Author + information
- Received August 17, 1995
- Revision received July 18, 1997
- Accepted August 12, 1997
- Published online November 15, 1997.
- S.Cora Verduyn, PhDA,
- Marc A Vos, PhDA,* (, )
- Jolanda van der Zande, BSA,
- Atilla Kulcsàr, PhDA and
- Hein J.J Wellens, MD, FACCA
- ↵*Dr. Marc A. Vos, Department of Cardiology, Cardiovascular Research Institute Maastricht, University of Limburg, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
Objectives. We sought to further elucidate the role of early afterdepolarizations (EADs) and interventricular dispersion of repolarization (ΔAPD) in the genesis of acquired torsade de pointes (TdP) arrhythmias.
Background. Administration of class III agents can be associated with TdP. We developed a dog model in which TdP can be reproducibly induced by pacing after d-sotalol. This model shows reproducible results over weeks.
Methods. In 14 anesthetized dogs with chronic complete atrioventricular block, two separate experiments were performed in which d-sotalol (2 mg/kg body weight) or almokalant (0.12 mg/kg) was administered. Monophasic action potentials were simultaneously recorded from the endocardium of the right and left ventricle to register EADs and to measure the action potential duration (APD). ΔAPD was defined as the APD of the left ventricle minus that of the right ventricle.
Results. Baseline conditions were identical in the serially performed experiments. The cycle length and QT time increased by 16% and 26% after d-sotalol and by 15% and 31% after almokalant, respectively. After both drugs the action potential of the left ventricle prolonged more than that of the right ventricle, thereby increasing ΔAPD (almokalant [mean ± SD]: 110 ± 60 ms; d-sotalol: 80 ± 45 ms, p < 0.05). The incidence of EADs (18 of 22 vs. 11 of 24, p < 0.05) and single ectopic beats (EBs) (1.5 ± 2 vs. 24 ± 32, p < 0.01) was more frequently observed after almokalant than after d-sotalol. Moreover, multiple EBs only occurred after almokalant. These beats interfered with the basic rhythm, leading to dynamic changes in left ventricular APD and to additional increases in ΔAPD. Spontaneous TdP was observed in 9 of 14 dogs after almokalant and could be increased to 12 of 14 with programmed electrical stimulation. After d-sotalol, TdP could only be induced by programmed electrical stimulation (5 of 14, p < 0.05).
Conclusions. In the same dog, almokalant induced more delay in repolarization, more EADs, multiple EBs and more ventricular inhomogeneity in APD than d-sotalol. These changes were related to a higher incidence of TdP and thereby confirm a strong association of the occurrence of EADs, multiple EBs and ΔAPD in the genesis of TdP. These findings also show the possible value of our model for evaluating the proarrhythmic potential of different drugs.
Antiarrhythmic drugs that prolong repolarization without affecting conduction have attracted interest because of their possible value in the prevention and suppression of reentrant tachycardias [1–3]. However, class III drugs do produce torsade de pointes (TdP) arrhythmias in ∼1% to 5% of patients [1, 2, 4–9].
Many reports have pointed to the relevance of early afterdepolarizations (EADs) and EAD-dependent ectopic beats (EBs) for the initiation of TdP arrhythmias [9–13]. Whether they are solely responsible for the initiation of TdP arrhythmias or whether other factors such as ventricular dispersion of repolarization also contribute is still a matter of discussion [14, 15]. Regional differences in the duration of the action potential can be present within the ventricular wall (transmural), within one ventricle (intraventricular) or between ventricles (interventricular).
In anesthetized dogs with chronic complete atrioventricular (AV) block, TdP could be reproducibly initiated using the combination of d-sotalol and pacing in 50% of experiments . We compared inducible versus noninducible TdP in this canine model and demonstrated that the number of EADs is higher and the amount of interventricular dispersion larger than in inducible dogs. Because the response is maintained over weeks , we compared the effects of two antiarrhythmic drugs, d-sotalol and almokalant, in their ability to induce TdP arrhythmias in the same dog. In this way we could assess whether differences in the occurrence of EADs, EAD-dependent EBs or interventricular dispersion or repolarization could explain spontaneous initiation of TdP.
The study protocol was approved by the Committee for Experiments on Animals of the University of Limburg, Maastricht, The Netherlands and was conducted in accordance with the guidelines of the American Physiological Society.
