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J Am Coll Cardiol, 2006; 48:1268-1276, doi:10.1016/j.jacc.2006.05.048 (Published online 25 August 2006).
© 2006 by the American College of Cardiology Foundation
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PRECLINICAL STUDY

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

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

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

Manuscript received March 29, 2006; revised manuscript received May 4, 2006, accepted May 9, 2006.

* Reprint requests and correspondence: Dr. Marc A. Vos, Department of Medical Physiology, Yalelaan 50, NL 3584 CM Utrecht, the Netherlands. (Email: m.a.vos{at}umcutrecht.nl).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We investigated whether increasing or decreasing beat-to-beat variability of repolarization (BVR) would change drug-induced proarrhythmic outcome accordingly.

BACKGROUND: Increased variability of repolarization has been suggested as a prelude to proarrhythmic circumstances in experimental and clinical situations.

METHODS: The non-cardiovascular, IKr-blocking drug sertindole was administered to anesthetized dogs with chronic atrioventricular block. Three interventions were used to prevent or suppress sertindole-induced torsades de pointes (TdP).

RESULTS: Supratherapeutic doses of sertindole (1.0 mg/kg intravenously) induced TdP in 10 of 13 dogs whereas 0.2 mg/kg induced no TdP, despite increases in QT intervals by both doses. The BVR, quantified as short-term variability (STV) from Poincaré plots, was the only parameter that predicted TdP outcome (1.0 mg/kg sertindole: 2.3 ± 0.7 ms to 5.1 ± 2.1 ms, p < 0.05; 0.2 mg/kg sertindole: 2.3 ± 0.8 ms to 3.2 ± 1.1 ms, p = NS). Interventions: 1) KCl, intravenous, reduced the incidence of sertindole-induced TdP from 6 of 7 to 1 of 7 dogs (p < 0.05) and prevented sertindole-related increase of STV: 3.0 ± 1.1 ms vs. 4.5 ± 1.3 ms (p < 0.05); 2) levcromakalim (IK,ATP activator) reduced sertindole-induced TdP and decreased STV from 4.9 ± 2.1 ms to 2.6 ± 0.9 ms (p < 0.05); 3) steady-state ventricular pacing (60 beats/min) abolished sertindole-induced TdP and decreased STV from 4.9 ± 1.5 to 3.2 ± 1.0 (p < 0.05). Torsades de pointes reappeared upon return to non-paced idioventricular rhythm. None of the 3 interventions reduced the sertindole-induced prolonged QT interval.

CONCLUSIONS: Proarrhythmic intervention is related to an increase in BVR, whereas antiarrhythmic treatment is associated with a decrease in BVR. The BVR is superior to QT interval prolongation in the prediction and prevention of drug-induced TdP in this experimental model.

Abbreviations and Acronyms
  BVR = beat-to-beat variability of repolarization
  CAVB = chronic atrioventricular block
  CL = cycle length
  IVR = idioventricular rhythm
  LV = left ventricle/ventricular
  MAPD = monophasic action potential duration
  QTc = heart rate–corrected QT intervals
  RV = right ventricle/ventricular
  STV = short-term variability
  TdP = torsades de pointes
  {Delta}MAPD = interventricular dispersion of repolarization duration

Drug-induced prolongation of the QT interval is often considered an important predictor of torsades de pointes (TdP) arrhythmia. Recently, the association between prolonged QT interval and proarrhythmic risk has been questioned by both clinical and experimental observations: 1) different drugs causing comparable absolute or relative increases in repolarization do not result in similar TdP incidences (1–7); 2) in serial experiments using various doses of the same drug, proarrhythmic outcome is not dependent on the degree of QT interval prolongation (3,8,9); 3) altering the infusion rate of a drug can change TdP incidence without affecting the prolonged QT interval (10–13); and 4) in animal studies, successful antiarrhythmic treatment does not need to be accompanied by QT interval shortening (14,15).

