(Circulation. 1995;92:1300-1311.)
© 1995 American Heart Association, Inc.
Articles |
Determinants and Mechanisms of Flecainide-Induced Promotion of Ventricular Tachycardia in Anesthetized Dogs
From the Department of Medicine (S.N.), Montreal Heart Institute and the University of Montreal, and Department of Pharmacology and Therapeutics (S.R., S.N.), McGill University, Montreal, Canada.
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Abstract |
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Background Class IC antiarrhythmic agents such as flecainide are known to have potentially significant ventricular proarrhythmic actions, but the underlying mechanisms are incompletely understood. While some studies have reported proarrhythmia in both healthy dogs and dogs that previously have had a myocardial infarction (MI), there are no published, controlled studies comparing proarrhythmia in healthy dogs vs in dogs with MI. In addition, the concentration dependence of proarrhythmia is unknown and the electrophysiological changes associated with proarrhythmia are not well established.
Methods We administered successive loading and maintenance infusions of flecainide until ventricular tachyarrhythmia or death occurred in 13 healthy dogs and 19 dogs with 72-hour-old MIs (MI dogs). Ventricular proarrhythmia, defined as reproducible ventricular tachycardia absent under control conditions and occurring in the presence of flecainide, was observed in 4 of 13 healthy dogs (31%) and 15 of 19 MI dogs (79%, P=.02), and drug-induced spontaneous ventricular tachycardia occurred in 8 of 19 MI dogs but in no healthy dogs (P=.007). Activation data at the time of proarrhythmia were available for 11 MI dogs and provided evidence for reentry in 9, with a complete epicardial reentry circuit identified in 4 dogs and a partial circuit in 5. While flecainide slowed ventricular conduction in both the longitudinal and transverse directions, there were no significant differences between overall drug-induced conduction changes in MI dogs compared with healthy dogs. However, in 7 MI dogs for whom activation data were available during ventricular pacing at concentrations comparable to those causing proarrhythmia, flecainide induced a new arc of block in 6 of 7, whereas an arc of block was never observed in the absence of proarrhythmia. Conduction block was induced transverse to fiber orientation in a rate-dependent fashion and was caused by a regionally-specific effect of the drug. No differences were noted between refractory periods proximal and distal to the site of block.
Conclusions Prior MI strongly predisposes dogs to flecainide proarrhythmia, which occurs in the majority of such dogs in a concentration-related way. In most cases, activation data suggest that anisotropic reentry around a localized arc of rate-dependent transverse conduction block underlies proarrhythmia. These results provide insights into the conditions and mechanisms underlying the ability of flecainide to promote the occurrence of ventricular tachycardia.
Key Words: myocardial infarction • antiarrhythmia agents • sodium • arrhythmia • death, sudden
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Introduction |
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Ventricular proarrhythmia, consisting of the de novo induction or aggravation of preexisting ventricular tachyarrhythmias (VTs) by an antiarrhythmic agent, is probably the most important factor limiting the application of antiarrhythmic drug therapy.1 2 Proarrhythmic responses are believed to underlie the propensity of class I drugs, particularly the IC agents flecainide and encainide, to increase the mortality rate in patients with a recent myocardial infarction (MI).3 4 Indirect evidence suggests that similar phenomena may be operative in patients resuscitated from sudden cardiac death5 and those with atrial fibrillation.6 7 Improved understanding of the mechanisms of drug-induced proarrhythmia is needed to develop strategies to optimize the risk to benefit ratio of antiarrhythmic drug therapy.
Several studies have suggested that class IC agents can result in the induction of VT by programmed electrical stimulation in dogs with a previous MI even when VT was not inducible before drug administration.8 9 10 11 12 13 14 Results have also been presented that suggest that flecainide causes proarrhythmia (including a 50% prevalence of sustained VT) in a large percentage of normal dogs.15 These findings raise questions about the need for a pathological substrate to promote proarrhythmia. Limitations of previous studies have included a lack of consideration of the concentration dependence of drug action, the variable definition of proarrhythmia that often did not require reproducibility of VT induction, study protocols that did not include observations in the presence of stable drug concentrations, and the lack of a comparison between healthy dogs and those with prior infarction. In addition, activation mapping studies of mechanisms have been presented in a very limited form (48-channel recordings from two dogs) in only one published study,12 and preliminary data from more detailed studies have been presented but published only in abstract form.10 A recent study showed that flecainide permitted the induction of sustained VT in rabbit hearts through a thin layer of surviving epicardial tissue after extensive ventricular cryoablation.16 Proarrhythmia in this model was associated with a small decrease in the wavelength for reentry and the induction of arcs of conduction block of variable location.
