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Circulation. 1995;91:451-461

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(Circulation. 1995;91:451-461.)
© 1995 American Heart Association, Inc.

Articles

Pharmacokinetics and Regional Electrophysiological Effects of Intracoronary Amiodarone Administration

John N. Nanas, MD, PhD; Jay W. Mason, MD, FACC

From the University of Athens (Greece) School of Medicine, Department of Clinical Therapeutics, and the University of Utah Health Sciences Center, Division of Cardiology, Salt Lake City.

Correspondence to Jay W. Mason, MD, FACC, University of Utah Health Sciences Center, Division of Cardiology, 50 North Medical Dr, Salt Lake City, UT 84132.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background The reason for the delay in onset of the electrophysiological effects and antiarrhythmic efficacy of amiodarone is not clear. The relation between the development of the electrophysiological effects of amiodarone and its myocardial concentration is unknown. We therefore examined the time course of development of electrophysiological effects during intracoronary infusion of amiodarone and related these changes to myocardial concentrations.

Methods and Results Amiodarone (0.139 mg/min) or normal saline was infused for 10 hours into the proximal left anterior descending coronary artery of 24 open-chest dogs. Nineteen animals received intracoronary amiodarone and 5 received normal saline (control group). Ten of the 19 that received amiodarone underwent electrophysiological study (amio-EPS group). Sixteen of the 19, including 7 from the amio-EPS group, underwent pharmacological study (PS group). In the amio-EPS group during pacing at a cycle length of 300 ms, changes in conduction velocities in drug-exposed myocardium referenced to nonexposed myocardium at 1 hour of infusion were -3.7% in the longitudinal direction (P=NS) and -7.2% in the transverse direction (P<.05); at 3 hours, -12.9% (P<.05) and -9.1% (P<.05); and at 9 hours, -32.9% (P<.02) and -31.7% (P<.01). These changes were dependent on amiodarone concentration (R2=.83). There was also an obvious rate-dependent effect that was more pronounced for transverse conduction velocities. This effect was also dependent on amiodarone concentration. In the PS group, amiodarone levels in the drug-exposed myocardium increased from a mean of 5.95 µg/g at 15 minutes of infusion to 188.88 µg/g at the 10th hour. This increase was time dependent (R2=.91). In the nonexposed myocardium, amiodarone levels were always low and increased minimally over time from a mean of 2.68 to 14.45 µg/g. This increase was also time dependent (R2=.97).

Conclusions Selective intracoronary amiodarone infusion resulted in selective drug accumulation and concomitant time-dependent reduction of myocardial conduction velocity. There was a significant correlation between the extent of reduction of conduction velocity and myocardial amiodarone concentration but not coronary arterial or systemic concentration. Repolarization was not significantly altered.


Key Words: amiodarone • pharmacokinetics • conduction


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Amiodarone prolongs repolarization intervals1 and depresses myocardial and His-Purkinje conduction velocities.2 3 There is a delay in onset of the electrophysiological effects and antiarrhythmic efficacy of amiodarone. It is not clear if this is due solely to a gradual increase in myocardial amiodarone concentration or to other time-dependent phenomena, such as change in thyroid status,4 5 6 7 delayed biochemical effects,8 or accumulation of an active metabolite. In addition, the time course of development of the two major electrophysiological effects of amiodarone, depression of conduction velocity and prolongation of repolarization, have not been correlated with myocardial concentration.

We therefore examined the time course of development of the electrophysiological effects of intracoronary amiodarone on cardiac ventricular muscle and related these effects to myocardial concentrations.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Animal Preparation
Twenty-four adult mongrel dogs of either sex (19 to 30 kg) were studied. Fifteen animals underwent electrophysiological study. Five of them received intracoronary normal saline (control group). Ten received intracoronary amiodarone (amio-EPS group). Nine additional animals received intracoronary amiodarone for pharmacokinetic studies only (PS-only group). Pharmacokinetic studies were also performed in 7 of the 10 amio-EPS dogs. Thus, pharmacokinetic studies were completed in 16 animals in all (PS group). The animals were anesthetized with sodium pentobarbital (30 mg/kg IV bolus) followed by additional doses as needed. They were then intubated and ventilated with a Harvard respirator. Arterial blood gases were obtained every 30 minutes, and pH was maintained between 7.35 and 7.45 by altering the rate or depth of ventilation. Catheters were inserted into the right femoral artery and both femoral veins for continuous arterial blood pressure monitoring, blood sampling, and drug infusion. Normal saline was infused intravenously as needed to maintain systolic arterial pressure above 80 mm Hg.