1.1 General Protocol
The experiments were performed in anesthetized adult male and female mongrel dogs with a body weight between 20 and 31 kg. In a preliminary operation, a right thoracotomy was performed to induce a permanent complete AV block by injection of 37% formaldehyde into the AV junction . During the same session, a pacing electrode (Bakken Research Center, Medtronic) was inserted at the apex of the left ventricle. The wire was exteriorized through the back of the neck of the dog. Six surface electrocardiographic leads and two endocardial monophasic action potential (MAP) signals were simultaneously registered and stored on optical disc. All drugs were administered through a cannula in the cephalic vein.
Anesthesia was induced by 1) intramuscular premedication (1 ml/5 kg: 10 mg of oxycodon, 1 mg of acepromazine and 0.5 mg of atropine), and 2) sodium pentobarbital (20 mg/kg body weight intravenously). The dogs were artificially ventilated through a cuffed endotracheal tube using a mixture of oxygen, nitrous oxide and halothane (vapor concentration 0.5% to 1%) by a respirator. Ventilation was controlled by continuous reading of the carbon dioxide concentration in the expired air. A thermal mattress was used to maintain adequate body temperature.
Proper care was taken before and after the experiments, including antibiotic (1,000 mg of ampicillin) and analgesic agents (0.015 mg/kg of intramuscular buprenorfine). A temporary ventricular pacemaker (VVI) was sometimes placed after the AV block operation and after the experiments. Pacing was switched off after a maximum of 24 h.
1.2 Determination of Almokalant Dose
In dogs in sinus rhythm, other investigators have shown that 0.35 mg/kg of almokalant had approximately two times the effect on repolarization as 3 mg/kg of d-sotalol. In our previous studies [16–18]we used 2 mg/kg d-sotalol to induce TdP by pacing. Because we wanted to obtain a similar effect on action potential duration (APD) prolongation, a dose of 0.12 mg/kg of almokalant (1/3 of 0.35 mg/kg = 0.12) was chosen.
In the 14 dogs tested, d-sotalol was given first ([mean ± SD] 4 ± 2.2 weeks after creation of complete AV block) in 11 dogs, followed by almokalant 3 ± 2.1 weeks later. In three dogs the order was reversed, with almokalant given at 5 ± 2.6 weeks and d-sotalol at 9 ± 3.1 weeks of chronic complete AV block.
1.3 Induction of TdP Arrhythmias
A detailed description of the TdP protocol is described elsewhere . In short, at least 2 weeks after creation of complete AV block, anesthetized animals received two defibrillation patches that were attached to both sides of the chest and connected with a defibrillator. At least 30 min after the onset of anesthesia, programmed electrical stimulation was performed from the epicardial electrode. Stimulation was done with a programmable stimulator capable of pacing synchronously to the QRS complexes. Unipolar stimuli were given using a pulse of 2 ms and a stimulus strength of twice diastolic threshold. As an indifferent electrode, a needle was placed through the skin.
Programmed electrical stimulation consisted of two different pacing protocols: 1) a short–long–short sequence (400 800 + extrastimulus, or 4∗600 1,200 + extrastimulus), and 2) eight basic stimuli followed by an extrastimulus. The interstimulus intervals were 600 or 1200 ms. The extrastimulus interval in both pacing protocols was shortened from 500 ms using steps of 50 ms until 300 ms. After completion of the basic pacing protocol, d-sotalol (2 mg/kg for 5 min) or almokalant (0.12 mg/kg for 10 min) was administered.
Pacing was resumed 10 min after the start of the infusion, unless spontaneous TdP had occurred during the observation period. When TdP occurred, we tried to perform the pacing protocol at 15 min. Pacing was always performed in random order. A TdP arrhythmiawas defined as a polymorphic ventricular tachycardia consisting of ≥5 beats twisting around the baseline in the setting of a prolonged QT(U) duration. TdP was terminated using cardioversion (60 to 70 J) when it lasted >10 s. A dog was said to have inducible TdP when TdP was induced three times or more using the same pacing mode or when spontaneous initiation of TdP occurred (three times or more). In one experiment, problems with cardioversion urged us to stop prematurely, so that reproducibility could not be assessed.
