(Circulation. 1995;91:864-872.)
© 1995 American Heart Association, Inc.
Articles |
Reproducible Induction of Early Afterdepolarizations and Torsade de Pointes Arrhythmias by d-Sotalol and Pacing in Dogs With Chronic Atrioventricular Block
From the Department of Cardiology, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, the Netherlands.
Correspondence to Marc A. Vos, PhD, Department of Cardiology, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Abstract It has been well established that antiarrhythmic drugs can also have proarrhythmic effects such as torsade de pointes (TdP) arrhythmias. It was the purpose of this study to create an animal model with a high incidence of reproducible TdP that occurs under clinically relevant circumstances. Experiments were performed in anesthetized dogs that had been in chronic atrioventricular block for 9±6 weeks. TdP inducibility was attempted using different pacing modes before and after the administration of 2 mg/kg d-sotalol. In some experiments, endocardial monophasic action potentials were recorded. d-Sotalol increased the cycle length of the idioventricular rhythm (1475±460 to 1730±570 ms, P<.01) and the QT time (390±65 to 480±85 ms, P<.01). In 10% of the experiments, spontaneous TdP occurred after d-sotalol. The incidence of pacing-dependent TdP was 52% (P<.01). In the inducible group, the cycle length of idioventricular rhythm and QT time were significantly longer despite equal percentage increases in these parameters after d-sotalol in both groups. The pacing modes consisting of more than one frequency change had a higher TdP induction rate (P<.05). Reproducibility of TdP induction (three times or more using the same pacing train) remained present for approximately 60 minutes after d-sotalol and was greater than 90% within the same animal over weeks. TdP induction was related to the presence of early afterdepolarizations on the monophasic action potential recordings: five of six in the inducible group versus two of six in the nonresponders. Inducibility could be further increased to 89% when a second bolus of d-sotalol was administered to noninducible dogs. On the other hand, decreasing QT time by faster basic pacing or administration of isoproterenol, or MgSO4 prevented TdP induction. This effect of MgSO4 coincided with the disappearance of early afterdepolarizations. Our animal model shows a high incidence of reproducible acquired TdP arrhythmias, allowing study of the mechanism and treatment of TdP. TdP induction was related to the combination of a slow ventricular rate, the prolongation of QT time, a sudden induced rate change that often required two or more cycle length changes, and the presence of early afterdepolarizations.
Key Words: tachycardia • electric stimulation • magnesium
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Torsade de pointes (TdP) arrhythmias can be congenital or acquired.1 Acquired TdP often occurs in the presence of drugs that prolong ventricular repolarization, such as class Ia and III drugs. By definition, one of the characteristics of drug-induced TdP is the prolongation of the QT(U) duration. Prolongation of the refractory period of cardiac muscle is at the same time the desired antiarrhythmic goal for the prevention of reentrant tachycardias.
Several canine models exist2 3 4 5 6 7 8 9 10 that enable the study of the morphological or mechanistic characteristics of TdP arrhythmias. TdP initiation is often associated with early afterdepolarizations (EADs).2 3 4 5 Still, we felt that the addition of a model that mimics the clinical circumstances of TdP is important for the comparison of the proarrhythmic potential of drugs to initiate TdP and the study of the mechanisms and treatment of TdP. The clinical conditions known to favor acquired TdP are bradycardia, therapeutic drug doses that prolong QT duration, sequences of short/long/short (SLS) intervals, and hypokalemia and/or hypomagnesemia.1
In the dog we developed a highly reproducible TdP model by mimicking the first three conditions by chronic atrioventricular block, administration of 2 mg/kg d-sotalol, and specific pacing modes. To investigate the model further, we increased basic heart rate by pacing, we administered MgSO4 and isoproterenol, and we recorded monophasic action potentials (MAPs) to demonstrate the involvement of EADs. Finally, we used different pacing modes to clarify the relevance of the number of cycle length changes (eg, the SLS sequence) needed to initiate TdP.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The study protocol was approved by the Committee for Experiments on Animals of the University of Limburg, Maastricht, the Netherlands, and conducted in accordance with the guidelines of the American Physiological Society.
Experiments were performed on 18 adult mongrel dogs of either sex having a body weight between 20 and 35 kg (26±5 kg). In preliminary surgery, a right thoracotomy was performed to induce a permanent complete atrioventricular block by injection of 37% formaldehyde into the atrioventricular junction.11 During the same session, pacing electrodes (Bakken Research Center, Medtronic) were inserted epicardially into the basal portion of the right ventricle and the apex of the left ventricle. The wires were exteriorized through the back of the neck.
Six surface ECG leads and one local ECG were continuously registered and stored on an optical disk. All drugs were administered through a cannula in a cephalic vein.
Anesthesia was induced by intramuscular premedication (1 mL/5 kg: 10 mg oxycodon, 1 mg acepromazine, 0.5 mg atropine) and sodium pentobarbital (20 mg/kg IV). Dogs were artificially ventilated through a cuffed endotracheal tube using a mixture of oxygen, nitrous oxide, and halothane (vapor concentration, 0.5%) 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 postoperatively, including antibiotics (1000 mg ampicillin) and analgesics (0.1 mg IM buprenorphine).
Pacing Modes
Stimulation was done preferably from the right
ventricular lead
with a programmable stimulator having a synchronizing
circuit.12 Unipolar stimuli were given using a pulse width
of 2 ms and a stimulus strength of twice the diastolic threshold. As
indifferent electrode, we used a needle placed through the skin.
