Mechanisms of depressed conduction from long-term amiodarone therapy in canine myocardium

SpearJH Levine, EN Moore, AH Kadish, HF Weisman, CW Balke, RF Hanich and JF

canine myocardiumMechanisms of depressed conduction from long-term amiodarone therapy in

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684

Mechanisms of Depressed ConductionFrom Long-term Amiodarone Therapy in

Canine MyocardiumJoseph H. Levine. MD, E. Neil Moore, DVM, PhD, Alan H. Kadish, MD,Harlan F. Weisman, MD, C. William Balke, MD, Robert F. Hanich, MD,

and Joseph F. Spear, PhD

Amiodarone therapy leads to a significant impairment in myocardial conduction, yet it causesonly a modest decrease in the maximum rate of depolarization of the action potential (dV/dT).To determine whether the decrease in dV/dT solely accounts for the impaired myocardialconduction or whether passive membrane properties may also be involved, we studied 21ventricular epicardial tissues from 14 beagles; six dogs received long-term treatment (3-6weeks) of amiodarone orally, and the remaining dogs served as controls. Amiodarone therapywas associated with a decrease in conduction velocity (0.41 ± 0.15 vs. 0.56 ± 0.05 m/sec;p<0.01). There was a trend toward a decrease in dV/dT and a significant decrease in the spaceconstant (0.69 ± 0.27 vs. 1.05 ± 0.25 mm; p = 0.01), of which the latter correlated closely withthe decrease in conduction velocity measured in the amiodarone-treated tissues (r= 0.85,p<0.05). These data indicate that the decrease in myocardial conduction velocity caused byamiodarone is primarily due to effects on overall resistance to passive current flow rather thaneffects on the inward sodium current. (Circulation 1988;78:684-691)

Amiodarone is singularly effective in the treat-ment of malignant ventricular tachyarrhyth-mias. In patients with ventricular tachycar-

dia refractory to other antiarrhythmics, there is a50-80% response rate to amiodarone.'-11The mechanism of amiodarone's antiarrhythmic

action is unknown. Ventricular tachycardia likelyresults from reentrant circuits that rely on criticalinteractions between the conduction characteristicsand refractoriness of the myocardium. Pharmacolog-ical alterations of these interactions effect an anti-arrhythmic (or proarrhythmic) response. Amiodaroneprolongs action potential duration and myocardialrefractoriness. 12-17Recent evidence also indicates that

From The Division of Cardiology, Department of Medicine,The Johns Hopkins Medical Institutions, Baltimore, Maryland;and the Department of Animal Biology, University of Pennsyl-vania, Philadelphia, Pennsylvania.

Supported in part by Grants HL-33593-03 and HL-28393-05from the National Institutes of Health and the W.W. Smith Chari-table Trust. J.H.L. and H.F.W. are the recipients of a ClinicianScientist Research Award of The Johns Hopkins Medical Institu-tions. A.H.K. is the recipient of an NIH First Award (R29 HL-40667-0). R.F.H. is the recipient of a Post-doctoral Fellowship fromthe American Heart Association, Maryland Affiliate.Address for correspondence: Joseph H. Levine, MD, Director

of the Arrhythmia and Pacemaker Center, St. Francis Hospital-Heart Center, 100 Port Washington Blvd., Roslyn, NY 11576.Received January 18, 1988; revision accepted May 19. 1988.

amiodarone binds to sodium channels that are in theinactivated state and, hence, amiodarone may alsoaffect myocardial conduction. 13-15 According torecent work, amiodarone reduces conduction veloc-ity in human myocardium and Purkinje tissue. 18-20Although sodium channel blockade may be an

important determinant of slow conduction inamiodarone-treated tissues, amiodarone may alsoalfect passive membrane properties that, in turn,may contribute to slowed conduction velocity. Alter-ations of passive membrane properties by amioda-rone may be particularly relevant in light of recentdata that suggest amiodarone is accumulated andconcentrated in many tissues, including myocar-dium.21,22 If amiodarone deposits in and aroundmyocardial cells, there may be alterations in overallresistance (intracellular and extracellular) to cur-rent flow and hence to conduction velocity.The purpose of the present experiments was to

demonstrate a depressant effect of amiodarone onconduction velocity in canine ventricular myocar-dium and to document that the decrement in con-duction was due, at least in part, to a decrease in thetissue space constant.