The heart was exposed through a median sternotomy and cradled in the pericardium. Care was taken to minimize blood loss. A quadripolar electrode plaque was placed on the right ventricle. Formalin was injected into the atrioventricular conduction system by a previously described method to interrupt atrioventricular conduction.9 An epoxy plaque with 64 flat unipolar silver electrodes (0.635 mm in diameter) in an 8x8 array with a 2-mm interelectrode distance (Fig 1Down) was affixed on the anterior left ventricular wall near the left anterior descending coronary artery (LAD) one third of the distance from apex to base in the area supplied by the LAD. The unipolar electrodes were referenced to a Wilson central terminal. A second epoxy plaque was placed on the posterior left ventricular wall in an area clearly not supplied by the LAD. The LAD was catheterized at the origin of the first diagonal branch with a 24-gauge plastic catheter pointing from the apex to base, and an infusion was started of 0.1 mL/min normal saline. Intracoronary saline was infused for the first half hour in all animals and for the 10 subsequent hours in the control group, and 0.139 mg/min amiodarone was infused for 10 hours in the treated groups. In the PS-only animals, the preparation was similar to that of the other animals, but no atrioventricular block was induced and no epoxy plaques were used. Heparin (5000 U IV) was given every 2 hours after LAD catheterization.



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  		Figure 1. Diagram shows epoxy plaque, with 64 flat unipolar electrodes with 2-mm interelectrode distance, used for the electrophysiological study and a schematic presentation of the experimental preparation. LAD indicates left anterior descending coronary artery.

Rectal temperature was obtained before the chest was opened and was kept within 0.5°C of the baseline temperature throughout the experiment using a thermal blanket. These experiments conformed to the guiding principles of the American Physiological Society, and the experimental protocol was approved by the University of Utah Internal Animal Care and Use Committee.

Electrophysiological Study
The system used for electrogram recordings has been described previously.3 A computer (microVAX II, Digital Electronics Corp) acquired data through an optically isolated interface and then stored it on a fixed disk. The data were transferred from the hard disk to high-speed digital magnetic tape for subsequent analysis. A smoothing procedure using parabolic least-squares fit was used to minimize effects of noise.10 11

Unipolar cathodal stimulation was applied first on one plaque and then on the other through an electrode on the plaque array with the anodal input directed to a needle inserted into the right chest wall. Stimulation was performed with an interval generator (World Precision Instruments) and a custom constant current source with 2-ms rectangular impulses and current adjusted to 0.01 mA above the diastolic capture threshold. Pacing thresholds were measured before each pacing sequence and were determined with 0.01 mA precision at the cycle length of 1000 ms. Unipolar electrograms from the remaining 63 electrodes of each plaque were recorded after continuous pacing for 1 minute at cycle lengths of 1000 and 300 ms during the control period and every hour thereafter. For each experiment and each plaque, two pairs of electrodes were chosen between which all conduction velocities for that experiment were calculated. The electrodes used to calculate conduction velocities were chosen by examination of the isochrone map of electrical activation. Activation time was defined as the time of the minimum negative derivative of the local potential.12 For each plaque activation, maps with 2-ms isochrones were constructed by a computer program based on the 63 available activation times recorded during the experiment (Fig 2Down). Rapid (longitudinal) and slow (transverse) directions of propagation were clearly discernible from the maps. A line was drawn from the pacing site to the outer edge of the map perpendicular to the most widely spaced isochrones. Longitudinal conduction velocity was estimated between two electrode sites collinear with this line by dividing the distance between them by the difference in their activation times. A second line perpendicular to the first was drawn through the densely spaced isochrones, and transverse conduction velocity was computed between two electrode sites collinear with the second line. For consistency, the isochrone map used to select electrodes for determination of conduction velocities was constructed from data obtained during pacing at a cycle length of 1000 ms. The electrode sites were carefully reviewed for evidence of indirect propagation, which can be identified by the presence of sudden changes in the density of isochrone lines, and electrode site selections were adjusted to avoid such areas. The distances between the pairs of electrodes used to compute conduction velocity in the longitudinal and transverse directions were 5.66 to 14.14 mm and 2.83 to 8.49 mm, respectively. The calculation of conduction velocity with this method presumes that the path of propagation is direct and in the superficial epicardial layer.



