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Am J Physiol Heart Circ Physiol 287: H2078 –H2084, 2004;
doi:10.1152/ajpheart.00027.2004.
Triggered activity due to delayed afterdepolarizations in sites of focal origin
of ischemic ventricular tachycardia
Dezhi Xing and James B. Martins
Division of Cardiovascular Diseases, Department of Internal Medicine, University of
Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa 52242
Submitted 12 January 2004; accepted in final form 25 June 2004
ventricles; myocardial infarction; endocardium
SUDDEN CARDIAC DEATH is a major public health problem. Ventricular tachycardia (VT) and fibrillation (VF) are responsible
for most cases of sudden cardiac death (22). The understanding
of mechanisms of VT and VF in early myocardial ischemia and
infarction is hampered in humans by rapidly changing substrate
over the first hours, which are rarely observed in the hospital.
Animal models have been studied instead (31). Although
reentry has been thought to underlie early VT (25, 36) and VF,
some studies have implicated focal mechanisms (1, 2, 10, 11,
25) in endocardial and Purkinje tissue (1, 2, 10). In vitro
models of acute ischemia (3, 20, 27, 32) involving Purkinje
tissue have suggested that triggered activity (TA) due to
delayed afterdepolarizations (DADs) may explain these focal
VTs. Abnormalities that may contribute to the occurrence of
these mechanisms in acute ischemia include increased free
fatty acids, oxygen free radials, acidosis, and catecholamines
(22). We studied our model of inducible VT (2) after acute
coronary artery occlusion employing three-dimensional activation mapping to investigate the hypothesis that TA due to
DADs may be found more frequently in endocardial and
Address for reprint requests and other correspondence: J. B. Martins, Div. of
Cardiovascular Diseases, Dept. of Internal Medicine, Univ. of Iowa College of
Medicine, 200 Hawkins Dr., E318-3 GH, Iowa City, IA 52242 (E-mail:
[email protected]).
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Purkinje tissues that were excised from sites of origin (SOOs)
of focal VT.
METHODS
Animal preparation. A total of 145 dogs of either gender, weighing
8 –20 kg, were studied. The protocol was approved by the University
of Iowa Animal Use and Care Committee and adhered to the standards
of the American Physiological Society. Anesthesia was initiated with
ketamine (5 mg/kg im) and thiopental sodium (300 mg iv) and
continued with ␣-chloralose given as a bolus (200 mg/kg iv) and then
constant infusion (1). The trachea was intubated, and ventilation was
maintained with a respirator (Harvard). The heart was exposed
through a median sternotomy to facilitate electrode placement for
mapping. A heating lamp was directed to the heart to maintain
temperature at 37°C.
Electrophysiological methods. The sinus node was clamped, and
the atrial appendage was paced with a stimulator with constant-current
outputs at twice diastolic threshold with pulses of 2 ms. Pacing rate
was 200 beats/min to control heart rates. Ventricular pacing of one
pole of a multipolar needle in the normal zone employed an anode (7
cm2 stainless steel) in the abdominal muscle.
Recording of electrograms. Surface ECG leads were recorded
continuously. To record transmural signals, twenty-three 16-pole
plunge-needle electrodes (J. Kassell, Fayetteville, NC) were inserted
into the myocardium in the risk zone of the left anterior descending
coronary artery as previously reported (1, 2, 36). The interneedle
distance was 8 –15 mm depending on the size of the heart and
coronary artery anatomy.
Experimental protocol and arrhythmia induction. After confirmation of physiological blood gases and adequate anesthesia, the anterior
descending artery was ligated 1 cm from the left atrial appendage and
just distal to the first diagonal branch. This site spares the septum, so
our mapping array covers and surrounds the risk zone (1). Ischemia
was defined as a ⱖ45% decrease in bipolar electrogram voltage (1, 2,
28, 36); all data in vivo or in vitro are reported as “ischemia” when
this definition in vivo was met. We waited 60 min because infarct size
in the open-chest dog is then ⬃75% of the risk zone (2). We paced the
endocardium at the base, apical septum, and lateral free wall in the
normal zone to induce VT with up to four extrastimuli (2) (Fig. 2).
The effective refractory period (ERP), defined as the longest S1-S2
that fails to capture the ventricle, defines the S1-S2 (where S1 is drive
pacing and S2 is the 1st extrastimulus) of the induction protocol, and
subsequent extrastimuli have progressively shorter coupling owing to
pealing back of ERP by the prior extrastimuli.
