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1 Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland 44195; and 2 Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Little is known about the
mechanisms of vulnerability and defibrillation under ischemic
conditions. We investigated these mechanisms in 18 Langendorff-perfused
rabbit hearts during 75% reduced-flow ischemia. Electrical
activity was optically mapped from the anterior epicardium during right
ventricular shocks applied at various phases of the cardiac cycle while
the excitation-contraction decoupler 2,3-butanedione monoxime (BDM; 15 mM) was used to suppress motion artifacts caused by contraction of the
heart. During ischemia, vulnerable window width increased
[from 30-90% of the action potential duration (APD) in the
control to 
10 to 100% of the APD in ischemia]. Moreover,
arrhythmia severity increased along with the reduction of APD (176 ± 9 ms in control and 129 ± 26 ms in ischemia,
P < 0.01) and increased dispersion of repolarization
(45 ± 17 ms in control and 73 ± 28 ms in ischemia,
P < 0.01). Shock-induced virtual electrode
polarization was preserved. Depolarizing (contrary to hyperpolarizing)
response time constants increased. Virtual electrode-induced wavefronts
of excitation had much more tortuous pathways leading to wavefront
fractionation. Defibrillation failure at all shock strengths was
observed in four hearts. Optical mapping revealed that the shock
extinguished the arrhythmia; however, the arrhythmia self-originated
after an isoelectric window of 339 ± 189 ms. In conclusion, in
most cases, virtual electrode-induced phase singularity (VEIPS) was
responsible for shock-induced arrhythmogenesis during acute global
ischemia. Enhancement of arrhythmogenesis was associated with
an increased dispersion of repolarization and altered deexcitation. In
four hearts, arrhythmogenesis could not be explained by VEIPS.
cardiac vulnerability; defibrillation; voltage-sensitive dye; optical mapping
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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UNCOVERING THE MECHANISM by which strong electric shocks extinguish life-threatening arrhythmias has been challenging researchers for many years since its discovery in 1899 (34). The last decade of research has resulted in a significant improvement of our understanding of the basic mechanisms of defibrillation summarized in the virtual electrode polarization hypothesis of defibrillation, which offers new insight into the effects of the electric shocks on the myocardium (15). This success was primarily due to earlier theoretical and experimental advancements that resulted in the formulation of the bidomain formalism of cardiac syncytium (19, 28, 44) and the fast fluorescent mapping of electrical activity in the heart (10). The virtual electrode polarization hypothesis of defibrillation (15) is based on numerous theoretical (18, 39, 41, 43) and experimental (6, 13, 14, 20, 26, 29, 50) studies. According to this hypothesis, a shock induces both positive and negative changes in preshock transmembrane potential. The success or failure of the shock is determined by this shock-induced polarization pattern. The induction of a shock-induced reentrant arrhythmia is via a virtual electrode-induced phase singularity mechanism (VEIPS). However, nearly all of these studies investigated defibrillation/vulnerability in the normal, nonischemic myocardium. Defibrillation/vulnerability under ischemic conditions was not intensively studied despite the fact that up to 70% of implantable cardioverter defibrillator patients have some form of coronary artery disease (21, 53). Behrens et al. (3) presented evidence of increased vulnerability during external shocks associated with increased heterogeneity of ventricular repolarization in acute global ischemia. However, the defibrillation threshold was not affected by acute myocardial ischemia in their study. Holley and Knisley (24) characterized the response of the ischemic tissue to electric shock and reported observations of virtual electrodes under ischemic conditions. However, the role of virtual electrodes in defibrillation failure and shock-induced vulnerability in ischemia remains unclear.
