Online Supplement
David E. Krummen, MD, FACC, FHRS1,2
Justin Hayase, MD1,2
David J. Morris, MD1,2
Jeffrey Ho, MD1,2
Miriam R. Smetak, BS2
Paul Clopton, MS2
Wouter-Jan Rappel, PhD1,2
Sanjiv M. Narayan, MD, PhD, FACC, FHRS1,2
1
2
University of California San Diego, San Diego, CA
Veterans Affairs San Diego Healthcare System, San Diego, CA
Page S1
Table of Contents
I.
Supplemental Movie Descriptions
page S3
II.
Data Supplement: Simulation of VF and Mapping
page S4
III.
Data Supplement: Comparison of VF by Induction Method
page S6
IV.
Data Supplement: Ventricular Activation during Rapid Pacing
page S7
V.
Data Supplement: Relationship between CL and Duration
page S8
VI.
Data Supplement: Comparison of Apical and Basal Mapping
page S9
VII.
References
page S11
Page S2
I. Supplemental Movie Descriptions
Supplemental Movie 1: Movie shows a left ventricular rotor in a 73 year old patient with an
ejection fraction of 25%. The rotor is observed in the mid-septal LV, and completes 15 counterclockwise rotations. The phase singularity around which rotation occurs is identified by the
stationary pink dot (center of image), which remains visible for the duration of the rotor. This
episode of ventricular fibrillation required defibrillation.
Supplemental Movies 2 and 3: These movies show samples of spatially conserved right
ventricular rotors during 2 consecutive VF inductions in a 63 year old patient with nonischemic
cardiomyopathy, recurrent VT, and an ejection fraction of 40%. The clockwise rotors both occur
in the posterior right ventricle, and persist for 48 and 34 consecutive clockwise rotations,
respectively. Both episodes of VF required defibrillation.
Supplemental Movie 4: Movie shows a left ventricular focal source in a 68 year old patient with
an ejection fraction of 32%. Notice the greater proportion of electrical diastole and lack of
rotation compared with the rotor examples. This episode of ventricular fibrillation terminated
spontaneously during defibrillator charging.
Supplemental Movie 5: Movie shows disorganized activity with no clear rotor or focal source in
a 52 year old patient with a normal EF. Activation patterns are varying and chaotic, spanning the
VF cycle.
Page S3
Supplemental Movie 6: This movie shows right (left side of image) and left (right side of
image) ventricular activation during rapid pacing from the RV at a cycle length (CL) of 220
msec. Activation shows centrifugal activation from the pacing site without evidence for rotors.
Image conventions are similar to those in online supplement figure S2 (below).
II. Data Supplement: Simulation of VF and Mapping
Prior work has shown that rotor filaments spanning from endocardium to epicardium
display spiral waves endocardially (1,2). To explore the effects of a non-endocardial rotor
filament configuration on endocardial mapping during VF, we created a 3D computational model
of spiral wave activity. For these experiments, the Barkley model (3) was implemented using a
200x100x100 grid with a grid space of dx=0.4 and a timestep of dt=10-4 (all units are
dimensionless). Parameters were set as follows: a=1.1, b=0.18, epsilon=0.02, and diffusion
constants set to 1, consistent with prior work (4). We examined a hairpin-shaped filament with
both ends terminating on the epicardium (figure S1A and S1B). This filament was initiated
using the procedure detailed in Dutta et al. (4).
This filament configuration results in focal activation on the endocardium (figure S1C)
and spiral waves on the epicardium (figure S1D).
Page S4
Figure S1. Half-maximal activation (orange wavefront) due to a rotor filament (red),
with both ends terminating on the epicardium, shown from an endocardial view (S1A), and an
epicardial view (S1B). Endocardial activation (S1C) shows focal activation, while epicardial
activation shows rotors (S1D).
These results are in concordance with prior work (5). Importantly, the majority of focal
sources in our study were not consistent with observed rotors; only 2/12 rotors (17%, p=NS) in
patients with 2 episodes of VF with focal activity were spatially conserved between VF
inductions. We therefore estimate the proportion of potential misclassified rotors as a minority
(<20%) of the observed focal sources. The majority may represent triggered activity (6),
Purkinje-muscle reentry (5), or alternative mechanisms. Future studies, using combined
endocardial and epicardial recordings, may clarify the nature of the observed focal activation.
Page S5
III. Data Supplement: Comparison of VF by Induction Method
Significant insights into VF mechanisms have been made studying VF induced by rapid
pacing (7-10) and T wave shock (11,12). Prior work evaluating differences in VF between rapid
pacing induction and T-wave shock have shown no difference in surface ECG dominant
frequency or defibrillation threshold (13). However, it is unclear whether differences in
intracardiac rate, regularity, rotor number, or rotor duration exist. We hypothesized that VF
characteristics would not be significantly different between these induction techniques.
