(Circulation. 1995;92:1034-1048.)
© 1995 American Heart Association, Inc.
Articles |
Nonreentrant Mechanisms Underlying Spontaneous Ventricular Arrhythmias in a Model of Nonischemic Heart Failure in Rabbits
From the Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Mo.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background The goal of this study was to define the mechanisms of spontaneously occurring ventricular arrhythmias in the setting of nonischemic heart failure.
Methods and Results Three-dimensional cardiac mapping from 232 intramural sites was performed in four rabbits with heart failure induced by combined aortic regurgitation and aortic stenosis and in four control rabbits. During the development of heart failure, serial echocardiographic examination demonstrated a progressive increase in left ventricular (LV) chamber dimensions and a decrease in LV systolic function over 19±2 months. Serial Holter monitoring demonstrated spontaneously occurring premature ventricular complexes (PVCs) (up to 13 000 per day) and couplets in all four rabbits with heart failure, and runs of nonsustained ventricular tachycardia (VT) up to 26 beats long in three. Mapping of spontaneous rhythm was performed for up to 60 minutes. None of the control rabbits demonstrated spontaneous arrhythmias during mapping. Three rabbits with heart failure demonstrated isolated PVCs, and two demonstrated couplets and runs of nonsustained VT up to 4 beats long. The three-dimensional activation sequence of 50 sinus beats (42 from rabbits with heart failure; 8 from control rabbits), 19 PVCs, and 37 beats of couplets and nonsustained VT was determined and the mechanism of arrhythmia defined for all ventricular ectopic beats analyzed. Normal sinus beats from the failing rabbits activated rapidly, with a total activation time of 28±1 ms (P=.18 versus sinus beats from control hearts, 26±1 ms). Sinus beats preceding PVCs in the rabbits with heart failure activated in a similar fashion, with a total activation time of 26±1 ms. In each case, these PVCs initiated in the subendocardium by a nonreentrant mechanism based on the absence of intervening electrical activity between the termination of the preceding beat and the initiation of the next (225±7 ms), despite the presence of multiple intervening electrode recording sites. Couplets and monomorphic and polymorphic VTs were due to repetitive nonreentrant activation at the same or different subendocardial sites. Total activation time of beats of VT averaged 44±1 ms and did not differ from that of isolated PVCs (43±2 ms, P=.65). Pathological analysis of tissue demonstrated myocardial fiber hypertrophy, degenerative changes, and interstitial fibrosis throughout the failing hearts.
Conclusions Spontaneously occurring PVCs, couplets, and VT in a model of nonischemic heart failure are due to nonreentrant mechanisms such as triggered activity or abnormal automaticity. Approaches to the treatment of spontaneously occurring ventricular arrhythmias in patients with nonischemic heart failure should be directed at nonreentrant mechanisms.
Key Words: tachycardia • heart failure • mapping
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Congestive heart failure, whether caused by ischemic or nonischemic processes, is associated with a very poor prognosis, with a 2-year mortality approaching 50% in patients in New York Heart Association classes III and IV.1 In nearly one half of the cases, death is sudden,2 usually caused by ventricular tachycardia (VT) that degenerates to ventricular fibrillation (VF).3 4 Currently available antiarrhythmic treatment of these malignant ventricular arrhythmias is ineffective5 and potentially proarrhythmic.6 The development of effective antiarrhythmic therapy will be facilitated by delineation of the underlying electrophysiological mechanisms, ie, determination of whether VT is due to reentry or to a focal nonreentrant mechanism such as triggered activity or abnormal automaticity.
Unfortunately, very little is known about the electrophysiological alterations and the underlying electrophysiological mechanisms responsible for ventricular arrhythmias in the failing heart. This is due primarily to a lack of experimental animal models of heart failure that demonstrate spontaneously occurring arrhythmias and in which arrhythmia mechanisms can be elucidated by use of state-of-the-art mapping procedures. Delineation of electrophysiological mechanisms of arrhythmias occurring in vivo requires simultaneous recording from multiple (several hundred) sites throughout the entire heart, ie, high-resolution three-dimensional (3D) cardiac mapping.7
Three-dimensional mapping of spontaneously occurring ventricular arrhythmias was performed recently in an experimental model of ischemic cardiomyopathy.8 Dogs with heart failure induced by multiple intracoronary microembolizations demonstrated a progressive decrease in left ventricular (LV) systolic function,9 pathological alterations comparable to human ischemic cardiomyopathy,8 9 and spontaneously occurring premature ventricular complexes (PVCs), couplets, and runs of VT.8 9 10 Mapping from 232 sites throughout the left and right ventricles and the interventricular septum has demonstrated that PVCs and VT initiate by a focal mechanism arising primarily from the subendocardium, with no evidence of macroreentry.8 Spontaneously occurring monomorphic and polymorphic VTs are due to repetitive focal activation.8
Determination of whether arrhythmias associated with nonischemic heart failure are initiated by reentry or a nonreentrant mechanism also requires mapping to be performed in an experimental animal preparation that demonstrates frequent spontaneously occurring arrhythmias. End-stage nonischemic heart failure in humans, resulting from cardiomyopathy or chronic pressure and/or volume overload, represents a final common outcome characterized by LV dilatation, LV systolic dysfunction, severe but relatively nonspecific histological alterations,11 12 and frequent spontaneously occurring ventricular arrhythmias; however, none of the currently available models of nonischemic heart failure demonstrates all of these characteristics.
Gilson et al13 recently developed a rabbit model of nonischemic heart failure that is induced by aortic regurgitation followed by aortic constriction. After 4 months, these rabbits demonstrated marked hypertrophy and a moderate degree of LV systolic dysfunction. However, the incidence of ventricular ectopy was not assessed.13 While this preparation did not demonstrate severe heart failure at that time, chronic pressure and volume overload of greater duration could potentially lead to a much greater degree of LV dilatation and systolic dysfunction, marked histological alterations, and spontaneously occurring ventricular arrhythmias.