Arrhythmia mapping. The three epicardial bipoles on each recording electrode were mapped (BARD Electrophysiology) utilizing a
personal computer-based system (Compaq Deskpro 286) with software that takes 64 channels of data at 12-bit resolution with a
sampling frequency of 1 kHz per channel filtering over 30 –300 Hz.
An additional customized computer (267-MHz Pentium II Gateway
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Xing, Dezhi, and James B. Martins. Triggered activity due to
delayed afterdepolarizations in sites of focal origin of ischemic ventricular tachycardia. Am J Physiol Heart Circ Physiol 287: H2078 –
H2084, 2004. doi:10.1152/ajpheart.00027.2004.—This study for the
first time systematically evaluated the site of origin of focal ventricular tachycardia (VT) induced 1–3 h after acute coronary artery
ligation in dogs. We determined whether delayed afterdepolarizations
(DADs) and triggered activity (TA) are more often recorded from
ischemic endocardium excised from focal sites of VT origin. A total
of 145 ␣-chloralose-anesthetized dogs were studied: in 54 dogs
without inducible VT, normal or ischemic endocardium was investigated in vitro; in 91 dogs, inducible VT was studied by threedimensional activation mapping, with in vitro study of 51 endocardial
foci compared with 40 endocardial ischemic sites not of VT origin.
Incidence of DADs (71% vs. 33%, P ⬍ 0.05) and TA (32% vs. 11%,
P ⬍ 0.05) was greater in ischemic than in normal Purkinje tissues.
Purkinje sites of origin of focal VT demonstrated the greatest frequency of DADs (92%, P ⬍ 0.05) and TA (75%, P ⬍ 0.05), with
repetitive TA predominating. Similar results were obtained in endocardial sites of origin. Action potentials were mildly depolarized and
prolonged in the focal sites of origin. These abnormalities were stable
up to 2.5 h of recording. This study demonstrated that DADs and TA
may underlie a majority of focal VTs in ischemic endocardium and
Purkinje tissue.
VENTRICULAR TACHYCARDIA DUE TO TRIGGERED ACTIVITY
correct for drift. Purkinje cells were identified by spontaneous phase
4 depolarization at cycle lengths ⬎1 s. Depolarization after phase 3 of
paced APs was defined as DAD. TA was defined as spontaneous
reproducible APs occurring at the peak of a DAD and linked to
previous stimulated DADs by cycle lengths ⬍1 s.
Statistics. Values are means ⫾ SE. Two-way ANOVA and Student’s t-test were employed for appropriate data. Pearson’s ␹2 test
analyzed frequencies of observations in groups. P ⬍ 0.05 was accepted as statistically significant.
RESULTS
Dogs with no inducible VT (n ⫽ 51) underwent extrastimuli
through S5, and ERP was 153 ⫾ 4 ms. Dogs with VT but with
excised tissues not taken from SOO (n ⫽ 43) were inducible
with S2 up to S5, and ERP was 150 ⫾ 3 ms; in 28 of these
dogs, induction of VT was sustained or nonsustained; in 15
dogs, VT accelerated to VF. Dogs with SOO (Fig. 1) excised
and studied in vitro (n ⫽ 51) were also induced with S2–S5,
and ERP was 156 ⫾ 3 ms: in 38 of these animals, VT was
inducible; in 13 dogs, VT accelerated to VF. All 94 dogs were
resuscitated, usually with burst pacing, so that mapping could
be performed to choose the SOO. Seventeen dogs with inducible VT were given pharmacological intervention in vivo,
which mainly consisted of adrenergic agonists and blockers.
The VTs described here were not present spontaneously as
previously reported after 24 h of ischemia (4, 6, 16, 19, 21).
Figures 2 and 3 show a typical induced focal Purkinje VT; the
complexes at the onset were slightly variable but then became
monomorphic VT with cycle length of 125 ms. Electrograms in
Fig. 2 show activation of all sites surrounding the focus
occurring within 57 ms (less than half the cycle length). The
first two VT complexes originate from the Purkinje focus
adjacent to the pacing site. The third VT complex originates at
an adjacent Purkinje site. The origin of the fourth complex is
distant from this electrogram grouping. In Fig. 3, the origin in
the Purkinje site rapidly activates the remaining layer, with
slower activation of the outer layers. Endocardial and Purkinje
foci of VT were distributed throughout the ischemic zone
(Fig. 1).
