Download Arrhythmogenesis by single ectopic beats originating in the Purkinje

Am J Physiol Heart Circ Physiol 299: H1002–H1011, 2010.
First published July 9, 2010; doi:10.1152/ajpheart.01237.2009.
Arrhythmogenesis by single ectopic beats originating in the Purkinje system
Makarand Deo,1 Patrick M. Boyle,2 Albert M. Kim,3 and Edward J. Vigmond2
1
Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan; 2Department of Electrical and Computer
Engineering/Centre for BioEngineering Research and Education, University of Calgary, Calgary, Alberta, Canada; and
3
Cardiac Electrophysiology Section, VA Boston Healthcare System, West Roxbury, Massachusetts
Submitted 24 December 2009; accepted in final form 6 July 2010
computer modeling; bundle branch reentry; afterdepolarizations
(EADs) are positive inflections in
membrane potential (Vm) that occur during the late phases of
the action potential (AP), before full repolarization. If sufficiently large, EADs can produce triggered activity and promote
reentrant arrhythmias, including bundle branch reentrant ventricular tachycardia (BBRT) (1). At the ionic level, EADs
result from decreased outward current, increased inward current, or combinations of the two. Electrophysiological studies
have been performed using pharmacological agents and slow
pacing modes to cause initial AP prolongation via rapidly
activating K⫹ current reduction (cesium, quinidine) (53),
slowed Na⫹ current (INa) inactivation (anthopleurin, veratradine) (10), and increased L-type Ca2⫹ current activity (BAY K
8644) (19). For a detailed description of ionic mechanisms of
EADs, refer to the review by Volders et al. (48).
Ectopic beats arising from EADs are thought to be more
common in the Purkinje system (PS) than in the ventricular
myocardium for several reasons. EADs are easily induced in
Purkinje cells by application of pharmacological agents that
EARLY AFTERDEPOLARIZATIONS
Address for reprint requests and other correspondence: E. J. Vigmond, Dept.
of Electrical and Computer Engineering/Centre for BioEngineering Research
and Education, Univ. of Calgary, 2500 Univ. Dr. NW, Calgary, Alberta,
Canada TZN 1N4 (e-mail: [email protected]).
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prolong the AP, which is already intrinsically longer than in
typical ventricular myocytes (39, 40). In contrast, coupled
ventricular cells have a shorter AP duration (APD) and become
reexcitable, while the PS is still repolarizing and susceptible to
EADs. Moreover, cells in the PS have a high membrane
resistance, which allows small charge displacements to cause
large changes in Vm (37). Finally, since Purkinje cells are only
coupled in one dimension, there is reduced electrotonic suppression of myocardial EAD propagation.
Persistent bundle branch reentry (BBR) as a mechanism of
sustained tachycardia has been observed in patients with significant conduction system impairment (6, 42, 50), which is
often manifested as His-ventricle (H-V) interval prolongation,
bundle branch block (BBB) QRS configuration, or both. Most
BBRT studies have reported prolonged H-V interval during
sinus rhythm, indicating underlying conduction abnormalities,
but the pathology has also been observed in patients with
idiopathic isolated conduction system disease and no apparent
structural heart abnormalities (17, 38). Furthermore, BBRT has
also been reported in patients with apparently normal His-PS
conduction (23). These patients exhibited functional transient
abnormalities in the conduction system that provided a substrate for reentry, such as temporary conduction block (CB) in
the bundles. Overall, the exact mechanisms of BBRT initiation
are not well understood.
Several experimental (14, 24) and computer modeling (2,
28, 37, 49) studies have documented how EADs generated in
PS cells propagate to coupled myocytes and induce ectopic
activity. However, the behavior of the PS changes significantly
when it is coupled to a large mass of ventricular muscle due to
electrotonic interactions and loading effects. Thus the EAD
initiation and propagation mechanisms must be revisited in an
anatomically realistic three-dimensional (3D) cardiac model.
Previously, our laboratory demonstrated that the PS is involved in initiation and maintenance of shock-induced arrhythmias, triggering postshock activations and providing alternative pathways for reentrant circuits (12), but it remains unclear
whether triggered activity originating in Purkinje cells may
induce reentry. Experimental difficulties in detecting and isolating Purkinje cells in subendocardial layers have restricted
measurements of the intact PS. In this paper, we use a 3D
computer model to investigate possible mechanisms of triggered activity and effects of conduction system disorders on
arrhythmia initiation. We hypothesize that a single ectopic beat
in the distal PS, if properly timed, can lead to arrhythmogenesis
in ventricular tissue with impaired conduction or by interacting
with sinus excitation. Furthermore, we hypothesize that a
single EAD originating in the PS can establish BBRT in
ventricles with reduced excitability and/or impaired conduction, whether or not functional BBB is present. We systematically examined conduction system abnormalities, such as
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Deo M, Boyle PM, Kim AM, Vigmond EJ. Arrhythmogenesis by
single ectopic beats originating in the Purkinje system. Am J Physiol
Heart Circ Physiol 299: H1002–H1011, 2010. First published July 9,
2010; doi:10.1152/ajpheart.01237.2009.—Cells in the Purkinje system (PS) are known to be more vulnerable than ventricular myocytes
to secondary excitations during the action potential (AP) plateau or
repolarization phases, known as early afterdepolarizations (EADs).
Since myocytes have a lower intrinsic AP duration than the PS cells
to which they are coupled, EADs occurring in distal branches of the
PS are more likely to result in propagating ectopic beats. In this study,
we use a computer model of the rabbit ventricles and PS to investigate
the consequences of EADs occurring at different times and places in
the cardiac conduction system. We quantify the role of tissue conductivity and excitability, as well as interaction with sinus excitation,
in determining whether an EAD-induced ectopic beat will establish
reentrant activity. We demonstrate how a single ectopic beat arising
from an EAD in the distal PS can give rise to reentrant arrhythmia; in
contrast, EADs in the proximal PS were unable to initiate reentry.
Clinical studies have established the PS as a potential substrate for
reentry, but the underlying mechanisms of these types of disorder are
not well understood, nor are conditions leading to their development
clearly defined; this work provides new insights into the role of the PS
in such circumstances. Our findings indicate that simulated EADs in
the distal PS can induce premature beats, which can lead to the
tachycardias involving the conduction system due to interactions with
sinus activity or impaired myocardial conduction velocity.