The present experiments were designed to address several questions regarding the ability of flecainide to induce proarrhythmic responses in anesthetized, open-chest dogs: (1) To what extent does a previous myocardial infarction predispose to such proarrhythmic responses, and at what drug concentrations do they occur? (2) What electrophysiological changes permit the development of drug-induced proarrhythmia? (3) How frequently can epicardial mapping reveal a functional mechanism of proarrhythmia, and what mechanisms are involved? Preliminary findings have been presented in abstract form.17 18
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Methods |
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Infarct Model
Mongrel dogs (17 to 27 kg) were anesthetized with sodium pentobarbital 30 mg/kg IV and ventilated through an endotracheal tube. A left thoracotomy was performed under sterile conditions, and a small opening was created in the pericardium. The left anterior descending coronary artery (LAD) was dissected proximal to the first diagonal branch and then occluded in two stages.19 Nadolol 0.5 mg/kg IV was given before occlusion and then daily (20 mg PO) for 2 days. Benzathine penicillin G 150 000 U and procaine penicillin G 150 000 U SC were also given daily. Levorphanol 0.056 mg/kg SC BID was used to control postoperative pain.
Study Procedures
The proarrhythmic effects of flecainide were
studied in 13
healthy dogs and 31 dogs subjected to LAD occlusion 72 hours before
study (MI dogs). On the day of study, dogs were anesthetized
with morphine 2 mg/kg SC and 
-chloralose 120 mg/kg IV, intubated,
and mechanically ventilated. Catheters were inserted into one femoral
artery and two femoral veins. Arterial blood gases were
measured at 1-hour intervals and maintained in the
physiological range (SAO2
>90%, pH 7.35 to 7.45) by adjusting the ventilator or using
supplementary oxygen. A left thoracotomy was performed at the fifth
intercostal space, and a pericardial cradle was created. The chest
cavity was covered with plastic wrap to prevent cooling or dehydration,
and body temperature was maintained at 37°C to 38°C with a heating
blanket.
An array of 56 or 112 bipolar electrodes in a 4x6-cm plastic sheet was sewn to the surface of the left ventricle over the LAD territory. A bipolar platinum electrode was fixed to the left atrial appendage to record the left atrial electrogram. ECG leads II, III, aVL, and aVR were filtered at 0.05 to 40 Hz, and electrograms were filtered at 30 to 400 Hz (amplifiers, Bloom Associates Ltd) recorded, along with stimulus artifacts and arterial pressure, with a paper recorder (MT-95000 Host Control, Astromed Inc).
Activation Mapping
Previously-described techniques were used
to create activation
maps.20 21 The interpolar distance was 2 mm, and
electrodes were arranged in a parallel fashion with an interelectrode
distance of 4 mm for the 112-electrode array and 6 mm for the
56-electrode array. The 56-electrode array was used in the first 18
dogs, and the 112-electrode array was used in the remaining 26 dogs. A
bipolar electrode at the center of the array was used for programmed
ventricular stimulation with the use of 2-ms current pulses
of twice diastolic threshold (model EP-2 Stimulator,
Digital Cardiovascular Instruments). Electrograms were
filtered at 40 to 300 Hz, digitized with 12-bit resolution and a 1-kHz
sampling rate, and transmitted by means of duplex fiber-optic cables
into a microcomputer. The activation time at each electrode site was
defined as the time of maximal rate of voltage change as calculated by
the computer. Each electrogram was reviewed manually to exclude
low-amplitude recordings resulting from poor contact,
electrical artifacts, and interference by electrical noise. The
presence of block was defined by a conduction velocity <0.1 m/s
between adjacent electrode sites, generally with an abrupt alteration
in the direction of wave front propagation across the line of block.
Isochrones were constructed with a computer-based interpolation
algorithm.
Experimental Procedures
Successively increasing doses of
flecainide (Table 1
) were administered until ventricular
proarrhythmia or death occurred in 19 MI dogs and 13
healthy dogs ("controlled series"). Under control conditions and
at each drug concentration, ventricular activation,
ventricular refractory period, and arrhythmia
occurrence were evaluated over a range of cycle lengths from 180 to 500
ms. Two minutes of stimulation were allowed at each basic cycle length
before the introduction of extrastimuli to determine the refractory
period. Single extrastimuli were then applied after every 15 basic
stimuli at the central electrode site to determine effective refractory
period (ERP, the longest S1S2 interval failing
to capture the ventricle) and to induce VT.
