Out of Phase T Wave Alternans in Left Ventricular Hypertrophy: Its Role in Ventricular Arrhythmogenesis

Presentation Time: Tuesday, 10:00 a.m. - 11:00 a.m.

Gan-Xin Yan, Ramarao S. Lankipalli, Ying Wu, Roger A. Marinchak, Peter R. Kowey, Main Line Health Heart Center, Wynnewood, Pennsylvania.

Presentation Number: 1160-107

Poster Board Number: 107

Keyword: Hypertrophy, Ventricular arrhythmia

T wave alternans (TWA) is characterized by beat to beat changes in T wave morphology, amplitude or polarity on the ECG and serves as an important prognostic marker of ventricular arrhythmias. It is hypothesized that ventricular action potential duration (APD) may alternate "out of phase’ with contraction force, i.e. APD and force increase and decrease in opposite phase, under conditions of electrical remodeling with a robust sarcoplasmic reticulum (SR) function. This was tested using an arterially perfused left ventricular wedge isolated from rabbits with left ventricular hypertrophy (LVH). Transmembrane action potentials from epicardium (Epi), endocardium (Endo) and/or subendocardium (Subendo) were simultaneously recorded with isometric contraction and a transmural ECG. LVH (renovascular hypertension model) resulted in "out of phase’ TWA in 26% of the preparations (6/23) under slow pacing rates (BCLs of 2000-4000 ms). TWA was largely determined by APD alteration in Endo and Subendo, thus leading to significant beat-to-beat changes in QT interval and transmural dispersion of repolarization (TDR). dl-Sotalol (0.01-0.03 mM) and 4-aminopuridine (2 mM) exaggerated "out of phase’ TWA and increased its incidence (13/23), whereas acceleration of pacing rate (BCLs: 500-1000 ms) attenuated it. Phase 2 early afterdepolarization (EAD) could be generated from Endo or Subendo during a beat with longer APD during TWA, leading to an "R on T’ extrasystole and polymorphic ventricular tachycardia (VT) in the absence of APD prolonging agents. Verapmil and ryanodine at 1 mM reduced contraction markedly and abolished TWA, EAD and extrasystoles. Interestingly, charybdotoxin (10 nM), a specific inhibitor of Ca2+ activated K+ current, inhibited TWA without significant influence on contraction, indicating a strong feedback of [Ca2+]_i to membrane currents involved in "out of phase’ TWA. In conclusion, bradycardia-dependent TWA in LVH, probably secondary to alteration in intracellular Ca2+ handling and Ca2+-dependent ionic currents, is associated with marked beat-to-beat changes in QT interval and TDR that predispose to the genesis of EADs and R-on-T extrasystoles capable of initiating polymorphic VT.