ARRHYTHMOGENESIS, ECTOPIC BEATS, AND THE PURKINJE SYSTEM
temporary unidirectional BBB due to ectopic activity originating in the PS. We also studied how variations in tissue
excitability and conductivity affect reentry initiation.
METHODS
Governing Equations and 3D Model
Cardiac electrical activity was described by the monodomain formulation (44):
ⵜ · ␴m ⵜ Vm ⫽ ␤Im
(1)
Im ⫽ Cm
dVm
dt
⫹ Iion(Vm,␯) ⫺ Itrans
(2)
where Cm is the membrane capacitance per unit area, and Iion is the
current density through ion channels, which depends on Vm and
several other variables that are represented by ␯, as described in the
rabbit ventricular AP model developed by Mahajan et al. (26). Itrans is
the transmembrane stimulus current density, as delivered by an
intracellular electrode and removed by an adjacent extracellular electrode.
The system of equations was solved by the finite-element method
using the CARP software package (46), with geometry and fiber
oriention based on rabbit ventricular data (43). The system comprised
⬃550,000 nodes with element edge lengths on the order of 300 ␮m.
Equation 1 is a parabolic equation, which was decoupled from the set
of ordinary differential equations (Eq. 2) describing ionic currents.
Both sets of equations were solved explicitly, as detailed elsewhere
(47). Simulations were carried out on four cores of an HP Opteron
cluster (2.4 GHz) running Linux with 2 GB of physical memory per
node.
Modeling the ventricular conduction system. To model an anatomically realistic heart, a one-dimensional finite-element branching Purkinje network explained in Ref. 45 was implemented, as shown in Fig. 1A.
This model enforced conservation of current at Purkinje-myocardial
junctions (PMJs). At each PMJ, the Purkinje cell was coupled to n
myocytes within a certain radius (rPMJ) by a fixed resistance RPMJ.
The current load on each terminal Purkinje cell was calculated by
summing the individual currents flowing into each junctional myocyte
and scaling the total by a loading factor (KPMJ) to account for sink
effects from surrounding tissue that was not directly coupled (4).
Thus, while the current injected into a particular myocyte is derived
Fig. 1. Computer model. A: three-dimensional
model of rabbit ventricles with branching Purkinje system (PS). Colors indicate membrane
potential (Vm; see the color bar). The same color
scheme is used throughout the paper. B: excitation of the ventricles by the PS during normal
sinus rhythm. Colors are as in A. C: action potentials (APs) in various parts of the conduction
system. AP duration (APD) is longer in the bundle of His and bundle branches than in distal
regions due to electrotonic interaction between
terminal Purkinje cells and coupled myocytes.
PMJ, Purkinje-myocardial junction.
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where Im is membrane current, ␤ is the tissue surface-to-volume ratio,
and ␴៮m is the monodomain conductivity tensor, which is the harmonic
mean of the intracellular and extracellular conductivity tensors. The
nominal extracellular conductivities in the longitudinal and transverse
directions were 0.625 and 0.236 S/m, respectively, and the corresponding intracellular conductivities were 0.174 and 0.019 S/m [based
on experiments by Clerc (9)].
Nonlinearities arising from the current-voltage relationship across
the membrane were described by:
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ARRHYTHMOGENESIS, ECTOPIC BEATS, AND THE PURKINJE SYSTEM
from the straightforward Ohmic relationship, the load on a particular
cable ending at xe is given by:
IL ⫽ KPMJ
兺n
␾i(xe) ⫺ ␾iM (xn)
RPMJ
(3)
where IL is current load, ␾i(xe) is the intracellular potential of the
terminal Purkinje cell, and ␾M
i (xn) is the intracellular potential of the
nth myocardial node inside the junctional radius. Model details can be
found elsewhere (4, 12, 45).
PS potentials were calculated using, from the parabolic equation:
␴i
⭸ 2␾ i
⭸ s2
⫽ ␤Cm
⭸ Vm
⭸t
⫹ Iion(Vm,v)
(4)
Ectopic Activity Triggered in the Distal PS
Ectopic activity was initiated in the left and right sides of the
distal PS. The side of ectopic activity was chosen near PMJs,
as observed in clinical studies (24). For the values of tEB
between 100 and 400 ms, three different scenarios were observed.
Failed ectopic activity. Ectopic beats induced when both the
distal PS and ventricular myocytes were refractory due to the
sinus rhythm failed to initiate ectopic activity (tEB ⬍ 190 ms).
These stimuli elevated the potential of refractory tissue, but
could not trigger new APs. This behavior is illustrated in Fig. 2B
(indicated by “F”).
Premature excitation and CB. If the distal PS and the
myocardium were excitable, but the proximal PS (His bundle
and branches) remained refractory (190 ms ⱕ tEB ⬍ 380 ms),
the ectopic beat excited the myocardium and propagated retrogradely to nearby parts of the distal PS. However, activation
was blocked at the refractory bundle branch, so retrograde
excitation was not conducted to the other side of the PS. Figure
2A shows examples of ectopic activity triggering a premature
AP in the PS.
In Fig. 3, an ectopic beat was induced in the right distal PS
at tEB ⫽ 370 ms. Excitation propagated into the right ventricle
(RV) (Fig. 3A) by anterograde propagation, but retrograde
conduction into the RBB was blocked (Fig. 3B) due to refractoriness. Individual AP traces in the right PS (see Fig. 3E)
clearly show the conduction failure in the RBB (shown by the
dotted line). The asterisk indicates the location of CB in the
RBB. Thus the left ventricle (LV) was excited after 45 ms by
transmission across the septum, instead of by activity from
within the PS. Shortly thereafter, LV activations propagated
Initiation of EADs in PS Cells
Ectopic activity in the distal PS was produced by injecting
current in five contiguous PS nodes near the PMJs, as described in
previous studies (28). In an alternative set of simulations, the PS
was excited in the proximal region adjacent to the left (LBB) and
right bundle branches (RBB). This approach, in contrast to altering
the ionic model to produce genuine EADs, allowed for fine-grain
control of the timing and location of simulated ectopic beats. Sinus
beats were simulated by injecting current at the bundle of His at a
fixed interval (tHis), which was varied between 600 and 1,000 ms
in steps of 50 ms. The interval between the last sinus beat and the
ectopic beat (tEB) was varied from 100 to 400 ms in steps of 10 ms.
