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Cardiovascular Research 2005 65(2):397-404; doi:10.1016/j.cardiores.2004.10.016
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Copyright © 2004, European Society of Cardiology

Transmural dispersion of repolarization as a key factor of arrhythmogenicity in a novel intact heart model of LQT3

Peter Milberga,*, Nico Reinscha, Kristina Wasmera, Gerold Mönniga, Jörg Stypmanna, Nani Osadab, Günter Breithardta, Wilhelm Haverkampa,1 and Lars Eckardta

aHospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology, Münster, Germany
bDepartment of Medical Informatics and Biomathematics, University of Münster, Germany

* Corresponding author. Medizinische Klinik und Poliklinik C, -Kardiologie und Angiologie-Universitätsklinikum Münster, Albert-Schweitzer Str. 33, D-48149 Münster, Germany. Tel.: +49 251 834 5160; fax: +49 251 834 9943. Email address: milbergp{at}uni-muenster.de

Received 31 July 2004; revised 5 October 2004; accepted 8 October 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Background: Congenital and acquired long QT syndrome (LQTS) are caused by abnormalities of ionic currents underlying ventricular repolarization. For a better understanding of the mechanisms by which functional electrical instability at the level of the whole heart leads to torsade de pointes (TdP), a novel model of LQT3 was developed and the role of transmural dispersion of repolarization for the development of proarrhythmia was evaluated.

Methods and results: In 11 Langendorff-perfused rabbit hearts, veratridine (0.1–0.5 µM), an inhibitor of sodium channel inactivation, led to a concentration-dependent increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p<0.05) and thereby mimicked LQT3. Veratridine reproducibly induced early afterdepolarizations (EADs) and TdP after lowering potassium concentration. In bradycardic (AV-blocked) hearts, the increase in MAP duration showed marked regional differences. It was significantly more pronounced on the left endocardium as compared to left or right epicardium. This resulted in a significant increase in dispersion of repolarization (24% at 0.1 µM, 92% at 0.25 µM, 208% at 0.5 µM; p<0.01). Left ventricular transmural dispersion of repolarization increased significantly more than interventricular dispersion (104 to 33 ms at 0.5 µM veratridine; p<0.05).

Conclusion: By inhibition of sodium channel inactivation, veratridine mimics LQT3 in this intact heart model. In bradycardic, hypokalemic hearts, it reproducibly induced EADs and TdP in the setting of significantly increased left ventricular transmural dispersion of repolarization. Based on these experimental data, reduction of transmural dispersion of repolarization may be considered an important target for the prevention of TdP in patients with LQT3.

KEYWORDS Torsade de pointes; Long QT syndrome; Action potential; prolongation; Transmural dispersion; Veratridine


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Congenital and acquired long QT syndrome (LQTS) are caused by abnormalities of ionic currents underlying ventricular repolarization [1]. For a better understanding of the mechanisms by which functional electrical instability at the level of the whole heart leads to torsade de pointes (TdP), a novel model of LQT3 was developed. One of the genes responsible for LQTS is SCN5A (LQT3) [2]. It is located on chromosome 3 and encodes for the cardiac fast sodium channel. Mutations lead to a persistent component of a small inward depolarizing ion current (INa) via continued re-opening of the sodium channel. This small inward sodium current is sufficient to delay repolarization and to prolong the QT-interval [3].

The present study aimed at (1) developing an in vitro intact heart model of LQT3 and (2) to evaluate the role of transmural as well as interventricular dispersion of repolarization for the development of proarrhythmia. In order to reproduce the electrophysiologic alterations of LQT3 veratridine, an inhibitor of sodium channel inactivation [4] was chosen. An intact heart model was used where the influence of cell-to-cell coupling, that attenuates the functional expression of heterogeneity of dispersion, was present. As there is evidence that prolongation of repolarization in LQT3 is associated with an exaggeration in dispersion of repolarization in the canine wedge preparation [5], we studied in particular the role of transmural dispersion for the occurrence of TdP. Dispersion of repolarization when preceded by early afterdepolarizations (EADs) can result in functional conduction block and set the stage for the development of tachyarrhythmias. However, the occurrence of significant transmural dispersion of repolarization in an intact heart model is still questioned in experimental and clinical studies.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
All experimental protocols were approved by the local animal care committee and conformed with the Guide for the Care and Use of Laboratory animals published by the US National Institutes of Health (NIH Publication No. 852-3, revised 1996).

