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1441
Focal Mechanisms Underlying
Ventricular Tachycardia During
Prolonged Ischemic Cardiomyopathy
Steven M. Pogwizd, MD
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Background The present study was performed to define the
mechanisms underlying spontaneously occurring ventricular
arrhythmias in the failing heart.
Methods and Results Three-dimensional cardiac mapping
from as many as 232 intramural sites was performed in five
dogs with ischemic cardiomyopathy induced by multiple intracoronary embolizations. After 5 to 10 weekly embolizations
with 90-,um latex microspheres into the left anterior and
circumflex coronary arteries, left ventricular ejection fraction
decreased from 63 ±3% to 22+3%. Subsequent weekly Holter
monitoring of dogs in the conscious state demonstrated frequent multiform premature ventricular complexes (PVCs)
(.2000/d), couplets, and runs of ventricular tachycardia (VT)
(<70 beats in duration and <560 beats per minute) in all dogs.
Three-dimensional mapping of spontaneous rhythm for 60
minutes was performed an average of 6.4 weeks after the last
embolization, during which time each dog demonstrated multiform PVCs, couplets, and runs of nonsustained VT at rates
comparable to those in the conscious state. Mapping was of
sufficient density to define the mechanism for 31 PVCs, 45
beats of ventricular couplets, and 99 beats of VT. Sinus beats
preceding PVCs (n=36) initiated in the septum and spread
rapidly with a total activation time (46±1 milliseconds) that
did not differ from that of sinus beats not preceding PVCs or
VT (46±2 milliseconds, n= 10, P=.69). PVCs and the first beat
of couplets or VT were initiated primarily in the subendocar-
dium by a focal mechanism, based on the lack of intervening
electrical activity between the termination of the preceding
(sinus) beat and initiation of the ectopic beat (225±23 milliseconds), despite the presence of multiple intervening intramural recording sites. All subsequent beats of VT also were
initiated by a focal mechanism, and their total activation time
(89±1 milliseconds) did not differ from that of the initiating
ectopic beats (86±2 milliseconds, P=.14), despite acceleration
of VT to a cycle length of 200 milliseconds. Monomorphic VT
was due to repetitive focal activation of subendocardial sites.
Polymorphic VT was due to sequential focal activation from
multiple sites arising in the subendocardium and, at times, in
the subepicardium. Comparison of mapping data with results
of detailed anatomic analysis of tissue demonstrated that focal
sites of initiation exhibited patchy nontransmural fibrosis.
Functional conduction delay of a moderate degree was evident
only when fibrosis extended transmurally.
Conclusions Spontaneously occurring PVCs, couplets,
and VT in a model of ischemic cardiomyopathy are initiated
and maintained by focal mechanisms with no evidence of
macroreentry. Thus, therapeutic regimens to treat or prevent
VT in the presence of ischemic cardiomyopathy will likely
require interruption of these focal mechanisms. (Circulation.
1994;90:1441-1458.)
Key Words * cardiomyopathy * tachycardia * mapping
* arrhythmias
C ongestive heart failure is a lethal disorder, with a
2-year mortality approaching 60% for class III
and IV patients.12 Nearly half of these deaths
occur suddenly,3 primarily from ventricular tachycardia
(VT) degenerating to ventricular fibrillation (VF).4
Current antiarrhythmic therapy is nonspecific, ineffective,5 and potentially proarrhythmic6,7 and can cause
hemodynamic and clinical deterioration.8 Development
of effective therapy will require delineation of the
precise electrophysiological mechanisms involved.
However, the electrophysiological mechanisms of
ventricular arrhythmias in the failing heart are unknown. In fact, very little is known about the electrophysiological alterations in the failing heart because of
the lack of suitable experimental preparations exhibiting stable heart failure with spontaneous arrhythmias.
Hypertrophied myocardium has been studied in vitro,
and the findings of heterogeneous electrical abnormalities9'10 as well as the occurrence of delayed afterdepolarizations and triggered activity" suggest, albeit indirectly, that reentrant or nonreentrant focal mechanisms,
or both, may be responsible. Although left ventricular
hypertrophy, a common feature of failing myocardium,
is potentially arrhythmogenic,'2 the electrophysiological
substrate of failing myocardium, with or without hypertrophy, is likely to be more complex. Electrophysiological alterations require definition in an experimental
preparation of heart failure that demonstrates the altered substrate for arrhythmogenesis as manifested by
spontaneously occurring ventricular arrhythmias.
Recently, Sabbah and colleagues'3 developed a preparation of ischemic cardiomyopathy in dogs in which
heart failure is induced by multiple sequential intracor-
Received December 17, 1993; revision accepted May 23, 1994.
From the Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St Louis, Mo.
Reprint requests to Steven M. Pogwizd, MD, Cardiovascular
Division, Box 8086, Washington University School of Medicine,
660 South Euclid Ave, St Louis, MO 63110.
C) 1994 American Heart Association, Inc.
onary embolizations. In addition to a marked decrease
in systolic function and pathological alterations'3 that
resemble ischemic cardiomyopathy in humans,14 these
dogs demonstrate spontaneously occurring ventricular
arrhythmias, including nonsustained VT.'1 These features make it a suitable model with which to study
arrhythmogenesis in the failing heart. Elucidation of the
mechanisms underlying the development of VT in this
1442
Circulation Vol 90, No 3 September 1994
I
: s W! P
HOLT ER
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ii
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4 v 4 s ' A.. K -
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h:
m
-.:01::-.::1 1 1 1 1:1
FIG 1. Diagrams of intramural recording sites. Basal aspect of
each transverse section for dogs 2 (left) and 4 (right) is shown.
Sections through IV are oriented with base of heart on top and
apex on bottom. Right ventricular (RV) and left ventricular (LV)
cavities are labeled on basalmost section of map from dog 2.
Black dots indicate location of LV, RV, and septal intramural
recording sites (see text).
preparation requires three-dimensional recording from
multiple sites throughout the heart.16-20
Accordingly, the present study was performed using
three-dimensional cardiac mapping in five dogs with
heart failure induced by multiple intracoronary embolizations to define the mechanisms responsible for the
development of spontaneously occurring ventricular arrhythmias in the failing heart.
1 1 1-
* ::
::| #
1 1.1241-l 1-}.l
l*X | | *
l,1.1-- 1:-
::
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FIG 2. Tracings of ventricular arrhythmias during Hotter monitoring and during three-dimensional mapping of dogs 2, 4, and
5. Top, To left of each column are surface ECG tracings from
Holter monitor recordings of spontaneous rhythm in conscious
dogs (HOLTER); to right are lead 11 surface ECGs during
open-chest three-dimensional mapping (MAPPING) of spontaneously occurring premature ventricular complexes (PVCs),
couplets, and runs of ventricular tachycardia (VT) with QRS
morphology and degree of complexity similar to that of ectopic
activity from each respective dog. Top left, Multiform PVCs,
couplets, and triplets from dog 2; top right, runs of monomorphic
VT from dog 4; and middle right, PVCs and runs of monomorphic
VT (with QRS morphology similar to that of PVC) and polymorphic VT from dog 5. Bottom, Surface ECG tracings from Holter
monitor recordings of long runs of spontaneously occurring
nonsustained VT from dogs 2, 4, and 5, respectively.
Methods
Embolization Protocol
Animal Preparations
Studies were performed on healthy male or female heartworm-negative dogs (40 to 55 lb). Ischemic cardiomyopathy
was induced by a method of multiple sequential intracoronary
Incidence of Spontaneous Ventricular Arrhythmias During Holter Monitoring in Conscious Dogs and
During Subsequent Mapping Study
Holter
Maximum No.
