Vol. 276, Issue 2, H413-H423, February 1999
Dispersion-based reentry: mechanism of initiation of
ventricular tachycardia in isolated rabbit hearts
Emmanuelle
Robert1,
A. Guy M.
Aya1,
Jean E.
de la
Coussaye1,
Pascale
Péray2,
Jean-Marie
Juan1,
Josep
Brugada3,
Jean-Marc
Davy4, and
Jean-Jacques
Eledjam1
1 Laboratory of Anesthesiology
and Cardiovascular Physiology, Medical School of
Montpellier-Nîmes, 30907 Nîmes; and
2 Department of Epidemiology and
Biostatistics, University-Hospital of Nîmes, 30029 Nîmes, France;
3 Arrhythmia Unit of Department of
Cardiology, Hospital Clinic, University of Barcelona, Barcelona, Spain;
and 4 Department of Cardiology,
University-Hospital of Montpellier, 34295 Montpellier,
France
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ABSTRACT |
The aim of the study was to determine whether
facilitation of reentry by potassium-channel openers is related to
dispersion of refractoriness and/or modification of anisotropic
properties of ventricular myocardium. The dispersion of ventricular
effective refractory period (VERP), longitudinal and transverse
ventricular conduction velocities (
L and T, respectively), and
wavelength [
= VERP × (L or T)] were studied in
Langendorff-perfused left ventricular epicardium in 20 rabbits during
infusion of incremental doses of levcromakalim or nicorandil.
Dispersion of refractoriness was assessed using standard deviation of
VERP mean (SD-VERP), dispersion index (DI; SD-VERP/mean VERP), and
maximum dispersion (Dmax = VERPmax 
VERPmin). Ventricular conduction
velocities and anisotropic ratio were not modified, whatever the dose
used. VERP and were significantly shortened at high concentrations of levcromakalim and nicorandil. At these doses, SD-VERP, DI, and
Dmax were increased significantly.
Analysis of ventricular tachycardia induction, performed using a
high-resolution ventricular mapping system, confirmed that
heterogeneity and shortening of VERP were factors inducing functional
conduction block. Our data suggest that, in rabbit left ventricular
epicardium, functional conduction block facilitating the occurrence of
reentry could be initiated by shortening and, especially, by dispersion
of refractoriness during infusion of potassium-channel openers.
heart; ventricular arrhythmia; epicardial mapping; potassium-channel openers
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INTRODUCTION |
MOST CARDIAC ARRHYTHMIAS are due to reentrant
mechanisms. It is well established that unidirectional conduction block
is required for the initiation of a reentry (27). This conduction block can be anatomic (5-7) or functional. The occurrence of functional block is facilitated by anisotropic changes, especially those in the
longitudinal direction (34, 37). Indeed, Clerc (11) and Spach et al.
(36, 37) demonstrated that there are directional differences in the
impulse propagation (i.e., longitudinal direction vs. transverse
direction). In addition to this mechanism, functional conduction block
can result from a marked slowing of conduction velocity, especially
that due to use dependency (2), as has been shown with class I
antiarrhythmic agents and drugs such as imipramine (8, 12, 31). Another
hypothesis is that increased dispersion of refractoriness could lead to
functional conduction blocks and reentrant arrhythmias (1, 22). Using
activation and refractory maps of the right ventricle in dogs 3-5
days postinfarction, Gough et al. (21) have shown that unidirectional
conduction block can be induced as a result of heterogeneity of
refractoriness. However, in this study, the nonuniform pattern of
conduction and repolarization was anatomically determined, because it
involved normal versus infarcted areas of heart. Thus, to our
knowledge, the possibility of occurrence of unidirectional conduction
block in ventricles with randomly heterogeneous refractoriness has
never been directly demonstrated.
Potassium-channel openers are known to act on potassium ATP-dependent
channels in cardiac tissue. The opening of this channel produces an
acceleration of repolarization with shortening of action potential
duration and effective refractory period (17). Moreover, the activation
of this channel has deleterious consequences on cardiac rhythm in
normoxic conditions, including ventricular fibrillation and tachycardia
(13, 39). Using a microelectrode technique on canine ventricular
myocardium, Di Diego and Antzelevitch (14) demonstrated that the
activation of ATP-dependent potassium channel by pinacidil leads to a
dispersion of repolarization and refractoriness in epicardium as well
as between epicardium and endocardium. Consequently, an extrasystolic
activity can occur, which is based on the mechanism that they called
"phase 2 reentry." In a previous
study (32) in isolated rabbit hearts, we demonstrated that both
levcromakalim and nicorandil produce reentrant ventricular tachycardia
without changing either longitudinal or transverse ventricular
conduction velocities. However, the precise mechanism leading to
reentry was not fully investigated. We hypothesized that conduction
block induced by potassium-channel openers is initiated by the
shortening of ventricular effective refractory period and by an
increased spatial dispersion of its value over the epicardium.
Therefore, the aim of the present mapping study was to determine the
role of potassium-channel opener-induced dispersion of refractoriness
in the initiation of conduction block and reentry.
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METHODS |
Heart preparation.
The principles for the care and treatment of animal experiments
complied with the national guidelines of the French Ministry of
Agriculture. Twenty New Zealand rabbits weighing 3.0 ± 0.5 kg were
anesthetized with ketamine (50 mg/kg im). In each rabbit, the trachea
was intubated and the lungs were mechanically ventilated with 100%
O2 (Logic 07, ATM, Maurepas,
France). As previously described (32), the chest was surgically opened
by a midsternal incision. After heparin (1,000 IU iv) was administered,
the heart was quickly removed and placed in a cold perfusion fluid. The aorta was immediately cannulated, and the heart was connected to a
Langendorff perfusion system using a Tyrode solution at a temperature
of 37°C. The coronary arteries were perfused with a constant flow
of 40-50 ml/min (Watson-Marlow 101U pump, Falmouth, UK), resulting
in a perfusion pressure of 70 ± 10 mmHg (Gould P23 transducer,
Oxnard, CA; CGR monitor, St-Cloud, France). Finally, all hearts
underwent destruction of the pulmonary and mitral valves to allow the
cryoprobe insertion. The composition of the Tyrode solution was 130 mmol/l NaCl, 20.1 mmol/l NaHCO3,
4.0 mmol/l KCl, 2.2 mmol/l CaCl2,
0.6 mmol/l MgCl2, 1.2 mmol/l
NaH2PO4,
and 12 mmol/l glucose. The solution was saturated with a mixture of
95% O2 and 5%
CO2, and pH was adjusted at 7.40 ± 0.02.
