Download The Effects of /3-Adrenergic Stimulation on the

1811
The Effects of /3-Adrenergic Stimulation on the
Frequency-Dependent Electrophysiologic
Actions of Amiodarone and
Sematilide in Humans
Philip T. Sager, MD; Christopher Follmer, PhD; Parveen Uppal, MD;
Clara Pruitt, RN; Robert Godfrey, RN
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Background The autonomic nervous system appears to play
an important role in the development of clinical ventricular
arrhythmias, and 3-adrenergic sympathetic stimulation may be
important in modulating the electrophysiologic effects of class
III antiarrhythmic agents. This study prospectively determined
the effects of isoproterenol on the frequency-dependent actions
of sematilide (a pure class III agent that selectively blocks the
delayed rectifier potassium current) and amiodarone (a class III
agent with a complex pharmacologic profile) on ventricular
repolarization, refractoriness, and conduction.
Methods and Results The frequency-dependent electrophysiologic effects of sematilide (n= 11) and amiodarone (n=22)
were determined at (1) drug-free baseline, (2) during steadystate (>48 hours) dosing with sematilide (455+±5 mg/d
[mean±SEM]) or after 10.5 days of amiodarone loading
(1618±32 mg/d), and (3) during isoproterenol administration
(35 ng/kg per minute) to patients receiving sematilide or
amiodarone. Electrophysiologic determinations were made at
paced cycle lengths of 300 to 500 ms. The two groups were
similar in all clinical characteristics. The ventricular action
potential duration at 90% repolarization (APD90) was significantly prolonged by sematilide (mean increase, 7±1%, P<.01
by ANOVA) and amiodarone (mean increase, 12±1%,
P<.001). However, while sematilide-induced APD90 prolongation was fully reversed to baseline values during isoproterenol
infusion, the APD90 in patients receiving amiodarone remained
significantly prolonged by a mean of 6±1% compared with
baseline (P=.005). The reduction in the APD,O was frequency
dependent for both agents, with a greater reduction at longer
than shorter paced cycle lengths (P<.02). During isoproterenol
infusion the right ventricular effective refractory period
(RVERP) in patients receiving sematilide was significantly
reduced to mean values of 8±2% below baseline (P<.05),
whereas the RVERP in patients receiving amiodarone remained significantly prolonged by a mean of 7±1% above
baseline values (P=.01). Sematilide and sematilide/isoproterenol had no effect on ventricular conduction. Amiodarone increased the QRS duration by 14±4% (paced cycle length, 500
ms) to 32±5o% (paced cycle length, 300 ms) compared with
baseline values. Isoproterenol attenuated amiodarone-induced
QRS prolongation by a mean of 5±1% (P=.005), without
frequency-dependent effects, consistent with isoproterenol-induced increases in the sodium current. During isoproterenol
infusion there was a trend for the sustained VT cycle length to
be reduced below baseline in patients receiving sematilide
(275±16 versus 298±55 ms, P=.06), whereas it remained significantly prolonged compared with baseline in patients receiving amiodarone (327±17 versus 257+12 ms, P<.001).
Conclusions Isoproterenol fully reversed the effects of selective potassium channel block with sematilide on the APD9o
and further reduced the RVERP to values significantly below
baseline; it partially attenuated but did not fully reverse
amiodarone-induced prolongation of the APD90 and RVERP,
which remained significantly prolonged beyond baseline values. Isoproterenol exerted frequency-dependent effects in
both patient groups on the APD90; it modestly attenuated
amiodarone-induced conduction slowing without frequencydependent actions; and the sustained VT cycle length remained significantly prolonged during isoproterenol administration to patients receiving amiodarone but not in those
receiving sematilide. These findings may have important clinical implications regarding protection from arrhythmia development in patients receiving pure class III agents or amiodarone. (Circultion. 1994;90:1811-1819.)
Key Words * amiodarone * sematilide * action
potential duration * isoproterenol
T Nhe negative results of the Cardiac Arrhythmia
Suppression Trial using class I antiarrhythmic
resulted in a major investigative effort in controlling
ventricular arrhythmias by lengthening ventricular repolarization. A large number of selective class III agents
(eg, sematilide,5-8 dofetilide,9 E-4031,10 and d-sotalol'l)
whose sole electrophysiologic action is to lengthen the
ventricular action potential duration (APD) have been
developed. Sematilide hydrochloride is a methysulfonylamino parasubstituted analogue of procainamide that
selectively blocks the delayed rectifier potassium current (IK)6-8 without other pharmacological effects in
animals or humans.5-8
3-Adrenergic sympathetic activity has been implicated as a provoker of malignant ventricular arrhythmias,12-14 and catecholamine administration has been
agents",2 and the high efficacy of amiodarone in
patients with sustained ventricular arrhythmias34 have
Received March 15, 1994; revision accepted May 31, 1994.
From the Division of Cardiology, Veterans Affairs Medical
Center of West Los Angeles, and the Department of Medicine,
UCLA School of Medicine, Los Angeles.
Presented in part during the 65th Scientific Sessions of the
American Heart Association, New Orleans, LA, November 16-19,
1992.
Correspondence to Philip T. Sager, MD, Division of Cardiology,
691/W1llE, West Los Angeles VAMC, Wilshire and Sawtelle
Boulevards, Los Angeles, CA 90073.