Materials and MethodsExperiments were performed in 21 tissues re-

moved from 14 beagles weighing 8-20 kg. The



Levine et al Depressed Conduction During Amiodarone Therapy 685

animals were anesthetized with intravenous sodiumpentobarbital (30 mg/kg body wt), and their chestswere opened by a left lateral thoracotomy. Thehearts were excised and ventricular epicardial tis-sues 1-3 mm thick, 2-3 cm long, and 2 cm widewere removed so that their long axis was parallel tothe observed superficial fiber orientation. We havepreviously subjected tissues obtained in a similarmanner to histological examination to confirm ourability to obtain parallel fiber orientation over thelength of the tissues.23 Nine tissues were removedfrom six animals that had received amiodarone (400mg/day orally for 2 weeks, followed by 200 mg/day)for a total of 3-6 weeks. Twelve tissues from eightnormal, control animals were removed in the samemanner. The tissues were placed in a 100-ml tissuebath and were superfused with standard oxygenatedTyrode's solution. The tissues were paced at acycle length of 1,000 msec with bipolar stimulatingelectrodes consisting of two Teflon-coated silverwires and were allowed to equilibrate for 30 min-utes. Constant-current rectangular pulses of 2-msecduration and twice diastolic threshold intensity wereused. Our techniques have been described in detailpreviously.23,24 Thin epicardial tissues such as thoseused in these studies can be maintained for up to 5hours without a significant decrement in their elec-trophysiological variables, indicating that perfusionand oxygenation are adequate in the superficial celllayers sampled.Transmembrane action potentials were recorded

from the superficial cell layers with standard 3Mpotassium-filled microelectrodes. The transmem-brane potentials, as well as their electronicallydifferentiated signals (dV/dT), were displayed on anoscilloscope and photographed on 35-mm film.Action potential variables (action potential ampli-tude, resting potential, action potential duration at100% repolarization) were measured by projectingthe 35-mm film onto a GTCO manual digitizer(Rockville, Maryland) interfaced with a Hewlett-Packard 9836 computer (Palo Alto, California). Thefirst 10 mV of the action potential foot was digi-tized, and its time constant was determined from asemilogarithmic plot of voltage and time.Conduction velocity was determined from multi-

ple microelectrode recordings made parallel to fiberorientation. Beginning approximately 2 mm from thestimulating electrode, sequential transmembranerecordings were made approximately every 0.5 mmfor a total of 4-10 mm. Distances between recordingsites were measured with an optical micrometer(resolution, 0.08 mm). The activation time of eachpoint was determined as the time difference betweenthe pacing stimulus artifact and the time ofmaximumrate of depolarization of the action potential recordedwith the roving microelectrode.

Conduction velocity was determined from a plotof activation time and distance, and it was equal tothe slope of the linear regression. These methodsprovided an average conduction velocity between

the multiple points. Because the slope of the regres-sion is used, the value obtained for conductionvelocity is independent of stimulus latency. An rvalue of 0.97 or greater for the regression wasconsidered acceptable and indicated uniform con-duction in the area of interest. In these tissues, anextracellular unipolar electrogram was also recordedto confirm nondiscontinuous conduction.25 Tissuesexhibiting nonuniform conduction (r<0.97 or notchesin the unipolar electrogram) were excluded from theanalyses.Space constants were recorded by a previously