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Proarrhythmia was defined
as the reproducible
occurrence of spontaneous or inducible VT (
5 successive
ventricular complexes) in the presence of flecainide but
absent under control conditions. Sustained VT was defined by the
occurrence of >30 successive ventricular complexes. Plasma
flecainide concentrations were measured by high-performance
liquid chromatography.22 Infarct size was
determined with triphenyl tetrazolium chloride.23
An additional 12 MI dogs ("additional series") were studied to relate the occurrence of proarrhythmia to infarct histopathology and to differences in ERP on either side of lines of block. The same drug infusion protocol described above was used, but instead of acquiring detailed mapping data at each dose, we identified the dose causing proarrhythmia and then determined the ERP at multiple sites on either side of the line of block. Portions of myocardium were cut into 0.3x1x2.4-cm sections, which were stained with hematoxylin-phloxine-saffron or Gomori's one-step trichrome24 and subjected to microscopic examination.
Data Analysis
Conduction velocity was analyzed by linear
regression of
interelectrode distance on activation time. Group values are
presented as mean±SD. Statistical comparisons were performed
by ANOVA with a range test (Student's t test with the
Bonferroni correction)25 or for contingency data by
Fisher's exact test or 
2 test. All comparisons
were two-tailed, and a value of P<.05 was taken to indicate
statistical significance.
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Results |
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Occurrence and Type of Proarrhythmia in Controlled Series
Flecainide caused proarrhythmic responses in 15 of 19 controlled series MI dogs, and 4 of 13 healthy dogs (P=.02). MI dogs also presented more severe forms of proarrhythmia, such as sustained and spontaneous VT (Fig 1
).
Spontaneous VT did not occur in healthy dogs, but
was observed in 8 of 19 MI dogs (P=.007). Drug
concentrations at the time of VT averaged 5.3±1.9 mg/L in healthy dogs
and 5.6±2.3 mg/L in MI dogs (P=NS). In dogs without
proarrhythmia, death occurred because of progressive
hypotension at plasma concentrations averaging 9.8±4.8 mg/L in healthy
dogs (n=9) and 10.4±1.9 mg/L in MI dogs (n=4,
P=NS versus
healthy dogs). Flecainide significantly reduced blood pressure in MI
dogs only at the highest doses, with blood pressure remaining unchanged
before proarrhythmia in most cases.
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General Determinants of Proarrhythmia
In the four MI dogs
without proarrhythmia, infarct
size averaged 3±2% of the left ventricle, compared with 32±5% in
dogs with proarrhythmia (P<.05). The cumulative
concentration-response curve for proarrhythmic responses in infarct
dogs is shown in Fig 2. The EC50 for
proarrhythmia was 
6 mg/L, and the maximum proarrhythmic
incidence of 79% occurred at a plasma concentration of 9 mg/L. Mean
plasma concentrations at the time of proarrhythmia were
higher for spontaneous VT (6.8±1.4 mg/L, n=7) than for sustained
(4.0±2.5 mg/L, n=7) and nonsustained (4.4±2.2 mg/L,
n=5) VT. When
multiple forms of VT occurred within a given dog, more severe forms
occurred later in the protocol at higher drug concentrations. Because
of the smaller number of normal dogs experiencing
proarrhythmia, a concentration-response curve for
proarrhythmia could not be constructed, but the mean drug
concentration at the time of proarrhythmia was similar to
that in MI dogs.
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Drug-Induced Changes in Conduction and
Refractoriness
Drug-induced conduction slowing that exceeds changes in
refractoriness is believed to play an important role in the
arrhythmogenic properties of class IC
drugs.1 16 26 27 28
Fig 3, left, shows an analysis of the effects of
flecainide on conduction velocity. Drug-induced conduction slowing was
not significantly different for longitudinal versus transverse
propagation and was not significantly different in infarcted versus
healthy hearts. Flecainide did not significantly alter
ventricular ERP in either infarcted or healthy hearts (Fig 3,
right). The very similar changes produced by the drug in healthy
versus infarcted hearts do not clarify the mechanism of the increased
susceptibility to proarrhythmia of the latter group.
