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Cardiovascular Research 2000 48(3):421-429; doi:10.1016/S0008-6363(00)00192-9
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Copyright © 2000, European Society of Cardiology

Observations on the onset of Torsade de Pointes arrhythmias in the acquired long QT syndrome

Marc A. Vosa,*, B. Gorenekb, S.Cora Verduyna, Ferenc F. van der Hulsta, Jet D. Leunissena, Leon Dohmena and Hein J. Wellensa

aDepartment of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
bDepartment of Cardiology, Osmangazi University Hospital, Eskisehir, Turkey

* Corresponding author. Tel.: +31-4338-75-101; fax: +31-4338-75-104 m.vos{at}cardio.azm.nl

Received 16 March 2000; accepted 18 July 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Premature ectopic beats may create a specific sequence of events (e.g. short–long–short) preceding Torsade de Pointes arrhythmias (TdP) in the long QT syndrome. The relevance of this sequence for the initiation of TdP is not clear. In our dog model of TdP, interventricular dispersion ({Delta}APD=left–right ventricular monophasic action potential duration: APD) is associated with TdP, therefore we tested the hypothesis that the ectopic beats contributes to {Delta}APD. Methods: In 17 anaesthetized dogs with chronic AV-block, which showed spontaneous TdP after class III medication, APD was analyzed to 1. quantitate the alterations due to (multiple) ectopic beats on the left and right APD (measured with endocardial catheters) and 2. compare the {Delta}APD prior to the occurrence of premature beats (steady state) in dogs with non-sudden onset of TdP (n = 10) and sudden onset TdP (n = 7). Three phases were distinguished: phase 1: steady state beats prior to ectopic beats, phase II: the beat(s) belonging to the dynamic phase, and phase III: the beat causing TdP. Because the coupling interval of premature beats in this condition often falls within the APD, the {Delta}APD50 was validated as an alternative for the previously applied {Delta}APD100 (r = 0.51, P<0.01). Results: In steady state (phase I) {Delta}APD50 is longer in the sudden onset TdP (130±35 ms) as in the non-sudden onset TdP (65±40 ms). In the non-sudden TdP group the dynamic phase II contribute to the heterogeneity in APD, i.e. LV-APD increases more than RV-APD leading to a {Delta}APD50 increase to 130±100 ms (P<0.01) just preceding TdP (phase III). Conclusion: The synergism between ectopic beats (short–long–short sequence) and {Delta}APD create the circumstances for TdP initiation.

KEYWORDS Ventricular arrhythmias; ECG; Long QT syndrome; Antiarrhythmic agents; Arrhythmia (mechanisms); Repolarization


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Torsade de Pointes arrhythmias (TdP) are polymorphic ventricular tachycardias that occur in the setting of long QT-intervals. On the basis of their aetiology, they have been divided into congenital and acquired TdP [1,2].

In patients, the mode of onset of TdP in the acquired long QT syndrome has been characterised as ‘pause dependent’ [3–5]. A slow acceleration in basic heart rate is frequently followed by the short–long–short phenomenon, which can be best described as follows [4]: 1. A premature beat generates a post-extrasystolic pause, 2. The following regular beat shows marked TU changes from which a subsequent premature ventricular beat arises, and 3. This beat initiates TdP. When repetition of this sequence is necessary to induce TdP, it has been referred to as the ‘cascade phenomenon’ [4]. More recently, the starting sequence of TdP in congenital long QT has been the subject of investigation [6]. That study, including a literature search, revealed that in 80% of congenital long QT, the TdP was directly preceded by a pause [6] which was often caused by a premature beat. This mode of initiation, therefore, resembles acquired TdP.

In the dog with chronic, complete AV-block (<2 weeks), we and others have described the reproducible occurrence of spontaneous TdP [7–10], which was associated with prolonged repolarization, early afterdepolarizations, early afterdepolarization-dependent (multiple) ectopic beats and (interventricular) dispersion of repolarization ({Delta}APD). All parameters share the property to be dependent on bradycardia and can possibly be modified by frequency shifts including pauses in the rhythm. In our dog model, most often TdP is preceded by ectopic beats usually in the characteristic (multiple) short–long–short sequences. The number of these beats and their QRS-morphology can vary substantially, while no information is available as to the coupling interval of these beats. Many authors have suggested that this specific sequence may lead to an increased dispersion of repolarization, allowing TdP to start [5,11–13].