2.1. Preparation of hearts for perfusion
The method has previously been described in detail [6,7]. In summary, male New Zealand white rabbits (n=11) weighing 2.5–3.0 kg were anaesthetized with sodium thiopental (200–300 mg i.v.). After midsternal incision and opening of the pericardium, the complete hearts were removed and immediately placed in an ice-cold Krebs–Henseleit solution (composition in mM: CaCl2 1.80, KCl 4.70, KH2PO4 1.18, MgSO4 0.83, NaCl 118, NaHCO3 24.88, Na-pyruvate 2.0 and D-glucose 5.55). The aorta was cannulated, the pulmonary artery was incised, and the spontaneously beating hearts were retrogradely perfused at constant flow (52 ml/min) with warm (36.8–37.2 °C) Krebs–Henseleit solution. Perfusion pressure was kept stable at 100 mm Hg. The hearts were placed in a heated, solution-filled tissue bath. After cannulation, the hearts were given 10 min to stabilize. The perfusate was equilibrated with 95% O2 and 5% CO2 (pH 7.35, 37 °C). The cannulated and perfused hearts were attached to a vertical Langendorff apparatus (Hugo Sachs Elektronic, Medical Research Instrumentation, March-Hugstetten, Germany). A deflated latex balloon was inserted into the left ventricle and connected to a pressure transducer to control hemodynamic stability. The atrioventricular (AV) node was ablated under surface electrogram-control by surgical tweezers to slow the intrinsic heart rate. This resulted in complete AV-dissociation with a ventricular escape rate below 60 beats/min.

2.2. Electrocardiographic and electrophysiologic measurements
Volume-conducted surface electrograms were recorded by complete immersion of the heart into a bath of Krebs–Henseleit solution that had been thermally equilibrated with the myocardial perfusate. Signals from a simulated "Einthoven" configuration were amplified by a standard ECG amplifier (filter settings: 0.1–300 Hz). Monophasic action potential (MAP) recordings and stimulation were accomplished simultaneously using contact MAP-pacing catheters (EP Technologies, Mountain View, CA, USA). The MAP electrograms were amplified and filtered (low pass 0.1 Hz, high pass 300 Hz). MAPs were analyzed using a software specifically designed by Franz et al. [8] permitting precise definition of the amplitude and duration of the digitized signals. The recordings were considered reproducible and, therefore, acceptable for analysis only if they had a stable baseline amplitude with a variation of less than 20% and a stable duration (action potential duration at 90% repolarization (MAP90) was reproducible within 4 ms). Seven MAPs were evenly spread in a circular pattern around both ventricles (five on the left ventricle, two on the right ventricle); one MAP was recorded from the left endocardium. One of the right ventricular catheters was used to pace the heart. Pacing at twice diastolic threshold was performed for one min at each cycle length (CL) from 900 to 300 ms using a programmable stimulator (Universal Programmable Stimulator, UHS 20, Biotronik, Germany), which delivered square-wave pulses of 2 ms pulse width. All data were digitized at a rate of 1 kHz with 12-bit resolution and subsequently stored on a removable hard disk (BARD LabSystem, Bard Electrophysiology, Murray Hill, MA, USA).