Pacing consisted of four different pacing modes, which represent, respectively, one, two, and three cycle length changes. The pacing modes for the one cycle length change consisted of three stimuli (NVS=3) and continuous pacing for 30 seconds. Both were performed with equal interstimulus intervals and shortened from 1200 to 400 ms in 100-ms steps for NVS=3, whereas continuous pacing was started just below the cycle length of the idioventricular rhythm (CL IVR) and reduced to 1200, 900, 600, and 400 ms. The pacing modes with more than one frequency change were a basic train of eight stimuli followed by an extrastimulus (8+1) and an SLS sequence. The extrastimulus was shortened from 350 ms in 10-ms steps until the effective refractory period (VERP) was reached. VERP was defined as the longest stimulus interval that was not followed by a ventricular complex. VERP was determined during IVR and at paced rates similar to the continuous pacing protocol. SLS sequence consisted of (1) four to eight paced beats with an interval of 600 ms followed by a beat with an interval of 1200 ms and finally an extrastimulus (4 to 8x600/1200/extra), (2) 400/800/extra, and/or (3) 2x300/900/extra. The pacing protocol needed 30 to 40 minutes for completion, and the different pacing modes were applied in a random manner.
TdP incidence was related to a specific pacing train and mode. Moreover, because TdP frequently started before the pacing train was completed, induction was also classified to the specific change in cycle length that seemed to be responsible for TdP initiation. When TdP was induced during the first eight paced beats of either continuous pacing or 8+1, it was classified as being induced after one frequency change. A dog was considered inducible when a TdP arrhythmia could be reproducibly induced by the same pacing train at least three times.
Definition of TdP
A TdP arrhythmia was defined as a
polymorphic ventricular
tachycardia consisting of five beats or more twisting around the
baseline having a rate of more than 200 beats per minute that occur in
the setting of a prolonged QT(U) duration.1 These
ventricular tachycardias either stop spontaneously or degenerate into
ventricular fibrillation. TdP was terminated using cardioversion (60 to
70 J) when it lasted longer than 10 seconds. Defibrillation was
performed maximally six times per experiment. TdP was differentiated
from ventricular fibrillation using the following characteristics: (1)
twisting QRS behavior using all six ECG leads, (2) the change in
amplitude of the QRS complex in a single ECG lead, and (3) the
frequency of the arrhythmia.
Experiments
At least 2 weeks after the creation of complete
atrioventricular
block, dogs were anesthetized (see above). A blood sample was taken to
measure plasma levels of calcium, sodium, potassium, and magnesium and
to establish kidney function by measuring urea and creatinine. Two
defibrillation patches connected to a defibrillator were attached at
both sides of the chest. Most dogs were tested at different weeks to
investigate the reproducibility of their response.
After the baseline pacing protocol, a bolus of d-sotalol (2 mg/kg per 5 minutes) was administered. Thereafter, 5 minutes elapsed before pacing was resumed. The experiments were divided into two groups: inducible and noninducible. In the inducibile group, we distinguished between TdP that occurred spontaneously after d-sotalol (spontaneous TdP) and TdP that was pacing dependent (pacing-dependent TdP). Because the number of cardioversions per experiment was limited, it was often not possible to repeat the complete pacing protocol in the inducible group.
In most of the experiments belonging to the noninducible group, we added another bolus of d-sotalol (2 mg/kg per 5 minutes) and repeated the pacing protocol.
When TdP was inducible, we performed three procedures. First, the inducibility and reproducibility of TdP arrhythmias were tested further using different pacing modes. Also, the length of the period (minutes) was determined during which a single bolus of d-sotalol in combination with pacing was able to induce TdP. Second, the basic ventricular rate was accelerated by pacing or administration of isoproterenol (10 µg/5 minutes IV). Thereafter, the specific pacing train responsible for TdP induction was repeated. Third, MgSO4 (100 mg/kg per 2 minutes) was administered to assess its suppressive effect against spontaneous TdP and to study its preventive effect against pacing-dependent TdP.
Monophasic Action Potentials
A single endocardial MAP
recording was made before and after
d-sotalol to detect EADs in 12 experiments. Through either
the jugularis vein (n=11) or the carotid artery (n=1), MAP
catheters
(Franz combination catheter, EPT No. 1650) were placed randomly under
fluoroscopy.13 MAP was amplified by a DC-coupled
differential amplifier, which is provided with a 20-mV calibration
pulse. MAP signals were sampled at a rate of 1 KHz. The recording sites
were chosen based on stability, quality of the signal, and an amplitude
that had to exceed 15 mV.13 The presence of an EAD on the
MAP recording was defined as a retardation in
repolarization.2 3 4 5
Data Analysis
The following parameters were measured in each
experiment by two
independent observers: CL IVR, QRS duration, and QT(U) duration.
QT(U)c duration was calculated according to Bazett's
formula.14
Statistics
For determination of statistical difference
(P<.05),
we used ANOVA for comparisons between more than two groups, followed by
Bonferroni's t test when the F value permitted. Paired
Student's t test was applied to compare data between two
groups, and 
2 testing was used when the data were
presented as percentages. All data are presented as mean±SD or
when indicated as mean±SEM.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
In 18 dogs, we performed 42 experiments (2.5±1.2 experiments per dog). The mean time interval between the first experiment and atrioventricular block was 9±6 weeks, and the time between experiments was 14±9 days. All dogs had normal electrolytes except for a slightly decreased potassium level of 3.4 mmol/L in one dog receiving diuretics because of heart failure.
