© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Magnesium abolishes inadequate kinetics of frequency adaptation of the Q-aT interval in the presence of sotalol
aDepartment of Internal Medicine, Karl-Franzens-University, Auenbruggerplatz 15, 8036 Graz, Austria
bDepartment of Medical Physics and Biophysics, Karl-Franzens-University, Auenbruggerplatz 15, Graz, Austria
* Corresponding author. Tel. +43 316 385-2012; Fax +43 316 385-3062; E-mail: starkg@balu.kfunigraz.ac.at
Received 24 June 1996; accepted 7 February 1997
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Abstract |
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Objective: It has been well established that class III antiarrhythmic drugs can also induce ventricular arrhythmias. Marked changes in the QT interval are correlated with an increased dispersion of repolarization which is an important factor for the induction of ventricular arrhythmias. The aim of the present study was to investigate the effects of sotalol alone and in combination with MgSO4 on the Q-aT interval during abrupt changes in heart rate. Methods: The experiments were performed on isolated guinea-pig hearts perfused by the method of Langendorff. The rate adaptation of the Q-aT interval was estimated after abruptly changing the ventricular pacing rate from 220 to 180 ms and back to 220 ms. Results: In the presence of 10 µM sotalol, at a constant pacing cycle length of 220 ms, the QT interval was prolonged significantly (P<0.01) from 152±4 to 166±3 ms (mean±s.e.m., n = 8 in each group). The addition of 3.4 mM MgSO4 caused a slight further prolongation of the QT interval. After abruptly shortening the pacing cycle length from 220 to 180 ms, the Q-aT interval shortened within 2 min by 11.3±0.5 ms with a time constant (
) of 77±9 beats under control conditions, by 15.4±0.9 ms (P<0.05 vs. control) with = 52±7 beats (P<0.05 vs. control) in the presence of sotalol, and by 13.1±1.2 ms with = 158±13 beats under the combination of sotalol (10 µM) and MgSO4 (3.4 mM). After abrupt shortening of the pacing cycle length the Q-aT interval of the first beat was shortened by 3.3±0.3 ms under control conditions, by 7.1±0.2 ms (P<0.01 vs. control) under sotalol, and by 4.2±0.2 ms with the combination of sotalol and MgSO4. If the pacing cycle length was abruptly increased from 180 to 220 ms, the effects were comparable to those described above. Conclusions: Sotalol led to inadequate kinetics of rate adaptation of the Q-aT interval indicated by a high amplitude of Q-aT interval change, especially within the first beat after abrupt change in the pacing rate. MgSO4 abolished this effect of sotalol. These findings suggest that MgSO4 could reduce sotalol-induced inadequate kinetics of rate adaptation and therefore also dispersion of repolarization, which may result in a reduction of sotalol- induced ventricular arrhythmias.
KEYWORDS Use dependence; Repolarization; QT interval; Sotalol; Magnesium; Guinea-pig, heart
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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At present class III antiarrhythmic agents are becoming increasingly popular for treatment of serious tachycardias [1]. Class III antiarrhythmic drugs are defined as antiarrhythmic drugs that act primarily by prolonging the action potential [2]. One agent in this class is sotalol, a beta-blocker with class III properties. It is believed that this drug acts primarily by blocking the outward delayed rectifier current, thereby prolonging the action potential and the effective refractory period [3–6]. The prolongation of the refractory period is the desired antiarrhythmic goal for the prevention of re-entrant tachycardias.
The effects of sotalol on the repolarization period depends on the heart rate. The higher the rate, the lower the effect of sotalol on the repolarization period will be [7]. This effect may decrease the antiarrhythmic activity of sotalol. Furthermore, in a recent clinical trial it was shown that the dextroenantiomer of sotalol increases mortality in high-risk patients after myocardial infarction [8]. This increase in mortality was presumed to be due primarily to arrhythmias. Therefore, it is possible to conclude that the effect on the repolarization period alone may be arrhythmogenic. Because of this fact as well as the fact that sotalol exerts a reverse use-dependent effect on the repolarization period, it would seem of interest to look at rate-adaptive phenomena of the repolarization period during heart rate changes in the presence of sotalol.
