Kimikazu Banba

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.

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.

Clinical significance of macroscopic T-wave alternans after sodium channel blocker administration in patients with Brugada syndrome.

Introduction: Macroscopic T‐wave alternans (TWA) is sometimes observed after sodium channel blocker administration in patients with Brugada syndrome (BS), but little is known about the association between occurrence of TWA and clinical characteristics in BS patients. We investigated the association between spontaneous ventricular fibrillation (VF) occurrence and TWA after pilsicainide, a sodium channel blocker administration in BS patients.

Abnormal restitution property of action potential duration and conduction delay in Brugada syndrome: both repolarization and depolarization abnormalities

AIMS This study sought to examine the action potential duration restitution (APDR) property and conduction delay in Brugada syndrome (BrS) patients. A steeply sloped APDR curve and conduction delay are known to be important determinants for the occurrence of ventricular fibrillation (VF). METHODS AND RESULTS Endocardial monophasic action potential was obtained from 39 BrS patients and 9 control subjects using the contact electrode method. Maximum slopes of the APDR curve were obtained at both the right ventricular outflow tract (RVOT) and the right ventricular apex (RVA). The onset of activation delay (OAD) after premature stimulation was examined as a marker of conduction delay. Maximum slope of the APDR curve in BrS patients was significantly steeper than that in control subjects at both the RVOT and the RVA (0.77 +/- 0.21 vs. 058 +/- 0.14 at RVOT, P = 0.009; 0.98 +/- 0.23 vs. 0.62 +/- 0.16 at RVA, P = 0.001). The dispersion of maximum slope of the APDR curve between the RVOT and the RVA was also larger in BrS patients than in control subjects. The OAD was significantly longer in BrS patients than in control subjects from the RVOT to RVA and from the RVA to RVOT (from RVOT to RVA: 256 +/- 12 vs. 243 +/- 7 ms, P = 0.003; from RVA to RVOT: 252 +/- 11 vs. 241 +/- 9 ms, P = 0.01). CONCLUSIONS Abnormal APDR properties and conduction delay were observed in BrS patients. Both repolarization and depolarization abnormalities are thought to be related to the development of VF in BrS patients.

Clinical features of and effects of angiotensin system antagonists on amiodarone-induced pulmonary toxicity

BACKGROUND Amiodarone (AMD) is a strong antiarrhythmic drug but has severe side effects such as pulmonary toxicity. There are no indicators or drugs that can prevent the development of amiodarone-induced pulmonary toxicity (AIPT). METHODS We collected data for 96 consecutive patients treated with AMD and analyzed clinical factors related to AIPT. In addition, we examined the effect of AMD and angiotensin II (Ang II) on human lung alveolar epithelial cells (AEC) and verified the protective efficacy of an Ang II type 1 receptor blocker (ARB) in vitro. RESULTS During a follow-up period of 33.8+/-34.6 months, AIPT developed in 11 patients (11.5%). There were no differences in the dose of AMD, left ventricular ejection fraction, serum KL-6 and %DLCO level before starting AMD between patients with and those without AIPT. However, repeated episodes of congestive heart failure (CHF) were observed more frequently in patients with AIPT than in patients without AIPT (81.8% vs. 41.2%, P<0.011). In vitro examination, AMD progressively increased apoptosis of AEC and Ang II enhanced this effect of AMD (P<0.001). However, ARB inhibited the enhancement by Ang II of the AMD-induced apoptosis effect (P<0.001). Furthermore, patients with AIPT were administrated a lower dose of angiotensin system antagonists than were those without AIPT (P<0.05). CONCLUSIONS The results indicate that Ang II induced by CHF increases the risk of AMD-induced pulmonary toxicity. An angiotensin-converting enzyme inhibitor or ARB should be given at a sufficient dose during AMD treatment.