The purpose of the present study was to define the electrophysiological mechanisms underlying spontaneously occurring VT in the setting of nonischemic end-stage heart failure. Accordingly, the following experiments were performed: (1) rabbits with combined aortic insufficiency and aortic stenosis were followed over a long term and subjected to serial two-dimensional (2D) echocardiography (to assess LV chamber size and systolic function) and Holter monitoring (to assess the incidence and frequency of spontaneously occurring ventricular arrhythmias); (2) 3D cardiac mapping of the spontaneous ventricular arrhythmias that developed was performed; and (3) histological analysis of tissue was performed to characterize the structure of regions participating in initiation or maintenance of the electrophysiological alterations.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animal Preparations
Studies were performed on healthy adult New Zealand White rabbits of either sex (2.9 to 3.5 kg). Heart failure was produced by induction of aortic insufficiency, which was followed 14 days later by constriction of the abdominal aorta.13 Three-dimensional cardiac mapping was performed in four rabbits in which heart failure was induced (HF rabbit group) and four control rabbits. The Washington University Animal Studies Committee reviewed and approved the experimental protocol.
Induction of Heart Failure
For the induction of aortic
insufficiency, rabbits were
anesthetized with ketamine (30 mg/kg), acepromazine (0.75 mg/kg), and
xylazine (7.5 mg/kg IM). After the rabbit was shaved and the neck
prepped, a 4F sheath was inserted into the left carotid artery. The
lead II surface ECG was monitored on a Lifepak 4 (Physio-Control). A
beveled polyethylene catheter (4F) connected to a pressure transducer
was then introduced into the carotid artery and pushed abruptly through
the aortic valve several times. Aortic insufficiency was considered
adequate when the aortic pulse pressure increased by at least
50%.13 The severity of aortic insufficiency was
subsequently assessed by 2D echocardiography with color-flow mapping
(see below). The carotid artery was then repaired, and the incision was
closed.
Aortic constriction was performed 14 days later under the same anesthetic regimen. The abdomen was shaved and prepped with betadine. The lead II surface ECG was monitored. A midline incision was made, and the abdominal aorta was isolated proximal to the renal arteries. A silk ligature was tightened around both the aorta and an adjacent piece of polyethylene catheter (2.42-mm OD). The catheter was withdrawn immediately, producing a reduction of aortic diameter of approximately 45%.13 The incision was then closed.
Echocardiography
Before the creation of aortic insufficiency
(baseline) and at
approximately 3- to 6-month intervals, each rabbit underwent
echocardiographic examination. Rabbits were sedated with ketamine (35
mg/kg IM) and placed in the right lateral decubitus position on a
specially designed table that had a 6x6-in square hole. This allowed
placement of a 5-MHz transducer on the right lateral thorax from below.
Standard short-axis views were obtained below the level of the mitral
valve leaflets. M-mode echocardiographic measurements of LV
end-diastolic (LVEDD) and end-systolic (LVESD) dimensions
were obtained, following American Society of Echocardiography
recommendations.14 Fractional shortening (FS) was
calculated as FS (%)=(LVEDD-LVESD)/LVEDD.
The severity of
aortic insufficiency (AI) was assessed by color-flow
Doppler examination of the diastolic LV outflow tract jet in the
parasternal long-axis view (obtained with the rabbit in a supine
position). A ratio of jet height to LV outflow tract height of 
65%
was considered severe AI; 25% to 64%, moderate AI; and <25%, mild
AI.15
In addition, aortic regurgitant fraction (RF) was
determined from the
time-velocity integral of the pulsed Doppler tracing of right
ventricular (TVI-RVOT) and LV (TVI-LVOT) outflow tract flow and
measurement of the RV (Area-RVOT) and LV (Area-LVOT) outflow tract
cross-sectional area (
r2, where r is half of
outflow tract diameter) based on the following
formula16 :
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Holter Monitoring
At baseline (before induction of aortic
regurgitation) and at an
average of once every 2 weeks after aortic constriction, Holter monitor
recordings were obtained from conscious rabbits. The chest was shaved
and five ECG electrodes were applied to the chest. For the first 12
months of the study, a specially designed nylon jacket (Alice King
Chatham) was put on, and the Holter monitor was strapped to the
rabbit's side. Beginning 12 to 15 months after aortic constriction,
Holter recordings were obtained continuously by placing the nylon
jacket on the rabbit and tunneling the lead wires through a long,
specially designed tether made of flexible metal tubing to a freely
rotating Holter recorder placed on top of the cage. Recordings were
made for 24-hour periods without the animal's movement being
restricted. Cassette tapes with two channels of ECG recordings were
analyzed by use of a computer-assisted Marquette Series 8500 Holter
analysis system to determine the frequency of PVCs, couplets, and
runs of VT. Arrhythmia frequency was verified by manual counting.
Mapping Protocol
Three-dimensional cardiac mapping was
performed in control
rabbits and in HF rabbits (20±2 months after aortic constriction) as
described previously.17 18 19 Briefly,
rabbits were
anesthetized with ketamine (10 mg/kg IM) and pentobarbital (40 mg/kg
IV, with additional doses of 16 to 32 mg IV as needed), intubated, and
mechanically ventilated. Body temperature was maintained at 37°C by a
thermostatic esophageal probe controlling an infrared lamp. Intramural
recordings were obtained from specially designed plunge-needle
electrodes that were described
previously.17 18 19
Twenty-five plunge electrodes, each containing eight bipolar electrode
pairs separated by 500 µm (200 sites), were placed in the left
ventricle. Eight electrodes, each containing two bipolar pairs
separated by 500 µm (16 sites), were placed in the right ventricle.
Four septal electrodes, each containing four bipolar pairs separated by
2.5 mm (16 sites), were placed in the anterior and posterior septum
under 2D echocardiographic guidance. All electrodes had an interbipole
spacing of 500 µm. The distance between plunge electrodes was 3 to 9
mm. During the experiment, warm (37°C) saline was applied to the
heart intermittently to prevent surface cooling and to moisten the
epicardium.
