(Circulation. 1997;96:2701-2708.)
© 1997 American Heart Association, Inc.
Articles |
ß-Adrenergic Augmentation of Flecainide-Induced Conduction Slowing in Canine Purkinje Fibers
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn.
Correspondence to Kevin T. Cragun, MD, Mayo Foundation/St Marys Hospital, 1216 2nd St SW, Room 4-416 Alfred Bldg, Rochester, MN 55902. E-mail packer{at}mayo.edu
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Abstract |
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Background This study was undertaken to test the hypothesis that ß-adrenergic stimulation in the setting of membrane depolarization will potentiate flecainide-induced conduction slowing.
Methods and Results To elucidate the potential mechanism
for the flecainide proarrhythmia observed in CAST, the voltage
dependence of ß-adrenergic modulation of impulse propagation in eight
flecainide-superfused canine Purkinje fibers was examined with a
dual-microelectrode technique. At physiological
membrane potentials (Vm)
([K+]o=5.4 µmol), 1 µmol
flecainide decreased 
max from 698±55 to 610±72 V/s
(P=.003) and squared conduction velocity (
2)
from 2.11±1.1 to 1.72±0.9 (m/s)2 (P=.001).
With K+ depolarization to Vm=-70 mV,
flecainide further reduced max from 306±101 to
245±65 V/s and 2 from 1.12±0.4 to 0.99±0.6
(m/s)2, producing a 2.0-mV hyperpolarizing shift of
apparent Na+ channel availability curves derived from
2. The addition of 1 µmol isoproterenol to
flecainide-superfused fibers at physiological
Vm increased 2 by 8% to 1.84±0.6
(m/s)2 (P<.01) without altering
max. At -70 mV, the addition of isoproterenol
magnified the flecainide-induced reduction of max an
additional 24% to 185±52 V/s (P<.01) and 2
by 17% to 0.82±0.5 (m/s)2 (P=.04), producing
an additional 1.8-mV (P=.002) and 1.9-mV (P=.002)
hyperpolarizing shift in the apparent Na+ channel
inactivation curves generated from max and
2, respectively. At physiological
Vm, the action potential duration (APD95) was
reduced from 307±35 to 269±27 ms (P<.001) by flecainide
and subsequently to 217±4 ms (P<.001) with isoproterenol
addition. With 12 mmol/L K+, APD95
decreased from 198±23 to 182±17 ms (P=.005) with
flecainide and to 164±10 ms (P=.004) with
isoproterenol.
Conclusions At depolarized Vm, isoproterenol
amplified the flecainide-induced reduction of max
and 2, suggesting a further adrenergic-mediated
reduction of Na+ current. Consequently, the synergy between
catecholamines and flecainide at depolarized Vm
and the shortened APD95 could facilitate arrhythmogenesis
in the presence of underlying ischemia.
Key Words: flecainide • isoproterenol • receptors, adrenergic, beta • sodium
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Introduction |
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The Cardiac Arrhythymia Suppression Trial (CAST) demonstrated that patients with ventricular ectopy after myocardial infarction treated with flecainide or encainide had a higher mortality rate than their placebo-treated counterparts.1 Although the underlying mechanism is unknown, subgroup analyses suggest that ischemia played an important role in enhancing antiarrhythmic drug risk. The total death and cardiac arrest rates were significantly higher in patients who sustained a non–Q-wave myocardial infarction2 and in those not treated previously with thrombolytic therapy1 than in their less ischemic counterparts. Both observations support the likelihood that ischemia-related alterations of local cellular ionic and electrical milieu had a provocative role in the observed CAST outcome.
Several studies also support an additional contribution from sympathoadrenergic modulation. Post hoc analysis of the CAST data demonstrated that relative mortality risk in patients treated with ß-blockers and flecainide or encainide reverted back to that seen in the placebo group.3 Such a deleterious effect of sympathoadrenergic modulation of local drug action in diseased myocardium is further supported by the reversal of flecainide-induced increases in ventricular ectopy by ß-blockade4 in patients with underlying cardiomyopathies.
The plausibility of an untoward effect of ß-adrenergic stimulation has also been suggested by recent cellular studies. Several investigators5 6 7 8 9 10 have demonstrated that INa is reduced by ß-adrenergic stimulation in a variety of cell lines studied under patch-clamp. Similarly, Munger et al11 documented an analogous voltage-dependent amplification of conduction slowing at depolarized potentials in the presence of isoproterenol and a hyperpolarizing shift in apparent Na+ channel availability similar to that seen with membrane-active antiarrhythmic agents. These findings suggest that adrenergic stimulation and Na+ channel blockers might have additive effects under certain circumstances. Therefore, this study was undertaken to characterize the effect of voltage-dependent ß-adrenergic modulation of flecainide-induced conduction delay in a simple propagating system to test the hypothesis that ß-adrenergic stimulation can potentiate the effects of flecainide.
