Vol. 282, Issue 1, H212-H218, January 2002
Regional prolongation of ARI and altered restitution
properties cause ventricular arrhythmia in heart failure
Tetsu
Watanabe1,
Michiyasu
Yamaki2,
Sou
Yamauchi1,
Osamu
Minamihaba1,
Takehiko
Miyashita1,
Isao
Kubota1, and
Hitonobu
Tomoike1
1 First Department of Internal Medicine and
2 Division of Medical Informatics, Yamagata University
School of Medicine, Yamagata 990-9585, Japan
 |
ABSTRACT |
The mechanism of
arrhythmogenicity in heart failure remains poorly understood. We
examined the relationship between electrical abnormalities and
ventricular arrhythmia by using experimental heart failure models.
Sixty unipolar electrograms were recorded from the entire cardiac
surface in control dogs (n = 13) and pacing-induced heart failure dogs (n = 16). In failing hearts,
activation time (AT) was delayed at the apex, and AT dispersion
increased in failing hearts. Activation-recovery intervals (ARI) were
prolonged mainly at the apex and ARI dispersion was significantly
augmented. The slope of the ARI restitution curve, interaction of
diastolic interval, and ARI in failing hearts was significantly steeper
than in control hearts. Ventricular fibrillation (VF) was easily
induced by programmed stimulation in failing hearts, whereas no
arrhythmia occurred in control hearts. Computer simulation studies
could reproduce the experimental results. Altering the ARI restitution
to the steep slope causes VF in a model heart. It is suggested that
electrical remodeling, especially steepness of electrical restitution,
may play a role in arrhythmogenicity in failing hearts.
restitution hypothesis; simulation
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INTRODUCTION |
ADVANCEMENTS IN MEDICAL
THERAPY have improved survival for patients with congestive heart
failure in the past decade (4, 16a). However, total mortality is still
high, and sudden deaths account for approximately half of the mortality
(11). Ventricular arrhythmia contributes significantly to
sudden death in patients with heart failure (11, 18) and
alterations in electrophysiological properties have been demonstrated.
Myocytes and isolated tissue from failing hearts of animals and humans
consistently reveal abnormalities mainly in repolarization such as
action potential prolongation (12, 16, 21). In general,
action potential prolongation can predispose to dispersion of
repolarization and the development of afterdepolarizations
(22). Dispersion of repolarization leads to reentrant
arrhythmia, and afterdepolarization leads to triggered arrhythmia.
However, the relationship between electrical alteration and ventricular
arrhythmia in failing hearts is poorly understood. The pacing-induced
heart failure model reliably reproduces the resulting abnormalities
similar to human heart failure (1, 27, 28), including
biventricular dysfunction (1), increases in plasma
norepinephrine and renin and atrial natriuretic factor (28), and altered gene expression (27). In
the present study, we examined the relation between
electrophysiological alterations and ventricular arrhythmia by use of
this experimental model and a three-dimensional heart model to verify
the mechanism of arrhythmogenicity in heart failure.
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MATERIALS AND METHODS |
Pacing-induced heart failure.
Twenty-two adult mongrel dogs were anesthetized by intravenous
administration of pentobarbital sodium (20 mg/kg body wt), and sterile
unipolar endocardial leads were placed sterilely under fluoroscopic
guidance at the right ventricular apex through the right internal
jugular vein. A programmable pacemaker was connected to the leads and
placed in a subcutaneous pocket at the base of the neck. Dogs were
allowed to fully recover from surgery for 7 days, after which pacing
was started at a cycle length of 300 ms for 3 wk. Thirteen dogs that
underwent sham operation skin incisions were used as a control group.
Experiments began a minimum of 2 days after the operation when the dogs
had completely recovered. This study conformed to the guiding
principles of animal experiments in Yamagata University School of
Medicine, Yamagata, Japan.
Protocols and measurements.
The dogs within the sham operation and heart failure groups (14-30
kg body wt) were anesthetized with pentobarbital sodium (25 mg/kg body
wt) and received supplemental doses as needed. A respirator ventilated
the dogs with room air supplemented with oxygen (3-5 l/min).
