Download Endocardial wave front organization during ventricular

Journal of the American College of Cardiology
© 2002 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 39, No. 1, 2002
ISSN 0735-1097/02/$22.00
PII S0735-1097(01)01696-5
Electrophysiology
Endocardial Wave Front Organization
During Ventricular Fibrillation in Humans
Gregory P. Walcott, MD,* G. Neal Kay, MD, FACC,* Vance J. Plumb, MD, FACC,*
William M. Smith, PHD,*† Jack M. Rogers, PHD,† Andrew E. Epstein, MD, FACC,*
Raymond E. Ideker, MD, PhD, FACC*†
Birmingham, Alabama
This study was designed to characterize the organization of ventricular fibrillation (VF) on the
endocardium of humans.
BACKGROUND Most proposed mechanisms for the maintenance of VF postulate the propagation of a number
of activation wave fronts that reenter to maintain the arrhythmia. We tested the hypothesis
that, in patients undergoing internal cardioverter-defibrillator implantation, VF consists
primarily of a few large wave fronts on the endocardium.
METHODS
Electrograms were recorded from a 36-electrode catheter in the left ventricle of 16 patients
during VF. Activation times were chosen for a 2-s epoch for each fibrillation episode, and a
two-dimensional Kolmogorov-Smirnov test was performed to determine if activation
occurred randomly along the catheter over that time interval. The maximum cross-correlation
was found for all possible pairs of electrodes on the catheter, and these values were plotted
relative to the distance between the two electrodes. An exponential curve was then fit to the
data, and a length constant was determined. Activation times were grouped into wave fronts
along the catheter, and the lengths of the wave fronts were estimated.
RESULTS
The Kolmogorov-Smirnov test showed that activation was not random along the catheter in
any of the patients studied. The correlation length determined was 9 ⫾ 2 cm. The number
of wave fronts recorded by the catheter was 9.2 ⫾ 2.9 wave fronts/s. The length of the
pathway of each wave front along the catheter was 6.5 ⫾ 4.5 cm.
CONCLUSIONS Ventricular fibrillation is well organized on the endocardial surface of humans, consisting
primarily of a few large wave fronts on the order of 6 to 9 cm. (J Am Coll Cardiol 2002;
39:109 –15) © 2002 by the American College of Cardiology
OBJECTIVES
The final common arrhythmia in a majority of patients
suffering sudden cardiac death is a hemodynamically unstable tachyarrhythmia, either ventricular fibrillation (VF) or
ventricular tachycardia, that eventually degenerates into VF
(1). Ventricular fibrillation is a difficult rhythm to study in
patients and animal models because of its complexity and
hemodynamic instability.
In 1887, MacWilliam characterized VF as a state in
which “the ventricular muscle is thrown into a state of
irregular arrhythmic contraction” (2). Wiggers used highspeed cinematography to describe four stages of progressive
disorganization through which VF transitions from initiation to cardiac quiescence (3). More recently, multi-channel
computerized electrical and optical cardiac mapping have
been used to record electrograms during VF (4 –10), and
quantitative measures have been developed to describe VF.
Correlation and coherence length have been used to estimate
the spatial organization of VF in animals (11,12). Rogers et al.
developed a series of metrics to describe VF recorded from 504
electrodes on the epicardium of pigs. These metrics include
From the *Division of Cardiovascular Diseases, Department of Medicine, and the
†Department of Biomedical Engineering, University of Alabama at Birmingham,
Birmingham, Alabama. Supported in part by NIH grant HL 66256 and a research
grant from Guidant Corp., St. Paul, Minnesota.
Manuscript received February 22, 2001; revised manuscript received September 5,
2001, accepted September 7, 2001.
wave front size, the number of wave front fragmentations and
collisions that occur per unit time, the conduction velocity of
the wave fronts and the repeatability of wave fronts over time
(13). Gray et al. (14 –16) have recently shown the applicability
of spiral-wave theory to VF. Almost all of these studies
reported that VF is organized with activation fronts following
pathways that are centimeters in size.