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Methods |
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Tissue Preparation
A left thoracotomy was performed on 17- to 23-kg mongrel dogs of either sex after the administration of 30 to 50 mg/kg IV pentobarbital anesthesia following a protocol approved by the Mayo Foundation Institutional Animal Care and Use Committee. The heart was rapidly excised and rinsed in chilled (1°C to 2°C) 20 mmol/L K+ gluconate solution. Unbranched Purkinje fibers 1.0 cm long were fixed in a fast-flow Lucite chamber and superfused with standard Tyrode's solution (in mmol/L: NaCl 129, NaHCO3 20, NaH2PO4 · H2O 0.9, dextrose 5.5, MgCl2 · 6H2O 0.5, CaCl2 2.5, and KCl 5.4) at a flow rate of 8 to 12 mL/min. Solution pH was maintained at 7.40±0.05 by equilibration with a 95% O2/5% CO2 gas mixture at 37±0.5°C.
Data Acquisition and Analysis
Glass micropipettes, beveled to a tip resistance of 10 to 12
M
and filled with 3.0 mol/L KCl, were coupled via a
Ag/AgCl wire to a high-impedance electrometer.11
Fibers were impaled at the middle and the distal end to record the
transmembrane potential (Vm). A 3 mol/L
K+ salt agar bridge held the bath at ground. Analog action
potentials were filtered, differentiated electronically, and held for
90 ms by a sample-hold peak detection circuit. The analog
differentiator max, derived from phase 0 of the
action potential, was linear from 50 to 800 V/s. In addition to serving
as an indirect indication of net membrane currents,
max served as a fiducial point for determining
interelectrode CD. Conduction velocity () was derived from the
interelectrode distance/CD (2.1±0.5 mm). Real-time membrane
potential (Vm) from the proximal microelectrode,
max from both microelectrodes, and CD were digitally
converted with an analog-to-digital conversion system at a sampling
frequency of 5 kHz at 15-bit accuracy.
Electrophysiological characteristics of the action
potentials were derived from digitized data with software developed in
our laboratory.
Stimulation Protocol
The proximal end of the Purkinje fiber was stimulated with a
1-ms constant-current pulse delivered by a pair of Teflon-coated silver
wires. A 700-ms stimulus interval was used throughout to maximize
flecainide-induced use-dependent changes in max and
CD while minimizing loss of tissue excitability seen at more rapid
stimulation rates. Stimulus intensity was set at 2.5 times
diastolic threshold immediately before initiation of each
stimulus protocol and was increased during K+ titration, if
needed, to maintain consistent latency over each run. Data were
rejected for analysis if conduction latency changed by >5%
while the stimulus intensity was varied from 1.5 to 3 times threshold
before each run, if conduction was discontinuous, or if impalements
were lost during the experiment.
Experimental Solutions and Protocol
After a 1-hour Purkinje fiber equilibration period in control
Tyrode's solution, data were obtained at a baseline
[K+]o=5.4 mmol/L. Continuous
max and CD measurements were made at progressively
less negative Vm accompanying subsequent K+
titration to [K+]o=12.0 mmol/L by
use of a technique described by Chen and Gettes12 and
Munger et al.11 This level was chosen to replicate the
[K+]o seen during early
ischemia.13 After depolarization and data
acquisition, the high-K+ solution was washed out to
[K+]o=5.4 mmol/L to restore all
parameters to baseline values. The Purkinje fibers were
superfused with micromolar flecainide for a 30- to 45-minute period to
reach steady-state effect before complete data acquisition was repeated
at normal Vm and during a repeat K+
titration/washout sequence. Flecainide with
1x10-6 mol/L isoproterenol was then
substituted, and the fibers were again superfused for a minimum of 15
to 20 minutes. This concentration has known effects on the
voltage-dependent modulation of INa in
vitro5 6 7 8 9 10 and is representative of
catecholamine release during peak
ischemia.14 15 At the new steady state, the
K+ titration/washout sequences were repeated in the
presence of the flecainide/isoproterenol solution.
Data Analysis
The relationships of 2, CD, and
max to Vm in each setting were
documented by continuous recordings during K+
titration in each test state and described further by the Boltzmann
function.11 All data are reported as the mean±SD. The
significance of differences between values was determined by the
two-tailed t test, with P<.05 considered
significant.
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Results |
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Effects of Flecainide at Physiological and Depolarized Vm
Compared with control conditions at physiological Vm, the addition of 1 µmol/L flecainide to eight Purkinje fibers reduced
max by 13% from 698±55 to 610±72 V/s
(P<.003) and reduced 2 by 18% from
2.11±1.1 to 1.72±0.9 (m/s)2 (P<.001) (Table 1
). The APD was reduced at 95%
repolarization from 307±35 to 269±27 ms (P<.001), as
reflected by Fig 1. Flecainide-induced
changes began within 3 minutes of solution change and gradually
increased during the 30 to 45 minutes required to reach steady state.