Maximum No.
of Ectopic
of Runs of VT
Beats per Hour
Dog
per Hour
1
238
18
2
608
3
3
86
3
4
1849
83
5
4377
141
VT indicates ventricular tachycardia.
Mapping
Longest
Run of VT,
Beats
38
22
23
39
70
:-
No. of Ectopic
Beats Over 1 Hour
65
211
42
616
411
No. of Runs of
VT Over 1 Hour
4
4
6
10
26
Longest
Run of VT,
Beats
3
3
5
7
12
~H
Pogwizd Mechanisms of Ventricular Tachycardia
B
A
NS
NS
A
PVC
NS
NS
PVC
n
D
.
. .'
!:
_
F
G
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380
FIG 3. Three-dimensional isochronal maps from a normal sinus
(NS) beat (A) and a sinus beat followed by a premature ventricular complex (PVC) (B) in dog 2. Top, Lead II surface ECGs;
boxes, beats whose maps are shown below. Isochrones are
drawn in 20-millisecond increments relative to initiation of each
sinus beat. First 10-millisecond isochrone for each beat is
indicated by dashed lines. Asterisks indicate earliest and
crosses indicate latest sites of activation for each beat.
embolizations.'3 There was 50% mortality usually within the
first 2 weeks. Five surviving dogs underwent subsequent
three-dimensional cardiac mapping. The experimental protocol was reviewed and approved by the Washington University
Animal Studies Committee.
A 4mvr_V[45
B 3mV
-
C 3 mV
D
I
E
F
3 mV
31
3mvi.
G
2 my
H
197
FIG 4. Initiation of premature ventricular complex (PVC) by a
focal mechanism. Left, Diagram of basalmost section of PVC
from Fig 3, with A through H representing selected individual
intramural recording sites. Right, Bipolar electrograms from each
site during a 291-millisecond interval, including termination of
sinus beat to initiation of PVC. Numbers to left indicate electrode
numbers and heights of autocalibrated electrogram. Vertical
cursors indicate activation times listed to upper right or left, in
milliseconds relative to initiation of sinus beat. After termination
of sinus beat at site A, there is no electrical activity at intermediate sites B through G (or at any recording site in heart) for 275
milliseconds, until the PVC initiates at right ventricular endocardial site H, by a focal mechanism with no evidence of reentry.
1443
B
C
D
~~~E
FIG 5. Left and right, lead 11 surface ECGs for eight multiform
premature ventricular complexes (PVCs) and their preceding
and subsequent sinus beats from dog 2, labeled by A through H
to indicate their site of initiation. Center, Schematic of heart of
dog 2, with A through H representing sites of initiation for PVCs
shown.
Embolization Protocol
Briefly, the animals were premedicated with diazepam
(0.165 mg/kg) and morphine sulfate (2.2 mg/kg), anesthetized
with pentobarbital (10 mg/kg), and intubated with mechanical
ventilation if needed. The lead II surface ECG was monitored
on a Lifepak 4 (PhysioControl). Under sterile conditions, the
distal femoral artery was isolated, and a 6F sheath was
inserted for arterial access and monitoring of blood pressure
(Stemtek). Left ventriculograms were performed with the
animals in the left lateral position during injection of 20 mL of
contrast material (lohexol, Winthrop Pharmaceuticals) as described previously20 and recorded on both 35-mm cine film and
videotape. Ejection fraction was determined from the left
ventricular end-systolic and end-diastolic chamber volumes,
calculated by the area-length method after correction for
image magnification.21 After ventriculography, the left anterior descending coronary artery (LAD) or circumflex coronary
artery was selectively catheterized with a 6F Judkins catheter.
A 2-mL suspension of polystyrene latex microspheres (average
size, 90 ,um; range, 77 to 102 ,um) (Polysciences, Inc) was
warmed to 37°C and agitated vigorously for 30 seconds; within
10 seconds, it was injected into one of the two branches of the
left coronary artery along with 1 mL of contrast media. The
arteriotomy was then repaired, and the skin was closed.
Naloxone (0.4 mg IM) was administered, and the animal was
returned to its cage. Each week, the dogs underwent a similar
series of procedures with left ventriculography and catheterization with embolization of latex microspheres into the LAD
or circumflex coronary artery on an alternating basis until both
the inferior and anterior left ventricular walls were severely
hypokinetic or akinetic. For the first 4 weeks, 2 mL of
microspheres was administered, after which 3 to 6 mL was
administered weekly. After the first two embolizations in dogs
1 through 3, propranolol was administered (1 mg/kg IV) in an
attempt to suppress arrhythmias in the immediate postembolization period. When the ejection fraction became less than
1444
Circulation Vol 90, No 3 September 1994
NS
XI
X2
X3
X4
I
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EI
¶
86
90
67
92
408
382
275
383
CI
FIG 6. Three-dimensional isochronal maps of a sinus beat (NS) and first four beats (Xl through X4) of an eight-beat run of monomorphic
ventricular tachycardia from dog 4. First beat of VT, Xl, represents a fusion beat. lsochrones are drawn relative to earliest activation (*)
for each beat. Listed below are total activation time (TA) and coupling interval (Cl) for each beat in milliseconds.
TA
49
35% (after a mean of 7 embolizations; range, 5 to 10), no
additional embolizations were performed. Ventriculograms
were then performed in all dogs 4±1 weeks before their
mapping study.
Holter Monitoring
Ambulatory Holter monitoring with animals in the conscious state was performed for 24 to 48 hours at baseline (at
least 2 days before the first catheterization) and weekly
beginning 2 weeks after the last embolization. The chest of
each dog was shaved, ECG leads were attached, and a
zippered nylon dog jacket (Alice King Chatham, Los Angeles,
Calif) was applied. The Holter monitor was placed in a pocket
of the jacket, and the dog's activities were unrestricted.
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 premature ventricular complexes (PVCs), couplets, and runs of VT.
Arrhythmia frequency was verified and edited by manual
counting.
Mapping Protocol
Three-dimensional cardiac mapping studies were performed, as previously described,17-1922-24 an average of 6.4
weeks after the last embolization, when weekly Holter monitoring of conscious dogs consistently demonstrated frequent
PVCs, occasional couplets, and runs of nonsustained VT.
Briefly, dogs were anesthetized with pentobarbital (150 to 250
mg IV with additional doses of 25 to 50 mg IV as needed) and
then intubated and mechanically ventilated. Body temperature
was maintained at 37°C by a thermostatic esophageal probe
controlling an infrared lamp. A left thoracotomy was performed, and the heart was supported in a pericardial cradle.
Fifty-four plunge-needle electrodes containing four bipolar
electrode pairs per needle (total of 216 intramural sites) were
placed throughout the heart (Fig 1).22,23 All electrodes had an
interbipole spacing of 500 gm, and the most proximal of the
electrode pairs was located 500 gm from the epicardial
surface. The left and right ventricular plunge-needle electrodes contained four bipolar pairs, each separated by 2.5 mm.
For assessment of right ventricular activation, only the three
epicardialmost pairs were consistently within the ventricular
myocardium, so that the distal (endocardialmost) bipolar pairs
in these regions were ignored during electrogram analysis. In
dogs 4 and 5, four additional septal plunge-needle electrodes,
each containing four bipolar pairs separated by 10 mm, were
placed in the anterior and posterior septa under two-dimensional echocardiographic guidance. During the experiment,
Pogwizd Mechanisms of Ventricular Tachycardia
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warm (37°C) saline was applied to the heart intermittently to
prevent surface cooling and to moisten the epicardium. A
thermistor on the epicardial surface ensured that the epicardial temperature was maintained at 37°C.
