Cardiovascular Research

Cardiovascular Research 1997 34(3):453-463; doi:10.1016/S0008-6363(97)00067-9
© 1997 by European Society of Cardiology

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Copyright © 1997, European Society of Cardiology

Role of interventricular dispersion of repolarization in acquired torsade-de-pointes arrhythmias: reversal by magnesium

S.C. Verduyn, M.A. Vos^*, J. van der Zande, F.F. van der Hulst and H.J. Wellens

Department of Cardiology, Cardiovascular Research Institute Maastricht, University of Limburg, Maastricht, P.O. Box 5800, 6202 AZ Maastricht, Netherlands

^* Corresponding author. Tel.: +31 (43) 3875095; fax: +31 (43) 3875104.

Received 9 July 1996; accepted 11 February 1997

	Abstract

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
Objective: The mechanism of acquired torsade-de-pointes arrhythmias (TdP) is not clear but is suggested to be based on several parameters including early afterdepolarizations (EADs) and/or dispersion of repolarization (APD). In our animal model of TdP (anaesthetized dogs with chronic AV block), we assessed the relevance of interventricular dispersion for the initiation of TdP. Methods: In 24 experiments, multiple endocardial monophasic action potential (MAP) recordings were made at baseline, after d-sotalol (2 mg/kg), and after MgSO₄ (100 mg/kg, n=11) to measure regional differences in action potential duration (APD). Rate-dependent behavior of the interventricular APD (APD of left minus right ventricle) and intraventricular dispersion was studied under the different circumstances. Results: Dogs with induction of TdP by d-sotalol and pacing (11/20=55%) had longer cycle lengths of idioventricular rhythm, longer QT-durations, increased presence of EADs (14/22 vs 5/18 MAPs, P<0.05) and increased interventricular APD (135±55 vs 60±40 ms, P<0.05) compared with non-inducible dogs. There were no differences in intraventricular dispersion. MgSO₄ diminished APD (110±45 to 55±60 ms, P<0.05) and prevented TdP (4/4). In contrast to intraventricular dispersion, interventricular APD is clearly bradycardia-dependent. Conclusions: Next to bradycardia, prolonged repolarization, and EADs, we propose that APD should be added to the relevant factors for the initiation of TdP. Interventricular dispersion is much larger than intraventricular dispersion and demonstrates a very strong bradycardia dependence.

KEYWORDS Arrhythmias; Monophasic action potential; Early afterdepolarization; Dog, anesthetized; Magnesium

	1 Introduction

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
Prolongation of QT-duration with (anti-arrhythmic) drugs has been associated with cardiac arrhythmias, like torsade de pointes (TdP, [1, 2]). Because repolarization parameters will lengthen when heart rate slows, the incidence of acquired TdP will increase under bradycardic circumstances. In recent years, evidence has accumulated that early afterdepolarizations (EADs) play a decisive role in the genesis of ectopic beats and the U-wave changes that often precede the spontaneously occurring TdP [3–8]. It has been demonstrated in vitro and in vivo that EADs are bradycardia-dependent and originate preferably in cells with prolonged action potential duration (APD) [8–12]. No evidence was provided that the EAD-dependent triggered activity also led to TdP [13].

In patients with congenital TdP, intraventricular dispersion of APD has been observed [14, 15]. Also, these studies provided evidence that EADs occurred at specific sites, thereby explaining (in part) the observed intraventricular dispersion [14–16]. More recently, interventricular dispersion was seen in combination with EADs in a patient with acquired TdP [17].

In our animal model of pacing-induced acquired TdP [18], our main objective was to investigate the relevance of interventricular dispersion of APD (APD) for the initiation of TdP. To relate APD to intraventricular dispersion, we also assessed the latter parameter in some experiments. For this purpose, multiple (simultaneously recorded) endocardial MAP recordings were made in both ventricles at baseline, after d-sotalol and after MgSO₄. MgSO₄ is an effective clinical drug in the treatment of TdP [19]. Based on experimental findings two anti-arrhythmic modes of action of MgSO₄ have been suggested to explain the prevention and termination of TdP: (1) suppression of EADs [7, 20, 21] and (2) a decrease in APD [7].

	2 Methods

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
All experiments performed conformed with the Guide for the Care and Use of Laboratory Animals (Publication No. 85-23, revised 1985) and were approved by the Committee for Experiments on Animals of the University of Limburg (Maastricht, The Netherlands).

