Relative Role of Alkalosis and Sodium Ions in Reversal of Class I Antiarrhythmic Drug–Induced Sodium Channel Blockade by Sodium Bicarbonate
Background Hypertonic sodium salts are used to treat sodium channel–blocking drug cardiotoxicity. The relative roles of alkalinization and increased sodium concentration ([Na+]o) for various drugs are incompletely known.
Methods and Results The effects of four class I drugs on action potential characteristics of canine Purkinje fibers at equi-effective concentrations (disopyramide 30 μmol/L, mexiletine 80 μmol/L, flecainide 7 μmol/L, imipramine 5 μmol/L) were studied in the presence of normal Tyrode solution and one altered solution (increased [Na+]o, increased bicarbonate concentration, or both) in each experiment. Combined increases in sodium and bicarbonate concentration significantly reduced the depressant effects of flecainide, imipramine, and mexiletine on phase 0 upstroke (Vmax) but did not alter the effects of disopyramide. The effects of sodium bicarbonate were entirely due to alkalinization in the case of imipramine, but both alkalinization and increased [Na+]o contributed to the interaction with flecainide and mexiletine. The reversal of Vmax depression by increased [Na+]o and pH was due in part to hyperpolarization. In addition, alkalosis directly reversed the hyperpolarizing shift in Vmax inactivation caused by flecainide and imipramine without altering the shift caused by disopyramide and mexiletine.
Conclusions Increases in sodium bicarbonate concentration reverse the effects of class I antiarrhythmic drugs to a varying extent, with drug-specific contributions of the sodium and bicarbonate moiety. The molecular basis for this drug specificity remains to be elucidated, but it has important potential implications for the use of hypertonic sodium salts to treat cardiotoxicity caused by sodium channel–blocking drugs.
Hypertonic sodium salts, in particular sodium bicarbonate and sodium lactate, have long been known to counteract cardiotoxic effects of class I antiarrhythmic drugs.1 2 3 Initially used to reverse adverse effects of quinidine and procainamide, they have been found to be useful in treating cardiotoxicity caused by a wide range of sodium channel–blocking drugs including tricyclic antidepressants4 5 6 7 and class Ic antiarrhythmic agents.8 9 10 11
Prudhommeaux et al12 provided the first evidence that alkalinization is responsible for the beneficial actions of sodium bicarbonate against imipramine toxicity. Conflicting results have been presented regarding the relative importance of pH change and sodium loading in the reversal of sodium channel blocker cardiotoxicity by sodium salts. In the case of tricyclic antidepressants, results have been presented suggesting a primary role for pH change,12 13 14 a primary role for sodium loading,15 and a contribution of both.16 Studies of O-desmethyl-encainide toxicity suggested that only the sodium moiety contributed to the reversal caused by hypertonic sodium bicarbonate administration.17
The present study was designed to test the hypothesis that various sodium channel blockers in clinical use respond to the moieties of sodium bicarbonate in drug-specific ways, ie, that increases in extracellular sodium concentration ([Na+]o) will antagonize the sodium channel–blocking actions of some agents, that increases in extracellular pH (pHo) will antagonize the actions of other agents, and that the actions of some compounds will respond to changes in both [Na+]o and pHo. To eliminate as much as possible interpreparation variability in action potential parameters and drug response, we exposed each preparation under continuous stable impalement of a single cell to at least four conditions: (1) control (“normal”) superfusate, (2) a superfusate with increased [Na+]o, pHo, or both, (3) and (4), the same solutions as in (1) and (2), but containing a sodium channel blocker at a concentration causing ≈50% reduction in maximum phase 0 upstroke velocity (Vmax) in control superfusate. Four drugs were chosen for study: three sodium channel–blocking antiarrhythmic agents (mexiletine, rapid kinetics, class 1a of the Singh-Vaughan Williams classification; disopyramide, intermediate kinetics, class 1b; flecainide, slow kinetics, class 1c) and a tricyclic antidepressant (imipramine, intermediate kinetics). Data were obtained under physiological conditions of temperature and ion concentrations with the use of the standard microelectrode technique, with Vmax as an indicator of net phase 0 inward current.
