(Circulation. 1999;100:666-674.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Mechanism of Procainamide-Induced Prevention of Spontaneous Wave Break During Ventricular Fibrillation
Insight Into the Maintenance of Fibrillation Wave Fronts
From the Divisions of Cardiology, Department of Medicine, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif (M.Y., T.-J.W., R.D., P.-S.C., H.S.K.), and the Division of Cardiology, Korea University, Seoul, Korea (Y.-H.K.).
Correspondence to Hrayr S. Karagueuzian, PhD, Division of Cardiology, Cedars-Sinai Medical Center, Davis Research Bldg, Room 6066, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail karagueuzian{at}csmc.edu
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Abstract |
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Background—Ventricular fibrillation (VF) is maintained by 2 mechanisms: first by reentry formation and second by spontaneous wave break or wave splitting. We hypothesized that spontaneous wave break results from a critical shortening of the action potential duration (APD) during VF and that its prevention by procainamide eliminates spontaneous wave break.
Methods and Results—The endocardial surfaces of 7 isolated, perfused swine right ventricles were mapped with a 3.2x3.8 cm plaque with 477 bipolar electrodes. Activation pattern during VF was visualized dynamically while simultaneously recording epicardial action potentials with a glass microelectrode. APD restitution curves were constructed during VF (dynamic) and during S1S2 protocols. At baseline, VF was maintained by 5.3±1 wavelets. Procainamide (PA) at 10 µg/mL decreased the number of wavelets to 3.5±1 (P<0.05). At baseline VF was maintained by spontaneous wave break and by new reentrant wave front formation. PA eliminated spontaneous wave break during VF while having no effect on reentry formation. PA increased the cycle length of the VF (148.5±41.2 ms vs 81±10 ms, P<0.01) and the core area of the reentry from 5.8 to 14.5 mm2 (P<0.05). Dynamic APD restitution curve during VF showed that PA eliminated the initiation of activation with APDs shorter than 30 ms. The effects of PA on cellular properties and wave front dynamics were reversed during 60 minutes of drug-free perfusion.
Conclusions—Critically short APDs during VF promote spontaneous wave break. Their elimination with PA, however, maintains VF by generating new reentrant wave front.
Key Words: fibrillation • waves • reentry • action potentials
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Introduction |
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We recently have shown that during ventricular fibrillation (VF), 2 different mechanisms continuously generate "daughter" wavelets that maintain the VF.1 2 The first mechanism, wave-wave interaction, leads to the formation of a reentry.1 2 Reentry by wave-wave interaction occurs when 2 fronts intersect perpendicularly. One front traveling north-south, for example, blocks at the site of residual refractoriness left behind by another wave that had just traveled east-west.1 2 Simulation studies have replicated the mechanism of reentry formation by wave-wave interaction.3 The second mechanism that sustains the VF is spontaneous wave break (wave splitting).2 4 According to this scenario conduction block occurs at a specific site along the wave front while the remaining portions of the front continue to propagate. The localized block, wave break, causes splitting of the mother wave front into 2 daughter wavelets. The mechanism(s) of spontaneous wave break remains poorly understood. Simulation studies suggest that spontaneous wave break occurs at sites where wave length (product of action potential duration, APD, and conduction velocity, CV) is critically short.5 6 Short wavelengths often result from very short APDs that frequently occur during rapid rates of activation due to myocardial cell APD restitution.5 7 Block with short APD is also shown to occur in isolated atrial tissue.8 In the present study we hypothesized that the development of spontaneous wave break during VF is related to the incidence of critically short APDs and that prevention of activation with such short APDs with procainamide (PA) prevents spontaneous wave break.