With 12 mmol/L K+-induced membrane
depolarization to at least -70 mV, CD in eight fibers increased by
36% to 2.62±0.9 ms (P<.002) while 2
decreased by 42% to 0.99±0.6 (m/s)2 (P<.03)
and max fell by 56% to 245±65 V/s
(P<.001). In addition, APD50,
APD75, and APD95 all declined significantly
(P<.002), as shown in Table 2.
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ß-Adrenergic Modulation of Flecainide Effects at
Physiological Vm
The addition of 1 µmol/L isoproterenol to the
flecainide superfusate at normal Vm partially
reversed the flecainide-induced conduction changes: CD fell to
1.84±0.6 ms (P<.001) and 2 increased to
1.86±0.9 (m/s)2 (P<.001). Thus, 40% of the
flecainide effect on CD and 33% of the effect on 2 were
reversed by isoproterenol at normal Vm, although
max was not altered. Further reductions of APD and
increases in action potential amplitude were also noted with
isoproterenol addition (Table 1
). These changes occurred within 3
minutes of the start of isoproterenol, and steady state was achieved
within 15 to 20 minutes.
Voltage Dependence of ß-Adrenergic Modulation of Flecainide
Effects
After washout of K+ to
physiological Vm, depolarization with
external K+ in the presence of flecainide/isoproterenol
magnified the effects produced by flecainide alone. Specifically, CD
increased by an additional 11% to 2.92±1.2 ms (P=NS),
2 decreased by 18% to 0.82±0.5 (m/s)2
(P<.05), and max declined by 24% to
185±52 V/s (P<.003). In addition, APD95 was
further abbreviated (P<.005).
Effects of Flecainide and Isoproterenol on Apparent Na+
Channel Inactivation
Boltzmann curves fit to the 2-Vm
relation for both flecainide and flecainide/isoproterenol demonstrated
a hyperpolarizing shift in apparent Na+ channel
availability, as shown from a single fiber in Fig 2 and for all fibers in Fig 3. Flecainide reduced 2
and max at all Vm (Fig 3a and 3b). When
normalized to maximum values during control conditions, flecainide
superfusion shifted the midpoint of the 2 inactivation
curve -2.0 mV, from -67.6±2.0 to -69.6±1.7 mV
(P<.004), and the midpoint of the max
curves -1.9 mV, from -70.0±2.5 to -71.9±1.8 mV
(P<.001).
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In contrast to the effects seen with flecainide alone, the increase in
2 at normal Vm and the reduction in
2 at -70 mV with isoproterenol produced a crossover in
the apparent inactivation curves at -75 mV (Fig 3a). A crossover in
the max inactivation curves was not seen (Fig 3b).
Relative to flecainide, isoproterenol addition shifted the midpoint of
the 2 inactivation curve another -1.9 mV (range, -0.3
to -3.7 mV) to -71.5±1.2 mV (P<.002) (Fig 3c). The
max inactivation curve shifted -1.8 mV (range,
-0.5 to -3.1 mV) to -73.7±1.3 mV (P<.002) (Fig 3d). The
slope of the Boltzmann relation derived from 2 was
unchanged, but it increased slightly, from -4.0±0.2 to -3.4±0.5
(P<.013), when derived from max.
Midpoints for the inactivation curves derived from 2
were 5 to 6 mV more depolarized than when derived from
max, and the slopes were slightly steeper.
Effect of Flecainide and Isoproterenol on the
2:max Relation
The effects of both flecainide and flecainide/isoproterenol on the
2:max relation were determined over
the range of Vm encountered with K+
depolarization. As seen in a single fiber in Fig 4a, normalized data in the absence of
drug demonstrated an increase in 2 with the initial 10%
decline in max. With further depolarization, the
decreases in 2 and max were more
proportional. The addition of flecainide reduced both 2
and max and blunted the enhanced excitability seen
with early K+ depolarization at baseline and distorted the
2:max relationship minimally. As also
seen in Figs 3a and 3b, the subsequent isoproterenol reversal of
flecainide-induced conduction slowing at normal Vm produced
an upward shift in the initial portion of the
2:max relationship. With further
K+ depolarization, the relationship remained essentially
linear, with comparable y intercepts of 0.17 to 0.18 (Fig 4b) in each state. The addition of flecainide decreased the slope
slightly, but the addition of isoproterenol returned the slope of the
relationship toward that seen in controls.
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ß-Adrenergic Modulation Dependent on Flecainide
Concentration
The effect of isoproterenol was dependent on the flecainide
concentration. Whereas 1 µmol/L flecainide increased CD
by 11% at normal Vm, 2.1 µmol/L flecainide
solution increased CD by 21% from 1.45±0.31 to 1.75±0.36 ms
(P=.001) (Fig 5).
