Download Mechanisms of Long-Duration Ventricular€Fibrillation in Human

JACC: CLINICAL ELECTROPHYSIOLOGY
VOL. 1, NO. 3, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
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PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacep.2015.04.003
Mechanisms of Long-Duration
Ventricular Fibrillation in Human
Hearts and Experimental Validation
in Canine Purkinje Fibers
Nicholas Jackson, MD,* Stéphane Massé, MASC,* Nima Zamiri, MD,* Mohammed Ali Azam, MBBS, PHD,*
Patrick F.H. Lai, MSC,* Marjan Kusha, MENG,* John Asta,* Kenneth Quadros, MD,* Benjamin King, MD,*
Peter Backx, DVM, PHD,* Raymond E. Ideker, MD, PHD,y Kumaraswamy Nanthakumar, MD*
ABSTRACT
OBJECTIVES This study sought to determine the characteristics of human LDVF, particularly as it contrasts with
short-duration VF (SDVF), and evaluate the role of Purkinje fibers in its maintenance.
BACKGROUND The electrophysiological mechanisms of long-duration ventricular fibrillation (LDVF) have not been
studied in the human heart.
METHODS VF was induced in 12 human Langendorff hearts, and the hearts were examined from initiation to LDVF
(10 min). Endocardial, epicardial, and transmural plunge needle mapping were performed on the hearts. Simulated LDVF
was studied in canine hearts to determine the potential role of Purkinje fiber automaticity.
RESULTS The mean age at transplant was 48 20 years, and the mean ejection fraction was <20%. The mean cycle
length of local activation times on the endocardium was 252 66 ms in SDVF and 441 80 ms in LDVF (p ¼ 0.0002).
On the endocardium and the epicardium in LDVF, cycle length was 441 80 ms and 590 88 ms, respectively
(p ¼ 0.0002). No endocardial to epicardial activation frequency gradient was seen in SDVF. Simultaneous transmural
needle activation was most common in SDVF, whereas endocardial to epicardial activation was most common in LDVF
(47.7% and 38.8% of activations, respectively [p ¼ 0.031]). Re-entry was less common in LDVF, and over time, wave
break (i.e., nontransmural propagation of wave fronts) developed. Isochronal maps of the left ventricular endocardium in
LDVF identified Purkinje potentials as preceding and predominating endocardial activations. In explanted canine heart
preparations, rapid pacing led to spontaneous Purkinje fiber activity that was dependent on pacing rate and duration.
CONCLUSIONS LDVF in human hearts is characterized by focal endocardial activity with mid-myocardial wave break
and not by re-entry. This arrhythmia is modulated by rapid activations in early VF that lead to spontaneous Purkinje fiber
activity. (J Am Coll Cardiol EP 2015;1:187–97) © 2015 by the American College of Cardiology Foundation.
S
urvival outcomes after cardiac arrest due to
characteristics of long-duration ventricular fibrilla-
ventricular fibrillation (VF) decrease exponen-
tion (LDVF) using animal models has shown periods
tially as time to defibrillation increases (1,2).
of organized and synchronous endocardial activation
Nonetheless, defibrillation can be performed success-
and has implicated abnormal automaticity or trig-
fully for some patients after 10 min or more of VF, and
gered activity from Purkinje fibers as possible drivers
some patients survive with relatively good clinical
of VF at this stage (3). These studies have shown
outcomes (1). Evaluation of the electrophysiological
endocardial
to
epicardial
activation
From the *University Health Network, Toronto, Ontario, Canada; and the yUniversity of Alabama at Birmingham, Birmingham,
Alabama. This work was supported by the Canadian Institute of Health Research (grant number MOP 77687). The authors have
reported that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received February 4, 2015; revised manuscript received April 3, 2015, accepted April 9, 2015.
frequency
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ABBREVIATIONS
gradients (4) and earliest activation in Pur-
of the 12 hearts, endocardial activation was mapped
AND ACRONYMS
kinje fibers after LDVF defibrillation failures
with a balloon array (unipolar and bipolar recording)
(5), and they have shown that chemical abla-
in 5 hearts, and epicardial activation mapping with
tion of the Purkinje system with Lugol solu-
a sock array was performed in 6 hearts. Because of
tion leads to earlier termination of VF and
limitations with signal processing and the feasibility
loss of the endocardial to epicardial activa-
of array positioning, all mapping techniques were
tion frequency gradients (4).
not used concurrently on each heart.