The pacing protocol consisted of interrupted, rapid pacing at decreasing cycle lengths to
induce VF, with a 1 minute recovery interval between pacing attempts. The duration of
continuous pacing immediately prior to VF induction was 13.7±7.9 seconds. For shock-on-T
induction, 3.2 seconds of rapid pacing preceded a 2 Joule T-wave shock. Both induction
methods were less than the 30 second threshold previously demonstrated for ischemia to
significantly affect VF mechanisms (7).
Using electrograms recorded from the biventricular basket catheters (128 electrodes), we
calculated VF rate both using dominant frequency (DF) (14) and with a validated autocorrelation
(autoCL) algorithm (15). We also calculated VF regularity using peak area ratio (PAR) (14,16)
and regularity index (RI) (17). Each measure was computed at each electrode over consecutive 1
second intervals for the duration of VF. These values were then averaged to determine the
global value in each VF episode.
We also compared the number and duration of VF rotors between the two induction
types. Shock-on-T and rapid pacing VF episodes were then matched by left ventricular EF,
Page S6
which has previously been shown to affect VF rate (18,19), and characteristics were evaluated
using the paired t test.
As shown in Table S1, there were no differences in any of the measured parameters.
These findings are in agreement with those by Zima and colleagues (13), and support the
hypothesis that VF mechanisms are conserved for different induction techniques.
Table S1. Comparison of Rapid Pacing-induced and Shock-induced VF
Characteristic
Dominant Frequency, Global (Hz)±SD
Autocorrelation CL, Global (msec)±SD
Peak Area Ration, Global±SD
Regularity Index, Global±SD
Number of Rotors±SD
Rotor Duration (msec)±SD
Pacing-Induced VF Shock-Induced VF
4.3±0.3
4.7±0.7
229±16
214±23
0.59±0.04
0.60±0.03
0.19±0.03
0.20±0.02
1.8±0.4
1.6±0.5
3181±249
2932±538
p
0.42
0.3
0.84
0.34
0.4
0.4
IV. Data Supplement: Ventricular Activation during Rapid Pacing
We examined ventricular activation during rapid pacing in all patients with induced VF
(n=19 patients). We mapped activation at the fastest paced rate achieved with 1:1 activation and
prior to induction of VF. The average paced cycle length (CL) evaluated was slower, but not
statistically different, than the final VF CL (evaluated paced CL: 220±32 msec; VF CL 210±26
msec; p=0.16).
Figure S2 (below) and supplemental movie 6 show biventricular activation during pacing
at a CL of 220 msec in a 73 year old patient with an ejection fraction of 25%. (VF initiated at a
paced CL of 210 msec in this patient, and the final VF CL was 199 msec). Notably, laminar
activation without rotation is shown in the isochronal plots, and no consistent phase singularity is
observed in the phase movie.
Page S7
Figure S2. Isochronal map of biventricular activation during pacing at CL 220 msec. Laminar
activation occurs during rapid pacing from the RV apex. No rotational activation is seen.
Overall, there was no evidence (0 of 19 patients) of rotors during rapid pacing prior to the
onset of VF. We conclude that mapping and motion artifact did not create the appearance of
rotors during rapid pacing at CLs approximating VF.
V. Data Supplement: Relationship between CL and Duration
In prior work, structural heart disease (LV size (18,19)) and electrical remodeling
(gradients in IK1 (20)) were found have an impact on VF dynamics. To further investigate the
importance of electrical remodeling on rotor formation, we analyzed the relationship between
rotor CL and temporal stability. As shown in figure S3, we found no significant correlation
(R2=0.02, p=0.4) between these rotor characteristics.
Page S8
Figure S3. Relationship between rotor cycle length and temporal stability (R2=0.02, p=0.4).
Future work should investigate the electrophysiologic properties of rotor sites to
determine the precise alterations which support rotor formation and stabilization in human VF.
VI. Data Supplement: Comparison of Apical and Basal Mapping
Ventricular anatomy varies from apex to base. To assess for differences in mapping
conditions between apical and basal basket electrodes, we compared rotor data from sustained
VF episodes according to location. We defined basal rotors as those rotors observed at basket
electrodes 7 and 8, and apical rotors as rotors observed at basket electrodes 1 and 2. Because
Page S9
patients could potentially contribute multiple rotors to the analysis, repeated measures analysis of
variance was used for statistical analysis.
There were no significant differences in rotor characteristics between apical and basal
rotor locations (table S2). Future studies should determine if larger rotor samples show evidence
of anatomically-based variance in VF characteristics.
Table S2. Comparison of apical and basal rotor characteristics in sustained VF.