Our goal was to investigate shock-induced vulnerability and defibrillation under the conditions of acute global ischemia produced by reduced flow in the Langendorff-perfused rabbit heart using voltage-sensitive dye and imaging techniques.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental preparation. Langendorff-perfused hearts (n = 18) from young rabbits (age: 60 ± 4.7 days) were used in the present study. A detailed description of the heart preparation has been previously published (12-14). Briefly, the rabbit was anesthetized with nembutal, and the heart was then removed and placed on a modified Langendorff apparatus for retrograde perfusion. A custom-made 10-mm platinum coil electrode (Guidant) was inserted into the right ventricular cavity through the pulmonary artery. A second similar electrode was positioned in the bath 1-2 cm above and 1-2 cm behind the heart. The heart was stained with a gradual injection of 350 µl of stock 1.25 mg/ml solution of the voltage-sensitive dye di-4-ANEPPS (Molecular Probes) in DMSO (Fisher Scientific) over 10-15 min. The excitation-contraction decoupler 2,3-butanedione monoxime (BDM; Fisher Scientific) (22) was added to the perfusate of the following composition (in mM): 15 BDM, 128.2 NaCl, 1.3 CaCl2, 4.7 KCl, 1.05 MgCl2, 1.19 NaH2PO4, 25 NaHCO3, and 11 glucose.
Global acute ischemia was produced by rapid reduction of the flow rate by 75% from 20 ml/min in control to 5 ml/min. Ischemia-induced electrophysiological changes were continuously monitored with electrograms and optical imaging. A relatively steady state of action potential (AP) duration (APD) was reached between 20 and 30 min of flow reduction in the hearts. Therefore, data collection was performed after 30 min of flow reduction during ischemia, and data were compared with control data collected at the normal flow rate of 20 ml/min.Optical mapping. The fluorescence was excited by a direct current-powered light source at 520 ± 45 nm. The emission was collected above 610 nm by a 16 × 16 element square matrix of photodiodes coupled to a computerized data conditioning and acquisition system. Data were filtered at 1 kHz and sampled at a rate of 1,894 frames/s, yielding a temporal resolution of 528 µs. The field of view was 16 × 16 mm in all experiments.
Optical APs were recorded before, during, and after the application of shocks. Typical data scans were 1-2 s and included the last basic beat AP, the onset of the next AP, and the shock-induced response. A single lead electrocardiogram (ECG) was recorded using two Ag/AgCl probes placed ~1 cm from the right and left side walls of the glass chamber relative to a Ag ground placed at the bottom of the chamber. This lead configuration produced an ECG qualitatively similar to the lead I of the body surface ECG.Experimental protocol.
The heart was positioned in a temperature-controlled, water-jacketed
glass chamber with the anterior wall facing the optical apparatus.
Figures
1-3
show the typical fields of view (square line, 16 × 16 mm) seen by the photodiode array. The heart was paced at a basic cycle
length (CL) of 300 ms by electrical stimuli of twice the diastolic
pacing threshold strength and 2-ms stimulus duration from the apex of
the heart. Truncated exponential monophasic shocks of 8 ms in duration
were delivered from a 150-µF capacitor defibrillator (HVS-02,
Ventritex) between the two electrodes described above. In 13 of 18 experiments, shocks with ±100-V strength were applied at various
phases of the cardiac cycle. A shock of 100 V was chosen because in our
previous study we reported the shock-induced vulnerability in the
structurally normal heart and demonstrated that 100-V shock could
induce 100% of arrhythmias when applied at the certain phases of APD
(52). We extended this investigation under
ischemic conditions in this study. Triggering of shocks at
variable coupling intervals from the last pacing stimulus was performed
via a custom pacing program embedded into the data acquisition and
analysis program, as previously described (14).
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Classification of shock-induced arrhythmia. In some cases, no extrasystole resulted from the shock. Occurrence of one or more extrasystole was defined as shock-induced arrhythmia, which can be further divided into nonsustained or sustained ones. Nonsustained shock-induced arrhythmia was defined as an arrhythmia that self-terminated in <1 min. Sustained shock-induced arrhythmia was defined as an arrhythmia that lasted >1 min and had a CL < 160 ms that required a defibrillation rescue shock to terminate it.
Time constants of cellular response to shock.