CL = cycle length
LAT = local activation time
LDVF = long-duration
ventricular fibrillation
LV = left ventricular
In contrast, the characteristics of short-
SDVF = short-duration
duration (<3 min) ventricular fibrillation
ventricular fibrillation
(SDVF) have been studied in detail in human
in vivo and ex vivo models. These studies suggest
that SDVF is most frequently characterized by transmural scroll wave activation, with intramural re-entry
most often localizing to regions with greater fibrosis
(6,7). In the clinical setting, it is at these earlier phases of cardiac arrest (SDVF) that pharmacological
therapies to improve defibrillation efficacy have been
studied (8,9). If VF is maintained by different mechanisms as the rhythm progresses over time, then
alternative therapeutic interventions may become
important in improving patient survival.
VF MAPPING. Human Langendorff hearts were per-
fused with modified Tyrode solution via the coronary
arteries, and VF was induced by burst pacing from
the right ventricular apex. With VF induction, perfusion was halted and pseudosurface electrocardiography was monitored to confirm irregular activity and
heart rate >220 beats/min (6). Details of the human
Langendorff methodology and VF mapping arrays
are included in the Online Appendix.
During VF mapping, the local activation times
(LATs) on unipolar recordings were taken as the
maximum negative dV/dt (change is voltage/change
in time) at each electrode, provided it was at least
–0.5 mV/ms (10). Early VF recordings were taken at 3 s
after onset (6), and LDVF recordings were taken at
SEE PAGE 198
In this study, we examined myocardial activation patterns in SDVF and LDVF in myopathic
Langendorff-perfused human hearts, with particular
attention to transmural activation gradients and
the role of Purkinje fibers in LDVF. We hypothesized
that focal activity from the endocardium
aids
in maintaining LDVF in its later stages and in creating endocardial to epicardial activation frequency
gradients.
up to 10 min (3,4,10). Purkinje fiber activations
were initially identified on the left ventricular (LV)
septum with the bipolar endocardial balloon during
basal pacing. Capture of the His-Purkinje system
allowed identification of high-frequency potentials
(1 to 2 ms duration) (11) preceding local ventricular
activation (Figure 1A). The corresponding electrodes
were later examined for Purkinje potentials during
VF on the bipolar and unipolar needles and endocardial balloon arrays. Local activation time for bipolar recordings was taken as the peak of the positive
METHODS
deflection (12).
Initially we sought to characterize the transmural
TRANSMURAL VF MAPPING. Transmural needle acti-
activation patterns of VF in 12 cardiomyopathic Lan-
vations were examined for simultaneous, endocardial
gendorff human hearts from onset to LDVF (10 min).
to epicardial, epicardial to endocardial, and nonuni-
Particular attention was given to the role of Purkinje
form multidirectional patterns (6). A <10 ms differ-
fibers and the presence of re-entry or focal activity as
ence among LATs of all 4 electrodes along a needle
VF progressed over time. A dog model was used to
defined simultaneous activation (6). To meet the
test the effect of rapid activations (simulated VF) on
criteria for uniform transmural activation, at least
Purkinje fibers because the Purkinje system in dogs is
3 of 4 electrograms had to be in the appropriate
most similar to that in humans compared to other
sequence, with the fourth not more than 20 ms out
mammals and allows for the isolation and mapping of
of sequence to allow for some heterogeneity in con-
individual Purkinje fibers.
duction and slanting or curved wave front propagation. Nonuniform multidirectional patterns were
was
defined as chaotic patterns that did not fit the se-
approved by the University Health Network Human
quences previously described. When analyzing the
Research Ethics Board and complies with the Decla-
needle data during LDVF, wave break (i.e., failure of
ration of Helsinki. Twelve patients with cardiomy-
a wave front to propagate transmurally) was seen (13).