Figure 4 shows intracellular microelectrode measurements
from the endocardial preparation removed from the focal
Fig. 1. Distribution of focal ventricular tachycardia (VT)
on endocardial and Purkinje layers. Horizontal bars indicate
coronary artery ligation site at the anterior base of the heart;
left margin is the left anterior descending coronary artery.
Asterisks and numbers indicate electrogram recording sites
in the risk zone, with numbers indicating frequency (1 per
dog) of site of origin (SOO) of VT at each site.
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2000) software system allowed us to resolve the Purkinje signals from
the inner bipoles on each endocardial multipolar electrode by sampling at 3 kHz per channel filtering at 3–1,300 Hz (1). The bipoles
between Purkinje tissue and epicardium were spaced to record the
intervening midwall to account for transmural conduction.
Mapping analysis was done offline. The computer selected activation times by using the first, maximum rate of voltage development.
Electrograms are included in maps when uniformly and reproducibly
registered with each drive stimulus; there was no exclusion based
arbitrarily on a low cutoff voltage of electrograms. Electrotonic
potentials were considered transiently present when a ⬎75% reduction of voltage occurred in an electrogram, with extrastimuli or VT
complexes produced by short coupling intervals; such electrotonus
suggests local, functional block of activation. Isochrones were calculated and drawn by hand. VT mechanisms were standard and defined
as described elsewhere (1, 2, 36), including focal VT occurring when
the electrode recording the earliest SOO was surrounded on six sides
by other electrodes within 1–2 cm that recorded progressive and
gradually later activity with no late (⬎50% cycle) electrical activity
on adjacent sites.
Mapping was done twice: The first maps were quickly constructed
to determine tissues at the presumptive SOO of induced VT for
selection of tissues for the in vitro study. The second map was
constructed formally at a later time (the latter are reported) to confirm
whether the tissues studied in vitro were taken from SOO. In this
report, we consider VT mechanisms as endocardial focal or Purkinje
with an SOO excised for in vitro study vs. ischemic sites far from the
SOO of VT.
Intracellular recording techniques. After mapping, the heart was
excised and placed in Tyrode solution, with the electrode recording
the focal SOO of VT left in situ. Other normal and ischemic tissues
were taken from sites where Purkinje spikes were recorded. Tissue
(free-running 5-mm-long Purkinje strands or 5 ⫻ 5 ⫻ 2 mm endocardial sections) was excised from the area of the mapping electrode
and placed endocardial-surface-up in a 3-ml tissue bath (Warner
Instrument) that was superfused with 37°C solution at 9 ml/min.
Fibers were stimulated with a bipolar electrode at twice diastolic
threshold. Action potential (AP) was measured during pacing at 1.5–5
Hz. The most superficial cells were impaled with 3 M KCl-filled glass
capillary microelectrodes with tip resistances of 3– 41 M⍀. Microelectrodes were connected to a high-input-impedance preamplifier
(Axoclamp-2A, Axon Instruments, Foster City, CA). The bath was
grounded with an Ag-AgCl pellet. Potentials were recorded and stored
on a computer with the use of software (Axon Instruments) with data
filtered at 1 kHz and sampled at 2 kHz. Zero offsets are recorded to
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VENTRICULAR TACHYCARDIA DUE TO TRIGGERED ACTIVITY
Purkinje SOO (Figs. 2 and 3), which demonstrates single,
repetitive, and sustained TA at cycle length of 700 ms due to
DADs. Figure 5 shows intracellular recordings from another
Purkinje VT showing DADs and TA recorded from a cell with
phase 4 depolarization.
Table 1 summarizes experiments in this study with and
without inducible VT mapped in three dimensions. Purkinje
and endocardial focal mechanisms predominate because
visible epicardial collaterals were not ligated (36). The large
number of ischemic sites that were not at the SOO of focal
VT were excised from dogs with epicardial reentry or
remote SOO. Offline mapping confirmed the first mapping
for selection of tissues from the SOO of VT to be 56% (51
of 91 foci). Those sites not confirmed to be SOOs were
added to ischemic sites from dogs without inducible VT.
