Author + information
- Received March 20, 1996
- Revision received February 19, 1997
- Accepted February 26, 1997
- Published online June 1, 1997.
- Tsunehiro Kondo, MDA,
- Michiyasu Yamaki, MDA,* (, )
- Isao Kubota, MDA,
- Hidetada Tachibana, MDA and
- Hitonobu Tomoike, MDA
- ↵*Dr. Michiyasu Yamaki, First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-23, Japan.
Objectives. The purpose of this study was to determine the effects of sodium channel blockade on anisotropic excitation propagation in the intact canine left ventricle.
Background. Anisotropic ventricular conduction—electric conductivity dependent on the myocardial fiber direction—is one of the important mechanisms of ventricular arrhythmia. However, the effects of sodium channel blockade, especially the differential effect of a subclass of this agent, on the anisotropic properties remain unknown.
Methods. In 28 anesthetized, open chest dogs, a small cannula was inserted into the left anterior descending coronary artery. Saline (control), disopyramide, lidocaine or flecainide was infused selectively into the cannula. An array of 64 epicardial electrodes was placed on the anterior surface of the ventricle. Activation time (AT) was measured along the longitudinal (L) and transverse (T) directions.
Results. High dose flecainide (100 μg/kg body weight per min) delayed the AT along the L direction markedly (mean [±SE] 227 ± 38%, p < 0.02) and mildly (121 ± 10%, p < 0.02) along the T direction in regular beats (p < 0.007, L vs. T). Lidocaine and disopyramide did not show direction-dependent prolongation of the AT on regular beats. When examined on premature beats, AT was delayed, depending on the coupling interval and the fiber direction when saline, flecainide or lidocaine was infused. The conduction blocks along the L direction were observed in three of seven dogs on regular beats after flecainide and ventricular fibrillation ensued in two of these three dogs.
Conclusions. A peculiar slowing of L conduction by flecainide may relate to the character of proarrhythmia.
(J Am Coll Cardiol 1997;29:1639–44)
Excitation conduction on the myocardium is dependent on myocardial fiber direction ([1–5]), which is known as “anisotropy.” Anisotropic properties of cardiac muscle cause block of an electric excitation owing to a reduced safety factor for conduction along with longitudinal (L) fiber orientation, although conduction velocity is faster ([2, 3]). Such conduction block contributes to the induction of reentrant activity as a component of the reentry circuit ([2, 3]).
Sodium channel blockade suppresses electric conductivity and is used to block the reentrant circuit as a class I antiarrhythmic agent. The class I agent was traditionally subclassified into Ia, Ib and Ic, mainly depending on the action potential duration (APD) (). Recently, heterogeneity of class I agents was emphasized on use dependency and state dependency (activation or inactivation) on sodium blocking action ([7–9]). Such heterogeneity in sodium channel blockade possibly affects anisotropic electric propagation. Nevertheless, the effect of each subclass of sodium channel blockers on anisotropism remains unknown. The purpose of this study was to evaluate the directional differences in ventricular conduction caused by sodium channel blockade. We examine the effects of disopyramide, lidocaine and flecainide on both L and transverse (T) electric propagation.
1.1 Surgical Preparation.
Twenty-eight adult mongrel dogs were anesthetized with sodium pentobarbital (30 mg/kg intravenously), intubated and ventilated by a respirator with room air supplemented with oxygen (3 to 5 liters/min). The thorax was opened in the fifth intercostal space; the pericardium was opened; and a pericardial cradle was made to support the heart at an appropriate position. The chest cavity was covered with plastic wrap to prevent cooling or dehydration. The body temperature was maintained at 37 to 38°C. An arterial line was inserted into the right femoral artery to continuously monitor the mean arterial pressure. Another polyvinyl catheter was inserted into the left ventricular cavity to measure left ventricular pressure. Lead II of the electrocardiogram as well as blood pressure was recorded simultaneously throughout the study (NEC Sanei, model 2G66, Tokyo, Japan).
A 24-gauge plastic cannula was inserted into the left anterior descending coronary artery (LAD) at the distal site of the second diagonal branch (Fig. 1). Heparin (10,000 IU) was intravenously administered before the LAD cannulation. The cannula was kept open by continuous infusion of saline in 1 ml/min.