A set of experiments was conducted in 5 of 18 rabbits to quantify the
transmembrane response to a defibrillation shock; the cellular time
constant (
) was calculated during delivery of the shock in control
and during the ischemia. Monophasic shocks (8 ms in duration,
150 µF) of ±100, ±130, ±160, ±190, and ±220 V were applied at
25%, 50%, and 75% of the APD. The polarizations were approximated
for both control and ischemia with single-exponential fits
using the Levenberg-Marquardt method (33). To automate the
processing of large amounts of data, a custom program was developed
using Microsoft Visual C++ to automatically analyze the data with the
ability for manual review and correction. The was calculated only
in the virtual electrode areas away from the shock electrode because
electroporation created near the shock electrode (1) would
contaminate the cellular response, and the virtual electrode areas have
been shown to provide the substrate for shock-induced arrhythmogenesis
and defibrillation failure (6, 14). Because the shock
electrode in this study was always inserted in the right ventricular
cavity and seen at the left edge of field of view (see Figs. 1-3),
was calculated from optical traces at the right side of field of
view only. To more accurately and objectively define the areas of
virtual electrodes at a distance from the shock electrode and thus
those traces accepted for analysis, the following exclusion criteria
were followed: 1) The virtual electrode polarization area
directly above the shock electrode was not included in the analysis to
avoid contamination of cellular responses by electroporation;
2) To improve the fidelity of measurement, only strong
transmembrane responses to the shock (amplitude > 10 mV) were
considered; 3) Also to improve fidelity of measurement, only traces
with a signal-to-noise ratio above 75 were considered. A total of
33,291 individual responses to a total of 300 shocks (150 shocks in
control and 150 shocks in ischemia) were included in the
analysis: 18,169 during control and 15,122 during ischemia from
five hearts.
Data analysis and visualization.
The signal analysis software programs used in this study have been
previously described (14). These programs automatically calculated from all 256 optical recordings maps of activation (37), repolarization (16), and APD
(52). Briefly, activation, repolarization, and APD were
calculated as follows: For each optical channel, we defined
depolarization (activation) time as the time difference between the
pacing stimulus and the maximum of the first derivative of the AP
upstroke. Assuming the base potential as 0% and maximum potential as
100%, we defined repolarization time as the time difference between
the pacing stimulus and the time when an optical signal repolarized to
the 10% level. APD was calculated as the difference between
repolarization and depolarization times. Thus the changes in resting
potential and AP amplitude (APA) brought by global ischemia
will not affect calculated time maps of activation, repolarization, and
APD. Because APD was calculated using the APD at 90% repolarization
(APD90) definition described above, all APD90
values will be referred to as APD throughout this report. For
transmembrane potential voltage maps, we assigned 0% for the resting
potential and 100% for the maximum APA and expressed all voltage maps
relative to the last basic beat for each individual channel (%APA).
Activation time (AT) was subtracted from coupling interval (CI),
defined as the time difference between the stimulus and the shock
application, to calculate the percent APD in each channel at which the
shock was applied according to the following formula: %APD = (CI AT)/APD × 100. The vulnerable window was defined by
excluding the coupling interval at which arrhythmia incidence was
significantly (P < 0.05) below 50% (52). Dispersion of repolarization was defined as the difference between the
shortest and longest repolarization times across the field of view
(3). The gradient of the transmembrane potential and its
derivative was calculated using a five-point algorithm similar to that
used in our previous report to calculate the conduction velocity
(37). An isoelectric window was calculated from the field
of view as a delay between the start of the shock application and the
upstroke of the first shock-induced response.
Statistical analysis. Group data were expressed as mean values ± SD. Statistical comparisons were performed using paired or unpaired t-tests. Differences were considered significant when P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of acute global ischemia on the electrical activity. Figure 2 shows a photograph of the experimental preparation used in the present study (A) and representative optical recordings of APs during different phases of acute ischemia (B). During ischemia, APD progressively shortened and became more triangular than that in control recordings. Figure 2C shows reduction of the mean APD during ischemia over the time. Shown data represent an average of 256 optical recordings collected from the preparation shown in Fig. 2A. Note that after 25-30 min of ischemia, APD reduction more or less stabilized.