Incidence of DADs was greater in these ischemic sites than
in normal sites. In vitro SOO of VT demonstrated similar
high occurrence of DADs, but TA were observed more
frequently, especially in repetitive form. To mimic in vivo
conditions, TA was facilitated by isoproterenol superfusion,
but in one-fourth of ischemic tissues, especially Purkinje,
TA occurred without this drug. No early afterdepolarizations were observed. Spontaneous activity at cycle lengths
of 500 –700 ms was recorded from zero to two depolarized
tissues in all ischemic categories as previously reported in
older ischemic preparations (4, 8, 16, 19); it resolved spontaneously as superfusion persisted, and subsequently DADs
and TA were observed in each tissue.
The cycle length of TA induced in vitro (420 – 840 ms) was
longer than that of VT in vivo (100 –200 ms). Given the
limitations of mapping spatially (resolution of 1 cm3) as well as
the DADs and TA observed in many of the ischemic tissues not
at the SOO of focal VT, other cells within the immediate
region of a focus may also serve as alternate foci that, with the
others in adjacent areas, produced faster VT rates with similar
morphological appearance on the ECG and map (Fig. 2, comAJP-Heart Circ Physiol • VOL
pare VT complexes 2 and 3). Alternatively, the effects of time,
isolation, superfusion, and details of pacing and adrenergic
protocols could have reduced the rate of TA.
APs from Purkinje and endocardial tissues (Table 2) were
depolarized in ischemic sites but not to the extent reported in
other models (4, 8, 15, 19). Prolonged AP duration in Purkinje
and endocardial SOOs has been reported in tissues studied after
2 h of coronary occlusion followed by 22 h of reperfusion (12).
The time of recording after coronary occlusion (3.5 ⫾ 0.3 h) in
the SOO group was not different from that in the ischemic, but
the non-SOO, group (3.6 ⫾ 0.5 h).
Table 3 shows data after 1–3.5 h (mean 2 h) of recording in
vitro; APs from ischemic zones continued to be depolarized but
tended to shorten. At this later time, DADs and TA were as
commonly induced or more frequently induced than at initial
impalement. This was especially true of SOOs of VT. These
results suggest the persistent effect of the previous ischemia in
this tissue.
DAD voltages are influenced by isoproterenol in ischemic
Purkinje tissues in two ways. Isoproterenol increased DAD
amplitude in the same cells (P ⬍ 0.05, n ⫽ 6) at all pacing
cycle lengths; i.e., at cycle length of 500 ms, DAD increased
from 2.6 ⫾ 1.3 to 4.8 ⫾ 2.7 mV, and at 285 ms, DAD
increased from 3.5 ⫾ 1.3 to 5.4 ⫾ 2.0 mV. However, the drug
also altered the cycle length dependency. Without isoproterenol, the amplitude of DAD plateaued at a cycle length of 285
ms. With isoproterenol, DAD amplitude increased further; i.e.,
at 200 ms, DAD amplitude was 6.9 ⫾ 2.2 mV, as previously
shown in other tissues (34). TA was not more likely with faster
pacing, and no relation was observed between pacing cycle
length and coupling interval of the TA: the correlation coefficient was 0.38. In individual experiments with TA at more than
two pacing cycle lengths, no correlations were observed. These
data are consistent with previous studies of TA produced by
any intervention, except digitalis toxicity.
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Fig. 2. Surface ECG leads II and V5R show
the last 2 drive and 2 premature stimulated
(ⴱ) complexes followed by 4 complexes of
VT. Intracardiac electrograms from Purkinje
(P), endocardium (E), and overlying (O) or
surrounding, in various directions such as
east (E), north (N), northwest (NW), southwest (SW), or south (S), focus (F) of VT.
Second drive complex shows Purkinje potentials marked by downward arrows in P-F,
P-SW, and P-S. Premature stimulation delays muscle from Purkinje at P-F but produces insufficient conduction delay to suggest reentry. Vertical lines mark onset of the
surface QRS of VT complexes 1 through 3.
Upward arrows mark earliest Purkinje potentials during complexes of VT, with subsequent activation of all surrounding areas,
which show conduction delay less than half
the cycle length of the VT. Downward arrows indicate conduction difference between
Purkinje and lead II.