1.2 Electrodes for Recording and Pacing.
An array of 64 unipolar electrodes (∼14 × 14 mm) was placed on the anterior surface of the left ventricle (Fig. 1). Each electrode was made of fine silver wires (0.005-in. [0.013-cm] diameter) and was insulated, except at the point of attachment. All recordings were referenced to the Wilson central terminal, and multichannel electrograms were digitized every millisecond using a multichannel data processing system (CD-G015, Chunichi Denshi, Nagoya, Japan), as described in a previous study (). Formalin was injected into the atrioventricular conduction system, according to a previously described method, to interrupt atrioventricular conduction (). Electric stimulation of 2-ms current pulses with twice the voltage of the threshold potential (model 8EN-7203, Nihon Koden, Tokyo, Japan) was applied to a bipolar electrode fixed at the corner of the array.
Activation time (AT) was defined as the time instant of the minimal derivative of the local electric potentials (). Activation time maps with 2-ms of isochronism were constructed for each activation array using the computerized devise, where the time zero was taken at the pacing artifact. The presence of conduction block was defined as a slowing of the conduction velocity <0.05 m/s between adjacent electrode sites. The percent difference of AT was calculated from the beat of the baseline measurement in protocol 1 or from the regular basic beat in protocol 2. The AT on lead A8was used to assess the L conduction, and those on lead H1the T conduction.
1.3 Experimental Protocol.
1.3.1 Protocol 1: Examination on Basal Regular Beats.
Physiologic salt solution (saline; n = 7), disopyramide (low dose: 20 μg/kg body weight per min; high dose: 200 μg/kg per min; n = 7), lidocaine (low dose: 0.12 mg/kg per min; high dose: 0.6 mg/kg per min; n = 7) or flecainide (low dose: 10 μg/kg per min; high dose: 100 μg/kg per min; n = 7) was intracoronarily infused. A lower dose of disopyramide, lidocaine or flecainide was almost 1% of that used intravenously in experimental studies ([12–14]), and a higher dose was 5% to 10%. After the baseline measurement, the low dose infusion was loaded during the first 20 min, and the high dose infusion was continued for the next 20 min. The heart was paced at a basic cycle length of 500 ms. Sixty-four epicardial electrograms were simultaneously recorded every 5 min. When spontaneous ventricular tachyarrhythmias occurred, the electrograms were also recorded.
1.3.2 Protocol 2: Effect of Coupling Interval on Anisotropic Conduction.
After the heart was paced by a basic cycle length of 500 ms for 1 min or longer, a single extrastimulus was applied on the same pacing site. The coupling interval of the extrastimuli was 300, 240, 220, 200, 195, 190 and 185 ms, if applicable, and 64 epicardial electrograms were simultaneously recorded during the stimulation. These procedures are repeated after loading the low dose of disopyramide, lidocaine, flecainide or saline.
1.4 Statistical Analysis.
Data are presented as mean value ± SE. Comparisons of dose-dependent or coupling interval–dependent changes in ATs were made by using analysis of variance for repeated measures and the Wilcoxon signed-rank test. Comparisons of ATs between L and T conduction or among the three types of sodium channel blockers and saline infusion were performed by analysis of variance, followed by the Sheffé test. Differences were considered significant at p < 0.05.
Twenty-eight dogs were studied: seven were given disopyamide, seven lidocaine, seven flecainide and seven saline. No significant changes in arterial pressure, left ventricular systolic pressure and left ventricular end-diastolic pressure were observed before and after each sodium channel blocker or saline infusion (Table 1).
2.1 Conduction Block and Ventricular Fibrillation.
Fig. 2, upper panel, shows isochronal maps of ATs before and after intracoronary infusion of flecainide in low and high doses. Ventricular pacing at a basic cycle length of 500 ms was performed at the site indicated by an asterisk. Propagation of excitation was faster in the L direction than in the T direction. Mean conduction velocity at the basal state was 0.55 ± 0.04 m/s in L conduction and 0.22 ± 0.02 m/s in T conduction (p < 0.01, L vs. T). After flecainide infusion, line density shown in isochronal maps increased mainly along the L axis, which was further exaggerated in a high dose. Slowed conduction area appeared mostly along the L direction, as shown in Fig. 2A. In the case of Fig. 2B, a conduction block was noted along the L direction between rows 6 and 7 after a high dose of flecainide. Such conduction block occurred in three of the 28 dogs. All three events were observed in a high dose of flecainide. The site of conduction block was always along the L direction. The area of conduction block gradually expanded, and ventricular fibrillation (VF) ensued (Fig. 2B, lower panel). In two of these three dogs, VF evolved, although VF did not occur in the other 25 dogs in which the conduction block did not appear.