opathy requiring heart transplant consented to use
Activation patterns with wave break were identified
of their explanted hearts for the study. Global trans-
when 2 or 3 local needle activations were seen, but
mural plunge needle mapping was performed in 11
propagation of activation to the remaining needle
HUMAN
LDVF
STUDY. The
study
protocol
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F I G U R E 1 Identification of Purkinje Potentials and the Canine Purkinje Fiber Preparation
(A) Purkinje potentials identified on the septal spline of the bipolar endocardial balloon during basal pacing. A pacing spike is followed by
discrete, sharp Purkinje potentials with activation from the base to the apex as subsequent myocardial activation proceeds in the opposite
direction (electrode numbers correspond to the isochronal maps in Figure 3A). (B) The tissue bath used to examine spontaneous Purkinje fiber
activation and for simulation of long-duration ventricular fibrillation by rapid pacing of canine heart tissue. Purkinje fiber strands are dissected
away from adjacent myocardium and corresponding pacing and sensing electrodes are labeled. Myocardial and Purkinje action potentials
recorded from the glass microelectrode are shown on the inset.
pole(s) was not seen. Examples of how transmural
then orthogonally along the length of the needle
and nontransmural wave front propagations were
as well.
classified are shown in Figures 2B and 2C.
INDUCTION OF FOCAL ACTIVITY FROM PURKINJE
CYCLE LENGTH DETERMINATION AND RE-ENTRY
FIBERS
DETECTION. To assess for re-entry and to compare
ACTIVATION IN EARLY VF. To explore the possibility
activation sequences, a cycle length (CL) for VF was
that focal activity from Purkinje fibers in late VF
defined (6). The median of the number of LATs on
could be promoted by rapid activation during early
each needle was used to define the number of “beats”
VF, we used a separate preparation with which
and defines the context in which the term “beat” is
Purkinje and myocardium can be visually separated
used hereafter in this paper. The number of beats
and recorded. Explanted canine hearts were dis-
divided by the duration of the analyzed VF segment
sected into islands of ventricular myocardium joined
determined the CL (6) (CL and median activation
by strands of Purkinje fibers and placed in a tissue
times for beats 11 and 12 in SDVF are shown in Online
bath (Figure 1B). A glass microelectrode was used to
Figure 1). Re-entry was evaluated in 2 orthogonal
impale muscle and Purkinje fibers to record action
planes (both parallel and perpendicular to the
potentials (Figure 1B, inset). Bipolar electrodes were
epicardium and endocardium). Each needle electrode
placed onto ventricular myocardium and Purkinje
in
re-entry
fibers to record local electrical activity. Rapid pacing
involving that electrode plus the 9 adjacent elec-
of the myocardium at 6 Hz for 5 min was used to
trodes around it. To meet the criteria for re-entry,
simulate LDVF (this rate approximated the dominant
one full rotation was required with progression of
frequency of canine LDVF found by Newton et al.
local activation on at least 75% of the 9 electrodes,
[14]) in the presence of ischemia (no perfusion) and
spanning $85% of the CL of the beat (6). Re-entry
0.2 ml of isoproterenol. After this, burst pacing of
was assessed in this way at all 4 layers of the
the ventricular myocardium at progressively faster
myocardium (endocardial to epicardial), in larger
rates (1 to 5 Hz CLs) and for progressively longer
groups of needles (with 16 and 25 needles), and
durations (5 to 20 s) was performed to look for
turn
was
examined
for
intramural
IN
LDVF
FROM
RAPID
MYOCARDIAL
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F I G U R E 2 Activation Patterns in SDVF and LDVF
(A) The activation patterns seen on each needle expressed as a percentage of the total local activations seen on the 25 needles across a 3-s
snapshot of short-duration ventricular fibrillation (SDVF) (at onset) and long-duration ventricular fibrillation (LDVF) (10 min), respectively.
Activation patterns are shown in B and C and are described in the Methods section. (B) Unipolar needle electrograms at VF onset with local
activation markers included. In this SDVF needle segment, each transmural activation is entirely simultaneous. (C) Examples of 6 activation
sequences on unipolar needle recordings during LDVF. From left to right: Epicardial to endocardial activation, endocardial to epicardial activation, endocardial to epicardial activation with wave break, simultaneous activation with wave break, endocardial to epicardial activation with
wave break, nonuniform multidirectional pattern with wave break, and endocardial to epicardial activation with wave break. Local activation is
marked at the maximum negative dV/dt slope.
subsequent spontaneous Purkinje fiber activation.
consisted of 5 women and 7 men with a mean age of
Because Purkinje strands were separated from adja-
48.4 19.6 years. The predominant disease was
cent myocardium, only true Purkinje activations
dilated cardiomyopathy with ejection fraction <20%,
could be detected at the corresponding bipolar
and the mean LV internal dimensions in diastole
and systole were 61.9 2.3 mm and 55.3 2.2 mm,
electrodes.