Conduction slowing alone appears to be insufficient to cause
proarrhythmic responses in a large percentage of hearts.
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Activation During Ventricular
Tachycardia
Fig 4 shows activation data at the onset of
VT in
one dog (dog No. 34): recordings of selected electrograms and a
surface ECG lead (top right) and maps of the first three activations of
VT (cycles 1 through 3, corresponding to the cycles delimited by the
vertical dashed lines on the analogue panel). All activation maps are
oriented in the same fashion, with the LAD running parallel to the long
axis of the array along its left border. Electrode locations indicated
by letters on each map correspond to the electrograms shown in the
analogue recordings. After the last basic stimulus
(S1) at a cycle length of 250 ms, a single extrastimulus is
applied (S1S2, 210 ms), initiating a run
of sustained VT (200 per minute). Selected activation times relative to
S2 are shown on the activation maps, along with 20-ms
isochrons. The activation initiated by S2 (cycle 1) is
shown at the upper left. The tissue underlying the top two thirds of
the array (toward the base of the heart) was not captured by the
extrastimulus, and a line of horizontal unidirectional block (solid
line) resulted. Propagation occurred slowly in the inferior
direction, and the counterclockwise limb propagated around the lateral
border of the arc of block near site E. The impulse then continued to
propagate counterclockwise around a transverse arc of functional block
to produce cycles 2 and 3, and all subsequent beats of VT displayed a
similar activation pattern.
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Fig 5 shows the initiation
of ventricular
tachycardia in another dog (dog No. 26). An extrastimulus
(S1S2, 145 ms; basic cycle length, 200
ms) initiates activity at the center of the array (activation times in
Fig 5A through 5C are referenced to S2), which
propagates
rapidly in the longitudinal direction (perpendicular to the LAD and
horizontally in Fig 5A) and more slowly in the transverse
direction. A
broad arc of conduction block is encountered (solid line), forcing the
impulse to travel around the lateral margin of the arc of block. The
impulse travels toward the LAD, past a shorter arc of transverse
conduction block, and then appears to propagate around the
inferior border of the array in a counterclockwise
direction (Fig 5B). The excitation of tissue at the
inferolateral
portion of the array then initiates a full counterclockwise reentry
circuit around the arc of transverse block, as shown in Fig 5C,
producing the first unstimulated beat of VT. A stable reentry pattern
results, with the activation shown in Fig 5D recorded several
seconds later during VT (vertical dashed lines in Fig 5F
delimit cycle
mapped in Fig 5D). The ECG and selected electrogram tracings
corresponding to Fig 5A through 5C are shown in Fig
5E, and those
corresponding to Fig 5D are shown in Fig 5F.
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Fig 6 shows activation during a spontaneously occurring
episode of VT in dog No. 42. An ECG and stimulus channel (showing lack
of stimulation) are provided on the bottom, and activation maps of
beats A through D on the ECG recording are shown in the
corresponding sections of the figure (Fig 6A through 6D).
Epicardial
breakthrough of the last sinus beat (Fig 6A) occurs at the site
marked
by an asterisk, and a large region of the LAD territory is
activated within 30 ms. Activation is delayed towards the apex,
as expected in the presence of an almost transmural infarction that
interferes with normal endocardial to epicardial impulse
propagation.29 A spontaneous ventricular
ectopic beat, with initial activation indicated by the asterisk in Fig
6B, initiates 14 beats of VT at a cycle length of 280 ms. The
propagating impulse encounters an arc of conduction block (solid line
in Fig 6B) and appears to turn around the arc of block at the
medial
border of the electrode array. Activation proceeds in a
counterclockwise direction beyond the arc of block. Initial activation
of the next cycle (C) occurs at the lateral border of the array, 106 ms
after the last recorded activation during the preceding cycle. The
impulse conducts medially, encountering an arc of block similar to that
shown in B, and returns in a counterclockwise direction beyond the arc
of block. A similar activation pattern was recorded for the next
beat (D) and for subsequent cycles of VT. Unlike the data shown in Figs
4
and 5, which show complete circuses of impulse
propagation
during VT, the activation data in Fig 6 account for only part
of a
potential reentry cycle. In addition, VT occurs spontaneously in Fig
6,
whereas it results from premature stimulation in the other figures. In
both cases of spontaneous VT recorded with the mapping system, the
ventricular beat initiating tachycardia had a
pattern of activation different from that recorded during VT,
consistent with the possibility that the mechanism of the
premature beat initiating reentry is different from the mechanism of
VT. Enhanced automaticity is known to cause ventricular
ectopy in this model30 31 32 and could
explain the
ventricular premature beat that initiated reentry.