In all hearts, an endocardial cryotechnique was used to completely
destroy the right ventricle, the interventricular septum, and the
endocardial and intramural layers of the free wall of the left
ventricle. This cryotechnique was used to avoid epicardial breakthrough
of longitudinal wave fronts from deeper layers and to allow complete
mapping of electrical activation in two dimensions. Briefly, a
cryoprobe was inserted through the pulmonary artery in the right
ventricle and filled with liquid
N2 (192°C). The probe
was maintained in the ventricle until it was completely frozen. During
freezing, the left ventricle was watered by the fluid perfusion to
prevent the epicardium from freezing. The heart was then immersed in a
tissue bath containing perfusion fluid at 30°C. The cryoprobe was
placed in the left ventricle through the left atrium, and the coronary
circulation was interrupted. The cryoprobe was filled with liquid
N2 for 3 min, and the coronary circulation was restored thereafter. The probe was removed and the
heart withdrawn from the tissue bath. During the rest of the experiment, the temperature of the heart was kept constant at 37°C.
As a result of this procedure, only a thin epicardial layer (~1 mm
thick) of the free wall of the left ventricle survived, with the rest
of the myocardium being completely destroyed (4). It was previously
demonstrated that in this thin surviving layer, refractoriness and
conduction velocities were not affected by the procedure and remained
stable for many hours, suggesting that the circulatory condition was
adequate (12, 31, 32). At the end of the experiment, the hearts were
dissected to verify the efficacy of the cryoprocedure. If the freezing
was not adequate, the heart was excluded from the study.
Protocol.
Twenty frozen hearts were randomly divided into two groups. One group
(n = 10) was given incremental
concentrations (1, 5, 10, and 50 µmol/l) of levcromakalim (BRL-38227,
a gift of SmithKline Beecham Laboratoires Pharmaceutiques, Unité
de Recherche, Saint-Grégoire, France), and the other group
(n = 10) received nicorandil infusion (RP-46417, a gift of Rhône-Poulenc Rorer, Centre de Recherche de
Vitry-Alforville, Vitry-sur-Seine, France) at 1, 5, 10, 50, 100, and
500 µmol/l.
Recording and induction of ventricular arrhythmia.
High-resolution mapping of epicardial excitation was performed by
applying a spoon-shaped electrode containing 256 unipolar electrodes to
the epicardial surface at a regular distance of 2.25 mm (Fig.
1). A computerized mapping system allowed
simultaneous recording, storage, and automatic analysis of all 256 electrograms and on-line presentation of color-coded activation maps
(Maptech System, Maastricht, The Netherlands) (3). Programmed
electrical stimulation was performed using a programmable constant
current stimulator. It delivered square pulses of 2 ms in duration at twice diastolic threshold for both regular stimulation and induction of
premature beats (Maptech System). Induction of ventricular arrhythmia
was performed with a bipolar stimulation protocol in all frozen hearts
and consisted of 1) application of
1, 2, and 3 premature stimuli (S2, S3, and S4, respectively) delivered
with decreasing coupling intervals after 10 basic stimuli (S1-S1)
at 300-ms intervals, and 2)
application of a train of 10 stimuli at a regular cycle length that was
progressively decreased at 10-ms steps until one-to-one capture of the
ventricle failed. After each concentration of
levcromakalim and nicorandil administered, the inducibility of
ventricular arrhythmia was tested again using the same protocol as
during the control. Once the protocol was completed, normal Tyrode
solution was infused for an ~45-min period to allow a return to
control conditions and to rule out the possibility of deterioration
over time (washout). Any occurrence of ventricular arrhythmia was
recorded and analyzed.
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Fig. 1.
Location of spoon-shaped electrode on left ventricle (LV). Unipolar
electrograms were recorded from mapping array (dotted area). Central
circle indicates main pacing site for measurement of conduction
velocities and ventricular effective refractory period (VERP). Boxed
areas on LV show 3 other sites at which VERP was measured. LAD, left
anterior descending coronary artery; FW, ventricular free wall.
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Electrophysiological measurements and data analysis.
The following parameters were measured or calculated in the two groups
at baseline, 20 min after each dose of levcromakalim or nicorandil, and
after washout: ventricular effective refractory period (VERP, in ms) at
four sites, longitudinal ventricular conduction velocity (L, in
m/s), transverse ventricular conduction velocity (T, in m/s),
anisotropic ratio (L/T), longitudinal and transverse wavelength
(, in mm), standard deviation of mean VERP (SD-VERP, in ms), index
of dispersion (DI), and maximum dispersion
(Dmax, in ms). As previously
described by Clerc (11) and Spach et al. (37), cardiac tissue has a
different axial resistance along and perpendicular to the fiber axis of
the myocardial fibers. This different axial resistance results in
direction-dependent differences in conduction velocity (anisotropic
conduction). Therefore, pacing at the center of the thin surviving
layer of the left ventricle produced an ellipsoidal spread of
propagation with fast conduction parallel to the fiber axis
(longitudinal conduction) and slow conduction perpendicular to the
former (transverse conduction). Conduction velocity was defined as the
distance traveled by the wave front per time unit. In each experiment,
both longitudinal and transverse conduction velocities and anisotropic
ratio were measured after 10 basic stimuli (S1-S1) at a 1,000-ms
interval. In addition, to test the use dependence of the drug, these 3 parameters were measured after 10 basic stimuli at 900-, 800-, 700-, 600-, 500-, 400-, 300-, 250-, and 200-ms intervals. These parameters were also calculated after the last stimulation inducing ventricular tachycardia to exhibit a premature beat-induced slowing of conduction velocities.