VENTRICULAR TACHYCARDIA DUE TO TRIGGERED ACTIVITY
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DISCUSSION
This study for the first time systematically evaluated the
SOO of focal VT induced after 1–3 h of acute myocardial
ischemia. Focal VT frequently originates in endocardial and
Purkinje tissue underlying the ischemic zone (1, 2). Our results
showed that the tissue at the SOO of focal Purkinje VT more
commonly demonstrated DADs and TA in vitro with and
without isoproterenol superfusion. The AP characteristics observed in ischemic sites and SOOs were consistent with mild
depolarization and AP duration prolongation. These changes
persisted for hours of superfusion.
Our model is unique among in vivo studies utilizing threedimensional computer-assisted activation mapping (1, 2) because we attempted to record Purkinje signals at each multipolar needle. In vivo studies of spontaneous VT have been
reported in many animal models focusing on the acute ischemic period defined as the first 2– 4 h (33). Acute ischemia may
produce VT and VF, which are thought to be reentry in the first
2–10 min (11, 25) and reentry or automaticity or TA thereafter.
Detailed three-dimensional mapping studies in humans (25)
and animals (11, 25, 35) also suggest the possibility of focal
mechanisms, which may be TA because of the absence of
adjacent conduction delay implicating reentry. Occasional PurAJP-Heart Circ Physiol • VOL
kinje potentials have been recorded before the onset of premature ventricular contractions (10) in the first hours after coronary artery occlusion, although three-dimensional mapping
techniques in the cat demonstrated that premature ventricular
contractions and VT originated from 24% (25) to 100% (35) of
focal endocardial sites. Even when macroreentry was recorded,
focal VT was observed to maintain VT or transition to VF (25).
None of these laboratories studied endocardial tissues from
SOOs in vitro.
We previously showed that Purkinje potentials were recorded at the origin of 60% of VT complexes in the first 30 min
after coronary artery occlusion (1). In the present study, we
continued to study inducible VT in the dog after the first hour
following coronary artery occlusion. This stable VT may be
studied with interventions (2). Although the infarction process
may be ongoing (5), we did not observe further increases in
infarct size after the first hour of observation (2, 36). It is not
clear whether this VT would occur spontaneously, although we
occasionally saw a spontaneously occurring morphology of
VT, which was induced later. We observed Purkinje signals
⬃50% of the time at the endocardial origin of induced focal
VT. We observed epicardial reentry frequently in this model
(⬃25% of inducible VTs), especially when we intentionally
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Fig. 3. Surfaces of activation of the anterior left ventricular wall of VT complex 2 shown in Fig. 2. On each rectangle, top is located
at the base of the heart, and left margin is located at the left anterior descending coronary artery. Epicardial (EPI), subepicardial
(S-EPI), midwall, subendocardial (S-ENDO), endocardial (ENDO), and Purkinje (PURK) surfaces are shown with numbers
indicating time (in ms) before or after onset of the surface QRS at 0. Isochrones are drawn every 20 ms, with earliest activity
(yellow) recorded in the Purkinje layer 34 ms before the QRS. Subsequent to activations after the QRS in darker colors, with the
latest QRS activated 80 ms on the epicardium, there is no retrograde epicardial-to-endocardial activation, eliminating reentrant
excitation originating from the epicardium.
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VENTRICULAR TACHYCARDIA DUE TO TRIGGERED ACTIVITY
ligated visible epicardial collaterals (36). Our mapping methods alone did not allow us to exclude microreentry; however,
published examples suggest that our methods would allow
reentry by showing a rotorlike activity. When we also used
pacing methods such as entrainment, our focal VTs did not
show any of the same characteristics. The present data also
provide an additional argument for a nonreentrant mechanism.
Focal VT may be due to a point source of cells characterized
by automaticity or TA; those exhibiting automaticity are suppressed by previous electrical activity. In previous studies, VT
with automaticity or TA was slower and irregular, occurring
later in the course of coronary occlusion (4, 6, 16, 19, 21); the
VTs reported here were induced by prior stimulation that was
faster, regular, and limited to endocardial focal sites. The
Fig. 5. Intracellular recording performed
with isoproterenol-containing solution. Top
left: DAD (10 mV) produced at pacing cycle
of 400 ms and 1 TA at 840 ms. Top right: at
pacing cycle of 400 ms, DAD resulted in
repetitive TA, which gradually decreased in
voltage; phase 4 depolarization was observed. Bottom left: pacing cycle of 400 ms
produced a single DAD of 9 mV; phase 4
depolarization was observed. Bottom right:
pacing cycle of 380 ms produced sustained
TA at 630 –720 ms.