2.3. Experimental protocol
After placing the MAP catheters and achieving complete AV block, cycle length-dependence was first investigated under baseline conditions by pacing the hearts at cycle lengths between 900 and 300 ms. Thereafter, veratridine (0.1–0.25–0.5 µM) was infused just above the heart. For this purpose, a veratridine solution with a concentration of 1 µM was produced in a separate bath and perfusion speed was adjusted to the perfusate flow rate. The experimental setup was designed to reproduce conditions and circumstances that are clinically known to be associated with an increased propensity to the development of TdP [9]. Pacing, MAP recording and measurement of ECG parameters were again started 10 min after drug infusion. Thereafter, the potassium concentration was lowered to 1.5 mM to provoke EADs and TdP. Therefore, a Krebs–Henseleit solution with low potassium concentration was mixed in a separate bath and the isolated heart was perfused with this solution. Five minutes later, the potassium concentration was increased to 5.8 mM and veratridine concentration was increased to the next dosage.

Dispersion was expressed as the difference between the minimum and the maximum of MAP90, simultaneously recorded in eight endocardial and epicardial catheters. To ensure reproducibility during the study and to compare the results of different hearts dispersion was always measured during the pacing part of the protocol. Interventricular dispersion was defined as the difference between the mean of five left and the mean of two right epicardial MAP catheters. Transmural dispersion was measured between one left endocardial and the mean of five left epicardial MAP catheters; typically, endocardial action potential recordings minus the mean of epicardial action potential recordings. EAD was defined as a positive voltage deflection that interrupted the smooth contour of phase 2 or 3 repolarization of the action potential [6,10]. TdP was defined as a polymorphic ventricular tachyarrhythmia of more than 5 beats with a changing ventricular axis and spontaneous termination.

2.4. Data acquisition and statistical analysis
Surface electrograms, pressure, volume and MAPs were recorded on a multi-channel recorder. Data were digitized online at a rate of 1 kHz with 12-bit resolution and stored on a disk. The observed data were entered onto a computerized database (Microsoft Excel 97) and statistically evaluated using SPSS Software Release 11.0.1. (Nov. 2001, Chicago). Before statistically testing, each continuous variable was analyzed explorative about its normal distribution ("Kolmogorov–Smirnov-test"). Categorical variables are expressed as frequency and percentage, whereas continuous variables are presented as mean ± S.D. Differences were considered significant at p<0.05. The Friedman-test and the Wilcoxon-test were used for comparison of non-parametric variables. All data are presented as mean ± S.D. The influence of veratridine on surface electrogram parameters and MAP duration, as well as dispersion of repolarization were assessed using the Friedman-test. The Wilcoxon-test was used to investigate cycle length dependence. To compare the incidence of EAD and TdP, the chi-squared-test and the Fisher-test were used.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
3.1. Dose-dependent effects of veratridine on QT interval, action potential duration and MAP configuration
All electrocardiographic parameters reached equilibrium within 10 min. After this stabilization period, MAP recordings and pacing thresholds (mean threshold 1.5 ± 1.0 mA) remained highly reproducible throughout the experimental protocol. The MAP amplitude did not change by more than 20% for the subsequent investigation period. Veratridine (0.1–0.5 µM, n=11) led to a significant increase in QT-interval and monophasic action potential duration (p<0.05) and thereby mimicked LQT3 (Fig. 1). In the presence of 0.1 µM veratridine, there was only a slight increase in action potential duration. After increasing the drug concentration to 0.25 µM, the prolongation ranged between 6% at a cycle length of 300 ms and 25% at a cycle length of 900 ms (p<0.05). This marked reverse use-dependence was more pronounced at a higher veratridine concentration (0.5 µM=11% at a cycle length of 300 ms, 61% at a cycle length of 900 ms). The increase in MAP90 was paralleled by an increase in QT-interval but not in MAP50. Under baseline conditions, the action potential duration at 90%-repolarization was similar to 50% repolarization, which resulted in an MAP90/MAP50 ratio of 1.26 (Fig. 2). With increasing drug concentration, MAP90 was markedly lengthened, whereas MAP50 was prolonged only moderately leading to an increase of MAP90/50 ratio from 1.33 at 0.1 µM veratridine to 1.51 at 0.25 µM and 1.70 at 0.5 µM, respectively, rendering the action potential configuration triangular.