VERP was defined as the shortest S1-S2 interval still resulting in
a propagated premature impulse during regular pacing with an S1-S1
interval of 300 ms. VERP was determined by decreasing the coupling
interval of the premature stimulus in steps of 1 ms. Measurement of
VERP was done at the same four sites throughout the experiment (Fig.
1). The wavelength was calculated as the product of VERP, measured on
the ventricular center site, and L or T, measured at a regular
pacing of 300 ms. The dispersion was quantified by SD-VERP. Second, DI
was defined as the quotient of SD-VERP and the mean of VERP after each
dose of levcromakalim and nicorandil.
Dmax was calculated as the
difference between the maximum and the minimum values of VERP at each
dose of the two drugs.
Definition of ventricular arrhythmia.
We defined ventricular arrhythmia as ventricular fibrillation or
sustained (SVT) or nonsustained ventricular tachycardia (NSVT). NSVT
was defined as a ventricular tachycardia lasting more than three
successive beats but <30 s before spontaneous termination. SVT was
defined as a ventricular tachycardia that lasted >30 s. Finally, a
separation into monomorphic (MVT) and polymorphic tachycardia (PVT) was
made. The term "monomorphic" implied a uniform beat-to-beat QRS
morphology. The term "polymorphic" was defined as the occurrence of continuous change in QRS configuration. When several types of
arrhythmia occurred during administration of one concentration in one
heart, the worst arrhythmia was taken into account.
Statistical analysis.
All parameters were expressed as means ± SD. Two-way analysis of
variance for repeated measures followed by a contrast method, Newman-Keuls test, and Bonferroni's correction were used to list dose
and/or frequency effect on the electrophysiological parameters. P < 0.05 was considered to be
statistically significant.
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RESULTS |
Effects on ventricular conduction velocities and anisotropic ratio.
The effects of levcromakalim and nicorandil on longitudinal and
transverse ventricular conduction velocities and on the anisotropic ratio at the pacing cycle length (PCL) of 1,000 ms are reported in
Tables 1 and 2.
Neither levcromakalim nor nicorandil modified these three
electrophysiological parameters. No use dependence was observed, and
ventricular conduction velocities were not modified (Fig.
2). Consequently, the anisotropic ratio
remained stable, regardless of the PCL and the dose of
potassium-channel openers. Longitudinal and transverse conduction
velocities were slightly slowed down during the stimulation inducing
ventricular tachycardia compared with velocities during a regular
pacing of 200 ms, from 0.71 ± 0.05 to 0.67 ± 0.07 m/s
and 0.72 ± 0.04 to 0.67 ± 0.08 m/s and from 0.35 ± 0.06 to
0.33 ± 0.07 m/s and 0.35 ± 0.045 to 0.30 ± 0.06 m/s during infusion of levcromakalim and nicorandil, respectively.
However, the anisotropic ratio was not modified during this
stimulation.
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Table 1.
Effect of levcromakalim on longitudinal and transverse ventricular
conduction velocities and on anisotropic ratio at a regular pacing of
1,000 ms
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Table 2.
Effect of nicorandil on longitudinal and transverse ventricular
conduction velocities and on anisotropic ratio at a regular pacing of
1,000 ms
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Fig. 2.
Effects of 10 µmol/l levcromakalim or 500 µmol/l nicorandil at each
pacing cycle length (PCL) on ventricular conduction velocities. Data
are expressed as means ± SD; n = 10 for levcromakalim group; n = 9 for
nicorandil group.  , Longitudinal velocity (L) in levcromakalim
group;  , L in nicorandil group;  , transverse velocity (T)
in levcromakalim group;  , T in nicorandil group.
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Effects on VERP and wavelength.
Both levcromakalim and nicorandil modified VERP and wavelength. Figures
3 and 4 show
changes of VERP and wavelength in each group. Levcromakalim shortened
VERP from 5 µmol/l (P < 0.05), whereas VERP was decreased from 100 µmol/l of nicorandil with a
significant effect at 500 µmol/l (P < 0.01). Because VERP was shortened and ventricular conduction
velocities were not modified, the longitudinal wavelength (L × VERP) was decreased from 108.7 ± 8.4 to 59.8 ± 17.8 mm
(P < 0.01) and the transverse
wavelength (T × VERP) was modified from 55.4 ± 9.1 to 28.3 ± 8.2 mm (P < 0.01) at 10 µmol/l levcromakalim. Nicorandil had the same effect on the
longitudinal and transverse wavelength, which decreased from 110.6 ± 17.6 and 52.1 ± 5.0 mm at baseline to 73.2 ± 7.6 (P < 0.01) and 34.1 ± 6.8 mm
(P < 0.01), respectively,
at 500 µmol/l.
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Fig. 3.
Effects of levcromakalim () or nicorandil () at each
concentration on VERP. Data are expressed as means ± SD;
n = 10 at baseline, 1 and 5 µmol/l,
and washout for both groups; n = 7 at
10 µmol/l levcromakalim; n = 9 at 50 and 100 µmol/l nicorandil; and n = 6 at 500 µmol/l nicorandil. * P < 0.05;  P < 0.01.
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Fig. 4.