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Fig. 4. Intracellular recording performed
with solution (equilibrated with 95% O2-5%
CO2) containing (in mM) 125 NaCl, 24
NaHCO3, 4.5 KCl, 1.8 CaCl2, 0.5 MgCl2,
0.25 Na2HPO4, and 5.5 dextrose (pH 7.4).
Endocardium was excised from the focal site
of origin of the Purkinje VT shown in Figs.
2 and 3. Long horizontal line indicates level
of zero potential; upward arrows indicate
pacing stimuli resulting in action potentials.
Calibrations at right of each trace indicate
2 s (horizontal) and 20 mV (vertical). Downward arrows indicate delayed afterdepolarization (DAD), which may reach threshold,
initiating triggered activity (TA). Top left:
DAD (4 mV) produced at baseline with
pacing cycle of 380 ms. Top right: with
isoproterenol superfusion, first DAD resulted 1 TA; no phase 4 depolarization was
observed. Bottom left: with isoproterenol superfusion, pacing at cycle of 600 ms produced DAD of 2 mV, but 5 occurrences of
TA were preceded by DADs, which gradually decreased in voltage. Bottom right: with
isoproterenol superfusion, pacing cycle of
380 ms produced sustained TA at 630 –720
ms.
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VENTRICULAR TACHYCARDIA DUE TO TRIGGERED ACTIVITY
Table 1. DADs and TA recorded from
Purkinje and endocardium
Table 3. Ischemic Purkinje action potential characteristics
TA, %
n
DADs, %
Total
Repetitive
11
32*
75*†
6
12
61*†
14
44*
73*†
14
26
52*†
Purkinje
Normal
Ischemic (not SOO)
SOO
18
32
28
33
71*
92*
Endocardium
Normal
Ischemic (not SOO)
SOO
14
30
23
22
77*
91*
Purkinje-muscle junctional cells may be particularly susceptible to TA, especially when Purkinje APs are prolonged (20).
Focal VT may also be due to microreentry, which may involve
abnormal Purkinje tissue alone (32), Purkinje-muscle preparations with ischemia-like conditions (7, 31), or even epicardium
(38), although chronically damaged tissue must be exposed to
isoproterenol for the latter. In the present study, we carefully
looked for evidence of reentry during focal VT as well as
substantial conduction delay of 50% of the cycle length at or
surrounding a focus (38); we found none. However, in this
study, we also have cellular evidence of greater frequency of
TA due to DADs in endocardial tissue to confirm the hypothesis that focal VT originated at that site.
In vitro studies of Purkinje fibers have been reported by
other laboratories but rarely in the first hours of coronary artery
occlusion (17), because VT recorded in dogs studied 24 and
48 h after coronary artery occlusion is much more stable. In the
latter, fibers were removed from visibly infarcted myocardium
with minimal or no mapping (4, 6, 13, 14, 16, 17, 19). In vivo
and in vitro correlation studies showed that spontaneous VT
originates in Purkinje tissue. Such fibers are severely depolarized at ⫺60 to ⫺80 mV with very prolonged APs and abnormal automaticity (16, 17, 19) or DADs, which may be facilitated with Ca2⫹ or catecholamine superfusion (4, 13). These
abnormalities occur after 6 h of occlusion (5), with only
Table 2. Action potential characteristics
n
MDP,
mV
APA,
mV
Overshoot,
mV
APD90,
ms
APD50,
ms
18⫾3
20⫾5
16⫾2
269⫾12
256⫾10
284⫾7*
188⫾10
155⫾9*
195⫾8*
21⫾3
19⫾3
15⫾2
198⫾13 140⫾11
225⫾8
155⫾7
256⫾10* 165⫾9
Purkinje
Normal
Ischemic (not SOO)
SOO
18 92⫾2 99⫾5
32 82⫾2* 97⫾4
28 84⫾2* 96⫾4
Normal
Ischemic (not SOO)
SOO
14 83⫾3
30 82⫾2
23 77⫾3
Endocardium
93⫾5
95⫾3
90⫾3
Values are means ⫾ SE; n, number of dogs. MDP, maximum diastolic
potential; APA, action potential amplitude; APD90 and APD50 action potential
duration at 50% and 90% repolarization. * P ⬍ 0.05 vs. normal.