2.1 General
The experiments were performed on anesthetized adult dogs with chronic AV block (5±3 weeks) of either sex with a body weight between 18 and 34 kg. Each dog had one epicardial electrode (Bakken Research Center, Medtronic, Maastricht, The Netherlands) implanted at the apex of the left ventricle, when a right-sided thoracotomy was performed to produce a complete AV block by injection of formaldehyde (37%) in the AV groove [18]. Between AV block and the experiment a minimum of 2 weeks elapsed.

Pacing was done with a programmable stimulator capable of pacing synchronously to the QRS complexes. Unipolar stimuli were given using a pulse width of 2 ms and a stimulus strength of twice the diastolic threshold. As indifferent electrode a needle was placed through the skin. Six surface electrocardiographic leads and 2 endocardial MAP signals were simultaneously registered and stored on hard disc. All drugs were administered through a canula in the cephalic vein.

For both types of experiment, anaesthesia was induced by (1) premedication i.m. (1 ml/5 kg: 10 mg oxycodon, 1 mg acepromazine and 0.5 mg atropine) and (2) sodium pentobarbital (20 mg/kg i.v.). The dogs were artificially ventilated through a cuffed endotracheal tube using a mixture of oxygen, nitrous oxide and halothane (vapor concentration 0.5–1%) 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.

Because the animals are tested chronically, proper care was taken after the experiments, including administration of antibiotics (1000 mg ampicillin) and analgesics (0.3 mg i.m. buprenorfine). Also, an externally placed temporary pacemaker (for a maximum of 24 h) was given after the AV block operation and after the TdP experiments.

Two sets of experiments were performed in the animals, one with the primary goal to assess the relevance of interventricular dispersion for the induction of acquired TdP (n=20: TdP dogs). In these experiments at least two endocardial MAPs were randomly placed, one in the right and the other in the left ventricle. In the second set of experiments (n=4) the emphasis was put on the relation between inter and intraventricular dispersion during baseline, and after d-sotalol and MgSO₄.

2.2 Induction of torsade-de-pointes arrhythmias
A detailed description of the TdP protocol is described elsewhere [18]. In short, anesthetized animals received two defibrillation patches that were attached to both sides of the chest and connected with a defibrillator. Half an hour after the onset of anaesthesia, pacing was done from the epicardial electrode and consisted of two different pacing modes: (1) short–long–short sequence and (2) 8 basic stimuli followed by an extra stimulus. The interstimulus interval was 400, 600 or 1200 ms; the extrastimulus was shortened from 500 ms with steps of 50 ms till 300 ms. After completing the pacing protocol, a bolus of d-sotalol (2 mg/kg/5 min) was administered. Pacing was resumed 10 min after the start of the bolus. A TdP arrhythmia was defined as a polymorphic ventricular tachycardia consisting of 5 beats, which twisted around its baseline in the presence of a prolonged QT(U) duration. When TdP did not stop spontaneously in 10 s or when it deteriorated into ventricular fibrillation, cardioversion (60–70 J) was performed.

This animal model of ‘pacing-induced’ TdP results in reproducible TdP arrhythmias in half of the animals [18]. In 20 consecutive experiments in which stable MAP recordings could be made, we induced TdP in 11 animals (inducible group). Inducibility was defined as the initiation of TdP for at least 3 times using the same pacing mode.

2.3 MgSO₄ administration
In the TdP dogs, MgSO₄ (100 mg/kg/2 min) was administered within 45 min after d-sotalol to 7/20 animals, 4 inducible and 3 non-inducible dogs. We have demonstrated that one bolus of d-sotalol is capable of reproducible induction of TdP for at least 60 min [18]. At 5 min after the start of the injection of MgSO₄, the pacing modes which led to TdP induction were repeated.

In the 4 intra/interventricular APD dogs, MgSO₄ was administered at 60 min d-sotalol.