After a stabilization period of 30 minutes, bipolar
electrogram
information was acquired simultaneously from each of the 232 transmural
sites and individually amplified, filtered (40 to 500 Hz), and
converted from analog to digital at a 2-kHz sampling rate. The digital
data, along with the lead II surface ECG tracing, were stored on tape
by use of a Sangamo Sabre IV high-density recorder (Fairchild Weston
Systems). Spontaneous rhythm was recorded continuously for up to 60
minutes (see the "Results" section). At the end of the
experiment, each animal was killed with KCl. The heart was then excised
and rinsed in normal saline. Detailed electrode localization was
performed as described
previously.17 18 19 Each plunge-needle
electrode was removed and replaced by a labeled pin. The heart was then
immersed and fixed in formalin for at least 24 hours. The pins were
replaced with small plastic brush bristles to facilitate sectioning of
the heart transversely into four transmural sections approximately 6 mm
thick. Each electrode was localized precisely as to its exact insertion
site and the direction at which it entered the myocardium. The outline
of each section was traced, showing the location of each recording site
(Fig 1
). Plunge-needle electrodes that lay along the
plane of sectioning were represented on sections both
apical and basal to the plane of sectioning. The tracings were enlarged
for later 3D construction of isochronal maps as described below.
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Analysis of Electrograms and Construction of Isochronal Maps
Electrogram data were analyzed off-line by use of a Micro-VAX
computer (Digital Equipment Corp) with interactive color graphics.
Details of the mapping system were given previously.20
Initially, the tape containing the electrogram data was played back,
and the accompanying surface lead II tracing was reviewed to find the
beat(s) of interest (eg, sinus beat, PVC, or VT). Electrograms were
displayed, and the activation times, assigned by the computer on the
basis of a peak criterion,21 were reviewed and manually
reassigned if required. An amplitude threshold of 0.25 mV was
considered indicative of activation of tissue by the depolarizing
wavefront.17 18 19 After review of all
bipolar electrograms,
the activation times for all sites were printed and assigned to their
respective intramyocardial location indicated by the detailed 3D
localization described previously. The 3D isochronal maps were then
constructed in 10-ms increments.
Serum Electrolytes and Arterial Blood Gases
Peripheral venous
blood samples for measurement of serum
potassium (K+) and magnesium (Mg2+) were
obtained from conscious HF rabbits within 3 weeks of the mapping study
and were within the normal range for all rabbits. During all 3D mapping
studies, serial arterial blood samples were obtained for arterial blood
gas and K+ measurements. Any hypokalemia before mapping was
corrected with intravenous KCl so that mapping was always performed in
rabbits with serum values of K+ within the normal
range.
Histological Analysis
After mapping analysis, transmural
fixed tissue samples (up
to 1.5x1.5x1.5 cm) from selected areas of interest from failing
hearts (sites of initiation of ectopic beats and other sites) and
control hearts were dehydrated, embedded in paraffin, and sectioned at
a thickness of 5 µm. Transmural tissue sections were stained with
hematoxylin and eosin or Masson's trichrome stain and examined by
light microscopy.
Supplies
Holter monitors were generously donated by Scole
Engineering and
Delmar-Avionics.
Data Analysis and Statistics
The total activation time for
each beat was the difference in
activation time between the earliest and latest sites of activity. The
mechanism of a particular beat was defined as reentrant when (1) there
was continuous depolarization from the preceding beat, (2) the site of
initiation of a premature beat was adjacent to the site of termination
of the preceding beat, and (3) the conduction velocity of the
activation wavefront from the site of termination of the preceding beat
to the site of initiation of the ectopic beat was similar to the
conduction velocity of the terminal portion of the activation wavefront
of the preceding beat.17 18 19 A
mechanism was defined as
nonreentrant when the site of initiation of a premature beat was remote
from the site of termination of the preceding beat with no intervening
depolarizations, despite multiple intermediate recording
sites.17 18 19 Data are expressed as
mean±SEM. Comparisons
of values for LVEDD, LVESD, FS, hemodynamics, total activation time,
and coupling interval data were done by Student's t test
(for paired or unpaired data), and a probability value of <.05 was
considered indicative of a significant difference.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Induction of Aortic Insufficiency and Stenosis
Perforation of the aortic valve with a beveled catheter resulted in an increase in the aortic pulse pressure from 16±1 to 30±3 mm Hg (P=.01). Color-flow Doppler echocardiography performed immediately afterward demonstrated that the degree of aortic insufficiency was severe in all four rabbits.
At 19±4 months after aortic constriction, color-flow Doppler echocardiography demonstrated severe aortic regurgitation in all four HF rabbits, and the aortic regurgitant fraction averaged 44±14%.
LV Chamber Dimension and Systolic Function
Over the course of
20±2 months, there was a progressive increase
in LV dimensions and a decrease in LV systolic function (Fig
2). LVEDD increased from 1.26±0.07 to 2.07±0.03
cm
(P=.003); LVESD increased from 0.74±0.06 to
1.62±0.02 cm
(P=.001). Sixty-five percent of the increase in LVEDD and
59% of the increase in LVESD occurred after the first 3 months. The
most rapid increase in LV size occurred in HF rabbit 4, in which LVEDD
increased from 1.08 to 1.96 cm and LVESD increased from 0.57 to 1.47 cm
within 3 months (85% and 83% of the total changes, respectively).
After the first 3 months, there was little additional chamber
enlargement in this rabbit.
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FS decreased from 0.42±0.02 to
0.21±0.02 (P=.004). Sixty
percent of this change occurred in the first 3 months. The most severe
depression of LV systolic function occurred in HF rabbit 2, in which FS
decreased from 0.39 to 0.17 within 15 months (Fig 2
). The most
rapid
change in LV function was in HF rabbit 4, in which FS decreased from
0.47 to 0.25 within 3 months.
Holter Monitoring
None of the rabbits demonstrated
ventricular ectopy at baseline.
After aortic regurgitation and aortic constriction, Holter monitoring
in conscious rabbits demonstrated a progressive increase in the
frequency and complexity of ventricular ectopic activity with the
development of PVCs (usually one to three distinct morphologies, which
were consistent from Holter to Holter, for each rabbit), couplets, and
runs of monomorphic and polymorphic VTs (Figs 3 and
4). Frequent (>100 per day) PVCs occurred consistently
in HF rabbits 1, 3, and 4 after 15 to 18 months. More frequent PVCs
(>1000 per day) occurred in HF rabbits 1 and 4 after 21 months. HF
rabbit 2 never developed more than 30 PVCs per day (Fig 4,
top).