Effects of levcromakalim or nicorandil at each concentration on
wavelength (). Data are expressed as means ± SD;
n = 10 at baseline, 1 and 5 µmol/l,
and washout for both groups; n = 7 at
10 µmol/l levcromakalim; n = 9 at 50 and 100 µmol/l nicorandil; and n = 6 at 500 µmol/l nicorandil. , Longitudinal wavelength in
levcromakalim group; , longitudinal wavelength in nicorandil group;
, transverse wavelength in levcromakalim group; , transverse
wavelength in nicorandil group.
* P < 0.05;
P < 0.01.
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To evaluate the refractoriness over the left epicardium, we calculated
the standard deviation of the mean of VERP (Fig.
5), which was modified significantly at
high doses of levcromakalim (P < 0.05) and nicorandil
(P < 0.01). DI was also significantly increased at these same
doses of levcromakalim (P < 0.01) and nicorandil (P < 0.01; Fig. 6). With regard
to the modification of DI during nicorandil infusion, the same rise was
observed (P < 0.01). Finally,
Dmax between values of VERP of
each heart was modified from 8.0 ± 2.9 ms at baseline to 16.2 ± 9.0 ms at 10 µmol/l levcromakalim and from 10.6 ± 5.6 to
25.8 ± 4.4 ms at 500 µmol/l nicorandil
(P < 0.05) (Fig.
7).
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Fig. 5.
Effects of levcromakalim () or nicorandil () at each
concentration on standard deviation of mean VERP (SD-VERP). Data are
expressed as means ± SD; n = 10 at
baseline, 1 and 5 µmol/l, and washout for both groups;
n = 6 at 10 µmol/l levcromakalim;
n = 10 at 50 µmol/l nicorandil;
n = 9 at 100 µmol/l nicorandil; and
n = 4 at 500 µmol/l nicorandil.
* P < 0.05;
P < 0.01.
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Fig. 6.
Effects of levcromakalim () or nicorandil () at each
concentration on dispersion index (DI). Data are expressed as
means ± SD; n = 10 at
baseline, 1 and 5 µmol/l, and washout for both groups;
n = 5 at 10 µmol/l levcromakalim;
n = 9 at 50 and 100 µmol/l
nicorandil; and n = 5 at 500 µmol/l
nicorandil. P < 0.01.
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Fig. 7.
Effects of levcromakalim () or nicorandil () at each
concentration on maximum dispersion
(Dmax). Data are expressed as
means ± SD; n = 10 at baseline, 1 and 5 µmol/l, and washout for both groups;
n = 6 at 10 µmol/l levcromakalim;
n = 9 at 50 and 100 µmol/l
nicorandil; and n = 5 at 500 µmol/l
nicorandil. * P < 0.05.
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Proarrhythmic effects.
No spontaneous arrhythmia was observed after the administration of each
concentration of levcromakalim and nicorandil. The inducibility of
arrhythmia was tested. No arrhythmia was obtained at control, 1 and 5 µmol/l of levcromakalim and nicorandil, and during washout.
Levcromakalim induced ventricular arrhythmias from 10 µmol/l (8 of
10), and all hearts had sustained ventricular tachycardia or
ventricular fibrillation at 50 µmol/l (6 of 6). One heart had a
sustained MVT with 50 µmol/l nicorandil. Ventricular arrhythmias
occurred in all hearts treated with 500 µmol/l of nicorandil (9 of
9). The types of arrhythmias and the results of their analysis are
summarized in Table 3. Four ventricular fibrillations were induced at 50 µmol/l levcromakalim. The analysis of their initiation was not performed because of their complexity ("no analysis"). The analysis of some sustained or nonsustained MVT or PVT did not allow us to determine their mechanisms of initiation ("no conclusion"). Finally, most of the ventricular tachycardias induced were initiated consecutively to a reentry ("based on
reentry"). Figures
8
and 9 show
the initiation of two ventricular tachycardias, one that was a
nonsustained polymorphic ventricular tachycardia (9 ventricular
tachycardia beats) obtained after the application of one extrastimulus
at 10 µmol/l levcromakalim (Fig. 8) and one that was sustained and
monomorphic, occurring at 50 µmol/l nicorandil induced by three
extrastimuli (Fig. 9). The upper left map of Fig.
8A describes the spread of ventricular
depolarization after the extrastimulus (S2) during infusion of 10 µmol/l levcromakalim. The stimulus was applied at the center of the
ventricle, and the wave propagated in all directions. It encountered a
line of conduction block near the apex and, because VERPs were
shortened, reactivation occurred around a pattern of eight lines of
functional conduction block at a time of 73 ms (VERP 40 ms).
Subsequently, several beats of tachycardia occurred following the same
pattern, although the position of the lines of block changed from beat
to beat, leading to a polymorphic pattern (Fig.
8B). The ventricular tachycardia advancement is shown in Fig. 8B; an
electrogram recorded on site 3 shows
the conduction block of the pacing influx and, therefore, the
reexcitation of this area by the influx that had surrounded the area
block.
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Fig. 8.
A: initiation of nonsustained
polymorphic reentrant ventricular tachycardia during administration of
10 µmol/l levcromakalim in frozen LV epicardium.
Top: electrogram recorded during
induction of ventricular tachycardia using 1 extrastimulus (S2).
Numbers above electrogram indicate time interval (in ms) between 2 ventricular activations. Six consecutive activation
maps show spread of depolarization. Numbers indicate local activation
times (in ms). Isochrones are drawn at 10-ms intervals. Thick
isochrones indicate local conduction blocks. Arrows indicate direction
of activation. Double bars indicate stop of influx propagation in
direction considered, and  represents pacing site. Circled
activation times indicate recording sites of electrograms shown in
B. Upper left map shows conduction
blockade resulting from the extrastimulus (S2). Upper right map shows
first beat of sustained ventricular tachycardia (1st VTB). Pattern of
depolarization during sustained monomorphic ventricular tachycardia
(2nd, 3rd, 4th, and 5th VTB) is shown consecutively in lower maps.