2.4 Monophasic action potentials
Endocardial monophasic action potentials were recorded simultaneously to observe the occurrence of EADs and to measure the (differences in) the duration of the action potential (APD). A quadripolar contact electrode (Franz combination catheter, EPT # 1650), that provides both pacing and MAP recording (22) capabilities was placed endocardially in the right and in the left ventricle. Placement was based on quality of the signal. Therefore a carotid and/or femoral artery and an external jugular and/or femoral vein were dissected free and the 7-French MAP catheter was introduced under fluoroscopy. After the experiment the used arteries and veins were sutured. The MAP signals were amplified with an isolated DC coupled differential amplifier with calibrated gains of 10, 20, 50, 100, 200 and 500 (custom made, University of Limburg). The offset of the amplifier is variable and can be adjusted to the recorded signal. All amplifiers are provided with a 20 mV calibration pulse. Data acquisition of the MAP signals is achieved by an 8-bit Analog to Digital Converter resulting in a 0.39% resolution of full scale. The MAP signals are sampled at a rate of 1 kHz per signal. MAP phases were defined according to the definitions used for transmembrane action potentials (TAP) [9]. In contrast to TAP, amplitude was defined between phase 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. Under baseline conditions, the shape of the MAP does not change. Only the amplitude can decrease during the course of an experiment (120 min). To correct for this decrease, the MAP signals were checked prior to drug administration. If necessary (<15 mV), adjustment was made by applying more pressure to the tip of the catheter.

EADs were defined as an interruption of the smooth contour of phase 2 or 3 of the action potential [4, 9]. The presence of EADs was examined in all MAPs. In the latter 4 experiments, we checked these visual interpretation of the EADs by using the first derivative of repolarization. EADs were identified on the basis of a slowing in repolarization.

2.5 Inter- and intraventricular difference in APD
In all experiments, two MAP catheters were placed randomly to measure the APD in the left and in the right ventricle. After the first 10 min of d-sotalol, we replaced these catheters to several sites [23] to measure intraventricular differences in APD in 7 of the 20 TdP experiments. To assess more carefully LV intraventricular differences especially with regard to EADs, we placed an additional LV MAP catheter, while the first MAP catheter remained at a stable site in 4/7 experiments. After placement of the moving MAP catheter, 5 paced beats were given using the MAP electrode to register the ECG (QRS morphology). Site of catheter placement was judged by comparing the QRS morphology and by using markers through a Siemens monoplane roentgen.

To examine the importance of intraventricular dispersion relative to the interventricular dispersion in more detail, 4 experiments in 4 dogs (all 5 weeks of AV block) were used to record the MAP signals from different preselected sites in the ventricle, without interference of PES to induce TdP. At different sites 4 MAPs were placed, two in the RV and two in the LV. In each ventricle one MAP was maintained at a stable position during the whole experiment, the other two MAPs were placed at different sites (see Fig. 1). Measurements were made during baseline, during and after administration of d-sotalol and after MgSO₄, keeping the CL constant by pacing. Interventricular dispersion was calculated as the difference between the LV and RV in 16 experiments with 2 MAPs, and between the two fixed sites in the remaining 4 experiments (TdP dogs). When catheters were moved, APD was determined between all sites registered, while the intraventricular dispersion was calculated between all registered MAPs within the ventricle.

View larger version (39K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Example of the different recording sites in the left and right ventricle and their respective action potential durations after administration of d-sotalol in one dog (animal #1). In this figure, the different sites in which a monophasic action potential recording was made in the right and left ventricle are shown (RV and LV, respectively). The ventricles were paced at a cycle length of 1520 ms (see ECG in top panel). After d-sotalol, the following action potentials were recorded. The durations are shown underneath each action potential, while the EADs are marked with an arrow. Paper speed was 25 mm/s and the amplitude of RV-MAP 1 was 35 mV. The mean LV-APD was 560 ms, the RV-APD was 460 ms, leading to an interventricular difference of 100±18 ms. The intraventricular dispersion in the RV ventricle amounts to 20±13 and that of the LV 16±10 ms. Thus, the differences within one ventricle are far smaller than the interventricular differences, while EADs occur more frequently in the LV than in the RV.

 
2.6 Frequency-related changes of APD and interventricular APD after d-sotalol
In 7/20 experiments a paced ventricular rhythm (on the epicardial electrode) with a paced cycle length (PCL) of 1000 and 500 ms was used to investigate the rate-related changes of the APD and the interventricular APD. At steady state (>2 min pacing) the APD was determined as the average of 5 beats. After administration of d-sotalol the APD measurements were repeated, and we could include a PCL of 1500 ms.

A similar protocol was performed in the 4 animals used to study intraventricular differences with the 4 MAPs.

2.7 Data analysis
All data were analyzed using a custom-made computer program with a resolution of 2 ms and adjustable gain and time scale. Using lead II, electrophysiological measurements of cycle length of the idioventricular rhythm (CL-IVR) and QT(U) time were performed before and after the administration of d-sotalol and MgSO₄. The QT_c time was calculated using the formula of Bazett (QT_c=QT/CL–IVR) [24], to correct for rate differences. All measurements are done during steady-state conditions (i.e., without interference of ectopic beats or pacing). The action potential duration was measured after total repolarization (=APD₁₀₀) and was determined for both ventricles at the same time points as the other parameters. Each value represents the mean of 5 consecutive beats. Additionally the incidence of spontaneous beats was scored which occurred during the first 10 min of d-sotalol.