Mongrel dogs of either sex (12 to 25 kg) were anesthetized with sodium pentobarbital (30 mg/kg IV). The hearts were rapidly removed through a lateral thoracotomy and placed into chilled, oxygenated, standard Tyrode solution. All usable false tendons from both ventricles were removed along with their muscle attachment. The standard Tyrode solution contained (mmol/L): NaCl 120, NaHCO3 22, KCl 4, MgCl2 0.5, CaCl2 1, NaH2PO4 0.9, dextrose 10; aerated with 95% O2/5% CO2 (pH=7.35 in the bath). Preparations were pinned to the Sylgard-covered floor of a 30-mL Lucite tissue chamber and superfused with normal Tyrode solution, which was identical to standard Tyrode solution except that NaHCO3 was reduced to 20 mmol/L and sucrose (40 mmol/L) was added to allow for the desired changes in Na+ and HCO3− concentrations in altered solutions while maintaining constant osmolarity (see Table 1⇓). The bath temperature was maintained at 37°C by a heating element and proportional power supply. All preparations were stimulated at 2 Hz for 1 hour in the presence of standard Tyrode solution to allow for equilibration before study.
Glass microelectrodes filled with 3 mol/L KCl and with tip resistances of 8 to 20 MΩ were coupled by a silver–silver chloride junction to a high-input impedance amplifier (WPI KS-700, World Precision Instruments). Amplified waveforms were digitized (Tecmar Labmaster A/D board), and standard action potential characteristics were analyzed on-line with an IBM PC according to previously described methods.18 An electronic differentiating circuit was calibrated to provide an output of 0.5 V per 100 V/s rate of change in transmembrane potential with output linearly related to rate of voltage rise between 100 and 1000 V/s. A peak memory unit was used to capture maximal output from the differentiator, which was then converted into digital format and analyzed with an IBM personal computer and customized software routines. A bipolar Teflon-coated platinum electrode was used to deliver square-wave pulses (2-ms duration, 1.5 times late-diastolic threshold current) controlled by a programmable stimulator (Bloom Instruments) to stimulate the preparation. The pH was measured with an IL1312 analyzer (Coulter Electronics of Canada), and ionized [Ca2+] was measured with an ion-sensitive electrode (Statprofile 9 Gas Analyzer System, Nova Biomedical).
To isolate the role of sodium and/or pH, the normal solution was modified to contain a high sodium concentration and/or increased pH while maintaining other ionic constituents and osmolarity constant. Sucrose, a metabolically inert substance,19 was added to solutions with a lower ionic content (as shown in Table 1⇑) to keep osmolarity constant among all solutions used. The Na+, HCO3−, and pH of the normal and various test solutions are listed in Table 1⇑, with other constituents being identical to the standard solution mentioned above. The solutions with increased Na+ and/or HCO3− concentration will be referred to as “altered Tyrode solutions.”
Modulation of Drug Actions on Action Potential Parameters by Test Solution
Each cell was studied under both normal and one modified solution under control conditions, and then after the addition of a study drug. The order in which solutions were studied was varied to avoid bias from time-dependent electrophysiological changes. Stable continuous impalement of a single cell throughout each experiment was required. Preliminary experiments were used to establish the concentration of each study drug needed to reduce Vmax at a frequency of 2 Hz by 50% in normal Tyrode solution. Concentrations reported in the literature to reduce Vmax by 30% to 70% were used in initial experiments and then modified as necessary until a concentration was found for each drug that reduced Vmax by ≈50% at 2 Hz. The concentrations defined were then used for all protocols described. The equi-effective concentrations identified were imipramine, 5 μmol/L; disopyramide, 30 μmol/L; mexiletine, 80 μmol/L; and flecainide, 7 μmol/L. Enough time was allowed for steady-state changes after any solution change. Steady-state conditions required 30 minutes after changing Tyrode solution and after the addition of flecainide or mexiletine, 60 minutes after the addition of disopyramide, and 90 minutes after the addition of imipramine. Action potential parameters were determined after 3 minutes of pacing at interstimulus intervals of 300, 400, 500, 800, and 1000 ms under each condition. Qualitatively similar results were obtained at all cycle lengths, and a cycle length of 500 ms was selected as in previous work20 for primary analyses. The following parameters were monitored: MAP (membrane potential at the onset of phase 0), AMP, APD50 and APD95, and Vmax. Percent reversal of drug effect on Vmax by an altered Tyrode solution was calculated on the basis of the reduction of drug effect caused by the solution divided by the drug effect in normal Tyrode solution, times 100%.