MAPs were recorded to observe the occurrence of EADs and to measure the duration of the action potential of the left and right ventricles. Quadripolar contact electrodes (Franz combination catheter, EPT No. 1650) that provide both pacing and MAP recording capabilities were placed endocardially in the right and left ventricles through the external jugular vein and the carotid artery under fluoroscopic guidance. MAP phases were defined according to the definitions used for transmembrane potentials . Amplitude was defined between phases 4 and 2 of the signal. Besides a minimal amplitude of 15 mV, the MAP had to have a constant configuration and a smooth shape during control circumstances. The MAP catheters were randomly placed in the ventricle and accepted for analysis if all these conditions were fulfilled. MAPs of good quality in both ventricles were present in 11 of 14 experiments with almokalant and in 12 of 14 experiments with d-sotalol. EADswere defined as an interruption of the smooth contour of phase 2 or 3 of the action potential . The presence of EADs was examined in both MAPs.
1.5 Data Analysis
With the use of a custom-made computer program with a resolution of 2 ms and adjustable gain and time scale, the following variables were measured every 30 s during the first 10 to 15 min after the start of the class III medication: cycle length of the idioventricular rhythm, QT time and APD. In case EBs occurred, measurements were made solely in single beats. Electrophysiologic data in the text and tables are the mean of 5 consecutive (single) beats. In the graphs the individual values are reported. All values were verified by an independent observer (A.K.) in blinded manner. Interventricular dispersion(ΔAPD) was defined as the difference between the left and right APD measured after total repolarization (APD100). Also, the number of spontaneous EBs after both drugs during this period were scored as single and multiple EBs (i.e., doublets, triplets or quadruplets).
Multiple measures analysis of variance, followed by a Bonferroni ttest, was used to compare the data between the two treatments, and a chi-square test was used for data as percentages. A p value ≤0.05 was considered significant. Results are presented as mean value ± SD. Furthermore, a regression analysis was performed to calculate the correlation between QT time and the other repolarization variables (left and right ventricular APDs and ΔAPD).
Baseline conditions were similar in each of the 14 serially tested animals (Table 1).
2.1 Electrophysiologic and Proarrhythmic Effects of d-Sotalol
Values for cycle length, QT duration, APD of both ventricles and ΔAPD are summarized in Table 1. At 10 min, d-sotalol had significantly prolonged cycle length by 16% and QT duration by 26% and also significantly increased the APD of both the left and right ventricles. Because prolongation of the action potential of the left ventricle was more pronounced (27% vs. 21%), ΔAPD increased significantly (Table 1).
In the first 10 min, EADs were seen in 11 of 24 MAPs after d-sotalol, which tended to appear more frequently in the left than in the right ventricle (p < 0.1) (Table 2). Single EBs developed in <50% of the dogs (Table 2), with a maximum of 5 during 10 min (range 0 to 5). No dog developed spontaneous TdP after d-sotalol.
The time-dependent electrophysiologic effects (0 to 10 min) for left and right ventricular APDs are illustrated for a specific dog in Fig. 1. It can be clearly seen that the left ventricular APD increased more than the right ventricular APD, leading to a maximum ΔAPD of 150 ms at 8 min. In this dog, no EBs occurred during this period, so there are no dynamic changes in the APD.
2.2 Electrophysiologic and Proarrhythmic Effects of Almokalant
Almokalant also significantly increased the cycle length and all repolarization variables. ΔAPD again increased (p ≤ 0.05) as a result of a more pronounced increase in the APD of the left than in the right ventricle (45% vs. 29%) (Table 1Figs. 2–4). In the first 10 min, almokalant administration resulted in the occurrence of EADs in 18 of 22 MAPs (Table 2) that occurred in both ventricles and contributed to ΔAPD. Single EBs developed in almost all dogs with almokalant. The maximal number was 109 single EBs/10 min (mean 24 ± 32). Moreover, multiple EBs were observed (Table 2), with a maximum of 13 doublets (4.2 ± 3.9), 8 triplets (2.3 ± 2.7) and 2 quadruplets (0.4 ± 0.7). In some experiments these spontaneous beats could be associated with triggering of EADs recorded with the MAP catheter (Fig. 4).
In the first 10 min, almokalant induced repetitive spontaneous TdP in nine dogs (10 ± 15 periods) (Figs. 4 and 5). ⇓The time-dependent electrophysiologic effect of almokalant (0 to 8 min) is illustrated in Fig. 2. In this dog, almokalant induced single EBs at 200 s (Fig. 3), multiple EBs at 280 s and spontaneous TdP at 6 min (Fig. 4). The occurrence of EBs was associated with dynamic changes leading to additional increases in the amount of ΔAPD due to the changes in LV APD in the post-extrasystolic beat (Fig. 3). Before TdP, ΔAPD was ∼200 ms (Figs. 2 and 4).