STATISTICAL ANALYSIS. Analyses were performed
with SAS version 9.1 (SAS Institute, Cary, North Car-
respectively.
TRANSMURAL ACTIVATION SEQUENCES DURING
olina), and results are expressed as mean SD where
HUMAN SDVF AND LDVF. Figure 2A shows the rela-
stated. Comparison of activation patterns in SDVF
tive frequency of different transmural activation
and LDVF in Figure 2 and comparison of re-entry
sequences in SDVF and LDVF from plunge needle
incidence in Table 1 were performed with a Wil-
data. The most frequent activation sequence seen
coxon signed rank test because of repeated measures.
(of those defined in Figure 2) in SDVF was simulta-
Comparison of endocardial and epicardial CLs in
neous activation of all 4 needle electrodes (47.7% of
SDVF and LDVF was performed by 2-way repeated
activations), whereas the most frequent activation
measures
sequence seen in LDVF was endocardial to epicardial
analysis
of
variance
with
Bonferroni
correction for multiple comparisons. A p value
activation (38.8%; p ¼ 0.031). Including endocardial
of <0.05 was considered statistically significant.
to epicardial activation with wave break, a total of
54.2% of all needle activations appeared to originate
RESULTS
at the endocardium in LDVF compared with 14.5%
(p ¼ 0.031) in SDVF. Wave break overall was a much
HUMAN
HEARTS. The
baseline characteristics of
more common phenomenon in LDVF than in SDVF
the 12 patients whose hearts were used in this
(27.9% vs. 3.3%; p ¼ 0.031). These differences in
study are summarized in Online Table 1. Patients
transmural activation between SDVF and LDVF are
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Mechanisms of Human Long-Duration VF
T A B L E 1 Re-Entry Incidence in SDVF and LDVF*
Region
SDVF
Endocardial
T A B L E 2 Epicardial and Endocardial CL in SDVF and LDVF*
LDVF
7/171 (4.1)
p Value
VF Timing and Location
2/72 (2.8)
0.063
SDVF, endocardium
252 66
SDVF, epicardium
248 73
Subendocardial
7/171 (4.1)
1/72 (1.4)
0.059
Subepicardial
6/171 (3.5)
0/72 (0)
0.06
Epicardial
5/171 (2.9)
0/72 (0)
0.10
Perpendicular to epicardium
and endocardium
2/100 (2)
Total re-entry
27/171 (15.8)
0/100 (0)
3/72 (4.2)
NA
0.035
Values are n/N (%). *The median incidence of re-entry at each layer of the
myocardium, perpendicular to the epicardium and endocardium (along the length
of the needle), along with total re-entry, are shown. Even in SDVF where scroll
waves or “mother rotors” migrate through the myocardium and sustain VF, the
total re-entry incidence is low because multiple disorganized wavelets that
propagate from these rotors do not meet the criteria for re-entry (6).
LDVF, endocardium
LDVF, epicardium
VF CL (ms)
p Value
0.99
0.002
0.0002
441 80
590 88
0.004
Values are mean SD. *Mean ventricular CLs averaged over 10 beats for SDVF (VF onset) and
LDVF (10 min) recorded on the endocardial balloon and the epicardial sock arrays. Pseudosurface
electrocardiography (the corollary of a rhythm strip in the clinical setting) shows higher frequency
activity in SDVF and LDVF than is reflected by the mean ventricular CLs defined in this study from
local electrogram recordings because surface recordings reflect the summation of myocardial
activity in VF and better demonstrate the global disorganization with amplitude and CL variation.
CL ¼ cycle length; LDVF ¼ long-duration ventricular fibrillation; SDVF ¼ short-duration ventricular fibrillation.
LDVF ¼ long-duration ventricular fibrillation; NA ¼ not applicable; SDVF ¼
short-duration ventricular fibrillation.