All of these studies, though, were performed in animals,
where the heart size is smaller and the activation rate of VF
is faster than in humans. Although several studies have
characterized VF in humans from body-surface electrodes
(17–19), single extracellular electrodes (20) or monophasic
action potential electrodes (21) and epicardial multi-site
mapping in Langendorff-perfused explanted hearts (22),
little has been done to map VF from multiple sites simultaneously in intact humans.
In this study, we tested the hypothesis that endocardial
activation during VF in humans consists primarily of a few
large wave fronts by simultaneously recording over a wide
expanse of the left ventricle (LV). We analyzed these
recordings to determine whether activation occurred randomly or in an organized pattern. We estimated the extent
of spatial organization during VF using the correlation
length. Finally, we grouped activations to estimate the size
and number of wave fronts recorded along the catheter.
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Mapping of Ventricular Fibrillation in Humans
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January 2, 2002:109–15
Abbreviations and Acronyms
LV ⫽ left ventricle, left ventricular
VF ⫽ ventricular fibrillation
From these data we estimated the size and number of wave
fronts in the human heart during VF.
METHODS
Study population. This protocol was approved by the
University of Alabama at Birmingham Internal Review
Board for human studies, and written informed consent was
obtained from each participant. Patients who were undergoing implantation of an internal cardioverter-defibrillator
and who had no contraindications to having an electrophysiology catheter placed in the LV were eligible to participate
in this study. Contraindications included a thrombus in the
LV, a mechanical aortic or mitral valve, peripheral vascular
disease including previous aorto-bifemoral bypass or
femoral-distal bypass surgery, or failure to obtain informed
consent.
Data collection. A 36-pole catheter with 1-mm platinum
bands spaced 4 mm apart (ElectroCatheter Corp., Rahway,
New Jersey) was advanced from a femoral artery and across
the aortic valve. It was positioned in the LV so that pole 1
(most distal) was in the antero-basal segment of the LV free
wall, poles 16 –22 were at the LV apex and pole 36 (most
proximal) was in the postero-basal segment of the interventricular septum (Fig. 1). A standard decapolar or hexapolar
catheter was placed in the coronary sinus. This catheter was
advanced as far as possible into the coronary sinus to record
electrograms from the base of the LV free wall.
In the first eight patients, electrograms were recorded
from every other pole of the 36-pole LV catheter and the
coronary sinus catheter using a 32-channel mapping system
(Pruka Engineering, Dallas, Texas). Unipolar electrograms
were recorded at a sampling rate of 1 kHz at a gain of 500
and band-pass filtered from 5 Hz to 500 Hz. Electrograms
were saved on an optical disk for off-line analysis.
In the last eight patients, a custom-designed 144-channel
mapping system was used to record unipolar electrograms
from all 36 poles of the LV catheter and all poles of the
coronary sinus catheter. Electrograms were recorded at a
gain of 100 and band-passed filtered from 5 Hz to 500 Hz.
Electrograms were recorded during the VF that was
induced during normal defibrillation testing, performed as
part of the defibrillator implantation procedure. Ventricular
fibrillation was induced by burst pacing and was allowed to
continue for 8 to 10 s before a defibrillation test shock was
delivered. The data analyzed in this paper were recorded in
the 2 s just before the delivery of the test shock. Either one
or two episodes of VF were analyzed from each patient.
Test of activation randomness along length of catheter. Activation times were determined using a computerized algorithm and were manually edited. The maximum
Figure 1. An anterior-posterior fluoroscopic image of a patient undergoing
the implantation of an implantable cardioverter-defibrillator and ventricular fibrillation mapping. A 36-pole catheter is in the left ventricular (LV)
cavity. The distal electrodes of the catheter are recording from the
antero-lateral wall of the left ventricle (LV). The proximal electrodes of the
catheter are recording from the postero-septal wall of the LV. A defibrillation catheter is positioned in the apex of the right ventricle. A six-pole
catheter is in the coronary sinus.
downslope of the electrogram was chosen as the local
activation time (23). The activation rate during VF was
calculated for each patient by averaging the R-R interval for
each electrogram over the 2 s of data analyzed. A
Kolmogorov-Smirnov test of randomness was performed on
the activation times (24). Briefly, this test determines the
probability that data in a two-dimensional plot are consistent with a uniform random distribution. In this case, the
two dimensions of data were electrode number and activation time. The data for each VF episode were considered
random if the p value determined for that episode was
⬎0.05.