Modulation by Alkalinization of the Vmax Inactivation Curve
Alkalinization caused a 4- to 5-mV hyperpolarization of the MAP (Table 2⇓, A). To determine whether changes in pH have any direct effect on the voltage dependence of inactivation of Vmax, we performed experiments in which Vmax was determined as a function of MAP by increasing extracellular K+ concentration ([K+o]) from 2.7 to 10 mmol/L and then returning to 2.7 mmol/L [K+o]. Data were obtained in each cell under normal and high pH conditions. Some cells for which impalement was particularly stable were studied at both pH values in the absence and then the presence of imipramine, flecainide, mexiletine, or disopyramide, while in other cells stable impalement was maintained under both pH values and all [K+o] conditions in either the absence or presence of drug, but not both. Alkalinization was found to cause a slight but significant decrease in ionized Ca2+ concentration, from 0.88±0.08 mmol/L at pH 7.3 to 0.81±0.1 mmol/L at pH 7.6 (P<.001). To evaluate the extent to which effects of alkalinization may have been due to changes in ionized [Ca2+], we performed experiments in which the voltage dependence of Vmax was determined at pH 7.3 and 7.6, but with total [Ca2+] in the alkaline Tyrode solution increased by 10% to ensure that ionized [Ca2+] was the same at both pH values.
Group data are represented as mean±SD. Student's paired and unpaired t tests were used for single statistical comparisons between groups. Multiple group means were compared by ANOVA with a range test (Scheffe´ test). A value of P<.05 was considered statistically significant.
Effects of Drugs and Altered Tyrode Solutions
Successful experiments were completed in a total of 84 Purkinje fibers from 68 dogs. Table 2⇑ (A) presents changes in action potential characteristics caused by altered Tyrode solutions. Increasing [Na+]o resulted in slight but statistically significant increases in MAP, APD, and Vmax. Increasing pH without altering [Na+]o caused significant hyperpolarization but did not alter APD or Vmax. Combined alkalosis and increased [Na+]o significantly increased MAP, APD50, and Vmax.
All drugs studied significantly reduced MAP, APD50, and Vmax (Table 2⇑, B). Flecainide, mexiletine, and imipramine significantly decreased APD95, whereas disopyramide had the opposite effect, delaying full repolarization.
Modulation of Drug-Induced Electrophysiological Changes by Various Test Solutions
Fig 1⇓ shows typical action potential recordings obtained in one cell at normal and high pH, in the absence and presence of imipramine. In the absence of the drug, alkalinization caused a slight hyperpolarization and increase in Vmax without significantly changing APD95. Imipramine in standard Tyrode solution reduced APD, MAP, and Vmax. In the presence of imipramine, the high pH solution caused a substantial increase in Vmax, along with a slight hyperpolarization and decrease in APD95.
The modulation of drug-induced changes by altered solutions is illustrated in Figs 2⇓ to 5. Fig 2⇓ shows values of Vmax measured under four conditions for each cell and each drug−normal Tyrode solution, altered Tyrode solution (with high pH, high [Na+], or the combination), drug in normal Tyrode solution, and then drug in the same altered solution previously used. The asterisks in the figure indicate a significant interaction (by ANOVA) between drug actions and the solution studied, ie, statistically significant modulation of drug action by the factor modified in the altered Tyrode solution. In the case of imipramine, solutions with increased pH attenuated the actions of the drug on Vmax, but increased [Na+] alone had no effect. For flecainide and mexiletine, changes in [Na+], pH, or both significantly modulated drug action. Effects of disopyramide were not altered by changes in pH or combined changes in pH and [Na+], although increases in [Na+]o alone appeared to produce weak modulation of drug action.
Modulation of drug effects by altered Tyrode solutions are further analyzed in Fig 3⇓. Alkalinization and increased [Na+] reversed the effect of both mexiletine and flecainide by about 15% to 20%, with the combination being more effective than either alone in the case of mexiletine, and significantly more effective than high [Na+] in the case of flecainide. For imipramine, high [Na+] had no effect, while alkalinization and the combination both resulted in about a 35% reduction in drug effect on Vmax, with either being substantially more effective than high [Na+] and neither significantly different from the other. High [Na+] reduced the action of disopyramide by a limited extent (≈10% on average), whereas alkalinization and the combination had no clear effect.