Four septal splines of the bipolar endocardial array
are shown.
further shown in the spatiotemporal activation plot
Isochronal maps of the corresponding endocardial
activation are shown in Figure 3A with earliest Pur-
in Online Figure 1.
kinje activation represented by a star. Rapid endoDIFFERENTIAL ACTIVATION RATES DURING HUMAN
cardial activation can be seen to spread out across
LDVF. The cycle lengths of SDVF and LDVF at the
the septum via the Purkinje network, with latest
endocardium
endocardial
activation consistently at the basal and lateral endo-
balloon and epicardial sock arrays are shown in
cardium. On beats 5 and 6, separate wave fronts
Table 2. Activation frequency gradients can be seen
originating in ventricular myocardium can be seen
between LDVF at the endocardium and LDVF at the
around splines 2 and 3 of the array and appear to
and
epicardium
from
epicardium (mean CL 441 80 ms vs. 590 88 ms,
contribute to even more rapid global endocardial
p ¼ 0.0002) and between SDVF and LDVF at both
activation. Endocardial activation on these beats
the endocardium and epicardium. These findings are
occurs within 100 ms.
consistent with the longer mean CLs seen in LDVF
Figure 4A shows unipolar endocardial and epicar-
than in SDVF and with the prevalence of endocardial
dial activation every 2 min from induction to 10 min
to epicardial activation with wave break seen on
of VF. Sharp and discrete Purkinje potentials can
plunge needle mapping (Figure 2A).
be seen more frequently and with increasing regu-
RE-ENTRY DURING HUMAN LDVF. The incidence of
re-entry in SDVF and LDVF at each of the 4 myocardial layers during a 3-s period of VF is shown in
Table 1. Overall, a greater number of wave fronts
met the criteria for re-entry in SDVF than in LDVF
(15.8% vs. 4.2%, p ¼ 0.035). Re-entry along the length
of the needle transmurally was seen only 2% of the
time in SDVF and never in LDVF. A greater number of
“beats” during 3 s of SDVF led to a greater number of
total wave fronts assessed for re-entry in SDVF than
in LDVF (171 vs. 72 beats).
larity on the septal endocardium as VF progresses.
A significantly greater activation rate on the endocardium with low-frequency, longer CL signals on
the epicardium shows that the endocardium drives
LDVF in myopathic human hearts with spontaneous
endocardial Purkinje activity.
Isochronal maps of endocardial needle activation
at 10 min of VF are shown in Figure 4B. These maps
correspond to the isochronal maps in Figure 3A;
however, the true septum was not mapped by the
transmural plunge needles and is not present on the
left-hand side of the maps. Purkinje potentials adja-
PURKINJE ACTIVITY DURING HUMAN LDVF. Wher-
cent to the septum and more laterally can be seen
eas frequent Purkinje-like potentials could be iden-
again to correspond with the points of earliest endo-
tified in all hearts during LDVF, Purkinje potentials
cardial activation on beats 3, 4, 5, 6, and 9. Multifocal
were only clearly identified at baseline in hearts 3
activations are also seen on beats 2, 3, 6, and 8 with
and 4 (from Online Table 1), so these hearts were
variable wave front propagation.
primarily used in constructing Figures 3 and 4. Examples of discrete Purkinje potentials preceding
FOCAL ACTIVITY FROM PURKINJE FIBERS IN LDVF IS
local ventricular activation are shown on bipolar
INDUCED BY RAPID ACTIVATIONS DURING EARLY VF. To
endocardial mapping in LDVF (arrows) in Figure 3B.
determine the mechanism for spontaneous focal
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F I G U R E 3 Purkinje Potentials Precede Local Activation in LDVF
(A) Isochronal maps of ventricular activation from the bipolar endocardial electrograms shown in B. Apical electrodes are shown at the center
and basal electrodes at the periphery. Eight beats of long-duration ventricular fibrillation (LDVF) are shown with earliest Purkinje activation
represented by a star. Rapid endocardial activation can be seen to spread out across the septum via the Purkinje network, with latest activation
consistently at the basolateral endocardium. On beats 5 and 6, separate focal activations away from the Purkinje system are also seen and
contribute further to rapid endocardial activation. (B) VF on pseudosurface electrocardiography followed by 4 adjacent, endocardial bipolar
traces from the left ventricular septum. Small, sharp Purkinje potentials can be identified preceding each local endocardial activation (arrows).
It is also demonstrated that the frequency of activity shown on pseudosurface electrocardiography in LDVF is more rapid than the regional cycle
length shown by the septal electrograms because it represents an amalgamation of the global myocardial activity.