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Although VT occurred as early as after 6 months in HF rabbits 1
and 3
(Fig 4, bottom), rabbits 1, 3, and 4 consistently demonstrated
spontaneous runs of VT after 15 to 18 months. The length of runs of VT
could vary considerably from day to day. The maximal length of VT for
HF rabbits 1, 3, and 4 was 8, 26, and 22 beats, respectively (Figs
3 and 4). HF rabbit 2 never demonstrated VT. The
Table
lists the maximal frequency of ectopy over 1 hour of Holter
monitoring.
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Comparison of the Holter data (Fig 4) with
the echocardiographic data
(Fig 2) revealed that development of VT in HF rabbits 1, 3, and
4 at 15
months occurred when FS had decreased to 0.27±0.02 and LVEDD and LVESD
had increased to 2.07±0.04 and 1.50±0.04 cm, respectively.
However,
HF rabbit 2 did not demonstrate VT after 15 months, despite a
comparable increase in LV chamber dimensions and a greater decrease in
FS (to 0.17). Thus, as in humans,4 development of VT did
not appear to be related only to the level of cardiac enlargement or LV
dysfunction.
Mapping of Spontaneously Occurring Ventricular Arrhythmias
Three-dimensional mapping of spontaneously occurring ventricular
arrhythmias from 232 intramural sites was performed for up to 60
consecutive minutes. Three HF rabbits (1, 3, and 4) demonstrated
frequent isolated PVCs, two demonstrated runs of nonsustained VT up to
4 beats long (the Table), while one (rabbit 2) exhibited no
ventricular
ectopy during mapping. The frequency, degree of complexity, and
morphology of the ventricular ectopy exhibited during mapping were
comparable to those observed during previous Holter monitor recordings
in conscious rabbits (the Table and Fig 3).
Mapping of the four control
rabbits for up to 60 consecutive minutes demonstrated no spontaneous
ectopy.
A total of 98 representative mapped beats from HF rabbits (42 sinus beats, 19 isolated PVCs, 18 beats of couplets, and 19 beats of VT from six runs of nonsustained VT) and 8 sinus beats from control rabbits were analyzed on the basis of a review of >24 000 electrograms obtained from intramural sites throughout the left and right ventricles and the interventricular septum. The mechanism of arrhythmia was defined for all the ventricular ectopic beats.
Sinus Rhythm in Control Rabbits
Sinus beats in the control
rabbits initiated in the
interventricular septum and spread rapidly to the apex and base and
from endocardium to epicardium. The coupling interval of sinus beats
averaged 290±11 ms, and the total activation time averaged 26±1
ms.
Fig 5 (left) gives an example of the 3D activation of a
control sinus beat. Initiation occurred in the interventricular septum
in level IV (asterisk). The depolarizing wavefront spread rapidly
throughout the heart, terminating in the epicardium of the anterior
septum in level I (the plus sign) with a total activation time of 31
ms.
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Sinus Rhythm in Rabbits With Heart Failure
Sinus rhythm in HF
rabbits initiated in the septum and spread
rapidly throughout the heart, with a coupling interval of 316±9 ms
(P=.12 versus control rabbits) and a total activation time
of 28±1 ms (n=8). The total activation times in the three
rabbits that
demonstrated ventricular ectopy (27±1 ms, n=6) were comparable
to the
time in rabbit 2 (29 ms, n=2), which did not demonstrate ventricular
ectopy during mapping, and to that in the four control rabbits (26±1
ms, n=8). Fig 5 (middle) shows an example of the
activation of a sinus
beat in the failing rabbit heart. The sinus beat (NS) initiated in the
septum in level II and was followed by early breakthrough in the
lateral LV (10-ms isochrones in levels I through IV). Activation then
spread rapidly throughout the heart, terminating in the epicardium of
the right ventricle in level II, with a total activation time of 29
ms.
PVCs
Sinus beats preceding PVCs demonstrated activation
sequences and
total activation times (26±1 ms) that were identical to sinus beats
not preceding PVCs or VT. All PVCs initiated in the subendocardium by a
nonreentrant mechanism, based on the lack of intervening electrical
activity (225±7 ms) between the termination of the preceding sinus
beat and the initiation of the PVC, despite the presence of multiple
intervening electrode sites. Six PVCs (32%) initiated in the left
ventricle, 1 (5%) in the right ventricle, and 12 (63%) in the
interventricular septum. PVCs initiated with a coupling interval of
253±18 ms (n=19) and conducted with a total activation time of
43±2
ms.
An example is shown in Fig 5 (right). The sinus beat
(NS) initiated in
the septum (level II) and spread rapidly throughout the heart, with an
activation sequence identical to that of a sinus beat not preceding a
PVC or VT (Fig 5, middle). After termination of the sinus beat
in the
basal portion of the right ventricle (level II, the plus sign) with a
total activation time of 29 ms, there was no electrical activation
recorded anywhere in the heart for 267 ms, after which the PVC
initiated by a nonreentrant mechanism at a subendocardial site in the
endocardium (level IV). This is shown in further detail in Fig
6. After termination of the sinus beat at site A, there
was no electrical activity at sites B through O or at any other
recording site for 267 ms, after which the PVC initiated at a distant
site P by a nonreentrant mechanism.
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Couplets and Nonsustained VT
Sinus beats preceding couplets
and runs of VT exhibited similar
activation sequences and identical total activation times (28±1 ms) to
those of sinus beats not preceding PVCs or VT (28±1 ms). Beats of
monomorphic and polymorphic couplets all initiated in the
subendocardium by a nonreentrant mechanism. The coupling interval of
the initiating beat of ventricular couplets averaged 291±3 ms; the
total activation of the beats of couplets averaged 41±2 ms.
Runs of VT that were mapped included four runs of 3-beat monomorphic VT from HF rabbit 3 and two runs of polymorphic VT (one 3-beat run and one 4-beat run) from HF rabbit 1. Nonsustained VT initiated at a coupling interval of 300±2 ms and was maintained at a coupling interval of 257±14 ms (P<.01). All beats of VT initiated in the subendocardium by a nonreentrant mechanism.
Monomorphic VT
Fig 7 shows 3D activation maps
of a sinus beat and
3 beats (X1 through X3) of a 3-beat run of
nonsustained VT. The sinus beat (NS) initiated in the septum in level
II and spread rapidly, with an activation sequence similar to that of
the isolated sinus beat and the sinus beat preceding the PVC in Fig
5.
