OBJECTIVE: We hypothesized that a combination of I(Na) and I(Ca) blockade may be more effective in causing loss of the epicardial action potential (AP) dome and precipitating the Brugada syndrome (BS). The present study was designed to test this hypothesis in an in vitro model of BS. BACKGROUND: The Brugada syndrome is characterized by an ST segment elevation in the right precordial ECG leads and a high risk of sudden death. The ECG sign of BS is often concealed, but can be unmasked with potent sodium channel blockers. Using canine right ventricular (RV) wedge preparations, we previously developed an experimental model of BS using flecainide to depress the AP dome in RV epicardium. METHODS: Intracellular APs and a transmural ECG were simultaneously recorded from canine RV wedge preparations. RESULTS: Terfenadine (5-10 microM)-induced block of I(Ca) and I(Na) caused heterogeneous loss of the epicardial AP dome, resulting in ST segment elevation, phase 2 reentry (12/16), and spontaneous polymorphic VT/VF (6/16). Flecainide (</=7.5 microM), ajmaline (</=20 microM), and procainamide (</=300 microM) failed to generate polymorphic VT in any preparation except when combined with a calcium channel blocker (verapamil, </=20 microM). Terfenadine-induced ST segment elevation was normalized and arrhythmias suppressed following I(to) block with 4-aminopyridine (0.5-2 mM). CONCLUSION: Our data suggest that combined sodium and calcium channel block may be more effective than sodium channel block alone in unmasking the Brugada syndrome and that pharmacologic agents that inhibit I(to) may be useful in preventing lethal arrhythmias in patients with the syndrome.
OBJECTIVE: We hypothesized that a combination of I(Na) and I(Ca) blockade may be more effective in causing loss of the epicardial action potential (AP) dome and precipitating the Brugada syndrome (BS). The present study was designed to test this hypothesis in an in vitro model of BS. BACKGROUND: The Brugada syndrome is characterized by an ST segment elevation in the right precordial ECG leads and a high risk of sudden death. The ECG sign of BS is often concealed, but can be unmasked with potent sodium channel blockers. Using canine right ventricular (RV) wedge preparations, we previously developed an experimental model of BS using flecainide to depress the AP dome in RV epicardium. METHODS: Intracellular APs and a transmural ECG were simultaneously recorded from canine RV wedge preparations. RESULTS:Terfenadine (5-10 microM)-induced block of I(Ca) and I(Na) caused heterogeneous loss of the epicardial AP dome, resulting in ST segment elevation, phase 2 reentry (12/16), and spontaneous polymorphic VT/VF (6/16). Flecainide (</=7.5 microM), ajmaline (</=20 microM), and procainamide (</=300 microM) failed to generate polymorphic VT in any preparation except when combined with a calcium channel blocker (verapamil, </=20 microM). Terfenadine-induced ST segment elevation was normalized and arrhythmias suppressed following I(to) block with 4-aminopyridine (0.5-2 mM). CONCLUSION: Our data suggest that combined sodium and calcium channel block may be more effective than sodium channel block alone in unmasking the Brugada syndrome and that pharmacologic agents that inhibit I(to) may be useful in preventing lethal arrhythmias in patients with the syndrome.
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