2.8 Statistics
A paired Student's t-test was applied to compare data under the different conditions (drugs). To compare differences between inducible and non-inducible dogs, an unpaired t-test was used. P-values 0.05 were considered significant. All data are presented as mean±standard deviation (s.d.).

	3 Results

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
3.1 Electrophysiological effects of d-sotalol
In the 20 dogs of the TdP protocol, d-sotalol significantly prolonged QT time from 405±75 to 500±90 ms and the CL-IVR from 1585±335 to 1890±385 ms (both P<0.001), while the QRS duration was not affected. All these measurements were performed at the start of d-sotalol (control) and at the end of the measurement period of 10 min. The APD of the LV (390±65 to 495±90 ms, P<0.01) prolonged more (both absolutely and relatively) than the RV (330±40 to 395±55 ms) leading to a larger interventricular APD after d-sotalol (from 60±30 to 100±65 ms, P<0.01).

We saw EADs only once under control conditions (1/20, see further). Within the 10 min observation period after d-sotalol spontaneous ectopic beats occurred in 12/20 dogs. The responsible EADs occurred in 14/20 dogs, and were present more predominantly in the LV (12/20) than in the RV (7/20).

3.2 Characteristics of APD, interventricular APD and intraventricular APD
Under baseline conditions, the LV-APD of the 20 TdP dogs showed a linear relation with QT time (r=0.81, P<0.01) and with CL-IVR (r=0.8, P<0.01). The APD of both ventricles increased when the PCL was lengthened from 500 to 1000 ms (Fig. 2). In addition, a clear frequency dependence was seen for the interventricular APD (P<0.05), because the LV-APD prolonged more than the RV-APD when the PCL increased. In the absence of EADs, similar observations were obtained after d-sotalol. The more pronounced increase of the LV-APD at the different PCL resulted again in bradycardic lengthening of the interventricular APD. However, d-sotalol did not increase the interventricular APD at these specific paced frequencies (Fig. 2).

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Frequency-dependent behavior of action potential duration (APD) and interventricular difference in APD (APD) before and after d-sotalol. In this graph the frequency-dependent behavior of the APD and the interventricular APD is shown. On the y-axis the APD is depicted of the left ventricle (LV, ) and the right ventricle (RV, ) during baseline (,) and after d-sotalol (,). The dogs (n=7) are paced at steady state through the left epicardial electrode. The x-axis represents the paced cycle length (PCL). At 500 ms the interventricular APD amounts to 35 ms during baseline. With an increase in cycle length to 1000 ms the APD of both ventricles is prolonged significantly. The LV-APD increases relatively more, leading to a significantly higher interventricular APD at the longer cycle length (P<0.05). d-Sotalol (dS, 2 mg/kg) increases the absolute value of both APDs. Interventricular APD displays bradycardia dependence although the amount of interventricular APD at a specific PCL in the absence of EADs does not increase.

 
In the 4 dogs tested solely to create insight in the distribution of the endocardial APD in both ventricles, we recorded a total number of 5.5±1.5 places in the right ventricle and 7±1.5 places in the left ventricle (Fig. 1). After MgSO₄ the 4 MAPs were no longer replaced because of the short duration of action of this drug.

In Table 1, the individual and mean values are presented for QT, APD of both ventricles, APD and the intraventricular differences (LV-APD, RV-APD). PCL was 1250±180 ms at baseline and 1450±205 ms with d-sotalol. At baseline the mean APD was ±70 ms, whereas the differences in APD within one ventricle were less than 20 ms. Administration of d-sotalol increased the interventricular differences significantly but did not increase the amount of intraventricular differences. Although we did not aim to induce TdP in these dogs, one dog (animal 2 in the table, the one with the largest APD) developed a spontaneous episode of TdP.

View this table: [in this window] [in a new window]   Table 1 Changes in inter- and intraventricular dispersion under baseline and d-sotalol during a paced rhythm

 
Magnesium shortened significantly the LV-APD to 455±35 and the RV-APD to 365±30 ms and returned the APD to the baseline value of 65±45 ms. Again, the intraventricular differences did not change after MgSO₄. A representative example of the behavior of the APDs in each ventricle at the different recording sites during baseline, d-sotalol and MgSO₄ is shown in Fig. 3.