Underlined activation times (S2 map) indicate sites between which
conduction velocity was measured. Conduction velocities were measured
in transverse and longitudinal directions. At a regular PCL of 300 ms,
L = 0.68 m/s and T = 0.30 m/s; at PCL = 200 ms, L = 0.62 m/s
and T = 0.31 m/s; and with premature pacing (S2), L = 0.60 m/s
and T = 0.28 m/s. All maps present same frontal view of heart; see
text for further description. B: 7 different electrograms recorded (at sites indicated in S2 map in
A) during initiation of nonsustained
polymorphic reentrant ventricular tachycardia with administration of 10 µmol/l levcromakalim in frozen LV epicardium using 1 extrastimulus
(S2). Study of these 7 electrograms shows functional conduction block
on site 3 and polymorphism of
reentrant ventricular tachycardia.
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Fig. 9.
A: initiation of sustained monomorphic reentrant ventricular
tachycardia during administration of 50 µmol/l nicorandil in frozen
LV epicardium. Top: electrogram
recorded during induction of ventricular tachycardia using 3 premature
stimuli (S2, S3, S4). Numbers above electrogram indicate time interval
(in ms) between 2 ventricular activations. Four consecutive activation
maps show spread of depolarization. Numbers indicate local activation
times (in ms). Isochrones are drawn at 10-ms intervals. Thick
isochrones indicate local conduction blocks. Arrows indicate direction
of activation. Double bars indicate stop of influx propagation in
direction considered, and represents pacing site. Circled
activation times indicate recording sites of electrograms in
B. Upper maps show conduction blockade
resulting from last stimulus (S4). Lower left map shows 1st VTB.
Pattern of depolarization during sustained monomorphic ventricular
tachycardia (2nd VTB) is shown in lower right map. Underlined
activation times (S4 map) indicate sites between which conduction
velocity was measured. Conduction velocity was not strictly in
transverse or longitudinal direction; at S1 (regular pacing at 300 ms),
= 0.56 m/s; at S2, = 0.59 m/s; at S3, = 0.48 m/s; and at
S4, = 0.50 m/s. A slight slowing was observed during premature
stimulation, but it was not responsible for the functional block. All
maps present same frontal view of heart. See text for further
description. B: 7 different
electrograms recorded (at sites indicated in S4 maps in
A) during initiation of sustained
monomorphic reentrant ventricular tachycardia with administration of 50 µmol/l nicorandil in frozen LV epicardium using 3 extrastimuli (S2,
S3, S4). Study of these 7 electrograms shows initiation, advancement,
and monomorphism of reentrant ventricular tachycardia observed during
analysis of tachycardia initiation.
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The second ventricular tachycardia, shown in Fig. 9, is a sustained MVT
obtained during the infusion of 50 µmol/l nicorandil. The upper left
map of Fig. 9A shows the
depolarization of the ventricle after the last extrastimulus (S4).
The pulse was stopped by a wide line of conduction block in the
direction of the apex and in the direction of the free wall. The
excitation wave could propagate only in the direction of the base. The
influx got around the block in the middle of the ventricle and
activated the epicardium near the septum. The pulse could depolarize
the area behind the line of block in the direction of the free wall
(Fig. 9A, upper right map) and
reactivated the area close to the base in a counterclockwise direction,
initiating reentrant tachycardia around a line of functional conduction
block (1st and 2nd VTB). This path of depolarization was possible
because of dispersion of the left ventricular refractoriness as
confirmed by VERP measurements. VERP was shorter at the base (139 ms)
than near the septum (151 ms) and then at the free wall (162 ms).
Recorded electrograms show the conduction block and the initiation of
this ventricular tachycardia on site 4 (Fig. 9B). Finally, the monomorphism of this tachycardia was
shown on this pattern (Fig. 9B).
| |
DISCUSSION |
The present study demonstrates that, in homogeneous left ventricular
epicardium, potassium-channel openers induce shortening and increase
dispersion of refractoriness without changing conduction velocities and
anisotropy. This leads to occurrence of functional conduction blocks
and reentrant ventricular arrhythmias.
Unidirectional block.
Unidirectional block is essential for the initiation of reentry. In
previous studies, its occurrence has been associated with different
mechanisms, including changes in anisotropic properties of the
myocardium (34, 36) and use dependency (2, 8, 12, 31). However, these
two mechanisms are not involved in potassium-channel opener-induced
conduction blocks. Indeed, we previously demonstrated that these agents
do not modify ventricular conduction velocities or anisotropic ratio
and that there is no use dependency (32). These results are confirmed
in the present study. On the other hand, one could argue that during
rapid pacing or premature stimuli, conduction velocities may be
affected (20, 21, 30), and this could have played a role in the
occurrence of conduction block in our experiments. Thus we calculated
conduction velocities and anisotropic ratios during the propagation of
premature stimuli and rapid pacing that induced arrhythmias. Because
these parameters did not significantly differ from those obtained
during baseline pacing, we can infer that changes in conduction
velocities are not involved in the initiation of unidirectional block
in our study, even during programmed stimulation.
Heterogeneity of refractoriness has been suggested as another putative
mechanism of initiation of functional conduction block and reentry. Han
and Moe (22) found differences of up to 30 ms between the longest and
the shortest refractory period in ventricular muscle and suggested that
dispersion might play a role in the initiation of tachycardia. In
open-chest dogs, Kuo et al. (24) reported that an increase in
dispersion of repolarization induced by hypothermia and regional warm
blood is arrhythmogenic. These authors demonstrated that an increased
dispersion enhances conduction delay, facilitating the occurrence of
arrhythmia when a premature stimulus is applied in the area with the
shortest repolarization. However, in their model, conduction velocities
were also modified. In microelectrode studies performed in epicardial
and endocardial sheets, investigators have shown that some drugs and
simulated ischemia produce a marked dispersion of
repolarization and refractoriness (14, 23, 26) in the epicardium and
between the epicardium and endocardium and that the resulting
extrasystolic activity is based on the so-called phase
2 reentry. However, in dog atrium, Spach et al. (35)
observed that neither repolarization heterogeneity nor anisotropic
propagation is the sole mechanism responsible for reentrant
tachycardia. These authors suggested that factors leading to a
reentrant tachycardia might be a combined mechanism due to spatial
repolarization and discontinuities of anisotropic propagation. Because
the anisotropic pattern of epicardial propagation was not affected in
our study, we can state that unidirectional conduction block results
from both the shortening and the increased dispersion of VERP.
