Abstract 17091: Cellular Mechanisms Underlying the Effects of Antidepressants to Unmask the Brugada Syndrome
Background: Amitriptyline, a widely used tricyclic antidepressant, has been reported to induce an ST segment elevation in the right precordial leads of the ECG, thus unmasking Brugada syndrome (BrS). The mechanism by which antidepressants induce the Brugada ECG phenotype and associated sudden death syndrome is not well established. The present study tests the hypothesis that amitriptyline, via its action to depress sodium channel current (INa), induces repolarization heterogeneities leading to the development of phase 2 reentry and polymorphic ventricular tachycardia (pVT).
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. NS5806 (8 µM) was used to augment Ito and thus mimic a genetic predisposition to BrS. Amitriptyline (0.2 µM) significantly increased notch magnitude (21±5 to 46±9, p <0.001; n=9) and notch index (681±167 to 2676±540, p <0.001; n=9) leading to ST-segment elevation in the ECG. All-or-none repolarization was observed at some epicardial sites but not others and phase 2 reentry developed as the epicardial AP dome propagated from sites where it was maintained to sites at which it was lost, generating closely coupled extrasystoles and pVT in 6 of 9 preparations. Washout of amitriptyline led to restoration of the AP dome and suppression of all arrhythmic activity (5/5 preparations). Isoproterenol (100 nM) or quinidine (10 mM) significantly reduced the epicardial notch and inhibited phase 2 reentry (4/4 preparations). In voltage-clamp studies using canine ventricular cardiomyocytes, amitriptyline inhibited INa in a use- and concentration-dependent manner (n=5) without significantly affecting potassium current. Amitriptyline also reduced peak current amplitude of SCN5A-WT current by 55% (p <0.01; n=5) and shifted half-inactivation voltage of the steady-state inactivation curve from −92 to −98 (p <0.01).
Conclusions: Our data suggest that amitriptyline-induced inhibition of INa unmasks the Brugada ECG phenotype and facilitates the development of an arrhythmogenic substrate via repolarization heterogeneities that give rise to phase 2 reentry and VT/VF.
- © 2010 by American Heart Association, Inc.