Quantitative assessment of the lability of repolarization duration has been suggested as a novel alternative to identify proarrhythmic conditions. Numerous methodologies have been proposed to quantify temporal repolarization lability, including the clinically used QT interval variability index (16–18), and the experimentally employed instability (4) and beat-to-beat variability of repolarization (BVR) (8,13,19–21). As previously reported, we have successfully used BVR in animals to predict drug-induced proarrhythmia using various cardiovascular drugs (8,13). In the present study, we have used supratherapeutic doses of the antipsychotic, IKr-blocking drug sertindole (9) to induce proarrhythmia. Besides extending the use of BVR to conditions with non-cardiovascular drugs, our hypothesis was that manipulation of BVR would directly alter proarrhythmic outcome independent of the QT interval: a critical increase in BVR is torsadogenic, whereas a decrease in BVR will be antiarrhythmic. Three interventions were employed to alter BVR and prevent or suppress sertindole-induced TdP: prevention of proarrhythmia by elevation of plasma [K+]; intervention of proarrhythmia by activation of the repolarizing IK,ATP current; and suppression of TdP incidence by ventricular pacing.


   Methods
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 Abstract
 Methods
Results
 Discussion
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General.   Animal handling was in accordance with the European Directive for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (86/609/EU). The Committee for Experiments on Animals of Utrecht University approved all experiments. In preliminary experiments, atrioventricular block was induced in 14 dogs (Marshall, New York) by radiofrequency ablation according to methods previously described (22). The dogs were left at spontaneous idioventricular rhythm (IVR) for >4 weeks, allowing cardiac remodeling to complete before experiments (22). Complete anesthesia was induced by sodium pentobarbital (20 mg/kg intravenously) and maintained by halothane (0.5% in O2 and N2O, 1:2). Besides surface electrocardiogram (ECG), monophasic action potentials (MAP) from the endocardium of the left ventricular (LV) and right ventricular (RV) free wall were recorded. Perioperative care, signal processing, and data recording have been described in detail previously (13). All drugs were administered intravenously. Plasma [K+] was measured from samples taken from a contralateral peripheral vein (ABL, Radiometer, Denmark).

Effects of pacing cycle length (CL) on BVR at baseline.   In 10 dogs, the effect of heart rate on repolarization duration and BVR was analyzed under drug-free circumstances. Steady-state ventricular pacing (>2 min) with CL from 400 to 1,200 ms was applied from the RV MAP catheter.

Dose-dependent induction of TdP.   Seventeen dogs received either 0.2 or 1.0 mg/kg sertindole (purchased from H. Lundbeck, Copenhagen, Denmark) over 5 min. Five dogs were investigated serially with both doses administered >1 week apart. Earlier, we have shown that the low dose results in plasma concentrations comparable to levels seen after therapeutic treatment in patients, whereas the high dose is considered supratherapeutic (9,23).

Prevention of TdP by elevating plasma-potassium concentrations.   Seven dogs received 1.0 mg/kg sertindole with and without potassium pre-treatment (30 to 60 mmol KCl infused over 2 h) in a random-crossover design. Plasma [K+] and ECG were monitored every 10 min.

Suppression of TdP by levcromakalim-induced activation of IK,ATP.   In 7 experiments, after sertindole-induced TdP, 2 consecutive doses of the IK,ATP opener levcromakalim (3 and 10 µg/kg in 3 min) were administered with a 10-min interval. Measurements were done and TdP frequency was quantified in a period 5 to 10 min after the start of levcromakalim administration. Because the higher dose of levcromakalim shortens repolarization parameters and thereby is antiarrhythmic (8,24,25), we selected the lower dose in an attempt to dissociate the effects of shortened repolarization and decreased BVR.

Prevention of recurrence of TdP by RV pacing.   Six dogs were paced from the RV MAP catheter (60 beats/min) directly after the reproducible occurrence of sertindole-induced TdP. Pacing was considered successful when no extrasystoles or TdP had occurred for 2 min.

Analysis.   Mean RR and QT intervals from lead II were measured manually (ECGview, Maastricht University, Maastricht, the Netherlands). Durations of the MAP to 90% repolarization (MAPD) were determined semiautomatically (ECG-Auto, EMKA Technologies, Paris, France) at a resolution of 2 ms. Interventricular dispersion of repolarization duration ({Delta}MAPD = LV – RV MAPD) and heart rate–corrected QT intervals (QTc [26]) were calculated. To assess BVR, Poincaré plots were drawn by plotting each LV MAPD against the LV MAPD of the former beat. Short-term variability (STVLV), describing the mean orthogonal distance to the line-of-identity on the Poincaré plot, was quantified (Formula , where D represents LV MAPD), as described earlier (8). Originally, STV is used in 24-h heart rate variability investigations, in which steady changes over time tend to follow the diagonal and sudden changes (i.e., STV) result in deviations from the diagonal. Additionally, STV of the RR intervals (STVRR) were calculated from these 30 beats to evaluate the influence of beat-to-beat variability of the underlying CL on BVR. The STV of RV MAPD was not evaluated because earlier studies have shown a low TdP-predictive value of this parameter (8,20). All measurements were performed during periods without extrasystolic activity as previously described (8). Dogs were considered inducible when 3 or more TdPs consisting of >5 beats were observed.