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Behavior of interventricular and interventricular dispersion under different conditions in an individual dog. In this graph, the individual action potentials (animal #2) are plotted of all right and left ventricle MAPs during control, d-sotalol and magnesium. The LV-APD () is in all cases larger than the RV-APD (). The APD increases quite homogeneously with d-sotalol and diminishes after MgSO4. The interventricular dispersion increases from 127±22 ms at baseline to 180±30 ms after d-sotalol and decreases again to 115±18 ms with magnesium. To indicate which sites were recorded after MgSO4, a line has been drawn to connect them to their previous points. The difference within the ventricle does not change during the different conditions, as indicated by the values.

 
The values of interventricular APD and intraventricular differences after d-sotalol were comparable with the data obtained in the 7 TdP dogs (4 I and 3 NI) in which multiple sites were recorded. In that subset of 7 dogs the mean interventricular APD at randomly chosen sites was 105±65 ms. The mean intraventricular difference in APD of the left and right ventricle only amounted to maximal 30±25 and 20±20 ms, respectively.

Unlike interventricular dispersion, the intraventricular differences did not show a clear frequency dependency in the 4 additional experiments. At a steady-state CL of 1000 ms the APD was 105±45 ms, while the intraventricular differences amounted to 22±8 (LV-APD) and 16±10 ms (RV-APD). At 500 ms, the APD significantly decreased to 30±14, while the LV-APD shortened to 10±12 and the RV-APD to 8±10 ms (not significant).

3.3 Torsade-de-pointes arrhythmias
When we divided the dogs in two groups (inducible and non-inducible), we found that under baseline conditions the electrophysiological values (CL-IVR and QT) of the susceptible dogs were longer than those of the non-inducible dogs [18] (Table 2). This was also the case for the LV, RV-APD and interventricular APD (75±30 vs 40±30 ms, p0.01), while the QT_c was similar.

View this table: [in this window] [in a new window]   Table 2 Electrophysiological changes after d-sotalol (2 mg/kg)

 
d-Sotalol further enhanced the length of the repolarization, as illustrated in Fig. 4. With the exception of interventricular APD in the non-inducible group, all parameters demonstrated a significant increase (Table 2), resulting in a large difference in interventricular APD (135±55 vs 60±40 ms, P<0.01) between the inducible and non-inducible group. The intraventricular differences did not differ between inducible and non-inducible dogs during baseline and d-sotalol as measured in the 7 TdP dogs. After d-sotalol, the 4 inducible dogs had a LV-APD of 30±24 ms and an RV-APD 23±19 ms, in the 3 non-inducible dogs this was 32±30 and 7±7 ms, respectively.

View larger version (101K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Initiation of a ‘pacing-induced’ torsade-de-pointes arrhythmia after d-sotalol. A 3-lead ECG and two monophasic action potential (MAP) signals recorded endocardially in the right (RV) and left ventricle (LV) are shown at a paper speed of 10 mm/s. A pacing train of 8*600 ms followed by an extrastimulus during control conditions does not induce any arrhythmic event (panel 1). Stimulation is shown by ‘S’. Interventricular APD amounts to 50 ms. In panel 2, administration of d-sotalol (2 mg/kg) leads to an increase in cycle length of the idioventricular rhythm, the QT time, and both the RV-MAP (350 to 460 ms) and the LV-MAP (400 to 600 ms). Because the increase in LV-APD is more pronounced, the interventricular APD is increased to 140 ms. Note the occurrence of EADs on both MAPs (see arrows). Repetition of the pacing train results in a TdP. The arrhythmia already starts during the pacing train by beats that are triggered by EADs (marked by an asterisk). Also subthreshold EADs can be clearly seen, especially in LV-MAP (arrows).

 
The development of EADs after d-sotalol was noticed in almost all inducible (10/11, Fig. 4) as well as in half of the non-inducible dogs (4/9). The ectopic beats did not differ in both groups (8/11 vs 4/9).

With the exception of one dog (see below) pacing under control conditions did not lead to TdP (Fig. 4, panel 1). Following d-sotalol, induction of TdP occurred often during the pacing train, because pacing exaggerated the occurrence of EADs and spontaneous beats (Fig. 4, panel 2). This in contrast to the non-inducible dogs, where pacing did not accentuate the EADs or led to EBs.