Correlation length determination. After the mean value
of the electrogram amplitude was subtracted from each
point of the electrogram (to remove any DC offset), crosscorrelations were calculated between every pair of electrograms with lags from ⫺2 s to 2 s. Cross-correlations were
normalized so that the auto-correlation for each electrode
was 1. Then the maximum correlation between each pair of
electrodes was plotted as a function of distance between the
two electrodes. Using non-linear regression, an exponential
curve of the equation Max(R) ⫽ e⫺d/␭, where Max(R) is the
maximum correlation between each pair of electrodes and d
is the distance between the two electrodes, was fit to the
data points to determine the length constant, ␭, the distance
at which the correlation falls to 0.37 (11). Analysis was
performed on a Sun Sparc station 20 (Sun Microsystems,
Sunnyvale, California) using MATLAB software (The
Mathworks Inc., Natick, Massachusetts).
Walcott et al.
Mapping of Ventricular Fibrillation in Humans
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January 2, 2002:109–15
111
Table 1. Patient Characteristics
Age
Men/Women
Cardiac disease
Coronary artery disease
Cardiomyopathy
Primary electrical disease
Indictation for ICD implantation
Ventricular fibrillation
Ventricular tachycardia
Ejection fraction
Antiarrhythmic drugs
Amiodarone
Beta-blocker
Ca⫹2 channel blocker
Digoxin
59 ⫾ 14 yrs
12/4
10
3
3
10
6
33% ⫾ 15%
3
7
2
4
ICD ⫽ implantable cardioverter-defibrillator.
Estimation of the size and number of wave fronts. The
activations determined as previously described were grouped
into wave fronts. Activations occurring within 40 ms of each
other on adjacent electrodes were grouped into a single wave
front. A minimum of three adjacent electrodes meeting this
criterion was required to define a wave front. The length of
the pathway of a wave front along the catheter was defined
as the number of electrodes grouped into the wave front
multiplied by the inter-electrode spacing (0.4 cm).
RESULTS
Sixteen patients, age 59 ⫾ 14 years, (mean ⫾ standard
deviation) were studied. Patient characteristics are shown in
Table 1. Electrode 1 of the catheter was always in an
antero-basal position, and electrode 36 of the catheter was
always in a postero-basal position. An example of recorded
electrograms from the 36-pole catheter is shown in Figure
2. Surface lead II is shown in the first trace. The subsequent
traces are electrograms from the LV catheter.
The activation interval during VF was 218 ⫾ 36 ms.
Figure 3A shows the activation times from a second patient.
For comparison, Figure 3B shows a plot with the same
number of data points as in panel A, but plotted in a
uniform random distribution. For each VF episode tested,
the distribution of activation over the catheter for the 2 s
analyzed was not consistent with a uniform random distribution, p ⬍ 0.05 for each episode.
Figure 4 shows electrograms from a third patient that
demonstrate highly organized activations on the endocardium, while the body surface lead II recording appears
disorganized. Figure 5 is a plot of maximum crosscorrelation between pairs of electrodes on the catheter as a
function of distance between the electrodes. The length
constant averaged 9 ⫾ 2 cm across the group of patients.
The total length of the line of electrodes on the catheter was
14 cm. Because the catheter spanned a large portion of the
endocardial surface, albeit only in one plane, these data
suggest that there are only a few wave fronts on the
endocardium at any given time during VF in humans.
The average number of wave fronts that were recorded by
Figure 2. Unipolar electrograms recorded from one episode of ventricular
fibrillation. The top trace is body surface lead II. The next 36 traces are
from the catheter in the left ventricle. Approximately 2 s of data are shown.
The time between plus symbols is 100 ms. The diamonds mark the 1-s
point in the data. The daggers mark the time when local activation was
judged to have occurred.
the catheter was 9.2 ⫾ 2.9 wave fronts/s. The size of the
wave fronts measured along the catheter was 6.5 ⫾ 4.5 cm.