After termination of the sinus beat in the RV epicardium in level II
(the plus sign), there was no electrical activity recorded anywhere in
the heart for 270 ms, after which the first beat of VT,
X1, initiated by a nonreentrant mechanism at the
same apical endocardial site in level IV at which the PVC in Fig
5
initiated. After initiation, activation of X1 was rapid,
terminating at an epicardial site in level I with a total activation
time of 37 ms. Beats X2 and X3 initiated at the
same apical subendocardial site in level IV by a nonreentrant
mechanism. The total activation time of each of these beats was 46
ms.
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The activation sequences of X2 and X3 were
identical and resembled the activation of X1. The only
difference was that X1 demonstrated earlier activation in
the anterior regions of levels I through III (20- to 40-ms
isochrones), most likely from the breakthrough of simultaneous
sinus activation (arising in level II) that resulted in X1
(and the PVC in Fig 5) being a fusion beat. This accounted for
the
slight difference in QRS morphology of the PVC and beat X1
versus beats X2 and X3.
As Fig 8
shows, X2 and X3
initiated by a nonreentrant mechanism, with no intervening activity
between the termination of X1 and X2 (site A)
and the initiation of X2 or X3 (site M),
despite the presence of multiple intervening electrode recording sites
(eg, sites B through L). In addition, once initiation at site M
occurred, there was rapid (within 45 ms) activation to adjacent sites B
through L.
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To further define factors responsible for the development of
monomorphic VT, analysis was performed of two PVCs, three couplets,
and three runs of monomorphic VT from rabbit 3, all of which
demonstrated similar morphology and initiated at the same site. As Fig
9 shows, isolated PVCs (P1 and P2) could vary in their
total activation times and coupling intervals. The initiating beats of
couplets C1 through C3 all demonstrated total activation times and
coupling intervals similar to those of PVC P1. The second beats
(X2) of all three couplets demonstrated total activation
times comparable to those of the first beats (X1), but they
occurred at a shorter coupling interval. The initiating two beats
(X1 and X2) of the three runs of VT
demonstrated coupling intervals and total activation times similar to
those of the couplets. The terminal beats (X3) of the three
runs of VT were similar to the preceding X2 beats. Thus,
PVCs, beats of monomorphic couplets, and runs of VT could demonstrate
nearly identical activation sequences (Figs 5 and
7) and comparable
total activation times and coupling intervals. Therefore, the
difference among PVCs, monomorphic couplets, and monomorphic VT
appeared to be the number of times a nonreentrant site fired rather
than any disparities in activation sequence, conduction delay, or
degree of prematurity of the initial ectopic beats.
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Polymorphic VT
Seven beats of polymorphic VT were mapped in
HF rabbit 1. All
beats arose in the subendocardium by a nonreentrant mechanism. Fig
10 shows 3D maps of a sinus beat (NS) followed by the 4
beats (X1 through X4) of a 4-beat run of
polymorphic VT. The sinus beat originated in the septum in level I
and spread rapidly through the heart, with an activation sequence and
total activation time (25 ms) identical to those of sinus beats not
preceding PVCs or VT in this rabbit. After termination of the sinus
beat at a posterior epicardial site in level I, there was no electrical
activity anywhere in the heart for 286 ms, after which the first beat
of VT, X1, initiated at a septal site in level III
by a nonreentrant mechanism. Beats X2 through
X4 initiated by nonreentrant mechanisms but at different
sites (asterisk).
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As Fig 11 shows, X3
initiated by a
nonreentrant mechanism, with no intervening electrical activity between
the termination of X2 (site A) and the initiation of
X3 (site X, arrow), despite the presence of multiple
immediately adjacent (0.5 to 4 mm) recording sites (sites B through W).
Once X3 initiated at site X, there was very rapid (
20 ms)
activation to adjacent sites B through X. The fourth beat of VT,
X4, initiated by a nonreentrant mechanism at septal
site Y.
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As Fig 12 shows, three of the four sites of
initiation
for X1 through X4 (A through C) were also sites
of initiation of isolated PVCs or beats of couplets and demonstrated
comparable total activation times and coupling intervals. Thus, the
factor distinguishing between multiform PVCs and polymorphic
couplets or VT appears to be the number of consecutive firings of the
different nonreentrant sites. Total activation times for all ectopic
beats mapped never exceeded 58 ms. The slowest conduction
velocity, 20 cm/s, was found during a beat of nonsustained VT in an HF
rabbit. There was no evidence of late activation (even <0.25 mV in
amplitude) or any slow conduction at nonreentrant initiation sites or
at immediately adjacent recording sites located 0.5 to 5 mm away in the
left and right ventricles (see Fig 11) and 0.5 to 6 mm away in
the
septum, making the presence of microreentry very unlikely.
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Pathology
All four failing hearts demonstrated marked diffuse
histological
alterations, including myocardial fiber hypertrophy and degenerative
changes, including myofibrillar loss and vacuolization and interstitial
fibrosis (Fig 13, middle and bottom); these alterations
were not evident in the control hearts (Fig 13, top).
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Histological sections from sites of nonreentrant initiation
(n=14) from
HF rabbits 1, 3, and 4 were examined in detail and compared with
sections from regions in these hearts subtending recording sites
(n=224) at which nonreentrant initiation did not occur. They were also
compared with sections subtending recording sites (n=40) from the heart
of HF rabbit 2, which never demonstrated VT by Holter recording or
during mapping, and with sections from control hearts. His-Purkinje
tissue was not evident in sections from sites of nonreentrant
activation, although this does not rule out a spatial relation between
Purkinje tissue and nonreentrant initiation. Tissue from regions in the
vicinity of nonreentrant initiation sites demonstrated areas of patchy
interstitial and replacement fibrosis, predominantly in the
subendocardium. The extent of local fibrosis varied from moderate (Fig
14, rows 1 and 2, right) to minimal (row 3, right) and
was never observed to occupy more than 15% of the transmural wall
thickness. In HF rabbits that demonstrated PVCs and VT (rabbits 1, 3,
and 4), myocardium from regions in which nonreentrant initiation did
not occur also demonstrated patchy interstitial and replacement
fibrosis, primarily in the subendocardium (Fig 14, bottom
left). The
distribution and severity of the fibrosis were comparable to those in
the vicinity of nonreentrant initiation sites and sometimes were even
more extensive (Fig 14, bottom left). Surprisingly, the most
extensive
diffuse interstitial fibrosis was noted in HF rabbit 2 (Fig
14, bottom
right), which never demonstrated spontaneous VT. Thus, patchy
interstitial fibrosis was present in the failing hearts, but its
presence or degree did not appear to be related to nonreentrant sites
of initiation or to the extent of conduction delay.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Three-dimensional mapping of spontaneously occurring ventricular ectopy in rabbits with severe nonischemic heart failure induced by combined aortic regurgitation and aortic stenosis has demonstrated that PVCs, couplets, and runs of VT all initiate by a nonreentrant mechanism arising in the subendocardium. Monomorphic and polymorphic VTs are due to repetitive nonreentrant activation from the same sites that are responsible for isolated PVCs.