Statistical analysis.   Pooled data are expressed as mean ± SD. Comparisons were performed with a Student paired t test, a 2-way analysis of variance (ANOVA), or a 1-way repeated measures ANOVA followed by appropriate Bonferroni comparisons. Torsades de pointes arrhythmia incidences were compared with a chi-square test. Statistical difference was acknowledged at p < 0.05.


   Results
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Discussion
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Effects of pacing CL on BVR at baseline.   Under drug-free circumstances, LV MAPD increased upon slowing the pacing rate, as expected (Fig. 1A). Minimum STVLV was observed at a pacing CL of 700 ms, whereas it was increased both at short and at long pacing CL (Fig. 1B). In the same animals, STVLV at IVR was similar to its value at longest paced CL: 2.2 ± 0.7 ms at CL IVR of 1,416 ± 309 ms versus STVLV of 1.9 ± 0.7 ms at 1,200 ms paced CL (p = NS, Student paired t test).


Figure 1
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  		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.

 
Dose-dependent induction of TdP.   All electrophysiological parameters were similar at the start of the dose-dependent sertindole experiments. No arrhythmias occurred after the low dose whereas 10 of 13 dogs developed recurrent TdP after 1.0 mg/kg sertindole (p < 0.05) (Table 1). QT and QTc intervals, LV and RV MAPD were all increased after the 2 doses of sertindole (Table 1). There was a significant increase in STVLV after 1.0 mg/kg sertindole, but not after 0.2 mg/kg (Table 1, Fig. 2). Furthermore, STVLV after 1.0 mg/kg sertindole was significantly larger than after 0.2 mg/kg; STVRR remained unchanged at either dose of sertindole (Table 1, Fig. 2).


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  		Table 1. Sertindole-Induced Changes in Electrophysiological Parameters and Proarrhythmia
 

Figure 2
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  		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).

 
Prevention of TdP by elevating plasma-potassium concentration.   Infusion of KCl increased plasma [K+] without altering ventricular electrophysiological parameters (Table 2, Fig. 3A) (QRS width: 81 ± 16 vs. 88 ± 15 ms, p = NS). In the serial comparison, baseline STVLV was not altered by elevated [K+] despite an increase in STVRR (Figs. 3B and 3C). Potassium pre-treatment reduced the sertindole-induced TdP incidence from 6 of 7 to 1 of 7, which was not associated with differential sertindole-induced changes in heart rate, QT, and QTc intervals, LV and RV MAPD, or STVRR (Table 2, Fig. 3C). Sertindole increased STVLV in control experiments but not in potassium experiments. Furthermore, the sertindole-induced STVLV was significantly higher in control experiments compared with potassium experiments (Table 2, Fig. 3B).


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  		Table 2. Sertindole-Induced Changes in Electrophysiological Parameters and Proarrhythmia in the Presence and Absence of Elevated Plasma-Potassium Concentrations (n = 7)
 

Figure 3
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  		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.

 
Suppression of TdP by levcromakalim-induced activation of IK,ATP.   Both 3 µg/kg and additionally 10 µg/kg levcromakalim were effective in preventing further arrhythmia (Fig. 4, Table 3). The 2 consecutive doses of levcromakalim reduced the number of TdP-inducible dogs from 6 of 7 after sertindole to 2 of 7 and 1 of 7, respectively. While leaving the heart rate unchanged, the high dose abbreviated the sertindole-prolonged QT and QTc intervals, LV and RV MAPD, and decreased STVLV. On the other hand, the lower dose had no statistically significant effect on heart rate, QT and QTc intervals, LV and RV MAPD (Table 3). Left ventricular STV was the only parameter that was decreased by the lower dose of levcromakalim, along with the reduction in proarrhythmia (Fig. 4, Table 3).