Alternatively, the beat initiating reentry could be a result of reentry
with a different epicardial breakthrough point compared with sustained
VT.
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Of 15 dogs with myocardial infarction and proarrhythmic VT in the
controlled series, activation data during VT were available in 11. In 4
dogs, a complete reentry circuit was resolved (Table 2),
as in Figs 4 and 5. In 5 other dogs, the
activation pattern was
consistent with reentry, but recorded activation times did
not account for all the reentry cycle. Among all dogs with a complete
or partial reentry circuit visualized, an arc of transverse conduction
block was noted between the central stimulation point and the apex of
the left ventricle.
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Activation During Ventricular Paced Rhythm and Relation
to Proarrhythmia
Transverse conduction block appeared to play a
central role in
proarrhythmic responses. We therefore evaluated the hypothesis that
while overall conduction changes caused by the drug were similar in
infarcted and normal hearts, infarction may predispose localized
regions to drug-induced conduction slowing. Figs 7 through
9 show activation in the
LAD territory before and after flecainide in a
representative healthy dog, an MI dog without
proarrhythmia, and an MI dog with
proarrhythmia, respectively. In the healthy dog (Fig 7),
flecainide slowed conduction by 16% at a cycle length of 400 ms,
without altering the pattern of activation (Fig 7C). When the
pacing
cycle length was decreased to 200 ms (Fig 7D), the drug slowed
conduction by 34% without changing the activation pattern. In MI dogs
without proarrhythmia (Fig 8), similar drug concentrations
produced conduction changes very similar to those in the healthy dogs.
Fig 9 shows corresponding results in a dog with
proarrhythmia. Under control conditions, activation in the
LAD territory was not perceptibly different from that in the healthy
dog in the absence of drug at either cycle length. Flecainide, at a
concentration similar to that in the healthy dog (Fig 7),
slowed
conduction by 18% at a cycle length of 400 ms (Fig 7C), without
changing activation pattern. When the pacing cycle length was shortened
to 200 ms (Fig 7D), conduction in the longitudinal and superior
(basal)
direction was uniformly slowed, as in the healthy dog in Fig
7D. In the
apical direction, however, an arc of conduction block appeared (solid
line).
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In 7 MI dogs with proarrhythmia, activation data
during ventricular pacing were obtained as part of the
controlled series study protocol at a plasma concentration 75%
(Table 2) of the concentration at which proarrhythmia
occurred. In 6 of these dogs, an arc of conduction block was observed
during rapid pacing. In all 6, conduction block was absent at slower
rates and the location of block during rapid ventricular
pacing remained the same as during VT. Arcs of block were never
observed in dogs without VT. In the additional 12 dogs studied to
evaluate regional refractoriness, all 6 with proarrhythmia
had arcs of block during rapid ventricular pacing and no
block was seen in the 6 without proarrhythmia.
Studies of Conduction and Refractoriness at Sites of
Block
The above data indicate a close association between the
development of regional block and the occurrence of
proarrhythmia, consistent with a potentially
important role for regional block in the mechanism of VT induced by
flecainide. Fig 10 presents an analysis of
results from the controlled series of dogs that was designed to
establish whether the susceptibility of dogs to
proarrhythmia was due to generally enhanced drug effects on
conduction or to regional factors at the site of block. For equivalent
drug concentrations, overall drug-induced conduction slowing during
both longitudinal and transverse propagation was similar for dogs with
(Fig 10, bottom) and without (Fig 10, top)
block. During rapid pacing
(bottom right), conduction slowing was much greater at the site of
transverse conduction block (filled bar) than elsewhere over the
infarct (bars with horizontal lines). In contrast also in Fig
10,
during slower pacing (bottom left) transverse conduction slowing was
the same at the site of block (filled bar) as in other regions
(horizontal lines). Thus, block was due to an interaction between rate
and the underlying substrate and not to a generalized susceptibility to
drug action.