The time between an ectopic beat being triggered in one bundle
branch and the same activation being picked up in the other was
defined as tBB, which measures the ventricular conduction delay
for either right bundle-ventricle-left bundle or left bundleventricle-right bundle pathways. To establish BBR, the effective
path length of the reentrant circuit in our model was increased by
reducing the conductivities and sodium channel conductance (gNa)
in both the PS and myocardium. Myocardial (␴VM) and PS conductivities (␴PS) were varied between 20 and 50% of normal, while
myocardial gNa was varied between 25 and 70%, and PS gNa was
kept constant at 50%.
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Fig. 2. A: ectopic activity had varying consequences, depending on the interval
between the last sinus beat and the ectopic beat (tEB): failure to elicit AP (tEB ⫽
180 ms), triggered activity with conduction block (CB) in the distal PS (tEB ⫽
190 ms), or triggered activity with CB in the bundle branch or proximal PS
(tEB ⫽ 180 ms). B: outcome of the ectopic activity originating in the right
proximal and distal PS at a range of tEB. F, failed ectopic activity; CBd, CB in
the distal PS; CBp, CB in the proximal PS; PE, propagation of the ectopic
activity without CB.
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where s is a vector along the fiber (45), and ␴i is intracellular
conductivity.
The DiFrancesco-Nobel equations (13) were used to govern membrane electrical activity in the PS. This allowed the model to reflect
the distinct electrophysiological features between Purkinje cells and
ventricular myocytes. Sodium conductance in the DiFrancesco-Nobel
model was increased threefold (5) to increase maximum upstroke
velocity (⳵Vm/⳵t) in uncoupled cells from 169 to 380 mV/ms, which
is closer to the in vitro value reported by Lu et al. (25). Purkinje cell
radius was set to 15 ␮m, and intracellular conductivity was set to 1.5
S/m to achieve the conduction velocity (CV) ratio of 4.4 with
reference to the myocardium (4), which is within the experimental
range (11).
Figure 1B shows ventricular excitation by the PS during normal
sinus rhythm. Parameters for sodium conductance, tissue conductivity, and gap junction resistance were adjusted to reproduce normal
ventricular activation patterns recorded during sinus rhythm (33). PMJ
parameters were tuned to obtain realistic transmission characteristics
(51), with retrograde propagation delays much shorter (⬇0.96 ms)
than anterograde delays (⬇9.69 ms). Figure 1C shows APD variation
between different parts of the system. Moving from the His bundle to
the distal branches of the PS, APD was gradually abbreviated until the
terminal cells at PMJs, which had APDs nearly as short as coupled
myocytes. This feature, caused by electrotonic loading at the interface
between tissues, made the PS an ideal substrate during reentry
establishment.
RESULTS
ARRHYTHMOGENESIS, ECTOPIC BEATS, AND THE PURKINJE SYSTEM
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retrogradely into the left PS (Fig. 3C), but reentry into the right
PS was prevented due to CB in the right BB (Fig. 3D). In other
cases (190 ms ⱕ tEB ⬍ 300 ms), retrograde activation did not
occur as in Fig. 3C due to residual refractoriness in the distal
PS (indicated by “CBd” in Fig. 2B).
Premature excitation with no CB. After 380 ms of recovery
from sinus excitation, bundle branches were excitable, along
with the distal PS network. Ectopic beats induced after this
instance (tEB ⱖ 380 ms) excited both the coupled ventricular
tissue and the proximal PS. PS-enabled activation of the other
ventricle occurred 40 ms after the ectopic beat. No CB was
observed in the PS.
Ectopic Activity Triggered in the Proximal PS
APDs in the proximal PS are longer than the distal PS due
to myocardial loading. Thus ectopic activity could not be
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initiated in the proximal PS branches for tEB ⱕ 300 ms (see
Fig. 2B). As above, functional CB was observed in the bundle
branches (“CBp”) for 300 ms ⱕ tEB ⬍ 380 ms, but CB did not
occur in the distal PS for any ectopic beats originating in the
proximal PS. Excitation patterns from premature stimuli with
tEB ⱖ 380 ms was similar to those observed for ectopic beats
originating in the distal PS.
Induction of Reentry by an Ectopic Beat Interacting with
Sinus Activity
When a sinus beat occurred while the tissue or part of the
tissue was still recovering from a premature beat, the interactions were complex. The sinus beat was conducted by only one
bundle branch due to refractoriness in the other, thus only one
ventricle was excited. Excitation propagated to the unexcited
ventricle through the myocardium, resulting in a delay. If the
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Fig. 3. Temporary CB in the PS. A: 372 ms. An ectopic beat triggered an AP in the right distal PS. Excitation spread to right ventricle (RV; white arrow) and
throughout the right distal PS (black arrow). B: 394 ms. The proximal right bundle branch (RBB) was still refractory, which caused temporary CB. C: 425 ms.
Excitation spread through myocardium across the ventricular to reach the left ventricle (LV) and excited the left distal PS. D: 432 ms. The excitation spread
through the left PS, and the left bundle branch (LBB), but the RBB was refractory, causing another temporary CB. E: individual AP traces (1–5) from five
locations show retrograde conduction failure (dotted line) in the RBB. *The occurrence of CB at the corresponding location. P-V, anterograde conduction from
PS to myocardium; V-P, retrograde conduction from myocardium to PS; P-P, retrograde conduction within the PS. Times are relative to the last His stimulation.
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ARRHYTHMOGENESIS, ECTOPIC BEATS, AND THE PURKINJE SYSTEM
680 ms) failed to propagate at all beyond the bundle branches.
For intermediate cases (680 ms ⱕ tHis ⱕ 1,000 ms), refractoriness in the RBB led to tachycardias with the RBB block
morphology, as illustrated in Fig. 4. For later sinus beats
(tHis ⬎ 1,000 ms), if interactions resulted in an arrhythmia, the
morphology was a tachycardia without BBB. Similar behavior
was observed when the ectopic beat originated in left PS (not
shown). Premature excitation spread through the LV and septum to reach the RV, producing asymmetric refractoriness in
the bundles with the LBB nonexcitable. The sinus beat coming
down the His bundle within 300 –500 ms after the ectopic beat
was thus conducted only through the RBB, resulting in left
BBB morphology.
In contrast, simulations with ectopic activity in the proximal
PS did not result in reentry. Since the values of tEB associated
with triggered activity for such stimuli were significantly
higher (ⱖ300 ms), the distal PS and both ventricles were
excitable and conducted the premature beats without CB. Thus,
when the following sinus beats interacted with these activation
patterns, there was no asymmetry between the LV and RV, and
reentry was avoided.