2.2 Anisotropic Effects of Sodium Channel Blockers in Basal Regular Beats.
The percent changes in ATs after intracoronary infusion of saline or sodium channel blockers were summarized in the L and T directions (Fig. 3). Dogs developing conduction block were excluded from this calculation. The number of excluded dogs was one for 30-min through 40-min measurements and two for the 40-min measurement during flecainide loading. After flecainide infusion, ATs were delayed along the L direction mildly (122 ± 10%, p < 0.02 vs. baseline) by a low dose and remarkably (227 ± 38%, p < 0.02 vs. baseline) by a high dose. In contrast, ATs along the T direction did not change by a low dose but were mildly delayed (121 ± 10%, p < 0.05 vs. baseline) by a high dose. Lidocaine infusion also mildly delayed electric propagation similarly along the L direction (122 ± 12%, p < 0.05 vs. baseline) and T direction (117 ± 8%, p < 0.05 vs. baseline). However, there were no significant differences in the degree of suppression between the L and T directions with lidocaine loading. Disopyramide infusion or saline did not affect ATs in either direction.
Mean conduction velocities after high dose loading were 0.24 ± 0.03 m/s (p < 0.02 vs. baseline) along L and 0.19 ± 0.03 m/s (p < 0.02 vs. baseline) along T with flecainide; 0.45 ± 0.04 m/s (p < 0.05 vs. baseline) along L and 0.19 ± 0.02 m/s (p < 0.05 vs. baseline) along T with lidocaine; and 0.50 ± 0.04 m/s along L and 0.22 ± 0.02 m/s along T with disopyramide.
2.3 Coupling Interval–Dependent Suppression of Anisotropic Conduction.
Effects of coupling intervals on anisotropic conduction were examined on the premature beats (Fig. 4). In the control state (saline infusion), delays in ATs were significant at a coupling interval ≤200 ms in both fiber directions. With flecainide loading, ATs along the L conduction were markedly delayed at a coupling interval ≤195 ms compared with ATs along the L conduction in the control state, as well as at a coupling interval ≤190 ms compared with ATs along the T conduction in flecainide loading. The same tendency was observed on the anisotropic conduction on the premature beats after loading with lidocaine. The differences in ATs between L and T conduction were statistically significant at a coupling interval ≤220 ms. With disopyramide loading, the premature stimuli failed at a coupling interval ≤220 ms because it prolonged the relative refractory period. Conduction suppression was subtle in cases of disopyramide infusion.
3.1 Experimental Design.
The effects of sodium channel blockade on anisotropic conduction remain debated. Several investigators reported a lack of different effects of sodium channel blockade between L and T conduction ([15–17]). It was also suggested that only toxic doses of the class Ic agent could cause such different effects (). Such controversies depend partly on the route of drug administration—intravenous or intracoronary. In the present study, the effects of sodium channel blockade, especially those of each subclass on the anisotropic properties of ventricular conduction, were examined on the epicardial surface of the canine ventricle. Agents were infused selectively into the distal portion of the LAD, and a multiple electrode array was applied to measure regional ATs parallel or perpendicular to the myocardial fiber orientation. The left ventricular epicardial surface is appropriate for the present study because the myocardial fiber orientation is visible and the ventricular myocardium predominates the electric excitation owing to anatomic remoteness from the conduction system.
We used AT as a marker of ventricular conduction. Changes in AT were evaluated by calculating percent changes. This variable permits us to estimate the degree of changes in conduction, even when it includes artifacts such as virtual cathode effects (). In this study, we defined the presence of conduction block as a conduction velocity <0.05 m/s. The reason we used this value is that it is just below the reported minimal conduction velocity ().
3.2 Basal Regular Beats.
In the present study, ventricular conduction was suppressed mainly by flecainide along the direction of L fibers. Its effect was mild (112 ± 10%) in a low dose and remarkable (227 ± 38%) in a high dose. Lidocaine and disopyramide did not show the conspicuous suppression when it was examined on the basal regular beats. It has been reported that conduction parallel to the L fiber direction is fragile, although the conduction velocity is faster ([1, 2]). The conduction disturbance or block, especially along the L direction, ensued after loading sodium channel blockers on the myocardium. The directional difference in conduction is explained by effective membrane capacitance and effective axial resistivity. Spach et al. () demonstrated that the relatively high membrane capacitance and low axial resistivity along the L direction was a producer of fragile conduction of this direction.
