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Complex Excitation Dynamics Underlie Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of LQT1

Authors
Journal
Heart Rhythm
1547-5271
Publisher
Elsevier
Identifiers
DOI: 10.1016/j.hrthm.2014.10.003
Keywords
  • Long Qt Syndrome
  • Early Afterdepolarization
  • Ventricular Tachycardia
  • Polymorphic Ventricular Tachycardia
  • Apd Dispersion
  • Optical Mapping
  • Bi-Excitability
Disciplines
  • Medicine

Abstract

Abstract Background Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current (IKs) that causes early afterdepolarizations (EADs) and polymorphic ventricular tachycardia (pVT). Objective We investigated the mechanisms underlying pVT using a transgenic rabbit model of LQT1. Methods Hearts were perfused retrogradely, and action potentials were recorded using a voltage-sensitive dye and CMOS cameras. Results Bolus injection of isoproterenol (140 nM) induced pVT initiated by focal excitations from the RV (n=16 out of 18 pVTs). After the pVT is initiated, complex focal excitations occur in both RV and LV that cause oscillations of the QRS complexes in the ECGs, consistent with the recent proposal of multiple shifting foci caused by EAD chaos. Moreover, the action potential upstroke in pVT showed a bimodal distribution, demonstrating the coexistence of two types of excitation that interact to produce complex pVT. Namely, Na+ current (INa)-mediated fast conduction and L-type Ca2+ current (ICa)-mediated slow conduction co-exist, manifesting as pVT. Addition of 2 μM TTX to reduce INa converted pVT into monomorphic VT. Reducing late INa in computer simulation converted pVT into a single dominant reentry, agreeing with experimental results. Conclusion Our study demonstrates that pVT in LQT1 rabbits is initiated by focal excitations from the RV and is maintained by multiple shifting foci in both ventricles. Moreover, the wave conduction in pVT exhibits bi-excitability, i.e., fast wavefronts driven by INa and slow wavefronts driven by ICa co-exist during pVT.

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