An example of the wave front isolation is shown in Figure 6.
DISCUSSION
The main findings from this study are threefold. First, the
activation pattern during human VF is not random. Second,
the correlation length along the catheter during VF is long,
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Walcott et al.
Mapping of Ventricular Fibrillation in Humans
Figure 3. (A) Activation times from another patient, each plotted as a
function of electrode number. The x-axis is time in milliseconds. The
y-axis is electrode number. Note that activation fronts propagate for long
distances along the catheter. (B) Simulated activation times as a function of
electrode number. The same number of activations are plotted as in A.
Activations are randomly distributed in time along the catheter.
9 ⫾ 2 cm. Third, activations could be grouped into wave
fronts with a mean length of 6.5 ⫾ 4.5 cm along the
catheter. All of these results suggest that 8 to 10 s after
electrical induction, VF in humans consists primarily of a
few large wave fronts on the endocardium at any given time.
Over the past 125 years, several electrophysiologic mechanisms have been proposed for the maintenance of VF (25).
Most proposed mechanisms postulate the propagation of a
number of activation wave fronts that reenter to maintain
the arrhythmia. Classically, VF is thought to consist of
multiple disorganized wavelets that follow constantly
changing reentrant pathways. Although some results sug-
JACC Vol. 39, No. 1, 2002
January 2, 2002:109–15
gest that the number of wandering wavelets is large, others
suggest that during the first minute of VF the number of
wave fronts is small, perhaps only one (14 –16). This
conclusion is supported by several pieces of evidence. First,
on the basis of cinematographic studies, Wiggers stated (26)
that soon after its onset VF cannot be described adequately
as asynchronous contraction of individual myocardial fibers,
but rather that coordination and synchrony are present over
large sections of myocardium (26). These large sections
progressively decrease in size and increase in number over
the first minutes of VF. Second, Garrey et al. (27) showed
that a critical mass of myocardium, at least one fourth of the
ventricular muscle in dogs, must be present for VF to
persist. Third, frequency analysis of humans and dogs
demonstrated a power spectrum with a well-defined peak
and higher harmonics (28), suggesting some degree of
organized activation during VF. Recent animal data suggest
that one or two primary wave fronts located in the regions
with the fastest activation rates may drive the rest of the
heart and that these one or two activating regions, not the
entire myocardium, are responsible for the maintenance of
fibrillation (29,30).
The Kolmogorov-Smirnov test is a non-parametric test
that determines whether a distribution of points is uniform
across space. The results of the Kolmogorov-Smirnov test
here showed that the activation times recorded during VF
on the 36-pole catheter did not occur randomly but rather in
an organized fashion in all patients. The simplest explanation for this organization is that individual wave fronts are
larger than the 4-mm inter-electrode spacing along the
catheter. These single wave fronts “sweep” along the catheter, activating multiple electrodes in sequence. In contrast,
if activation wave fronts were smaller than 4 mm, then
individual wave fronts would activate single electrodes,
giving rise to a random activation pattern.
In order to better define the size of activation wave fronts
during VF, we used a spatial correlation length measure.
Correlation length is a widely used measure of spatial
organization. Longer correlation lengths are associated with
larger structures and more organized behavior. Correlation
length has been used to help understand a wide variety of
complex systems (31–33). The correlation length has recently been proposed as an estimate of the size of the
reentrant pathway for both atrial fibrillation (34,35) and VF
(11).
The correlation length measured here in humans is much
longer than that in pigs, which was 4 to 10 mm (11). There
are several possible reasons for this difference. First, the
activation rate during VF is almost twice as fast in pigs as it
is in humans. Second, the animal hearts were normal,
whereas a majority of the patients had some form of
structural heart disease. Third, and probably most important, we mapped the endocardial surface, whereas the
epicardial surface of the heart was mapped in pigs. Worley
et al. (36) recorded electrograms from electrodes along a
plunge needle that was positioned transmurally in dog
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Walcott et al.
