel, has been reported to be causally related to BrS. However, little is known about the relationships of atrial arrhythmias with genetic, clinical, and electrophysiological backgrounds of BrS. METHODS Seventy-three BrS patients (49 +/- 12 years of age, men/women = 72/1) were studied. The existence of SCN5A mutation and clinical variables (syncopal episode, documented ventricular fibrillation [VF], and family history of sudden death) were compared with spontaneous AF episodes. Genetic and clinical variables were also compared with electrophysiologic (EP) parameters: atrial refractory period, interatrial conduction time (CT), repetitive atrial firing, and AF induction by atrial extra-stimulus testing. RESULTS Spontaneous AF occurred in 10 (13.7%) of the BrS patients and SCN5A mutation was detected in 15 patients. Spontaneous AF was associated with higher incidence of syncopal episodes (60.0% vs. 22.2%, p < 0.03) and documented VF (40.0% vs. 14.3%, p < 0.05). SCN5A mutation was associated with prolonged CT (p < 0.03) and AF induction (p < 0.05) in EP study, but not related to the spontaneous AF episode and other clinical variables. In patients with documented VF, higher incidence of spontaneous AF (30.8% vs. 10.0%, p < 0.05), AF induction (53.8% vs. 20.0%, p < 0.03), and prolonged CT was observed. CONCLUSIONS Spontaneous AF and VF are closely linked clinically and electrophysiologically in BrS patients. Patients with spontaneous AF have more severe clinical backgrounds in BrS. SCN5A mutation is associated with electrical abnormality but not disease severity.

Site-Specific Arrhythmogenesis in Patients with Brugada Syndrome

Introduction: It has been believed that electrophysiologic abnormality of the epicardial region of the right ventricular free wall may play an important role in arrhythmogenesis of phase 2 reentry in Brugada syndrome, but clinical evidence of the occurrence of ventricular arrhythmias at the right ventricular free wall has not been evaluated. In this study, we evaluated the site‐specific inducibility of ventricular fibrillation (VF) and the origin of spontaneous premature ventricular contractions (PVCs) in patients with Brugada syndrome.

Prognostic significance of early repolarization in inferolateral leads in Brugada patients with documented ventricular fibrillation: A novel risk factor for Brugada syndrome with ventricular fibrillation

BACKGROUND Little is known about the clinical and prognostic impact of early repolarization (ER) on patients with Brugada syndrome (BrS), especially those with documented ventricular fibrillation (VF). OBJECTIVE To investigate the prevalence and prognostic significance of ER in inferolateral leads in patients with BrS and documented VF. METHODS We investigated 10 different 12-lead electrocardiograms (ECGs) recorded on different days to identify the presence of ER, which was defined as J-point elevation ≥0.1 mV in inferior (II, III, aVF) or lateral leads (I, aVL, V₄-V₆), in 49 individuals (46 men; age 46 ± 13 years) with a type 1 ECG of BrS and previous history of VF. RESULTS ER was observed persistently (in all ECGs) in 15 patients (31%; P group), intermittently (in at least one but not in all ECGs) in 16 patients (33%; I group), and not observed in 18 patients (37%; N group), yielding an overall ER incidence of 63% (31/49). During the follow-up period (7.7 years), recurrence of VF was documented in all 15 patients (100%) in the P group, and less in 12 patients (75%) in the I group and in 8 patients (44%) in the N group. The P group showed a worse prognosis than N group (P = .0001) by Kaplan-Meier analysis. Either persistent or intermittent ER in an inferolateral lead was an independent predictor of fatal arrhythmic events (hazard ratio 4.88, 95% confidence interval 2.02-12.7, P = .0004; and hazard ratio 2.50, 95% confidence interval 1.03-6.43, P = .043, respectively). CONCLUSION The prevalence of ER in inferolateral leads was high and an especially persistent form of ER was associated with a worse outcome in BrS patients with documented VF.