Hemodynamic variables were measured with a micromanometer (Millar
Instruments; Houston, Texas) after cessation of rapid ventricular
pacing. Under controlled respiration, the thorax was opened in the
fifth intercostal space, the pericardium was opened, and the
pericardial cradle supported the heart at an appropriate position. The
sinus node was crushed (19, 20, 23), and the right atrium
was paced at several basic cycle lengths using a model SEN-7203
stimulator (Nihon Koden; Tokyo, Japan). A sock-shaped electrode array
was placed on the ventricular surface for simultaneous recording of
electrograms from 60 epicardial sites. Each unipolar electrode
consisted of fine silver wire (0.2 mm diameter) sutured to the
electrode array (19, 20, 23), which consisted of 6 rows
and 10 columns. All recording electrodes were referenced to the
Wilson's central terminal, and multichannel electrograms were
digitized every millisecond using a multiplexed data processing system
(CD-G015, Chunichi Denshi; Nagoya, Japan) as described in previous
studies (19, 20, 23). The thoracic cavity was covered with
plastic wrap to prevent cooling and dehumidifying, and body temperature
was maintained at 37-38°C. An arterial line was inserted into
the right femoral artery to continuously monitor mean arterial
pressure. The electrocardiogram lead II and blood pressure were
monitored throughout the study on a recorder (model 2G66, NEC San-ei;
Tokyo, Japan).
Analysis of multichannel epicardial electrograms.
Multichannel epicardial electrograms were processed on an off-line
microcomputer (model SUN 4/2, SUN Microsystems; Mountain View, CA).
Epicardial activation of each electrogram was defined as the minimal
derivative of the QRS signal (17). The earliest activation
was assigned to time 0, and the activation time (AT) was
determined as the interval between time 0 and each
activation. Recovery time (RT) was defined as the maximal derivative in
the T wave. Activation-recovery intervals (ARI), defined as the time from AT to RT, were also measured (9). ARI is known to be
well correlated to the action potential duration (APD) and effective refractory periods (9). We measured the dispersion of AT,
RT, or ARI, defined as the difference between the longest and the shortest measured values in the same heart to evaluate electrical heterogeneity.
The relationship between ARI and diastolic interval (DI) was examined
during atrial pacing at cycle lengths from 600 to 300 ms in steps of
100 ms and from 300 ms to the Wenckebach block in steps of 10 to 20 ms.
The relationship between ARI and DI was fitted to a function of the
type ARI = b(1 
e
a · DI), where
b is a constant, to quantify them as an electrical
restitution curve. The plateau level of b and the time
course as the maximal slope of the restitution curve was derived in
control and failing hearts.
Susceptibility of ventricular arrhythmia was investigated by programmed
stimulation. The ventricular effective refractory period was determined
with use of a driving train (S1) of 10 beats at a cycle length of 400 ms, followed by an extra stimulus (S2) that was decreased in 10-ms
intervals. The ventricular effective refractory period was defined as
the longest S1-S2 interval at which S2 failed to elicit ventricular
activation. The second extrastimulus (S3) was started with the S1-S2
interval fixed at 40 ms longer than the ventricular effective
refractory period. S2-S3 interval decrements until S3 failed to elicit
ventricular activation. If double extrastimuli failed to initiate
arrhythmia, a third extrastimulus (S4) was also added.
At the end of the study, the heart was rapidly excised after induction
of ventricular fibrillation (VF). At this point, biventricular weight
was measured. The myocardium underlying the left and right ventricular
free wall and apex was stained with hematoxylin-eosin for histological
assessment of fibrosis and/or the size of myocardium.
Heart model and simulation protocol.
A simulation study using the Wei-Harumi model was performed (8,
24). The heart model included atria and ventricles and was
comprised of 50,000 discrete units (model cells). The model cells were
categorized into eight types: sinus node, atria, atrioventricular node,
bundle of His, bundle branch, Purkinje fibers, ventricular cells, and
connective element. The electrophysiological properties of each model
cell were specified as in previous reports (29) and were
also specified as measurements in a representative pacing-induced heart
failure model. Excitation automaticity was assigned only to sinus node
cells. Other types of cells were activated from neighboring cells when
those cells became excitable. When cells were absolutely refractory,
conduction was completely blocked.
A parameter called the dynamic coefficient (DC) was associated with the
coupling interval (CI)-dependent APD change (6). DC was
defined as the difference in APDs divided by the difference in CIs.
This parameter yields APD change with CI and is uniquely determined for
each cell type.
The value of APD at time t is defined as
APD(t) = APD(t 1) + DC · 
CI where CI is the change in CI for the model cell
at time t.
Surface electrocardiograms were simulated by the heart model under the
following simulation protocols: 1) normal condition; 2) slow conduction and prolonged APD; or 3) slow
conduction, prolonged APD, and greater DC. Each was the simulation of
"normal heart," "failing heart with normal restitution," or
"failing heart with abnormal restitution." Parameters of
ventricular cells, APDs, or DCs were determined based on the present
experimental data to replicate the experimental observations.