© 1994 American Heart Association, Inc.
1812
Circulation Vol 90, No 4 October 1994
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shown to facilitate the induction of ventricular arrhythmias during programmed stimulation in patients without inducible ventricular tachycardia (VT) in the baseline drug-free state.1516 Furthermore, it has recently
been demonstrated that ,3-adrenergic catecholamine
administration can reverse the electrophysiologic effects
of various class I antiarrhythmic agents17-22 and facilitate the induction of ventricular arrhythmias during
electrophysiologic study in patients receiving these medications.17'18 This may explain in part the recurrence of
clinical ventricular arrhythmias despite predicted efficacy during electrophysiologic testing in patients receiving these medications.
,3-Adrenergic catecholamines may modulate antiarrhythmic drug action by stimulating a number of currents in ventricular cells, including the inward sodium
current (INa),23-26 the delayed rectifier potassium current
(IK),27-29 the Na-K pump current,30 the transient outward potassium current (Ito ),31 the chloride current,32
the slow inward calcium current,33 and the pacemaker
current (f).34 The overall effect in humans is for the
ventricular APD and refractory period to shorten.35
Isoproterenol fully reversed E-4031-induced prolongation of the refractory period in isolated guinea pig
ventricular myocytes,10 but no studies in humans have
examined the effects of /8-adrenergic catecholamines on
the electrophysiologic effects of pure class III agents.
Modulation of the electrophysiologic actions of these
agents by 3-adrenergic catecholamines may have important ramifications regarding the clinical use of these
agents. In addition, amiodarone has antiadrenergic actions that may render it less susceptible to reversal
during catecholamine administration. One previous
study has shown that epinephrine partially attenuates
amiodarone-induced increases irn the ventricular effective refractory period,22 but no studies have examined
the effects of l3-adrenergic catecholamines on amiodarone-induced prolongation of the APD, ventricular
conduction, or modulation of the agent's frequencydependent actions. These are important issues because
amiodarone exerts its clinical actions in part by slowing
conduction and lengthening refractoriness by both voltage-dependent (secondary to APD prolongation) and
time-dependent (independent of APD) processes.36-38
The purpose of this study was to determine the effects
of isoproterenol on the frequency-dependent actions of
sematilide and amiodarone on ventricular repolarization, refractoriness, and conduction.
Methods
Patient Population
Patients were eligible for this prospective study if they had
(1) clinical sustained VT, ventricular fibrillation, aborted
sudden cardiac death, or syncope resulting from VT, (2)
inducible sustained VT during baseline drug-free electrophysiologic study, and (3) they were treated for clinical indications
with either sematilide or amiodarone. Exclusion criteria included myocardial infarction within the last 2 months, greater
than class II angina, and ongoing therapy with 13-blockers or
calcium channel blockers. All patients were chemically euthyroid. Four patients were studied while receiving both sematilide and amiodarone on different days, and their baseline data
were used in both analyses. The study was approved by the
West Los Angeles VA Medical Center Human Investigations
Committee, and all patients gave informed consent.
Study Protocol
Patients underwent electrophysiologic study in the baseline
drug-free state and were treated with either sematilide or
amiodarone, as dictated by the patient's clinical scenario.
Sematilide was initiated as previously described5 at 100 mg PO
q 8 hours and increased to 125 to 150 mg PO q 8 hours.
Electrophysiologic study was performed at steady state (> 48
hours, since the elimination half-life is approximately 8 hours).
Patients receiving amiodarone were loaded with 800 mg PO q
12 hours, and electrophysiologic study was repeated after
approximately 10 days of oral therapy. After the electrophysiologic determinations were made in patients receiving sematilide or amiodarone, electrophysiologic measurements were
repeated during continuous isoproterenol (35 ng/kg per
minute) infusion after a 12-minute equilibration period. This
dose of isoproterenol has been shown to result in an approximately 25% to 30% increase in the heart rate of patients not
receiving antiarrhythmic therapy20'35 and thus approximates
the heart rate changes associated with moderate exercise.
Electrophysiologic Study
Electrophysiologic study was performed in the baseline
drug-free state after discontinuation of ,8-blockers, antiarrhythmic agents, and calcium channel blockers for >6 halflives. Electropharmacological testing was performed 6 to 8
hours after the last dose of sematilide or amiodarone. A 7F
catheter with a silver-silver chloride distal electrode pair was
placed at the right ventricular (RV) apex and used to record
the monophasic action potential duration (EP Technology).
The catheter has a second pair of platinum ring electrodes
(located 2 mm from the catheter tip) that were used for pacing,
thus permitting the determination of ventricular repolarization
and refractoriness at the same ventricular site.39
Pacing Protocol
The electrophysiologic measurements were performed at (1)
drug-free baseline, (2) during drug therapy, and (3) during
concomitant drug therapy and isoproterenol. Ventricular pacing was performed at a pulse width of 2 ms at twice diastolic
threshold. Monophasic action potential (MAP) recordings
were determined at paced cycle lengths of 300, 350, 400, and
500 ms for 150 to 200 beats. The catheter position was
recorded during the baseline electrophysiologic study and
placed in a similar position during the subsequent electropharmacological study. The tracings were recorded at a paper
speed of 100 to 150 mm/s (MIDAS, PPG Industry). MAP
amplitude was determined from the diastolic baseline to the
plateau, and the APD90 was measured from the beginning of
phase 0 until repolarization was 90% complete. Only MAP
recordings .8 ,uV were used. Three APD complexes were
measured at each paced cycle length by one blinded observer.