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Methods |
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Surgical Methods
Seven farm pigs (weight 27 to 35 kg) of either sex were anesthetized with sodium thiopental 20 mg/kg IV . The chest was opened with a median sternotomy, the hearts were removed, and the right ventricle (RV) was perfused through the right coronary artery as described previously.9 The RV was perfused with 37°C Tyrode's solution gassed with 95% O2 and 5% CO2 at a flow rate of 20 mL/min. The composition of the solution was as follows (mmol/L): NaCl 125.0, KCl 4.5, MgCl2 0.5, CaCl2 0.54, NaH2PO4 1.2, NaHCO3 24.0, and glucose 5.5, with a pH of 7.35.9 The isolated RV was placed with the endocardial side down in a tissue bath, and the entire tissue was also superfused with warmed (37°C) oxygenated Tyrode's solution. Two bipolar electrodes were placed on the RV for continuous recording and pacing the tissue. A pair of defibrillation coil electrodes (CPI) were placed on either side of the tissue bath and were connected to a HVS-02 external defibrillator (Ventritex).
Computerized Mapping Studies
At the bottom of the tissue bath was a built-in electrode array
containing 477 active bipolar recording electrodes in a
21-column and a 25-row plaque. The interelectrode distance was 1.6
mm, and the interpolar distance was 0.5 mm measured from center to
center. The electrodes were connected to a computerized mapping system
that we described previously.9 10 11 12 The patterns of
activation were visualized dynamically on the computer screen, in which
each electrode site was illuminated when an activation was
recorded.1 9 11 12 Each site (dot) initially turned
red, then pink, then yellow, then green, and finally purple before
fading to background (black) color. The core size of the reentry was
measured during dynamic display by tracing the inner most edge of the
wave front (tip) after 1 complete rotation.2 13 The number
of wave fronts was defined as the number of sites depolarized that were
separated from each other by recovered tissue.9 The length
of each wavelet was measured by counting the number of continuous
adjacent sites undergoing depolarization and then by multiplying this
number by 1.6 mm when propagation was parallel to the axes of the
plaque and by 2.26 mm when it was diagonal to them. CV during VF
was determined by analyzing 1 of the 2 interacting wave fronts that was
parallel to the axes of the plaque and then by dividing the distance
(number of consecutive electrodes multiplied by 1.6 mm) by the
time taken to travel that distance.2
Recording of Transmembrane Action Potentials
Transmembrane action potentials were recorded from 1
randomly chosen epicardial site with a standard glass microelectrode
filled with 3 mol/L KCl and digitized at 3.13 kHz with 12-bit accuracy
(Axon Instruments, Inc).9 11
Study Protocol
In all isolated RV tissues, spontaneous VF occurred during the
isolation procedure and persisted in the tissue bath. Several 8-second
VF data were acquired while continuously recording
transmembrane action potentials.
Protocol 1
In 4 tissues, VF was allowed to continue undisturbed, and PA (5
µg/mL) then was added to the perfusate and maintained for 30
minutes. Every 5 minutes during infusion of PA, transmembrane
potential recordings and mapping studies were repeated.
The concentration of PA was then progressively increased to 10 and 15
µg/mL until VF terminated or converted to monomorphic
tachycardia (MVT). Reversibility of drug effect was
evaluated 60 minutes after drug-free Tyrode's perfusion.
Protocol 2
In 3 tissues, after acquisition of simultaneous
action potential and activation map data during VF at predrug, baseline
state, biphasic shocks of 1.5 to 3.0 J were used to defibrillate the
RV. The RV was then paced with twice diastolic threshold
current at 400-ms cycle length (CL) and the APD restitution curve
constructed by the extrastimulus method14 15 VF was then
induced by rapid pacing, and the effects of PA were evaluated as in
protocol 1.
Dynamic APD Restitution During VF
The APD restitution curves were constructed during VF (dynamic
restitution) with the use of a custom-written program in which the
selection of action potentials during VF was based on the criterion of
(dV/dt)max >5 V/s.9 CL was defined
by the temporal difference between consecutive action potential
upstrokes. APD to 90% repolarization time
(APD90) was measured along with
diastolic interval (DI), defined as the difference between
CL and APD90. A dynamic APD restitution curve was
then constructed by plotting APD90 versus DI. If
an action potential occurred before 90% repolarization of the previous
one, its DI was considered to be zero.9
Statistical Analysis
Data are presented as mean±SD. Student's t
test was used when appropriate. ANOVA with a Newman-Keuls test was used
when multiple comparisons were performed.16 A value
of P
0.05 was considered significant.
