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Background-Microvolt T-wave alternans (TWA) is reported to be closely associated with sudden cardiac death (SCD) and ventricular tachycardia (VT). Animal experiments revealed that microvolt TWA is highly dependent on heart rate. The purpose of this study was to determine whether patients with TWA at relatively low heart rates have increased vulnerability to ventricular tachyarrhythmias. Methods and Results-Subjects were 248 consecutive patients (158 men, 90 women; mean age, 59Ϯ17 years) who underwent electrophysiological study from 1997 to 2000. TWA recording was made in sinus rhythm and at atrial pacing rates of 90, 100, 110, and 120 bpm with the Cambridge Heart CH2000 system. Alternans voltage (V alt ) was measured when the alternans ratio was Ͼ3 for a period of Ͼ1 minute in VM, X, Y, Z, or 2 adjacent precordial leads. Study end point was the first appearance of VT, ventricular fibrillation (VF), appropriate implantable cardioverter-defibrillator therapy with pacing or shocks, or SCD. During the 37Ϯ12-month follow-up period, 22 patients had sustained VT, and 5 patients died of SCD. In patients with Ͼ1.9-V V alt at rates of 90, 100, and 110 bpm, the incidence of VT/VF/SCD was 56%, 28%, and 18%, respectively. V alt of Ͼ2.9 V at a heart rate of 90 bpm had a 70% positive predictive value for VT/VF/SCD. However, when V alt was Ͻ0.9 V at a rate of 120 bpm, negative predictive value was 100%. Conclusions-Patients with TWA at relatively low heart rates are susceptible to ventricular tachyarrhythmias.

Background Wenxin Keli (WK), a Chinese herb extract, is reported to be effective in the treatment of atrial and ventricular cardiac arrhythmias. Recent studies suggest that WK inhibits the transient outward current (Ito). Objective The present study examines the effectiveness of WK, alone and in combination with quinidine, to suppress arrhythmogenesis in an experimental model of Brugada syndrome (BrS). Methods and Results Action potential and ECG recordings were obtained from epicardial and endocardial sites of coronary-perfused canine right ventricular wedge preparations. The Ito agonist NS5806 (10–15 μM) was used to pharmacologically mimic a genetic predisposition to BrS. The Ito agonist induced Phase 2 reentry (P2R) in 13/19 preparations and polymorphic ventricular tachycardia (pVT) in 11/19 wedge preparations. WK (10g/L) suppressed P2R and pVT in 100% (3/3) of preparations. A lower concentration of WK (5g/L) suppressed P2R in 60% (3/5) and pVT in 50% (2/4), but in combination with a low concentration of quinidine (5 μM) was 100% effective in suppressing P2R and pVT. Quinidine alone suppressed P2R and pVT in 60% (3/5) and 50% (2/4), respectively and in combination with WK (5g/L) suppressed P2R and pVT by 80% (4/5) and 75% (3/4), respectively. WK reduced Ito, ICa and contractility in single cardiomyocytes, but dose-dependently increased contractility in intact wedge preparations, an effect mimicked by tyramine. Conclusions Our data provide support for the hypothesis that Wenxin Keli, particularly in combination with quinidine, effectively suppresses arrhythmogenesis in an experimental model of BrS via inhibition of Ito and indirect adrenergic sympathomimetic effects.

Aims Heart failure (HF) is associated with development of AF and life‐threatening ventricular tachycardia and fibrillation (VT/VF). Vulnerability to development of AF and VT/VF at different stages of HF and the underlying pathophysiological mechanisms are poorly defined. The present study was designed to determine the time‐course of development of electrical and structural remodelling of the atria and ventricles, and their contribution to induction of AF and VT/VF in a canine model of HF. Methods and results Dogs were ventricular tachypaced (VTP) for 2–3 weeks or 5–6 weeks (‘early’ and ‘late’ HF, respectively). Electrophysiological studies were performed in isolated atrial and ventricular preparations and correlated with cardiac dimensions and haemodynamic parameters recorded in vivo. Vulnerability to programmed electrical stimulation‐induced AF was greater in early vs. late stages of HF (78% vs. 38%). In contrast, VT/VF was inducible in late but not in early stages of HF (38% vs. 0%). The temporal distinction in atrial and ventricular arrhythmia susceptibility was associated with a much more rapid development of electrical and structural remodelling in atria. Vulnerability to AF developed following moderate electro‐structural remodelling and waned with further progression to severe remodelling, which averted rapid atrial activation. Conclusions A temporal window of vulnerability for AF appears relatively early during development of VTP‐induced HF in dogs, whereas VT/VF vulnerability is observed at more advanced stages of HF. These findings, if confirmed in humans, may have clinical implications with regard to prognosis and approach to therapy of patients with HF.

Introduction Tricyclic antidepressants are known to induce cardiac arrhythmias at therapeutic or supratherapeutic doses. The tricyclic antidepressant, amitriptyline, is reported to induce ST segment elevation in the right precordial electrocardiogram (ECG) leads, thus unmasking Brugada syndrome (BrS). The mechanism by which antidepressants induce the BrS phenotype and associated sudden death is not well established. Methods and Results Action potentials (AP) were simultaneously recorded from epicardial and endocardial sites of isolated coronary-perfused canine right ventricular wedge preparations, together with a transmural pseudo-ECG. Amitriptyline alone (0.2 μM–1 mM) failed to induce a BrS phenotype. NS5806 (8 μM), a transient outward potassium channel current (Ito) agonist, was used to produce an outward shift of current mimicking a genetic predisposition to BrS. In the presence of NS5806, a therapeutic concentration of amitriptyline (0.2 μM) accentuated the epicardial AP notch leading to ST-segment elevation of the ECG. All-or-none repolarization at some epicardial sites but not others gave rise to phase-2-reentry and polymorphic ventricular tachycardia (VT) in 6 of 9 preparations. Isoproterenol (100 nM) or quinidine (10 μM) reversed the effects of amitriptyline aborting phase 2 reentry and VT (4/4). Using voltage-clamp techniques applied to isolated canine ventricular myocytes, 0.2 μM amitriptyline was shown to produce use-dependent inhibition of sodium channel current (INa), without significantly affecting Ito (n = 5). Conclusions Our data suggest that amitriptyline-induced inhibition of INa unmasks the Brugada ECG phenotype and facilitates development of an arrhythmogenic substrate only in the setting of a genetic predisposition by creating repolarization heterogeneities that give rise to phase 2 reentry and VT.