Next to this non-sudden onset of TdP, our animal model also shows occasionally sudden onset TdP: start of TdP after one extra beat, which is not preceded by other ectopic beats.

Using selected data from 60 consecutive experiments retrospectively, it was the purpose of this study 1. to quantify the possible contribution of the ectopic beats to the right and left ventricular APD and the {Delta}APD in the group with non-sudden TdP onset and 2. to investigate the relevance of {Delta}APD for TdP by comparing {Delta}APD in steady state before sudden and non-sudden onset of the first TdP.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
Animal handling was in accordance with the ‘Dutch Law on Animal Experimentation’ and the ‘European Directive for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (86.609/EU)’. The experiments were approved by the ‘Committee for Experiments on Animals’ of Maastricht University.

Dogs with at least 2 weeks complete AV-block were anaesthetised with pentobarbital (20 mg/kg). Anaesthesia was maintained by ventilation (N2O: O2) and halothane (0.5%). A standard ECG was recorded. For a detailed description of induction of AV-block; structural, haemodynamic, and electrical adaptations as a result of AV-block, we refer to previous publications [8–10].

Previous studies in our laboratory show using multiple monophasic action potential catheters that intraventricular dispersion is relatively small in comparison with {Delta}APD [9] and not influenced by class III drugs. Therefore, we consider placement of two MAP catheters (one in the right and the other in the left ventricle) sufficient to determine interventricular dispersion. Placement was based upon the quality and stability of the signal.

2.1 Experiment selection
Between 1993 and 1997, we performed TdP experiments in 60 dogs: 26 using 2 mg/kg d-sotalol, 22 with 0.12 mg/kg almokalant, and 12 with 0.05–0.1 mg/kg ibutilide. In 26 experiments TdP occurred spontaneously after drug administration (26/60=43%), while in 14 animals programmed electrical stimulation [8] was necessary to induce TdP, leaving a third of the animals non-responsive to this arrhythmic protocol. From now on, we use the term class III to refer to the different drugs.

In 7 of the 26 experiments with episodes of spontaneously occurring acquired TdP, an ectopic beat directly initiated TdP (sudden onset TdP, Fig. 1 and Table 1), in the other 19 animals ectopic beats preceded the first episode of TdP (see Table 1). In total 17 experiments were analysed into detail, 1. all 7 sudden onset TdP's and 2. 10 episodes of non-sudden onset TdP aiming at a similar incidence of almokalant and ibutilide (Table 1, last column) were used to complement the sudden onset group.


Figure 1
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  		Fig. 1 Sudden onset TdP. Three ECG leads (I, II, AVR) and two endocardially recorded monophasic action potentials (MAP) from both ventricles (LV- and RV-MAP) are illustrated at a paper speed of 10 mm/s under control (left panel) and after administration of a class III agent (right panel). Approximately 3 min after the start of the 5 min infusion, a sudden onset TdP occurred which stopped spontaneously. Looking at the events preceding the TdP, it can be noticed that the QT-time and APDs are prolonged after the class III (e.g. APD50 increased from 355 to 475 ms). This increase was more pronounced in the left as compared to the right ventricle leading to an increase in interventricular dispersion from 115 to 155 ms. The cycle length of the idioventricular rhythm stayed similar just until TdP, when a lengthening from 1550 to 1850 ms occurred. Moreover, the QRS-morphology of the next beat changed, which was followed by an ectopic beat with again different QRS morphology (coupling interval of 560 ms) that triggered TdP.

 

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  		Table 1 Overview of the electrophysiological characteristics accompanying the first episode of TdP in the different groupsa

 
2.2 Data analysis
Six surface ECG leads and 2 Monophasic Action Potential signals were simultaneously registered and stored on hard disk with a sampling rate of 1 kHz. Applying a custom made computer program (ECG View, Maastricht University, Maastricht, The Netherlands) with a resolution of 2 ms, and an adjustable gain and time scale. Electrophysiological parameters and APD measurements were performed semi-automatically off-line, including APD50 and APD100. {Delta}APD was defined as the difference between the left and right ventricular APD at a certain time point. To gain insight in the APD changes induced by ectopic beats, we choose to use APD50 instead of the normally applied APD100 [9,10]. This allowed measurements of the LV-and RV-APD (and thus {Delta}APD) in case the ectopic beat occurred before repolarization had ended. During steady state rhythms, we validated APD50, especially in regard to the calculation of interventricular dispersion. Correlation of APD50 with APD100 (r = 0.72, P<0.01) and {Delta}APD50 with {Delta}APD100 (r = 0.51, P<0.01) before and after class III drugs allowed us to use this parameter.