Pacing Under Control Conditions
We were not able to induce
TdP by pacing under baseline
conditions. However in three dogs, we noticed transient episodes of
repolarization abnormalities (occurrence of U waves) in the first
spontaneous beats directly after pacing.
Electrophysiological Effects of d-Sotalol
Administration of d-sotalol resulted in a marked
increase in the CL IVR from 1475±460 to 1730±570 ms
(P<.01) and QT duration from 390±65 to 480±85 ms
(P<.01), often occurring in the presence of U waves.
In a
subset of dogs (n=8), we investigated the duration of these
electrophysiological changes (Fig 1
). The increases in
CL IVR and QT duration diminished in time but remained present
during the investigational period of 50 minutes. Also, QTc
showed a similar behavior. No changes were observed in QRS duration.
|
VERP during spontaneous IVR increased from 265±60 to
325±65 ms
(P<.05). The effect of d-sotalol on VERP was
reverse use-dependent: the relative increase of VERP was greater at
slower heart rates (+23%) than at faster ones (+2%,
P
.01).
Spontaneous TdP Arrhythmias After d-Sotalol
After
d-sotalol administration, we noticed four
spontaneous appearances of a TdP arrhythmia (4 of 42=10%; Fig
2, panel
3). These episodes were repetitive and often needed
interventions, such as cardioversion and backup pacing at faster rates
to suppress the arrhythmia. More frequently (50%), ectopic beats with
different configurations often arising from the end of the T(U) wave
were observed (Fig 2, panel 2).
|
Inducibility of TdP Arrhythmias After d-Sotalol
After the first bolus of d-sotalol, pacing resulted in
reproducible TdP in 22 of 42 experiments (52%, P<.01
versus spontaneous), which appeared in 12 of the 18 dogs. An example is
presented in Fig 3. In all dogs with spontaneous
TdP, pacing also resulted in TdP induction. Inducibility remained
present with the use of similar pacing modes for at least 60
minutes in the 3 dogs in which this was tested.
|
Inducibility was
related to CL IVR and QT(U) duration (Table 1). In the
noninducible group (n=20), CL IVR and QT time
were significantly shorter, although the relative increase induced by
d-sotalol was comparable for both parameters in both groups.
Correction for QRS duration (JT interval) revealed no differences in
the quantification of the parameter of repolarization.
|
In only two dogs, one inducible and one noninducible dog, the response in a subsequent experiment changed. All other dogs showed similar responses, either induction or lack of induction. Therefore, the reproducibility is quite high (38 of 42=90%).
Registration of EADs by MAP Recordings
EADs were registered
in 7 of 12 experiments (Figs 4 through
6). In half of the MAP
experiments, TdP could be induced. The occurrence of ectopic beats was
related to the presence of EADs in 4 of 5 experiments (Fig 4).
EADs
were seen in 5 of 6 inducible and in 2 of 6 noninducible experiments.
Fig 5 presents an example of a TdP induction by pacing that is
initiated by EAD-dependent triggered beats. Often, EAD amplitude was
pronounced during the pacing train.
|
) can be
clearly seen. Also, phase 3 EADs (
) can be seen that triggered and
induced ectopic beats.
|
|
Effect of Pacing Mode on Inducibility of TdP Arrhythmias
In a
subgroup of subsequent, inducible experiments (n=11),
we analyzed the induction of 55 episodes of TdP in relation to the
pacing mode. Defibrillation was performed in 21 cases, whereas
spontaneous termination occurred in 34 TdPs. Induction occurred either
during the pacing train or directly thereafter (Figs 3
and
5). In the
case of continuous pacing, induction was always seen in the beginning
of the pacing train. The incidence of TdP in relation to pacing mode is
presented in Table 2. It can be seen that the 8+1
and SLS modes are equally effective and possess a greater ability to
induce TdP than the other two modes (P<.05), whereas NVS=3
is more successful than continuous pacing (P<.05).
|
Induction was related to the number of cycle length changes: Half of
the inductions occurred after one change in cycle length, ie, starting
during or directly after protocols 1 or 2 or during the first frequency
change of protocols 3 and 4 (Table 2, presented as first
change).
However, inducibility was only possible in the other half of the
experiments by at least two frequency changes, as illustrated in Figs
3 and 5.
Inducibility in the Noninducible Group After a Second Bolus of
d-Sotalol
After administration of a second bolus of
d-sotalol in
14 of the 20 noninducible experiments, inducibility increased to a
total of 32 of 36 (89%, P<.01 versus first bolus of
d-sotalol). This was accompanied by increases in CL IVR from
1340±190 to 1690±500 ms (P.05) and QT(U) duration
from
450±60 to 490±55 ms (P.05).
Prevention of TdP
Increasing Heart Rate
The
basic heart rate was increased by continuous pacing to ±65%
of spontaneous CL IVR (n=3). Inducibility was completely prevented but
returned when continuous pacing was stopped. Administration of
isoproterenol (n=2) decreased CL IVR to ±70% and resulted in
complete
prevention of inducibility. Thirty minutes after isoproterenol, CL IVR
and QT duration returned to their original values, and TdP arrhythmias
became inducible again.