Compared with the animals given almokalant that did not develop spontaneous TdP, the occurrence of TdP was associated with 1) a significantly larger ΔAPD (140 ± 55 vs. 75 ± 40 ms, p ≤ 0.05) and LV APD, and 2) the presence of multiple EBs (Table 2). No significant difference in the number of single EBs was observed between the two groups (19 ± 10 vs. 30 ± 50 EBs).
2.3 Regression Analysis Between QT Duration and Other Repolarization Variables
The measured repolarization with the MAP catheters showed good correlation with the QT duration (Table 3) (LV APD: y = 0.83x + 51; RV APD: y = 0.55x + 109). There was also a positive although weak correlation between ΔAPD and QT duration (y = 0.27x − 58, r2= 0.32). However, when the separate conditions were taken into consideration (i.e., baseline vs. class III), the correlation between QT and ΔAPD is absent, whereas the correlation between QT and LV and RV APD remained present (Table 3).
2.4 Comparison of d-Sotalol and Almokalant
When d-sotalol and almokalant were compared, no differences were found in the amount of prolongation of the cycle length. However, the effect on the repolarization variables was greater after almokalant, including ΔAPD (Table 1). The number of EADs and single EBs was also higher after almokalant (1.5 ± 2 vs. 24 ± 32 beats/10 min, p ≤ 0.01). In addition, multiple EBs were only seen after almokalant (Table 2). These EBs interfered with the idioventricular rhythm, leading to APD adaptations. The fact that this APD adaptation was most pronounced in the left ventricle led to further increases in the ΔAPD and to the occurrence of spontaneous TdP.
2.5 Induction of TdP After Programmed Electrical Stimulation
After d-sotalol, programmed electrical stimulation resulted in the induction of TdP in five dogs. Programmed electrical stimulation could not be performed in four of nine dogs with spontaneously inducible TdP almokalant because ectopic activity and periods of TdP prohibited this (Fig. 5, Table 2). Pacing induced TdP in four of the other five dogs (Table 2). Of the five dogs without spontaneous arrhythmias, pacing resulted in TdP in three. Therefore, a total of 12 of 14 dogs (9 spontaneous, 3 after pacing) developed TdP after almokalant.
A representative illustration of the difference in response to d-sotalol and almokalant in the same dog is shown in Fig. 6(the same dog as in Fig. 1). After d-sotalol, ΔAPD is 90 ms before pacing (Figs. 1 and 6). The APDs are smooth, and no ectopic activity or TdP can be induced. After almokalant, this dog demonstrated an ΔAPD of 115 ms, with EADs in both ventricles. Pacing now resulted in the induction of a spontaneously terminating TdP. Dogs with inducible TdP by pacing had a higher ΔAPD (120 ± 55 vs. 75 ± 30 ms, p ≤ 0.05) than dogs with noninducible TdP.
2.6 Sequence of Drug Administration
When d-sotalol was compared with almokalant, all dogs with inducible TdP during d-sotalol also had inducible TdP with almokalant (Table 2). These observations were independent of the sequence of experiments. In two dogs, d-sotalol was administered in a third experiment. The response was similar to that in the first experiment, thereby confirming reproducibility.
The exact contribution of the different factors leading to the initiation of TdP is still a matter of discussion. Besides the accepted variables, bradycardia and (class III induced) prolonged QT time, EADs and dispersion of repolarization have been indicated. By using MAP catheters, the in vivo appearance of EADs has been associated with EAD-triggered EBs and a changed or more marked configuration of the T or TU waves . Similarly, an increased intraventricular dispersion has been found in patients with congenital or acquired TdP . However, only one case report has shown a causal relation between the occurrence of EAD-triggered EBs and ΔAPD of repolarization to initiate spontaneous acquired TdP . In the present study we tried to elucidate the relevance of both variables and acquired spontaneous and pacing-induced TdP by comparing the proarrhythmic effects of almokalant with d-sotalol.