It is noteworthy that only flecainide slowed the directional difference on conduction at both high and low doses, whereas the other sodium channel blockers did not show such differences in both doses at regular basic beats. Doses of sodium channel blocker were determined by referencing reported experimental studies of intravenous use in dogs or rabbits. We supposed that these doses might be higher than those in therapeutic use in humans, even in low doses. This result cannot directly extend to clinical use of those agents. However, the present study provided evidence that only flecainide potentially causes a peculiar slowing of L conduction in regular beats.
One possible explanation for this phenomenon is the differences in unbinding from the sodium channel among sodium channel blockers. The recovery time constant of flecainide was reported to be 15.5 s (), and it was classified as a slow kinetic drug. In contrast, that of lidocaine was only 0.23 s (), and it was classified as a fast kinetic drug. Because the cycle length of regular beats was 500 ms, binded lidocaine is removed from the sodium channel by the next beat. Consequently, the sodium channel blocking effect of flecainide would be remarkably greater than that of lidocaine. Another possible explanation is an open-state blocking action of flecainide (). The open time of sodium channels is prolonged more along the L propagation than the T propagation (). Conduction suppression by open-state sodium channel blockade should be more prominent along the L propagation than the T propagation. However, these may not fully explain the effects of disopyramide, which was classified as an intermediate kinetic and open-state blocking drug ([8, 9]). To clarify the mechanisms of anisotropic effects of sodium channel blockers, further examination will be needed.
3.3 Coupling Interval–Dependent Action.
Premature depolarization is characterized by a markedly depressed V̇max(i.e., weak inward current). However, a coupling interval dependency of the effects of sodium channel blockade on the coupling intervals was not fully examined. In the present study, it is hypothesized that the sodium channel blockade suppresses L propagation more prominently than T propagation, because L propagation is already fragile ([1, 2]). When the coupling interval of the premature beats became shorter than 240 ms, ATs were delayed in the saline group and even more delayed after flecainide or lidocaine loading. The conduction parallel to the L fiber orientation was depressed more than that of the T orientation.
The effects of lodocaine on anisotropic conduction became apparent when a coupling interval was short. This action of lidocaine suggests that the use dependency may be a central mechanism. Lidocaine has a short recovery time constant. Therefore, lidocaine slowed conduction anisotropically only when the coupling interval was enough short. In contrast, disopyramide did not show such apparent suppression. This is because prolongation of refractory periods by disopyramide causes a failure of premature stimuli at short coupling intervals.
3.4 New, Unexpected Effect of Flecainide: Spontaneous Induction of VF on Intact Myocardium.
Anisotropic properties in excitation propagation are known as one of the important mechanisms of arrhythmia ([1–3, 5, 22]). The action of sodium channel blockers, as a factor that augments the anisotropic nature, is sometimes proarrhythmic. The present experiment showed first that flecainide itself causes VF in the intact myocardium. The proarrhythmic effects of flecainide has been reported in the subacute phase of infarct (3 to 5 days after ligation) in dogs, in which reentrant ventricular arrhythmia was easily inducible ([15, 16, 23]). Usui et al. () measured the VF threshold by a train stimulus and concluded that flecainide dose dependently decreased the fibrillation threshold in the intact myocardium (). However, no reports have described the induction of spontaneous VF by sodium channel blockers in the intact myocardium. Surprisingly, after flecainide infusion into the coronary artery, VF spontaneously occurred. The fact that block of the L propagation preceded the arrhythmia suggests that the mechanism of this arrhythmia is “anisotropic reentry.” We suppose that this type of agent should be carefully selected for clinical use even if there is no additional abnormal condition, such as ischemia or heart failure.
Flecainide caused a peculiar slowing and block of the L conduction in regular beats of the intact myocardium. This conduction block was related to the spontaneous induction of VF. “Anisotropic reentry” may be one of the important mechanisms of proarrhythmia in sodium channel blockade, especially with flecainide.
☆ This study was supported in part by Grant 07670749 from the Ministry of Education, Science and Culture, Tokyo, Japan and by grants from the Japan Research Foundation for Clinical Pharmacology, Tokyo and the Suzuken Memorial Foundation, Nagoya.
- action potential duration
- activation time
- left anterior descending coronary artery
- ventricular fibrillation
- Received March 20, 1996.
- Revision received February 19, 1997.
- Accepted February 26, 1997.
- The American College of Cardiology
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