Abstract 571: Triggered Delayed Afterdepolarizations induce Multifocal and Bidirectional Ventricular Tachycardia in a Model of Andersen-Tawil (Long QT 7) syndrome
(Introduction) Andersen syndrome (AS) is a rare channelopathy induced by the mutation of KCNJ2, which encodes the inward rectifier potassium current (IK1) Kir2.1. ECG shows prolonged QT interval, large U waves and frequent multifocal ventricular tachycardia (VT), which is often bidirectional VT. Torsades de pointes (tdp) is rare. We investigated the mechanism of VT in AS using cesium chloride (Cs), an IK1 blocker, in canine ventricular tissues.
(Method and Results) Using an optical mapping system, we mapped action potentials (APs) at 256 sites on the cut-exposed transmural surfaces of 16 canine left ventricular preparations. Tissues were perfused by Tyrode solution having normal potassium (K = 4.7 mEq, n = 7) or low K concentration (K = 2.5 mEq, n = 9). Pacing (cycle length, CL = 4000 - 400 ms) was performed in control, Cs (5–10 mM) and Cs with isoproterenol (Cs+ISP, 0.15 uM) preparations. Cs prolonged the QT interval and AP duration (APD) at both K concentrations, but more so in low K Tyrode (normal K: endocardial APD control 254 ± 17, Cs 385 ± 16 ms, p<0.01; low K: endocardial APD control 293 ± 19, Cs 459 ± 22 ms, p<0.01). Midmyocardial APDs did not show excessive APD prolongation (i.e., no M cell behavior). Rapid pacing (CL 1000 - 400 ms) induced delayed afterdepolarizations (DAD) at both K concentrations with Cs (occurrence of DAD: low K 100%, Normal K 11%) and ISP increased DAD prevalence in normal K (Normal K 67%). DADs often appeared in mid wall and endocardium sites and resulted in large U waves in 11 tissues. Repetitive triggered activity from DADs induced multifocal VT at both K concentrations with Cs+ISP (VT occurrence: low K 100%, normal K 56%). Migration of DAD-VT foci within transmural tissues from mid to endocardium resulted multifocal VT. Alternating discharge of 2 DAD foci resulted in bidirectional VT in 4 tissues with low K. VT was sustained and had multiple foci in low K Tyrode compared to normal K Tyrode (VT duration: low K 10.9 ± 7.2, normal K 1.3 ± 1.5 min, p<0.01; number of foci: low K 5.2 ± 2.0, normal K 1.9 ± 1.5, p<0.01). Early afterdepolarizations and tdp did not occur in this model. Verapamil abolished DADs in all tissues.
(Conclusion) IK1 blockade mimicking AS induced long QT and manifest U waves. Migration of multiple DAD-VT foci induced multifocal and bidirectional VT.