Figure 1
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  		Fig. 1 Concentration dependent effect of veratridine (n=11) on MAP90 as compared to control in isolated Langendorff perfused rabbit hearts (left top corner), (*=p<0.05 as compared to its respective baseline). (+) baseline, ({diamond}) 0.1 µM veratridine, (Figure 1) 0.25 µM veratridine, (bullet) 0.5 µM veratridine. (CL=cycle length; each value as representative mean in ms).

 

Figure 2
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  		Fig. 2 Relation between MAP90 and MAP50. The ratio at increasing concentrations of veratridine shows significant higher values as compared to baseline (ratio-values as mean of stimulation rates between 900 and 300 ms).

 
3.2. Effect on dispersion of repolarization
In bradycardic (AV-blocked) hearts, the eight simultaneously recorded epicardial and endocardial MAPs demonstrated a significant increase in dispersion of repolarization with increasing drug concentration (baseline 33 ± 10 ms, 0.1 µM 40 ± 20 ms; 0.25 µM 63 ± 30 ms; 0.5 µM 101 ± 50 ms). To assess regional differences, the mean values of action potentials recorded from the left ventricular epicardium were compared to the means of the right epicardially recorded action potentials and the endocardial action potential (Table 1, Fig. 3). There was a significant increase in interventricular dispersion of repolarization between the left and right epicardially recorded action potentials. Moreover, there was an even more pronounced increase in left ventricular transmural dispersion of repolarization. This increase was significantly higher than the increase in interventricular dispersion and the increase in action potential duration (Table 1). It was caused by a very marked left endocardial MAP prolongation especially seen at slow heart rates, due to veratridine (0.25 and 0.5 µM) (Table 1, Fig. 3).


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  		Table 1 Concentration dependent effect of veratridine on MAP duration (MAP90) and dispersion of repolarization

 

Figure 3
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  		Fig. 3 (A) MAP prolongation in left ventricle, right ventricle and endocardium in response to veratridine in increasing concentrations (LV=left ventricle, RV=right ventricle, Endo=left endocardium; values as mean of action potentials recorded from LV, RV and endo at stimulation rates between 900 and 300 ms). (B) Examples of typical MAP recordings at baseline and at the different veratridine concentrations.

 
3.3. Early afterdepolarizations and torsade de pointes
In the presence of veratridine, EADs and triggered activity were a frequent finding. After complete AV-block and lowering of potassium concentration from 5.88 to 1.5 mM, 4 of 11 hearts showed EADs at a concentration of 0.1 µM veratridine. With higher drug concentration, the incidence of EADs increased to 10 of 11 veratridine-treated hearts at concentrations of 0.25 and 0.5 µM (Table 2). TdP (Fig. 4) were always associated with EADs (veratridine p<0.05, Fisher-test). Veratridine reproducibly led to TdP in 2 of 11 hearts (20 single episodes during a period of 5 min) at a concentration of 0.1 µM. With 0.25 and 0.5 µM veratridine, 9 hearts showed TdP (79 single episodes and 84 single episodes, respectively, Table 2). The higher incidence of TdP correlated to the increase in MAP90/50 ratio (triangulation).


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  		Table 2 Number of hearts showing EAD and number of TdP episodes in n=11 studied hearts in increasing veratridine concentration

 

Figure 4
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  		Fig. 4 Representative example of EADs and TdP in the presence of veratridine (0.1, 0.25 and 0.5 µM), AV-block and hypokalemia in an isolated Langendorff-perfused rabbit heart. Electrocardiographic characteristics and MAP recordings. Occurrence of EADs 11 min after increasing veratridine-infusion to 0.5 µM and 60 s after lowering potassium concentration to 1.5 mM. Occurrence of typical TdP 12 min 23 s after increasing the drug-concentration to 0.5 µM and 2 min 23 s after lowering potassium concentration (MAP 1=left ventricular base anterior; MAP 2=right ventricular apex anterolateral; MAP 3=right ventricular base anterolateral; MAP 4=left ventricular base posterior; MAP 5=left ventricular between base and apex posterolateral; MAP 6=left ventricular between base and apex lateral; MAP 7=left ventricular apex; MAP 8=left endocardium apex).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 Acknowledgments
 References
 