described technique.24,26,27 A silver-silver chlorideextracellular contact electrode catheter was posi-tioned at one end of the tissue so that a monophasicaction potential was recorded, indicating partialaccess to the intracellular space. Subthresholdrectangular-wave pulses (10-30 uA, 80 msec dura-tion) were delivered by a constant current sourcebetween the silver-silver chloride electrode at thecatheter tip and a distant bath ground. Four to 10sequential transmembrane potentials were sampledat distances up to 2 mm from the wall of the contactelectrode catheter. The signals were amplified by adifferential electrometer (World Precision Instru-ments, New Haven, Connecticut) that measuredthe difference between the roving microelectrodeand a reference microelectrode positioned in thebath within 1.0 mm of the recording microelectrode.During space-constant determinations, the tissueswere paced at a cycle length of 1 second, and thecurrent pulses were delivered after the impaled cellhad undergone repolarization after the conductedbeat. The electrotonic potentials were displayed onan oscilloscope, photographed on 35-mm film, andthe amplitude of the potential was measured to thenearest 0.1 mV. The distance of the impalementfrom the contact electrode was determined with anoptical micrometer (resolution, 0.08 mm). The spaceconstant was calculated from a semilogarithmic plotof the steady-state electrotonic potential amplitudeand distance, assuming an infinitely linear cable, andwas defined as the distance at which the potential atthe site of injection (V0) fell to a value of V0/e.As in all multicellular preparations in which cable

analysis has been applied, certain assumptions mustbe made, and therefore, any analysis provides onlyan approximation. In approaching cardiac muscle, amethod that can deliver current to a large number ofcells is important. The theoretical basis and justifi-cation for our method of space-constant determina-tion has been described and is based upon thenormal anisotropy of ventricular muscle.24-29 Clerc29found a 9: 1 difference in internal resistance betweenthe longitudinal and transverse directions. He andothers have attributed the anisotropy to more junc-tions per distance in the direction perpendicular tofiber orientation. Similarly, conduction from thesuperficial to deep fibers in our tissue preparationsis transverse to fiber orientation.



686 Circulation Vol 78, No 3, September 1988

TABLE 1. Action Potential Variables for Tissues From Control and Amiodarone-treated dogsResting Action potential Action potential Conduction Spacepotential amplitude dV/dT duration velocity constant Tf

Tissue (mV) (mV) (V/sec) (msec) (m/sec) (mm) (msec)Control

1 81.4 97.7 154.4 179.9 0.57 0.51 0.902 77.3 93.5 147.0 196.8 0.49 0.92 0.933 81.4 100.2 163.0 226.3 0.50 1.45 1 .2'i4 84.2 82.9 135.7 179.7 0.60 .. 1 15 92.8 102.2 140.0 ... 0.52 0.82 0.796 97.4 111.4 150.6 0.61 1.00 0.887 97.9 109.0 174.8 ... 0.54 1.18 0.858 84.5 120.0 170.3 219.5 0.58 0.91 0.779 103.3 113.3 125.7 183.7 0.55 1.32 1.1010 96.2 103.3 155.6 167.3 0.49 1.23 0.8611 100.1 115.7 138.0 . . . 0.62 1.16 1 .3712 98.0 105.8 171.0 181.5 0.60 1.06 0.96

Mean + SD 91.2 + 8.8 104.6±+ 10.3 152.2 ± 15.6 191.2±21.3 0.56± 0.05 1.05 ±0.25 0.98±0.18Amiodarone

1 87.5 94.8 164.9 160.8 0.49 0.87 1.162 80.8 98.9 182.5 174.8 0.45 0.85 0.943 87.2 98.0 154.2 175.4 0.43 0.52 1.254 90.4 92.6 125.0 256.8 0.68 1.16 1.225 84.5 76.6 90.0 267.6 0.21 0.56 1.676 81.8 96.6 189.8 225.4 0.37 0.49 1.407 107.7 89.0 100.0 242.2 0.22 0.34 1.598 93.3 101.2 82.2 292.0 0.35 0.76 1.669 78.8 77.3 97.8 299.0 0.52 1 49

Mean+SD 88.0±8.7 91.7±9.1 131.8±41.8 232.7±52.0 0.41 ±0.15 0.69±0.27 1.38±0.25p =NS p <0.01 p =NS p = 0.05 p <0.0l p =0.01 p <0.001