In all 17 experiments analysed, APD50 of the left and right ventricle were measured at least every 30 s during class III administration using a mean of 5 consecutive beats until TdP occurred. A premature ectopic beat was defined as a ventricular complex with a coupling interval of less than 50% of the cycle length of the idioventricular rhythm during steady state.

The following phases were examined (Fig. 2) on a beat to beat basis: 1. the end of the steady state period (phase I), 2. the dynamic period in which ectopic beats occurred (phase II) and 3. the beat directly preceding TdP (phase III).


Figure 2
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  		Fig. 2 Classical short–long–short sequence preceding TdP. Similar composition and abbreviations as in Fig. 1. The classification of the different beats preceding TdP (phases I, II and III) are indicated with a bar. Again class III medication led to an increase in APDs which now under steady state conditions was quite homogeneous: no increase in interventricular dispersion (45 ms). However, the interruption of the regular rhythm by an ectopic beat (II) with a different QRS morphology led to an increase in the LV-APD50 (from 390 to 425 ms) but a decrease in the RV-APD50 (345–315 ms) in the next regular beat creating an dispersion of 110 ms. The next ectopic beat induced TdP which had to be cardioverted.

 
During phase I, the APD of the last beat of the idioventricular rhythm was compared with the average of 10 beats preceding it to study APD stability. The phase II could be non-existing (sudden onset TdP, Fig. 1), as short as one ectopic beat (short–long–short sequence, Fig. 2) or consisting of long episodes of repetitive ectopic activity (the cascade phenomenon, Fig. 3). Only the APDs of the regular beats of the idioventricular rhythm were measured.


Figure 3
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  		Fig. 3 Repetitive prolonged ectopic activity preceding TdP (Cascade phenomenon). Holter recording of lead II of the ECG to document a number of TdP-episodes after class III administration in a specific experiment. The first TdP occurred after a long period of repetitive ectopic activity in which QRS-morphologies of the regular rhythm and the number and QRS-morphologies of the ectopic beats changed dramatically. The second TdP was a sudden onset TdP, while the third and fourth episode of TdP was preceded again by ectopic activity. All TdP-episodes stopped spontaneously. In Fig. 4, the electrophysiological characteristics of specific episodes (A–D) are shown using the endocardially recorded MAPs. The star symbol is a marker used in Fig. 5, where the dynamic, temporal response of the APDs to class III is depicted.

 
2.3 Statistics
Pooled data are expressed as mean±standard deviation. Intergroup comparisons were performed with the Student-t test for unpaired and paired data groups, while correlation and regression lines were determined using ‘Primer of Biostatistics’, McGraw-Hill Inc. Differences were considered significant if P≤0.05.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
In Table 1 the electrophysiological characteristics of all first TdP episodes in the 26 experiments are given in respect to the mode of onset and to the drug. No electrophysiological differences were present between the selected and non selected non-sudden TdP episodes.

Table 2 shows the increase in repolarization parameters due to class III administration (monitored just prior to the 1st TdP) in the 17 selected experiments. It can be observed that the APD50 shows the same relative increase as the APD100 in both ventricles as well as in {Delta}APD.


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  		Table 2 Comparison between APD100 and APD50 (n = 17) in steady state at baseline and after class III administration just before TdP (phase I)a

 
3.1 Contribution of ectopic beats to interventricular dispersion of repolarization
Examples of the three different TdP initiation sequences (sudden, short–long–short, and prolonged non-sudden onset, i.e. cascade) are illustrated in Figs. 1–3GoGo.

Assessing the relevance of (multiple) ectopic beats for the APD of both ventricles during phase II and III revealed an inhomogeneous response of the ventricles due the ectopic activity on the APD of the subsequent regular idioventricular beat. This dynamic response lengthened APD50 of the left (P<0.05) but had no effect on APD50 of the right ventricle (Table 3). Therefore the ectopic beats caused an increase in {Delta}APD50 with ±20 ms (P<0.05) during phase II and an additional 40 ms increase was observed just before the first TdP occurred (phase III). Because the occurrence of TdP is often not a single event (Fig. 3), we had the opportunity to confirm and extend our data using different TdP starting sequences in the same dog (Fig. 4). The different starting points of the second and third TdP (points A and C in Fig. 3) were compared to similar events (points B and D) in which the QRS-morphology and interval of the regular and ectopic beat were comparable but not resulting in TdP (Fig. 4). Irrespective of the possible limitations, it is clear that just preceding TdP the left ventricular APD50 and the {Delta}APD50 is longer than in sequences not leading to TdP.