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Results |
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Activation Wave Front Dynamics During VF: Effects of PA
All isolated RVs developed spontaneous VF during mounting in the tissue bath. At baseline, VF was characterized by the presence of 4 to 5 wavelets, with an average CL of 65.2±9.8 ms (Figure 1
and Table). Identification of
reentrant wave fronts completing 1 full rotation allowed us to
determine reentry CL and its core size (Table). At baseline, the
average reentry CL was 82±10 ms, with a central core area of
5.8±1.3 mm2 (Figure 2A and Table). PA decreased the
number of wavelets, VF CL, and the core area of the reentry in a
concentration-dependent manner (Figure 2 and Table). PA
also increased the length of wave front continuity (2.48±0.62 cm vs
1.2±0.27 cm, P<0.01) (Figures 1, 2, and 4). CV during VF was decreased after PA in a
concentration-dependent manner from 78±15 cm/s (control) to 50±14
cm/s (10 µg/mL) and to 46±9 cm/s (15 µg/mL) (P<0.01
for all comparisons), as in previous in situ
studies.2 PA did not further reduce CV during VF even
after 30 minutes of infusion with 15 µg/mL of PA, when VF converted
to ventricular tachycardia (VT). All PA effects
were reversible on 60 minutes of drug-free Tyrode's perfusion
(Table).
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Wave Front Dynamics During VF: Effects of PA
At baseline, wave-wave interaction and spontaneous wave break were
present. Figure 3 illustrates an
example of reentry formation by wave-wave interaction at baseline. The
wave front numbered 1, propagating east-west, leaves behind a
refractory tail that becomes encroached by a second front (No. 2)
propagating upward from the mid-right of the plaque. Wave break occurs
at the tail of the wave front 1 (double horizontal lines in frame c).
The broken wave front 2 then rotates around the site of block (frame d)
in a counterclockwise direction and completes 1 full reentrant rotation
with a period of 70 ms (frames e through h). Spontaneous wave break
frequently occurred at baseline, as in the in situ canine
VF.2 Figure 4A
illustrates
one such example. In this episode, 3 wavelets, a, b and c, are
present during the VF. At time 1752 (frame b), while wave front a
was propagating toward the bottom (2 single arrows), spontaneous block
occurs in its center (frame c). However, the 2 split edges of the
front, a1 and a2 (frames c
and d), continue to propagate. Wavelet c at the top (frame a) also
undergoes breakup into 2 wavelets, c1 and
c2, which propagate in opposite directions (frame
b). A breakthrough excitation occurs at site d, (frame c), which
propagates in 2 directions, d1 and
d2 (frame d). Wave front b also breaks up
spontaneously into b1 and
b2 (frame b), which propagate outside the mapped
area. During PA infusion (Figure 4B), absence of spontaneous
wave break becomes conspicuously evident (Figure 4B).
Elimination of spontaneous wave splitting was associated as expected
with a significant reduction in the number of wavelets, a slowing of
the VF CL, and longer wavelet continuity than baseline (2.48±0.62 cm
vs 1.2±0.27 cm, P<0.01) (Figure 1 and
Table). PA, however, had no effect on the mechanism of reentry
formation by wave-wave interaction. Reentry still occurred, albeit
around a larger central core (Table and Figure 2) and
with a longer CL than baseline (148±21 ms vs 82±10 ms,
P<0.01). Figure 5 illustrates
one such episode. Two wavelets, 1 and 2, interact roughly perpendicular
to each other (frame c), resulting in wave break at a point located at
the lower edge of the double vertical lines in frame c. Propagation
below this point proceeds while above it blocks (frames c through f).
The site allowing propagation just next to the blocked site (lower edge
of the double vertical lines in frame c) was activation 90 ms earlier.