Since Na+ channels can be inactivated by reductions in MAP, particularly in the presence of sodium channel blockers, it is important to consider the potential role of changes in MAP in mediating alterations in Vmax. Fig 4⇓ presents the changes in MAP observed with various solutions in the presence and absence of the drugs studied. As indicated in Table 2⇑, high [Na+] produced a slight but statistically significant hyperpolarization, while alkalosis and the combination produced a more pronounced hyperpolarization. Each of the drugs studied produced a slight but consistent depolarization. As shown in Fig 4⇓, while the above changes were observed consistently, there were no significant interactions between the various test solutions and drug actions.
Many drugs bind preferentially to the inactivated state of the Na+ channel. Changes in APD can therefore mediate alterations in drug action. Fig 5⇓ shows changes in APD95 caused by the various drugs studied in the presence of different solutions. All results shown are at a basic cycle length of 500 ms. For disopyramide, flecainide, and mexiletine, altered solutions showed either no interaction with drug effects on APD or a slight interaction of weak statistical significance. In the absence of a significant interaction, changes in APD were unlikely to have played a role in the ability of increased [Na+] and increased pH to attenuate the effect of flecainide on Vmax or the ability of increased [Na+] to reverse the effect of mexiletine or imipramine on Vmax. On the other hand, increased pH slightly but significantly increased the APD-reducing action of imipramine and mexiletine, and the combination of increased [Na] and pH significantly enhanced the APD-reducing properties of flecainide, imipramine, and mexiletine. By attenuating drug binding to the inactivated state of the Na channel, these effects could have contributed to reducing drug-induced Vmax inhibition under these conditions.
Modulation of Vmax Inactivation Curves
Because increased pH caused substantial hyperpolarization, and class I drugs are known to cause hyperpolarizing shifts in Na channel inactivation, much of the reversal of drug action on Vmax at increased pH may have been due to hyperpolarization alone. We therefore sought to determine the extent to which changes in drug effects caused by alkalosis were due to direct, activation potential–independent interactions. Vmax inactivation curves were obtained by exposing preparations to varying superfusate K+ concentrations. Fig 6⇓ shows examples of such curves obtained at normal and high pH values and in the absence and presence of each drug in a representative preparation.
Under control conditions, alkalosis produces a small but consistent hyperpolarizing shift of the inactivation curve. All the drugs studied caused a hyperpolarizing shift in the inactivation curve. Alkalosis-induced changes in the voltage dependence of inactivation in the presence of drugs varied with the drug studied. In the presence of imipramine, alkalosis partially reversed the drug-induced hyperpolarizing shift, resulting in an alkalosis-induced change opposite in direction to that observed in the absence of the drug. In the presence of flecainide, changes in pH did not change the voltage dependence of inactivation. Alkalosis produced a modest hyperpolarizing shift in the presence of mexiletine and a strong hyperpolarizing shift in the presence of disopyramide.
The inactivation curves were analyzed quantitatively by nonlinear curve-fitting to a Boltzmann distribution, producing the type of curve fits shown in Fig 6⇑ and the mean characterizing constants summarized in Table 3⇓. Under control conditions, alkalosis produced a highly significant, >3-mV shift in inactivation as indicated by the changes in voltage for 50% inactivation (V50). All drugs studied shifted the inactivation voltage in a hyperpolarizing way, with the most negative V50 in the presence of imipramine and the least negative in the presence of disopyramide. Alkalosis caused a significant depolarizing shift in the presence of imipramine, a significant hyperpolarizing shift in the presence of disopyramide, and no significant changes in the presence of the other drugs.
As mentioned in “Methods,” alkalosis caused a small but significant reduction in ionized [Ca2+]. To determine pH effects in the absence of changes in [Ca2+], we performed five additional experiments in which additional Ca2+ was added to the high pH superfusate to maintain a constant ionized [Ca2+]. Fig 7⇓ shows typical inactivation curves at normal and high pH with a constant ionized [Ca2+]. With the latter variable controlled, alkalosis no longer produced a perceptible shift in inactivation. Mean data for the five experiments are provided in Table 3⇑. When results at high pH in the presence of antiarrhythmic drugs are corrected for changes induced by altered [Ca2+], the depolarizing shift (ie, reversal of drug-induced hyperpolarizing shift) in the presence of imipramine is increased, and a small depolarizing shift appears for flecainide. The changes observed with mexiletine and disopyramide decrease greatly, suggesting that they are largely attributable to pH effects on ionized [Ca2+] when the latter is not corrected.