MgSO4 has also been used for the treatment of ventricular arrhythmias and torsades de pointes [9]. However, the mechanism of action of MgSO4 is not understood. Especially in the case of torsades de pointes, unlike isoproterenol infusion and cardiac pacing, MgSO4 prevents the recurrence of torsades de pointes without shortening the QT interval [9].
To ascertain the possibility of inadequate rate adaptation of the repolarization period in the presence of sotalol, it is necessary to know about beat-by-beat changes of the repolarization period during abrupt heart rate changes.
We therefore investigated the beat-by-beat changes induced by sotalol in QT duration during abruptly changing heart rate in isolated guinea-pig hearts. Furthermore, the influence of increased concentrations of magnesium on the rate adaptation of the QT interval in the presence of sotalol was studied.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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2.1 Animals
Thirty-two white guinea-pigs of either sex, weighing 200–300 g, fed ad libitum, were divided into 4 groups: control group (n = 4), magnesium group (n = 8), sotalol group (n = 8), and sotalol and magnesium group (n = 12). Complete results were obtained from 26 of 32 preparations studied.
2.2 Experimental protocol
Guinea-pigs were injected intraperitoneally with 250 IU of heparin 1 h before being killed by dislocation of the neck. The chest was quickly opened, the heart removed and attached to a modified non-recirculating Langendorff perfusion system (Anton Paar, Graz, Austria). All procedures met the guidelines set by the Committee on Animal Care at our medical center. Tyrode's solution, satured with a mixture of oxygen (95%) and carbon dioxide (5%) and warmed to 36°C, was used as perfusate (in mM: NaCl 132.1, KCl 3.7, CaCl2 2.5, MgCl2 1.15, NaHCO3 24.0, NaH2PO4 0.42, D-glucose 5.6). Immediately after the heart had been attached to the Langendorff perfusion system, electrocardiographic (ECG) recordings were taken from the epicardial surface. The perfusion rate was progressively increased until it reached 8 ml/min or a perfusion pressure of 60 cmH2O so that atrioventricular conduction, a sensitive parameter for acute ischaemia in this preparation, was shorter than 65 ms and the spontaneous sinus rate was about 200 beats/min. Each heart was allowed to equilibrate for 30 min. If rhythm irregularities (third-degree AV block, ventricular fibrillation) occurred during the equilibration period, the heart was discarded.
Two FeCl3-chloridized silver wire electrodes (wire 0.3 mm, 1.5 mm electrode tip) were placed on the epicardial surface of the heart free to move with the contractions. Both electrodes were positioned in the AV-valve plane, anteriorly near to the origin of the interventricular artery and posteriorly between the two auricles, respectively. The unfiltered signals were amplified by a factor of 100 with an instrumentation amplifier (Anton Paar, Graz, Austria) with AC input (fc=0.72 Hz). His-bundle activity was visible in the bipolarly recorded ECG signals which were monitored on a digital storage oscilloscope and stored on a tape recorder with sampling at 5 kHz. Details of this high-resolution ECG recording technique are described in earlier publications [10, 11]. The ECG signals were further digitized by an analog-to-digital converter (TL-125, Axon Instruments, USA) and monitored and stored on a personal computer (486/50 MHz) for further analysis.
2.3 Parameters measured
After the equilibration period the right atrium with the sinus node was crushed and the heart paced at the right ventricular apex at a pacing cycle length of 220 ms. In 8 experiments the effect of increasing concentrations of sotalol on the QT interval during constant pacing at a pacing cycle length of 220 ms was studied. Each heart served as its own control. Complete data were collected in 6 experiments because of rhythm irregularities (intermittent third-degree AV block) in two experiments at a concentration of 10 µM sotalol.
In a further group of 8 experiments the effect of increasing concentrations of MgSO4 on the QT interval during constant pacing at a cycle length of 220 ms and on the kinetics of rate adaptation of the Q-aT interval was studied. Each heart served as its own control. Only in 6 experiments was it possible to get the complete data during abrupt changing of the heart rate. In two experiments it was not possible to get the complete data because the computer was not able to detect the apex of the T-wave.
Furthermore, in 12 experiments the effects of 10 µM sotalol alone and after the addition of 2.3 and 3.4 mM MgSO4 on the QT interval during constant pacing at a pacing cycle length of 220 ms and the kinetics of rate adaptation of the Q-aT interval during abrupt changing of the pacing rate was studied. Each heart served as its own control. Because of rhythm irregularities only in 11 experiments was it possible to get complete data about the effects on the QT interval. In 4 experiments it was not possible for the computer to detect clearly the apex of the T-wave.