One of the susceptible dogs already showed prominent U-waves when the dog was tested consciously prior to the experiment. When anesthetized, this dog possessed EADs and a large interventricular dispersion under baseline conditions (Fig. 5, panel 1) and pacing led to TdP. After treatment with MgSO₄ the ECG normalized and the induction of TdP by pacing was prevented. Thirty-five minutes after MgSO₄, d-sotalol induced spontaneously triggered beats resulting several times in episodes of spontaneous TdP (Fig. 5, panel 2). For a second time MgSO₄ was administered to this dog to abolish the effect of d-sotalol (Fig. 6).

View larger version (80K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 5 Spontaneous TdP after d-sotalol. In this figure a 6-lead ECG is shown together with MAP recordings in the right (RV-MAP) and in the left ventricle (LV-MAP) recorded at a paper speed of 10 mm/s. Under control conditions this dog already had a pronounced interventricular dispersion of APD (APD) of 115 ms and EADs can be seen on the LV-MAP (arrow, panel 1). Administration of d-sotalol (2 mg/kg, panel 2) increases the CL-IVR, QT time, RV-APD to 460 ms and LV-APD to 640 ms, resulting in a dispersion of 180 ms. Also, negative T-waves develop and the EADs became more pronounced (see arrows), leading to ectopic beats (asterisk) and spontaneous TdP. This self-terminating TdP starts in the classical way of a short–long–short sequence triggered by the EADs occurring on the LV-MAP.

 

View larger version (76K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 6 Effect of MgSO4. Same dog and composition as in Fig. 5. At the start of MgSO4 (100 mg/kg, 20 min after d-sotalol) a bigemic rhythm exists. The LV-MAP is markedly prolonged compared with the RV-APD and has very pronounced EADs that trigger ectopic beats (panel 1). Three minutes after start of MgSO4 the repolarization process has changed (disappearance of the negative U-waves), the ectopic beats are suppressed and the QT time, RV-APD and the LV-APD are shortened markedly, resulting in less dispersion. All this takes place while the CL-IVR increases (!) to 4180 ms. The EADs of LV-MAP have disappeared completely, while the EADs in RV-MAP remain present but appear with less amplitude.

 
3.4 Effects of MgSO₄
MgSO₄ was administered at 35±8 min after d-sotalol to 7/20 TdP dogs (4 I and 3 NI). Because the electrophysiological effects of d-sotalol decrease with time [18], the value ‘d-sotalol 35'’ was introduced representing the electrophysiologic measurements at the start of MgSO₄ administration. No significant differences were found between d-sotalol 10' and ‘d-sotalol 35'’. In 6/7 animals EADs (both inducible and non-inducible for TdP) and in 2/7 animals ectopic beats were present at the time of MgSO₄ administration. The effect of MgSO₄ was most pronounced at 3 min after the start of the injection. Although the CL-IVR increased, MgSO₄ (1) diminished QT-time (Table 3), (2) suppressed ectopic beats (2/2) (Fig. 6, panels 1–2), and (3) either suppressed (3/6) or diminished the amplitude of EADs (3/6, e.g., Fig. 6, panel 2), and (4) shortened RV- and LV-APD. Because of the more overt decrease of the LV-APD, the interventricular APD (55±60 ms) was significantly decreased to values comparable with baseline (60±35 ms, Table 3). MgSO₄ prevented TdP induction (4/4). The magnitude of the electrophysiological effects of MgSO₄ was more pronounced for the CL-IVR, LV-APD and RV-APD in the inducible dogs, while interventricular APD was halved in both groups.

View this table: [in this window] [in a new window]   Table 3 Electrophysiologic effects of MgSO4 (100 mg/kg) in 7 dogs (4 inducible and 3 non-inducible)

 

	4 Discussion

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
In our opinion, this study presents new information regarding the relevance of interventricular APD (inhomogeneous repolarization) for the initiation of acquired TdP arrhythmias in our animal model. Therefore this parameter should be added to the list of relevant factors such as bradycardia, prolonged repolarization and presence of EADs. Although APD has been suggested by others [13, 17], we have made the following important observations: (1) In the absence of EADs, interventricular APD demonstrates bradycardia dependence: there is an increase in interventricular APD when the heart rate slows. (2) After d-sotalol, interventricular APD is increased primarily by slowing of the IVR and site-specific occurrence of EADs. (3) Endocardially measured interventricular APD is always greater than intraventricular differences in APD. (4) The interventricular APD is larger in the inducible dogs, while the amount of intraventricular dispersion does not differ. (5) Suppression or prevention of TdP by MgSO₄ is related to diminution of interventricular APD and disappearance of EADs.