Purkinje fiber activations in LDVF, Purkinje fibers
Purkinje tissue can be seen initially (Figure 5A).
were isolated from canine myocardium. During
After 3 min of pacing, 1:1 capture of local Pur-
simulation of VF by rapidly pacing canine ventricular
kinje tissue continues with variable and significantly
myocardium, 1:1 capture of myocardium and adjacent
less-frequent capture of ventricular myocardium
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F I G U R E 4 Purkinje Potentials Become More Prevalent Over Time as VF Progresses
(A) Unipolar needle recordings every 2 min from short-duration ventricular fibrillation (SDVF) (time zero) through to long-duration
ventricular fibrillation (LDVF) (10 min), with endocardial (Endo) activation shown above epicardial (Epi) activation at each time point. As VF
progresses, more frequent sharp, Purkinje potentials can be seen on the endocardium (arrows). Purkinje potentials are high-frequency spikes
that appear to fire regularly but propagate variably to the epicardium, where lower frequency activations with significantly longer cycle
lengths are seen. (B) Isochronal maps of ventricular activation that correspond with the endocardial needle electrodes shown at 10 min in A.
Apical electrodes are shown at the center and basal electrodes at the periphery. On beats 3, 4, 5, 6, and 9, earliest ventricular activation
occurs in the regions of identified Purkinje potentials (stars) and propagates variably from there. Early activations on other beats may
represent unidentified Purkinje activation or activation from working ventricular myocardium.
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F I G U R E 5 Purkinje Fibers Demonstrate Rate and Duration Dependent Spontaneous Activity
(A) 1:1 capture of ventricular myocardium (top tracing) and Purkinje fiber (bottom tracing) at the onset of rapid pacing to simulate longduration ventricular fibrillation. (B) 1:1 capture of Purkinje tissue; however, ventricular myocardial capture is variable and less frequent after
3 min of pacing. (C) A single Purkinje fiber extrasystole occurring after rapid ventricular pacing for 5 s. (D) Multiple, relatively rapid Purkinje
extrasystoles that then conduct to adjacent myocardium (top tracing) with pacing of 20-s duration. (E) Purkinje extrasystoles (asterisks) that
occur after pacing at progressively more rapid rates (1 to 5 Hz). More frequent and rapid Purkinje activations are seen as the pace train rate
increases. CL ¼ cycle length; EGM ¼ electrograms.
(Figure 5B). No ventricular myocardial capture was
Purkinje extrasystoles are seen as the CL of burst
seen beyond 4 min.
pacing decreases.
After a rapid burst pacing protocol for 5 s, a single
Purkinje extrasystole can be seen that conducts
DISCUSSION
to adjacent myocardium. When this burst pacing
protocol is continued for 20 s, multiple Purkinje
This study demonstrates the following findings in
extrasystoles are induced that then conduct to adja-
isolated human hearts. An endocardial to epicardial
cent ventricular myocardium (Figures 5B and 5C).
gradient in activation rate develops during LDVF in
A rate-dependent aspect to this phenomenon is also
humans. The dominant pattern of activation is not
shown in Figure 5D, when more frequent spontaneous
re-entry or scroll wave activation but predominately
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Mechanisms of Human Long-Duration VF
activation from the endocardium with increasing
of
breakdown of wave front propagation toward the
oxygenated LV blood pool (16). Despite the relatively
epicardium. Focal Purkinje potentials precede local
regular endocardial activity in LDVF shown in
ventricular activation on the endocardium. Our ex-
Figure 2C, the phenomenon of wave break at variable
periments are consistent with the hypothesis that
myocardial levels is likely to contribute to the dis-
this focal activity is modulated by rapid endocardial
organized appearance of VF on the surface electro-
activations during SDVF. Together these findings
cardiography (17).
suggest that during the development of LDVF in
humans, a progressive change occurs from a rhythm
driven by re-entry (6) to one driven by focal activations from Purkinje fibers on the endocardium.
Although this study was performed in cardiomyopathic human hearts, the findings are consistent
with those from noncardiomyopathic animal heart
preparations in previous studies (3–5). This is a
mechanistic evaluation of a rhythm that is responsible for the majority of sudden cardiac deaths (15)
and may have implications for different treatment
strategies for VF in its later stages.