Parameters of Purkinje fibers, including 80% of DC, were determined
based on the reported experimental data (7).
Trains of electrical stimuli were delivered to an anterior apex cell at
a cycle length of 160 ms. The heart model was considered to be located
inside a homogeneous torso model (Fig.
1). Surface potentials on the model torso
generated by the heart model were calculated by means of the prescribed
transmembrane action potential distribution (8, 24). This
simulation generated a torso surface electrocardiogram, because we
employed the boundary element method for calculation.
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Fig. 1.
Models of heart and torso. A: setup of the failing
heart. Cells with different degrees of action potential duration (APD)
prolongation and delayed conduction velocity were arranged surrounding
the apex with the longest APD being in the apex. B: model
heart positioned in a homogeneous torso model. ATR, atrial myocytes;
VTR, ventricular myocytes; TD, transitional cells, HF, myocytes with
heart failure electrophysiology; arrows, direction of the slices, basal
to apical.
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Statistical analysis.
Quantitative data are reported as means ± SD. Statistical
analysis was performed with ANOVA. A confidence level of 95% was considered statistically significant.
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RESULTS |
Clinical features and hemodynamics at the basal state.
Thirteen sham-operated dogs had no apparent signs of pump failure
throughout the observation period. Among 22 tachypacing dogs, six dogs
(27%) suddenly died (four during pacing period and two due to the
second surgical procedure). The remaining 16 dogs of the heart failure
group were studied.
Hemodynamic measurements at baseline are summarized in Table
1. Compared with the control group, there
were reduced left ventricular systolic pressure, elevated left
ventricular end-diastolic pressure, and decreased peak positive and
negative first derivatives of left ventricular pressure
(dP/dt) in failing hearts. Hemodynamic results
confirmed the presence of both systolic and diastolic dysfunction in
the heart failure group.
Heterogeneity of ARI.
In the 13 control and 16 failing dogs, surface distributions of AT, RT,
and ARI were examined during right atrial pacing at a cycle length of
300 to 600 ms. Representative traces of AT, RT, and ARI maps in a
control heart are shown in Fig.
2A. The earliest activation
appears on the anterior right ventricle. Conduction delay is not
recognized, and distribution of RT or ARI was almost uniform. A maximal
ARI of 198 ms was located on the left anterior base. Figure
2B shows representative traces of AT, RT, and ARI maps in a
failing heart. Prolongation of both RT and ARI is recognized mainly at
the ventricular apex. Maximal ARI was 238 ms. Delayed ATs were also
observed at the ventricular apex.
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Fig. 2.
Representative traces of activation time (AT), recovery time (RT),
and activation recovery interval (ARI) maps during atrial pacing at a
cycle length of 500 ms in a control heart (A) and a failing
heart (B). The display format is an apical polar projection
of ventricles with the left ventricular apex in the center. *Earliest
activation.
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The maximal ARI in the failing group was significantly longer than in
the control group at a cycle length of 300 to 600 ms (Fig.
3). We measured dispersion (d) of AT, RT,
and ARI (ATd, RTd and ARId) to evaluate spatial heterogeneity (Fig.
4). ATd, RTd, or ARId significantly
increased in the failing group compared with the control group.
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Fig. 3.
Comparison of rate-dependent ARI prolongation between
control and failing hearts. BCL, basic cycle length.
 P < 0.05 vs. control; *P < 0.05 vs.
BCL of 300 ms.
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Fig. 4.
Dispersion (d) of ATd, RTd, and ARId in control or failing hearts.
P < 0.05 vs. control; *P < 0.05 vs.
BCL of 300 ms.
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Restitution property of ARI.
The restitution relation between ARI and DI was examined at the apical
and the basal myocardium. Figure
5A shows the representative ARI restitution curves in two control and two failing hearts, and Fig.
5B shows the group difference in the maximal slopes between control (n = 6) and failing hearts (n = 6). In the representative curves, the slopes of the ARI
restitution in failing hearts were steep at short DI compared with
control hearts. Average data confirmed that the slope of the ARI
restitution curve at the apex of failing hearts was significantly
steeper than that of control hearts (Fig. 5B). However, the
slope of the ventricular base, where ARI was not prolonged, was almost
equal to that of the control hearts.
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Fig. 5.
A: representative ARI restitution curves in control and
failing hearts measured at the apical myocardium. Slopes of the ARI
restitution curves in failing hearts were steep at short diastolic
interval (DI) compared with control hearts. B: maximal
slopes of the restitution curves in control (n = 6) and failing hearts (n = 6) on apical or basal
myocardium. NS, not significant.
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Programmed electrical stimulation.