Intraobserver variability was <5%.
The RV effective refractory period (RVERP) was measured
at the same site from which the MAP recordings were obtained. An extrastimulus was applied during late diastole after
a 14-beat drive run and a 1-second pause between drive runs.
The coupling interval of the extrastimulus was successively
decremented by 5 ms, and the effective refractory period was
reached when the extrastimulus failed to provoke an extrasystole on two successive attempts.
The QRS duration was used as a measure of ventricular
conduction and was determined during steady-state ventricular pacing by measuring from the beginning to the end of the
QRS complex in ECG lead II. One blinded observer measured
two QRS complexes at each paced cycle length. The intraobserver variability was <5%.
After the above determinations were made in patients
receiving sematilide or amiodarone, attempts were made to
induce sustained monomorphic VT using programmed ventricular stimulation at the RV apex and RV outflow tract using
<3 premature extrastimuli as previously described.40 VT was
Sager et al f.8Adrenergic Stimulation
Clinical Characteristics
Sematilide
Amiodarone
ventricular ejection fraction, or left ventricular dimensions in the two study groups. (See Table.)
Sinus Cycle Length and Blood Pressure
The sinus cycle length was not altered by sematilide
administration (843±57 to 811±39 ms, P=NS) but with
the addition of isoproterenol was significantly reduced
to 545±36 ms (33% decrease from sematilide alone;
P<.001 versus sematilide or baseline by repeated-measures ANOVA). During amiodarone therapy the sinus
cycle length increased from 768±26 to 871±33 ms
(P=.01) and decreased to 625 ±30 ms during isoproterenol infusion in patients receiving amiodarone (28%
decrease versus amiodarone alone; P<.001 versus amiodarone or baseline). The reduction in the sinus cycle
length during isoproterenol infusion compared with
drug therapy alone was similar in patients receiving
sematilide or amiodarone (266±51 versus 246±31 ms;
P=NS).
The administration of isoproterenol to patients receiving sematilide or amiodarone did not significantly
alter systolic blood pressure (sematilide: 119±9 versus
121±10 mm Hg, P=NS; amiodarone: 124±5 versus
116±4 mm Hg, P=NS) or diastolic blood pressure
(sematilide: 74±6 versus 73±3 mm Hg, P=NS; amiodarone: 74±3 versus 69±3 mm Hg, P=NS).
Effect on Repolarization
After sematilide administration (Fig 1), the APD90
was significantly increased by 10±4 ms (5%), 14±5 ms
(6%), 14±5 ms (6%), and 24±7 ms (10%) above
baseline values at paced cycle lengths of 300, 350, 400,
and 500 ms, respectively (P=.01 by ANOVA). There
was a trend (P=.07 by ANOVA) over the paced cycle
lengths examined for sematilide to prolong the APD90 to
a greater extent at longer than at shorter paced cycle
lengths (ie, "reverse" frequency-dependence). During
isoproterenol infusion, the sematilide-induced prolongation of the APD90 was reduced by 13±4 ms (6%),
19±4 ms (8%), 24±4 ms (10%), and 34±9 ms (12%) at
paced cycle lengths of 300, 350, 400, and 500 ms
(P<.001). Thus, sematilide-induced increases in the
APD90 were fully reversed, and there was a nonsignificant trend for the values to be reduced by 1±2% to
5±2% below baseline values (P=NS). Isoproterenol
exerted significant frequency-dependent actions on the
APD90 in patients receiving sematilide. The reduction in
the APD9o during isoproterenol infusion was more
P
22
11
n
455±5
1618±32
Drug dose, mg/d
NS
58±4
63±2
Age,y
NS
66%
55%
Clinical SUS VT/VF
64%
NS
45%
Hx of Ml
NS
55%
59%
Clinical CHF
NS
34±3
35±3
LVEF, %
46±3
NS
45±5
LVESD, mm
62±3
63±4
NS
LVEDD, mm
SUS VT/VF indicates sustained ventricular tachycardia/ventricular fibrillation; Ml, myocardial infarction; CHF, congestive
heart failure; LVESD, left ventricular end-systolic dimension; and
LVEDD, left ventricular end-diastolic dimension.
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
considered sustained if it lasted >30 seconds or required
premature termination because of hemodynamic compromise.
If a hemodynamically stable sustained VT was induced during
the electropharmacological study, attempts were made to
reinduce the same morphologic ventricular tachycardia during
isoproterenol administration. No attempt was made to induce
sustained VT during isoproterenol infusion if VT was not
induced during pharmacological therapy alone.
Data Analysis
The Fisher's exact test was used to analyze categorical data
and the Student's paired t test (two tailed) for means of clinical
data. The means of electrophysiologic or hemodynamic data,
the changes in the APD90, RVERP, QRS duration, and
RVERP/APD90 during drug therapy and isoproterenol administration, and the consistency of these changes compared with
drug therapy or baseline as a function of the paced cycle length
were determined using repeated-measures ANOVA with the
Greenhouse-Geisser4' correction for within-subject correlations. Data are expressed as mean±SEM. Significance was
defined as a probability level of 5.05.