In the present experiments, the large diameter ofthe contact electrode relative to fiber dimensionensured a uniform distribution of intracellular cur-rent among a large population of cells, and theanisotropic nature of the preparation offered a pref-erential pathway for current flow in one spatialdimension. Because all space-constant determina-tions were performed parallel to fiber orientation,the preferential path for current flow resulting fromanisotropy may have accounted for the exponentialfalloff of voltage with distance and may provide abasis for assuming a one-dimensional cable in approx-imating the space constant. The finding that thespace-constant determinations are little influencedby the absolute amount of subthreshold currentinjected is further support for the validity of thetechnique.27 Similarly, that the results of these, aswell as previous experiments, fit the predicted ana-lytical relations expected from cable analysis be-tween the space constant, conduction velocity, andthe action potential foot further suggest that thesemethods are justified in approximating determinantsof conduction.24.27A limitation to this method of determining the

space constant lies in the inability to determine theexact ratio of intracellular to extracellular current to

be delivered. The input resistance cannot be mea-sured and therefore cannot be used to determinemembrane resistance. Another problem is that thedepolarizing responses used to measure the spaceconstant may be associated with voltage-dependentactive components, rectification of steady-state out-ward currents, and voltage-dependent, steady-stateinward currents that may contribute to the sub-threshold response. These factors will tend to causea deviation from a purely exponential voltage dropwith distance of the subthreshold response. Unfor-tunately, hyperpolarizing pulses are frequentlyaccompanied by regenerative activation of the tis-sue at the current source and hence are not optimalto evaluate passive membrane properties either.Because of these issues, as well as the fact that thetissues from amiodarone-treated animals may beless sensitive to these factors because of theirdecreased excitability (due to the amiodarone), con-trol tissue space constants were measured in tissuesin which depolarizing or hyperpolarizing pulseswere delivered. The results with these two tech-niques were not significantly different from eachother, and hence, the data are presented together.Depolarizing pulses were used in the amiodarone-treated tissues. The required correlation coefficient



Levine et al Depressed Conduction During Amiodarone Therapy

12

81

U,.bz

5.04.03.0

2.0

1.0

5 10 15 20 25 30

tideFIGURE 1. Plot of distance and activation time forcontrol and amiodarone-treated tissues. Note that con-

duction was linear in both but that the conduction veloc-ity was lower in the amiodarone-treated tissue.

for the regression of the exponential voltage dropwith distance was 0.9 or greater to ensure that any

error introduced by these factors was small. Never-theless, our measurements can yield only an approx-imation of the tissue space constant.

Statistical MethodsAll tabular data are expressed as mean SD.

Variable means were compared by unpaired t tests.Linear fits were made with linear regression tech-niques. Exponential fits were made by linear regres-sion of the logarithmic transform of the data. A pvalue less than or equal to 0.05 was consideredsignificant for these determinations.

ResultsAction Potential Characteristics

Table 1 contains the action potential variables fortissues from control and amiodarone-treated dogs.During pacing at a cycle length of 1,000 msec,amiodarone treatment was associated with a signif-icant reduction in mean action potential amplitude(91.7 + 9.1 vs. 104.6 10.3 mV, p<0.01) and a sig-nificant prolongation of action potential duration(232.7 + 52.0 vs. 191.2 + 21.3 msec, p = 0.05). Incontrast, the trend toward a reduction in dV/dT wasnot significant (131.8 + 41.8 vs. 152 + 15.6 V/sec).Similarly, there was no difference in resting mem-brane potential between tissues from amiodarone-treated or control dogs (88.7 + 8.7 vs. 91.2 + 8.8 mV).Conduction velocity was reduced in tissues from

amiodarone-treated dogs. Figure 1 shows examplesof conduction velocity plots for a tissue from con-trol and a tissue from an amiodarone-treated ani-mal. Note that the relation between activation timeand distance was linear in each case (r2=0.99),which indicates uniform conduction over the dis-tance sampled. Conduction velocity, determined as

N 0.4 SPACE COSAT:0.3 cONRL(X30.93

S AIO (o): 0.2 -

0.2

0.10.0 0.5 1.0 1.5 2.0

OZSTAA/CE (-I

FIGURE 2. Semilogarithmic plot of potential amplitudeand distance for subthreshold potentials injected intocontrol and amiodarone-treated tissues. Note that thefalloff of potential with distance of the subthresholdpotential was faster in the amiodarone-treated tissue,resulting in a smaller measured space constant.

the slope of the best fit linear regression of activa-tion time and distance from the stimulating elec-trodes, was lower in the tissue from the amiodarone-treated animal (0.21 vs. 0.61 m/sec). The measuredconduction velocities for each tissue are shown inTable 1. There was a significant difference in meanconduction velocity in tissues from the amiodarone-treated animals compared with that measured innormal, control tissues (0.41 0.15 vs. 0.56 +0.05m/sec, p <0.0I).