Fig. 4. Reentry induced by an ectopic beat. A: 705 ms. A sinus beat originated at the His bundle at a fixed interval (tHis) ⫽ 700 ms (black arrow), following an
ectopic activation in the right PS (tEB ⫽ 370 ms). B: 731 ms. Due to refractoriness in the RBB from the premature beat, sinus activation propagated into the
left PS and ventricle but not into the right PS due to temporary CB. C: 800 ms. Activation spread across the septum from LV to RV, and the right distal PS,
now fully excitable, was activated by retrograde propagation (white arrow). D: 860 ms. Reentry was initiated. E: individual APs at various locations in the PS.
Traces 2 and 3 show conduction of the sinus beat in the LBB, while traces 4 and 5 show CB in the RBB (indicated by asterisks). Dotted line indicates the instance
of sinus beat. Labels are as in Fig. 3.
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PS in that ventricle was excitable by the time this delay was
elapsed, retrograde conduction occurred, forming a reentrant
circuit.
One such scenario is summarized in Fig. 4. An ectopic beat
induced in the right distal PS (tEB ⫽ 370 ms) produced a
premature ventricular depolarization. During the next sinus
activation at 700 ms (Fig. 4A), the left bundle was excitable
and conducted the His activation (Fig. 4E, traces 2 and 3), but
the right bundle was still refractory and blocked conduction
into the right distal PS (Fig. 4B). AP traces 4 and 5 in Fig. 4E
show CB in the RBB (indicated by asterisks). Consequently,
the sinus beat only activated the LV (Fig. 4B, white arrow). By
800 ms, activation reached the RV by transseptal conduction,
and retrograde propagation into the right distal PS occurred
(Fig. 4C). At this point, the RBB was no longer refractory, and
excitation continued through the bundles and left distal PS,
establishing a reentrant circuit (Fig. 4D). Thus unidirectional
block in the RBB due to an ectopic beat provided the necessary
substrate for reentry for the next sinus activation.
For ectopic activity in the right distal PS (tEB ⫽ 370 ms, ␴PS
and ␴VM at 33.33% of base values), early sinus beats (tHis ⬍
ARRHYTHMOGENESIS, ECTOPIC BEATS, AND THE PURKINJE SYSTEM
Reentry Induction by Ectopic Beat in Presence of
Slow Conduction
BBRT
Figure 6 shows a typical activation sequence during successful BBRT induction by ectopic activity (tEB ⫽ 370 ms) in the
right distal PS. Excitation spread through the right distal PS
(traces 1 and 2 in Fig. 6E) and the RV (white arrow, Fig. 6A),
but retrograde CB occurred in the RBB (asterisk in trace 3 in
Fig. 6E). Myocardial excitation reached the LV by transseptal
conduction (black arrow, Fig. 6B). The left PS was activated by
retrograde propagation 165 ms after the ectopic beat (trace 4 in
Fig. 6E). Due to slow conduction through the PS and myocardium, activations reached the RBB, now excitable, 185 ms
after the ectopic beat (Fig. 6C, and trace 5 in Fig. 6E), and the
BBRT circuit was established by propagation into the right PS
and RV (denoted by a two-way arrow between traces 1 and 3
in Fig. 6E). Thus the anterograde and retrograde limbs of the
BBRT circuit are formed by the RBB and LBB, respectively,
as shown schematically in Fig. 7.
Interestingly, BBRT was not observed for ectopic activity
originating in the left or right proximal PS. In this case, the
ectopic activity spread rapidly through the entire distal PS,
leading to near-simultaneous excitation of the LV and RV.
This reduced the path length of the reentrant circuit, making
the establishment of BBRT impossible.
Classification Based on Conduction Time
To quantify the effects of slowed ventricular conduction, we
looked at the time between an ectopic beat in one bundle
branch and the associated wave front exciting the other bundle
branch. Figure 8A classifies events based on tBB for ectopic
activity in the right PS (tEB ⫽ 370 ms). In the scenario of just
the CB in RBB, the average tBB was 109 ⫾ 15 ms (n ⫽ 10). To
produce tachycardia involving the conduction system, considerable slow conduction was required in the tissue with an
average tBB ⫽ 138 ⫾ 0.7 ms (n ⫽ 2), whereas BBRT was
produced at extremely slow conduction velocities in myocardial mass as well as PS. The average tBB recorded in the cases
with BBRT was 165 ⫾ 4 ms (n ⫽ 3). These trends are in
agreement with the longer H-V intervals observed in most of
the patients with BBRT and tachycardia involving His-PS
(6, 27).
Figure 8B shows longitudinal CV for each combination of
reduced conductivities (␴PS and ␴VM) and myocardial gNa. CV
during normal excitation was 0.5 m/s. Reducing the conductivities to 50% lowered CV to 0.36 m/s. Further reductions had
the same effect as reducing gNa with higher conductivity. In
Fig. 8, combinations yielding the same CV are grouped diagonally. Reducing conductivities to 25% roughly halved CV.
Note that white-on-black highlighted combinations correspond
to states resulting in BBRT, with CV in the range of 0.24 – 0.25
m/s. CV in the PS, which was ⬃1.6 m/s in normal conditions,
was reduced to 1.35 m/s with ␴PS ⫽ ␴VM ⫽ 50%, and 0.8 m/s
for ␴PS ⫽ ␴VM ⫽ 30%.
DISCUSSION
Fig. 5. Outcome of ectopic activity with varying tissue conductivities [PS (␴PS)
and myocardial (␴VM)] and myocardial sodium channel conductance (gNa).
BBR, bundle branch reentry; F, failure to trigger propagated premature
activations; CB, CB in the bundle branch (no reentry); T, tachycardia. The
shaded rectangle indicates the vulnerable region.