Dispersion of refractoriness.
To test the heterogeneity of epicardial refractoriness, SD-VERP, DI,
and Dmax were determined. These
three parameters reflected a great spatial inhomogeneity of the
epicardial repolarization after infusion of high doses of levcromakalim
and nicorandil. DI values obtained were in accordance with those
observed by Ogawa et al. (28) in a canine model of myocardial
infarction. These authors found that the value in the group in which
ventricular fibrillation or tachycardia was induced was 13.6%, whereas
the value for the control group was 6.2%. They reported that this increase in DI should be associated with the creation of epicardial functional block and the induction of ventricular fibrillation and
tachycardia. In our study, SD-VERP increased significantly at the dose
associated with arrhythmia, as shown by Ogawa et al. (28). The
occurrence of arrhythmia is associated with an increased dispersion of
VERP. Current data do not allow us to specify the respective part of
each factor (i.e., shortening and dispersion) in the arrhythmogenicity.
We are not aware of a study in which the role of shortening of VERP
without dispersion, or dispersion of VERP without prolongation or
shortening, has been determined. Nevertheless, because the homogeneous
prolongation of VERP is considered to be antiarrhythmic (10, 33), since
arrhythmias are usually observed in the case of both prolongation and
dispersion of refractoriness (16), we can suggest that the dispersion
of refractoriness could probably play a major role in the initiation of
reentry in our study.
Wavelength.
In the present study, we also demonstrated that the wavelength concept,
which is a good predictive parameter of arrhythmia inducibility in the
atrium (30), could also be useful in the ventricular epicardium. The
decrease in wavelength occurs in the same manner as that of VERP
because of ventricular conduction velocity stability. The maximum
proarrhythmogenic effect of potassium-channel openers is reached at 10 µmol/l levcromakalim and 500 µmol/l nicorandil; at these doses,
wavelengths are also the shortest. Similar to the manner in which the
atrial impulse wavelength in normal conscious dogs allows the
correlation between modification of electrophysiological parameters and
the inducibility of atrial arrhythmia (30), the wavelength determined
in the left ventricular epicardium could be used as an indicative
parameter of proarrhythmogenic effect. The decrease of the wavelength
exhibits that the initiation of a circuit would require a small area of
functional conduction block. Therefore, a little dispersion of VERP
could easily lead to a reentry. However, because VERPs are dispersed,
the wavelength calculated could vary according to the VERP considered.
Study limitations.
It would have been useful to know the VERP value near the functional
block. In the present study, we measured VERP in four sites located in
four different regions of the left epicardium. Given the spatial
resolution achieved and the fact that conduction block could occur
anywhere over the left epicardium, it is currently impossible for us to
know the VERP near the conduction block. Moreover, VERP could not be
measured in all sites, because the shortening of the coupling interval
performed by pacing in some sites could lead to the initiation of a
sustained arrhythmia.
Another difficulty was in the analysis of ventricular tachycardias.
Because wavelengths were significantly reduced by potassium-channel openers, and because the thin epicardial rim yielded some cellular layers, a reentrant circuit initiated in the transmural dimension could
not be excluded. This type of reentry cannot be mapped with our
technique, and in this case we cannot determine the real initiation mechanism.
Care must be taken in extrapolating our results to the clinical
setting. We studied solely the ventricular epicardium of isolated rabbit hearts, and some studies demonstrated that a dispersion of
refractoriness exists within the ventricular wall. The presence of
prominent transient outward currents in the epicardium, but not in the
endocardium, and the differential ATP sensitivity of potassium channels
between these tissues could explain the difference in their response to
drugs and ischemia, and then in the repolarization dispersion
(14, 19, 23). A difference in the responsiveness to
potassium-channel openers is also observed between atria and ventricles
(29). These different effects on different cardiac tissues could lead
to a disparity in refractoriness and, as demonstrated in this study,
could contribute to reentrant arrhythmias. Moreover, the concentrations
used in our study were in a toxic range with the exception of the
concentration of 1 µmol/l nicorandil, which is considered a clinical
dose (18). Levcromakalim is not available for clinical use in humans.
Brugada and Wellens (9) postulated that the mechanism called prolonged
repolarization-dependent reexcitation is due to a dispersion of
repolarization between contiguous structures. Early afterdepolarization
at low membrane potentials could induce a difference in refractoriness
and should be considered as a mechanism of torsade de pointes with a
long Q-T interval. Initiation of this arrhythmia could be due to
triggered activity resulting from early afterpotential, but
perpetuation of the arrhythmia is considered a reentrant mechanism
related to dispersion of refractoriness, despite a long wavelength
associated with an increase in action potential duration, VERP, and Q-T
interval (15, 38). In contrast, Leenhardt et al. (25) reported some
cases of unusual torsade de pointes with a short coupling interval of
the first beat of the arrhythmia. We could therefore hypothesize that
large doses of potassium-channel openers could facilitate such
polymorphic arrhythmias with a decrease in Q-T duration and a rise in
dispersion of repolarization.