Programmed electrical stimulation was performed to examine
arrhythmogenicity in failing hearts. Ventricular tachycardia (VT) was
easily initiated by double extrastimuli at a drive cycle length of 400 ms in all failing hearts (10 of 10 dogs), whereas no ventricular arrhythmias were initiated by the same extrastimuli in control hearts
(0 of 8 dogs). Induced VT in failing hearts degenerated into VF (9 of
10 episodes). Figure 6 illustrates the
initiation of VF caused by double extrastimuli on the left ventricle
(Fig. 6A) or the right ventricle (Fig. 6B) in a
failing heart. In the S3 excitation, conduction was blocked on the left
posterior ventricular wall (Fig. 6A). Spontaneous excitation
(VT1) initiated near the block line of the beat S3. Excitation of VT1
was again blocked on the left posterior ventricular wall, widely
rotated around the apex, and reached the opposite site. Figure
6B shows a case of right ventricle stimuli. Block line was
located on the right anterior wall. The excitation was blocked on this
area and then rotated around the apex. In this dog, the excitation
easily degenerates to VF.
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Fig. 6.
Representative activation sequence at initiation of
ventricular arrhythmia caused by the left ventricle stimuli
(A) or the right ventricle stimuli (B) in a
failing heart. Bold lines, conduction block; S1, driving stimulation;
S2, first extrastimulus; S3, second extra stimulus; VT1, first beat of
spontaneous ventricular excitation.
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Simulation study using a heart model.
We performed simulation studies in following three setups:
1) normal heart, simulation 1; 2)
heart with slow conduction and prolonged APD, simulation 2;
and 3) heart with slow conduction, prolonged APD, and an
increase in DC, simulation 3.
In simulation 1, we assigned 255 ms of APD, 0.5 m/s
conduction velocity, and 0.4 of DC to each ventricular cell. In
simulation 2, we assigned 295 ms of APD and 0.4 m/s of
conduction velocity to apical ventricular cells, and assigned 255 ms of
APD and 0.5 m/s of conduction velocity to basal ventricular
cells. APDs were gradually changed between apical and basal in
the experimental study. Therefore 265, 275, or 285 ms of APD were
assigned to transitional cells between apical and basal. In a
transitional cell, DC was defined as 0.4, and conduction velocity was
defined as 0.5 m/s. In simulation 3, DC on apical
ventricular cells was defined as 0.75, and DC on basal ventricular
cells was 0.4. In this simulation, the other setups were the same as
simulation 2.
Figure 7A shows simulation
results after four trains of stimulation are applied to each model
heart. VF continued only when greater DC was applied (simulation
3). Increase in DC is essential for the induction of VF in the
model heart. Figure 7B shows activation sequences at the
initial phase of VF induction. These activation patterns support
reentry as a mechanism of the arrhythmia.
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Fig. 7.
A: simulation results after three trains of stimulation
and induction of ventricular fibrillation (VF) in 1) the
normal heart, 2) the heart with slow conduction and
prolonged APD, and 3) the heart with slow conduction,
prolonged APD, and increased dynamic coefficient (DC). VF continued
only in the heart with slow conduction, prolonged APD, and increased DC
(simulation 3). Increase in DC is essential for the
induction of VF due to three-train stimulation. B:
activation sequences at the initial phase of VF induction in
simulation 3. Activation patterns support reentry as a
mechanism of the arrhythmia. The numeral in figure indicates the ATs.
Arrows, direction of the activation sequence.
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Pathological findings in failing hearts.
The hearts of the failing dogs showed visible dilation and pericardial
effusion. However, there was no significant difference in either total
ventricular weight or weight normalized for body weight between control
and failing groups (Table 1). No significant change in body weight was
recognized between the control and failing group. On histological
examination, myocyte length, width and nuclear size appeared to be
increased in the failing hearts.
| |
DISCUSSION |
In the present study, we examined the relation between
electrophysiological alterations and ventricular arrhythmia in heart failure using a pacing-induced tachycardia heart failure model, which
exhibited lethargic behavior, cardiac dysfunction, and fluid retention.
The results suggested that 1) regional conduction
disturbance, 2) augmented inhomogeneity of refractoriness,
and 3) steepness of electrical restitution curve are
important for arrhythmia vulnerability in heart failure. The simulation
study verified that an increase in DC was essential for the induction
of VF. Altered electrical restitution properties may play an important
role for arrhythmogenicity in heart failure.
Inducibility of ventricular arrhythmia.