After a stabilization period of 30 minutes, bipolar electrogram information was simultaneously acquired from each of
the 216 to 232 transmural sites and individually amplified,
filtered (40 to 500 Hz), converted from analog to digital at a
2-kHz sampling rate, and stored, along with the lead II surface
ECG tracing, on tape by use of a Sangamo Sabre IV highdensity recorder (Fairchild Weston Systems). Spontaneous
rhythm was recorded continuously for 60 minutes, during
which time each dog demonstrated PVCs, couplets, and runs
of VT at a rate comparable to that detected in the conscious
state by Holter monitoring (see "Results"). At the end of the
experiment, each animal was killed by an injection of KCl.
Detailed electrode localization was performed as described
previously.'7-19 Each plunge-needle electrode was removed
and replaced by a labeled pin. The heart was then excised and
rinsed in normal saline. A polyethylene catheter (PE 60) was
placed into both coronary ostia, and the arterial tree was
perfused with 10% sodium phosphate-buffered Formalin. 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 1.7 cm thick. Because of
contraction of the heart during fixation, the cavity sizes were
decreased and the wall thickness in some areas exceeded that
observed during life. Each electrode was precisely localized 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). Plungeneedle 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 three-dimensional construction of isochronal maps as described below.
Spacing between plunge-needle electrodes around sites of
initiation averaged 5 to 10 mm.
Electrogram Analysis and Construction of
Isochronal Maps
Electrogram data were analyzed off-line by use of a MicroVAX-II computer (Digital Equipment Corp) with interactive
color graphics. Details of the mapping analysis system have
been described previously.17-192223 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 or beats of VT). Electrograms were
displayed, and the activation times, assigned by the computer
based on a peak criterion,1415 were reviewed and manually
reassigned if required. Analyzable tracings were obtained from
97% of bipolar intramural recording sites. An amplitude
threshold of 0.25 mV was considered indicative of activation
of tissue by the depolarizing wave front.17-'9 After all bipolar
electrograms were reviewed, the activation times for all sites
were printed and assigned to their respective intramyocardial location, as indicated by the detailed three-dimensional
localization described previously. Three-dimensional isochronal maps were then constructed manually in 20-millisecond increments.
Serum Electrolytes and Arterial Blood Gases
Peripheral venous blood samples for measurement of serum
potassium (K') and magnesium (Mg2+) were obtained from
conscious dogs within 1 week of the mapping study (Just before
institution of ambulatory Holter monitoring) and were all
within the normal range. Serum K' was measured immediately
preceding administration of anesthetic (before three-dimensional mapping) and was normal. Serial arterial blood samples
were obtained for blood gas and K' measurements, and any
1445
X3
LN
X3
A
-741
408
20
7mV
B
C
D
E
F
x4
|
F7
2mV
C
l2mV V'
F177 |2-20
7mV
80I 30
4mV
s 1
]3mV
W1
14
d'
1
G
H
3mVI~
___ 8
lmV |
Fl1-s 17
llmV
I
25
Fl116
J
14mV |
K
6mV
|
40
L
M
N
4mV
1E10
44
7mV
'
111E
3mV
FIG 7. Top left, Apical two sections (111 and IV) of the isochronal
map of beats X3 from Fig 6 (dog 4). Top right, Schematic of
sections Ill and IV from dog 4, with A through N representing
individual electrode recording sites. Bottom, Bipolar electrograms from each site during a 438-millisecond interval during
activation of X3 and initiation of X4.
hypokalemia was corrected with intravenous KCI. Serum K'
was in the normal range at the time of the mapping studies.
Histological Analysis
After mapping analysis, transmural tissue samples (up to
1.5 x 1.5 x 1.5 cm) from selected areas of interest from all five
dogs (in particular, sites of focal initiation and regions of slow
conduction) were embedded in paraffin and sectioned perpendicular to the epicardial surface at a thickness of 5 ,um. Tissue
1446
Circulation Vol 90, No 3 September 1994
NS
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TA
Xi
X3
X12
53
92
84
102
328
373
396
FIG 8. Three-dimensional isochronal maps for a sinus beat (NS) and 1st (Xl), 3rd (X3), and 12th (Xl 2) beats of a 12-beat run of
spontaneously occurring monomorphic ventricular tachycardia from dog 5. lsochrones are drawn relative to earliest activation (*) for
each beat. Listed below are total activation time (TA) and coupling interval (Cl) in milliseconds.
CI
sections were stained with Masson's trichrome for examination
by light microscopy.
Supplies
Holter monitors were generously donated by Scole Engineering (Culver City, Calif) and Delmar-Avionics (Irvine,
Calif).
Data and Statistical Analyses
The total activation time for each beat was defined as the
difference in activation time between the earliest and latest
sites of activation. The mechanism responsible for a particular
premature beat was defined as macroreentrant 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 wave front 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 wave front of the preceding
beat.17-'9 A mechanism was defined as focal when the site of
initiation of a premature beat demonstrated radial spread of
activation and was remote from the site of termination of the
preceding beat with no intervening depolarizations despite
multiple (four or more) intermediate recording sites.24 A focal
mechanism does not exclude the possibility of microreentry.
Data are expressed as mean±SEM. Comparisons of values for
ejection fraction, total activation time, and coupling interval
data were performed by Student's t test (for paired or unpaired data), and P<.05 was considered indicative of a significant difference.
Results
Incidence of Spontaneous Arrhythmias During
Ischemic Cardiomyopathy
Baseline 24-hour Holter monitoring demonstrated no
ventricular ectopic activity in any of the five dogs. After
an average of 7 (range, 5 to 10) embolizations, the left
ventricular ejection fraction decreased from 63 ±3% to
22±3% (P<.OO1). Weekly 24- to 48-hour Holter monitoring, starting 2 weeks after the last embolization,
revealed a progressive increase in the degree of ventricular ectopic activity. Each dog demonstrated frequent
multiform PVCs, couplets, and runs of VT (Table, left)
that were either monomorphic or polymorphic (Fig 2).
The maximal hourly frequency of ectopic beats and runs
of VT for each dog during weekly Holter monitoring is
listed in the Table (left). Dogs 4 and 5 demonstrated
more frequent PVCs and runs of VT than did dogs 1
through 3 (Table); however, ejection fractions were
Pogwizd Mechanisms of Ventricular Tachycardia
Ill
:::
1i
fli T11::!;
;; ::.;
1447
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::
400t
CI 350
(msec)
300
250
2001
1
A
Xi X2
A1
1
120
100 _
TA
1
1
Xi
XI X2 X3 X4 XS X6 X7 X8 X9 XI4
1 2
80
80-.
(msec) 60
40.
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20.
2
)4
X2X3
4
'Al: 11
-JJ
400r
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(msec)
350 F
)(67 ) q4)oYl X,2
FIG 9. Plots of coupling interval (Cl)
and total activation time (TA) for each
beat of similar QRS morphology (horizontal axis) for which every beat was
mapped three dimensionally. Top,
Premature ventricular complex (PVC),
couplet, and runs of 3-beat and 12beat monomorphic ventricular tachycardia (VT) from dog 5. With the exception of beat X3 of the 12-beat run of VT
(which is also shown in Fig 8), all of
these ectopic beats were initiated at
the same right ventricular subendocardial site adjacent to but distinct from
the right ventricular site of initiation of
normal sinus rhythm. Bottom, PVC,
couplet, and runs of 3-beat and 5-beat
VT from dog 4. All of these ectopic
beats were initiated from a distinct right
ventricular subendocardial site, distant
from the posteroseptal site of initiation
of normal sinus rhythm.