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We then determined whether the interaction is due to a
progressive
reduction in conduction velocity at the site of block with increased
rate in the presence of flecainide. Fig 11 shows the
cycle length dependence of transverse conduction velocity at the site
of block under control conditions and in the presence of flecainide in
the 7 MI dogs with block. While conduction tended to slow with
decreased cycle length in the presence of the drug, in all but 1 dog
(dog No. 26) there was an abrupt decrease in conduction velocity
(averaging 58±17%) associated with block at the shortest cycle
length.
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The final possibility that we evaluated was that block results
from
spatially determined drug effects on refractoriness, with ERP prolonged
to a greater extent distal (versus proximal) to the site of block. In
an additional series of 12 dogs studied to evaluate this possibility,
block occurred in 6. For each of these dogs, ERP was determined by
local stimulation on either side of the arc of block at a cycle length
similar to the VT cycle length in that dog. As shown in Fig
12, no systematic differences in ERP were observed
between sites proximal and distal to the site of block. Overall, ERP
averaged 246±16 ms at 13 sites proximal to the arc of block and
246±21 ms at 13 sites distal to the arc of block.
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Histological Analysis
Examination of histological sections
confirmed
that epicardial muscle fibers were oriented in the direction of rapid
impulse propagation, ie, perpendicular to the LAD. Infarctions became
progressively denser and more transmural toward the apex, and at the
zones of block there were areas in which the infarction extended to the
epicardial surface (ie, zones in which there were no surviving
epicardial cells). However, similar zones were present in dogs
without an arc of block, so that no qualitative
histological differences could be identified with the
occurrence of an arc of block.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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We have shown that the presence of a prior MI predisposes dogs to the ventricular proarrhythmic actions of flecainide. The occurrence of proarrhythmia in our dogs was related to plasma drug concentration, and the mechanism of proarrhythmia appeared to be reentry involving an arc of rate-related transverse conduction block in the presence of the drug.
Comparison With Previous Studies of Flecainide-Induced
Proarrhythmia in Dogs
Several studies have shown that flecainide can
facilitate the
occurrence of VT in dogs with prior
MI.8 9 10 11 12 13
In addition,
one group reported a high incidence of flecainide
proarrhythmia at high concentrations in dogs with healthy
hearts.15 We found that under controlled conditions, dogs
with healthy hearts are relatively resistant to flecainide
proarrhythmia, whereas MI dogs that do not experience
proarrhythmia have relatively small infarctions. While
clinical experience suggests that diseased hearts are predisposed to
flecainide proarrhythmia,27 the present
study comprises, to our knowledge, the first direct experimental
demonstration of this phenomenon.
Little information is available about changes in activation that underlie flecainide proarrhythmia. Only one published study12 presented activation data that were obtained in two dogs with a 48-electrode array. The limited data presented in that paper are consistent with the arrhythmia mechanism that we observed, reentry around a drug-induced arc of conduction block. Another study, published only in abstract form,10 showed that flecainide induced VT in four dogs by extending the line of block transverse to fiber orientation while slowing conduction equally in the longitudinal and transverse directions.
Mechanism of Proarrhythmia
In 9 of 11 MI dogs in the
controlled series for which activation
maps during proarrhythmic VT were available, activation compatible with
a reentry circuit could be mapped around an arc of conduction block,
which always occurred in the direction transverse to fiber orientation.
The anisotropic properties of myocardium thus played an
important role in proarrhythmia. According to the original
descriptions of VT inducibility by programmed electrical stimulation in
dogs with prior
MI,33 34 35 36 epicardial
mapping studies showed
that VT in this model is due to reentry around an arc of conduction
block within the infarct,37 38 with block occurring
in the
direction of impulse propagation transverse to myocardial fiber
bundles.39 40 The intrinsically anisotropic
properties of
myocardial conduction41 appear to play an important role
in producing this type of VT,39 40 which has been
called
"anisotropic reentry."40 Similar mechanisms underlay
proarrhythmic VT in our dogs. While in normal tissues, the safety
factor for impulse propagation is greater in the transverse
direction,41 42 transverse conduction block is
predicted
to occur more readily than longitudinal when active membrane properties
are impaired.43 A lower safety factor for transverse
impulse propagation has been observed in the presence of
hyperkalemia,43 and the intrinsically
anisotropic properties of myocardial cell coupling44 are
believed to play a central role in the genesis of reentrant clinical
arrhythmias related to MI.45 46 47 We
obtained
evidence that suggested that flecainide caused
proarrhythmia by inducing reentry around arcs of transverse
conduction block, as also noted in infarcted hearts in the absence of
drugs.39 40 Block was rate related and appeared
abruptly
at critical cycle lengths (see Figs 10 and
11). These findings are
compatible with computer simulations of the behavior of anisotropic
tissues in the presence of impaired active properties and suggest that
flecainide causes proarrhythmic VT by impairing active membrane
properties and causing conduction to fail in the direction of weaker
cell-to-cell coupling, ie, transverse-to-fiber orientation.