Characteristic, Sustained VF
Percent of Observed Rotors
Rotor Core Cycle Length (msec)
Rotor Prevalence (% of VF Cycles)
Maximum Rotor Stability (Consecutive VF Cycles)
Page S10
Apical Rotors
21%
212±33
79±17%
16.2±8.0
Basal Rotors
21%
205±9
67±23%
16.0±9.1
p
1
0.65
0.38
0.97
VII.
References
1.
Fenton F, Karma A. Vortex dynamics in three-dimensional continuous myocardium with
fiber rotation: Filament instability and fibrillation. Chaos 1998;8:20-47.
Rappel WJ. Filament instability and rotational tissue anisotropy: A numerical study using
detailed cardiac models. Chaos 2001;11:71-80.
Barkley D. A Model for Fast Computer-Simulation of Waves in Excitable Media.
Physica D 1991;49:61-70.
Dutta S, Steinbock O. Steady motion of hairpin-shaped vortex filaments in excitable
systems. Physical Review E 2010;81.
Berenfeld O, Jalife J. Purkinje-muscle reentry as a mechanism of polymorphic ventricular
arrhythmias in a 3-dimensional model of the ventricles. Circ Res 1998;82:1063-77.
Pogwizd SM, Corr B. The contribution of nonreentrant mechanisms to malignant
ventricular arrhythmias. Basic research in cardiology 1992;87 Suppl 2:115-29.
Bradley CP, Clayton RH, Nash MP, et al. Human ventricular fibrillation during global
ischemia and reperfusion: paradoxical changes in activation rate and wavefront
complexity. Circulation. Arrhythmia and electrophysiology 2011;4:684-91.
Cao JM, Qu Z, Kim YH, et al. Spatiotemporal heterogeneity in the induction of
ventricular fibrillation by rapid pacing: importance of cardiac restitution properties.
Circulation research 1999;84:1318-31.
Pak HN, Kim GI, Lim HE, et al. Both Purkinje cells and left ventricular posteroseptal
reentry contribute to the maintenance of ventricular fibrillation in open-chest dogs and
swine: effects of catheter ablation and the ventricular cut-and-sew operation. Circulation
journal : official journal of the Japanese Circulation Society 2008;72:1185-92.
Zaitsev AV, Berenfeld O, Mironov SF, Jalife J, Pertsov AM. Distribution of excitation
frequencies on the epicardial and endocardial surfaces of fibrillating ventricular wall of
the sheep heart. Circulation research 2000;86:408-17.
Russo AM, Sauer W, Gerstenfeld EP, et al. Defibrillation threshold testing: is it really
necessary at the time of implantable cardioverter-defibrillator insertion? Heart Rhythm
2005;2:456-61.
Zaitsev AV, Guha PK, Sarmast F, et al. Wavebreak formation during ventricular
fibrillation in the isolated, regionally ischemic pig heart. Circulation research
2003;92:546-53.
Zima E, Gergely M, Soos P, et al. The effect of induction method on defibrillation
threshold and ventricular fibrillation cycle length. Journal of cardiovascular
electrophysiology 2006;17:377-81.
Krummen DE, Peng KA, Bullinga JR, Narayan SM. Centrifugal gradients of rate and
organization in human atrial fibrillation. Pacing Clin Electrophysiol 2009;32:1366-78.
Ravi KC, Krummen DE, Tran AJ, Bullinga JR, Narayan SM. Electrocardiographic
measurements of regional atrial fibrillation cycle length. Pacing Clin Electrophysiol
2009;32 Suppl 1:S66-71.
Hoppe BL, Kahn AM, Feld GK, Hassankhani A, Narayan SM. Separating atrial flutter
from atrial fibrillation with apparent electrocardiographic organization using dominant
and narrow F-wave spectra. J Am Coll Cardiol 2005;46:2079-87.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
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17.
18.
19.
20.
Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of
high-frequency excitation in the posterior left atrium of the isolated sheep heart during
atrial fibrillation. Circulation 2006;113:626-33.
Watanabe H, Chinushi M, Sugiura H, et al. Unsuccessful internal defibrillation in
Brugada syndrome: focus on refractoriness and ventricular fibrillation cycle length.
Journal of cardiovascular electrophysiology 2005;16:262-6.
Fenelon G, Stambler BS, Huvelle E, Brugada P, Stevenson WG. Left ventricular
dysfunction is associated with prolonged average ventricular fibrillation cycle length in
patients with implantable cardioverter defibrillators. Journal of interventional cardiac
electrophysiology : an international journal of arrhythmias and pacing 2002;7:249-54.
Samie FH, Berenfeld O, Anumonwo J, et al. Rectification of the background potassium
current: a determinant of rotor dynamics in ventricular fibrillation. Circulation research
2001;89:1216-23.
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