In conclusion, the present study highlights on the mechanism of
initiation of potassium-channel opener-induced ventricular reentrant
tachycardia, which is based on both shortening of VERP and
refractoriness dispersion with no change of ventricular conduction velocities and anisotropic ratio. This allows conditions for functional conduction blocks, facilitating the occurrence of arrhythmia by reentry.
| |
ACKNOWLEDGEMENTS |
We thank the entire Pharmacy Staff of the University-Hospital of
Nîmes, Patrick Chartreux, Christian Francou, and the entire personnel of Medical School Laboratory, and Robert Sempéré
for skillful technical assistance and Margaret Manson for assistance with English.
| |
FOOTNOTES |
This work was supported by special grants of the Conseil Régional
du Languedoc-Roussillon and Conseil Général du
Département du Gard and by special grants of the Fondation pour
la Recherche Médicale Française.
Address for reprint requests: J. E. de La Coussaye, Département
de l'Urgence, Centre Hospitalier Universitaire Gaston Doumergue, 5 rue
Hoche, 30029 Nîmes Cedex, France.
Received 23 December 1997; accepted in final form 28 September
1998.
| |
REFERENCES |
1.
Allessie, M. A.,
F. I. M. Bonke,
and
F. J. G. Schopman.
Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of non-uniform recovery of excitability in the occurrence of unidirectional blocks, as studied with multiple microelectrodes.
Circ. Res.
39:
168-177,
1976[Abstract/Free Full Text].
2.
Allessie, M. A.,
F. I. M. Bonke,
and
F. J. G. Schopman.
Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The "leading circle" concept: a new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle.
Circ. Res.
41:
9-18,
1977[Free Full Text].
3.
Allessie, M. A.,
A. P. G. Hoeks,
G. M. L. Schmitz,
and
R. S. Reneman.
On-line mapping system for the visualisation of the electrical activation of the heart.
Int. J. Card. Imaging
2:
59-63,
1987.
4.
Allessie, M. A.,
M. J. Schalij,
C. Kirchhof,
L. Boersma,
M. Huybers,
and
J. Hollen.
Experimental electrophysiology and arrhythmogenecity: anisotropy and ventricular tachycardia.
Eur. Heart J.
10:
8-14,
1989[Abstract/Free Full Text].
5.
Berstein, R. C.,
and
L. H. Frame.
Ventricular reentry around a fixed barrier: resetting with advancement in an in vitro model.
Circulation
81:
267-280,
1990[Abstract/Free Full Text].
6.
Boersma, L.,
J. Brugada,
C. Kirchhof,
and
M. A. Allessie.
Mapping of reset of anatomic and functional reentry in anisotropic rabbit ventricular myocardium.
Circulation
89:
852-862,
1994[Abstract/Free Full Text].
7.
Boyden, P.,
L. H. Frame,
and
B. F. Hoffman.
Activation mapping of reentry around an anatomic barrier in the canine atrium: observations during entrainment and termination.
Circulation
79:
406-416,
1989[Abstract/Free Full Text].
8.
Brugada, J.,
L. Boersma,
C. Kirchhof,
and
M. A. Allessie.
Proarrhythmic effects of flecainide: evidence for increase susceptibility to reentrant arrhythmias.
Circulation
84:
1808-1818,
1991[Abstract/Free Full Text].
9.
Brugada, P.,
and
H. J. J. Wellens.
Early afterdepolarization. Role in conduction block, "prolonged repolarization-dependent reexcitation", and tachyarrhythmias in the human heart.
Pacing Clin. Electrophysiol.
8:
889-896,
1985[Medline].
10.
Cha, Y.,
A. Wales,
P. Wolf,
S. Shahrokni,
N. Sawhney,
and
G. K. Feld.
Electrophysiologic effects of the new class III antiarrhythmic drug dofetilide compared to the class IA antiarrhythmic drug quinidine in experimental canine atrial flutter: role of dispersion of refractoriness in antiarrhythmic efficacy.
J. Cardiovasc. Electrophysiol.
7:
809-827,
1996[Medline].
11.
Clerc, L.
Directional differences on impulse spread in trabecular muscle from mammalian heart.
J. Physiol. (Lond.)
255:
335-346,
1976[Abstract/Free Full Text].
12.
De La Coussaye, J. E.,
J. Brugada,
and
M. A. Allessie.
Electrophysiologic and antiarrhythmogenic effects of bupivacaine: a study with high resolution ventricular epicardial mapping in rabbit hearts.
Anesthesiology
77:
132-141,
1992[Medline].
13.
De La Coussaye, J. E.,
J. J. Eledjam,
P. Bruelle,
P. A. Péray,
B. P. Bassoul,
J. P. Gagnol,
and
A. Sassine.
Electrophysiologic and arrhythmogenic effects of the potassium channel agonist BRL 38227 in anesthetized dogs.
J. Cardiovasc. Pharmacol.
22:
722-730,
1993[Medline].
14.
Di Diego, J. M.,
and
C. Antzelevitch.
Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues: does activation of ATP-regulated potassium current promote phase 2 reentry?
Circulation
88:
1177-1189,
1993[Abstract/Free Full Text].
15.
El-Sherif, N.
Early afterdepolarizations and arrhythmogenesis. Experimental and clinical aspects.
Arch. Mal. Coeur Vaiss.
84:
227-234,
1991[Medline].
16.
El-Sherif, N.,
E. B. Caref,
H. Yin,
and
M. Restivo.
The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome. Tridimensional mapping of activation and recovery patterns.
Circ. Res.
79:
474-492,
1996[Abstract/Free Full Text].
17.
Escande, D.,
D. Thuringer,
S. Le Guern,
M. Courteix,
M. Laville,
and
I. Cavero.
Potassium channel openers act through an activation of ATP-sensitive K+ channels in guinea-pig cardiac myocytes.
Pflügers Arch.
414:
669-675,
1989[Medline].
18.
Frydman, A.
Pharmacokinetic profile of nicorandil in humans: an overview.
J. Cardiovasc. Pharmacol.
20:
S34-S44,
1992.
19.