In the present study, applying double extrastimuli induced VF in
failing but not in normal hearts. It has been postulated that triggered
activity and automaticity are the mechanisms of ventricular
tachyarrhythmia in failing hearts (13, 22, 30). Indeed, VT
was not sustained, and VF was reproducibly induced (12,
30). However, analysis of the activation sequence (Fig. 6)
suggested that the VT1 wave was blocked at the apex along the border of
prolonged ARI and then rotated around the apex. We assumed that the
prolonged refractoriness at the apex might contribute to the formation
of the conduction block and reentrant arrhythmia.
Restitution hypothesis and electrical instability in failing
hearts.
Recently, restitution properties have been focused on the transition
between VT and VF (the restitution hypothesis) (15, 25).
In a case of steep slope of the restitution curve, small changes of DI
(extrastimuli) produced a larger change in the APD of the next beat.
The larger the APD changes, the larger the DI changes. Therefore,
alteration in the APD and DI was augmented, and finally VF occurred.
Riccio et al. (15) reported that a steep slope of the
electrical restitution curve was a prerequisite for VF, and reduction
of the restitution slope prevented the development of VF. The
simulation study using a model is an important process for linking the
hypothesis to the observed phenomena. Therefore, we constructed the
three-dimensional heart model simulating failing heart
electrophysiology. The simulation results showed that increase in a
parameter DC was essential for VF in heart failure. Because an increase
in DC is compatible with steepness of ARI restitution, it confirmed the
importance of restitution hypothesis on the mechanism of VF in heart
failure. In the present study, the slope of ARI restitution at the
ventricular base was almost equal to that of control hearts. It became
steep only at the apex where the repolarization remodeling was seen.
It is suggested that a slope over 1 of restitution relation facilitates
the induction of APD alternans (15). In the present study,
the mean steepness of the ARI restitution slope was 0.74 at the apex in
the failing heart during atrial pacing. However, VF was induced by
ventricular extrastimuli. Because CIs were definitely shorter during
ventricular extrastimuli than during atrial pacing, the slope of
restitution relation might become more steep during ventricular
extrastimuli. Therefore, VF was induced by ventricular extrastimuli.
Conversely, in the control studies with normal restitution slope, VF
was not induced. It suggests that the steep slope of the ARI-DI
relationship might be the substrate of ventricular arrhythmia even when
it was below 1.
Spatial dispersion of refractoriness.
Action potential prolongation is a consistent finding in human heart
failure (3, 21) and experimental cardiac insufficiency (12-14, 30). In the present study, ARI, a compatible
measure of APD, was prolonged mainly at the apex of the failing heart. The mechanism of action potential prolongation has been increasingly investigated on experimental failing myocytes (12, 26).
These studies suggest a concomitant reduction in the transient outward current (Ito) density with a reduction in
channel density. Because Ito is an important
current in setting the level of plateau currents, a decrease in this
current contributes to early deviation of action potential
configuration and action potential prolongation. The reduction on
inward rectified K+ current (3, 12) and slow
inactivation of L-type calcium channel current are also reported in
failing hearts (16). Total balance of these altered ion
channels may determine the APD on failing hearts.
Slowing of ventricular conduction and an increase in dispersion of
refractoriness were also seen. Clinically, interlead variability in the
Q-T interval (Q-T dispersion) is a more powerful indicator of sudden
death than the Q-T interval itself (2, 5). Q-T dispersion
thoroughly reflects inhomogeneous recovery and should be the substrate
of ventricular arrhythmia in chronic heart failure (2). A
difference in ARI between the apex and the base contributed to
augmented dispersion in repolarization in the present experiments. APD
significantly increased in failing hearts. This may be explained by
histological changes characterized by interstitial edema and fibrosis.
Both conduction delay and an increase in dispersion of recovery should
be the substrate of arrhythmia in failing hearts.
In conclusions, the present study suggested that the restitution
hypothesis is important for the development of VF in heart failure.
Weiss et al. (25) suggested that pharmacological therapy that reduces the slope of the restitution relationship would be expected to suppress the development of VF. The approach for
controlling arrhythmia based on the restitution hypothesis may provide
new insights into the antiarrhythmic strategy in patients with heart failure.
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ACKNOWLEDGEMENTS |
This study was supported in part by grants from the Japan Heart
Foundation, Pfizer (for Research on Hypertension and Vascular Metabolism), and the Fukuda Foundation for Medical Technology.
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FOOTNOTES |
Address for reprint requests and other correspondence: M. Yamaki, Division of Medical Informatics, Yamagata Univ. School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan (E-mail: myamaki{at}med.id.yamagata-u.ac.jp).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 9 February 2001; accepted in final form 24 September 2001.
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