The present study shows that veratridine, by inhibition of sodium channel inactivation, represents a novel intact heart model of LQT3, leading to significant prolongation of repolarization, EADs and TdP. Veratridine led to a marked increase of transmural dispersion of repolarization mainly due to excessive prolongation of left endocardial repolarization in relation to left and right epicardial tissue. This suggests that sodium current density may not be uniform across the ventricular wall. Zygmunt et al. [11] have previously demonstrated that the density of late sodium conductance is significantly higher in the midmyocardium than in other regions. Although we used an intact heart model, which included cell-to-cell coupling effects, the differences between epicardial and endocardial action potentials in our study were very pronounced. This indicates that action potential differences across the ventricular myocardium may be important for the genesis of TdP in LQT3. Transmural action potential heterogeneity may support reentrant mechanisms responsible for the perpetuation of TdP, after being initiated by EAD. In our study, the tachyarrhythmias were always induced by spontaneous premature beats as is observed clinically and not by stimulated premature beats. They exhibited a polymorphic undulating ECG morphology, were only initiated in the setting of a prolonged QT-interval, and were almost always self-terminated.

Veratridine caused marked reverse use-dependence, which increased the risk for TdP at slow heart rates because of extreme QT-interval lengthening. With increasing drug concentration, MAP90 was markedly lengthened, whereas MAP50 was prolonged only moderately. This resulted in an increase of the MAP90/50 ratio rendering the action potential configuration triangular. The increasing triangulation of the action potential correlated to a higher incidence of TdP. We recently demonstrated for cardiovascular [12] as well as non-cardiovascular [13] drugs that a triangular MAP-shape is related to proarrhythmia, whereas a rectangular MAP configuration, even in the presence of extreme prolongation of repolarization, is not associated with TdP. These previous observations are supported by the present study, which demonstrated that in an experimental LQT3 model, triangulation is also associated with an increased risk for TdP. Thus, action potential configuration has to be added to the relevant factors of arrhythmogenesis in LQT3.

Prolongation of the repolarization phase acts as a primary step for the generation of EADs and may be associated with increased dispersion of repolarization. In the present study, the occurrence of TdP correlated to the development of EADs and an increase in dispersion of repolarization. EADs have earlier been acknowledged as the most important mechanism underlying TdP in numerous experimental models [9]. In the present setting, there was a high incidence of EADs in veratridine-treated rabbit hearts at low levels of extracellular potassium and at slow heart rates. Utilizing tridimensional mapping of activation in a canine model of LQT3, El Sherif et al. [14] showed that the occurrence of TdP was due to EAD-triggered premature activation in the presence of an underlying substrate, which is dispersion of repolarization. The relation of EADs as the trigger and dispersion as the substrate for TdP has also been documented in experimental models of LQT1 [15] and LQT2 [12]. Moreover, clinical observations using monophasic action potential recordings support the hypothesis that EAD-induced triggered activity initiates TdP, that is maintained by a reentrant mechanism [16]. Triggered activity seems to be the most probable cause for the appearance of ectopic beats preceding TdP, at least for the first beat in a run of TdP, when EADs reach the critical threshold for activation of a depolarizing current.