New Findings and Potential Significance
The present study is
the first to study experimentally the
dose-response relation for flecainide proarrhythmia in an
organized fashion, to evaluate associated
electrophysiological changes in the
presence of stable plasma concentrations, and to compare directly
proarrhythmia and
electrophysiological changes produced by
flecainide in infarcted hearts with those in control dogs studied in
parallel. While limited mapping data previously have been reported
during flecainide-induced VT,10 12 the present study
provides a systematic analysis of activation during VT and
relates this to ventricular activation at a series of basic
cycle lengths under control and drug conditions in healthy and
infarcted hearts.
The specific proarrhythmic risks associated with class IC antiarrhythmic drugs were first noted in the early 1980s48 49 50 51 and led to a distinction between proarrhythmic responses to drugs that block sodium channels compared with those that prolong action potential duration.27 28 The presence of structural heart disease, a substrate that can support VT, and rapid escalation of flecainide dose have been identified as factors that increase the likelihood of proarrhythmia.52 53 In addition, exercise has been identified to be especially likely to precipitate proarrhythmic reactions, particularly during flecainide therapy,54 55 possibly by causing a sinus tachycardia.
The present study sheds light on potential mechanisms underlying these clinical findings. Anisotropic reentry, strongly facilitated by the presence of previous infarction, was found to be the likely mechanism underlying VT in 9 of our 11 MI dogs for which activation data during VT were available. Abrupt conduction block at rapid rates appeared to underlie the rate dependence of drug-induced proarrhythmia. While use-dependent sodium channel blockade causes progressive conduction slowing in the presence of sodium channel blockers,26 56 sudden decreases in conduction velocity are not seen in healthy tissues.56 Sudden rate-dependent failure of transverse conduction occurs in infarcted hearts not exposed to antiarrhythmic drugs37 40 and is predicted to occur during transverse propagation when sodium current is depressed.43 Thus, in addition to enhancing drug-induced sodium channel block, tachycardia favors the occurrence of transverse block by exposing critical discrepancies in the source-sink relation. Our findings suggest that proarrhythmia is due to interaction among cycle length, the underlying substrate, and drug effects on conduction.
Model Limitations and Results
We found that, while
proarrhythmia could be induced by
flecainide in dogs with prior MI, relatively high drug concentrations
were necessary in most dogs. These observations are consistent
with clinical findings that therapeutic flecainide concentrations cause
sustained VT to be inducible in a relatively small fraction (7% to
29%) of patients.57 58 59 It is difficult
to know to what
extent the mechanisms of flecainide-induced VT in our dogs apply to
drug-induced VT in humans. Because of important interspecies
differences in drug sensitivity, it is important to evaluate indexes of
drug pharmacodynamics to relate the effects of drugs seen in animal
models to those noted in man. At therapeutic doses, flecainide slows
intraventricular conduction (as indicated by the
QRS duration) by 25% in humans.51 This degree of
conduction slowing is in the range of the mean changes that we observed
in our dogs (Fig 3). Furthermore, the risk of clinical
proarrhythmia increases with increasing flecainide
dose,52 as does the degree of
intraventricular conduction slowing.51
In a well-documented series of patients with VT that was caused by a
pharmacologically similar class IC agent, encainide, drug-induced QRS
prolongation averaged 46±10%,48 suggesting a degree of
conduction slowing in the range that we observed in dogs exposed to 5
to 6 mg/L plasma flecainide concentrations (Fig 3). Thus, while
VT in
some dogs required concentrations that are equivalent to toxic levels
in man, the similarity in conduction slowing to values in patients
experiencing proarrhythmia at therapeutic doses suggests
pharmacodynamic equivalence and possible relevance to clinical
phenomena. Proarrhythmia in our dogs was always associated
with significant conduction slowing. Clinical drug-induced VT can occur
in the absence of substantial ventricular conduction
slowing,50 in which case it may be due to idiosyncratic
predisposition to other drug-induced arrhythmia mechanisms.