Furukawa, T.,
S. Kimura,
N. Furukawa,
A. L. Basset,
and
R. J. Myerburg.
Role of cardiac ATP-regulated potassium channels in differential responses of endocardial and epicardial cells to ischemia.
Circ. Res.
68:
1693-1702,
1991[Abstract/Free Full Text].
20.
Girouard, S. D.,
J. M. Pastore,
K. R. Laurita,
K. W. Gregory,
and
D. S. Rosenbaum.
Optical mapping in a new guinea-pig model of ventricular tachycardia reveals mechanisms for multiple wavelengths in a single reentrant circuit.
Circulation
93:
603-613,
1996[Abstract/Free Full Text].
21.
Gough, W. B.,
R. Mehra,
M. Restivo,
R. H. Zeiler,
and
N. El-Sherif.
Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog. 13. Correlation of activation and refractory maps.
Circ. Res.
57:
432-442,
1985[Abstract/Free Full Text].
22.
Han, J.,
and
G. K. Moe.
Nonuniform recovery of excitability in ventricular muscle.
Circ. Res.
14:
44-60,
1964[Abstract/Free Full Text].
23.
Krishnan, S. C.,
and
C. Antzelevitch.
Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry?
Circulation
87:
562-572,
1993[Abstract/Free Full Text].
24.
Kuo, C. S.,
K. Munakata,
P. Reddy,
and
B. Surawicz.
Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential duration.
Circulation
67:
1356-1367,
1983[Abstract/Free Full Text].
25.
Leenhardt, A.,
E. Glaser,
M. Burguera,
M. Nürnberg,
P. Maison-Blanche,
and
P. Coumel.
Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
Circulation
89:
206-215,
1994[Abstract/Free Full Text].
26.
Lukas, A.,
and
C. Antzelevitch.
Phase 2 reentry as a mechanism of initiation of circus movement reentry in canine epicardium exposed to simulated ischemia.
Cardiovasc. Res.
32:
593-603,
1996[Medline].
27.
Mines, G. R.
On dynamic equilibrium in the heart.
J. Physiol. (Lond.)
46:
349-382,
1913.
28.
Ogawa, S.,
I. Furuno,
Y. Satoh,
S. Yoh,
K. Saeki,
T. Sadanaga,
H. Katoh,
and
Y. Nakamura.
Quantitative indices of dispersion of refractoriness for identification of propensity to re-entrant ventricular tachycardia in a canine model of myocardial infarction.
Cardiovasc. Res.
25:
378-383,
1991[Abstract/Free Full Text].
29.
Oghaghebriel, A.,
and
A. Shrier.
Differential responsiveness of atrial and ventricular myocytes to potassium channel openers.
J. Cardiovasc. Pharmacol.
25:
65-74,
1995[Medline].
30.
Rensma, P. L.,
M. A. Allessie,
W. J. Lammers,
F. I. M. Bonke,
and
M. J. Schalij.
Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs.
Circ. Res.
62:
395-410,
1988[Abstract/Free Full Text].
31.
Robert, E.,
P. Bruelle,
J. E. de La Coussaye,
J. M. Juan,
J. Brugada,
P. Péray,
M. Dauzat,
and
J. J. Eledjam.
Electrophysiologic and proarrhythmogenic effects of therapeutic and toxic doses of imipramine. A study with high resolution ventricular epicardial mapping in rabbit hearts.
J. Pharmacol. Exp. Ther.
278:
170-178,
1996[Abstract/Free Full Text].
32.
Robert, E.,
B. Delye,
G. Aya,
P. Péray,
J. M. Juan,
A. Sassine,
J. E. de La Coussaye,
and
J. J. Eledjam.
Comparison of proarrhythmogenic effects of two potassium channel openers, levcromakalim (BRL 38227) vs. nicorandil (RP 46417): a high resolution mapping study on rabbit hearts.
J. Cardiovasc. Pharmacol.
29:
109-118,
1997[Medline].
33.
Sager, P. T.,
K. Nademanee,
M. Antimisiaris,
A. Pacifico,
C. Pruitt,
R. Godfrey,
and
B. N. Singh.
Antiarrhythmic effects of selective prolongation of refractoriness. Electrophysiologic actions of sematilide HCl in humans.
Circulation
88:
1072-1082,
1993[Abstract/Free Full Text].
34.
Schalij, M. J.,
W. J. Lammers,
P. L. Rensma,
and
M. A. Allessie.
Anisotropic conduction and reentry in perfused epicardium of rabbit left ventricle.
Am. J. Physiol.
263 (Heart Circ. Physiol. 32):
H1466-H1478,
1992[Abstract/Free Full Text].
35.
Spach, M. S.,
P. C. Dolber,
and
J. F. Heidlage.
Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria. A mechanism for both preventing and initiating reentry.
Circ. Res.
65:
1612-1631,
1989[Abstract/Free Full Text].
36.
Spach, M. S.,
W. I. Miller,
P. C. Dolber,
J. M. Kootsey,
J. R. Sommer,
and
C. E. Mosher.
The functional role of structural complexities in the propagation of depolarization in the atrium of the dog: cardiac conduction disturbances due to discontinuities of effective axial resistivity.
Circ. Res.
50:
175-191,
1982[Free Full Text].
37.
Spach, M. S.,
W. T. Miller, Jr.,
D. B. Geselowitz,
R. C. Barr,
J. M. Kootsey,
and
E. A. Johnson.
The discontinuous nature of propagation in normal canine cardiac muscle: evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents.
Circ. Res.
48:
39-54,
1981[Free Full Text].
38.
Surawicz, B.
Electrophysiologic substrate of torsade de pointes. Dispersion of repolarization or early afterdepolarizations?
J. Am. Coll. Cardiol.
14:
172-184,
1989[Abstract].
39.
Wilde, A. A. M.
K+ATP-channel opening and arrhythmogenesis.
J. Cardiovasc. Pharmacol.
24:
S35-S40,
1994.
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