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ACE angiotensin converting enzyme BAL bronchoalveolar lavage CRT cardiac resynchronization therapy CT computed tomography 18 F-FDG fluorine-18 fluorodeoxyglucose 67 Ga gallium-67 HRCT high resolution computed tomography ICD implantable cardioverter defibrillator MRI magnetic resonance imaging PET positron emission tomography sIL-2R soluble interleukin 2 recepter SPECT single photon emission computed tomography JCS GUIDELINES

Background-Tumor necrosis factor-␣ (TNF-␣) and angiotensin II (Ang II) modulate heart failure in part by provoking the hypertrophic response. Signal transduction pathways of those factors are implicated in reactive oxygen intermediates (ROIs). Therefore, we hypothesized that TNF-␣ and Ang II might cause myocyte hypertrophy via the generation of ROIs. Methods and Results-To test the hypothesis, we tested whether TNF-␣ and Ang II could induce the generation of ROIs and whether antioxidants such as butylated hydroxyanisole (BHA), vitamin E, and catalase might inhibit the hypertrophy in cultured neonatal rat cardiac myocytes. ROIs were measured by the ROI-specific probe 2Ј,7Ј-dichlorofluorescin diacetate in cultured cardiac myocytes. We demonstrated that TNF-␣ and Ang II induced the generation of ROIs in a dose-dependent manner. TNF-␣ (10 ng/mL) and Ang II (100 nmol/L) enlarged cardiac myocytes and increased [ 3 H]leucine uptake, and BHA (10 mol/L) significantly inhibited both effects. Other antioxidants, such as vitamin E (1 g/mL) and catalase (100 U/mL), also inhibited the enlargement of cardiac myocytes induced by TNF-␣. Conclusions-These

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.