Early on, Hondeghem et al. [17] and later our own group [13] speculated that prolonging phase 3 of the repolarization process may generate EADs by spending too much time in the window voltage for calcium channel reactivation. By prolonging action potential duration within the L-type Ca2+ "window" voltage range, EADs and thereby TdP are likely to be generated [18]. The subsequent beats may then result from circus movement reentry due to dispersion of repolarization [19]. In the present study, the importance of dispersion of repolarization as the underlying substrate for TdP was measured by eight simultaneously recorded MAP. Using epicardial and endocardial MAP recordings, differences in action potentials recorded from different layers of myocardium were evident. The increase in transmural dispersion of repolarization (significant higher increase than in interventricular dispersion; table one) was due to a marked increase in endocardial action potential duration and created a vulnerable window for the development of reentry. Our findings are in agreement with a previous study on LQT2 by Akar et al. [20]. They demonstrated the presence of a marked spatial dispersion of MAP in a surrogate model of LQT and showed very nicely a transmural repolarization gradient with disproportionate action potential prolongation in M-cells, forming the substrate for reentrant excitation in TdP. The area with longest repolarization was in endocardial and subendocardial cells. Regarding the typical M-cell MAP-shape [21] and the characteristic response to an inhibitor of sodium channel inactivation [5], we may speculate, in the face of a very thin endocardium in the rabbit heart, that our endocardial catheter recorded endocardial- and M-cell-potentials simultaneously. In a study by Restivo et al. [22], tridimensional mapping in a canine LQT3 model has shown that during spontaneous episodes of TdP, functional conduction block occurred when a subendocardial focal beat encountered regions of marked dispersion commonly between epicardial and mid-myocardial zones. The spatial distribution of repolarization is the key to the formation of conduction block necessary for the initiation and sustenance of reentrant circuits.

The optimal treatment of patients with LQT syndrome is still under debate. The initial therapy of choice for the large majority of patients with the congenital LQTS is a beta-blocking drug [23]. In LQT3, the sodium channel blocker mexiletine may be a therapeutic tool in abbreviating the QT interval and reducing the incidence of arrhythmogenesis [5]. Certainly, the effectiveness of an intervention to abbreviate the QT-interval is not necessarily congruent with its efficacy to reduce the incidence of arrhythmogenesis or risk of sudden death. Shimizu and Antzelevitch [5] have shown in arterially perfused wedge of left canine ventricle that reduction of transmural dispersion of repolarization is a more reliable marker in LQT3. In another study, they demonstrated the ability of nicorandil, a potassium channel opener, to prevent TdP by reducing transmural dispersion of repolarization [24].

4.1. Limitations of the study
Our experimental study was performed in the isolated rabbit heart and extrapolation of experimental results to the human heart may be difficult although a lot of experimental studies show that the experimental findings are in agreement with clinical observations in humans. Although MAP recordings accurately depict the voltage–time course of cellular action potentials, the combined use of arterially perfused wedge preparations may be of additional value. As already described, we may speculate that our endocardial catheter recorded endocardial and M-cell-potentials simultaneously, especially because M-cells displaying the longest action potentials are often localized close to endocardial cells in the subendocardium [25]. A clear distinction between these two subpopulations is not possible with our setup. Due to the use of just one endocardial MAP the information on transmural dispersion is limited in the present study. However, it is almost impossible to record more than one endocardial MAP in the relatively small rabbit heart.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
Acknowledgments
 References
 
By inhibition of sodium channel inactivation, veratridine mimics LQT3 in an intact heart model. We could demonstrate that this model of LQT3 is a viable system for studying the electrophysiologic consequences of nonuniform action potential distribution. In bradycardic, hypokalemic hearts, veratridine reproducibly caused EADs and TdP in the setting of significantly increased left ventricular transmural dispersion of repolarization. Based on these experimental data, reduction of transmural dispersion of repolarization via shortening of endocardial action potential duration may be effective in preventing TdP and might be a therapeutic approach in the treatment of LQTS.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
References
 
We thank Irina Schulz for excellent technical assistance.


   Notes
 
1 Dr. Haverkamp's present address is: Department of Cardiology, Campus Virchow Clinic, Charité-University Medicine Berlin, Germany. Back

Time for primary review 23 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 

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