Isoproterenol reversed 45% of the CD due to 1 µmol/L
flecainide (P=.008) but only 15% of that due to 2.1
µmol/L flecainide (P=.045). At depolarized
Vm, the 1 and 2.1 µmol/L flecainide increased
CD by 22% and 48% relative to control, whereas the addition of
isoproterenol prolonged CD an additional 58% (P=.047) and
21% (P=.25), respectively. The higher flecainide
concentration reduced max from 332±76 to 188±43
V/s (P<.001) at depolarized Vm, with an
additional decrease to 151±60 V/s with isoproterenol addition.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, ß-adrenergic modulation of flecainide-induced conduction slowing in canine Purkinje fibers was voltage dependent. Although the flecainide effect was partially reversed at normal membrane potentials, isoproterenol amplified flecainide-induced reductions in
max and 2 at
depolarized potentials and shifted apparent inactivation curves in a
hyperpolarizing direction. Additionally, the relationship between
max and 2 during
K+-induced membrane depolarization remained nearly linear
both in the presence of flecainide and with ß-adrenergic
stimulation.
Flecainide Effects on Conduction
Flecainide-induced changes in conduction were concentration
dependent and proportional to reductions in max
observed in this and other studies of canine Purkinje fibers at
comparable drug concentrations.16 17 The shift in the
apparent Na+ channel inactivation curve derived from
2 was also consistent with those derived from
normalized Vmax.18 19 Flecainide-induced
changes in 2 were also linearly related to reductions in
max as predicted by the cable equation and as seen
with other antiarrhythmic drugs.20 21 Therefore,
flecainide-induced reductions in 2 reasonably reflected
apparent drug-channel interaction in this simple one-dimensional
propagating system.
Voltage-Dependent Effects of Isoproterenol on Conduction
The adrenergic modulation of flecainide-induced conduction slowing
was effectively voltage dependent. Isoproterenol reversed
flecainide-induced conduction slowing at normal Vm but
amplified it at depolarized potentials. Candidate mechanisms for the
"apparent" adrenergic reduction of flecainide effect at
physiological membrane potentials include the
modification of unbound channels yielding increased
INa, modification of flecainide-binding
kinetics, or alteration of passive membrane properties. Whole-cell and
voltage-clamp studies conducted at normal or hyperpolarized membrane
potentials have demonstrated a 10% to 56% isoproterenol-mediated
increase of INa,22 23 and studies
performed with Purkinje fibers have shown a 12% increase in
2.11 Similar cAMP-mediated22
or PKC-mediated10 24 increments in
INa22 under such conditions have
also been documented. An increase in egress of drug from a resting
channel should also decrease net block. In preliminary work, such an
increase in lr describing flecainide unbinding
due to isoproterenol has been observed.25
Whether 2 augmentation is due solely to
adrenergic-mediated Na+ channel modulation in this study,
however, is challenged by the finding that 2 and
max were differentially affected by isoproterenol at
normal Vm. Isoproterenol reversed the flecainide reduction
in 2 without altering max,
consistent with the possibility that altered passive membrane
properties were responsible for isoproterenol's enhancement of
conduction at normal resting Vm. This is evident in Fig 5
and is supported by the previous finding of DeMello26 27
that micromolar isoproterenol increases gj by 40% through
cAMP-dependent protein kinase action. It has been estimated that
conduction could increase by 10%28 with this magnitude of
change in gj, which is consistent with our
findings.
Isoproterenol Potentiation of Conduction Slowing
The isoproterenol-mediated amplification of flecainide effect at
depolarized membrane potentials contrasts with the observations made at
normal Vm. The hyperpolarizing shift in the apparent
Na+ channel inactivation curve derived from
2 was consistent with the observations of others
using max11 or
INa as measures of sodium conductance reduction
by isoproterenol.5 6 7 8 29 The maintenance of the
linear relationship between max and 2
observed under control conditions and in the presence of flecainide and
isoproterenol also supports the modulation of active membrane
properties as the predominant mechanism of ß-adrenergic augmentation
of flecainide effect.
It is possible that the observed decreases in max
and 2 are simply manifestations of the voltage-dependent
isoproterenol modulation of unbound Na+ channels. Previous
investigations have demonstrated that isoproterenol reduces
max by 25% to 51%11 30 and
INa by 41% to 45%5 6 7 31 in the
setting of membrane depolarization. Other investigators have also seen
isoproterenol-induced decreases in INa in intact
tissue. Kirstein et al9 observed 37% decreases in rat
papillary muscle INa studied from depolarized
holding potentials under loose attached patch. In contrast,
INa increased by 68% when the preparations were
studied from hyperpolarized membrane potentials.9 Murray
et al32 documented clear reductions in
INa from expressed recombinant human cardiac
Na+ channels with PKC activation by phorbol
myristate acetate, an effect that was partially abated by point
mutation of a consensus PKC phosphorylation site
(serine 1503) in the II-IV interdomain linker. Li et al33
also observed that phosphorylation mediated by
cAMP-dependent protein kinase reduced peak rat brain
INa, but only in the presence of OAG
pretreatment, indicating that PKC phosphorylation was
required for the cAMP–protein kinase effector response. These data
suggest that decreases in INa due to
cAMP-dependent protein kinase occur because of
phosphorylation at one or more of the four consensus
phosphorylation sites in the interloop I/II region of
the 
-subunit of the Na+ channel, but only when a serine
moiety in the interloop III/IV region is permissibly
phosphorylated in a reaction involving
PKC.10 34
Minor modulation of passive properties could contribute to changes in
impulse propagation in the presence of flecainide. Increases in
[Ca2+]i related to isoproterenol could
decrease gj and thereby slow conduction. Prior studies,
however, indicate that changes in intracellular calcium may be too
small to alter gj,35 36 37 even under conditions
of marked membrane depolarization with up to 50 mmol/L
K+.35 Furthermore, the general preservation of
the linear relationship between 2 and
max during K+ depolarization, even in
the presence of isoproterenol, militates against appreciable
modifications of passive properties.
