(Circulation. 1995;91:451-461.)
© 1995 American Heart Association, Inc.
Articles |
Pharmacokinetics and Regional Electrophysiological Effects of Intracoronary Amiodarone Administration
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.
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Abstract |
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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
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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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 1
) 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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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 2). 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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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
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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:
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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.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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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 1
and 2), 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
1). The difference of the percent change of conduction
velocities (CV)
is given by the equation
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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 3, 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 3, top). At a pacing
cycle length of 300 ms, amiodarone further depressed both
longitudinal and transverse conduction velocities (Table 2
).
Fig 3,
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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and
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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 4, 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
4,
bottom). This effect was also dependent on amiodarone
concentration:
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and
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The
rate-dependent depression of the conduction velocity with
increased pacing rate was more pronounced in the longitudinal than in
the transverse direction (Fig 4, bottom). The difference
between the
two directions became significant after the second hour of
amiodarone infusion (Fig 5).
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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 3 and
4). 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 3 and 4). 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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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 5 and
6). 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
6). The amiodarone concentrations were time
dependent (R2=.91) and given by the
equation
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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
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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.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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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 4
). 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 3, 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
3,
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 3, 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
4).
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 5). 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 
- 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.
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