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  		Figure 2. Activation map with 2-ms isochrones constructed on the base of activation times recorded by the epoxy plaque placed in the region perfused by the left anterior descending coronary artery (amiodarone-exposed myocardium). Solid cycles represent the sites of the 64 electrodes (interelectrode distance, 2 mm). Pacing was performed from the site indicated with an asterisk. The line perpendicular to the widest isochrones was considered the longitudinal path (L). The two electrode sites (A1 and A2) within the triangulars along this line were used to compute conduction velocity. The line perpendicular to the first indicates the transverse direction (T). The electrodes (B1 and B2) within the diamonds along that line were used to compute transverse conduction velocity.

For each experiment, the two peripheral electrode sites on the plaque that were chosen for determination of conduction velocities in the two directions were also used for measurement of repolarization intervals. The repolarization time was defined as the time of the maximum first derivative of the potential of the T wave of the local electrogram as previously described.10 This corresponds to the time of maximum rate of change of voltage during phase 3 of the action potential.12 The repolarization interval for an electrode site was defined as the difference between the repolarization time and the activation time obtained at that site and was determined after 1 minute of pacing.

Pharmacokinetic Study
In the animals used for the pharmacokinetic study, a piece of the right atrium was taken and a sample of femoral arterial blood withdrawn into a heparinized tube before the infusion was started. The blood sample was centrifuged at 10°C and the serum removed and saved. The atrial tissue and serum were frozen in separate tubes. Subsequently, at 15 minutes, 30 minutes, and 1, 2, 3, 5, 7, and 10 hours of intracoronary amiodarone infusion, a piece of left ventricular myocardium taken from the LAD perfused region (amiodarone-exposed myocardium), a piece of right atrium (amiodarone-nonexposed myocardium), and coronary and femoral arterial samples were obtained. Right atrial samples were not taken at 30 minutes and at hours 2 and 7. At the end of six experiments, the amiodarone levels were determined in the right atrial and left ventricular nonexposed myocardium, and no significant difference was found (right atrial, 6.5±8.7 µg/g; left ventricular, 10±11.3 µg/g). Amiodarone was measured in serum and myocardial tissue homogenates by a modification3 of a previously reported high-performance liquid chromatographic procedure.13

Statistical Analysis
Values are expressed as mean±SD. One-way ANOVA and unpaired t tests without the Bonferroni correction were used to compare the percent changes of electrophysiological parameters over time and to evaluate the significance of the amiodarone concentration changes over time in the coronary and femoral arterial serums and in the amiodarone-exposed and -nonexposed myocardium. A linear regression analysis was used to define the relation between amiodarone concentrations in the exposed myocardium and changes in conduction velocity as well as the rate dependence of those changes. The effect of the duration of intracoronary amiodarone infusion on amiodarone concentrations in the exposed and nonexposed myocardium was also analyzed by linear regression.

Longitudinal and transverse conduction velocities, rate-dependent effect on conduction velocities, and repolarization intervals were normalized to the control value obtained at time zero before amiodarone initiation.

The percent changes of the normalized values were obtained by the equations


where xt is the value during infusion and x0 is the mean baseline value.

Subsequently, the calculated percent change for each individual measurement obtained in the nonexposed myocardium was subtracted from the respective percent change obtained in the exposed myocardium as follows:



where EM is the exposed myocardium and NEM is the nonexposed myocardium.

These values were used as the real percent changes induced by drug or normal saline in the exposed myocardium.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Conduction Velocities
In the control animals, conduction velocities in the saline-exposed and -nonexposed myocardium increased over time in a fashion similar to that seen in the nonexposed myocardium of the amiodarone-treated animals (Tables 1Down and 2Down), and no significant differences were seen between the two sites. In the amiodarone-treated animals during pacing at a cycle length of 1000 ms, the conduction velocities in the longitudinal direction increased over time at both sites up to the 10th hour (Table 1Down). The difference of the percent change of conduction velocities (CV) is given by the equation


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  		Table 1. Longitudinal and Transverse Conduction Velocities in Amiodarone-Exposed and -Nonexposed Myocardium With 1000-ms Pacing Cycle Length


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  		Table 1B. Continued


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  		Table 2. Longitudinal and Transverse Conduction Velocities in Amiodarone-Exposed and -Nonexposed Myocardium With 300-ms Pacing Cycle Length