Hypertonic sodium salts are commonly used to treat cardiotoxic effects of sodium channel–blocking drugs. The major novel finding of the present study is that there is great interdrug variability in the extent of reversal of drug action on Vmax by increased [Na+]o, increased pH, and the combination and in the relative role of the Na+ and HCO3− moieties. The potential mechanisms of reversal appear to be complex and can include changes in diastolic potential, in APD, in ionized [Ca2+], and in the direct interaction between drugs and the sodium channel as reflected in the Vmax inactivation curve.
Comparison With Previous Studies of Modulation of Antiarrhythmic Drug Action by Sodium Salts
Several previous studies have evaluated the effects of sodium salts on Na+ channel–blocking drug action. Sodium lactate reverses the effect of quinidine on Vmax, an action largely attributed to the Na+ moiety.21 Jensen and Katzung22 23 showed that increases in [Na+]o reverse the depressant effects of phenytoin on Vmax and conduction. Kohlhardt24 found that decreases in [Na+]o enhance the actions of a variety of Na+ channel blockers.
Relatively few studies have attempted to separate the respective roles of pH change and the Na+ moiety in the ability of Na salts to reverse Na+ channel–blocking drug cardiotoxicity. In vivo studies have suggested that pH change is the primary factor in NaHCO3 reversal of amitriptyline cardiotoxicity14 and that the Na+ moiety may be of prime importance for O-desmethyl-encainide17 and desipramine.15 In vitro studies pointed toward a role for both the Na+ moiety and pH change in the interaction15 between [NaHCO3] and amitriptyline on Vmax in canine cardiac Purkinje fibers.16 The present study is the first to compare systematically the response to increased [Na+] alone, increased pH alone, and the combination for a variety of Na+ channel–blocking drugs. Our results indicate important variability among the responses of different drugs to a combination of increased [Na+] and pH, as occurs with NaHCO3 administration, as well as important variability in the respective role of [Na+] and pH.
Potential Underlying Mechanisms
Our data point to a variety of potential mechanisms for the modulation of drug action by changes in [Na+]o and pH. In addition to direct alterations of the drug-receptor interaction, drug effects may be altered by changes in activation potential (Fig 4⇑), in APD (Fig 5⇑), and in ionized Ca2+ concentration (Table 3⇑).
Changes in pH have complex effects on the direct interactions between sodium channels and blocking drugs. Acidosis slows the unbinding of a variety of drugs from the Na+ channel,25 26 27 but complex changes in state-dependent block occur and result in no significant change in net blocking action of lidocaine as a result of acidosis when holding potential is controlled.28 External alkalosis enhances a rapid component of block by lidocaine, disopyramide, and mexiletine,29 30 an effect interpreted as due to enhanced interaction of uncharged drug molecules with the inactivated30 or activated29 state, respectively. On the other hand, block by imipramine is reduced by alkalosis, apparently as a result of more ready dissociation of uncharged drug from the various states of the channel. (F. Bou-Abboud, MD; V. Nesterenko, PhD; S. Nattel, MD; unpublished data, 1996). The nature of the drug-pH interaction may also depend on the relative magnitude of intracellular and extracellular pH change, which may affect the blocking actions of various drugs in qualitatively different ways.32
Electrostatic repulsion has been postulated to explain the reduction in Na+ channel drug-blocking action when [Na+]o is increased,33 and changes in the magnitude of INa as a result of altered [Na+]o have been thought to be important.24 The results of studies of cocaine block of batrachotoxin-altered Na+ channels in lipid bilayers favor an electrostatic “knock-off” type of mechanism for the interaction between Na+ and blocking drugs, with a straightforward competitive interaction less likely.34 Our laboratory has shown that [Na+]o modulates the interaction between flecainide and its Na+ channel receptor, even under conditions that prevent Na+ flux across the channel.35
Potential Significance of Our Findings
Sodium salts have been used widely to treat cardiotoxic effects of a variety of Na+ channel–blocking drugs.1 4 8 9 Our results indicate that drugs may differ widely in the response to Na+ salts and that caution is therefore appropriate in their choice and use. For example, the effects of disopyramide were not altered by NaHCO3, suggesting that the latter might not be effective in treating disopyramide cardiotoxicity. Since fluid, acid-base, and electrolyte abnormalities can result from the administration of hypertonic NaHCO3 solutions, use of the latter might be counterproductive in a patient intoxicated with disopyramide. On the other hand, NaHCO3 strongly inhibited the actions of imipramine, with actions fully attributable to pH change. Thus, hyperventilation might be a reasonable and rapidly reversible alternative to hypertonic Na+ salts in patients with imipramine overdose on a mechanical ventilator.