AJP-Heart Circ Physiol • VOL
APA,
mV
Overshoot,
mV
APD90,
ms
APD50,
ms
86⫾3
84⫾4
97⫾5
95⫾5
17⫾3
16⫾3
258⫾6
233⫾4
179⫾5
167⫾3
Values are means ⫾ SE; n ⫽ 13.
depolarization and AP shortening (5, 17) early, similar to the
timing of the present studies. They clearly show mildly depolarized Purkinje tissues with TA more frequently observed at
the SOO of induced VT documented by mapping, which
implies causality.
TA due to DADs occurs in tissues with Na⫹ or Ca2⫹
overload, such as that produced by digitalis intoxication or
high external Ca2⫹ (32), although Purkinje fibers may be
particularly susceptible (15, 30). In coronary sinus, mitral
valve, and some atrial preparations, catecholamines may also
produce TA (32). Ischemia serves as a typical model as well,
because the acute process produces intracellular Ca2⫹ (18) as
well as Na⫹ (14) overload. The addition of catecholamines
may also facilitate TA but is not required.
APs (Table 2) giving rise to TA show mild depolarization, as
shown in previous studies (5, 17). The overshoot is preserved,
in contrast to previous ischemic studies, suggesting that Na⫹
current depression is not severe. Therefore, the Na⫹ gradient
may be adequate as a charge carrier for TA. Taken together,
these findings suggest that the SOO of Purkinje VT may be less
ischemic, perhaps better nourished by cavity blood (33). Thus
our model of TA due to DADs is dissimilar to other models of
this mechanism occurring at depolarized levels of ⫺76 to ⫺84
mV. Otherwise, DADs observed in ischemia usually are single,
unless TA is present (Figs. 4 and 5) (4, 32). The voltage of
DADs increased with pacing cycle length to a plateau at 285
ms, unless isoproterenol was superfused (32). However, cycle
length of pacing did not predict the presence or coupling
interval of single TA or cycle length of repetitive TA. In
general, induced TA in vitro was self-terminating, with
slowing before cessation, probably resulting from activation
of the Na⫹-K⫹ pump causing recovery of the membrane
potential (32).
Limitations. It is possible that the very commonly recorded
TA in ischemic tissues is not different from that recorded in the
SOO of VT. We cannot totally exclude this possibility. However, the almost double frequency of TA, which was more
frequently sustained in Purkinje tissue from the SOO of VT,
makes a reasonable causal argument. The very common frequency of TA in all ischemic tissues suggests that multiple
cells in the vicinity of that one cell from which we recorded
were also triggered and, therefore, could produce faster VT in
vivo than the TA recorded in vitro. Further pharmacological
proof of a causal relation in VT due to TA and DADs should
be sought; i.e., a Ca2⫹ entry blocker might block inducible
focal VT in vivo and TA in vitro. Treatment with such agents
in this model could lead to trials of patients in the coronary care
unit (9, 29). Case reports have suggested the benefit of Ca2⫹
antagonists (22, 37) in patients with normal systolic function.
Conclusions. Acute myocardial ischemia promotes DADs in
endocardium and Purkinje tissue. TA due to DADs occurs
frequently in acutely ischemic tissues, especially at the sites of
287 • NOVEMBER 2004 •
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A total of 145 dogs were studied; n, number of tissues. DADs, delayed
afterdepolarizations; TA, triggered activity; normal, nonischemic endocardial
sites; ischemic, ischemic sites defined in vivo from dogs with or without VT;
SOO, sites of origin of focal ventricular tachycardia. * P ⬍ 0.05 vs. normal
sites; †P ⬍ 0.02 vs. noninducible or not SOO sites. Approximately 75% of
data obtained with isoproterenol superfusion.
Initial
1–3.5
MDP,
mV
H2084
VENTRICULAR TACHYCARDIA DUE TO TRIGGERED ACTIVITY
focal origin of VT. These results support the hypothesis that
DADs and TA may underlie a majority of focal VTs in
ischemic endocardium and Purkinje tissue.
19.
GRANTS
20.
This study was supported by grants from the American Heart Association,
Iowa Affiliate (Des Moines, IA), and the Veterans Administration Medical
Center (Iowa City, IA).
21.
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