Administration of MgSO4
MgSO4 was administered to six pacing-dependent TdP
experiments. Two of these dogs also showed spontaneous TdP. In two
experiments, a MAP signal was registered. At the time of
MgSO4 administration, spontaneous ectopic beats were seen
in two experiments (Fig 6, panel 1). MgSO4
suppressed the
ectopic beats (panels 2 and 3) and prevented the induction of TdP in
all dogs tested (panel 4). This was accompanied by the disappearance of
the subthreshold EADs on the MAP recordings. Also, the pacing protocol
was completed without the occurrence of ectopic beats.
Electrophysiologically, MgSO4 shortened the QT time (Table
3). The QTc duration decreased even more
because of the fact that MgSO4 increased the CL IVR.
|
In two experiments, reinduction of TdP was seen after the effect of MgSO4 had disappeared.
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
When we summarize the results in this animal model, it becomes obvious that to reproducibly induce TdP arrhythmias, the CL IVR and QT time have to be sufficiently long at the start of the experiment. Shortening of the QT duration by either an increase in heart rate by pacing or administration of isoproterenol or MgSO4 will prevent induction, whereas a second bolus of d-sotalol, which further lengthens QT time and CL IVR, will tend to make the nonsusceptible animals inducible. Both the spontaneous and pacing-dependent TdP rely for their induction on the presence of EADs. Finally, a sudden rate change, often consisting of two or more cycle length changes, is needed to induce TdP under the above conditions.
In recent years, the interest in animal models of TdP arrhythmias has increased considerably.1 2 3 4 5 6 7 8 9 10 Attention has focused on (1) the ionic mechanisms underlying the induction and perpetuation of TdP arrhythmias, (2) screening for parameters and/or circumstances that could predict possible proarrhythmic effects of antiarrhythmic drugs, especially new class III drugs, and (3) TdP prevention by specific interventions, including changes of the activity of the autonomic nervous system and specific antiarrhythmic drugs, including new drugs such as Ik activators.2 3 4 5 6 7 8 9 10 15 16 17 18 19
The intervention most widely used to induce TdP arrhythmias in animals is cesium administration.3 5 7 9 18 In anesthetized dogs with chronic atrioventricular block, we developed a TdP model that shows a high incidence of TdP inducibility together with a high reproducibility. Depending on whether one or two d-sotalol doses are used, the TdP incidence is 52% or 89%, respectively. Reproducibility of TdP induction was present during an experiment for approximately 60 minutes and in repeated experiments over weeks in 90% of the attempts. In most experiments, inducibility depended on abrupt changes in the cycle length applied by pacing.
During the course of our experiments, an article was published that reported a similar approach,10 although important differences exist between the two methodologies. Weissenburger et al10 studied spontaneous induction of TdP arrhythmias in conscious dogs with chronic atrioventricular block. To achieve that, they needed higher doses of the antiarrhythmic drugs in the presence of hypokalemia, ß-blockade, or both.
The electrophysiological effects of d-sotalol are in agreement with a therapeutic dose of this drug, and they do represent clinically achieved values.20 The observed reverse use-dependency of VERP has also been described as a property of d-sotalol.21 22 Next to the increases in QT time and VERP, d-sotalol slowed the heart rate (increase in CL IVR). Similar findings for d-sotalol but also other class III agents have recently been reported for dogs in sinus rhythm.23 24 This negative chronotropic effect of class III agents has been attributed almost entirely to prolonged repolarization.
Relevance of the Number of Cycle Length Changes
Spontaneous,
drug-induced TdP arrhythmias often show a
specific initiating sequence related to the occurrence of spontaneous
ectopic beats: SLS intervals that represent three abrupt cycle
length changes in a short period of
time.1 6 10 15 19
Using a similar pacing mode, we tried to imitate this sequence. Because
there is controversy in the literature about the specificity of this
sequence,1 25 26 27 we also
used other pacing modes to study
their possible relevance. Two pacing modes were clearly superior in
initiating TdP arrhythmias in our model: SLS and 8+1. The equal
incidence of the 8+1 pacing mode is especially of interest because this
is worldwide the most often used pacing mode during
electrophysiological studies.
Using the MAP catheter, we saw the
occurrence of triggered EADs
directly after the start of pacing (Fig 5) when the rate was
relatively
fast and the action potential duration relatively short compared with
the IVR. This observation indicates that inadequate adaptation of the
duration of the action potential to abrupt changes in cycle length is
important for TdP induction. This has also been suggested by
others.28 Support for this line of thinking comes from the
results of the two pacing modes with fixed interstimulus intervals but
differences in duration (NVS=3 versus continuous pacing). The higher
inducibility of NVS=3 underscores the importance of an abrupt frequency
change rather than the duration of pacing. Additional confirmation
comes from the observations that (1) in the case of continuous pacing,
TdP always started within the first 10 beats and (2) one cycle length
change already induced TdP in half of the experiments. However, when a
second or a third interval change is added, inducibility is doubled.
The fact that prolonged pacing is often used to prevent induction of spontaneous drug-induced TdP is another argument for stressing the importance of the abruptness of the cycle length change.
These data should be interpreted with some caution. Because we allowed ourselves only a small number of cardioversions per experiment, we could not always study all pacing modes in the same experiment. We tried to correct this by using the other pacing modes in a subsequent experiment with the same animal. Still, we cannot answer questions concerning cycle length dependence (interstimulus interval) and/or possible interference of different pacing modes on TdP inducibility.