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  		Table 3 Changes in APD and {Delta}APD after ectopic beats (phase III) preceding TdP episodes in the non-sudden TdP group compared with the absence of ectopic beats in the sudden onset TdP groupa

 

Figure 4
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  		Fig. 4 Electrophysiologic comparison of two pairs of events of Fig. 3. Four specific (combinations of) beats were selected from the previous figure on basis of their QRS morphology to compare the electrophysiological characteristics, which did or did not lead to TdP. All ectopic beats seem to occur from the endocardium of the left ventricle where they clearly interrupted the APD. The first comparison showed that a second and perhaps a third ectopic beat only occurred in A prior to TdP where the absolute APD50 length and interventricular dispersion were a fraction longer than in B, whereas the coupling interval of the first ectopic beat was the same. A similar observation can be made in the second comparison C vs. D: APD50 length (e.g. 535 vs. 465 ms) and interventricular dispersion (235 vs. 190 ms) were more pronounced in C prior to TdP as in D, whereas the coupling interval between the idioventricular beat and the ectopic beat was equal.

 
In Fig. 5, we have illustrated the time course of APD changes for the two experiments depicted in earlier figures, being a sudden (Fig. 1) and a non-sudden onset TdP (Fig. 3). Especially in the latter situation, it is shown that the ectopic beats contribute to the interventricular dispersion because of the LV-APD response to frequency changes is quite different from the RV-APD.


Figure 5
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  		Fig. 5 Temporal behaviour of APD after class III. A beat to beat temporal comparison of the duration of the left and right ventricular action potential (APD50) until the first TdP were performed in the experiments of Figs. 1 and 3Go starting at the moment of class III administration. In the top panel (see Fig. 1), a sudden TdP starts after one ectopic beat interrupts the idioventricular rhythm of a dog with a pronounced dispersion of repolarization. In the lower panel, the dynamic interaction of the (multiple) ectopic beats increases the dispersion creating the substrate for TdP (see Figs. 3–4Go). Only the APD50s of the regular idioventricular beats have been measured. After each episode of TdP, the increase in heart rate during the arrhythmia decreases dispersion temporarily, but then the sequence starts again giving rise to repeated TdP episodes.

 
3.2 Electrophysiologic differences between sudden and non-sudden onset TdP
Comparison of the sudden onset TdP revealed that the {Delta}APD50 just before the TdP was identical to the {Delta}APD50 reached after the ectopic beats of the non-sudden onset group (Table 3). At phase 1, most other repolarization parameters were longer in the sudden onset group, which was independent whether we applied APD50 or APD100 or corrected for cycle length. The time to TdP occurrence (285±135 vs. 295±115 s) after the start of the medication, and the coupling interval of the responsible ectopic beats (580±190 vs. 585±125 ms) were not different between the two groups.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The results of this study can be summarised as follows:

  • {Delta}APD50 and {Delta}APD100 are parameters, which represent similar information and therefore can be used alternatively in this study.
  • The short–long–short sequence and the cascade phenomenon contribute to the heterogeneity in APD, especially because of the response of LV-APD, thereby increasing {Delta}APD50 favouring initiation of TdP.
  • In steady state (phase I), {Delta}APD100 and {Delta}APD50 are larger in the sudden onset as compared to the non-sudden onset TdP group, indicating that {Delta}APD is associated with the occurrence of spontaneous TdP after class III medication in this dog model.
  • All three events (sudden onset, short–long–short or cascade) can be present in the same animal, indicating that {Delta}APD is not a stable parameter but very dynamic in nature and possibly influenced by many different interventions.

4.1 Starting sequences of congenital and acquired TdP in patients
It has been shown that the classical classification defining congenital LQTS as ‘adrenergic dependent’ and acquired LQTS as ‘pause dependent’ has to be abandoned [6]. Already in 1988, Jackman et al. pointed to the overlap between different patient groups, while more recently in relation to genotype, different modes of TdP onset including pause-dependency have been described [1,2,6].