Figure 2 shows semilogarithmic plots of thesteady-state amplitude of the subthreshold depo-larization and distance for tissues from anamiodarone-treated and a control dog. The fallolfof amplitude with distance of the subthresholddepolarization was greater in the tissue from theamiodarone-treated animals compared with tissuefrom control animals. The measured space con-stant in the amiodarone-treated tissue was 0.52mm, whereas the space constant in the normaltissue was 0.93 mm. Table 1 contains the spaceconstants from 11 normal and eight amiodarone-treated tissues. The mean space constant measuredin the amiodarone-treated tissues was significantlyless than that measured in control tissues (0.69-+0.27 vs. 1.05 + 0.26 mm; p = 0.01).

Determinants of Slow ConductionTo examine the determinants of slow conduction

in amiodarone-treated tissues, the statistical rela-tions demonstrated in earlier studies, as well asthose relations predicted with one-dimensional cablemodels between conduction velocity and actionpotential variables, or the space constant, werestudied, Equation 1 is the relation developed byTasaki and Hagiwara30:

U 0

687

n




G,

0.5.

0.0

y-O.08 + 0.49xR-0.85p<0.05

0.0 0.5 1.0

SPACE CONSTANT (yinFIGURE 3. Linear regression plot of conduction velocityand the measured space constant in the amiodarone-treated tissues.

0= A (Tfoot Tm)112 (1)where 0 is conduction velocity, A is space constant,Tfo,, is time constant of the action potential foot, andTm is membrane time constant. This equation pre-dicts a linear relation between conduction velocityand the space constant. Similarly, Equation 2 is theapproximation of Hunter et a131:

O2 = (a/Cm x Ri) (VmaxlVP) (2)where 0 is conduction velocity, a is fiber radius, Cmis specific capacitance of the membrane, Ri is spe-cific internal axial resistance, Vmax is maximal rateof rise of the action potential upstroke, and Vp isactional potential amplitude. This equation predictsa linear relation between conduction velocity andthe square root of the maximal rate of depolariza-tion of the action potential upstroke and the inverseof the square root of the action potential amplitude.These relations, which are predicted from one-dimensional cable theory, have been demonstratedalso in earlier experiments with multicellular myo-cardial preparations such as those used in theseexperiments.24,27,32Although there was a wide range for the mea-

sured space constant in the amiodarone-treatedtissues, there was a significant linear relation be-tween the space constant and conduction velocity(Figure 3). The equation for this regression was

0=0.06 + 0.49 (A) (3)r=0.85, p<0.01: where 0 is conduction velocity,and A is space constant. Conversely, no relationwas found between conduction velocity and thesquare root of the maximal rate of upstroke velocityor between conduction velocity and the inverse ofthe square root of action potential amplitude.

In a multivariate model, including each of thethree independent variables, that is, the space con-stant (A), the square root of the maximal rate of

upstroke velocity (Vmax), and the square root ofaction potential amplitude (Vp), conduction velocitywas appropriately predicted. The equation for thisregression was

0. 34 + 0.23 (Vma)12 -4.99() - +0.45 (A) (4)

F=8.24; r=0.93; p<0.05. This partial multivariateanalysis confirmed that the only independent predic-tor of conduction velocity was the space constant(p <0.02). In contrast, changes in conduction veloc-ity in these experiments were independent of changesin the maximal rate of upstroke velocity (p 0.24)and in action potential amplitude (p =0.57). Thesedata suggest that the decrement in conduction in theamiodarone-treated tissues was largely due to thedecreased space constant. The small decreases inaction potential amplitude and the maximal rate ofupstroke velocity (probably reflecting changes insodium channel activity) did not play a significantrole in the decreased conduction velocity.