3001
250[
1
200'-
1
Xi X2
120
100
TA 80
(msec) 60
40
20
0
X
Xi X2
XI X2X3 X4 XS
XI X2 X3
XI X2 X3 X4X5
comparable. The longest and fastest run of nonsustained VT was a 70-beat run at a rate of 560 beats per
minute in dog 5 (Fig 2, bottom).
Three-dimensional Mapping
Three-dimensional mapping of spontaneous rhythm
from as many as 232 intramural sites was performed
6.4±1 weeks after the last embolization. The technique
of inserting multiple (<60) plunge-needle electrodes
into the canine heart has been validated in previous in
vivo studies and has been shown not to alter heart rate,
mean arterial blood pressure, or cardiac output.23 In the
present study, insertion of 56 to 60 plunge-needle
electrodes did not alter heart rate (164±6 to 169±6
beats per minute, P=.56) or mean arterial blood pressure (101± 9 to 105±7 mm Hg, P=.30). On the surface
ECG, QRS duration was unaltered. QRS morphology
of sinus beats was unaltered except for a slight decrease
in R-wave amplitude in two dogs, most likely due to
slight anterior displacement of the heart by the posterior plunge-needle electrodes.
During the 60-minute recording interval, each dog
demonstrated multiform PVCs, couplets, and nonsustained runs of monomorphic or polymorphic VT with
QRS morphologies (Fig 2) and frequencies (Table) that
were comparable to those demonstrated on previous
Holter monitoring of respective conscious dogs. However, the longest run of VT recorded during mapping
was 12 beats and the fastest was a 3-beat run of VT at
a rate of 268 beats per minute. PVCs and VT were more
frequent during mapping in dogs 4 and 5, findings
similar to those noted on Holter monitoring (Table).
The three-dimensional activation sequences of 105
sinus beats, 36 PVCs, 56 beats of ventricular couplets,
124 beats of VT (from 15 runs of monomorphic VT and
16 runs of polymorphic VT), and 3 ventricular escape
1448
Circulation Vol 90, No 3 September 1994
NS PVC
INIT SITE
TA
CI
NS
A
97
320
NS
INIT SITE
TA
Cl
NS
Xi
A
NS
X2
NS
Xi
x2
X3
I
B
86 91
323 352
Xi
X2
X3
NS
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U
INIT SITE
TA
CI
A
B C
97 89 88
328 362 248
A20
280
S
FIG 1 0. Left, Surface ECG of a premature ventricular complex (PVC), couplet, and run of three-beat ventricular tachycardia (VT) along
with preceding sinus beats (NS) from dog 2 in which there is an identical QRS morphology of the initial beats. Listed below are total
activation time (TA) and coupling intervals (Cl) for each beat in milliseconds and initiation sites (INIT SITE) (A through C, right). Right,
Three-dimensional isochronal maps for sinus beat (NS) and three beats (Xl through X3) of the run of three-beat VT from dog 2 (bottom
left). Initiation sites of Xl through X3 (A through C, respectively) are shown in levels and 11.
beats were delineated based on the analysis of more
than 72 000 individual bipolar electrograms. In dogs 1
through 3, mapping was of sufficient density to fulfill
criteria for arrhythmia mechanism (see "Methods") for
65% of PVCs, couplets, and VT that were analyzed.
Mechanisms could not be defined for 35% of ventricular
ectopic beats due to insufficient electrode density in the
interventricular septum. In the two remaining dogs (4
and 5), the use of specially designed septal plungeneedle electrodes to record from 16 sites in the interventricular septum resulted in a mechanism being defined for every ectopic beat. Arrhythmia mechanisms
were thus assigned for a total of 31 PVCs, 45 beats of
ventricular couplets, and 99 beats of VT from the five
dogs.
Sinus Rhythm
Sinus beats that preceded other sinus beats were
initiated in the septum or the right ventricle and spread
rapidly throughout the heart with no evidence of slow
conduction or conduction block. The total activation
time averaged 46±2 milliseconds, and the coupling
interval averaged 383±+19 milliseconds (n=10). The
total activation time for sinus beats from the two dogs
with more frequent PVCs and VT (dogs 4 and 5, 51±3
milliseconds) was not significantly different from that
from dogs 1 through 3 (43 +2 milliseconds, P=.053). An
example of an activation map of a sinus beat is shown in
Fig 3A. After initiation in the septum (level 111*),
activation during the sinus beat proceeds rapidly to the
apex and base and from endocardium to epicardium,
terminating in the basolateral left ventricle in level I (+)
with a total activation time of 45 milliseconds.
PVCs and Couplets
Sinus beats preceding PVCs exhibited activation sequences and total activation times (46±1 milliseconds,
n=36) that were identical to those of sinus beats not
preceding PVCs (P=.69). After termination of the sinus
beats, there was no electrical activity at any recording
site in the heart for 244+12 milliseconds, after which
the PVCs were initiated in the subendocardium by a
focal mechanism with no evidence of macroreentry.
An example of the initiation of a PVC is shown in Fig
3B. The activation of the sinus beat (NS) preceding the
PVC was identical to that of sinus beats shown in Fig
3A, with initiation in the septum (level 111*) and
termination in the basolateral left ventricle (level It).
There was no electrical activity at any recording site in
the heart for 275 milliseconds, after which the PVC
were initiated on the other side of the heart in the
subendocardium of the right ventricle (beat PVC, level
1*) by a focal mechanism with a coupling interval of 320
milliseconds. The PVC then spread throughout the
heart from the right ventricle to the left ventricle and
terminated with a total activation time of 97 milliseconds. The initiation of the PVC by a focal mechanism is
shown in greater detail in Fig 4. After termination of the
sinus beat NS at left ventricular epicardial site A, there
was no electrical activity at selected sites B to G or at
Pogwizd Mechanisms of Ventricular Tachycardia
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any other recording site in the heart for 275 milliseconds, after which the PVC was initiated at the right
ventricular subendocardial site H by a focal mechanism.
PVCs demonstrated only moderate conduction delay,
with a total activation time averaging 83+2 milliseconds
and a coupling interval of 283±9 milliseconds. Multiform PVCs arose from different subendocardial sites
from the left ventricle (33% of cases), the right ventricle
(53%), and the interventricular septum (14%). Although PVCs of a particular morphology usually arose
from the same site, at times they could arise from one of
several nonadjacent sites (Fig 5, sites E and H). Furthermore, PVCs arising at closely adjacent sites could
exhibit considerably different activation patterns and
QRS morphologies (sites B and C) because of marked
differences in the direction of spread of their threedimensional activation wave fronts. At times, PVCs
arose from the same sites at which normal sinus beats
were initiated (site F) (see Fig 3A).
All ventricular couplets, both monomorphic and polymorphic, were initiated and maintained by a focal mechanism arising in the subendocardium (93% of cases) or
the epicardium (7%) (see "Epicardial Activation"). Sinus beats preceding couplets were identical to sinus beats
preceding PVCs, with a total activation time of 46±1
milliseconds. The total activation time of the initiating
beat of the couplets was 84±2 milliseconds, whereas that
of subsequent beats was 87±2 milliseconds (P=.39).