The most effective treatments for clinical acquired TdP are rapid ventricular pacing or isoproterenol or magnesium administration.1 These treatments were all tested and considered effective in preventing TdP arrhythmias.
EAD-Dependent TdP
Several studies have addressed the
involvement of triggered
activity resulting from EADs in the initiation of
TdP.2 3 4 5 15 18 19
Although the contribution of EADs is
still not completely resolved, evidence is becoming more convincing
that EADs play an important role in the induction of acquired TdP. As
seen in the present study, the presence of EADs seems to be related
to spontaneous as well as pacing-dependent TdP. However, it is
difficult to demonstrate the causal relation between the presence of
EADs, triggered beats elicited by EADs, and the actual TdP. The
continuous shift in the site of origin of EADs and the elicited beats
together with the speed of the arrhythmias complicate the MAP
registrations. This technique itself also has some technical
difficulties, such as stability and the possibility of registering
artifacts. We relied on some good fortune to be at the site of origin
of the EAD (Figs 4 through 6).
Still, we are convinced that these
recordings in a few experiments are representative for the
model. We also believe that the experiments with MgSO4
demonstrate that the EADs are not artifacts. Therefore, we think that
TdP initiation is EAD dependent. Whether the same mechanism is also
responsible for the perpetuation of the arrhythmia has to be
established.
Relevance of This Animal Model
A relatively low incidence of
spontaneous TdP arrhythmias
occurring after d-sotalol administration was observed in
these experiments. We defined TdP as five beats or more. More
frequently (±50%), ectopic beats occurred arising from the TU wave
that seemed to be dependent on EADs. These beats occurred as singles,
doubles, or triplets. Reproducible initiation of TdP arrhythmias
required cycle length changes that were induced by pacing. Still, we
believe that this pacing-dependent TdP can be used to study the
mechanism and treatment of spontaneous acquired TdP because (1) in dogs
showing spontaneous TdP, pacing was also able to induce TdP
reproducibly, (2) both forms of TdP seem to be dependent for their
initiation on the presence of EADs (Figs 4 and
5), (3) pacing-dependent
TdP showed the same specific ECG characteristics as spontaneous TdP and
often terminated spontaneously, and (4) both forms of TdP could be
suppressed by MgSO4 (Fig 6),
levcromakalim,17
or flunarizine29 and by increasing heart rate.
In this model, we tested the dogs at a relatively long period after application of atrioventricular block (9±6 weeks). The bradycardia-related volume overload and subsequent biventricular hypertrophy (personal observations) could be of importance for the TdP inducibility. Currently, we are documenting these changes over time, both echocardiographically and electrophysiologically, and we are testing the relevance of these changes for TdP inducibility. The observation by Strauss et al21 that application of acute atrioventricular block together with a similar dose of d-sotalol did not result in TdP arrhythmias indicates that additional changes have to be present.
We are currently testing other drugs that prolong action potential duration. Our results indicate that this animal model can be used to compare the proarrhythmic potential of different drugs. Whether this model is suitable for predicting the occurrence of TdP in patients treated with these drugs has to be determined.
In conclusion, this animal model shows a high incidence of reproducible, acquired TdP arrhythmias, allowing the study of the mechanism and treatment of these triggered tachycardias.
|
Acknowledgments |
|---|
This study was supported by a grant from the Dutch Heart Foundation (No. 91.104). The technical assistance of H.D.M. Leunissen and J. van der Zande in performing the experiments and B. van der Steld, MS, for the development of the hardware and software allowing data collection and analysis is greatly appreciated. Also the authors would like to acknowledge the help of the Bakken Research Center (Medtronic), Maastricht, the Netherlands, in providing electrodes.
Received May 10, 1994; accepted August 31, 1994.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT-syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis. 1988;31:115-172. [Medline] [Order article via Infotrieve]
2.
El-Sherif N, Zeiler RH, Craelius W, Gough WB, Henkin R. QTU
prolongation and polymorphic ventricular tachyarrhythmias due to
bradycardia dependent early after-depolarizations. Circ Res. 1988;63:286-305.
3.
Ben David J, Zipes DP. Differential response to right and
left ansae subclaviae stimulation of early afterdepolarizations and
ventricular tachycardia induced by cesium in dogs.
Circulation. 1988;78:1241-1250.
4. Patterson E, Szabo B, Scherlag BJ, Lazzara R. Early and delayed afterdepolarizations associated with cesium chloride induced arrhythmias in the dog. J Cardiovasc Pharmacol. 1990;15:323-331. [Medline] [Order article via Infotrieve]
5.
Hanich RF, Levine JH, Spear JF, Moore EN. Autonomic
modulation of ventricular arrhythmia in cesium chloride induced long QT
syndrome. Circulation. 1988;77:1149-1161.
6.
Brachmann J, Scherlag BJ, Rosenshtraukh LV, Lazzara R.
Bradycardia-dependent triggered activity: relevance to drug-induced
multiform ventricular tachycardia. Circulation. 1983;68:846-856.
7. Nayebpour M, Solymoss BC, Nattel S. Cardiovascular and metabolic effects of caesium chloride injection in dogs: limitations as a model for the long QT syndrome. Cardiovasc Res. 1989;23:756-766. [Medline] [Order article via Infotrieve]
8.
Bardy GH, Ungerleider RM, Smith WM, Ideker RE. A mechanism of
torsade de pointes in a canine model. Circulation. 1983;67:52-59.