4.1 Interventricular and intraventricular dispersion in APD
Since the description of TdP arrhythmias more than 25 years ago [25], several mechanisms have been proposed to explain its occurrence, such as EAD-dependent triggered activity (ectopic beats) and re-entry based on dispersion. In the intact heart, both parameters (i.e., EADs and dispersion) can be measured by the use of MAP catheters which provide information on regional repolarization [22, 26]. In patient studies, both intra- and interventricular differences in APD have been indicated to be related to TdP [14–17]. When EADs originate at specific sites, APD will prolong regionally and by definition dispersion will increase. Recent studies have also indicated an increased dispersion of repolarization in acquired TdP by measuring QT intervals in multiple ECG leads [27–29].

Rate-dependent behavior of repolarization parameters and EADs is widely acknowledged (see, e.g., [1, 4, 9, 10]). Data concerning the frequency dependence of APD dispersion are scarce. Nevertheless, there is some evidence that differences in APD are smaller at faster rates [30, 31]. In the present study 2 MAPs were recorded simultaneously. For the first time, we present evidence that the sensitivity of the APD to prolong when the heart frequency decreases is different for the LV than the RV, resulting in an increase in interventricular APD (bradycardia dependence). This, in contrast to endocardially recorded intraventricular differences, is not significantly influenced by changes in frequency. These observations are obtained during steady state in the absence of EADs on the registered MAPs, so that in this case the increase cannot be explained by the contribution of EADs to interventricular APD. Similar information can be obtained from Table 2, but now in the presence of EADs. Comparing the different cycle lengths in the groups with and without d-sotalol, a clear lengthening of the interventricular APD is seen as the CL-IVR between groups increases.

Although d-sotalol will not increase interventricular APD at steady state CL in the absence of EADs (Fig. 2), administration of the drug will influence interventricular APD in several ways: (1) increase in CL IVR, and (2) occurrence of (site-specific) EADs.

A second indication that EADs and interventricular APD are two independent phenomena is indicated by the effects of MgSO₄. The induced increase in CL-IVR would normally be associated with an increase in APD and interventricular APD. When extrapolation of the APD to a CL of 2400 ms is allowed (using Table 2, baseline values, no EADs), the calculated LV-APD would be approximately 510 ms, while the RV has a length around 380 ms. The mean values that were observed after MgSO₄ are however much less: LV-APD of 435 ms and RV-APD of 380 ms, resulting in a interventricular APD of 55 ms similar to baseline (Table 3). The shorter LV-APD is partially caused by the disappearance of the EAD but to a larger extent to homogenization of repolarization by a more pronounced shortening of the LV-APD.

Whether the pronounced interventricular APD is related to the presence of chronic complete AV block seems indicated by the results of a recent study [33]. To determine the exact contribution of EADs to interventricular APD, further studies need to be performed.

Differences in APD within the ventricle (intraventricular dispersion) could also contribute to dispersion of repolarization. Systematic analysis of the APD at 7 sites in the LV and 5.5 sites in the RV (Table 1, Fig. 1), combined with the random placement of MAP at multiple sites in a subset of the TdP dogs showed that the observed intraventricular differences are much less than interventricular APD. In contrast to the interventricular APD, the intraventricular differences were not influenced by the PCL, by the addition of d-sotalol or MgSO₄. So it seems that the ventricles themselves behave more uniformly.

A possible explanation for the substantially larger effect on the LV-APD with a frequency change and d-sotalol might be the presence of M-cells [32]. The canine myocardium is said to exist of circa 40% of M-cells. Under baseline conditions the M-cells of the LV show more prolongation at slower cycle lengths than the RV M-cells, leading to an interventricular APD of approximately 100 ms at 2000 ms (Fig. 4 of Ref. [12]). Regional development of EADs by class III drugs will contribute to the dispersion and it is known that M-cells are also more sensitive than endo- and epicardial cells to develop EADs after drugs such as quinidine, dl-sotalol, and Bay K 8644 [12].

4.2 Induction of TdP
Based on our data, we cannot assess the exact contribution of EADs to interventricular APD. But we do believe that we provide evidence that both EADs and interventricular APD, as suggested by others [1, 13, 17], have to be present in a certain number to induce TdP. Inducible dogs have a higher incidence of EADs, a similar incidence of ectopic beats and intraventricular difference compared with non-inducible dogs, but possess a more pronounced interventricular APD. Because EADs and ectopic beats are also present in the non-inducible group, their appearance alone does not seem sufficient to induce TdP. The fact that the presence of ectopic beats does not lead to spontaneous TdP nor seems related to pacing-induced TdP could be explained by (1) the differences in coupling interval, (2) the number of beats in the pacing train, (3) the lack of interventricular APD, or (4) a combination of these factors.