Potent sodium channel blockers such as flecainide strongly increase the
risk of ventricular fibrillation during acute
ischemia60 61 62 at concentrations much
lower than
those required for proarrhythmia in the present
model.63 This mechanism may well play an important role in
class I drug effects on mortality.
We were able to account for a complete reentry circuit in just under half the dogs (4 of 9) in which reentrant activity could be mapped. In the other 5 dogs, activation accounting for part of a potential reentry circuit was obtained. As for most previous studies in the literature in this arrhythmia model, mapping was limited to epicardial sites over the infarct zone. Intramural and endocardial activation were not recorded. Our inability to account fully for reentry in some dogs may have been due to the involvement of intramural and subendocardial tissues in the reentry circuit, as previously demonstrated in both dog models64 65 66 and human hearts with inducible VT.67 Alternatively, some of the reentry circuit may have been epicardial but outside the field covered by our electrode array. This condition may also account for the fact that the circuits we mapped had only one limb of reentry, whereas reentry in the postinfarction VT model is frequently associated with a figure eight pattern.39 40 66 Another possibility, particularly when activation data do not reveal evidence for reentry or account for only part of a reentry circuit, would be the participation of other arrhythmia mechanisms, such as abnormal and triggered automaticity, that can occur in infarcted preparations.33 68
In any case, it is important to be aware that the results presented in this manuscript, while pointing strongly to reentry mechanisms (particularly when a complete circuit is mapped), do not provide absolute proof for reentry. We were able to satisfy two of the Mines criteria for demonstrating reentry,69 the identification of unidirectional block and the delineation of a repetitive recirculating wave front during tachycardia. We did not attempt to satisfy the final criterion, the termination of tachycardia by anatomic disruption of the reentry circuit, because the demanding technical requirements of such a demonstration (requiring a stable and hemodynamically tolerated tachycardia, rapid on-line delineation of the circuit, and precise localized interruption of the circuit without disruption of function in a beating heart) place it beyond the scope of the present study.
The model we used simulates many conditions of clinical ventricular tachyarrhythmia occurring after recovery from acute MI.33 34 35 36 37 38 39 40 67 68 Nevertheless, the model cannot be considered to mimic directly any specific clinical condition, and many aspects of the procedures involved (general anesthesia, open-chest preparation, intravenous drug administration, and programmed electrical stimulation) create potentially important differences from the clinical setting in which proarrhythmia typically occurs. Caution is therefore warranted in extrapolating the results of the present studies to man.
Several studies have suggested that sodium channel blockers may have more profound effects on longitudinal versus transverse conduction.70 71 72 73 74 However, the relative magnitude of directional differences was highly variable, and at some concentrations no differences were seen.71 The apparent discrepancy may be due to differences in action between flecainide and previously studied drugs (procainamide,70 mexiletine,71 quinidine,71 amiodarone,72 lidocaine,73 and 0–desmethyl encainide74 ), to the drug concentrations studied, or to some other technical factor.
Conclusions
We have shown that flecainide promotes the
occurrence of
ventricular tachyarrhythmias in a
concentration-dependent fashion in a large proportion of dogs with
prior MI. The presence and extent of infarction are important in
determining the likelihood of VT, which appears to be caused by reentry
around an arc of functional transverse conduction block. The occurrence
of block is rate dependent and appears to be caused by an interaction
between sodium channel blockade and the underlying substrate. These
experiments support the importance of the anisotropy of
ventricular conduction in the genesis of cardiac
arrhythmias, particularly when intercellular coupling and
active membrane properties are disturbed by MI and potent sodium
channel blocking drugs.
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Acknowledgments |
|---|
This work was supported by the Medical Research Council of Canada, the Quebec Heart Foundation, and the Fonds de Recherche de l'Institut de Cardiologie de Montréal. Suzanne Ranger was supported by a studentship award from the Fonds pour la Formation de Chercheurs et de l'Aide à la Recherche (FCAR). We thank Emma De Blasio, Carol Matthews, and Christine Villemaire for technical assistance, Mary Morello for typing the manuscript, Drs Jean-Gilles Latour and Tack Ki Leung for advice and technical support for infarct size measurement and histologic analysis, and 3M-Riker Pharmaceuticals for supplying the flecainide used in the present experiments.
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Footnotes |
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Reprint requests to Dr Stanley Nattel, Research Center, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada.
Received January 24, 1995; accepted February 27, 1995.
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References |
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