All the measurements were performed 20 min after the addition of each drug concentration.
In a control group of 4 experiments different methods of measurement of the repolarization period were compared.
2.4 Measurement of the QT interval
To evaluate whether automated measurement of the QT interval is as good as manual measurement, 3 different methods of measurement were compared. First the QT interval was measured from the stimulus at the beginning of the ventricular complex to the end of the repolarization period (T-wave) by hand. In 4 experiments (control group), after abrupt shortening of the pacing cycle length from 220 to 180 ms, 250 consecutive beats were measured. Afterwards the QT interval was measured from the stimulus to the apex of the T-wave by hand (Q-aT). With a computer program that was able to detect the apex of the T-wave automatically, the Q-aT interval was again measured automatically from the beginning of the stimulus to the apex of the T-wave (Fig. 1). The algorithm used to detect the apex of the T-wave differentiated the segment after the ventricular complex. The point where the first derivative (d amplitude/d time) changed from positive to negative was defined as the apex of the T-wave.
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Linear regression analysis compared the automated measurement of the Q-aT interval (stimulus to the apex of the T-wave) made by the computer and that made by hand. A further linear regression analysis was performed to compare the automated measurement of the QT interval from the stimulus at the beginning of the ventricular complex to the apex of the T-wave (Q-aT) and the QT interval measurement made by hand from the stimulus to the end of the T-wave.
2.5 Pacing protocol
The time constants of the Q-aT length changes (Q-aT interval was automatically measured by a computer from the stimulus at the beginning of the ventricular complex to the apex of the T-wave) were estimated after an abrupt increase (pacing cycle length: 220 to 180 ms) and a subsequent decrease (pacing cycle length: 180 to 220 ms) of the pacing rate in the presence of 10 µM sotalol alone and in combination with elevated (2.3 and 3.4 mM) MgSO4 concentrations. The pacing cycle length of 180 ms was the shortest cycle length at which a clear measurement of the Q-aT interval was possible. If the pacing cycle length was further shortened, Q-aT measurement was no longer possible because, with the prolongation of the Q-aT interval by the added drugs, the end of the T-wave was interrupted by the following ventricular complex. The interval from the stimulus to the beginning of the ventricular complex was not affected significantly by any of the substances used nor by changes in the pacing cycle length. Twenty min after addition of each drug or drug combination the Q-aT interval was measured at a pacing cycle length of 220 ms. After 2 min of pacing at an intensity of twice the late diastolic threshold, the pacing cycle length was abruptly shortened from 220 to 180 ms, and kept at this new rate for another 2 min. Afterwards the pacing cycle length was abruptly increased from 180 to 220 ms for a further 2 min. The Q-aT interval was measured continuously, beat to beat, throughout the experiment (Fig. 2).
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A non-linear regression analysis (Sigma Plot software package) was performed [12]:
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on is a time constant expressed as a number of beats. off was evaluated by the following equation: |
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2.6 Expression and statistical analysis of the results
All values are expressed as means±standard error of the mean (s.e.m.). The data were compared using a Wilcoxon test after a test of homogeneity of variance. Repeated-measures ANOVA followed by Bonferroni's method were used to compare the differences of time constants and Q-aT intervals in response to different concentrations of MgSO4 using a personal computer (Statgraphics, version 6.0). A value of P<0.05 was considered to be significant.
2.7 Drugs used
(d,l)-Sotalol (Sigma, Germany) dissolved in Tyrodeés solution was prepared before each experiment. The measurements were performed after a perfusion period of 20 min. Pilot experiments (n = 3, data not presented in this paper) had shown that 20 min of perfusion with sotalol are necessary to achieve an electrophysiological steady state. Control measurements were made in the presence of Tyrodeés solution. Sotalol (10 µM) corresponds to a high therapeutic concentration (with regard to plasma protein binding) [13]. At this concentration of sotalol, rate-dependent changes of the Q-aT interval were clearly measurable with our computer system.