Secondly, prevention of TdP by MgSO₄ is achieved through a more pronounced reduction of repolarization in the left ventricle leading to less interventricular APD. Similar data that we obtained in a different study confirm this observation: in the same dog the higher occurrence of (spontaneous) TdP after almokalant was associated with a higher interventricular APD and more EADs compared with d-sotalol [34].

This study again emphasizes the role of bradycardia in the genesis of TdP. EADs, APD, interventricular APD all show bradycardia dependence. Acceleration of the rate either by isoprenaline or ventricular pacing prevents the occurrence of TdP [18]. And a further slowing of the rate by a second bolus of d-sotalol in the non-inducible dogs increases inducibility to 70–80% [18]. However, intraventricular dispersion does not seem to possess such frequency-dependent behavior.

4.3 Possible consequences of dispersion for the mechanism of TdP
A non-uniform repolarization of the heart (dispersion) has for a long time been acknowledged as a substrate for lethal ventricular arrhythmias [35]. Differences in repolarization will favor re-entry which could perpetuate the ectopic impulse formation after the first triggered beat(s) and so initiate TdP. One of the possibilities is spiral wave re-entry which causes polymorphic patterns in epicardial sheets. The spiral wave re-entry is due to a gradient in dispersion or conduction velocity [36], but can also occur in homogenous tissue. APD is not likely to play a role in re-entrant arrhythmias because the dispersion is located too far apart. However, APD could be an indicator for transmural differences in repolarization. Intramural re-entry caused by transmural dispersion has been described [12, 37] Using activation recovery intervals, the continuation of the TdP was suggested to be due to wandering foci and/or to foci alternating with re-entrant pathways [37].

Also other research groups who used three-dimensional mapping suggested the presence of different foci [38, 39] originating from the endocardium as the perpetuation substrate of the arrhythmia. The present study is not able to discriminate between triggered activity or re-entry for the mechanism of continuation of TdP.

4.4 Limitations
Our data point to the involvement of interventricular APD or inhomogeneous repolarization for the initiation of pacing-induced TdP. However, a critical value of interventricular APD cannot be presented by us to predict the occurrence of TdP because a small overlap in the values of the interventricular APD between inducible and non-inducible dogs is present.

Pacing-induced TdP is not similar to spontaneously occurring TdP. However, we believe that there are many resemblances [18] that validate generalization of the results obtained in this model for the spontaneous initiation of TdP.

It may be important to note that not only the rate-dependent effects of the differences in APD are reported during steady-state paced cycle lengths or during a relatively stable CL-IVR [30, 31], but also the electrophysiological measurements of APD took place during steady state. A sudden rate change after d-sotalol (i.e., by programmed electrical stimulation or by triggered beats) may increase interventricular APD, due to a (temporal) accentuation in EADs (see, e.g., Fig. 4, panel 2). This can provide the trigger for the initiation of TdP, either due to the triggering of the accentuated EADs or due to the prolonged interventricular APD. The dynamic behavior of EADs and interventricular APD in relation to frequency changes therefore needs further investigation.

During spontaneous IVR the activation times will differ depending on the origin of the focus. This may influence differences in APD when we consider a relation between the time of activation and AP duration [40, 41]. There are numerous places for impulse formation in our dogs. Therefore, we do not believe that a specific activation site will markedly influence dispersion in APD.

Although we show that intraventricular differences in repolarization are relatively small compared with the interventricular dispersion in repolarization, this study does not provide data concerning the possible transmural differences and their effect on the occurrence of TdP.

	5 Conclusions

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
Next to bradycardia, prolonged repolarization, and EADs, we propose that APD or inhomogeneous repolarization should be added to the relevant factors for the initiation of TdP. In contrast to intraventricular dispersion, interventricular APD demonstrates a very strong frequency dependence during steady-state rhythms. The intraventricular differences in APD are much smaller than in APD and seem to be less important for the induction of TdP.

Time for primary review 29 days.

	Acknowledgements

 
We thank the Bakken Research Institute (Medtronic), Maastricht, The Netherlands, for providing the epicardial electrodes. This study was supported by grants from the Netherlands Heart Foundation (#91.104 and #94.010).

	References

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