Oscillations of the RR interval, typically of the short–long–short type, precede the initiation of TdP in patients with acquired prolongation of repolarization [4]. The premature beat (the trigger) creates a post-extrasystolic pause, which is often followed by the next beat of the regular rhythm showing a bizarre T-wave morphology. Especially, when the amplitude of the oscillatory initiation sequences increases (with shorter short and longer long intervals) the probability of TdP increases. Such a sequence would be expected to increase APD or QT, which might facilitate early afterdepolarization-dependent triggered activity. Gilmour et al. clearly demonstrated that in acquired long QT, the QT interval preceding TdP was longest and that a critical prolongation of QT interval occurred by the prodromal pause [5]. Moreover, the lengthening of the QT interval was a summation of the preceding events (cascade). When this prolongation in APD is heterogeneous, dispersion will become more manifest and the requirements for TdP initiation (the substrate) will be met.

4.2 Animal model of TdP
The dog with chronic, complete AV-block has an enhanced susceptibility for acquired TdP arrhythmias, both under conscious [7], and anaesthetised circumstances [8–10]. In the weeks after AV-block many important cellular adaptation processes lead to mechanical [14–16], structural [10,16,17], and electrical remodeling [10,17] in this animal model, all favouring the initiation of TdP. These acquired TdP arrhythmias may occur spontaneously or can be induced by pacing, with most of them terminating spontaneously. The former can be further divided into sudden onset and non-sudden onset TdP, which allowed us to study the electrophysiological differences and similarities in these two groups. However, it is important to state that the different initiation sequences are not separate entities but that they can occur in the same dog (Fig. 3).

In our model, we have shown that class III drug administration prior to spontaneous TdP leads to 1. an increase in the cycle length of the idioventricular rhythm (Table 2), 2. inhomogeneous lengthening of APD as recorded by endocardially placed MAP catheters in the two ventricles, thereby increasing {Delta}APD100, 3. the occurrence of early afterdepolarizations, which can also increase {Delta}APD [13,18], and 4. the appearance of (multiple) ectopic beats. Because the latter most frequently occur within the QT-interval (i.e. LV-APD) of the regular rhythm, APD100 is not capable of measuring the APD changes induced by these beats. Therefore, we validated that APD50 could be used as an alternative (method section and Table 2), an assumption that was based on cellular data [17].

4.3 Sudden vs. non-sudden acquired TdP
Our hypothesis that {Delta}APD represents a crucial factor in our model was confirmed by the data of the sudden onset TdP group that had a very large {Delta}APD100 of 150±85 ms during steady state circumstances and required only one ectopic beat to initiate TdP. In contrast non-sudden TdP, occurring in the majority of dogs, had an {Delta}APD100 of 85±45 ms (P<0.01) in phase I, which was insufficient to start TdP by one ectopic beat. They needed longer lasting RR interval changes (dynamic interplay) to create sufficient {Delta}APD. The similarity in coupling interval of the ectopic beats (around 580–585 ms) and the starting point of TdP (around 285 s) in the two groups indicated that these factors were not of crucial importance.

4.4 Electrophysiologic mechanism(s) underlying acquired TdP arrhythmias
It is clear that almost all drugs belonging to class III of the Vaughan Williams classification can induce TdP under specific circumstances. Two mechanisms are suggested in the initiation (trigger) and perpetuation (substrate) of acquired TdP [22], being focal ectopic activity from the subendocardium of the ventricles and dispersion of repolarization or refractoriness. Since the classical description of dispersion of refractoriness by Han and Moe [19], spatial and temporal dispersion received much attention. The same authors showed that dispersion was bradycardia dependent [20], which since then has been confirmed for transmural [21] and interventricular dispersion of repolarization [9].

In this study, we focused on the interplay between triggered activity and dispersion of repolarization and demonstrated that they are not independent but that (multiple) short–long–short sequences of ectopic beats (trigger) will add to the substrate by increasing {Delta}APD. This concept has been referred to as modulated dispersion [23] or synergism between the trigger and the substrate [24].