Determination of a nonreentrant mechanism for the initiation of PVCs and VT was based on the absence of any electrical activity between the termination of the preceding beat and the initiation of the next, despite the presence of multiple intervening intramural recording sites.17 18 19 Mapping from the endocardial and/or epicardial surfaces would have left a large portion of the heart unmapped and would have precluded determination of the mechanism of arrhythmia. In addition, mapping from 232 sites in the rabbit heart, which is approximately 1/12 the size of the canine heart, would be comparable to mapping from >2700 sites in the canine heart. Thus, the enhanced resolution possible with studies in the rabbit heart further support the concept that nonreentrant mechanisms are critical in the development of arrhythmias in this model of nonischemic cardiomyopathy.
Bundle-branch reentry can initiate focally and has been found to underlie spontaneous monomorphic VT in approximately 6% of patients with cardiomyopathy.22 23 Although there were no recordings of His-bundle activation in the present study to definitively exclude this possibility, the finding that focal initiation occurred at the same site as the earliest sites during sinus rhythm in only one isolated PVC makes bundle-branch reentry an unlikely mechanism.
Although the possibility of microreentry cannot be definitively
excluded by results of the present study, it is extremely unlikely
for the following reasons. First, there was no intervening electrical
activity between termination and initiation sites, which often were at
opposite ends of the heart (see Figs 6 and 8).
Second, on the basis of
the VT cycle lengths, a microreentrant circuit small enough to escape
detection by mapping with the resolution of that in the present
study would have required a conduction velocity more than an order of
magnitude slower than the slowest velocity measured, even during VT.
Third, there was no evidence of any slow conduction in and around
initiation sites (see Fig 11). Even with microreentrant
circuits as
small as those demonstrated in the chronically infarcted canine
epicardium in vitro by high-density grid electrode mapping (with an
interelectrode distance of 350 µm),24 there was evidence
of conduction delay on the order of 100 ms between sites 1 to 2 cm
apart. That was never seen in the present study. In fact, no
ventricular ectopic beat demonstrated a total activation time exceeding
58 ms.
Nature of Nonreentrant Mechanisms
The nature of the
nonreentrant mechanism is unknown but may be
caused by triggered activity arising from delayed afterdepolarizations
(DADs), early afterdepolarizations,25 or altered
automaticity. The repetitive firing from single subendocardial sites
with decreasing coupling intervals is consistent with experimental
studies of triggered activity.25 DADs and triggered
activity have been demonstrated in hypertrophied myocardium in
vitro26 and in human ventricular myocardium from patients
with ischemic
cardiomyopathy.27 Whether DADs could
occur in subendocardial myocytes or Purkinje cells by turning on of the
transient inward current (Iti)28 remains to be
determined. However, increased levels of intracellular
calcium,25 which are critical for the development of
Iti and in turn DADs, have been demonstrated in myocytes
from experimental animal preparations of nonischemic heart
failure29 30 and in myocytes from hearts of patients
with
dilated cardiomyopathy.31 32
Myocardium from
hypertrophied33 or failing34
hearts demonstrates prolongation of action potential duration, which
could potentially lead to early afterdepolarizations.35
However, the occurrence of spontaneous arrhythmias at short coupling
intervals makes this a less likely mechanism. Enhanced automaticity
would also be unlikely in light of the short coupling intervals of
ectopic activity observed in the present study and the degree of
irregularity (Figs 10 and 12).
Although
there was no evidence of slow conduction or the development of
reentry in the genesis of spontaneous ventricular arrhythmias in this
preparation, reentry could potentially contribute to the development of
nonsustained and/or sustained VT. The presence of marked interstitial
fibrosis such as that in HF rabbit 2 (Fig 13), while
insufficient to
lead to conduction delay during sinus rhythm, could, in the setting of
premature stimulation, lead to functional conduction delay caused by
altered anisotropic conduction36 37 and the
development of
reentry. Such a finding has been demonstrated in the human heart in
some patients with idiopathic dilated
cardiomyopathy undergoing localized epicardial
mapping at the time of heart transplantation.38
Furthermore, the development of VF from VT may also involve reentry
because intramural reentry appears to be the common mechanism for VF in
a number of pathological settings.18 19
Animal Preparation of Nonischemic Cardiomyopathy
The animal
preparation of combined aortic regurgitation and aortic
stenosis demonstrates both volume and pressure overload of the left
ventricle13 and leads to a greater degree of LV
hypertrophy than either aortic regurgitation or aortic stenosis
alone.39 After 4 months, rabbits demonstrate a moderate
decrease in LV systolic function, along with a decrease in
ß-adrenergic responsiveness resulting from a decrease in ß-receptor
number.13 In the present study, after 15 to 26 months,
there was severe depression of LV function along with marked
histological alterations and spontaneously occurring ventricular
arrhythmias.
Nonetheless, the frequency and complexity of the spontaneous ventricular arrhythmias did not appear to be related only to the degree of LV dysfunction. This was also found to be the case in dogs with ischemic cardiomyopathy induced by multiple intracoronary microembolizations10 and in humans.4 These findings suggest a potential role for neurohumoral mechanisms,2 hemodynamic factors such as LV stretch,40 and other factors yet to be determined. In addition, the presence and complexity of nonreentrant ventricular arrhythmias were not related only to the presence of interstitial fibrosis.