Figure 3 shows maps of activation, repolarization, and APD during control and ischemia from another representative preparation. The activation pattern remained similar with only a slight slowing of the conduction in ischemia compared with that in control. The average conduction time across the filed of view (minimum AT subtracted from maximum AT) was 34.1 ± 9.1 and 36.8 ± 10.2 ms (P = 0.061, n = 13 rabbits) in control and after 30 min of ischemia, respectively. In contrast, repolarization underwent significant changes during acute ischemia. The average repolarization time was significantly reduced. Repolarization in control was 232 ± 16 ms. Repolarization after 30 min of ischemia was 186 ± 30 ms (P < 0.01, n = 13 rabbits). Dispersion of repolarization increased (P < 0.01, 45 ± 17 ms in control and 73 ± 28 ms in ischemia, n = 13 rabbits). The repolarization pattern became highly heterogeneous, as can be easily seen in the repolarization and APD maps in Fig. 3. Furthermore, in all hearts (n = 13), we found a significant (P < 0.01) reduction of APD90: 176 ± 9 ms in control and 129 ± 26 ms after 30 min of ischemia. These findings confirm previous observations during acute ischemia in various species (3, 11, 38, 40, 46, 47).Shock-induced vulnerability is enhanced by acute ischemia.
Figure 4 shows the incidence of
shock-induced arrhythmia provoked by ±100-V, 8-ms monophasic
shocks delivered at various phases of APD. In this case, we considered
all types of arrhythmia, including sustained and nonsustained. In
control, arrhythmia incidence was observed mainly during the T wave
(APD > 50%), whereas in ischemia it was evident at any
phase of APD. The width of vulnerable window increased from
30-90% of APD in control to 10 to 100% of APD in
ischemia. Average incidence was 36% and 61% in control and ischemia, respectively (P < 0.01). These data
summarized a total of 307 and 152 shocks from 13 hearts under control
and ischemic conditions, respectively. Noteworthy, out of all
shock-induced arrhythmias, average incidence of sustained arrhythmias
were significantly different: 16% and 53% in control and
ischemia, respectively (P < 0.01). Thus in
control in this preparation, arrhythmias were primarily
self-terminating, lasting <1 min. In contrast, in ischemia, arrhythmias were primarily sustained and required defibrillation.
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Virtual electrode polarization and deexcitation in acute
ischemia.
Figure 5 shows contour maps of the
transmembrane voltage at the end of 100-V, 8-ms shocks applied at
15%, 40%, and 60% of APD juxtaposed with isochronal maps of
postshock activation under control and ischemic conditions. All
maps were recorded from the same field of view in the representative
heart shown in Fig. 2. A 100-V cathodal shock produced the virtual
electrode polarization pattern with an area of positive polarization
near the shock electrode (virtual cathode) and adjacent area of
negative polarization (virtual anode). No significant qualitative
differences were evident in the virtual electrode polarization patterns
at the end of the shock between control and ischemia applied at
the same phase of APD.
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Observation of defibrillation failure during ischemia due
to self-fibrillation: evidence of isoelectric window.
In a majority of hearts (9 of 13) under ischemic conditions,
mechanisms of shock-induced arrhythmogenesis appeared similar to that
under control conditions. Namely, arrhythmia was induced by the VEIPS
mechanism (14). Figure 8
illustrates a representative example. This record was obtained from the
same heart as in Fig. 1. Notice that the time scale is the same as in
the stack plot of Fig. 1. Comparison of Figs 1 and 8 illustrates
similarities between the two types of arrhythmogenesis under control
and ischemic conditions: both are reentrant waves rotating in a
counterclockwise direction. However, this comparison also illustrates
significant differences. Under ischemic conditions, the pathway
was significantly more tortuous and discontinuous compared with
control. This was due to shortening of APD, significant dispersion of
repolarization, and local deceleration of conduction, which caused a
higher degree of fractionation of conduction wavefronts.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we confirmed that global acute
ischemia produces a significant reduction of APD and increase
of dispersion of repolarization in the whole rabbit heart, which is in
agreement with findings from others (3, 11, 38, 40, 46,
47). Also in an agreement with the observations by Behrens et
al. (3) during externally delivered shocks, we
demonstrated that ischemia resulted in a significant increase
of vulnerability to shock-induced arrhythmias during internal
defibrillation-strength shocks. This was evident from widening of the
vulnerable window (from 30-90% of APD in control to 10 to 100%
of APD in ischemia) and increased propensity of sustained
arrhythmias (16% in control vs. 53% in ischemia).