In another canine TdP model, El-Sherif and co-workers [12] have also looked at this phenomenon using activation patterns and activation recovery intervals recorded by inserting multiple needles. There are important differences present in these two studies: First, a LQT3 surrogate (anthopleurin A) in acute AV-block vs. IKr block in chronic AV block with electrical remodeling. Second, in their study ectopic beats infringed on the pattern of dispersion leading to conduction block and TdP occurrence by reentrant excitation. Transmural dispersion in closely adjacent sites hardly increased (from 19±8 ms to 38±12 ms (P<0.01). In our study, interventricular dispersion ({Delta}APD50) increased dramatically from 65±40 ms (phase I, Table 3) to 85±80 ms in phase II to 130±100 ms just prior to TdP (phase III), a value remarkably close to the steady state {Delta}APD50 (130±35 ms) of the sudden onset group. Third, although they could map the initiation and propagation of the arrhythmia in great detail, they reported no sudden onset TdP [12] enabling them to link dispersion with TdP. For these reasons, we believe that our study is extending the knowledge concerning initiation of TdP and is calling attention to the septum where the ventricles merge as an important site for the arrhythmogenic substrate.

4.5 Location of dispersion of repolarization
Dispersion should be located in adjoining sites to be involved in the perpetuation of the arrhythmia. In recent experiments, we have shown (with intramural needles) the existence of a transseptal repolarization gradient going from left endocardium (longest APD) to right endocardium (shortest APD). The difference over the needle was comparable with {Delta}APD. In addition transmural gradients of similar magnitude were seen in the dog with chronic AV block [25,26]. Activation recovery intervals with 64 transmural needles confirmed these measurements [27].

4.6 Ionic mechanism underlying the increase in {Delta}APD
Premature ectopic beats create longer repolarization times of the post-extrasystolic beat, which has been explained on the basis of an interaction of Ito and IK [28]. However, this dynamic response in the chronic AV block dog differs tremendously between the two ventricles leading to an increase in {Delta}APD. This is in our opinion based on a smaller repolarization reserve of the left ventricle. In sinus rhythm, the right ventricle has a shorter APD and more Ito and IKs than the left ventricle [29,30]. After AV block there is a reduction in IKs and IKr that might explain the more pronounced differences [31]. The more labile repolarization of the left may therefore well show a very different reaction to bradycardia, to a further prolongation of the APD after IKr blockade and to rate changes caused by ectopic beats, all contributing to {Delta}APD.

Almokalant prolongs the repolarization based on its IKr blockade [32] whereas ibutilide also affects the Na+ inward current [33]. This possible difference in mode of action does not affect the initiation mode. Furthermore in the same experiment the different initiation sequences co-exist (Fig. 3).

4.7 Clinical relevance
Our observations explain why in some patients the ‘cascade phenomenon’ [4] is required before TdP occurs. The presence of different starting sequences of TdP (single beat, short–long–short, or cascade) within a short time interval in the same dog indicate that the precipitating variables are very dynamic in nature. When applicable to patients (using medication), this means that prediction of pro-arrhythmic events is very difficult, perhaps impossible. Therefore, it seems prudent to consider the patient developing TdP after a cascade as being also at risk for TdP induction after a single ventricular premature beat.

4.8 Limitations
Neither the mechanism of TdP nor the site of origin of the ectopic beats were assessed or elucidated in this study. Dynamics of QT adaptation are complex (bi-exponential [34]) and perhaps not thoroughly assessed.

APD50 and APD100 seem to contain similar information. However, they may also differ because of the occurrence of early afterdepolarizations, especially when they appear in phase 3 of repolarization.

The importance of the activation sequence, especially of the ectopic beats, was not studied. This may play an important role in the initiation of TdP [22], as suggested in Fig. 3, and requires further study.

Time primary review 29 days.


   Acknowledgements
 
The authors would like to express their gratitude to P. Laudy, BS for the development of the software for automatic APD analysis. Supported by a grant of Netherlands Heart Foundation (NHS #94.010 (SCV, FvdH), and by a grant of TUBITAK (The Scientific and Technical Research Council of Turkey, BG).


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

  1. Jackman W.M., Friday K.J., Anderson J.L., Aliot E.M., Clark M., Lazzara R. The Long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis (1988) 31:118–172.
  2. Zareba W., Moss A.J., Schwartz P.J., et al. Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT syndrome Registry Group. New Engl J Med (1998) 339:960–965.[Abstract/Free Full Text]
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  5. Gilmour R.F., Riccio M.L., Locati E.H., et al. Time- and rate-dependent alterations of the QT interval precede the onset of Torsade de Pointes in patients with acquired QT prolongation. J Am Coll Cardiol (1997) 30:209–217.[Abstract]
  6. Viskin S., Alla S.R., Barron H.V., et al. Mode of onset of Torsade de Pointes in congenital Long QT syndrome. J Am Coll Cardiol (1996) 28:1262–1268.[Abstract]
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