Results
Patient Population
There were 11 patients in the sematilide group and 22
patients in the amiodarone group. The mean dose of
sematilide was 455±5 mg/d and of amiodarone was
1618±32 mg/d administered over a mean of 10.5±.5
days before electropharmacological testing. There were
no differences in age, history of clinical arrhythmias, left
30 r
1813
* AMIODARONE
o AMBo/isoP
BASELINE
V
280 k
FIG 1. Graphs show frequency-dependent effects
on the APD90. Left, Sematilide and sematilide plus
isoproterenol. Right, Amiodarone and amiodarone
plus isoproterenol. Sematilide-induced APD90 prolongation was fully reversed by isoproterenol,
whereas amiodarone's effects on the APD90 were
attenuated with isoproterenol but remained significantly prolonged compared with baseline values
0
~
260
260 F
240
240 F
a
C)
220
p,c.01
MO
pe.001 AMIO
vn ELINE
vs
p.005 AOSO
300
400
500
CYCLE LENGTH (ms)
300
400
AmIOSOP
P
vs
BMELINE
500
CYCLE LENGTH (me)
(P=.005).
1814
280
Circulation Vol 90, No 4 October 1994
* SEMATILIDE
O SEM/WSOP
v
280
-
BASELINE
260
260
to
E
CL
a-
w
240
E
240
CL
220-
Z 220
200
200
p=.02 SEM vs BASELINE
p'.001 SEM vs SEMWISOP
p<.O5 SEWA/ISOP vs BASELINE
180
300
10BU
Itnan
-v r_
300
500
400
p' 001 AMIO vs BASELINE
p<.O01 AMIO vs AMIO/ISOP
p= 01 AMIO/ISOP vs BASELINE
400
500
CYCLE LENGTH (ms)
CYCLE LENGTH (ms)
36±9 ms (16%) to values significantly below baseline
(P<.05). In patients receiving sematilide, the reductions
below baseline values were 21±9 ms (10%), 19±9 ms
(9 %), 19±8 ms (8%), and 11+8 ms (4%) at paced cycle
lengths of 300, 350, 400, and 500 ms, respectively
(P<.05). Isoproterenol-induced changes in the RVERP
in patients receiving sematilide were not frequency
dependent.
During amiodarone therapy, the RVERP (Fig 2) was
increased by 34±4 ms (17%), 37±5 ms (18%), 38±5 ms
(17%), and 43±6 ms (19%) at paced cycle lengths of
300, 350, 400, and 500 ms without significant frequencydependent effects. Similar to the results evaluating the
APD9O, isoproterenol administration attenuated but did
not reverse amiodarone-induced RVERP prolongation.
During isoproterenol administration the RVERP was
reduced by 23±5 ms (9%), 27±6 ms (10%), 28±5 ms
(10%), and 26±5 ms (9%) at paced cycle lengths of 300,
350, 400, and 500 ms, respectively (P<.001). However,
the RVERP remained significantly prolonged above
baseline values by 13±3 ms (7%), 14±3 ms (7%), 12±3
ms (6%), and 17±3 ms (8%) at paced cycle lengths of
300, 350, 400, and 500 ms, respectively (P=.01). Isoproterenol's effects on the RVERP were not frequency
dependent.
Effects on Conduction
Sematilide alone (Fig 3) and after isoproterenol did
not effect ventricular conduction as determined by the
QRS duration. Amiodarone (Fig 3) increased the QRS
duration in a frequency-dependent manner with significantly greater prolongation at longer than at shorter
marked at longer than at shorter paced cycle lengths
(P< .02).
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Amiodarone significantly prolonged the APD90 (Fig
1) by 26±5 ms (13%), 28±5 ms (13%), 31±4 ms (13%),
and 27±4 ms (11%) at paced cycle lengths of 300, 350,
400, and 500 ms, respectively (P<.0001 by ANOVA)
without frequency-dependent effects. During isoproterenol administration to patients receiving amiodarone, the
APD90 was reduced by 13±3 ms (5%), 20±4 ms (7%),
18±3 ms (7%), and 21±4 ms (7%) at paced cycle lengths
of 300, 350, 400, and 500 ms, respectively (P<.001). In
contrast to sematilide, amiodarone-induced APD90 prolongation was attenuated but not reversed during isoproterenol administration, and the APD90 during isoproterenol remained significantly prolonged by 4±2% to 8±2%
compared with baseline values (P=.005). Similar to patients receiving sematilide, the reduction in the APD90
during isoproterenol infusion was greater at longer than
at shorter paced cycle lengths (P<.02). There were no
frequency-dependent effects between baseline and
amiodarone/isoproterenol.