TRANSMURAL ACTIVATION SEQUENCES DURING
HUMAN SDVF AND LDVF. The incidence of simulta-
neous transmural needle activations in SDVF in this
epicardial
cardiomyocytes,
away
from
the
RE-ENTRY IS UNCOMMON DURING HUMAN LDVF. Given
the endocardial to epicardial activation rate gradients
in LDVF, it is possible that intramural re-entry within
the surviving endocardium and subendocardium is
responsible for maintaining fibrillation. The criteria
for re-entry in this study, however, were only met in
3 instances in LDVF, all on the endocardium or subendocardium (Table 1). These findings are consistent
with those of other studies that have found less reentry and increasingly frequent focal endocardial
activations as VF progresses over time (5,10,11,18). We
did not look for re-entry in a diagonal line, however,
and needle spacing may have failed to identify small
re-entry circuits in this study.
PURKINJE ACTIVITY DETERMINES ENDOCARDIAL
study was similar to that found by Nair et al. (6)
ACTIVITY
(48.7% (6) vs. 47.7%). The incidence of re-entry in
LDVF, Purkinje potentials could be seen to arise focally
DURING
HUMAN
LDVF. During human
SDVF was also similar (14.3% (6) vs. 15.8%) and is
(occasionally from more than one Purkinje site) and
consistent with the transmural scroll waves or
then activate the endocardium rapidly via the Purkinje
“mother rotors” that were seen migrating though the
system (Figure 3A). At times endocardial foci away
myocardium in SDVF and giving rise to multiple
from the Purkinje network were also seen (Figure 3A,
smaller chaotic wave fronts (6). In LDVF, however,
beats 5 and 6), which also appear to contribute to rapid
wave break or nontransmural propagation of wave
LV endocardial activation. Purkinje fibers have been
fronts occurred 27.9% of the time and the re-entry
shown to be more resistant to ischemia than ventric-
incidence was only 4.2%, suggesting that transmural
ular myocardium and to receive oxygen by diffusion
scroll wave activation is not a predominant feature
from the blood pool (19,20). In combination with this
in human LDVF. In Online Figure 1, LDVF frequently
phenomenon, Purkinje fiber activation has been
displays a different number of beats with different
shown to precede myocardial activation after LDVF
median activation times across adjacent plunge nee-
defibrillation failures in canines, and chemical abla-
dles, which is also inconsistent with regional organi-
tion of the Purkinje system has been shown to lead to
zation from migrating transmural scroll waves.
earlier spontaneous termination of LDVF (4). We did
In LDVF, the greater presence of endocardial to
not perform Purkinje fiber ablation with Lugol solution
epicardial needle activation patterns (54.2% of all
in this study because the endocardial necrosis is not
activation patterns) and the more rapid CL on the
specific to Purkinje fibers, and we found that non-
endocardium compared with the epicardium (441 perfused human hearts were only capable of sustain-
80 ms vs. 590 88 ms) suggests that this phase of the
ing one complete LDVF protocol.
arrhythmia is primarily driven by the endocardium,
Upon unipolar mapping, sharp Purkinje potentials
as has previously been reported in dogs but not pigs
become more prominent on the endocardium as VF
(14,16). The presence of wave break in 27.9% of all
progresses, whereas on the epicardium, the local CL
wave fronts was also a unique finding to LDVF in this
slows and lower frequency signals are seen (Figure 4).
study. Endocardial to epicardial activation with wave
Newton et al. (14) showed that in both canines and
break (seen 15.4% of the time) predominantly ac-
pigs, the regions with dominant frequency in LDVF
counts for the endocardial to epicardial activation
are those where the Purkinje fibers distribute (epi-
rate gradient seen in LDVF (Table 2). This develop-
cardially in pigs and endocardially in canines). Pur-
ment of an endocardial to epicardial activation
kinje potentials may be more difficult to see in SDVF
rate gradient likely relates to greater ischemia
(Figure 4, VF onset) because they are overdrive
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Jackson et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 3, 2015
JUNE 2015:187–97
Mechanisms of Human Long-Duration VF
suppressed by more rapid re-entrant wave fronts or,
given that VF is far more likely to occur in this setting
conversely, persistent bombardment by these rapid
than in structurally normal hearts.
wave fronts may lead to abnormal automaticity in
Purkinje fiber identification in the intact, car-
Purkinje fibers as seen in canine Purkinje fibers in
diomyopathic human heart is challenging (particu-
this study and previously in a sheep model (21).