This interval reflects the refractory period during VF after
PA.1 2 With this approach, the refractory period
during VF was significantly (P<0.01) prolonged after PA
(104±11 ms vs 60±5 ms).
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PA and Conversion of VF to VT
Progressive reduction in the number of wavelets during VF
eventually led to a single stationary reentrant wave front that was
expressed as a stable monomorphic VT (MV) with a mean CL of 148±41 ms
(Table). In all 7 tissues studied, PA converted VF to MVT. The
concentration associated with conversion to MVT were 5 µg/mL (n=1),
10 µg/mL (n=3), and 15 µg/mL (n=3). In each case a minimum of 20
minutes or PA perfusion was necessary to cause the conversion.
Effects of PA on APD Restitution
PA-induced reduction in the number of wavelets was reflected by a
progressive increase in the CL and the diastolic intervals
between consecutive action potentials recorded during VF (Figure 6 and Table). Figure 6
illustrates concentration-dependent progressive increase in the CL and
APD evolving to a stable and periodic activation. Activation maps
during this periodic activity showed a single stationary spiral wave
(Figure 1). To determine the basis of APD prolongation
(rate-dependent effect caused by fewer wavelets from drug-induced
cellular effects), we constructed dynamic and standard
(S1S2) APD restitution
curves before and after PA. Figure 7
shows that PA increased the APD at all diastolic intervals
and prevented the initiation of action potentials with duration <210
ms with the use of the S1S2
method. Figure 8 illustrates examples of
dynamic APD restitution curves during VF and PA effects. PA completely
eliminated action potentials during VF with duration <30 ms (all
concentrations) and significantly (P<0.05) reduced the
incidence of action potentials with duration <50 ms in a
concentration-dependent manner (Figure 8). APDs with <50 ms
occurred 18.87±5.3% of the times at baseline, 9.7±7.9% with 5
µg/mL PA, to 5.5±5.1% with 10 µg/mL PA, and finally with
3.8±3.5% with 15 µg/mL PA (500 to 600 consecutive action potentials
analyzed for each concentration in each isolated RV).
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Reversal of PA Effects
All of the effects of PA on activation wave front dynamics and APD
restitution were reversible within 60 minutes with drug-free Tyrode's
perfusion (Figure 8B). In 4 isolated RVs, the MVT present at
the start of PA washout spontaneously degenerated into VF. In the
remaining 3 tissues, VF was readily induced by rapid pacing 1 hour
after drug-free Tyrode's perfusion. Rapid pacing failed to induced VF
during the MVT while PA was present.
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Discussion |
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The ability of PA to simultaneously prevent spontaneous wave break during VF and initiation of action potentials with critically short (<30 ms) duration constitute the major findings of the present study. Maintenance of VF after PA was not supported by spontaneous wave break. These effects of PA caused the VF to be maintained with fewer but longer wavelets and at longer CLs.
Reentry and Wave-Wave Interaction
Although PA prevented spontaneous wave break during VF, it had no
effect on reentry formation by wave-wave interaction. Generation of new
reentrant wave fronts by wave-wave interaction may be a major mechanism
that maintains the VF during PA infusion.
Mechanism of Spontaneous Wave Break
PA-induced complete elimination of action potential initiation
with duration <30 ms provides a new insight into the mechanism of
spontaneous wave break. The shortest wavelength with 30 ms APD and a CV
of 20 cm/s (greatest slowing of CV with PA) corresponds to 6 mm.
This suggests that during VF a segment of the wave front with a
wavelength shorter than 6 mm would undergo breakup. Simulation
studies have shown that when a segment of the front becomes critically
short, it undergoes breakup.6 A segment of the front with
a critically shortened wavelength carries insufficient depolarizing
current strength (weak source) to depolarize recovering cells during VF
(sink).5 17 18 Such a "mismatch" causes splitting
(breakup) of the wave front at the point of diminished current source
(Figure 4A). The amount of wavelength shortening necessary for
breakup, however, depends, among other factors, on tissue recovery
(restitution). Other factors, such as tissue anatomy, including
tissue thickness,12 cellular coupling,17 18
and tissue anisotropy,19 20 might also exert an influence
on the causation of source-sink mismatch and subsequent wave break.