Initiation of very late coupled ventricular ectopic
beats (isolated PVCs or the first beats of either couplets
or runs of VT) occasionally led to fusion beats. The
coupling interval of these fusion beats (380±11 milliseconds, n=10) was nearly identical to that of sinus
beats (P=.91). The QRS morphology of the fusion beat
was usually intermediate between that of sinus beats
and PVCs, as was the total activation time (55±2
milliseconds compared with 46±2 milliseconds for sinus
beats and 83±2 milliseconds for PVCs).
VT
All beats of monomorphic and polymorphic VT were
initiated and maintained by a focal mechanism, which
arose from the subendocardium in 96% of cases, from
the midmyocardium in 1%, and from the epicardium in
3% (see below). In 6% of cases, beats of VT were
initiated at the same site as earliest activation during
normal sinus rhythm. Sinus beats preceding the first
beats of VT were identical to sinus beats not preceding
PVCs or VT, with a total activation time of 47±1
milliseconds (n=31). The total activation times of the
initiating beats of VT averaged 86±2 milliseconds,
whereas those of subsequent beats averaged 89±1 milliseconds (P=.14).
Monomorphic VT
All beats of monomorphic VT were initiated and
maintained in the subendocardium by a focal mechanism. Beats of monomorphic VT arose from the left
ventricle in 22% of cases, the right ventricle in 48%, and
the interventricular septum in 30%. Focal activation
usually arose from the same site for each beat but on
rare occasions arose from a different nonadjacent site.
Examples are shown in Figs 6 to 8.
The isochronal maps for a sinus beat and the first four
beats of an eight-beat run of VT are shown in Fig 6. The
INITIATION
SITE
TA
54
93 104 101 99
1449
80
FIG 11. Top, Surface ECG for a sinus beat (NS) and a five-beat
run of polymorphic ventricular tachycardia (Xl through X5)
followed by an additional sinus beat (NS) from dog 5. Below
each beat are listed its initiation site and its total activation time
(TA) in milliseconds. Bottom, Schematic of heart of dog 5 with
NS indicating site of initiation of sinus beats and A through C
indicating sites of focal initiation of Xl through X5.
sinus beat was initiated in the posterior septum in level
III, with a coupling interval of 406 milliseconds, and
spread rapidly with a total activation time of 49 milliseconds. The late-coupled (coupling interval, 383 milliseconds) first beat of VT, Xl, was initiated at an apical
subendocardial site in level IV by a focal mechanism
similar to beats X3 through X8. However, unlike X3
through X8, Xl exhibited early activation of the basal
right ventricle and septum (40-millisecond isochrones in
levels I to III) due to concurrent activation by a sinus
beat beginning 23 milliseconds after initiation at the
apex. Thus, Xl is a fusion complex with a total activa-
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Circulation Vol 90, No 3 September 1994
xl
NS
Xl
I
20
i4
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Il
t ~~~1
InI
]mX
A 7 |
A 7mV
-4
46
.
B2
B 42mVI
C
D
2mV
4mV
257
280
294
FIG 12. Left, Three-dimensional isochronal map of a sinus beat and first beat (X1) of a three-beat run of ventricular tachycardia that was
initiated in epicardium by a focal mechanism from dog 3. Top right, Detailed view of level from isochronal map of beat Xi. Middle right,
Schematic of level I from dog 3, with A indicating epicardial site of initiation of Xl and B through D indicating adjacent recording sites.
Bottom right, Bipolar electrograms from A through D over a 144-millisecond interval during which Xl was initiated.
tion time of 67 milliseconds, which was considerably less
than that of beat X3 or X4. X2 was initiated at a distant
subendocardial site in the basal posterior septum (level
II) by a focal mechanism. Beats X3 through X8 were all
initiated at the same apical site in level IV as Xl and
exhibited nearly identical activation sequences with
total activation times in the range of 86 to 92 milliseconds. The initiation of beat X3 is shown in greater detail
in Fig 7. After focal initiation of X3 at site A, the
depolarizing wave front spread rapidly in all directions,
activating adjacent sites B through N within 44 milliseconds. Terminal activation during X3 occurred in the
basal anterior right ventricle in level I (see Fig 6), 89
milliseconds after initiation at site A. There was no
electrical activity at any recording site in the heart
(including sites B through N) for 319 milliseconds, after
which X4 was initiated at site A by a focal mechanism.
Although microreentry could not be ruled out, the
absence of any slow conduction or delay at or around
the focal initiation site A suggests that microreentry is
very unlikely.
Shown in Fig 8 are the three-dimensional activation
sequences for the sinus beat NS and VT beats Xl, X3,
and X12 for a 12-beat run of monomorphic VT (dog 5).
The sinus beat was initiated at a subendocardial site in
the right ventricle (level III) and spread rapidly, terminating in the lateral left ventricle (60-millisecond isochrone, level III) with a total activation time of 53
milliseconds. There was no electrical activity at any
recording site for 320 milliseconds, after which the first
beat of VT, Xl, was initiated at a right ventricular site
in level III, adjacent to the initiation site of the preceding sinus beat, by a focal mechanism. Beats X2 through
X12 all demonstrated focal initiation at the same right
ventricular site as Xl, except for beat X3, which was
initiated at a posterior septal site in level II by a focal
mechanism. As shown in Fig 8, X12 demonstrated not
only the same initiation site as Xl but also a nearly
identical activation sequence and a comparable total
activation time (102 milliseconds versus 92 milliseconds
for X1). Thus, monomorphic VT was initiated and
maintained by repetitive focal activation, usually arising
at the same subendocardial site.
To elucidate possible factors influencing the development of monomorphic VT, the three-dimensional maps
of PVCs, couplets, and runs of monomorphic VT that
Pogwizd Mechanisms of Ventricular Tachycardia
NS
X, X2 X3
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M
A
B
I-J,
K
4mV
r
|
L
8 n1V1
w
8 mV
C
M 8X 1
I
D
N
2
1 4-1
5
ESC
FIG 13. Top, Lead II surface ECGs.
Upper middle, Level II of three-dimensional isochronal maps for X3, third
beat of a three-beat run of ventricular
tachycardia (VT) (left), and a ventricular
escape beat (ESC) that followed a
three-beat run of VT (right), both of
which initiated focally in the midmyocardium (*) of dog 1. Lower middle,
Schematics of level 11, with A through H
and K through R representing individual intramural recording sites. Bottom,
Bipolar electrograms for sites A
through H (left) and K through R (right)
as well as from midmyocardial sites
immediately basal (sites and S from
level l; map not shown) and apical
(sites J and T from level ll; not shown)
to midmyocardial initiation site. Earliest
activations arising in midmyocardium
are indicated by arrow.
1I
Ui
1451
I7
mv
11- 732
E
F
1
G
H
MIS
13
P 23mV|
S 27mv~|
10nm,
Q
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R
.
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-
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36_
.