9. Leichter D, Danilo P Jr, Boyden P, Rosen TS, Rosen MR. A canine model of torsade de pointes. PACE. 1988;11:2235-2245.
10. Weissenburger J, Chezalviel F, Davy JM, Lainee P, Guhennec C, Penin E, Engel F, Cynober L, Motte G, Cheymol G. Methods and limitations of an experimental model of long QT syndrome. J Pharmacol Meth. 1991;26:23-42. [Medline] [Order article via Infotrieve]
11.
Steiner CH, Kovalik ATHW. A simple technique for production of
chronic complete heart block in dogs. J Appl Physiol. 1968;25:631-632.
12. Steld AVD, Dassen W, Gorgels APM, Beekman HDM, Wellens HJJ. Flexible multiprocessor system to support electrophysiological investigation in animals. Comput Cardiol. 1984;11:525-528.
13. Franz MR, Chin MC, Sharkey HR, Griffin JC, Scheinmann MM. A new single catheter technique for simultaneous measurement of action potential duration and refractory period in vivo. J Am Coll Cardiol. 1990;16:878-886. [Abstract]
14. Bazett HC. An analysis of the time relations of electrocardiograms. Heart. 1920;7:353-368.
15.
Carlsson L, Abrahamsson C, Drews L, Duker G. Anti-arrhythmic
effects of potassium channel openers in rhythm abnormalities related to
delayed repolarization. Circulation. 1992;85:1491-1500.
16.
Fish FA, Prahesh C, Roden DM. Suppression of
repolarization-related arrhythmias in vitro and in vivo by low dose
potassium channel activators. Circulation. 1990;82:1362-1369.
17. Vos MA, Gorgels AOM, Lipcsei GE, de Groot SHM, Leunissen HDM, Wellens HJJ. Mechanism specific anti-arrhythmic effects of the potassium channel activator Levcrokalim against repolarization dependent tachycardias. J Cardiovasc Electrophysiol. 1994;5:731-742.[Medline] [Order article via Infotrieve]
18.
Bardy DS, Inoue H, Kaseda S, Ben-David J, Zipes DP. Magnesium
suppression of early afterdepolarizations and ventricular
tachyarrhythmias induced by cesium in dogs. Circulation. 1988;77:1395-1402.
19. Buchanan LV, Kabell G, Brunden MN, Gibson JK. Comparative assessment of ibutilide, d-sotalol, clofilium, E-4031 and UK-68,798 in a rabbit model of pro-arrhythmia. J Cardiovasc Pharmacol. 1993;220:540-549.
20. Antonaccio MJ, Gomoll AW. Sotalol: pharmacological and anti-arrhythmic effects. Cardiovasc Drug Rev. 1988;6:239-263.
21. Strauss HC, Bigger JT, Hoffman BF. Electrophysiological and beta receptor blocking effects of MJ 1999 on dog and rabbit cardiac tissue. Circ Res. 1970;24:661-671.
22.
Hondeghem LM, Snijders DJ. Class III antiarrhythmic agents
have a lot of potential but a long way to go. Circulation. 1990;81:686-690.
23. Duker G, Almgren O, Carlsson L. Electrophysiologic and hemodynamic effects of H234/09 (Almokalant), quinidine and d-sotalol in the anaesthetized dog. J Cardiovasc Pharmacol. 1992;20:458-465. [Medline] [Order article via Infotrieve]
24. Mortensen E, Yang T, Refsum H. Class III anti-arrhythmic action and inotropy: effects of dofetilide in acute ischemic heart failure in dogs. J Cardiovasc Pharmacol. 1992;19:216-221. [Medline] [Order article via Infotrieve]
25. Kay GN, Plumb VJ, Arciniegas JG, Henthorn RW, Waldo AL. Torsade de pointes: the long-short initiating sequence and other clinical features. J Am Coll Cardiol. 1983;2:806-817. [Abstract]
26. Evans ER, Curry PVL, Fitchett DH, Krikler DM. Torsade de pointes initiated by electrical ventricular stimulation. J Electrocardiol. 1976;9:255-258. [Medline] [Order article via Infotrieve]
27.
Horowitz L, Greenspan AM, Spielman SR, Josephson ME. Torsade
de pointes: electrophysiologic studies in patients without transient
pharmacologic or metabolic abnormalities. Circulation. 1981;63:1120-1128.