Finally, it is possible that phosphorylation of the channel proteins could enhance flecainide binding or reduce flecainide egress from the channel interior. Because flecainide (pKa=9.3) is an active-state blocker,18 38 any shift in the hyperpolarizing direction, leading to increased channel inactivation, may lead to drug trapping and therefore accumulation of block at depolarized potentials. Furthermore, the limited additional conduction slowing when isoproterenol was added to fibers exposed to 2.1 µmol/L flecainide favors ß-adrenergic modulation of unbound Na+ channels.
These findings are at odds with those of Lee et al,39 however, who found that isoproterenol reversed lidocaine-induced INa examined at normal Vm by whole-cell patch techniques applied to rabbit ventricular myocytes. No isoproterenol effect was observed at depolarized Vm.39 This variance may be related to differences in species, pulse protocols, or study drugs used.
Mechanistic and Clinical Implications for Proarrhythmia
Our demonstration of the voltage-dependent effects of
isoproterenol on flecainide-induced conduction slowing has several
important implications. First, an extrapolation of these data to the
intact heart suggests that ß-adrenergic modulation should reverse
conduction slowing and prolongation of refractoriness produced by
flecainide under normal conditions, as seen with other agents in a
variety of cellular,39 40 intact-animal,41 42
and clinical studies.43 44 45 46 47 Although this could be
beneficial in the setting of drug toxicity, such reversal of drug
effects may be counterproductive in terms of drug efficacy in other
cases.45 46 47 This has led to the recommendation that
ß-blockers be administered concomitantly to patients receiving type I
antiarrhythmic agents in an effort to counter such a reversal of
beneficial drug effects occurring during enhanced
catecholamine states.45 46
These data also further elucidate an additional contributor to flecainide proarrhythmia under ischemic conditions. In such a setting, the development of hyperkalemia, hypoxia, acidosis, catecholamine release, and accompanying membrane depolarization may profoundly affect drug binding and unbinding of antiarrhythmic drugs,20 48 49 leading to electrophysiological behaviors substantively different from those observed in the absence of ischemia.
In theory, the additional catecholamine amplification of
flecainide action could also increase the propensity for untoward
arrhythmias. First, the decrease in apparent Na+
currents, as reflected by changes in 2 or
max, translate into a further decline in source
current for subsequent impulse propagation. Thus, additional decreases
in excitability and further increases in conduction slowing would be
expected to lead to a greater propensity for or vulnerability to
unidirectional block in response to a premature
complex.50 51 52 53 The difference in flecainide effect observed
in the depolarized versus normally repolarized tissue may also
translate into further dispersions of excitability and conduction
favoring the occurrence of reentrant arrhythmia.
Catecholamine effects may contribute to arrhythmogenesis by yet another mechanism. Brugada et al54 demonstrated that the wavelength of a reentrant ventricular tachycardia, defined as the product of the refractory period and conduction velocity, may suddenly decrease during programmed ventricular stimulation. In some cases, the superimposition of a second wave front within the same circuit occurred in flecainide-treated myocardium.53 In the presence of ischemia and further adrenergically mediated reductions in refractoriness, the likelihood of sustained double reentrant arrhythmias should increase. This, along with the production of multiple reentrant circuits of smaller dimensions,53 might more realistically explain the unstable arrhythmias leading to sudden death in the CAST trial, although proof of both mechanisms in humans must await further clinical studies.
Such a catecholamine contribution to proarrhythmia is suggested by the findings of Peters et al,55 who noted a peak in mortality rates during early morning waking hours, the time when catecholamines reach show peak diurnal levels.56 The demonstration by Myerburg et al4 of a ß-blocker–mediated reduction in flecainide-induced increases in ventricular ectopy in patients with dilated cardiomyopathies provides additional support. The reversal of the negative flecainide effect in CAST by ß-blockers in post hoc subgroup analyses provides the strongest support for such a detrimental role of adrenergic modulation of drug effects in facilitating proarrhythmia.3
Limitations
Several study limitations should be borne in mind when
interpreting these data. First, the specific relationship between
sodium conductance and max is unclear11
and may or may not be further distorted by the addition of
isoproterenol. Other contaminating currents could also lead to a
distortion of the max measured in these Purkinje
fibers. By manual alteration of the sampling period of the voltage
differentiator, however, a slow ICa contributor
to the upstroke of the action potential could be readily isolated from
the first, or rapid, phase of the action potential upstroke. Previous
studies from our laboratory have also shown a persistence of
isoproterenol potentiation of conduction slowing at depolarized
membrane potentials in the presence of the calcium channel blocker
nisoldipine.11 It is also unlikely that a
voltage-independent reduction in max, attributable
to suppression of a background K+
conductance,57 altered our quantitative results, given the
consistency of changes in max and
2 with identical K+ titration procedures
used during all protocol stages. Finally, these data derived from
Purkinje fibers may not apply to intact ventricular
myocardium, given the differences in intrinsic
currents.