However, the demonstration of PA-induced prevention of spontaneous wave
break at a site where spontaneous breakup occurred before exposure to
drug (Figure 4B) suggests that drug-induced prevention of APD
shortening per se played a decisive role in causing spontaneous wave
break in the present study. The occasional occurrence of APDs with
duration between 50 and 30 ms during VF (Figure 8B) might
reflect possible recordings made from a cell near the core of a
meandering reentrant wave front known to be characterized with
shortened APD.21 In an additional isolated, perfused RV we
recorded 620 consecutive action potentials during VF from the
endocardial surface before and after PA. As in the epicardial
recordings, PA at 10 µg/mL completely eliminated APDs <30 ms
on the dynamic APD restitution curve during VF.
Mechanism of PA-Induced Increase of VF Cycle Length
Our results show that PA might prolong VF CL by 2 different
mechanisms. First, prevention of spontaneous wave break decreases the
number of wavelets and VF thus becomes maintained with fewer wavelets,
causing less frequent activation and therefore an increase of CL. The
second mechanism of PA-induced slowing of VF might result from the
larger central core of reentry formed during VF. Functional reentry
around a larger core has a longer rotation period than reentry around a
smaller core.22 Our data suggest that both mechanisms
might act in concert to increase the VF CL after PA.
PA and Conversion of VF to MVT
PA-induced elimination of spontaneous wave break led to a
progressive decrease in the number of wavelets, eventually ending up
with a single stationary reentrant wave front. Such a dynamic scenario
was associated with conversion of VF to MVT (Figure 1). The
conversion of VF to MVT, however, was a concentration- and a
time-dependent phenomenon. No conversion would occur in <15 minutes of
continuous perfusion of PA, often requiring PA concentrations >5
µg/mL. Finally, the ability of PA to convert nonstationary to
stationary reentry needs to be addressed. The ability of PA to
"flatten" the APD restitution curves (dynamic and standard) by
eliminating short APDs and large variations in consecutive APDs are
prevented both in time and space (dispersion of repolarization).
PA-induced elimination of these tempo-spatial gradients of APD and
excitability14 23 known to promote
nonstationarity24 may convert nonstationary to stationary
reentry.
Limitations of the Study
One limitation of the study is that the effects of PA on VF
mechanism(s) were evaluated in the isolated RV and during continuous
perfusion with oxygenated Tyrode's solution (no
ischemia). Although these conditions do not mimic VF in situ
setting,2 the ability afforded by this model to map
virtually the entire isolated RV endocardial surface and to
simultaneously record transmembrane action potentials
made the determination of the mechanism of spontaneous wave break
possible. Another limitation of the present study might be that
activation maps and simultaneous action potential
recordings were done on different surfaces of the RV. However,
the demonstration that PA blocks spontaneous wave break on both
epicardial and endocardial surfaces with concomitant demonstration of
elimination of both epicardial and endocardial APDs <30 ms indicate
that critically shortened APDs promote spontaneous wave break during VF
in the isolated RV, as in simulation studies.6
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Acknowledgments |
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This study was supported in part by an NIH SCOR grant (HL-52319), an NIH FIRST Award (HL-50259), the Pauline and Harold Price Endowment, the Cedars-Sinai ECHO Foundation, the Ralph M. Parsons Foundation, Los Angeles, Calif; an AHA National Center Grant-in-Aid (9750623N), an AHA Wyeth-Ayerst Established Investigatorship Award, the UC Tobacco Related Disease Research Program (6RT-0020), and the Uemara Memorial Foundation (M.Y.). We thank Prediman K. Shah, MD, for his support; Toshihiko Ohara, MD, for preparing the manuscript; Avile McCullen and Mei Ling Yuan for technical assistance; and Elaine Lebowitz for secretarial assistance.
Received December 16, 1998; revision received March 18, 1999; accepted April 9, 1999.
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