Besides ventricular repolarization heterogeneity as an important contributing factor, we speculate that an enhanced susceptibility to deexcitation due to ischemia might also contribute to such dramatic difference in vulnerability. Normally, deexcitation during the absolute refractory period is of an all-or-nothing nature, whereas during the relative refractory period it is of a gradual nature (23, 49, 52). Only the latter provides the substrate for arrhythmogenesis, whereas the former is antiarrhythmic. That explains the vulnerable window in the normal condition. Ischemia makes it possible to deexcite cells in a gradual fashion during nearly the entire refractory period, which leads to a possibility of arrhythmogenesis at any coupling interval of shock application in ischemic hearts. However, additional studies are required to explore this hypothesis at a cellular level.
Our data indicate (see Figs. 5, 6, and 8) that, during ischemia, a VEIPS mechanism is responsible for shock-induced arrhythmogenesis in the majority of cases: break excitation wavefronts were produced at the areas of maximum gradient between the virtual cathode and virtual anode as during control. However, these wavefronts had much more tortuous pathways and increased instability due to increased dispersion of activation and repolarization. These instabilities lead to wavefront fractionation and development of ventricular fibrillation.
The virtual electrode polarization pattern remained grossly similar in
ischemia compared with that in control (Fig. 5). However, there
was a different effect of ischemia on depolarizing and
hyperpolarizing cellular responses
(+/
), with + being
increased by ischemia and unaltered. We
speculate that increased + in ischemia might be
related to an increase in intracellular resistance caused by gap
junction uncoupling (32, 36, 25, 51). The resultant
slowing conduction of wavefront of activation is considered a risk
factor for arrhythmogenesis, which may contribute to defibrillation
failure of electric shock. However, the exact cellular
mechanism of the difference in +/
during ischemia remains unknown. Further pharmacological
studies are required to explore the ionic currents involved.
Furthermore, we observed persistent self-refibrillation in four hearts after a number of shocks. The presence of a significant isoelectric window (339 ± 189 ms) indicates that the refibrillation was not due to shock-induced break excitation. We observed that in these hearts, conduction in the area adjacent to the shock electrode was significantly slowed, which contributed to postshock wave fractionation and reentry, and deteriorated into fibrillation (Fig. 10). The presence of large isoelectric windows (>300 ms) observed only under ischemic conditions and only in four hearts cannot be explained by intramural propagation of virtual electrode-induced scroll waves as under normal and some ischemic condition (Fig. 6, bottom left), which was <60 ms (8). It is noteworthy that this type of failure was not observed until a certain number of shocks were delivered to the ischemic heart. We never observed this type of failure and large (>60 ms) isoelectric windows in nonischemic hearts. This suggests that shock-induced damage superimposed with ischemia provides the substrate for either a focal or reentrant mechanism of arrhythmogenesis (or both) not directly related to shock-induced break excitation. Additional studies are required to elucidate the exact mechanisms of this type of defibrillation failure.
Study limitations. First, shock-induced arrhythmias are complex three-dimensional phenomena. Therefore, the two-dimensional mapping technique used in this study provides only limited insights into the mechanism. For example, our ability to reveal the mechanism of the isoelectric window is limited. Nevertheless, our data strongly indicate that the observed phenomenon can be extended to the three-dimensional situation. Unfortunately, no experimental technique is available at present to assess the three-dimensional map of electrical activity. Computer simulations may provide the missing link.