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  		Table 2B. Continued


where t is the time after amiodarone infusion was started and 0 is time zero during normal saline infusion and immediately before amiodarone was started. The difference in changes of the longitudinal conduction velocities between exposed and nonexposed myocardium during pacing at a cycle length of 1000 ms showed a trend of reduction over time as shown in Fig 3Down, top. This means that amiodarone tended to decrease longitudinal conduction velocity but not to a statistically significant degree. Amiodarone depressed conduction in the transverse direction to a greater degree, and this became statistically significant after the third hour of amiodarone infusion (Fig 3Down, top). At a pacing cycle length of 300 ms, amiodarone further depressed both longitudinal and transverse conduction velocities (Table 2Up). Fig 3Down, bottom, shows that this reduction became statistically significant after the first hour of intracoronary infusion. These changes were dependent on amiodarone concentration and were given by the equations




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  		Figure 3. Line graphs show difference in changes of longitudinal and transverse conduction velocities (CV) between exposed (EM) and nonexposed (NEM) myocardium expressed as percentage of control values. Top, Pacing cycle length (CL)=1000 ms; bottom, pacing cycle length=300 ms.



and



where superscript L indicates longitudinal direction and superscript T, transverse direction.

Rate Dependency of Depression of Conduction Velocity
The effect of shortening pacing cycle length on conduction velocities was evaluated. The change in conduction velocity at each time period, which resulted from reducing the pacing cycle length from 1000 to 300 ms (CV300-CV1000), was expressed as a percentage of the conduction velocities during pacing at a 1000-ms cycle length at that specific time: [(CV300-CV1000)/CV1000]x100.

This represents the rate dependency of depression of conduction velocity. Longitudinal and transverse conduction velocities did not change significantly with more rapid pacing in both exposed and nonexposed myocardium of control animals and in nonexposed myocardium of amiodarone-treated animals (Fig 4Down, top). In the amiodarone-exposed myocardium, longitudinal and transverse conduction velocities did not change during the baseline period as a result of more rapid pacing. In contrast, during the amiodarone infusion period, longitudinal and transverse conduction velocities were significantly decreased when the cycle length was reduced from 1000 to 300 ms. This rate-dependent depression of longitudinal conduction velocity became significant at the first hour of amiodarone infusion and increased further throughout the experiment. The rate-dependent depression of transverse conduction velocity showed a trend that became significant after the sixth hour of infusion (Fig 4Down, bottom). This effect was also dependent on amiodarone concentration:




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  		Figure 4. Line graphs show difference in changes of longitudinal and transverse conduction velocities (CV) between nonexposed myocardium (NEM, top) and exposed myocardium (EM, bottom) expressed as percentage of control values. Top, Conduction velocities did not change when the pacing cycle length decreased from 1000 to 300 ms in either the longitudinal or transverse direction throughout the 10 hours of the experiment. Bottom, There was an obvious reduction of conduction velocity in the longitudinal direction when the pacing cycle length decreased from 1000 to 300 ms, whereas in the transverse direction it became apparent after the seventh hour of amiodarone intracoronary infusion.



and



The rate-dependent depression of the conduction velocity with increased pacing rate was more pronounced in the longitudinal than in the transverse direction (Fig 4Up, bottom). The difference between the two directions became significant after the second hour of amiodarone infusion (Fig 5Down).



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  		Figure 5. Line graph shows difference in reduction between longitudinal and transverse conduction velocities (CV) in the amiodarone-exposed myocardium when pacing cycle length decreased from 1000 to 300 ms. Reduction was more pronounced in the longitudinal (L) than in the transverse (T) direction. This difference became apparent after the third hour of amiodarone intracoronary infusion and reached a plateau after the fourth hour.

Repolarization Intervals
Repolarization intervals decreased over time in control animals in both saline-exposed and -nonexposed myocardium and in the nonexposed myocardium of the amiodarone-treated animals (Tables 3Down and 4Down). There were no significant differences between the two recording sites. In the amiodarone-treated animals, repolarization intervals in the drug-exposed myocardium had a lesser tendency to decrease than in the nonexposed myocardium over the first hours of amiodarone infusion and subsequently a tendency to increase after the sixth hour (Tables 3Down and 4Down). The difference in percent changes of the repolarization intervals (RI) between the amiodarone-exposed and -nonexposed myocardium given by the equation


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  		Table 3. Longitudinal and Transverse Repolarization Intervals in Amiodarone-Exposed and -Nonexposed Myocardium With 1000-ms Pacing Cycle Length


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  		Table 3B. Continued


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  		Table 4. Longitudinal and Transverse Repolarization Intervals in Amiodarone-Exposed and -Nonexposed Myocardium With 300-ms Pacing Cycle Length


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  		Table 4B. Continued


showed no statistically significant changes throughout the experiment.