The delineation of the mechanism of spontaneously occurring
ventricular arrhythmias in nonischemic heart failure was made
possible by the development of a model demonstrating frequent
ventricular ectopy and by the use of a computerized mapping system with
a large data storage capacity. Three of four rabbits were studied at
the time when serial Holter monitoring demonstrated ventricular ectopic
activity that was frequent enough that 3D mapping with continuous data
recording from 232 simultaneous sites for up to 60 minutes would yield
occasional PVCs, couplets, and runs of VT. The ventricular ectopic
activity that was mapped demonstrated a frequency, level of complexity,
and QRS morphology comparable to those of spontaneous rhythms recorded
by Holter monitoring in conscious rabbits (Fig 4). These
spontaneously
occurring arrhythmias were not induced by plunge electrode placement,
as evidenced by the complete lack of ectopic activity during recording
for up to 60 minutes in the four control rabbit hearts.
Three-dimensional mapping with specially designed electrodes has been
validated extensively in a number of animal species and in a variety of
pathological
states8 17 18 19 41
and shown not to alter
activation during sinus rhythm or the inducibility of ventricular
arrhythmia by programmed stimulation.
Although mapping was performed in only four rabbits with heart failure, the extensive characterization of LV function and arrhythmia development over a period of 15 to 27 months, the consistent findings between mapped beats and spontaneously occurring ectopic beats in conscious rabbits, the extensive number of spontaneously occurring sinus and ectopic beats mapped (representing analysis of >24 000 individual electrograms), and the extraordinary consistency with which every mapped ectopic beat demonstrated both nonreentrant initiation and the absence of significant conduction delay suggest that the findings of this study are representative of this nonischemic heart failure model.
The findings of nonreentrant
initiation of spontaneous PVCs and VT in
this rabbit model of nonischemic heart failure are very similar
to the recent findings of focal initiation of spontaneously occurring
PVCs and VT in dogs with ischemic
cardiomyopathy induced by multiple intracoronary
embolizations.8 These two studies demonstrate that
nonreentrant mechanisms underlie VT in the setting of both
ischemic and nonischemic heart failure and that slow
conduction and the development of reentry play minor roles, if any, in
the genesis of spontaneous ventricular ectopy in these settings. The
contribution of reentry and nonreentrant mechanisms to the development
of sustained VT induced by programmed electrical stimulation in the
setting of nonischemic heart failure was not assessed in the
present study and remains to be determined. Sustained ventricular
arrhythmias are inducible in up to 80% of patients with
nonischemic heart failure and a history of sustained
VT42 and 28% of those with a history of nonsustained
VT.43 Thus, it is likely that sustained VT may be induced
in this preparation of nonischemic heart failure that
demonstrates spontaneously occurring VT (up to 26 beats long, Fig
3) in
the setting of severe LV systolic dysfunction and marked pathological
alterations that resemble human nonischemic
cardiomyopathy.
Hearts from rabbits with end-stage nonischemic heart failure demonstrate marked histological alterations, including marked hypertrophy, degenerative cellular changes, and interstitial fibrosis. Although induction of the combination of LV pressure and volume overload does not directly cause alterations in myocytes such as those observed in cardiomyopathies (eg, induced by toxins), the result of this long-term overload is marked cellular alterations that are common to heart failure of a wide variety of causes, including nonischemic and idiopathic dilated cardiomyopathy in humans.11 12 Thus, the pathological alterations in this model, the marked systolic dysfunction, and the spontaneous ventricular arrhythmias are similar to those associated with nonischemic heart failure in man.
Study Implications
The implications of the study findings are
multiple. The role of
nonreentrant mechanisms in the development of VT in the setting of
nonischemic heart failure could explain the lack of therapeutic
benefit to patients treated with antiarrhythmic agents that alter
conduction and the development of reentry.5 The
facts that the response to programmed electrical stimulation is a poor
predictor of efficacy of antiarrhythmic therapy44 45
and
that late potentials occur infrequently in patients with idiopathic
dilated cardiomyopathy46
further suggest a potential role of nonreentrant mechanisms
in the development of sustained VT in this setting. Recent 3D
intraoperative mapping studies in patients with
ischemic heart failure demonstrated that inducible sustained
monomorphic VT is due to a focal mechanism in 50% of
cases,47 further supporting a potential role for
nonreentrant mechanisms in the failing human heart.
Conclusions
Spontaneous ventricular arrhythmias in a rabbit
model of
nonischemic heart failure are due to nonreentrant
mechanisms. Approaches to the treatment of ventricular arrhythmias in
the human heart with nonischemic heart failure should be
directed at such mechanisms.
|
Acknowledgments |
|---|
Work from the Washington University School of Medicine Laboratory was supported in part by NIH grant HL-46929. I would like to thank William Petty, Teng-Xian Liu, and Jerome Peirick for technical assistance; Ava Ysaguirre for preparation of the manuscript; Dr Jeffrey Saffitz for assistance with pathological analysis; Dr Kathryn A. Yamada for review of the manuscript; and Dr Peter B. Corr for invaluable support and advice throughout the project.
|
Footnotes |
|---|
Reprint requests to Steven M. Pogwizd, MD, Cardiovascular Division, Box 8086, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110.
Received November 14, 1994; revision received January 23, 1995; accepted February 10, 1995.