Relationship between circulating levels of monocyte chemoattractant protein-1 and systolic dysfunction in patients with hypertrophic cardiomyopathy

BACKGROUND Progression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism of the transition from hypertrophy to dysfunction has not been elucidated. It has been reported that circulating levels of monocyte chemoattractant protein-1 (MCP-1), which is a major factor promoting the accumulation of macrophages, are increased in patients with congestive heart failure. We measured circulating levels of MCP-1 in patients with HCM and examined whether MCP-1 was expressed in the myocardium of HCM patients. We also examined whether circulating levels of MCP-1 were correlated with left ventricular dysfunction. METHODS Circulating levels of MCP-1 were measured by an enzyme immunoassay in 26 patients with HCM (60+/-2 years old) and 20 control subjects (57+/-2 years old). Cardiac function was evaluated by two-dimensional echocardiography and cardiac catheterization. RESULTS HCM patients had significantly elevated levels of MCP-1 (HCM: 309+/-30 vs. control: 178+/-8 pg/ml, P<.001). MCP-1 levels in patients with systolic dysfunction were significantly higher than those in patients without systolic dysfunction (P<.05) and were also significantly higher than those in patients with outflow obstruction (P<.05). Immunohistochemical analysis revealed that MCP-1 was expressed in endomyocardial biopsy samples obtained from HCM patients with systolic dysfunction. Furthermore, MCP-1 levels were inversely correlated with fractional shortening (r=-.401, P<.05) and correlated with left ventricular end-diastolic pressure (r=-.579, P<.01). CONCLUSION These results show that MCP-1 is associated with, and might be involved in the pathogenesis of, left ventricular systolic dysfunction in patients with HCM.

The relationship between the magnitude of T wave alternans and amplitude of the corresponding T wave in patients with Brugada syndrome

Response to the Editor: Dr. Madias has made an interesting suggestion. He has described the impact of corresponding T wave amplitudes on the magnitude of T wave alternans (TWA) in patients with congestive heart failure.1 Whether the same applies in Brugada syndrome is an intriguing question, and this may have important implications about quantitative assessment and reproducibility of TWA. In our study, we attempted to evaluate TWA quantitatively, but we failed to do so because we found not only amplitude changes but also morphological changes in TWA.2 As Dr. Madias suggested, we rechecked T waves in five ECG leads, V1–3 and V1 and V2 at the third intercostal space in 14 patients who had TWA after pilsicainide administration. We found TWA in all five leads in 3 patients and in four leads in 4 patients, and there was a tendency for large TWA to be observed in leads with a high amplitude of T wave. We thought that there might be some correlation between the magnitude of TWA and amplitude of the corresponding T wave. There are circadian and daily fluctuations of ST elevation in patients with Brugada syndrome.3-5 So if the magnitude of TWA is T-wave-amplitude-dependent, there may be circadian and daily fluctuations in the occurrence of TWA. However, we performed the pilsicainide provocation test only once and did not confirm the reproducibility of TWA after pilsicainide administration. Further research on the relationship between the magnitude of TWA and amplitude of the corresponding T wave and on the reproducibility of TWA is needed.

IMPACT OF PULMONARY VEIN ISOLATION TO PAROXISMAL ATRIAL FIBRILLATION FOR ATRIAL ASYNCHRONY AND GLOBAL STRAIN ASSESSED BY 3D STRAIN ECHOCARDIOGRAPHY

results: Patients background was identical between two groups. Before PVI TP-SD of PAF group was signiicantly higher than control group (10.0 ± 5.2% vs. 4.8 ± 2.3%, P<0.002) and global strain was signiicantly smaller (48.2 ± 20.2% vs. 84.4 ± 32.9%, P<0.001). Signiicant improvement of TPSD and global strain was detected 3-months after PVI (10.0 ± 5.2% to 6.8 ± 3.0%, P=0.012 for TP-SD and 48.2 ± 20.2% to 58.1 ± 21.2%, P=0.018 for global strain, respectively). There still remained signiicant difference between PAF group 3-months after PVI and control group (6.8 ± 3.0% vs. 4.8 ± 2.3%, P=0.049 for TP-SD, 58.1 ± 21.2% vs. 84.4 ± 32.9%, P=0.014 for global strain )