Additional studies will obviously be required to extend these data to ventricular myocardium and to further examine the additional effects of acidosis, hypoxia, and changes in cellular coupling, as present during ischemia but incompletely replicated by our model. Nevertheless, these data demonstrate voltage-dependent modulation of flecainide effects by isoproterenol. Such augmentation of flecainide-induced conduction slowing by adrenergic agonists may help explain the excess morbidity and mortality in CAST patients with coronary artery disease and previous myocardial infarctions that were reduced by concomitant treatment with ß-blockers.
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Acknowledgments |
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This study was supported in part by Grant-in-Aid 92-012820 from the National American Heart Association.
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Footnotes |
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Reprint requests to Douglas L. Packer, MD, Mayo Foundation/St Marys Hospital, 1216 2nd St SW, Room 4-416 Alfred Bldg, Rochester, MN 55902.
Received October 30, 1996; revision received May 12, 1997; accepted May 22, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. CAST Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction: the Cardiac Arrhythmia Suppression Trial (CAST) Investigators. N Engl J Med. 1989;321:406-412.[Abstract]
2.
Anderson J, Platia E, Hallstrom A, Henthorn R,
Buckingham T, Carlson M, Carson P. Interaction of baseline
characteristics with the hazard of encainide, flecainide, and
moricizine therapy in patients with myocardial infarction: a possible
explanation for increased mortality in the Cardiac Arrhythmia
Suppression Trial (CAST). Circulation. 1994;90:2843-2852.
3. Kennedy H, Brooks M, Barker A, Bergstrant R, Huther M, Beanlands D, Biller J, Goldstein CI. Beta-blocker therapy in the cardiac suppression trial. Am J Cardiol. 1994;74:674-680.[Medline] [Order article via Infotrieve]
4.
Myerburg RJ, Kessler KM, Cox MM, Huikuri H, Terracall
E, Interian AJ, Fernandez P, Castellanos A. Reversal of
proarrhythmic effects of flecainide acetate and encainide hydrochloride
by propranolol. Circulation. 1989;80:1571-1579.
5.
Schubert B, Vandongen AM, Kirsch GE, Brown AM.
Inhibition of cardiac Na+ currents by
isoproterenol. Am J Physiol. 1990;258:H977-H982.
6.
Schubert B, VanDongen AM, Kirsch GE, Brown AM.
Beta-adrenergic inhibition of cardiac sodium channels by dual G-protein
pathways. Science. 1989;245:516-519.
7.
Ono K, Kiyosue T, Arita M. Isoproterenol,
DBcAMP, and forskolin inhibit cardiac sodium current.
Am J Physiol. 1989;256:C1131-C1137.
8.
Ono K, Fozzard H, Hanck D. Mechanism of
cAMP-dependent modulation of cardiac sodium channel current
kinetics. Circ Res. 1993;72:807-815.
9. Kirstein M, Eickhorn R, Langenfeld H, Kochsiek K, Antoni H. Influence of ß-adrenergic stimulation on the fast sodium current in the intact rat papillary muscle. Basic Res Cardiol. 1991;86:441-448.[Medline] [Order article via Infotrieve]
10.
Li M, West H, Numann R, Murphy B, Scheuer T, Catterall
W. Convergent regulation of sodium channels by protein kinase C
and cAMP-dependent protein kinase. Science. 1993;261:1439-1442.
11.
Munger T, Johnson S, Packer D. Voltage
dependence of ß-adrenergic modulation of conduction in the canine
Purkinje fiber. Circ Res. 1994;75:511-519.
12. Chen C, Gettes L. Combined effects of rate, membrane potential, and drugs on maximum rate of rise (Vmax) of action potential upstroke of guinea pig papillary muscle. Circ Res. 1976;1976:464-469.
13.
Hill J, Gettes L. Effects of acute
coronary artery occlusion on local myocardial extracellular
K+ activity in swine. Circulation. 1980;61:768-778.