larly with left bundle branch block). So the human
FOCAL ACTIVITY FROM PURKINJE FIBERS IN LDVF
MAY BE INDUCED BY RAPID ACTIVATIONS DURING
EARLY VF. By simulating rapid activation during
early VF with rapid pacing, focal Purkinje fiber activity occurred that increased in frequency with
increases in both pacing duration and pacing rate
(Figures 5C and 5D). In addition, we were able to show
a greater resistance to ischemia and a greater capacity
for continued 1:1 capture of Purkinje fibers compared
hearts could remain intact, a canine model was used
because the Purkinje fiber distribution in dogs is most
similar to that of humans compared with other
mammals, and the Purkinje fibers can be identified
readily on the canine endocardium. In this model,
simulated VF (with rapid pacing) was used, which
may also lead to different Purkinje fiber effects than
true VF in the human heart.
CONCLUSIONS
with ventricular myocardium (Figures 5A and 5B). It
has been shown previously in animal myocardial
Human LDVF is characterized by an endocardial to
infarct models that after infarction Purkinje fibers
epicardial activation frequency gradient created by
display spontaneous automaticity, enhanced re-
focal endocardial activations with mid-myocardial
sponses to adrenergic interventions, and a tendency
wave break. Re-entry is an uncommon mechanism
to triggered activity (22–24). These mechanisms may
in human LDVF; instead, focal endocardial activa-
also underlie the spontaneous Purkinje fiber activity
tions originate most commonly from Purkinje fibers.
seen in this canine model and in human LDVF in this
Rapid activations during early VF may mediate focal
study. Repeating this LDVF protocol with continued
activity in LDVF and facilitate its maintenance.
perfusion in future studies may help clarify the precise mechanism of Purkinje automaticity.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
The observation in this study of a changing mech-
Kumaraswamy Nanthakumar, The Hull Family Car-
anism sustaining human VF over time suggests that
diac Fibrillation Management Laboratory, Division of
conventional cardiac arrest drugs such as amiodarone
Cardiology, University Health Network, Toronto
(8) or lidocaine (9) may not be the optimal choice in
General Hospital, 150 Gerrard Street West, GW3-526,
VF of longer durations. Instead, medications that
Toronto, Ontario M5G 2C4, Canada. E-mail: kumar.
decrease triggered Purkinje fiber activity (by stabi-
[email protected].
lizing ryanodine receptor calcium release [25], for
example) may be more effective adjuvants when VF
PERSPECTIVES
is resistant to defibrillation or constantly reinitiates.
In the current era, VF is often treated early by
COMPETENCY IN MEDICAL KNOWLEDGE: VF is
implantable cardioverter-defibrillators; however, in
the rhythm most frequently responsible for sudden
patients whose first presentation is out-of-hospital
cardiac death. In humans, VF changes over time from a
cardiac arrest or when implantable cardioverter-
rhythm characterized by re-entry and transmural
defibrillators are not readily available for financial
scroll waves to one dominated by focal endocardial
reasons, patients may experience 10 min or more of
Purkinje fiber activations with mid-myocardial wave
VF before defibrillation. Provided cardiopulmonary
break. It is not clear whether the optimal adjunctive
resuscitation is performed, these patients can survive
strategies for treating VF should also change as the
with good clinical outcomes (1) and may benefit from
rhythm progresses in time.
newer adjunctive therapies for LDVF.
STUDY LIMITATIONS. The use of explanted human
hearts has inherent limitations such as a lack of
autonomic innervation of the myocardium. However,
there are no ethical means of studying the mechanisms of nonperfused human LDVF in in vivo hearts.
The human hearts studied are myopathic, because
normal hearts from deceased donors are used for
transplantation at our institution. Myopathic hearts,
however, are the most relevant substrate to study
TRANSLATIONAL OUTLOOK: Additional research
is needed to further improve outcomes for patients
who experience cardiac arrest as a result of VF. This
research may include the investigation of medications
to reduce Purkinje fiber–triggered activity (such as
ryanodine receptor stabilizing medications) to
improve the efficacy of defibrillation and prevent
refibrillation in LDVF.
Jackson et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 3, 2015
JUNE 2015:187–97
Mechanisms of Human Long-Duration VF
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