4!!-
.v
T42mV
a
lJ
Ts163
demonstrated the same QRS morphology were analyzed. Shown in Fig 9 is a summary of the total
activation time and coupling interval data for such a
series of beats from dog 5 (top) and dog 4 (bottom); all
beats were mapped and found to be initiated by a focal
mechanism arising in the subendocardium. Beats of
monomorphic VT exhibited total activation times and
coupling intervals that were comparable to those of
isolated PVCs and couplets. In addition, late beats of
VT demonstrated total activation times that were comparable to those of initiating beats, even when there was
acceleration of VT as evidenced by decreasing coupling
intervals (Fig 8 and Fig 9, bottom). Runs of monomorphic VT terminated after 3 to 12 beats, with the
terminal beats initiating at the same subendocardial
sites as preceding beats. There was no significant difference in the coupling interval between the penultimate
beat (Xn -) and the terminal beat Xn (319+16 versus
286+23 milliseconds; n=15, P=.10). The total activation time of the last beat (X,) was only 9% greater than
that of the penultimate beat (X, ,) (92+2 versus 84±3
milliseconds; n= 15, P=.002).
Polymorphic VT
Beats of polymorphic VT usually demonstrated the
same morphology as isolated PVCs (Fig 2) and usually
arose from the same or closely adjacent site as the PVC
whose morphology it resembled. The total activation
times of the initiating beats of polymorphic VT (89±+2
milliseconds, n=54) were only 7% greater than those of
isolated PVCs (83±2 milliseconds, P=.01). The coupling intervals did not differ (306±15 versus 282±9
milliseconds, P=.18).
To delineate how polymorphic VT developed, analysis was performed on PVCs, couplets, and runs of
polymorphic VT with comparable QRS morphologies.
An example is shown in Fig 10. The QRS morphologies
of the PVC, the first beat of the couplet, and the first
beat of the run of VT were identical, as were the second
beats of the couplet and the run of VT. The activation
maps for the sinus beat NS and the three beats of VT
(Xl through X3) are shown in Fig 10 (right). The
isolated PVC was initiated at a right ventricular subendocardial site in level I by a focal mechanism (see Fig
3B). The first beats, Xl, of the couplet and the triplet in
Fig 10 (right; beat Xl, level I) was also initiated at site
A, with a nearly identical coupling interval, total activation time, and activation sequence. Although no
ectopic activation followed the isolated PVC, the initiating beats of the couplet and the run of VT, both
labeled Xl, were followed by an ectopic beat, X2. Both
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Circulation Vol 90, No 3 September 1994
A
X
F16
C 12mV
TA=48ms
CI = 406 ms
29
l0-I
A' 8 mV
B [2XI
D
426
_
26
~
16 mVI
A
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A'
B
C
D
TA=91 ms
Cl=343ms
28
A I3rnVI
A'
B
8 mV
C
D
12 mV
16 mV
A
9 mV
2 mV|
36
17167
2
TA= 57 ms
CI =383ms
9mV
50
s
-/
45
1_
16mVW
B
F7-6-
2 mV
36*
| fll
._28
TA= 84ms
CI = 344ms
C
12mV I
D
16mV
`
'
__
|
'
'
Pogwizd Mechanisms of Ventricular Tachycardia
FIG 14. Facing page. Slow conduction observed during ventricular tachycardia (VT) in dog 4. Left, Lead II surface ECGs,
total activation time (TA), and coupling interval (Cl) of a sinus
beat (NS) (top); first beat, Xl, of a three-beat run of VT (second
panel); and first beat, Xl, of couplets (third panel and bottom)
from dog 4. Center, lsochronal maps of two apicalmost sections
(111 and IV) for beats enclosed in boxes on left. A, A', B, C, and D
are intramural recording sites shown on isochronal map of sinus
rhythm (top). Right, Bipolar electrograms over 114-millisecond
intervals during activation of each beat. Activation between A
and A' during first beat of VT (second panel) is markedly
delayed, with more rapid continuous activation occurring from A
to B to C to D to A'.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
X2 beats were initiated focally at a basaolateral subendocardial site in level I (labeled B at left and shown at
right in beat X2, level I) with no intervening electrical
activity (for 265 milliseconds) at any site in the heart
including the 14 intermediate sites between the termination of Xl in level 11 (t) and the initiation of X2 in
level 1 (B). Both X2 beats demonstrated nearly identical
total activation times, coupling intervals, and activation
patterns. No ectopic activation followed X2 of the
couplet. However, the second beat of VT, X2, was
followed by focal initiation from a different subendocardial site in the lateral left ventricular wall (level II). X3
was activated for only 88 milliseconds, after which the
tachycardia terminated. Thus, like monomorphic VT,
polymorphic VT was due to consecutive focal activation, here involving multiple subendocardial sites with
comparable degrees of conduction delay and
prematurity.
Another example of polymorphic VT is shown in Fig 11.
After sequential focal activation from multiple sites (A
through C) for beats Xl through X3, there was repetitive
firing from one particular site (C) for beats X3 through
X5, all with comparable degrees of conduction delay. This
led to a monomorphic phase of the tachycardia, after
which the tachycardia terminated. For all runs of polymorphic VT analyzed (n=15), the initiating and subsequent
beats demonstrated similar total activation times (89±3
versus 89±2 milliseconds, P=.93) and coupling intervals
(306± 15 versus 309±10 milliseconds, P=.88). Although
there was no difference between the total activation times
of penultimate beats (87±3 milliseconds) and those of
terminal beats (87±3 milliseconds, P=.89), the coupling
interval of the terminal beat was 13% less than that of the
penultimate beat (287±18 versus 331±15 milliseconds,
P=.04).
Epicardial Activation
In six cases, beats of couplets or polymorphic VT
were initiated in the epicardium of the right ventricle by
a focal mechanism. The total activation times averaged
99±2 milliseconds, and the coupling intervals averaged
250±23 milliseconds (n=6). An example is shown in Fig
12, with the activation map of a sinus beat and Xl, the
first beat of a three-beat run of VT in dog 3. After
termination of the sinus beat in the lateral left ventricle
in level I (t), with a total activation time of 39 milliseconds, there was no electrical activity at any recording
site in the heart for 225 milliseconds. Xl was then
initiated on the other side of the heart, at a right
ventricular epicardial site (site A in Fig 12B) by a focal
mechanism. Activation of Xl proceeded from epicar-
1453
dium (A) to endocardium (B) and then counterclockwise (to C) and clockwise (to D).
Midmyocardial Activation
One ectopic beat, the third beat (X3) of a run of
polymorphic VT from dog 1, was initiated from a left
ventricular midmyocardial site by a focal mechanism
(Fig 13, left). After termination of the preceding beat of
VT, X2, at a right ventricular epicardial site in level I
(not shown), there was no electrical activity at any
recording site in the heart for 159 milliseconds, after
which X3 was initiated at a midmyocardial site in level
II by a focal mechanism. The total activation time was
104 milliseconds, and the coupling interval was 257
milliseconds. The electrograms (Fig 13, bottom left)
demonstrated that midmyocardial activation at site C in
level II preceded activation from both adjacent endocardial (A) and epicardial (D) sites and led to rapid
spread to other adjacent sites, E through H, as well as
basally to adjacent midmyocardial site I in level I and
apically to midmyocardial site J in level III (maps of
levels I and III are not shown).
Escape Beats
During mapping, three isolated ventricular escape
beats occurred, each following three-beat runs of VT in
dog 1. All three escape beats were initiated at the same
left ventricular midmyocardial site in level II, which was
different from the midmyocardial site of initiation of VT
shown in Fig 13 (left). The total activation times averaged 100±1 milliseconds, and the coupling interval
averaged 595 +22 milliseconds. An example is shown in
Fig 13 (right). After termination of X3, the third beat of
VT in level II, there was no electrical activity at any
recording site in the heart for 545 milliseconds. The
escape beat then initiated at a midmyocardial site L by
a focal mechanism with rapid spread to adjacent endocardial (K) and epicardial sites (N). Activation then
proceeded in both a clockwise and counterclockwise
direction (sites 0 through R) and basally (to site S in
level I, map not shown) and apically (to site T in level
III, map not shown). The total activation time of the
escape beat was 99 milliseconds.