Effects on Refractoriness
During sematilide administration the RVERP (Fig 2)
was increased from baseline by 15±9 ms (8%), 21±8 ms
(11%), 23±8 ms (11%), and 28±8 ms (12%) at paced
cycle lengths of 300, 350, 400, and 500 ms (P=.02 by
ANOVA). Sematilide-induced APD9o prolongation was
greater at longer than at shorter paced cycle lengths
(P=.05). During isoproterenol administration, the
RVERP in patients receiving sematilide was reduced by
31±5 ms (14%), 36±3 ms (16%), 36±5 ms (15%), and
220
*
O
V
O
200
220
SEMATILIDE
SEM/ISOP
BASELINE
E
- 180
f
*
o
V
AMIODARONE
AMIO/iSOP
BASELINE
FIG 3. Graphs show frequency-dependent effects
0
0
160
.
U)
a
140
140~
p<.001 AMIO
ps.005 AMIO
pNS
120
400
500
CYCLE LENGTH (ms)
vs
BASELINE
vs
AMOISOP
pC.001 AM/MSOP vS BASELINE
120
300
ORS duration. Left, Sematilide and sematilide
plus isoproterenol. Right, Amiodarone and amiodarone plus isoproterenol. Sematilide or sematilide
plus isoproterenol had no effect on ORS duration.
Isoproterenol administration during amiodarone
decreased QRS duration by a fixed amount of 4%
to 6% independent of the paced cycle length
(P=.005).
on
180
o iso
CM 160
cn)
CY
a
200
z
z
FIG 2. Graphs show frequency-dependent effects
on the right ventricular effective refractory period
(RVERP). Left, Sematilide and sematilide plus isoproterenol. Right, Amiodarone and amiodarone
plus isoproterenol. Sematilide-induced RVERP
prolongation was reversed by isoproterenol to values significantly below baseline (P<.05). Amiodarone's effects on the RVERP were attenuated
with isoproterenol but remained significantly prolonged compared with baseline values (P=.01).
300
400
500
CYCLE LENGTH (ms)
Sager et al 1B-Adrenergic Stimulation
1.1
r
1.1 r
* SEMATILUDE
O SEMISOP
v BASELINE
* AMIODARONE
o AMIO/iSOP
BASELINE
V
1.0
1.0o
0-
a.
a-
cc
> 0.9
0.9
pNS SEM vs BASELINE
pc.02 SEM vs SEMRSOP
p=NS SEWISOP vs BASELINE
0.8
300
400
[
pc.04 AMIO vs BASELINE
paNS AMIO vs AMIO/ISOP
paNS AMIO/ISOP vs BASELINE
0.8
500
300
CYCLE LENGTH (ms)
400
1815
FIG 4. Graphs show frequency-dependent effects
on the ratio of the right ventricular effective refractory period and the action potential duration at 90%
repolarization (RVERP/APD9o). Left, Sematilide and
sematilide plus isoproterenol. Right, Amiodarone
and amiodarone plus isoproterenol. During isoproterenol administration to patients receiving sematilide, the RVERP/APD90 ratio was significantly
reduced (P=.02). Amiodarone significantly increased the RVERP/APD90 compared with baseline
values (P<.04), and isoproterenol had no significant effect on the RVERP/APD00.
50
CYCLE LENGTH (ms)
paced cycle lengths (P<.001 by ANOVA). The QRS
duration was increased from baseline by 23 6 ms (14%)
at a paced cycle length of 500 ms and by 52±8 ms (32%)
at a paced cycle length of 300 ms (P<.001). During
isoproterenol administration in patients receiving amiodarone, the QRS duration was reduced by 8±4 ms
(4%), 10±4 ms (5%), 8±4 ms (5%), and 10±3 ms (6%)
at paced cycle lengths of 300, 350, 400, and 500 ms,
respectively (P=.005), indicating isoproterenol-induced
facilitation of ventricular conduction. Isoproterenol did
not alter the frequency-dependent relation of amiodarone on ventricular conduction compared with
baseline.
±
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RVERP/APD90 Ratio
The baseline RVERP/APD90 ratio was increased at
shorter paced cycle lengths in both patient groups
(P<.01 by ANOVA). Sematilide (Fig 4) had no effect
on the RVERP/APD90 ratio compared with baseline.
However, during isoproterenol administration, the ratio
was significantly reduced compared with sematilide
alone (P<.04 versus sematilide), consistent with a
greater reduction in the RVERP than the APD%0 by
isoproterenol, particularly at shorter cycle lengths.
Amiodarone (Fig 4) significantly increased the
RVERP/APD90 ratio compared with baseline (P=.04),
consistent with greater prolongation of refractoriness
than repolarization. Isoproterenol had no significant
effect on this ratio (P=NS versus baseline or amiodarone alone).