14. Hirche H, Franz C, Boes L, Bissig R, Schrann M. Myocardial extracellular K+ and H+ increase and noradrenaline release as possible causes of early arrhythmias following acute coronary artery occlusion in pigs. J Mol Cell Cardiol. 1980;12:579-593.[Medline] [Order article via Infotrieve]
15. Lammerant J, DeHert P, DeSchryver C. Direct release of catecholamine into the left heart chambers: the enhancing effect of acute coronary occlusion. Arch Int Pharmacodyn Ther. 1966;163:219-229.[Medline] [Order article via Infotrieve]
16. Kinnaird A, Lederman C, Man R. Electrophysiological actions of flecainide in normal and infarcted canine Purkinje fibers. Eur J Pharmacol. 1985;112:57-64.[Medline] [Order article via Infotrieve]
17. Ikeda N, Singh BN, Davis LD, Hauswirth O. Effects of flecainide on the electrophysiologic properties of isolated canine and rabbit myocardial fibers. J Am Coll Cardiol. 1985;5:303-310.[Abstract]
18.
Anno T, Hondeghem L. Interactions of flecainide
with guinea pig cardiac sodium channels. Circ Res. 1990;66:789-803.
19. Konzen G, Reichardt B, Hauswirth O. Fast and slow blockade of sodium channels by flecainide in rabbit cardiac Purkinje fibers. Naunyn Schmiedebergs Arch Pharmacol. 1990;341:565-576.[Medline] [Order article via Infotrieve]
20.
Buchanan JJ, Saito T, Gettes L. The effects of
antiarrhythmic drugs, stimulation frequency, and potassium-induced
resting membrane potential changes on conduction velocity and dV/dtmax
in guinea pig myocardium. Circ Res. 1985;56:696-703.
21. Packer DL, Grant AO, Strauss HC, Starmer CF. Characterization of concentration- and use-dependent effects of quinidine from conduction delay and declining conduction velocity in canine Purkinje fibers. J Clin Invest. 1989;83:2109-2119.
22. Ono K, Hidaka H, Fozzard H. Na+ channel kinetic changes by cAMP and isoproterenol in canine cardiac ventricular cells. Biophys J. 1992;61:A112. Abstract.
23.
Matsuda JJ, Lee H, Shibata EF. Enhancement of
rabbit cardiac sodium channels by beta-adrenergic stimulation.
Circ Res. 1992;70:199-207.
24.
West J, Numann R, Murphy B, Scheuer T, Catterall
W. A phosphorylation site in the Na+
channel required for modulation by protein kinase C.
Science. 1991;254:866-868.
25. Cragun K, Johnson S, Packer D. Direct characterization of flecainide binding rates from use-dependent conduction delay in canine Purkinje fibers. J Am Coll Cardiol. 1995;25:284A. Abstract.
26. DeMello W. Effect of isoproterenol and 3-isobutyl-1-methylxanthine on junctional conductance in heart cell pairs. Biochim Biophys Acta. 1989;1012:291-298.[Medline] [Order article via Infotrieve]
27. DeMello W. Further studies on the influence of cAMP-dependent protein kinase on junctional conductance in isolated heart cell pairs. J Mol Cell Cardiol. 1991;23:371-379.[Medline] [Order article via Infotrieve]
28.
Spray D, Burt J. Structure-activity relations of
the cardiac gap junction channel. Am J Physiol. 1990;258:C195-C205.
29. Hisatome I, Kiyosue T, Imanishi S, Arita M. Isoproterenol inhibits residual fast channel via stimulation of beta-adrenoceptors in guinea-pig ventricular muscle. J Mol Cell Cardiol. 1985;17:657-665.[Medline] [Order article via Infotrieve]
30. Hashimoto K, Moe GK. Effect of external potassium and acetylstrophanthidin on conduction velocity of isolated canine Purkinje fibers. Jpn J Pharmacol. 1985;37:355-363.[Medline] [Order article via Infotrieve]
31.
Qu Y, Rogers J, Tanada T, Scheuer T, Catterall
WA. Modulation of cardiac Na+ channels expressed in
a mammalian cell line and in ventricular myocytes by
protein kinase C. Proc Natl Acad Sci U S A. 1994;91:3289-3293.
32.
Murray K, Hu N, Daw J, Shin H, Watson M, Mashburn A,
George A. Functional effects of protein kinase C activation on
the human cardiac Na+ channel. Circ Res. 1997;80:370-376.
33. Li M, West JW, Lai Y, Scheuer T, Catterall WA. Functional modulation of brain sodium channels by cAMP-dependent phosphorylation. Neuron. 1992;8:1151-1159.[Medline] [Order article via Infotrieve]
34.
Murphy BJ, Rossie S, De Jongh KS, Catterall WA.
Identification of the sites of selective
phosphorylation and dephosphorylation
of the rat brain Na+ channel alpha subunit by
cAMP-dependent protein kinase and phosphoprotein phosphatases.
J Biol Chem. 1993;268:27355-27362.
35. Sheu SS, Sharma VK, Korth M. Voltage-dependent effects of isoproterenol on cytosolic Ca++ concentration in rat heart. Am J Physiol. 1987.
36. Maurer P, Weingart R. Cell pairs isolated from adult guinea pig and rat hearts: effects of (Ca++)i on nexal membrane resistance. Pflugers Arch. 1987;409:394-402.[Medline] [Order article via Infotrieve]
37. Spray DC, White RL, Mazet F, Bennett MVL. Regulation of gap junctional conductance. Am J Physiol. 1985;248:H753-H764.