Figure 4
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  		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.

 

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  		Table 3. Dose-Dependent Changes in Electrophysiological Parameters and Proarrhythmic Frequency Induced by Levcromakalim (n = 7)
 
Prevention of recurrence of TdP by ventricular pacing.   A representative example of pacing-induced prevention of recurrence of TdP is shown in Figure 5A. Shortening the CL of the IVR from 1,398 ± 207 to a paced CL of 1,000 ms under drug-free circumstances did not alter the QT interval, LV MAPD (Fig. 5B), or STVLV (Fig. 5C). Sertindole prolonged repolarization both at IVR and at 1,000 ms paced CL (Fig. 5B). Without pacing, sertindole induced TdP in 5 of 6 dogs, which was momentarily abolished by pacing. When pacing was discontinued, TdP reappeared in all experiments. When the effect of pacing was compared with the non-paced period preceding the first drug-induced extrasystole, the QT (489 ± 72 ms vs. 486 ± 89 ms), QTc (448 ± 70 ms vs. 491 ± 83 ms), LV MAPD (414 ± 78 ms vs. 403 ± 114 ms) (Fig. 5B), RV MAPD (370 ± 76 ms vs. 351 ± 77 ms), and {Delta}MAPD (45 ± 36 ms vs. 52 ± 45 ms, p = NS for all parameters using 1-way repeated measures ANOVAs) were all similar. Only the STVLV was reduced (4.9 ± 1.5 ms to 3.2 ± 1.0 ms, p < 0.05) (Fig. 5C) as a consequence of pacing. Comparing the 2 periods of pacing, STVLV was increased as a consequence of sertindole administration in the absence of variability in the paced CL (Figs. 5C and 5D). Further evidence that RR variability did not influence BVR in the present experiments was seen by the sertindole-induced increase in STVLV that occurred without concomitant increase in STVRR (Figs. 5D and 5E).


Figure 5
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  		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).

 

   Discussion
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 Results
 Discussion
References
 
Increasing BVR and proarrhythmia.   The dose-dependent proarrhythmic properties of the antipsychotic drug sertindole were assessed to establish whether BVR is capable of predicting differences in the induction of TdP by non-cardiovascular drugs. Earlier, we showed that sertindole is a selective blocker of IHERG and native canine IKr, which translates into prolongation of repolarization in vitro and in vivo (9). There were no differences in the absolute QT intervals or LV MAPD after 0.2 or 1.0 mg/kg sertindole; however, there was a trend towards an increase in {Delta}MAPD after the high dose only (p = 0.064 vs. control). Torsades de pointes arrhythmia was only initiated after the high, supratherapeutic dose in this animal model (Table 1) (9,23); STVLV was the only parameter that showed a statistically significant difference between doses, suggesting a tight association between BVR and proarrhythmia. We have not evaluated STVQT because previous studies in chronic atrioventricular block (CAVB) dogs have shown a lower predictive value of BVR analyzed from the QT interval (8,20).

Potassium levels, BVR, and proarrhythmia.   Baseline levels of plasma [K+] were unexpectedly low in these CAVB dogs (2.8 ± 0.2 mM) (12,27). This appears to be characteristic for these dogs, because control dogs in sinus rhythm also had low [K+] under anesthesia (2.7 ± 0.3 mM; n = 8; p = NS vs. CAVB). However, anesthesia itself tended to decrease plasma [K+] (awake CAVB: 3.1 ± 0.2 mM; n = 5; p < 0.05 vs. anesthetized).

Raising [K+] by KCl infusion did not change the ventricular electrophysiological parameters, including RR, QT, QRS, STVLV, and STVRR, although T-wave morphology did show slight changes, suggesting an effect of elevated [K+] on repolarization (Fig. 3A). An apparent increase in sinus rate (Fig. 3A) (PP intervals: 670 ± 177 ms to 487 ± 73 ms, p < 0.05) can be attributed to an increased hyperpolarizing-activated inward current, If, at increased extracellular [K+] (28). Increasing extracellular [K+] in vitro results in a slower inactivation of IKr, thereby enhancing ventricular repolarization (29). Humans with normal repolarization show no change in QT intervals upon a modest increase in [K+] (30,31). Only patients with acquired or congenital long-QT syndromes who experience elevation of [K+] respond by shortening their QT intervals (30–32). The behavior of repolarization lability in long-QT patients and control subjects receiving potassium is currently unknown.