Mapping of Ventricular Fibrillation in Humans
113
Figure 4. Recorded electrograms from a third patient during ventricular fibrillation. The top trace is body surface lead II. The next 12 traces are from
electrodes 13 through 24 from the 36-pole catheter in the left ventricle (LV). Approximately 2 s of data are shown. These recordings represent the electrical
activity from the antero-lateral wall of the LV.
hearts. They showed that after 1 to 2 min of VF the
electrograms recorded from the endocardium were sharper
and less complex than those recorded from the epicardium.
Future studies need to be performed to better understand
this difference.
Wave front isolation showed that the average size of a
wave front was 6.5 ⫾ 4.5 cm. Taken together with the
correlation length, we can estimate the number of wave
fronts on the endocardial surface at any given time. If it is
assumed that all parts of the endocardium behave similarly
during VF, simple scaling arguments can be used to estimate the global complexity of fibrillation. If wave fronts on
the endocardium are on average 6.5 to 9 cm (the range given
by our two measures of wave front size, the correlation
length and wave front isolation), then each wave front may
cover an area of 42 to 81 cm2 (6.5 cm2 to 9 cm2) (11). If we
assume an endocardial area of 154 cm2 (␲*(length of the
catheter/2)2), then we would estimate that two to four areas
of activation should exist on the endocardium at any given
time. Though a rough calculation, these numbers suggest
that VF on the endocardium of humans consists primarily of
a few relatively large wave fronts at any given time.
Figure 5. Maximum correlation between the electrogram potentials as a
function of distance between electrodes from one patient. Each point
represents the maximum cross-correlation from one pair of electrograms.
The solid line represents the exponential curve that was fit to the data. The
value of lambda, the length constant, is approximately 10 cm for this
episode of ventricular fibrillation.
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Figure 6. Wave front isolation from one episode of ventricular fibrillation. Activations along the catheter are grouped into a wave front if adjacent activation
times are within 0.04 s of each other.
Study limitations. The major limitation of this study is
that the recordings were made only from the endocardium
and from a single line of electrodes. Ventricular fibrillation
is likely to be more complex than the view that this catheter
provides. The heart is a three-dimensional structure, and
the wave fronts of VF can propagate in all three directions
(37). As multipolar three-dimensional catheters become
available and/or epicardial plaque mapping of patients
undergoing open-heart surgery is performed (38), it may be
possible to map fibrillation more completely and come to
more complete conclusions about the size and number of
wave fronts that support the arrhythmia, as well as to
describe how those wave fronts interact to perpetuate the
arrhythmia.
We did not differentiate between VF and polymorphic
tachycardia. The differentiation between these two rhythms
is usually based on rate. We did not see the number or size
of wave fronts change with the activation rate; therefore,
there is no reason to think that our results are skewed by
episodes of polymorphic tachycardia.
Clinical implications. Understanding the patterns of activation during VF may lead to more effective therapeutic
options for halting arrhythmias. If there are many small
wave fronts in the ventricle during fibrillation, then there is
little possibility of “synchronizing” a shock to some feature
of the fibrillation in order to lower the defibrillation threshold. If there are only a few large wave fronts during VF, then
there is a greater possibility of “synchronizing” a defibrillation shock.
It may also be possible to use pacing-sized stimuli to help
lower the defibrillation threshold in humans. KenKnight et
al. (39) have shown that there is an excitable gap during VF
in pigs on the epicardium and that 5 to 20 cm2 can be
“captured” by pacing during the arrhythmia (40). Our data
suggest that there are fewer wave fronts on the endocardium
during VF in humans than there are on the epicardium of
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January 2, 2002:109–15
pigs. Therefore, it may be easier to stimulate and capture the
ventricle during fibrillation in humans, and it may be
possible to stimulate a larger region of the heart with each
pacing pulse. Controlling activation in a region of the heart
during fibrillation, especially in a region that contains the
earliest sites of global activation after failed defibrillation
shocks, may help lower the defibrillation threshold.
Conclusions. Ventricular fibrillation in patients who have
suffered cardiac arrest or sustained VF is characterized by a
few large wave fronts of activation.
Reprint requests and correspondence: Dr. Gregory P. Walcott,
B140 Volker Hall, 1670 University Blvd., University of Alabama at
Birmingham, Birmingham, Alabama 35294. E-mail: gpw@crml.
uab.edu.
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