3.1 Factors Contributing to Interventricular Dispersion
In a recent paper , we demonstrated that ΔAPD is bradycardia dependent. Both d-sotalol and almokalant prolong the cycle length of the idioventricular rhythm equally. Almokalant increased the different repolarization variables to a greater extent than d-sotalol. In addition, EADs occurred more frequently after almokalant, contributing to ΔAPD. Furthermore, we indicated that the appearance of especially multiple EBs leads to further prolongation of the ΔAPD. This abnormal rate adaptation is especially observed in the LV APD and is present in the post-extrasystolic beat after temporary increases in rate. Longer periods of a increased rate show a normal rate adaptation (i.e., shortening of the APD).
QT duration can be best predicted on the basis of the LV APD. Because the LV APD determines ΔAPD, the latter variable is also correlated with QT duration, although the regression coefficient is much lower (Table 3). By concentrating on the specific circumstances (baseline or class III), we put less emphasis on bradycardia and demonstrated the lack of correlation between ΔAPD and QT duration, indicating that ΔAPD is an independent factor.
Similar findings were observed with MgSO4in a previous report , where MgSO4administration after d-sotalol returned the ΔAPD to baseline, but the other repolarization variables (QT duration and both APDs) where still significantly prolonged .
3.2 Factors Associated With Spontaneous TdP
In order of appearance, spontaneous occurrence of TdP after almokalant (Figs. 2–4) was preceded by 1) an inhomogeneous increase in left and right ventricular APD, 2) the occurrence of (subthreshold) EADs, 3) the occurrence of single followed by multiple EBs, and 4) a further increase in ΔAPD resulting from the dynamic response of the left ventricular APD because of frequency changes. Spontaneous TdP was associated with the appearance of multiple EBs and with a large ΔAPD. The EBs seemed to be generated by the EADs, as clearly shown in Fig. 4and indicated by the fact that they always appeared after the occurrence of EADs.
It should be mentioned that in the experiments with almokalant, electrophysiologic measurements were often hampered by the recurrent presence of EBs and episodes of TdP. This recurrence will lead to an underestimation of the electrophysiologic effects of almokalant.
3.3 Factors Associated With Pacing-Induced TdP
When spontaneous episodes of TdP occur, pacing will normally also lead to the reproducible induction of these arrhythmias (Table 2) . As shown in a previous study and confirmed in the present study, the main difference between dogs with pacing-inducible and noninducible TdP is ΔAPD. Prevention or suppression, or both, of pacing-induced TdP resulted from the disappearance of EADs [13, 16]and diminishment of ΔAPD by MgSO4.
The finding that the presence of single EBs does not differ between dogs with pacing inducible and noninducible TdP indicates that these beats occur during insufficient ΔAPD or that the frequency changes induced by these beats do not lead to a marked variation in APD (ΔAPD). That pacing is capable of inducing TdP is possibly related to the coupling interval of the paced beats or the generation of multiple beats. Until now we have not been able to determine the dynamic changes within the pacing train or the relevance of the pacing site for the induction of TdP.
3.4 Possible Causes of Interventricular Dispersion
In dogs with chronic complete AV block, ΔAPD is present under baseline conditions and shows bradycardia dependence: Decreasing heart rate will increase ΔAPD . By their effect on heart rate, class III agents will thus increase the interventricular differences in APD.
In vitro studies using isolated canine myocytes showed that under baseline conditions, the APD of the left endocardial (and epicardial) cells is longer than that of the right ventricle, thereby creating ΔAPD. This difference has been described as even more pronounced for the M cell, located within the myocardium.
Like the Purkinje fiber, the M cell has greater sensitivity for class III agents in its ability to prolong the APD and to develop EADs . The increase in ΔAPD in our experiments after class III drugs is primarily due to a larger increase in the APD of the left ventricle. The effect of almokalant (or d-sotalol) could be different for the various tissues involved in the heart, thus explaining the ΔAPD.
The M cells are not only present in dogs ; recent studies also report the existence of these M cells in normal human myocardium. It is not known to what extent the M cells contribute to the APD, as recorded by the endocardially placed MAP catheter.
Regional appearances of EADs can also explain the increase in ΔAPD. d-Sotalol predominantly induced EADs in the left ventricle, whereas almokalant produced EADs in both ventricles. Because administration of almokalant led to a more pronounced increase in ΔAPD than administration of d-sotalol, the relative contribution of the amplitude of the EADs might also be important.