Relatively benign clinical course in asymptomatic patients with brugada-type electrocardiogram without family history of sudden death

Asymptomatic Brugada‐Type ECG. Introduction: The incidence of sudden death or ventricular fibrillation (VF) in asymptomatic Brugada syndrome patients with a family history of sudden death is reported to be very high. However, there are few reports on the prognosis of asymptomatic Brugada syndrome patients without a family history of sudden death.

Electrocardiographic parameters and fatal arrhythmic events in patients with brugada syndrome: Combination of depolarization and repolarization abnormalities

OBJECTIVES This study aimed to determine the usefulness of the combination of several electrocardiographic markers on risk assessment of ventricular fibrillation (VF) in patients with Brugada syndrome (BrS). BACKGROUND Detection of high-/low-risk BrS patients using a noninvasive method is an important issue in the clinical setting. Several electrocardiographic markers related to depolarization and repolarization abnormalities have been reported, but the relationship and usefulness of these parameters in VF events are unclear. METHODS Baseline characteristics of 246 consecutive patients (236 men; mean age, 47.6 ± 13.6 years) with a Brugada-type electrocardiogram, including 13 patients with a history of VF and 40 patients with a history of syncope episodes, were retrospectively analyzed. During the mean follow-up period of 45.1 months, VF in 23 patients and sudden cardiac death (SCD) in 1 patient were observed. Clinical/genetic and electrocardiographic parameters were compared with VF/SCD events. RESULTS On univariate analysis, a history of VF and syncope episodes, paroxysmal atrial fibrillation, spontaneous type 1 pattern in the precordial leads, and electrocardiographic markers of depolarization abnormalities (QRS duration ≥120 ms, and fragmented QRS [f-QRS]) and those of repolarization abnormalities (inferolateral early repolarization [ER] pattern and QT prolongation) were associated with later cardiac events. On multivariable analysis, a history of VF and syncope episodes, inferolateral ER pattern, and f-QRS were independent predictors of documented VF and SCD (odds ratios: 19.61, 28.57, 2.87, and 5.21, respectively; p < 0.05). Kaplan-Meier curves showed that the presence/absence of inferolateral ER and f-QRS predicted a worse/better prognosis (log-rank test, p < 0.01). CONCLUSIONS The combination of depolarization and repolarization abnormalities in BrS is associated with later VF events. The combination of these abnormalities is useful for detecting high- and low-risk BrS patients.

Longer Repolarization in the Epicardium at the Right Ventricular Outflow Tract Causes Type 1 Electrocardiogram in Patients With Brugada Syndrome

OBJECTIVES We examined the relationship between repolarization abnormality and coved-type ST-segment elevation with terminal inverted T-wave (type 1 electrocardiogram [ECG]) in patients with Brugada syndrome (BrS). BACKGROUND Recent experimental studies have suggested that accentuation of the right ventricular action potential (AP) notch preferentially prolongs epicardial AP causing inversion of the T-wave. METHODS In 19 patients with BrS and 3 control subjects, activation-recovery intervals (ARIs) and repolarization times (RTs) in the epicardium and endocardium were directly examined with the use of local unipolar electrograms at the right ventricular outflow tract. Surface ECG, ARI, and RT were examined before and after administration of pilsicainide. RESULTS Type 1 ECG was observed in 10 of the 19 BrS patients before the administration of pilsicainide and in all of the 19 patients after the administration of pilsicainide. We found that ARI and RT in the epicardium were shorter than those in the endocardium in all 9 BrS patients without type 1 ECG under baseline conditions and in all control subjects regardless of pilsicainide administration. However, longer epicardial ARI than endocardial ARI was observed in 8 of the 10 BrS patients manifesting type 1 ECG under baseline conditions and in all of the BrS patients after the administration of pilsicainide. Also, epicardial RT was longer than endocardial RT in all patients manifesting type 1 ECG regardless of pilsicainide administration. CONCLUSIONS Our data provide support for the hypothesis that the negative T-wave associated with type 1 BrS ECG is due to a preferential prolongation of the epicardial AP secondary to accentuation of the AP notch in the region of the right ventricular outflow tract.