DiscussionThe major finding in this study is that long-term

amiodarone administration is associated with adepression of the space constant. This decrease inthe space constant accounted in large part for themeasured decrease in conduction velocity. In con-trast, only minor changes in action potential ampli-tude and the maximal rate of upstroke velocity werenoted.Amiodarone has been shown to exert several

electrophysiological effects. It has long been knownthat amiodarone treatment leads to prolongation ofrepolarization.12-17 Amiodarone administration hasbeen associated with prolongation of action poten-tial duration in vitro and of the QT interval andmonophasic action potential duration in vivo. Theantiarrhythmic effects of amiodarone were orig-inally attributed to these alterations in repolariza-tion. Recently, it has been demonstrated that amio-darone has effects on myocardial conduction aswell. 18-20 Amiodarone's depression of conductionvelocity has been attributed to sodium channelblockade. 13-15 The reductions in both action poten-tial amplitude and maximal rate of upstroke velocityare consistent with amiodarone-induced sodiumchannel blockade (Table 1). The amiodarone-induced reduction of the maximal rate of upstrokevelocity measured, however, was not statisticallysignificant in our nonischemic preparations thatwere paced at a cycle length of 1,000 msec. Theanalysis was limited, however, by small sample sizeand the large variance in the determinations; the 3error was 0.36. Conversely, if the reductions inmeasured conduction velocity were due entirely tothe decrease in the maximal rate of upstroke veloc-ity, then Equation 2 predicts that the mean value ofthe maximal rate of upstroke velocity would be 81V/sec. Given 1) the assumption that the controlgroup mean is representative, 2) that the pooledvariance is 878, and 3) that the significance level (a)

00

a



Levine et al Depressed Conduction During Amiodarone Therapy

is 0.05, the power or probability of detecting adifference in dV/dT that would be physiologicallysignificant (i.e., a change from control to the pre-dicted mean of 81 V/sec) is greater than 0.9999.Hence, it is highly unlikely even given our smallsample size to have missed an amiodarone-inducedchange in the maximal rate of upstroke velocitylarge enough to account for the reduction in con-duction velocity (,B error <0.0001). Furthermore, inthe univariate and multivariate analyses of the deter-minants of conduction in the amiodarone-treatedtissues, neither the maximal rate of upstroke veloc-ity nor action potential amplitude was an indepen-dent predictor of conduction velocity. Thus, even ifthe amiodarone-induced trend toward the reductionin the maximal rate of upstroke velocity had reachedstatistical significance, it would be highly unlikelyto account for the decrease in the measured con-duction velocity. These data imply, therefore, thatalthough sodium channel blockade may be impor-tant in explaining some of the use-dependent prop-erties of amiodarone13-15 as well as effects in injuredor ischemic myocardium, sodium channel blockadedoes not explain the depression in conduction veloc-ity during resting, stable conditions.Myocardial conduction velocity is determined, in

part, by passive membrane properties. Alterationsin these properties may therefore account forchanges in conduction velocity. We could notdirectly measure the membrane time constant in ourexperiments; however, the increase in time con-stant of the foot of the action potential may reflectan effect of amiodarone on that variable. Though wecould not measure membrane resistance or axialresistance, we could, however, estimate the overalleffectiveness of cell coupling by measuring thefalloff of voltage with distance of a subthresholdpotential and by calculating the tissue space con-stant (Figure 2). The space constant in theamiodarone-treated tissues was significantlydecreased compared with that in the normal, con-trol tissues (Table 1).As predicted from one-dimensional cable theory,

the decline in conduction velocity was closely cor-related with that of the space constant (Figure 3). Inaddition, in the multivariate analysis, only the spaceconstant proved to be an independent predictor ofconduction velocity. Thus, the depression in con-duction velocity in our tissues was accounted for bychanges in the space constant and not by the rela-tively small changes in sodium channel-mediatedaction potential amplitude and maximal rate ofupstroke velocity.Although we have shown that the space constant

is reduced in amiodarone-treated tissues, we havenot delineated a mechanism. Equation 5 shows therelation between the space constant and internalcellular, membrane, and extracellular resistance:

A2=rml(ri+ro) (5)

where A is space constant, rm is membrane resis-tance, ri is internal axial resistance, and r. is resis-tance of the extracellular space. A decrease in thespace constant could be due to a decrease in mem-brane resistance or to an increase in internal axialresistance and resistance of the extracellular space.Unfortunately, we were unable to measure theinput resistance in our experiments and, therefore,could not determine which of these factors contrib-uted to the reduced space constant. In addition,resistance of the extracellular space may beincreased by amiodarone deposition in the intersti-tial space. Finally, amiodarone may become incor-porated into the cell membrane and affect passivecurrent flow.