3.5 Almokalant and d-Sotalol: Proarrhythmic and Electrophysiologic Effects
The proarrhythmic potential of class III agents is well known [1–9]. Prolongation of repolarization is the mechanism of the antiarrhythmic effect of class III drugs, but prolongation is also associated with the risk of development of TdP. Measurement of the absolute QT interval does not predict proarrhythmic potential in clinical conditions , as shown in our animal model . Currently, QT dispersion (as a variable of nonhomogenous repolarization) is frequently mentioned as a possible tool for predicting proarrhythmic risk as well as antiarrhythmic efficacy. The QT dispersion measured in multiple ECG leads correlates with the dispersion in regional repolarization measured by epicardial MAPs . Because QT dispersion shows large variation due to different methodologies and different patient characteristics, the question of its use as a general arrhythmic marker has yet to be resolved .
It is thus important to screen new class III agents for their proarrhythmic potential in an animal model. Most animal TdP models have used nonclinically relevant drugs such as cesium [10, 13, 27]or Bay K8644 . The only exceptions are an awake AV block dog model with hypokalemia and beta-blockade followed by antiarrhythmic drugs and a rabbit model . In the awake dog it is not yet possible to measure MAPs and thereby correlate proarrhythmic findings with EADs and APD. In the rabbit, TdP develops at relatively fast heart rates after administration of class III agents and concomitant alpha-adrenergic stimulation. To our knowledge, comparison between different agents in the same animal concomitant with MAP recordings have not been described until the present study [29–31].
Because the response of the dog is maintained over weeks, serial comparison for screening of proarrhythmic effects of (antiarrhythmic) drugs is feasible. Although this information cannot be translated into the exact incidence of TdP in the patient population, it allows an estimation of the relative risk of drugs and their risk/benefit ratio.
Almokalant and d-sotalol both prolong the APD by blockade of K+currents [32–34]. Although almokalant is a selective blocker of the rapid component of the delayed rectifier current (IKr) [32, 34], the published data are not consistent for d-sotalol, which might also affect other K+channels, such as the inward rectifier current (IK1), the slow component of the delayed rectifier current (IKs) and transient outward current (Ito) [34–36]. In addition, d-sotalol has some beta-blocking effects (<5% of dl-sotalol ), whereas almokalant is devoid of beta-blocking activity .
3.6 Limitations and Implications
In the present study we randomly placed two MAP catheters, one in the left and the other in the right ventricle, to provide local information about the differences in repolarization between the two ventricles (ΔAPD). Possible transmual or intraventricular differences in APD were not assessed in this study. Placement of multiple catheters with d-sotalol revealed that the intraventricular difference amounted only to 20% to 30% of the ΔAPD . We do not know the type and number of cells contributing to the MAP. Similarly, whether the presence of EADs on the MAP is real or based on differences in transmural repolarization is not known . However, interventions specifically directed to suppression of EAD formation, such as pacing and drugs, leads to the disappearance of these EADs [16, 17]. Transmural differences have been implicated in the mechanism of TdP [21, 38]. In addition to their relevance for the occurrence of EADs, differences in APD have been shown to create the substrate for a reentrant tachycardia. Whether reentry plays a role in the initiation and continuation of TdP is still unclear. It is conceivable that reentry succeeds or alternates with triggered activity [38, 40], or both, and is certainly the case when TdP progresses to ventricular fibrillation.
ΔAPD is not likely to play a role in reentrant arrhythmias because spatial dispersion is located so far apart. Still the polymorphic appearance of TdP can be explained by ΔAPD. The appearance of EBs from a single foci can lead to TdP when this “monomorphic tachycardia” encounters continuously shifting areas of repolarization. The situation becomes more complicated when triggered EBs arise from multiple sites in the ventricles.
Spontaneous TdP is associated with prolongation of repolarization, the occurrence of EADs, the appearance of (multiple) EBs and ΔAPD. The first three factors all contribute to a further increase in ΔAPD. These findings also show that the present canine model of TdP can be used to screen new class III agents for their proarrhythmic potential.
☆ This study was supported by Grant 91.104 from The Netherlands Heart Foundation, The Hague. ASTRA Nederland, Rijswijk, The Netherlands provided the almokalant; Bristol Myers Squibb, Woerden, The Netherlands provided the d-sotalol; and the Bakken Research Institute (Medtronic), Maastricht, The Netherlands provided the epicardial electrodes used in this study.
- action potential duration
- early afterdepolarizations
- ectopic beats
- left ventricular
- monophasic action potential
- right ventricular
- torsade de pointes
- interventricular dispersion
- Received August 17, 1995.
- Revision received July 18, 1997.
- Accepted August 12, 1997.
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