AJP-Heart Circ Physiol • VOL
This paper investigates the effects of conduction system
abnormalities on reentry induction. Specifically, we examined
how ectopic foci in the PS might induce arrhythmias during
pathological states conducive to BBRT. The main findings of
this research are as follows: 1) EADs originating in the distal
PS may initiate reentry in the ventricles due to temporary CB;
2) EADs originating in the proximal PS could not initiate
similar reentry despite producing CB; 3) a single, critically
timed ectopic beat was sufficient to produce reentry involving
the His-PS; and 4) in the presence of extremely slow or
impaired ventricular conduction, a single ectopic beat could
initiate BBRT. We reproduced common features of patients
suffering from BBRT, such as slow conduction, transient CB in
the PS, and reduced myocardial excitability. The results presented help explain the mechanisms involved at the Purkinje-
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Initiation of BBRT requires unidirectional block in one
bundle branch and slow conduction in the other. A subset of
simulations was performed with impaired conduction in the
tissue to reproduce conditions in which the BBB morphology
can occur. Slower conduction in the ventricles and in the PS
increased the effective path length for establishing reentrant
circuits with ectopic beats. Figure 5 shows the outcome of
ectopic activity (tEB ⫽ 370 ms) for several tissue conductivities
(both ␴PS and ␴VM) and myocardial gNa. PS gNa was kept
constant at 50%. For lower values of myocardial gNa, APs
could not be elicited due to insufficient depolarizing current; in
contrast, for higher values, a temporary CB was observed in the
LBB. In the latter cases, no reentry through the bundles was
observed, as the RBB was refractory when activation reached
the RV. BBRT was observed for ␴PS ⫽ ␴VM ⫽ 35% with
gNa ⫽ 50%, ␴PS ⫽ ␴VM ⫽ 30% with gNa ⫽ 58%, and ␴PS ⫽
␴VM ⫽ 25% with gNa ⫽ 67%. Other combinations, indicated
by “T”, produced tachycardia involving the bundle branches
and PS, but not BBRT. The shaded region (between the two
lines) represents the tachycardia-prone parameter range. Reentrant activations were considered tachycardias if they were
sustained for at least 500 ms.
If either of ␴PS or ␴VM was slightly increased, BBRT was
converted into normal tachycardia; if any of ␴PS, ␴VM, or gNa
was increased substantially, the BBRT degraded into temporary CB, and the reentry died down.
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ARRHYTHMOGENESIS, ECTOPIC BEATS, AND THE PURKINJE SYSTEM
myocardial interface and the conditions necessary for the
initiation of arrhythmias due to EADs originating in the PS.
Ectopic Activity Triggered by the PS
Purkinje cells are susceptible to EAD formation because of
their higher membrane resistance and longer APD (37), which
provides sufficient time for L-type calcium channel reactivation, leading to EAD formation. Coupled myocardial cells have
a shorter APD and become reexcitable while PS cells are still
repolarizing. Consequently, the incidence of phase II or II
EADs in Purkinje fibers is increased, which can give rise to
propagated ectopic beats. Triggered activity depends on differences in Vm between connected cells and also on the excitability threshold of already-repolarized cells (48). Several experimental studies have documented how EADs generated in the
PS propagate to ventricular muscle cells (24, 14). Computer
modeling studies have shown that suppression or facilitation of
triggered activity depends on the connection between conductive and myocardial tissue (28, 37). Very high resistance at
PMJs and certain physiological circumstances resulting in poor
AJP-Heart Circ Physiol • VOL
coupling between the two cell types facilitate triggered activity
(49). EADs in the PS cause reactivation of INa in nearby groups
of coupled cells, generating triggered APs that propagate to the
ventricular myocardium as ectopic activity (37).
Although we have constantly referred to EADs, delayed
afterdepolarizations (DADs) are also calcium-mediated events
leading to premature depolarizations, but, after the cell has
fully repolarized, DADs can also lead to ectopic beats in the PS
(52, 16). Thus propagated DADs may trigger reentry as well,
and the arguments we put forth apply to the timing of the
ectopic beat, whether it be an EAD or DAD, and do not
distinguish between the two.
Previously, simulations have studied the possibility of EAD
propagation based on two-cell models (15, 49) or one-dimensional models (30, 36) by analyzing the effects of different
factors, such as electrical coupling, EAD conditions, and stimulation frequency. A more recent study by Monserrat et al. (28)
was based on a two-dimensional computer model of Purkinje
fibers connected to a thin sheet of myocardium. Our study
differs from previous work, because it used an anatomically
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Fig. 6. Bundle branch reentrant tachycardia (BBRT). A: ectopic activity spread through the right distal PS and into the RV (white arrow). CB was observed in
the RBB. B: activations reached the LV by transseptal conduction (black arrow) and were picked up by the left PS 165 ms after the ectopic beat (white arrow).
C: activations were conducted retrogradely through the LBB and bundle of His to reach the RBB after 185 ms. D: excitation spread through the right distal PS
and RV. E: individual AP traces at various locations in the PS. Ectopic beat was originated near trace 1. *Retrograde CB in the RBB. The two-way arrow between
dotted lines in the lefthand traces (between trace 1 and 4) indicate the time required by the ectopic beat to travel from right PS to the left PS (through septum).
The two-way arrow between the dotted lines in the righthand traces (between trace 1 and 3) indicate the time taken by the ectopic activation to reach back to
the RBB via LBB and His bundle.
ARRHYTHMOGENESIS, ECTOPIC BEATS, AND THE PURKINJE SYSTEM
realistic 3D ventricular model, complete with a PS, to analyze
organ level behavior. PS junctional parameters were tuned to
match experimental observations under normal conditions. The
timing of EAD induction from phases II and III of repolarization was systematically varied to study propagation or suppression of premature beats under these conditions.
gered behavior (20). The effects of ATP, nicorandil, and
verapamil were evaluated in 17 patients with bundle block
ventricular tachycardia (VT), which was found to be EADs and
DADs. VT sensitive to ATP but not verapamil was caused by
triggered activity from the PS. If a Purkinje fiber has abnormal
automaticity in a deep resting potential, an L-type calcium
blocker such as verapamil might not affect it, but ATP suppresses such triggered activity (20, 22). Nicorandil was found
to abolish VT arising from afterpolarizations in long-QT syndrome. In another case study, BBRT with no structural heart
disease was reproducibly terminated by intravenous adenosine
(35). During an electrophysiology study, BBRT was repeatedly
initiated by isoproterenol infusion, suggesting that it originated
from triggered activity (35). Schafferhofer-Steltzer et al. (37)
have also shown how to induce EADs in Purkinje fibers by
locally superfusing them with isoproterenol solution. In a study
of RyR2/RyR2R4496C mutated mice hearts, both calcium overload and adrenergic stimulation produced catecholaminergic
polymorphic VT (7). Epicardial breakthroughs and endocardial
mapping in these cases revealed that all episodes of catecholaminergic polymorphic VT originated from focal sources
in the His-PS, which were EAD/DAD-induced triggered activities.