patients receiving sematilide was significantly correlated
to the reduction in RVERP (r=.95, P=.014) but not to
changes in the APD9o (r=.68, P=NS) or QRS duration
(r=.52, P=NS). In the amiodarone group, sustained
monomorphic VT was induced in 17 patients and
sustained polymorphic VT in 5 patients during drugfree baseline electrophysiologic study. After amiodarone administration, sustained monomorphic VT was
inducible in 16 patients, sustained polymorphic VT was
inducible in 2 patients, and 4 patients had no inducible
sustained VT. Amiodarone significantly prolonged the
cycle length of morphologically similar monomorphic
ventricular tachycardias compared with baseline values
SEMATILIDE
D=.06
p=.06
"
400
I
350
p=.006
-
z
i
300
250
200
CO
BASELINE
SEM
SEM
lSOP
AMIODARONE
D<.001
1
400
p-.001
fD=.01 5
I
Ventricular Tachycardia Cycle Length
In the sematilide group, sustained monomorphic VT
was induced in 10 patients and sustained polymorphic
VT in 1 patient in the drug-free state. After sematilide
administration, sustained monomorphic VT was induced in 7 patients, and 4 patients had no inducible
sustained VT. When morphologically similar monomorphic VTs were compared, there was a nonsignificant
increase in the VT cycle length during sematilide therapy compared with baseline (Fig 5) but a significant
decrease in the VT cycle length during isoproterenol
administration compared with patients receiving sematilide (n=6; 317±19 versus 275+15 ms; P=.006). In
addition, there was a trend for the VT cycle length to be
decreased below baseline (n=6; 275±15 versus 298±55
ms; P=.06) during sematilide and isoproterenol. The
reduction in VT cycle length during isoproterenol to
350
z
W
W
300
250
C1)
200 _
FIG 5. Graphs show effect on sustained monomorphic ventricular tachycardia (VT) cycle length. Top, Baseline, sematilide,
and sematilide plus isoproterenol. Bottom, Baseline, amiodarone, and amiodarone plus isoproterenol. During isoproterenol
administration to patients receiving sematilide, the sustained VT
(SUS VT) cycle length was significantly reduced (P=.006) compared with sematilide alone and nonsignificantly reduced
(P=.06) compared with baseline drug-free values. Whereas
isoproterenol administration to patients receiving amiodarone
significantly reduced (P=.01 5) the sustained VT cycle length, the
sustained VT cycle length remained significantly prolonged
(P<.001) compared with baseline drug-free values.
1816
Circulation Vol 90, No 4 October 1994
(Fig 5), and the VT cycle length was significantly
decreased during isoproterenol administration (n=14;
363±19 to 329±19 ms, P=.015) compared with amiodarone alone. In contrast to sematilide, the VT cycle
length of patients receiving amiodarone and isoproterenol remained significantly prolonged compared with
baseline drug-free values (327±17 versus 257+12 ms,
P<.001). The reduction in VT cycle length during
isoproterenol in patients receiving amiodarone was not
significantly correlated to reductions in RVERP (r=.18,
P=NS), APD90 (r=.38, P=NS), or QRS duration
(r=.23, P=NS).
Discussion
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We have previously described the individual frequency-dependent actions of amiodarone36 and sematilide.5
This is the first study to examine the effects of /-adrenergic catecholamines on the electrophysiologic effects of
a pure class III agent and on the frequency-dependent
effects of amiodarone. The new findings of this study are
that (1) isoproterenol administration fully reversed the
effects of sematilide on the APD90 and further reduced
the RVERP to values significantly below baseline determinations; (2) isoproterenol partially attenuated but
did not fully reverse amiodarone-induced prolongation
of the APD¶0 and RVERP, which remained significantly
prolonged from baseline values; (3) isoproterenol exerted frequency-dependent effects in both patient
groups on the APD90, with a greater reduction in the
APD90 at longer than at shorter paced cycle lengths; (4)
isoproterenol modestly attenuated amiodarone-induced
conduction slowing without frequency-dependent effects; and (5) the sustained VT cycle length remained
significantly prolonged during isoproterenol administration to patients receiving amiodarone but not in patients
receiving sematilide.
Effects on Conduction
Sematilide, as previously described,5 had no effect on
ventricular conduction, and isoproterenol did not modify the QRS duration. Amiodarone's frequency-dependent slowing of ventricular conduction is consistent with
the drug's known ability to decrease Vmax by blocking Na
channels and slowing their recovery during the interpulse interval.3637 The observed partial reversal of
amiodarone's effects on conduction are consistent with
the finding that isoproterenol increases the inward
sodium current (INa) in rabbit cardiac myocytes23,24 and
guinea pig myocytes,26 although this has not been a
universal finding in isolated cells.42,43 Most pertinent to
the current study, Lee et a124 have recently shown that
isoproterenol antagonizes lidocaine-induced sodium
channel block in isolated rabbit cardiac myocytes and
attenuates but does not fully reverse lidocaine-induced
conduction slowing in isolated rabbit hearts. Epstein et
a144 have demonstrated that isoproterenol (approximately 150 ng/kg per minute) reversed amiodaroneinduced increases in His-Purkinje conduction time in
canines. We have extended these findings to humans by
demonstrating that isoproterenol partially reversed amiodarone-induced slowing of ventricular conduction and
that this attenuation of conduction slowing is not frequency dependent. The QRS duration was reduced by a
fixed amount of 4% to 6% at each paced cycle length.