Second, we used the excitation-contraction uncoupler BDM in this study. On one hand, BDM is known to have an antifibrillatory effect (27, 35), and the protective effect of BDM from ischemia-reperfusion injury is also well known (2, 4, 45). These effects of BDM could bias our estimates of vulnerable window toward smaller degree. However, even though these protective effects of BDM exist, our study indicates that fibrillation was readily inducible under ischemia, whereas it was not readily inducible under control conditions. On the other hand, BDM is a general phosphatase acting on numerous proteins (9, 31, 42). It is reported that BDM has various other effects. For example, a recent report suggests that the Na/Ca exchanger is also inhibited by BDM by unknown mechanisms other than phosphatase activity (48). Thus caution should be taken in interpretation of present data from this study. Third, the present study was performed under experimental constraints. During ischemia, the vulnerable window and the value of were determined over a period of time during which there were ongoing
changing electrophysiological states of the ventricular myocardium. It
is very difficult, if not impossible, to keep myocardial ischemia at equilibrium over time. Measurements were begun 30 min after the onset of ischemia, because the APD duration was significantly altered at this time and tended toward a quasi
equilibrium for the subsequent period of time. We measured the
vulnerable window and in a separate set of experiments in an
attempt to reduce the time of data collection during ischemia
to a minimum.
Finally, in the present study, we investigated the effects of global
rather than regional ischemia. Global ischemia affects the heart in a more homogeneous way compared with that of regional ischemia, such as acute myocardial infarction, which occurs in a distinct territory of the heart. This may contribute to discrepancies in the exact pattern of virtual electrodes to that of global
ischemia. We are presently working on a regional
ischemia/infarct model to address this limitation.
In conclusion, in the present study, we confirmed in our model a
well-known effect of ischemia resulting in dramatic reduction of the APD along with increased dispersion of repolarization. We
observed the widened vulnerable window and increased severity of
arrhythmias during ischemia. The shock-induced virtual
electrode polarization pattern remains similar between control and
ischemia. In ischemia, depolarizing response time
constants increased, whereas hyperpolarizing response time constants
were unaltered. A VEIPS mechanism was responsible for shock-induced
arrhythmogenesis during ischemia in the majority of cases.
However, in ischemia, virtual electrode-induced wavefronts of
break excitation had much more tortuous pathways in the
three-dimensional myocardium and increased instability leading to
wavefront fractionation. The increased propensity to shock-induced
arrhythmias in ischemia is due to the increased dispersion of
repolarization and altered deexcitation. We further demonstrated that
in some cases, persistent self-reinitiating arrhythmia occurred after
an isoelectric window under acute ischemic conditions after
rescue shocks first terminated the arrhythmia. This was probably due to
either a focal or reentrant mechanism of arrhythmogenesis (or both)
accelerated by discontinuous conduction and wavefront fractionation,
which was not directly related to shock-induced break excitation.
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ACKNOWLEDGEMENTS |
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We thank Brian Wollenzier for expert assistance in experiments and Michael Tchou for assistance in data analysis. We are grateful to Guidant for providing custom-made leads.
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FOOTNOTES |
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This study was supported in part by National Heart, Lung, and Blood Institute Grant R01-HL-59464 (to I. R. Efimov) and by American Heart Association Southern and Ohio Valley Research Consortium Grants 9807894W (to I. R. Efimov) and 9960384V (to Y. Cheng).
This work was presented in part at the 73th Annual Scientific Session of the American Heart Association and published in abstract form in Circulation 102: II-339, 2000.
Address for reprint requests and other correspondence: Y. Cheng, Dept. of Cardiovascular Medicine, Desk FF1-06, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195 (E-mail: chengy{at}ccf.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 21, 2002;10.1152/ajpheart.00561.2001
Received 27 June 2001; accepted in final form 15 February 2002.
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TOP
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METHODS
RESULTS
DISCUSSION
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, recording site illustrated in
B. The bipolar electrode, which was used for pacing, is
shown at the apex of the heart. The shock electrode in this study was
always inserted in the RV cavity (red wire), positioned at the left
edge of the field of view. B: representative optical
recordings of APs during control (0 min), 10, 15, and 30 min of
low-flow global ischemia. C: plot of mean APD [APD
at 90% repolarization (APD90)] during the
ischemia over time. Data represent an average of 256 optical
recordings.