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3 Results |
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3.1 Changes in QT interval
The QT interval was significantly prolonged by 10 µM sotalol. Concentrations of 1 and 3 µM sotalol did not affect the repolarization period. MgSO4 up to a concentration of 3.4 mM also did not affect the repolarization period. When 10 µM sotalol was combined with a concentration of 3.4 mM MgSO4, the QT interval was significantly (P<0.05) further prolonged as compared to sotalol (10 µM) alone (Table 1).
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3.2 Different methods of QT measurement
If the QT interval, after abrupt change in the heart rate, was measured from the beginning of the stimulus at the beginning of the ventricular complex to the end of the T-wave by hand, the data were very inhomogeneous (Fig. 3). This was due to difficulty in defining the end of the T-wave (Fig. 1). There was no difference if the Q-aT interval, measured from the stimulus at the beginning of the ventricular complex to the apex of the T-wave, was estimated by hand or automatically by computer. There was a significant and high correlation between these two methods of measurement (Fig. 4). Therefore, we measured the Q-aT interval from the stimulus at the beginning of the ventricular complex to the apex of the T-wave automatically. There was a poor but significant correlation between the measurement of the QT interval from the stimulus to the apex (Q-aT) or end of the T-wave, indicating that the segment from the apex to the end of the T-wave does not change during rate adaptation of the T-wave (Fig. 5).
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3.3 Rate-dependent effect of MgSO4 on the Q-aT interval
In control experiments abrupt changes in heart rate caused by a shortening and subsequent prolongation of the pacing cycle length from 220 to 180 ms and back to 220 ms produced rate-dependent changes in the Q-aT interval. The Q-aT interval decreased progressively as an exponential function of the beat number after abrupt shortening of the pacing cycle length and increased to baseline values after the pacing cycle length had returned to 220 ms (Fig. 2). An increase in the concentration of MgSO4 in the perfusate up to a concentration of 3.4 mM did not affect the magnitude of Q-aT changes or the time constant characterizing the kinetics of changes of the Q-aT interval during abrupt change in the pacing cycle length (Table 2). The changes in the Q-aT interval of the first beat after abrupt change in the pacing cycle length were not affected by MgSO4 (Fig. 6).
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3.4 Rate-dependent effect of sotalol alone and in combination with MgSO4 on the Q-aT interval
The Q-aT interval also decreased progressively as an exponential function of the beat number in the presence of sotalol after abrupt shortening of the pacing cycle length. The magnitude of shortening was significantly higher in the presence of sotalol alone, whereas it was similar to control when MgSO4 was added to the perfusate. The time constant characterizing the kinetics of adaptation of the Q-aT interval to the changed pacing cycle length was shorter in the presence of sotalol than under control conditions. This effect on the time constant was also abolished after the addition of MgSO4 (Table 3). Sotalol led to a significant increase in the changes of the Q-aT interval of the first beat after abrupt change in the pacing cycle length. This effect was also abolished after the addition of MgSO4 (Fig. 7Fig. 8). If the changes in the Q-aT interval of the first beat after abruptly changing the pacing rate were not included in the non-linear regression analysis, no significant differences between the time constants under control conditions, sotalol alone and in the presence of the combination of sotalol with MgSO4 could be observed (data not shown).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The results of this study show that the kinetics of rate adaptation of the repolarization period is inadequate (i.e., that the prolongation or shortening of the QT interval during abrupt increase or decrease of the pacing rate is higher and faster) in the presence of sotalol compared to control. This effect of sotalol could be abolished by the addition of magnesium.
4.1 QT measurement
Previous reports have shown that the heart rate dependency of the QT interval is mainly concentrated in the interval as far as the apex of the T-wave, and that the portion from the T-wave apex to the end of the T-wave is independent of heart rate [14, 15]. Our findings fit well with these results. However, the problem in our experiments was that it was hard to define the end of the T-wave. The result was very inhomogeneous data and therefore a poor correlation between the QT interval measured from the beginning of the ventricular complex to the apex (Q-aT) and that measured to the end of the T-wave. That the first portion of the QT interval is dependent on heart rate was also shown in the presence of a prolonged QT interval in patients with long QT syndrome [16]. For this reason and because measurement from the beginning of the ventricular complex to the apex of the T-wave could be made very accurately, we measured the QT interval this way (Q-aT interval).