Thus, isoproterenol may increase INa without altering
the steady-state kinetics of Na channel activation or
inactivation by amiodarone. This is consistent with the
finding in isolated rabbit myocytes that isoproterenol
increases INa without altering the kinetics of sodium
channel blockade or recovery by lidocaine (which has
similar Na channel-blocking kinetics as amiodarone).24
In addition to possible direct effects on the inward
sodium current, isoproterenol may improve conduction
during amiodarone administration (1) by decreasing the
APD,o with subsequent increases in the interpulse interval, allowing a longer time period for Na channel
recovery and subsequent facilitation of ventricular conduction; (2) by shortening the plateau, whereby there
may be less amiodarone binding to Na channels and less
amiodarone-induced reduction in INa45; (3) by causing
hyperpolarization of the cell with subsequent reduction
in amiodarone-induced Na blockade45; and (4) possibly
by facilitating conduction across gap junctions or improving cell-to-cell coupling.46
Effects on Repolarization and Refractoriness
This study demonstrates that a dose of isoproterenol
that results in physiological changes in heart rate in the
drug-free state consistent with moderate physical exercise caused sematilide-induced APD90 prolongation to
be fully reversed. Isoproterenol activates a variety of
ventricular myocyte currents including the delayed rectifier potassium current (IK), the Na-K pump current,
the transient outward potassium current ('to), the chloride current (Ici), and the slow inward calcium current
(ICa).'3'3 Although the effect of isoproterenol on isolated myocytes can be an increase or decrease in the
APD90,0 based on the relative activation of different
currents (eg, increases in IK or the Na-K pump current
shorten the APD90, whereas increases in Ica prolong
repolarization), we observed a consistent decrease in
sematilide and amiodarone-induced APD9o prolongation. The specific mechanism by which isoproterenol
reverses sematilide's effect on the APD90 is beyond the
scope of this study. However, in isolated guinea pig
myocytes, E-4031 (a specific blocker of the rapidly
activating component of the delayed rectifier potassium
current [IKr])-induced prolongation of the RVERP and
APD90 is reversed by isoproterenol secondary to isolated increases in lyS (the slowly activating component of
the delayed rectifier) and the chloride current.10 The
relative effects of sematilide on IKS and lK, have not been
defined, but it seems likely, based on the known effects
of isoproterenol, that isoproterenol reverses sematilide's effects by increasing one or more components of
the delayed rectifier (IK) along with the chloride
current.
When the RVERP/APD90 ratio is examined at baseline or after sematilide alone, the ratio increased at
shorter cycle lengths compared with longer cycle lengths
(P<.01), consistent with lengthening of the RVERP
relative to the APD90. This most likely reflects the lack
of full recovery of sodium channels during the interpulse interval with a mild subsequent prolongation of
the RVERP relative to the APD90 (ie, time-dependent
refractoriness).36'37'47 This phenomenon was not observed during isoproterenol in patients receiving sematilide. The significant reduction in the RVERP/APD9,
ratio during isoproterenol infusion compared with sematilide alone is consistent with the RVERP being
Sager et al f3-Adrenergic Stimulation
more sensitive to isoproterenol than is the APD90.
Overall, the RVERP was reduced by an additional
21±4 ms (P=.007) compared with the APD9O during
isoproterenol administration to patients receiving sematilide. Possible explanations for the lack of postrepolarization refractoriness during rapid pacing and isoproterenol infusion include (1) isoproterenol-induced
increases in the inward sodium current23 at each depolarization negating the RVERP prolonging effects of a
lack of full recovery of Na channels at the end of
repolarization, (2) shortening of the plateau with subsequent enhanced recovery of sodium channels, (3)
hyperpolarization of myocardial cells with more sodium
channels available at a fixed diastolic interval,25 and (4)
possibly an increase in the space constant by sematilide
enhancing the effects on the RVERP of any increase in
INa by isoproterenol.48
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In contrast to the results obtained with selective
delayed rectifier (IK) block by sematilide, amiodaroneinduced prolongation of the APD90 and RVERP was
attenuated during isoproterenol but still remained significantly prolonged beyond baseline. Thus, even during
moderate P-adrenergic stimulation, amiodarone still
exerted significant pharmacological effects. During isoproterenol, the sinus cycle length was reduced to values
below baseline, and the reduction in sinus cycle length
was similar to that observed during sematilide, whereas
the alterations in repolarization and refractoriness in
the amiodarone group were considerably less marked.
Although the difference in the response to jB-adrenergic
catecholamines during amiodarone at the sinus node
and in the ventricle may be explained by different
sensitivities of sinus nodal and ventricular tissue to
f3-adrenergic catecholamines, it raises the possibility
that amiodarone's relative protection from reversal of
repolarization and refractoriness during isoproterenol
may not be solely secondary to its antiadrenergic actions
but might also be related to direct effects on ionic
currents, such as nonselective block of IK.
It is interesting that there was a more marked reduction in the APD90 in both patient groups by isoproterenol at longer than at shorter paced cycle lengths.
Jurkiewicz and Sanguinetti49 have shown that during
rapid pacing, there is incomplete deactivation of the
slowly activating component of the delayed rectifier (IEG)
in myocytes exposed to dofetilide (a selective IKr
blocker), and Sanguinetti et a110 have demonstrated that
isoproterenol reverses APD90 prolongation by E-4031
by increasing IKS and the chloride current. Thus, if
isoproterenol-induced attenuation of amiodarone's or
sematilide's effect on repolarization is, in part, by
increasing IKS, these effects may be less pronounced at
shorter cycle lengths because rapid pacing has already
resulted in significant increases in IKS. Subsequently,
there is less contribution by isoproterenol to outward
repolarizing K currents at short paced cycle lengths.