38. Nitta J, Sunami A, Marumo F, Hiraoka M. States and sites of actions of flecainide on guinea-pig cardiac sodium channels. Eur J Pharmacol. 1992;214:191-197.[Medline] [Order article via Infotrieve]
39. Lee HC, Matsuda JJ, Reynertson SI, Martins JB, Shibata EF. Reversal of lidocaine effects on sodium currents by isoproterenol in rabbit hearts and heart cells. J Clin Invest. 1993;91:693-701.
40.
Munger T, Steck S, Packer D. Reversal of
adrenergic modification of quinidine-induced suppression of conduction
velocity in the canine Purkinje fiber: the uncoupling of
2 from Vmax. Pacing Clin
Electrophysiol. 1991;14:726.
41. Newman D, Herre J, Chin M, Garcia J, Franz M, Sheinman M, Katzung B. Effects of sympathetic tone and action potential duration on in vivo use-dependence. Circulation. 1988;78(suppl II):II-146. Abstract.
42. Avitall B, Hare J, Tchou P, Jazayeri M, Akhtar M. Flecainide toxicity: reversal of drug effects by isoproterenol infusion. J Cardiovasc Electrophysiol. 1991;2:431-440.
43. Morady F, Kou WH, Kadish AH, Nelson SD, Toivonen LK, Kushner JA, Schmaltz S, deBuitleir M. Antagonism of quinidine's electrophysiologic effects by epinephrine in patients with ventricular tachycardia. J Am Coll Cardiol. 1988;12:388-394.[Abstract]
44. Sager P, Ahmen R, Behboodikhah M, Follmer C, Pruitt C, Singh B. Differential electrophysiologic actions of beta-adrenergic stimulation on sotalol and quinidine in humans. J Am Coll Cardiol. 1993;21:245A. Abstract.
45. Jazayeri MR, Van WG, Avitall B, McKinnie J, Tchou P, Akhtar M. Isoproterenol reversal of antiarrhythmic effects in patients with inducible sustained ventricular tachyarrhythmias. J Am Coll Cardiol. 1989;14:705-711.[Abstract]
46. Niazi I, Naccarelli G, Dougherty A, Rinkenberger R, Tchou P, Akhtar M. Treatment of atrioventricular node reentrant tachycardia with encainide: reversal of drug effect with isoproterenol. J Am Coll Cardiol. 1989;13:904-910.[Abstract]
47.
Markel M, Miles W, Luck J, Klein L, Prystowsky
E. Differential effects of isoproterenol on sustained
ventricular tachycardia before and during
procainamide and quinidine antiarrhythmic drug therapy.
Circulation. 1993;87:783-792.
48.
Grant A, Trantham J, Brown K, Strauss H.
pH-dependent effects of quinidine on the kinetics of dV/dtmax in guinea
pig ventricular myocardium. Circ
Res. 1982;50:210-217.
49.
Hille B. The pH-dependent rate of action of
local anesthetics on the node of Ranvier. J Gen
Physiol. 1977;69:475-496.
50.
Ranger S, Nattel S. Determinants and mechanisms
of flecainide-induced promotion of ventricular
tachycardia in anesthetized dogs.
Circulation. 1995;92:1300-1311.
51.
Coromilas J, Saltman A, Waldecker B, Dillon S,
Wit A. Electrophysiological effects of
flecainide on anisotropic conduction and reentry in infarcted canine
hearts. Circulation. 1995;91:2245-2263.
52.
Starmer C, Lastra A, Nesterenko V, Grant A.
Proarrhythmic response to sodium channel blockade: theoretical model on
numerical experiments. Circulation. 1991;84:1364-1377.
53.
Brugada J, Boersma L, Kirchhof C, Allessie M.
Proarrhythmic effects of flecainide: experimental evidence for
increased susceptibility to reentrant arrhythmias.
Circulation. 1991;84:1808-1818.
54.
Brugada J, Boersma L, Kirchhof C, Brugada P, Havenith
M, Wellens H, Allessie M. Double-wave reentry as a mechanism of
acceleration of ventricular
tachycardia. Circulation. 1990;81:1633-1643.
55. Peters RW, Muller JE, Goldstein S, Byington R, Friedman LM. Propranolol and the morning increase in the frequency of sudden cardiac death (BHAT Study). Am J Cardiol. 1989;63:1518-1520.[Medline] [Order article via Infotrieve]
56. Turton M, Deegan T. Circadian variations of plasma catecholamine, cortisol, and immunoreactive insulin concentrations in supine subjects. Clin Chim Acta. 1974;55:389-397.[Medline] [Order article via Infotrieve]
57.
Whalley D, Wendt D, Starmer C, Rudy Y, Grant A.
Voltage-independent effects of extracellular K+ on the
Na+ current and phase 0 of the action potential in isolated
cardiac myocytes. Circ Res. 1994;75:491-502.
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