Pharmacokinetic Study
Mean coronary arterial serum amiodarone levels varied between 0.72 and 2.06 µg/mL during the entire period of intracoronary amiodarone infusion, without a significant increase over time, and desethylamiodarone was undetectable (Tables 5Down and 6Down). The mean femoral arterial amiodarone serum concentration varied between 0.15 and 0.45 µg/mL during the entire period of intracoronary amiodarone infusion without significant increase over time, and desethylamiodarone was undetectable. The mean myocardial levels of amiodarone in the amiodarone-exposed myocardium showed an increase over time from 5.95±7.7 µg/g on the 15th minute of intracoronary amiodarone infusion to 188.88±134.1 µg/g on the 10th hour of infusion. The concentration reached the usual clinical chronic therapeutic level after the second hour of infusion (Fig 6Down). The amiodarone concentrations were time dependent (R2=.91) and given by the equation


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  		Table 5. Amiodarone Concentrations in Amiodarone-Exposed and -Nonexposed Myocardium and Coronary and Femoral Arterial Serums


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  		Table 6. Desethylamiodarone Concentrations in Amiodarone-Exposed and -Nonexposed Myocardium and Coronary and Femoral Arterial Serums



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  		Figure 6. Line graph shows amiodarone concentrations in exposed (EM) and nonexposed (NEM) myocardium during 10 hours of amiodarone intracoronary infusion.



Desethylamiodarone levels in the amiodarone-exposed myocardium varied between 0.11±0.26 and 2.97±4.45 µg/g without a significant difference in concentrations among the different time intervals of observation. In the amiodarone-nonexposed myocardium, the amiodarone concentration showed a trend (P=NS) of increase over time from 2.68±3.19 µg/g on the 15th minute of intracoronary amiodarone infusion to 14.45±17.44 µg/g on the 10th hour. The mean increase was time dependent (R2=.97) and was best given by the equation



The ratio of amiodarone levels in the amiodarone-exposed myocardium to those of coronary arterial serum showed an increase over time, and the usual clinical chronic therapeutic ratio was reached after the second hour of intracoronary infusion.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
Experimental Procedure
Our animal model permitted comparison of the electrophysiological status of myocardium that was and was not exposed to amiodarone in the same heart under identical hemodynamic, metabolic, and extracellular electrolytic conditions. This design is superior to the conventional approach of comparing two groups of animals because the electrophysiological status of open-chest animals changes over time. These changes were obvious in our control group and in the myocardium not exposed to amiodarone in our treated group (Tables 1 through 4UpUpUpUp).

A potential weakness of this model is possible induction of ischemia of the drug-exposed myocardium by coronary artery catheterization and infusion. To explore this possibility, we gave five control animals intracoronary normal saline instead of amiodarone. In these animals, the electrophysiological variables in the normal saline-exposed and -nonexposed myocardium did not differ. It is known that ischemia reduces transverse conduction velocity and repolarization intervals.14 The similarity of the electrophysiological changes seen in the saline-exposed and -nonexposed myocardium in the control animals excludes the possibility that ischemia accounts for the changes observed in amiodarone-exposed myocardium. Differences in anterior and posterior myocardial temperature may occur in the open-chest dog. We took care to approximate the sternum whenever possible, and we covered the anterior chest with a blanket. Once again, observations in the control group exclude a significant effect of temperature. Thus, we believe that this is a reliable method for testing electrophysiological actions of antiarrhythmic drugs that have high affinity for myocardium, such as amiodarone.13

Conduction Velocities
Longitudinal conduction velocity was not affected by amiodarone when the pacing cycle length was 1000 ms. Transverse conduction velocity was significantly reduced although the extent of reduction was small (Fig 3Up, top). In contrast, during rapid pacing (cycle length of 300 ms), longitudinal and transverse conduction velocities were both extensively decreased to a similar level (Fig 3Up, bottom). The percent reduction of conduction velocity when the pacing cycle length changed from 1000 to 300 ms was significantly more pronounced in the longitudinal than in the transverse direction (Figs 4, bottom, and 5). This difference might be due to the fact that conduction velocity in the longitudinal direction was not affected when the pacing cycle length was 1000 ms, whereas in the transverse direction it was significantly reduced (Fig 3Up, top), eliminating further reduction.

