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Beat-to-Beat Variability of Repolarization Determines Proarrhythmic Outcome in Dogs Susceptible to Drug-Induced Torsades de Pointes

Morten B. Thomsen, PhD^_*,,2,_*, Paul G.A. Volders, MD, PhD^,1, Jet D.M. Beekman^_*, Jørgen Matz, PhD^,3 and Marc A. Vos, PhD^_*

^_* Department of Medical Physiology, Heart Lung Center Utrecht, University Medical Center Utrecht, Utrecht, the Netherlands
Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
Center of Excellence, Cardiovascular Research, H. Lundbeck, Copenhagen, Denmark.

View larger version (11K): [in a new window]   Figure 1 Effects of paced cycle length on left ventricular (LV) monophasic action potential duration (MAPD) (A) and LV short-term variability (B). Line in A shows best monoexponential fit to the data points. Ten anesthetized dogs were paced at varying cycle length from the endocardium of the right ventricle. *p < 0.05; Student paired t test versus 700 ms cycle length.

View larger version (17K): [in a new window]   Figure 2 Poincaré plots obtained from 30 left ventricular (LV) monophasic action potential duration (MAPD) (upper panels) and simultaneous RR intervals (lower panels) in a dog under the influence of low- (0.2 mg/kg, left panels) or high-dose (1.0 mg/kg, right panels) sertindole. At control (open arrows), comparable low LV short-term variability (2.3 and 2.5 ms, respectively) and LV MAPD are present. After administration of sertindole (closed arrows), the mean LV MAPD prolongs to similar levels, whereas LV short-term variability is only increased after the proarrhythmic high dose (2.6 and 5.2 ms, respectively). The RR short-term variability of the same beats remains unaltered although sertindole prolongs the mean RR interval (lower panels).

View larger version (50K): [in a new window]   Figure 3 (A) Time-dependent changes in plasma [K+], RR, and QT intervals during 2 h KCl infusion (left; n = 7). [K+] was significantly increased from 30 min and forward, whereas no changes were observed in the RR (blue circles) or QT (red circles) intervals. *p < 0.05 versus baseline (1-way repeated measures analysis of variance). (Right) Representative example of the electrocardiogram before and after elevation of plasma [K+]. RR and QT intervals are noted above and below lead II. LL refers to a precordial lead placed in the 6th intercostal space on the left lateral side of the thorax. Paper speed: 1 cm/s. QRS duration is 65 ms at both time points. (B, top) Representative examples of Poincaré plots of the left ventricular (LV) monophasic action potential duration (MAPD) from the same dog with and without potassium pre-treatment at baseline (green) and after administration of 1.0 mg/kg sertindole (brown). (B, bottom) Composite data of the LV MAPD and the short-term variability (STV)LV from 7 dogs presented. *p < 0.05 (2-way analysis of variance); No K+, no potassium pre-treatment; K+, elevated plasma [K+]. (C) Poincaré plots, RR intervals, and STVRR of the same beats measured in B. Potassium, but not sertindole, increases the variability of the RR interval despite that elevated [K+] prevents sertindole-induced increase of STVLV.

View larger version (77K): [in a new window]   Figure 4 (A) Representative electrocardiogram tracings from an experiment with sertindole-induced torsades de pointes arrhythmia followed by an intervention using 2 consecutive doses of the IK,ATP activator levcromakalim (levcro.). Two electrocardiogram leads, left ventricular (LV) and right ventricular (RV) monophasic action potential (MAP) recordings in each panel. RR below and QT time above lead II. Monophasic action potential durations (MAPDs) are below each signal. Paper speed: 1 cm/s. (B) Poincaré plots from the 4 panels in (A). Note the absence of shortening of repolarization duration despite a smaller Poincaré plot after 3 µg/kg levcro.

View larger version (56K): [in a new window]   Figure 5 (A) Electrophysiological changes during a representative experiment employing sertindole (1.0 mg/kg) to induce torsades de pointes arrhythmia and pacing to prevent further arrhythmia. Two electrocardiogram leads, left ventricular (LV) and right ventricular (RV) monophasic action potential (MAP) recordings, are shown in each panel at a paper speed of 1 cm/s. Steady-state pacing (1,000 ms) or cycle length (CL) of the idioventricular rhythm (IVR) are shown at the top. QT interval and monophasic action potential duration (MAPD) are below each signal. Time (t) is relative to start of sertindole administration. Short-term variability (STV)LV is noted under each panel. In the control situation (b) with an RR interval of 1,340 ms and during pacing with a CL of 1,000 ms (a), STVLV were low and comparable. Sertindole administration prolonged repolarization, increased STVLV, induced extrasystoles (c), consequently precipitating torsades de pointes arrhythmia (d). When CL was decreased to 1,000 ms, torsades de pointes arrhythmia was temporarily prevented, and STVLV decreased along with minor changes in the duration of repolarization (e). (B) Sertindole prolonged LV MAPD independent of CL (*p < 0.05 [1-way repeated measures analysis of variance]; n = 6), whereas pacing to prevent recurrence of torsades de pointes arrhythmia did not decrease the LV MAPD. (C) Sertindole increased STVLV independent of CL, and STVLV decreased significantly as a consequence of pacing to stop torsades de pointes arrhythmia. (D) Representative examples of Poincaré plots of the LV MAPD during pacing, of the RR interval at IVR, and of the concomitant LV MAPD. Green = control group; brown = 1 mg/kg sertindole. Y-axes scaling identical to the X axes. Sertindole increases STVLV both when the RR variability is absent (pacing) and present (IVR); however, sertindole did not change the RR variability. (E) Composite data of the STVRR before (green) and after (brown) sertindole (p = NS; n = 6).