In their study of unidirectional CB in a one-dimensional
cable of modeled cardiomyocytes, Qu et al. (32) systematically
demonstrate that the critical refractoriness gradient is larger in
cases where the blocked wave front is travelling in the opposite
direction relative to the preceding wave. In configurations
where BBRT occurred in this study, the spatial dispersion of
Arrhythmia Induction by Triggered Activity
We observed that triggered activity from diseased PS (slow
conduction) led to tachycardia induction when facilitated by
temporary CB and/or confronted with sinus activation. Electrotonic interactions at PMJs shortened APD in the distal PS, as
has been observed experimentally. Thus a considerable APD
gradient developed within the PS, facilitating functional CB in
the bundles.
Myerburg et al. (29) reported a progressive increase in
Purkinje APD, reaching a maximum in the distal PS before
decreasing again at the insertion sites. This distal shortening of
APD can be explained by electrotonic loading from the ventricular mass, as reproduced in our model. Based on their
observations, they proposed a “gating mechanism” at distal
sites, which collectively acted as “limiting segments” for the
passage of premature impulses between the two tissues. This
was in agreement with Hoffman et al. (18), who suggested that
peripheral Purkinje fibers might be especially prone to CB
during premature impulses. However, Lazzara et al. (21) later
pointed out that in vitro preparations studied by Myerburg et al.
(29) were dissected so that a false tendon was the sole bridge
between islands of tissue barring conduction through shorter
and quicker pathways to the myocardium through interior
fibers of the LBB and septal fibers of the RBB. In fact, Lazzara
et al. (21) showed that, in the intact PS, the bundle branches are
the preferential sites for CB during premature activations. Our
findings are in agreement with this observation.
Previous experimental studies have used pharmalogical intervention to test whether tachyarrhythmias with left BBB and
right BBB patterns arise from enhanced automaticity or trigAJP-Heart Circ Physiol • VOL
Fig. 8. A: classification of events based on average time between an ectopic
beat being triggered in one bundle branch and the same activation being picked
up in the other (tBB) values during CB, tachycardia involving His-PS (T), and
BBRT. B: variation in longitudinal conduction velocity (m/s) in ventricular
myocytes with varying ␴PS and ␴VM and myocardial gNa (numbers given as
percentage of nominal values). Combinations yielding similar conduction
velocity are grouped diagonally; combinations leading to BBRT are highlighted as white on black.
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Fig. 7. BBRT reentrant circuit as described in text. The retrograde (LBB) and
anterograde (RBB) limbs are easily identified.
H1009
H1010
ARRHYTHMOGENESIS, ECTOPIC BEATS, AND THE PURKINJE SYSTEM
refractoriness that gave rise to reentry was analogous, since the
wave front from the ectopic beat blocked in the bundle branch
following a sinus beat. Here, the incidence of BBRT suggests
that the APD gradient due to myocardial loading effects in the
distal PS, also observed experimentally (29), is a sufficiently
large barrier to produce CB.
Favorable Conditions for Reentry
AJP-Heart Circ Physiol • VOL
While we used a rabbit model and not human, rabbits have
similar PS penetration depths as humans, as well as a similar
effective electrical size (31). A homogeneous APD distribution
was used in the ventricles. This would have altered specific
timings for reentry occurrence, but would not alter the basic
phenomenon of one-sided BBB. Similarly, variations in the
physical structure of the PS and the parameters responsible for
PMJ coupling would surely result in the formation of different
reentrant circuits, and the size and timing of window of
vulnerability might also be affected. Nonetheless, as long as
the critical PS features emphasized in this study, rapid propagation, retrograde and anterograde transmission, electrical isolation from the ventricles except at endpoints, and a pronounced gradient in refractoriness from distal to proximal sites
due to electrotonic loading, the key phenomena demonstrated,
such as arrhythmogenesis from a single well-timed ectopic beat
in the PS, would continue to be observed.
Conclusions
We have presented a computer simulation study of arrhythmogenesis due to conduction system disorders in the PS.
Ectopic excitation in the distal PS led to triggered activity in
the ventricles, which induced reentrant VT when facilitated by
functional CB within the proximal PS and/or interaction with
sinus activity. A single, well-timed ectopic beat in the distal PS
could initiate reentry involving the His-PS, whereas ectopic
activity in the proximal PS could not. Initiation of BBRT
required extremely slow conduction in the ventricles and temporary CB in one of the bundle branches. This paper describes
possible mechanisms of arrhythmia initiation involving the
specialized ventricular conduction system. Our findings may
help clarify the elements underlying clinical entities, such as
BBRT and fascicular tachycardias.
ACKNOWLEDGMENTS
The authors acknowledge the provision of computational resources by
WestGrid.
GRANTS
This research was supported by the Natural Sciences and Engineering
Research Council of Canada, the Alberta Ingenuity Fund, and the Mathematics
of Information Technology and Complex Systems NCE.
DISCLOSURES
E. J. Vigmond holds equity in Cardiosolv LLC.
REFERENCES
1. Akhtar M, Damato AN, Batsford WP, Ruskin JN, Ogunkelu JB,
Vargas G. Demonstration of re-entry within the his-Purkinje system in
man. Circulation 50: 1150 –1162, 1974.
2. Aslanidi OV, Stewart P, Boyett MR, Zhang H. Optimal velocity and
safety of discontinuous conduction through the heterogeneous purkinjeventricular junction. Biophys J 97: 20 –39, 2009.
3. Berenfeld O, Jalife J. Purkinje-muscle reentry as a mechanism of polymorphic ventricular arrhythmias in a 3-dimensional model of the ventricles. Circ Res 82: 1063–1077, 1998.
4. Boyle P, Deo M, Plank G, Vigmond E. The role of the Purkinje system
in the response of the quiescent ventricles to defibrillation-strength shocks:
a computer modeling study. Ann Biomed Eng 38: 456 –468, 2010.
5. Cabo C, Barr RC. Propagation model using the DiFrancesco-Noble
equations: comparison to reported experimental results. Med Biol Eng
Comput 30: 292–302, 1992.
299 • OCTOBER 2010 •
www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.5 on May 5, 2017
We reduced the excitability (sodium channel conductance)
and tissue conductivities in both the PS and myocytes to induce
reentry involving the conduction system. It is evident from the
results that reentry involving the His-PS cannot occur under
healthy conditions, since the effective reentrant path length in
such cases is too short. Path length can be increased in the
scenario where conduction is hampered in both conductive
tissue and the ventricular mass. This is in agreement with
clinical observations that sustained BBRT occurs in patients
with delays in Purkinje-ventricle activation time and interventricular conductance (6, 27). Anti-arrhythmic drug-induced
slowing of CV has been shown to favor the incidence of
macro-reentrant VT involving the His-PS (8). In another clinical report, amiodarone-induced slowing of CV within the
His-PS led to the occurrence of recurrent BBRT or interfascicular tachycardias in patients (34).