4.2 Sotalol-dependent effect on the rate adaptation of the Q-aT interval
Sotalol is known to block the rapid component of the delayed rectifier potassium current (IKr) [17]. Furthermore, it is well known that sotalol exhibits reverse use-dependent effects, meaning that during normal heart rate the action potential duration is prolonged but the magnitude of prolongation declines as heart rate is increased [7]. This fact explains why after an abrupt increase in the pacing rate the magnitude of reduction of the Q-aT interval was higher in the presence of sotalol than in controls. Within the first beat after an abrupt change in the pacing rate, the difference in the magnitude of the Q-aT interval changes was highest in the presence of sotalol. For the following beats the magnitude of Q-aT changes tended to be decreased from beat to beat until a steady state was reached (Fig. 8). The reason for this may be the physiological adaptation of the action potential duration after change in the heart rate, which may also influence the binding of sotalol to the channel. Sotalol binds mainly during the resting state of the delayed outward rectifier and therefore the action potential prolongation declines by abruptly increasing heart rate (because the time period of the resting state of the delayed outward rectifier is shortened) [7, 18]. However, when the heart rate is increased, physiologically the action potential will shorten beat-by-beat and therefore the time period of the resting state of the delayed outward rectifier will increase. This effect will lead to a beat-by-beat increase in binding of sotalol to the IK channel which may outweigh a part of the loss of binding induced by increasing the heart rate. Therefore, it is possible to conclude that the reverse use-dependent effect of a class III antiarrhythmic drug is influenced by the duration of tachycardia.
4.3 Magnesium-dependent effect on the rate adaptation of the Q-aT interval
Magnesium itself does not influence the rate-dependent adaptation of the repolarization period. However, magnesium was able to abolish the inadequate rate adaptation of the repolarization period in the presence of sotalol. Magnesium has been shown to inhibit both L- and T-type channel currents. It is thought that magnesium enters the open channels and competes with Ca2+ permeation [19, 20]. The inhibitory effects are dose-dependent and at low concentrations magnesium inhibition of the T-type Ca2+ current exceeds that of L-type Ca2+ current [21]. One explanation for the effects observed in our study may be that an increased influx of Ca2+ during prolongation of the repolarization period by sotalol will be antagonized by magnesium. The increased Ca2+ influx in the cell in the presence of sotalol alone will activate Ca2+-activated K+ channels [22]. Their opening would additionally contribute to the rapid and marked shortening of the repolarization period during abrupt increase in the heart rate in the presence of sotalol.
On the other hand, magnesium is a co-factor of sodium–potassium ATPase activity. By facilitating the influx of potassium into the cells it stabilizes membrane potential, correcting the inadequate rate-dependent repolarization process [13].
4.4 Limitations
The major limitation of this study is that the experiments were performed in isolated hearts and thus the influence of the autonomic nervous system on the effects of the drugs used could not be evaluated. In vivo the sympathetic tone itself alters the repolarization properties. Furthermore, the sympathetic tone in vivo is additionally influenced by magnesium and the beta receptor antagonistic effect of sotalol. Therfeore, extrapolation of the findings of our study to the clinical setting should be drawn with caution.
4.5 Implications
In the presence of sotalol the amplitude of the changes in the QT interval after abruptly increasing or decreasing the heart rate was higher than under control conditions or in the presence of the combination of magnesium and sotalol, indicating inadequate kinetics of rate adaptation of the QT interval which may cause an increased dispersion of repolarization [23, 24]. This phenomenon may be a further explanation for the arrhythmogenic effect of the dextroenantiomer of sotalol observed in a recent clinical trial [8]. This phenomenon of inadequate kinetics of rate adaptation of the QT interval in the presence of sotalol was abolished by magnesium.
In conclusion, sotalol leads to inadequate kinetics of rate adaptation of the repolarization period, indicated by a high amplitude of Q-aT interval changes, especially within the first beat after an abrupt change in the pacing rate. This effect of sotalol is abolished by high concentrations of magnesium. Therefore, combination of sotalol with elevated concentrations of magnesium will protect the heart against inadequate kinetics of rate adaptation in the repolarization period and maybe therefore also against ventricular arrhythmias.
Time for primary review 22 days.
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Acknowledgements |
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This work was supported by Grant No. P10239 [GenBank] from the Austrian Research Foundation and Grant No. 5913 from the Österreichische Nationalbank. The authors want to thank Peter Labak for generating the computer programs.
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