Decreasing BVR and proarrhythmia.   Earlier we described that levcromakalim possesses electrophysiological and antiarrhythmic properties, presumably by IK,ATP activation, leading to QT shortening, a decrease in BVR, and effective prevention of TdP (8,24,25). The experiments reported here employed a titration of levcromakalim in order to separate QT abbreviation and BVR reduction, and to elucidate which of the 2 parameters had the closest association with TdP induction. In Table 3, data are presented that illustrate a significant decrease in proarrhythmia paralleled by a decrease in STVLV after 3 µg/kg levcromakalim. This was neither accompanied by shortened repolarization (QT interval or LV MAPD) nor by decreased interventricular dispersion of repolarization.

In Figure 1B, the rate-dependent behavior of STVLV under drug-free circumstances is depicted in detail. Minimal STVLV was present at CL similar to sinus rhythm (600 to 700 ms). Within the range of slow heart rates seen in the CAVB dog, STVLV did not vary with the paced ventricular frequency under drug-free circumstances. When the same pacing was performed in periods of sertindole-induced proarrhythmia, BVR was significantly decreased (Fig. 5C). This was accompanied by a reduction in TdP incidence, but not by an abbreviation of the prolonged repolarization. Comparing pacing at control and under the influence of sertindole illustrates a drug-induced rate-independent increase of STVLV. Hence, when controlling for the bradycardic effect inherent to IKr blockers, BVR was still increased by proarrhythmic drugs. Furthermore, sertindole did not increase STVRR in periods where STVLV was measured (Figs. 2, 3, and 5, Table 1), confirming our earlier results that indicate that BVR is independent of heart rate variability during bradycardia in CAVB dogs (8).

The use of BVR for risk assessment.   Our group has showed the proarrhythmia-predictive value of BVR in anesthetized dogs with CAVB challenged with a number of drugs (8,13,20,33). Independently, the method has successfully been used for drug testing both in vivo (19,21,34) and in vitro (35,36).

Often drug-induced TdP is perceived as the final hit in a series of events, each reducing the repolarization reserve of the individual. Earlier, we have proposed that repolarization reserve is regarded as the ability of the heart to withstand a challenge on repolarization (8). We hypothesized that BVR is inversely related to repolarization reserve. Whereas previous reports have concluded that increased BVR is proarrhythmic, the present study is the first to show that a decrease in BVR predicts successful antiarrhythmic treatment in an animal model of TdP.

Study limitations.   This study limits BVR to invasive, endocardial MAP recordings in anesthetized dogs with a high susceptibility for drug-induced TdP. Although the relative increases of the majority of electrophysiological parameters in Table 1 are numerically higher after 1.0 mg/kg sertindole (e.g., QT, LV MAPD, and {Delta}MAPD), considerably larger group sizes were estimated to be necessary if statistical significance should be reached. In the present state of our knowledge, no adequate explanation can be given for the mechanisms responsible for BVR. Until global high-resolution temporal and spatial repolarization maps become available, little can be concluded on the relative importance of BVR and spatial dispersion of repolarization in the initiation and perpetuation of TdP arrhythmias. Caution should be taken when comparing heart rate–induced alterations in repolarization generated by pacing and by altered adrenergic drive.

Conclusions.   In the intact CAVB dog, manipulation of BVR is feasible and is associated with altered proarrhythmic outcome. A critical increase in BVR is associated with eminent onset of TdP arrhythmia. Vice versa, under these conditions successful antiarrhythmic treatment is attended by a decrease in BVR. Prolongation of repolarization duration is not proarrhythmic if it does not coincide with an increased BVR. The pro- and antiarrhythmic effects are directly related to altered BVR and not secondary to altered heart rate variability.


   Acknowledgments
 
The authors would like to thank N. Atteveld for technical assistance.


   Footnotes
 
1 Dr. Volders was supported by the Netherlands Organization for Health and Development (ZonMw 906-02-068). Back

2 Dr. Thomsen was supported, in part, by H. Lundbeck. Back

3 Dr. Matz is an employee and shareholder of H. Lundbeck. Back


   References
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 References
 

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