Two types of reentry were observed. In the first, triggered
activity conducted through diseased PS and myocardium was
confronted by sinus activation, inducing reentry. This could
also occur due to interaction with excitation from some other
source coming down the bundle or the proximal PS. In the
second, the triggered activity itself induced BBRT due to slow
conduction and temporary retrograde CB in the distal PS. This
case depended on the extent of CV reduction in the ventricles
and the PS. This is in accord with the model work of Ten
Tusscher and Panfilov (41), who also had to increase effective
path length of reentry in their human ventricular model by
decreasing PS conductance to 12.5% and lowering INa in both
PS and myocardium to 40% to produce BBRT. Likewise, in
their early simulation analysis of arrhythmias involving the PS,
Berenfeld and Jalife (3) employed a FitzHugh-Nagumo ionic
kinetics, which results in reduced excitability due to slower
upstroke. Clinical reports have also documented prolonged
H-V intervals in most BBRT patients (6, 27), indicating slow
conduction through the PS.
In most clinical studies, though, the cause of BBRT initiation has not been clear. Typically, a diseased PS with either of
the branches blocked and slower conduction through the other
branch are considered as precursors to reentry (27). We observed that ectopic activity originating in the distal PS could
result in temporary functional CB in either bundle branch,
which provided a substrate for reentry. Structural impairment
of the conduction system was not needed, so no H-V prolongation was necessary. Our observations agree with the clinical
findings of Li et al. (23), who observed BBRT in patients with
normal H-V intervals in the presence of functional conduction
impairment. Moreover, our results show that a single ectopic
beat, occurring during the specific time window when the distal
PS and myocardium are reexcitable, but the proximal PS is still
refractory, was sufficient to induce reentry in tissue with
reduced CV, which approximate diseased ventricles.
Limitations
ARRHYTHMOGENESIS, ECTOPIC BEATS, AND THE PURKINJE SYSTEM
AJP-Heart Circ Physiol • VOL
29. Myerburg RJ, Stewart JW, Hoffman BF. Electrophysiological properties of the canine peripheral A-V conducting system. Circ Res 26:
361–378, 1970.
30. Nordin C. Computer model of electrophysiological instability in very
small heterogeneous ventricular syncytia. Am J Physiol Heart Circ Physiol
272: H1838 –H1856, 1997.
31. Panfilov AV. Is heart size a factor in ventricular fibrillation? Or how close
are rabbit and human hearts? Heart Rhythm 3: 862–864, 2006.
32. Qu Z, Garfinkel A, Weiss JN. Vulnerable window for conduction block
in a one-dimensional cable of cardiac cells. 1. Single extrasystoles.
Biophys J 91: 793–804, 2006.
33. Ramanathan C, Jia P, Ghanem R, Ruy K, Rudy Y. Activation and
repolarization of the normal human heart under complete physiological
conditions. Proc Natl Acad Sci USA 103: 6309 –6314, 2006.
34. Reithmann C, Hahnefeld A, Oversohl N, Ulbrich M, Remp T, Steinbeck G. Reinitiation of ventricular macroreentry within the his-Purkinje
system by back-up ventricular pacing-a mechanism of ventricular tachycardia storm. Pacing Clin Electrophysiol 30: 225–235, 2007.
35. Rubenstein DS, Burke MC, Kall JG, Kinder CA, Kopp DE, Wilber
DJ. Adenosine-sensitive bundle branch reentry. J Cardiovasc Electrophysiol 8: 80 –88, 1997.
36. Saiz J, Ferrero JJM, Monserrat M, Ferrero JM, Thakor NV. Influence
of electrical coupling on early afterdepolarizations in ventricular myocytes. IEEE Trans Biomed Eng 46: 138 –147, 1999.
37. Schafferhofer-Steltzer I, Hofer E, Huelsing DJ, Bishop S, Pollard A.
Contributions of Purkinje-myocardial coupling to suppression and facilitation of early afterdepolarization-induced triggered activity. IEEE Trans
Biomed Eng 52: 1522–1531, 2005.
38. Simons GR, Sorrentino RA, Zimerman LI, Wharton JM, Natale A.
Bundle branch reentry tachycardia and possible sustained interfascicular
reentry tachycardia with a shared unusual induction pattern. J Cardiovasc
Electrophysiol 7: 44 –50, 1996.
39. Szabo B, Kovacs T, Lazzara R. Role of calcium loading in early
afterdepolarizations generated by Cs⫹ in canine and guinea pig Purkinje
fibers. J Cardiovasc Electrophysiol 6: 796 –812, 1995.
40. Szabo B, Sweidan R, Rajagopalan CV, Lazzara R. Role of Na⫹:Ca2⫹
exchange current in Cs⫹-induced early afterdepolarizations in Purkinje
fibers. J Cardiovasc Electrophysiol 5: 933–944, 1994.
41. Ten Tusscher K, Panfilov AV. Modelling of the ventricular conduction
system. Prog Biophys Mol Biol 96: 152–170, 2008.
42. Touboul P, Kirkorian G, Atallah G, Moleur P. Bundle branch reentry:
a possible mechanism of ventricular tachycardia. Circulation 67: 674 –
680, 1983.
43. Vetter F, McCulloch A. Three-dimensional analysis of regional cardiac
function: a model of rabbit ventricular anatomy. Prog Biophys Mol Biol
69: 157–183, 1998.
44. Vigmond E, Aguel F, Trayanova N. Computational techniques for
solving the bidomain equations in three dimensions. IEEE Trans Biomed
Eng 49: 1260 –1269, 2002.
45. Vigmond EJ, Clements C. Construction of a computer model to investigate sawtooth effects in the Purkinje system. IEEE Trans Biomed Eng
54: 389 –399, 2007.
46. Vigmond EJ, Hughes M, Plank G, Leon LJ. Computational tools for
modeling electrical activity in cardiac tissue. J Electrocardiol 36, Suppl:
69 –74, 2003.
47. Vigmond EJ, Weber Dos Santos R, Prassl AJ, Deo M, Plank G.
Solvers for the cardiac bidomain equations. Prog Biophys Mol Biol 96:
3–18, 2008.
48. Volders P, Vos M, Szabo B, Sipido K, Groot S, Gorgels A, Wellens H,
Lazzara R. Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts. Cardiovasc Res 42: 376 –392, 2000.