Another possibility is that isoproterenol-induced potassium translocation into cells may decrease the normal
accumulation of potassium between cells during rapid
pacing, which has been shown to increase outward
potassium currents and enhance repolarization at short
cycle lengths.50,51
Previous Studies
Our results are consistent with those of Calkins et
al,22 who examined the reversal of amiodarone-induced
1817
prolongation of the RVERP during epinephrine infusion and observed a 20% to 36% relative reduction in
amiodarone-induced RVERP prolongation (frequencydependent effects and conduction were not measured).
The somewhat larger reductions in the RVERP in our
study along with the mild decrease in the VT cycle
length during isoproterenol in patients receiving amiodarone is probably related to the more potent P-adrenergic stimulation in the current investigation. Calkins et
a122 used epinephrine, which, on a weight basis, is not as
potent a stimulator of cardiac ,l-receptors as is isoproterenol. They only observed a reduction in the sinus
cycle length of 4.5% to 7.7% during epinephrine administration in patients receiving amiodarone compared
with 28% observed in the current study. In addition,
epinephrine stimulates a-receptors, which lengthens the
RVERP and may attenuate the effects of ,B-stimulation
on refractoriness.52 Brugada et a153 reported a significant reduction in antegrade accessory pathway effective
refractory period during isoproterenol infusion in patients receiving low-dose (200 mg/d) amiodarone therapy. Since the baseline accessory pathway ERP was not
determined, it is difficult to assess whether amiodarone's effects were fully reversed or simply attenuated.
In addition, the amiodarone dose used in the current
study was considerably higher and amiodarone's sensitivity to reversal may be dose related.
Clinical Implications
This is the first study in humans to examine the
potential for pure class III agents to have their electrophysiologic actions reversed by f3-adrenergic catecholamines, and the findings may have important clinical
implications. The full reversal of all of sematilide's
electrophysiological effects to values at or below baseline during isoproterenol administration suggests that
the antiarrhythmic actions of sematilide, and possibly
compounds with a similar electrophysiologic profile,
may be readily reversed during daily physical activities.
This could potentially leave patients without antiarrhythmic protection for variable periods of time and
may account for some episodes of arrhythmic recurrence despite favorable results during electropharmacological testing. Indeed, we have previously reported that
two of three arrhythmic recurrences that we have observed during sematilide therapy occurred during high
catecholaminergic states.5 Our findings raise the question of whether pure class III agents should be administered in conjunction with j3-blockers, although there is
a concern that bradycardia might increase the risk of
torsade de pointes. While this can only be answered by a
clinical trial, preliminary data do not appear to indicate
that d,l-sotalol has a higher incidence of torsade than
either d-sotalol or sematilide,5,54 and amiodarone, which
slows the heart rate and lengthens the APD90, has an
unusually low incidence of torsade de pointes. In addition, d,l-sotalol-induced increases in the APD90 and
RVERP are not attenuated during isoproterenol administration (similar dosing as used in this study), presumably due to the p-blocker properties of this compound.55
In contrast to the findings with sematilide, the continued
maintenance of electrophysiologic effects of amiodarone
during isoproterenol suggests that the high efficacy of this
agent may be due in part to its continued antiarrhythmic
effects during p-adrenergic stimulation. In addition to
1818
Circulation Vol 90, No 4 October 1994
maintained prolongation of the ventricular RVERP,
APD90, and conduction by amiodarone, the reduction in
the VT cycle length during isoproterenol administration
was only modest (mean, 34 ms), and the VT cycle length
remained significantly prolonged above baseline values,
suggesting that ,-adrenergic stimulation in patients receiving amiodarone is not likely to make a hemodynamically stable arrhythmia unstable by markedly decreasing
the VT cycle length.
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Limitations
Only a relatively narrow range of cycle lengths (300 to
500 ms) could be tested because of sinus interference at
longer cycle lengths and hemodynamic effects at shorter
paced cycle lengths. Effects on ventricular conduction
were inferred by measuring the QRS duration because
it correlates closely with changes in Vm,, in vitro.56
Because of time considerations, it was not possible to
administer an intravenous p-blocker during isoproterenol infusion to determine if ,B-blockade would reverse
all of the electrophysiologic effects of isoproterenol.
The effects of sematilide, amiodarone, or isoproterenol
on the electrophysiologic parameters of cells comprising
the arrhythmic circuit may be different from those at the
RV recording site.
Conclusions
The effects of pure IK block with sematilide on the
APD90 and RVERP are reduced to values at or significantly below baseline during isoproterenol administration, whereas amiodarone's effects on the APD9O,
RVERP, ventricular conduction, and VT cycle length
are attenuated but remain significantly prolonged beyond baseline during isoproterenol infusion. These findings may have important clinical implications regarding
protection from arrhythmia development in patients
receiving pure class III agents or amiodarone.
Acknowledgments
This study was supported in part by Veterans Administration Research Service funds and Berlex Laboratories (Wayne,
NJ). The authors would like to acknowledge Michael Antimisiaris, MD, for his expert assistance in performing the electrophysiologic studies, Peter Christenson, PhD, for statistical
analysis, and Diane Gertschen for preparation of the
manuscript.
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P T Sager, C Follmer, P Uppal, C Pruitt and R Godfrey
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Circulation. 1994;90:1811-1819
doi: 10.1161/01.CIR.90.4.1811
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