28. Atwell D, Lee JA. A cellular basis for the primary long QT syndromes. Lancet. 1988;1:1136-1139. [Medline] [Order article via Infotrieve]
29. Vos MA, Verduyn SC, Lipcsei GE, van der Zande J, Leunissen HDM, Gorgels APM. Induction of acquired bradycardia dependent torsade de pointes arrhythmias is prevented by flunarizine: a comparison with MgSO4. Circulation. 1992;86(suppl I):I-560. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  P. Kirchhof, M. R. Franz, A. Bardai, and A. M. Wilde Giant T-U Waves Precede Torsades de Pointes in Long QT Syndrome A Systematic Electrocardiographic Analysis in Patients With Acquired and Congenital QT Prolongation. J. Am. Coll. Cardiol., July 7, 2009; 54(2): 143 - 149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Qi, Y.-H. Yeh, D. Chartier, L. Xiao, Y. Tsuji, B. J.J.M. Brundel, I. Kodama, and S. Nattel The Calcium/Calmodulin/Kinase System and Arrhythmogenic Afterdepolarizations in Bradycardia-Related Acquired Long-QT Syndrome Circ Arrhythm Electrophysiol, June 1, 2009; 2(3): 295 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Antoons and K. R. Sipido Targeting calcium handling in arrhythmias Europace, December 1, 2008; 10(12): 1364 - 1369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Burashnikov, W. Shimizu, and C. Antzelevitch Fever Accentuates Transmural Dispersion of Repolarization and Facilitates Development of Early Afterdepolarizations and Torsade de Pointes Under Long-QT Conditions Circ Arrhythm Electrophysiol, August 1, 2008; 1(3): 202 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K.G. Winckels, M. B. Thomsen, P. Oosterhoff, A. Oros, J. D.M. Beekman, N. J.M. Attevelt, L. Kretzers, and M. A. Vos High-Septal Pacing Reduces Ventricular Electrical Remodeling and Proarrhythmia in Chronic Atrioventricular Block Dogs J. Am. Coll. Cardiol., August 28, 2007; 50(9): 906 - 913. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kijtawornrat, Y. Nishijima, B. M. Roche, B. W. Keene, and R. L. Hamlin Use of a Failing Rabbit Heart as a Model to Predict Torsadogenicity Toxicol. Sci., September 1, 2006; 93(1): 205 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tsuji, S. Zicha, X.-Y. Qi, I. Kodama, and S. Nattel Potassium Channel Subunit Remodeling in Rabbits Exposed to Long-Term Bradycardia or Tachycardia: Discrete Arrhythmogenic Consequences Related to Differential Delayed-Rectifier Changes Circulation, January 24, 2006; 113(3): 345 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Hamlin A Search to Predict Potential for Drug-Induced Cardiovascular Toxicity Toxicol Pathol, January 1, 2006; 34(1): 75 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Spragg, F. G. Akar, R. H. Helm, R. S. Tunin, G. F. Tomaselli, and D. A. Kass Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts Cardiovasc Res, July 1, 2005; 67(1): 77 - 86. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Aiba, W. Shimizu, M. Inagaki, T. Noda, S. Miyoshi, W.-G. Ding, D. P. Zankov, F. Toyoda, H. Matsuura, M. Horie, et al. Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil J. Am. Coll. Cardiol., January 18, 2005; 45(2): 300 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Schreiner, K. Kelemen, J. Zehelein, R. Becker, J. C. Senges, A. Bauer, F. Voss, P. Kraft, H. A. Katus, and W. Schoels Biventricular hypertrophy in dogs with chronic AV block: effects of cyclosporin A on morphology and electrophysiology Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2891 - H2898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Gralinski The Dog's Role in the Preclinical Assessment of QT Interval Prolongation Toxicol Pathol, January 1, 2003; 31(1_suppl): 11 - 16. [Abstract] [PDF]
|
|
|
|
|
|
Y. Tsuji, T. Opthof, K. Yasui, Y. Inden, H. Takemura, N. Niwa, Z. Lu, J.-K. Lee, H. Honjo, K. Kamiya, et al. Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block Circulation, October 8, 2002; 106(15): 2012 - 2018. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Suto, S. A. Cahill, G. J. Wilson, R. M. Hamilton, I. Greenwald, and G. J. Gross A novel rabbit model of variably compensated complete heart block J Appl Physiol, March 1, 2002; 92(3): 1199 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Eckardt, G. Breithardt, and W. Haverkamp Electrophysiologic Characterization of the Antipsychotic Drug Sertindole in a Rabbit Heart Model of Torsade de Pointes: Low Torsadogenic Potential Despite QT Prolongation J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 64 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Johansson and L. Carlsson Female Gender Does Not Influence the Magnitude of Ibutilide-Induced Repolarization Delay and Incidence of Torsades de Pointes in an In Vivo Rabbit Model of the Acquired Long QT Syndrome Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2001; 6(3): 247 - 254. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch Heterogeneity of cellular repolarization in LQTS: the role of M cells Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K2 - K16. [Abstract] [PDF]
|
|
|
|
|
|
D. Escande Inhibition of repolarizing ionic currents by drugs Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K17 - K22. [Abstract] [PDF]
|
|
|
|
|
|
C. Antzelevitch Transmural dispersion of repolarization and the T wave Cardiovasc Res, June 1, 2001; 50(3): 426 - 431. [Full Text] [PDF]
|
|
|
|
|
|