Anderson et al3 found similar effects of chronically administered amiodarone when the pacing cycle length was decreased. They observed that changes in conduction velocities were more pronounced in the longitudinal than the transverse direction, although the differences were not statistically significant. Other investigators have found little or no depression of Vmax by acutely administered amiodarone during stimulation at cycle lengths of 1000 ms.15 16 17 18 19 In patients taking amiodarone chronically, the QRS complex duration increases slightly but significantly at resting heart rates.20 21 Myocardial conduction velocity can be reduced by an elevation of extracellular potassium,22 acidosis,22 increased intracellular calcium,23 and ischemia.14 As noted above, the similarity of electrophysiological measures in myocardium exposed to normal saline infusion and nonexposed myocardium makes a significant influence of any of these factors unlikely. Although the reason for progressive changes of conduction velocity and repolarization interval seen over time in the amiodarone-nonexposed myocardium are not clear, they were probably related to the experimental environment and were uniform throughout the preparation.

Effects on Repolarization Intervals
It has been shown experimentally that there is a temporal coincidence of the rapid phase of repolarization of the action potential and the maximum first derivative of the extracellular potential of the local T wave. There is a high correlation between repolarization interval and refractory period in the presence or absence of sympathetic stimulation10 and after long-term amiodarone treatment.3 Our study has shown that repolarization intervals show only a very slight, nonsignificant trend to prolong during the initial 10 hours of drug infusion (Table 4Up).

Short-term Versus Long-term Effects of Amiodarone
Long-term amiodarone treatment markedly increases action potential duration and refractory periods.2 3 15 19 24 25 26 27 28 Increases in atrial and ventricular refractoriness appear after 2 to 4 weeks of amiodarone treatment, with little or no short-term change after intravenous administration.20 25 26 27 29 30 31 32 Similar results have been observed for the QT interval.31 33 34 35 Work36 performed in isolated, spontaneously beating pig hearts perfused by the Langendorff method showed that desethylamiodarone but not amiodarone prolonged the QT interval.36

Our study demonstrates that the discrepancy between short- and long-term effects of amiodarone cannot be explained solely on the basis of amiodarone myocardial concentration. Coronary arterial concentrations of amiodarone and myocardial concentrations after the second hour of intracoronary infusion in our study were in the same range as those observed after long-term amiodarone treatment3 37 38 39 ; however, only conduction velocity was affected. Furthermore, our findings suggest that the effect of amiodarone on conduction can be achieved rapidly if sufficient drug is taken up by the myocardium but that its effect on repolarization cannot. Desethylamiodarone levels in the amiodarone-exposed and -nonexposed myocardium were low or undetectable throughout our experiments. In contrast, during long-term, high-dose amiodarone therapy, significant serum concentrations of desethylamiodarone are obtained within 1 week and increase thereafter. It is possible that desethylamiodarone is responsible for the change in repolarization observed during long-term administration of amiodarone in dogs and humans. Alternatively, the discrepancy between short- and long-term effects could be explained by an as yet undefined time-dependent or delayed effect of amiodarone on myocellular electrophysiology. Perhaps the short-term efficacy of intravenous amiodarone is solely due to decreased conduction velocity.

Myocardial Uptake of Amiodarone
Our observations regarding amiodarone pharmacokinetics may be helpful in understanding the delay of electrophysiological and antiarrhythmic effects after initiation of oral therapy. In the present study, amiodarone was administered by LAD infusion at a constant rate of 0.139 mg/min. The myocardial levels of amiodarone in the area perfused by the LAD showed a constant increase over time during 10 hours of infusion. In contrast, after amiodarone 5 mg/kg IV bolus administration, serum and myocardial concentration curves became parallel after the second hour, as shown by Latini et al.40 It is of interest that in that study the peak concentration of amiodarone in the myocardium was reached 10 to 30 minutes after drug administration and was nearly as high as the peak plasma concentrations (32.8±7.8 µg/g versus 37.2±13.6 µg/mL). That finding suggests that myocardial amiodarone uptake to the level of plasma is rapid. The continuous increase in the myocardial amiodarone concentration over the 10 hours of intracoronary infusion in the present study suggests that the rate of myocardial amiodarone accumulation in excess of the plasma level is slower. The amiodarone plasma concentration of the LAD blood in these animals varied between 0.72 and 2.06 µg/mL. The expected partition coefficient between myocardium and plasma is approximately 90.13 Thus, we would predict steady-state myocardial levels between 64.8 and 185.4 µg/g, which were achieved after the second hour of amiodarone infusion in our study (Table 5Up). Taking into account the fact that amiodarone reaches an early peak plasma level that lasts for a short period of time after a single intravenous or single large oral dose, it seems likely that with a large single oral dose40 or intravenous bolus41 42 43 44 the maximum myocardial level will be reached earlier than with divided doses or a continuous intravenous infusion. It is likely that the initial delay and progressive increase in electrophysiological effects of amiodarone observed in our study can be explained by the progressive accumulation of amiodarone in myocardium.