Conduction Slowing
Although the total activation time never exceeded 104
milliseconds for any PVC or beat of couplets or VT, one
dog (dog 5) occasionally demonstrated considerable local
slowing of conduction in the anterior left ventricular wall
during VT compared with sinus rhythm; an example is
shown in Fig 14. Activation between two adjacent midmyocardial sites in level III (A and A') was very rapid (<5
milliseconds) during normal sinus rhythm (Fig 14, top).
However, activation during the first beat of a three-beat
run of VT (Fig 14, second panel) demonstrated conduction delay of 60 milliseconds between sites A and A',
whereas activation was continuous and more rapid along
the pathway A-B-C-D-A' shown at the right. Although
slow conduction from A to A' was in general more
frequent at shorter coupling intervals, this was not always
the case. During the first beats (X1) of each of two
couplets, which were initiated at a comparable coupling
interval to the preceding run of VT, activation between A
and A' was much more rapid (Fig 14, third panel and
bottom). Thus, functional conduction delay can develop at
1454
Circulation Vol 90, No 3 September 1994
FIG 15. Low-magnification photomicrograph (left) and corresponding tracing
(right) of a representative section of trichrome-stained left ventricular myocardium
from cardiomyopathic dog 5. Fibrotic tissue
is indicated in black.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
short coupling intervals but appears to be dependent on
other factors, such as the pattern of activation of the
ectopic beat.
Comparison of Pathological Specimens
Pathological analysis of myocardium demonstrated
areas of patchy nontransmural fibrosis throughout the
distribution of the LAD and circumflex coronary artery.
There was diffuse involvement of the left ventricular
free wall and septum and focal involvement of the right
ventricular free wall, particularly in regions close to the
attachment to the septum, in all five cardiomyopathic
dogs. The nontransmural fibrosis was most prominent in
the subendocardium and midmyocardium but also was
present in the epicardium. The pattern and extent of
fibrosis are shown in a representative trichrome-stained
section from the left ventricular myocardium of dog 5
(Fig 15, top).
Histological sections from sites of focal initiation
(n=18) were examined in detail, and distribution and
extent of fibrosis were compared with those in sections
from regions subtending recording sites (n=379), which
were not sites of focal initiation. Sites of focal initiation
were characterized by patchy nontransmural fibrosis
that was most marked in the subendocardium but also
involving the midmyocardium and subepicardium. The
degree of fibrosis ranged from minimal to moderate but
was always nontransmural and rarely involved more
than 25% of transmural wall thickness. The pattern and
distribution of fibrosis were characteristic not only of
focal initiation sites responsible for monomorphic VT
(Fig 16) or other ectopic beats but also of sites at which
focal initiation did not occur (Fig 15, top).
The region of slow conduction from dog 4 (shown in
Fig 14) was examined. In marked contrast to areas of
focal initiation, this area of slow conduction was characterized by a much greater degree of fibrosis, which
was completely transmural between sites A and A' (Fig
17). Interestingly, as shown in Fig 14, conduction in this
region was rapid during sinus rhythm as well as during
many other ectopic beats, even at a coupling interval
comparable to that at which slow conduction was ob-
served. Slowing of conduction thus appeared to be
dependent on both the degree of prematurity and the
direction of the activation wave front, suggesting functional conduction alterations occurring in the regions
surrounding the area of transmural fibrosis.
Discussion
Mechanism of VT
The results of the present study demonstrate for the
first time that spontaneously occurring PVCs and VT in
a model of ischemic cardiomyopathy are initiated and
maintained by a focal mechanism, without any evidence
of macroreentry. There was no continuous electrical
activity or intervening electrical activity between the
termination of the preceding beat and the initiation of
the next beat, despite the presence of multiple intervening intramural recording sites. These sinus beats
preceding PVCs or VT demonstrated activation patterns and times that were identical to those of sinus
beats not preceding PVCs or VT. In fact, no sinus beat
ever demonstrated a total activation time of more than
58 milliseconds (based on analysis of more than 24 000
electrograms from 105 sinus beats that were mapped).
Monomorphic and polymorphic VTs were due to
repetitive focal initiation from either the same or different sites. Acceleration of VT was not associated with
increased conduction delay or any evidence of macroreentry. The total activation time of ectopic beats
never exceeded 107 milliseconds, even for runs of VT as
long as 12 beats.
Although microreentry within the region of focal activation cannot be excluded definitively, it is unlikely for
several reasons. (1) There was no electrical activity at any
intermediate intramural electrode site between the site
of termination of the preceding beat and the focal
initiation site (based on analysis of more than 40 000
electrograms from 175 ectopic beats), even down to a
resolution of 125 gV. (2) Based on the cycle length of the
tachycardias, the presence of a microreentrant circuit
that was small enough to go undetected by techniques
used in the present study would require a conduction
velocity more than an order of magnitude slower than
Pogwizd Mechanisms of Ventricular Tachycardia
NS
XI
1455
X2 X3 X4 X5 X6 X7 X8 X9 XIOXIt XK2
1\1,41 X x.
B
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A
B
FIG 16. Top, Lead II surface ECGs for the runs of monomorphic ventricular tachycardia (VT) from dogs 5 and 4, respectively (see Figs
8 and 6). In boxes are beats that were initiated at a single site by a focal mechanism. Middle, Schematics of a midapical section (level
111) from dog 5 and an apical section from dog 4 with asterisks indicating site of focal initiation of beats of VT shown in boxes above.
Bottom, Trichrome-stained sections and their corresponding tracings (below) obtained from these focal initiation sites, demonstrating
patchy nontransmural fibrosis similar to that observed in regions that are not focal initiation sites (Fig 15).
the slowest conduction velocities measured even during
VT. (3) There was no evidence of slow conduction at any
recording site immediately adjacent to sites of initiation
of a focus. Even with microreentrant circuits as small as
those demonstrated in the infarcted canine epicardium in
response to isoproterenol (as assessed by high-density
grid electrode mapping),25 there was evidence of slow
conduction on the order of 100 milliseconds between the
initiation site and sites 1 to 2 cm away. That was not
found in the present study (Fig 7).
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Circulation Vol 90, No 3 September 1994
..
b
me
a
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FIG 17. Top left, Schematics of a region of slow conduction (a) in a midapical section (level l1l) from dog 4, along with location of a
histological preparation (b) (bottom left) between midmyocardial electrode recording sites A and A' shown in Fig 14 (second panel).
Right, Trichrome-stained section (b) and its corresponding tracing below, demonstrating transmural fibrosis in region between sites A
and A'.
For only 6% of VT beats, focal activation arose from
the same site as earliest activation during sinus rhythm
(terminal breakthrough sites of the left or right bundle
branch). This suggests the possibility of bundle-branch
reentry, which has been shown to underlie sustained
monomorphic VT in about 6% of patients with dilated
cardiomyopathy26 No recordings of His bundle activation were obtained during three-dimensional mapping in the present study to exclude this possibility.
However, the data supporting this potential mechanism are a small percentage of the total ectopic beats
analyzed.