J.M van Opstal, S.C Verduyn, H.D.M Leunissen, S.H.M de Groot, H.J.J Wellens, and M.A Vos Electrophysiological parameters indicative of sudden cardiac death in the dog with chronic complete AV-block Cardiovasc Res, May 1, 2001; 50(2): 354 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Chevalier, C. Rodriguez, L. Bontemps, M. Miquel, G. Kirkorian, R. Rousson, F. Potet, J.-J. Schott, I. Baro, and P. Touboul Non-invasive testing of acquired long QT syndrome: Evidence for multiple arrhythmogenic substrates Cardiovasc Res, May 1, 2001; 50(2): 386 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-S. Chen, L. S Chen, J.-M. Cao, B. Sharifi, H. S Karagueuzian, and M. C Fishbein Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 409 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Verduyn, J. M. v. Opstal, J. D. Leunissen, and M. A. Vos Assessment of the Pro-Arrhythmic Potential of Anti-Arrhythmic Drugs: An Experimental Approach Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2001; 6(1): 89 - 97. [PDF]
|
|
|
|
|
|
M. A. Vos, B. Gorenek, S.C. Verduyn, F. F. van der Hulst, J. D. Leunissen, L. Dohmen, and H. J. Wellens Observations on the onset of Torsade de Pointes arrhythmias in the acquired long QT syndrome Cardiovasc Res, December 1, 2000; 48(3): 421 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W Haverkamp, G Breithardt, A.J Camm, M.J Janse, M.R Rosen, C Antzelevitch, D Escande, M Franz, M Malik, A Moss, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology Eur. Heart J., August 1, 2000; 21(15): 1216 - 1231. [PDF]
|
|
|
|
|
|
W. Haverkamp, G. Breithardt, A.J. Camm, M. J Janse, M. R Rosen, C. Antzelevitch, D. Escande, M. Franz, M. Malik, A. Moss, et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: Clinical and regulatory implications: Report on a Policy Conference of the European Society of Cardiology Cardiovasc Res, August 1, 2000; 47(2): 219 - 233. [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Cao, L. S. Chen, B. H. KenKnight, T. Ohara, M.-H. Lee, J. Tsai, W. W. Lai, H. S. Karagueuzian, P. L. Wolf, M. C. Fishbein, et al. Nerve Sprouting and Sudden Cardiac Death Circ. Res., April 14, 2000; 86(7): 816 - 821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bénardeau, J. Weissenburger, L. Hondeghem, and E. A. Ertel Effects of the T-Type Ca2+ Channel Blocker Mibefradil on Repolarization of Guinea Pig, Rabbit, Dog, Monkey, and Human Cardiac Tissue J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 561 - 575. [Abstract] [Full Text]
|
|
|
|
|
|
P. G. A. Volders, K. R. Sipido, M. A. Vos, R. L. H. M. G. Spatjens, J. D. M. Leunissen, E. Carmeliet, and H. J. J. Wellens Downregulation of Delayed Rectifier K+ Currents in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsades de Pointes Circulation, December 14, 1999; 100(24): 2455 - 2461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C Viswanathan and Y. Rudy Pause induced early afterdepolarizations in the long QT syndrome: a simulation study Cardiovasc Res, May 1, 1999; 42(2): 530 - 542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lacroix, F. Extramiana, P. Delfaut, M. Adamantidis, D. Grandmougin, D. Klug, S. Kacet, and B. Dupuis Factors affecting epicardial dispersion of repolarization: a mapping study in the isolated porcine heart Cardiovasc Res, March 1, 1999; 41(3): 563 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R Franz Current status of monophasic action potential recording: theories, measurements and interpretations Cardiovasc Res, January 1, 1999; 41(1): 25 - 40. [Full Text] [PDF]
|
|
|
|
|
|
M. A. Vos, S. H. M. de Groot, S. C. Verduyn, J. van der Zande, H. D. M. Leunissen, J. P. M. Cleutjens, M. van Bilsen, M. J. A. P. Daemen, J. J. Schreuder, M. A. Allessie, et al. Enhanced Susceptibility for Acquired Torsade de Pointes Arrhythmias in the Dog With Chronic, Complete AV Block Is Related to Cardiac Hypertrophy and Electrical Remodeling Circulation, September 15, 1998; 98(11): 1125 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. A. Volders, K. R. Sipido, M. A. Vos, A. Kulcsar, S. C. Verduyn, and H. J. J. Wellens Cellular Basis of Biventricular Hypertrophy and Arrhythmogenesis in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsade de Pointes Circulation, September 15, 1998; 98(11): 1136 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Eckardt, W. Haverkamp, M. Borggrefe, and G. Breithardt Experimental models of torsade de pointes Cardiovasc Res, July 1, 1998; 39(1): 178 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Derakhchan, R. Cardinal, S. Brunet, D. Klug, C. Pharand, T. Kus, and B. I. Sasyniuk Polymorphic ventricular tachycardias induced by D-sotalol and phenylephrine in canine preparations of atrioventricular block: initiation in the conduction system followed by spatially unstable re-entry Cardiovasc Res, June 1, 1998; 38(3): 617 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nattel Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs Cardiovasc Res, March 1, 1998; 37(3): 567 - 577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Shimizu and C. Antzelevitch Sodium Channel Block With Mexiletine Is Effective in Reducing Dispersion of Repolarization and Preventing Torsade de Pointes in LQT2 and LQT3 Models of the Long-QT Syndrome Circulation, September 16, 1997; 96(6): 2038 - 2047. [Abstract] [Full Text]
|
|
|
|
|
|
S.C. Verduyn, M.A. Vos, J. van der Zande, F.F. van der Hulst, and H.J. Wellens Role of interventricular dispersion of repolarization in acquired torsade-de-pointes arrhythmias: reversal by magnesium Cardiovasc Res, June 1, 1997; 34(3): 453 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sicouri, S. Moro, and M. V. Elizari d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Epicardial or Endocardial Cells of the Canine Ventricle Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1997; 2(1): 27 - 37. [Abstract] [PDF]
|
|
|
|
|
|
D. O. Kozhevnikov, K. Yamamoto, D. Robotis, M. Restivo, and N. El-Sherif Electrophysiological Mechanism of Enhanced Susceptibility of Hypertrophied Heart to Acquired Torsade de Pointes Arrhythmias: Tridimensional Mapping of Activation and Recovery Patterns Circulation, March 5, 2002; 105(9): 1128 - 1134. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||