49. Wagner MB, Gibb WJ, Lesh MD. A model study of propagation of early
afterdepolarizations. IEEE Trans Biomed Eng 42: 991–997, 1995.
50. Welch WJ, Strasberg B, Coelho A, Rosen KM. Sustained macroreentrant ventricular tachycardia. Am Heart J 104: 166 –169, 1982.
51. Wiedmann RT, Tan RC, Joyner RW. Discontinuous conduction at
Purkinje-ventricular muscle junction. Am J Physiol Heart Circ Physiol
271: H1507–H1516, 1996.
52. Wit AL, Rosen MR. Pathophysiologic mechanisms of cardiac arrhythmias. Am Heart J 106: 798 –811, 1983.
53. Zeng J, Rudy Y. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J 68: 949 –964, 1995.
299 • OCTOBER 2010 •
www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.5 on May 5, 2017
6. Caceres J, Jazayeri M, McKinnie J, Avitall B, Denker ST, Tchou P,
Akhtar M. Sustained bundle branch reentry as a mechanism of clinical
tachycardia. Circulation 79: 256 –270, 1989.
7. Cerrone M, Noujaim SF, Tolkacheva EG, Talkachou A, O’Connell R,
Berenfeld O, Anumonwo J, Pandit SV, Vikstrom K, Napolitano C,
Priori SG, Jalife J. Arrhythmogenic mechanisms in a mouse model of
catecholaminergic polymorphic ventricular tachycardia. Circ Res 101:
1039 –1048, 2007.
8. Chalvidan T, Cellarier G, Deharo JC, Colin R, Savon N, Barra N,
Peyre JP, Djiane P. His-Purkinje system reentry as a proarrhythmic effect
of flecainide. Pacing Clin Electrophysiol 23: 530 –533, 2000.
9. Clerc L. Directional differences of impulse spread in trabecular muscle
from mammalian heart. J Physiol 255: 335–346, 1976.
10. Clusin WT. Calcium and cardiac arrhythmias: DADs, EADs, and alternans. Crit Rev Clin Lab Sci 40: 337–375, 2003.
11. Coghlan HC, Coghlan AR, Buckberg GD, Cox JL. “The electrical
spiral of the heart”: its role in the helical continuum, the hypothesis of the
anisotropic conducting matrix. Eur J Cardiothorac Surg 29: S178 –S187,
2006.
12. Deo M, Boyle P, Plank G, Vigmond E. Arrhythmogenic mechanisms of
the purkinje system during electric shocks: a modeling study. Heart
Rhythm 6: 1782–1789, 2009.
13. DiFrancesco D, Nobel D. A model of cardiac electrical activity incorporating ionic pumps and concentration changes. Philos Trans R Soc Lond B
Biol Sci 307: 353–398, 1985.
14. el Sherif N, Zeiler RH, Craelius W, Gough WB, Henkin R. QTU
prolongation and polymorphic ventricular tachyarrhythmias due to bradycardia-dependent early afterdepolarizations. Afterdepolarizations and ventricular arrhythmias. Circ Res 63: 286 –305, 1988.
15. Gibb WJ, Wagner MB, Lesh MD. Modeling triggered cardiac activity:
an analysis of the interactions between potassium blockade, rhythm
pauses, and cellular coupling. Math Biosci 137: 101–133, 1996.
16. Gough WB, el Sherif N. Dependence of delayed afterdepolarizations on
diastolic potentials in ischemic purkinje fibers. Am J Physiol Heart Circ
Physiol 257: H770 –H777, 1989.
17. Gupta AK, Vajifdar BU, Vora AM. Bundle branch re-entrant ventricular
tachycardia in a patient with structurally normal heart. Indian Heart J 51:
80 –82, 1999.
18. Hoffman BF, Moore EN, Stuckey JH, Cranefield PF. Functional
properties of the atrioventricular conduction system. Circ Res 13: 308 –
328, 1963.
19. January C, Riddle J, Salata J. A model for early afterdepolarizations
with the calcium channel agonist bayk8644. Circ Res 62: 563–571, 1988.
20. Kobayashi Y, Yazawa T, Adachi T, Kawamura M, Ryu S, Asano T,
Obara C, Katagiri T. Ventricular arrhythmias with left bundle branch
block pattern and inferior axis: assessment of their mechanisms on the
basis of response to ATP, nicorandil and verapamil. Jpn Circ J 64:
835–841, 2000.
21. Lazzara R, El-Sherif N, Befeler B, Scherlag B. Regional refractoriness
within the ventricular conduction system. An evaluation of the “gate”
hypothesis. Circ Res 39: 254 –262, 1976.
22. Lerman B, Belardinelli L, West G, Berne R, DiMarco J. Adenosinesensitive ventricular tachycardia: evidence suggesting cyclic AMP-mediated triggered activity. Circulation 74: 270 –280, 1986.
23. Li YG, Grnefeld G, Israel C, Bogun F, Hohnloser SH. Bundle branch
reentrant tachycardia in patients with apparent normal his-Purkinje conduction: the role of functional conduction impairment. J Cardiovasc
Electrophysiol 13: 1233–1239, 2002.
24. Li ZY, Maldonado C, Zee-Cheng C, Hiromasa S, Kupersmith J.
Purkinje fibre-papillary muscle interaction in the genesis of triggered
activity in a guinea pig model. Cardiovasc Res 26: 543–548, 1992.
25. Lu HR, Marin R, Saels A, Clerck FD. Species plays an important role
in drug-induced prolongation of action potential duration and early afterdepolarizations in isolated purkinje fibers. J Cardiovasc Electrophysiol 12:
93–102, 2001.
26. Mahajan A, Shiferaw Y, Sato D, Baher A, Olcese R, Xie LH, Yang
MJ, Chen PS, Restrepo JG, Karma A, Grafinkel A, Qu Z, Weiss J. A
rabbit ventricular action potential model replicating cardiac dynamics at
rapid heart rates. Biophys J 94: 392–410, 2008.
27. Mazur A, Kusniec J, Strasberg B. Bundle branch reentrant ventricular
tachycardia. Indian Pacing Electrophysiol J 5: 86 –95, 2005.
28. Monserrat M, Saiz J, Ferrero JMJ, Ferrero JM, Thakor NV. Ectopic
activity in ventricular cells induced by early afterdepolarizations developed in Purkinje cells. Ann Biomed Eng 28: 1343–1351, 2000.
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