Our results point to the complexity of the drug-pH and drug-[Na+]o interaction. Net effects will depend on direct interactions between pH, [Na+]o, and drugs at the level of the Na+ channel receptor but also potentially on indirect changes caused by alterations in ionized [Ca2+], resting potential, and APD.
We used standard microelectrode techniques, with Vmax as an indicator of maximum phase 0 INa. The relationship between Vmax and INa is nonlinear,36 37 although the discrepancy decreases as temperature approaches the physiological range.37 On the other hand, Vmax is likely to be related linearly to net phase 0 inward current.38 Standard microelectrode techniques allow for the use of highly physiological conditions, which do not permit accurate voltage clamp of INa with present technology. Reduced temperature, almost always needed for studies of whole-cell INa, can cause qualitative and quantitative changes in INa-blocking drug action,39 as can the reduced [Na+]o that is usually necessary. Standard microelectrode techniques also allow for the evaluation of important physiological variables, such as resting potential and APD, which are not monitored during voltage clamp studies. Finally, multicellular preparations in general (and Vmax in particular) are much more stable over time than single cells and their INa. This allows for multiple interventions to be studied under stable conditions in the same cell, resulting in more controlled and powerful statistical comparisons.
These experiments were conducted in canine cardiac Purkinje fibers. Extrapolation to changes in human ventricular muscle, particularly in the presence of cardiac disease, requires caution. It is difficult to relate directly the drug concentrations we used to a corresponding clinical concentration because of important potential interspecies differences in sensitivity to antiarrhythmic drugs.40 There is theoretical and experimental evidence that in vivo changes in QRS duration are proportional to the inverse of the square root of changes in Vmax.41 On the basis of this relation, concentrations that cause a 50% decrease in Vmax (as used in the present study) should correspond to those producing a 41% prolongation in QRS duration in vivo, of the same order as seen in many patients with mild to moderate toxicity due to sodium channel–blocking drugs.5 6 7 8 9 10 11 The concentrations that we studied were in the clinically toxic but relevant range for flecainide (concentration studied, 7 μmol/L; therapeutic range, 0.5 to 2.4 μmol/L),42 disopyramide (concentration studied, 30 μmol/L; therapeutic range, 8.8 to 23.6 μmol/L),42 and imipramine (concentration studied, 5 μmol/L; toxic tricyclic antidepressant concentrations >3.6 μmol/L).43 For mexiletine, the concentration we studied (80 μmol/L) was well in excess of the therapeutic range (4.5 to 11 μmol/L),42 but clinical doses of mexiletine are limited by noncardiovascular toxicity, and our choice of concentration was justified on the pharmacological basis of selecting equi-effective sodium channel–blocking concentrations.
We have shown that the actions of a variety of class I drugs are modulated in different ways by changing extracellular [Na+], pH, and the combination. Caution is warranted when using hypertonic NaHCO3 to treat class I cardiotoxicity, since such therapy may not be beneficial for all drugs. The relative role of the Na+ moiety and pH varies among drugs, and for some agents more specific therapy may be provided by altering one or the other rather than both. Finally, the mechanisms by which [Na+] and pH can alter class I cardiotoxicity are potentially complex and varied.
Selected Abbreviations and Acronyms
|AMP||=||action potential amplitude|
|APD||=||action potential duration|
|APD50||=||APD at 50% repolarization|
|APD95||=||APD at 95% repolarization|
|MAP||=||membrane activation potential|
|Vmax||=||maximal rate of voltage rise during phase 0 of action potential|
This study was supported by grants from the Medical Research Council of Canada, the Quebec Heart Foundation, and the Fonds de Recherche de l'Institut de Cardiologie de Montre´al. The authors thank Emma De Blasio for technical support, Dr Rene´ Cardinal for useful discussion and suggestions, and Carolyn Gillis for typing the manuscript.
- Received November 13, 1995.
- Revision received April 17, 1996.
- Accepted April 23, 1996.
- Copyright © 1996 by American Heart Association
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