Histopathologically, focal sites of initiation demonstrated patchy nontransmural fibrosis surrounded by
areas of viable myocardium, accounting for the general
lack of conduction delay during sinus rhythm and VT in
these hearts with severe depression of left ventricular
function and spontaneously occurring VT. Although in
the present study there was no slowing of overall
conduction, even during long runs of VT, localized
functional slowing of conduction developed in one dog
(Fig 14). Here, pathological analysis demonstrated that
the region of slow conduction between two electrode
sites corresponded to an area of transmural fibrosis.
Functional conduction delay in this area was not evident
during sinus rhythm or during other ectopic beats at a
comparable coupling interval in the same dog and may
be due to heterogeneity of electrophysiological alterations or to alterations in anisotropic conduction27 and
cellular coupling28,29 due to interstitial fibrosis in adjacent regions. Although focal mechanisms alone were
found to underlie the initiation and maintenance of
spontaneous VT in cardiomyopathic hearts in the present study, the presence of functional conduction delay,
albeit rare, suggests that macroreentry could contribute
to the development of VF, which has been shown to
involve intramural reentry.17-19
Nature of Focal Mechanism
The nature of the focal activation observed is unknown, but it may be due to abnormal automaticity or
triggered activity arising from either delayed or early
afterdepolarizations. The finding in the present study
that focal activity can at times arise in the epicardium
suggests a mechanism other than normal or abnormal
automaticity arising from Purkinje fibers, since Purkinje
fibers in the canine heart do not extend to the epicardium.3(1 Delayed afterdepolarizations have been induced in hypertrophied rat myocardium,11 the hypertensive diabetic rat heart,31 the infarcted feline heart,32 and
Pogwizd Mechanisms of Ventricular Tachycardia
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failing human myocardium in vitro.33 Myocardium from
patients with end-stage heart failure demonstrates an
increased duration of the calcium transient, as assessed
by the bioluminescent calcium indicator aequrorin, with
two distinct components reflecting impairment of calcium uptake by the sarcoplasmic reticulum.34 In addition, myocardium from failing human hearts exhibits a
reduced capacity to restore low intracellular calcium
levels during diastole.34 Increases in the diastolic level
of calcium could turn on a transient inward current35
and lead to delayed afterdepolarizations and triggered
activity.
Dangman et a136 demonstrated delayed afterdepolarizations and triggered activity in the subepicardial ventricular muscle cells from the border zone of the 1-dayold infarcted canine heart. This may be related to the
focal activity occasionally arising from the epicardium
seen in the present study. The possibility of focal
activation of an ectopic beat arising in the midmyocardium is intriguing and implicates involvement of M cells
that are located in the midmyocardial region.37 These
cells can demonstrate prolongation of action potential
duration and, in the presence of acetylstrophanthidin or
Bay K 8644, can demonstrate both delayed and early
afterdepolarizations.38 The focal activation of escape
beats from midmyocardial sites could also involve M
cells and suggests an origin of ventricular escape activity
other than from the His-Purkinje system.
Canine Preparation of Heart Failure
Defining arrhythmia mechanisms in the present study
required an experimental preparation of heart failure
that demonstrates spontaneously occurring ventricular
arrhythmias, including nonsustained VT. Although a
number of experimental preparations of left ventricular
hypertrophy and heart failure have been developed,39
most do not demonstrate spontaneously occurring ventricular arrhythmias. The preparation of ischemic cardiomyopathy induced by multiple sequential intracoronary
embolization, developed by Sabbah et al,13,15 is characterized by a progressive decrease in left ventricular
systolic function, increased serum catecholamine levels,
and pathological alterations comparable to those in
human ischemic cardiomyopathy. In addition, this preparation is associated with marked electrophysiological
alterations, including a 10% to 15% incidence of sudden
death,15 and spontaneously occurring ventricular arrhythmias, including nonsustained VT.15 Whether the electrical instability demonstrated by this preparation is due to
the degree of irreversible left ventricular dysfunction, the
extent and/or nature of pathological alterations, or the
effects of hemodynamic, neurohumoral, or other electrophysiological alterations is unknown. Nonetheless, this
preparation provides a unique opportunity to determine
electrophysiological mechanisms underlying arrhythmogenesis in the failing heart and could serve as a preparation for evaluation of the effectiveness of therapeutic
interventions.
In the present study, all five dogs that underwent
cardiac mapping demonstrated, while conscious, frequent PVCs, couplets, and runs of monomorphic and
polymorphic VTs (of as many as 70 beats and with rates
as high as 560 beats per minute) on weekly 24- to
48-hour Holter monitoring. Although Sabbah et al'5
reported nonsustained VT in only 33% of the cardio-
1457
myopathic dogs evaluated, this was based on only one 7to 8-hour Holter monitor recording. Patients with ischemic cardiomyopathy40 exhibit considerable day-to-day
variability in Holter recordings, and results have shown
that one brief Holter monitor recording will fail to
detect spontaneously occurring nonsustained VT in a
significant number of cases.40
Three-dimensional Mapping
Three-dimensional cardiac mapping of spontaneously
occurring VT from as many as 232 sites and for as long
as 60 minutes was possible because of the extensive
data-storage capacity of the mapping system. During
this interval, all of the dogs demonstrated PVCs, couplets, and occasional runs of VT with QRS morphologies and incidence that were comparable to those
observed with Holter monitoring of conscious animals,
not only in frequency and level of complexity but also in
morphology. Mapping for 60 minutes from intramural
sites throughout the left and right ventricles and the
interventricular septum allowed delineation of mechanism for at least four runs of nonsustained VT for each
dog and for longer runs of monomorphic and polymorphic VTs (< 12 beats) that were comparable to long
runs occurring in the conscious state. Recording from
the endocardial or epicardial surfaces alone would have
left a large portion of the heart unmapped and would
have precluded defining the underlying mechanism of
arrhythmias in the failing heart.
Findings in the present study suggest that focal
mechanisms could contribute to the development of
spontaneously occurring VT in the cardiomyopathic
human heart. We have recently performed intraoperative three-dimensional cardiac mapping studies in 13
patients with ischemic cardiomyopathy who were undergoing surgical ablation for refractory VT.24 Although 5
of the 10 runs of sustained monomorphic VT induced by
programmed electrical stimulation were initiated by
intramural reentry, the other 5 runs of induced, sustained monomorphic VT arose by a focal mechanism
with no evidence of macroreentry. Thus, focal mechanisms appear to play a role in the development of VT in
human cardiomyopathy.
The finding that spontaneous VT arises by a focal
mechanism also suggests that the current use of antiarrhythmic agents directed primarily at altering conduction and the development of reentry may account for
both their lack of efficacy and their proarrhythmic
effects in patients with heart failure.6,7 Other factors
that are related to development of ventricular arrhythmias in the failing heart, such as electrolyte imbalance,
catecholamines, inotropic agents, and digitalis,3 may
exacerbate arrhythmias arising from focal mechanisms
since all of these factors can enhance delayed afterdepolarizations and lead to triggered activity in vivo as
well as in vitro. Thus, approaches to the treatment of
ventricular arrhythmias in the failing heart should be
directed at focal mechanisms.
Acknowledgments
This work was supported in part by National Institutes of
Health grant HL-46929. The author would like to thank Mr
William Petty, Mr Lawrence Schwartz, Mr Jerome Peirick,
and Dr Scott Beau for technical assistance; Mr Ross Henry,
Ms Janey Wang, and Ms Carrie Kelly for assistance with data
1458
Circulation Vol 90, No 3 September 1994
analysis; Ms 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.
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Circulation. 1994;90:1441-1458
doi: 10.1161/01.CIR.90.3.1441
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