Clinical Implications
The findings of this study have implications for understanding the mechanism of the short-term effects of amiodarone. We achieved steady-state coronary arterial serum amiodarone levels lower than levels achieved by a 5 mg/kg bolus.34 This produced rate-dependent depression of conduction velocity. However, the effect was initially very small and became pronounced only after several hours. In addition, no significant change in repolarization interval was observed at any time. Our data suggest that termination of ongoing ventricular tachycardia or ventricular fibrillation45 by intravenous amiodarone is not a result of prolonged repolarization and may not be a result of depressed conduction. However, it is also possible that human myocardium is more sensitive than canine myocardium to the effect of amiodarone or that the twofold to threefold higher levels that may be achieved with a large bolus are sufficient to substantially decrease conduction velocity. In addition, diseased myocardium, which might be responsible for ventricular tachycardia or ventricular fibrillation, might be more sensitive. Depolarized tissue is more susceptible to conduction depression by amiodarone.15 Noncompetitive {alpha}- or ß-receptor blockade, block of L-type calcium channels, inhibition of depolarization-induced automaticity, and coronary or systemic arterial dilatation are among the other known actions of amiodarone that might account for its efficacy in terminating ventricular tachycardia or ventricular fibrillation by intravenous bolus.

Delayed accumulation in myocardial tissue of desethylamiodarone (or other metabolites) is one potential explanation for increased repolarization time and refractoriness occurring only after long-term amiodarone therapy. The delayed effect on repolarization could also result from changes in thyroid metabolism,4 5 6 but this possibility is controversial.4 5 6 8 46 47 48

Finally, observations in the present study demonstrate that extensive, localized myocardial electrophysiological effects can be achieved by selective coronary infusion of amiodarone, with insignificant systemic levels. Both global cardiac and systemic toxicity of long-term amiodarone therapy might be avoidable by this route of administration.

Limitations
Conduction velocities were estimated between electrodes on the epicardial surface of the left ventricle. Activation of the tissue between electrodes can only be assumed to be direct. Although use of the term "conduction time" instead of "conduction velocity" might obviate the assumption, we are, in fact, interested in comparing velocities. We suspect that variation in the path of conduction between compared interventions was rare in the small regions of myocardium that we examined, in which our electrode density was 32/cm2. We did not observe activation patterns that suggested new directions of activation.

We were not able to obtain tissue for measurement of amiodarone concentration repeatedly from the posterior wall, where the plaque for measuring electrograms from the nonexposed myocardium was located, because of the technical difficulty and induction of ischemia and hypotension associated with lifting of the heart. We chose the right atrial myocardium instead of right ventricular tissue as a surrogate because the right ventricle is supplied in part by the LAD in the dog. Fortunately, we found no difference in amiodarone levels in the right atrium and posterior wall samples obtained at the conclusion of the experiments.

One minute of pacing may not be sufficient to achieve absolute steady state of repolarization intervals. We did not pace for longer periods, as it would have made completion of the protocol difficult. Near steady state is reached in 1 minute. Since all recordings were obtained under the same conditions in the same heart, we doubt that the shorter duration of pacing introduced significant error.

Conclusions
Selective intracoronary infusion of amiodarone resulted in selective drug accumulation and concomitant time-dependent reduction of myocardial conduction velocity. There was a significant correlation between the extent of reduction of conduction velocity and myocardial amiodarone concentration but not coronary arterial or systemic concentration. Repolarization was not significantly altered.

Received April 6, 1994; accepted August 8, 1994.


*    References
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*References
 

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