Other factors, such as voltage-dependent activecomponents, rectification of steady-state inwardcurrents, and voltage-dependent outward currentsmay also contribute to subthreshold responses.These factors tend to cause a deviation from thepurely exponential relation between voltage dropand distance of the subthreshold response. That thecorrelation coefficients for the exponential relationbetween voltage drop and distance were close tounity (r-0.90) suggests that these factors were ofminor significance. Similarly, complex interactionscaused by changes in intercellular resistance inanisotropic myocardium must also be considered inevaluating the factors relating the space constantand conduction velocity in our tissues.The findings of this study are clinically relevant.

Reentrant tachyarrhythmias are dependent upon amyocardial substrate that exhibits areas of slowconduction and block. Slow conduction in isch-emic, sublethally ischemic, or recently infarctedmyocardium stems not only from a depression inaction potential amplitude and maximum rate ofupstroke velocity (sodium channel-mediated phe-nomena) but also from cell-to-cell electricaluncoupling.24,27,33 Under these circumstances, agentsaffecting myocardial conduction through eithersodium channel blockade or cell-to-cell couplingmay be effective antiarrhythmics because affectingeither abnormal mechanism should lead to morepronounced slowing of conduction. Conventionalantiarrhythmic agents, which are often effectiveclinically in the setting of acute ischemia or infarc-tion, further depress conduction through sodiumchannel blockade and, thereby, may interrupt reen-try by this effect. Most of these agents, however,are relatively ineffective in managing severe, life-threatening ventricular tachyarrhythmias that arisefrom a substrate of chronic scar.Recent experimental studies indicate a basis for

this relative resistance of tachyarrhythmias inchronic infarction to conventional sodium channelblockers. As canine infarcts age, action potentialcharacteristics (sodium channel-mediated phenom-ena) have been shown to normalize even thoughslow inhomogeneous conduction and fractionatedelectrograms persist.34 The slow conduction in these

689




experimental infarcts has been attributed to cell-to-cell electrical uncoupling due to the interposition ofcollagen between islands of surviving, normalmyocardium.27 If slow conduction and reentranttachyarrhythmias are dependent upon a myocardialsubstrate that exhibits abnormal cell-to-cell cou-pling but normal sodium channel-mediated charac-teristics (action potential amplitude and maximumrate of upstroke velocity), it follows that agentsaimed at the "weak link" of conduction (cell-to-cellcoupling) may be more effective antiarrhythmicagents. Our experiments demonstrate that one ofamiodarone's primary mechanisms is to depressoverall axial resistance as indexed by a reducedspace constant. This hypothesis, therefore, is con-sistent with the clinical findings of relative efficacyof sodium channel blockers in patients with acuteischemic syndromes. More importantly, this hypoth-esis helps to explain not only the relative inefficacyof conventional antiarrhythmic agents but also themarked effects of amiodarone in the treatment ofclinical tachyarrhythmias in patients with chronicmyocardial scar.

It should be noted, however, that the effect on thespace constant described in this study is not theonly potential mechanism of antiarrhythmic actionof amiodarone. For example, at faster heart rates,amiodarone-induced sodium channel blockade and,hence, depression of myocardial conduction willlikely be enhanced. In addition, amiodarone alsoaffects myocardial refractoriness. Furthermore, asnoted, the presence of acute or subacute ischemiamay be associated with action potential changes aswell as changes in overall axial resistance. Thus,the interactions of the drug and myocardial sub-strate are likely complex, and all may influence theefficacy of the agent. Nevertheless, that long-termamiodarone therapy leads to a decrease in thespace constant may explain its unique antiarrhythmiceffects in patients with refractory ventricular arrhyth-mia arising from a substrate of chronically scarredmyocardium.

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KEY WORDS * amiodarone myocardial conductionarrhythmia * space constant



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Mechanisms of depressed conduction from long-term amiodarone therapy in canine myocardium