|
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M. R. Abraham, C. A. Henrikson, L. Tung, M. G. Chang, M. Aon, T. Xue, R. A. Li, B. O' Rourke, and E. Marban Antiarrhythmic Engineering of Skeletal Myoblasts for Cardiac Transplantation Circ. Res., July 22, 2005; 97(2): 159 - 167. [Abstract] [Full Text] [PDF]
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X. Ai and S. M. Pogwizd Connexin 43 Downregulation and Dephosphorylation in Nonischemic Heart Failure Is Associated With Enhanced Colocalized Protein Phosphatase Type 2A Circ. Res., January 7, 2005; 96(1): 54 - 63. [Abstract] [Full Text] [PDF]
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L. Yin, H. Bien, and E. Entcheva Scaffold topography alters intracellular calcium dynamics in cultured cardiomyocyte networks Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1276 - H1285. [Abstract] [Full Text] [PDF]
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M. J Janse Electrophysiological changes in heart failure and their relationship to arrhythmogenesis Cardiovasc Res, February 1, 2004; 61(2): 208 - 217. [Abstract] [Full Text] [PDF]
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F R Quinn, S Currie, A M Duncan, S Miller, R Sayeed, S M Cobbe, and G L Smith Myocardial infarction causes increased expression but decreased activity of the myocardial Na+--Ca2+ exchanger in the rabbit J. Physiol., November 15, 2003; 553(1): 229 - 242. [Abstract] [Full Text] [PDF]
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S. M Pogwizd, K. R Sipido, F. Verdonck, and D. M Bers Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis Cardiovasc Res, March 15, 2003; 57(4): 887 - 896. [Full Text] [PDF]
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W. Schillinger, J. W Fiolet, K. Schlotthauer, and G. Hasenfuss Relevance of Na+-Ca2+ exchange in heart failure Cardiovasc Res, March 15, 2003; 57(4): 921 - 933. [Full Text] [PDF]
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A. Arutunyan, L. M. Swift, and N. Sarvazyan Initiation and propagation of ectopic waves: insights from an in vitro model of ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H741 - H749. [Abstract] [Full Text] [PDF]
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K. R Sipido, P. G.A Volders, M. A Vos, and F. Verdonck Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res, March 1, 2002; 53(4): 782 - 805. [Abstract] [Full Text] [PDF]
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S. Adachi-Akahane and Y. Kurachi New Era for Translational Research in Cardiac Arrhythmias Circ. Res., June 8, 2001; 88(11): 1095 - 1096. [Full Text] [PDF]
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K. R. Laurita and A. Singal Mapping action potentials and calcium transients simultaneously from the intact heart Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2053 - H2060. [Abstract] [Full Text] [PDF]
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J.M van Opstal, S.C Verduyn, H.D.M Leunissen, S.H.M de Groot, H.J.J Wellens, and M.A Vos Electrophysiological parameters indicative of sudden cardiac death in the dog with chronic complete AV-block Cardiovasc Res, May 1, 2001; 50(2): 354 - 361. [Abstract] [Full Text] [PDF]
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K. Schlotthauer and D. M. Bers Sarcoplasmic Reticulum Ca2+ Release Causes Myocyte Depolarization : Underlying Mechanism and Threshold for Triggered Action Potentials Circ. Res., October 27, 2000; 87(9): 774 - 780. [Abstract] [Full Text] [PDF]
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S. H. M. de Groot, M. Schoenmakers, M. M. C. Molenschot, J. D. M. Leunissen, H. J. J. Wellens, and M. A. Vos Contractile Adaptations Preserving Cardiac Output Predispose the Hypertrophied Canine Heart to Delayed Afterdepolarization-Dependent Ventricular Arrhythmias Circulation, October 24, 2000; 102(17): 2145 - 2151. [Abstract] [Full Text] [PDF]
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S. M. Pogwizd Increased Na+-Ca2+ Exchanger in the Failing Heart Circ. Res., October 13, 2000; 87(8): 641 - 643. [Full Text] [PDF]
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R. Becker and W. Schoels Re: 'Ventricular arrhythmias induced by endothelin-1 or by acute ischemia: a comparative analysis using three-dimensional mapping' (Cardiovasc Res 2000;45:310-320) Cardiovasc Res, June 1, 2000; 46(3): 606 - 607. [Full Text] [PDF]
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R. Becker, B. Merkely, A. Bauer, L. Geller, L. Fazekas, K. D. Freigang, F. Voss, J. C. Senges, W. Kuebler, and W. Schoels Ventricular arrhythmias induced by endothelin-1 or by acute ischemia: a comparative analysis using three-dimensional mapping Cardiovasc Res, January 14, 2000; 45(2): 310 - 320. [Abstract] [Full Text] [PDF]
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M.A. McIntosh, S.M. Cobbe, and G.L. Smith Heterogeneous changes in action potential and intracellular Ca2+ in left ventricular myocyte sub-types from rabbits with heart failure Cardiovasc Res, January 14, 2000; 45(2): 397 - 409. [Abstract] [Full Text] [PDF]
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J. I. Goldhaber Sodium-Calcium Exchange : The Phantom Menace Circ. Res., November 26, 1999; 85(11): 982 - 984. [Full Text] [PDF]
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S. M. Pogwizd, M. Qi, W. Yuan, A. M. Samarel, and D. M. Bers Upregulation of Na+/Ca2+ Exchanger Expression and Function in an Arrhythmogenic Rabbit Model of Heart Failure Circ. Res., November 26, 1999; 85(11): 1009 - 1019. [Abstract] [Full Text] [PDF]
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S. M. Pogwizd, J. P. McKenzie, and M. E. Cain Mechanisms Underlying Spontaneous and Induced Ventricular Arrhythmias in Patients With Idiopathic Dilated Cardiomyopathy Circulation, December 1, 1998; 98(22): 2404 - 2414. [Abstract] [Full Text] [PDF]
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H. F. Clemo, B. S. Stambler, and C. M. Baumgarten Persistent Activation of a Swelling-Activated Cation Current in Ventricular Myocytes From Dogs With Tachycardia-Induced Congestive Heart Failure Circ. Res., July 27, 1998; 83(2): 147 - 157. [Abstract] [Full Text] [PDF]
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O. Berenfeld and J. Jalife Purkinje-Muscle Reentry as a Mechanism of Polymorphic Ventricular Arrhythmias in a 3-Dimensional Model of the Ventricles Circ. Res., June 1, 1998; 82(10): 1063 - 1077. [Abstract] [Full Text] [PDF]
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P. Assayag, F. Carre, B. Chevalier, C. Delcayre, P. Mansier, and B. Swynghedauw Compensated cardiac hypertrophy: arrhythmogenicity and the new myocardial phenotype. I. Fibrosis Cardiovasc Res, June 1, 1997; 34(3): 439 - 444. [Abstract] [Full Text] [PDF]
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S. M. Pogwizd, K. Schlotthauer, L. Li, W. Yuan, and D. M. Bers Arrhythmogenesis and Contractile Dysfunction in Heart Failure : Roles of Sodium-Calcium Exchange, Inward Rectifier Potassium Current, and Residual {beta}-Adrenergic Responsiveness Circ. Res., June 8, 2001; 88(11): 1159 - 1167. [Abstract] [Full Text] [PDF]
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