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Departments of 1 Physiology and Biophysics, 2 Biomedical Engineering, 3 Medicine, and 4 Biostatistics, University of Alabama, Birmingham, Alabama 35294
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested whether the interventions typically required for optical mapping affect activation patterns during ventricular fibrillation (VF). A 21 × 24 unipolar electrode array (1.5 mm spacing) was sutured to the left ventricular epicardium of 16 anesthetized pigs, and four episodes of electrically induced VF (30-s duration) were recorded. The hearts were then rapidly excised and connected to a Langendorff perfusion apparatus. Four of the hearts were controls, in which 24 additional VF episodes were then mapped. In the remaining 12 hearts, four VF episodes were mapped after isolation, four more episodes were mapped after exposure to the voltage-sensitive dye di-4-ANEPPS, and six more episodes were mapped after exposure to the electromechanical uncoupling agents diacetyl monoxime (DAM; 20 mmol/l, n = 6) or cytochalasin D (CytoD; 10 µmol/l, n = 6). VF episodes were separated by 4 min. VF activation patterns were quantified using custom pattern analysis algorithms. From comparisons with time-corrected control data, all interventions significantly changed VF patterns. Most changes were broadly consistent with slowing and regularization due to loss of excitability. Heart isolation had the largest effect on VF patterns, followed by CytoD, DAM, and dye.
activation pattern; optical mapping; di-4-ANEPPS; diacetyl monoxime; cytochalasin D
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IN OPTICAL MAPPING, the myocardium is stained with a voltage-sensitive dye and illuminated with a powerful light source. The resulting fluorescence contains a signal proportional to the transmembrane potential (10, 21). Because repolarization is normally associated with the end of refractoriness, optical mapping has become a powerful tool for studying ventricular fibrillation (VF), in which the interplay between excitation wavefronts and refractory tissue is thought to play a key role (23).
Unlike electrical mapping, in which cardiac potentials are usually recorded from in vivo preparations, optical mapping is usually performed in heart or tissue preparations that are isolated from the animal and artificially perfused. To record excitation and repolarization at the same site without motion artifacts, tissue motion must be inhibited or eliminated. If the mapped region is relatively small, the tissue can often be restrained mechanically (5, 10). Frequently, electromechanical uncoupling agents are used to prevent contractions (7, 18). Another alternative is to reduce extracellular calcium.
Thus preparing myocardium for optical mapping typically requires three major interventions: isolation from the animal, exposure to voltage-sensitive dye, and exposure to an electromechanical uncoupler. However, there is limited information on the effects of these interventions on VF patterns. Optical recordings in whole hearts using the dye di-4-ANNEPS were shown to reproduce action potential tracings recorded with microelectrodes (10) and to provide stable signals for hours (21). However, it has also been shown that the action potential in isolated myocytes can be severely affected by di-4-ANEPPS combined with light exposure (28). Although a potent inhibitor of heart contraction, diacetyl monoxime (DAM) has many additional effects, such as decreasing the effective refractory period, action potential duration (APD), and conduction velocity (12, 20), which may change VF activation patterns. Cytochalasin D (CytoD), another potent electromechanical uncoupler, has been shown to have little impact on action potential parameters obtained with a microelectrode (3), the pattern of depolarization, APD, or propagation velocity (33) in slabs of canine ventricular myocardium. It has also been reported to affect VF patterns less than DAM in swine myocardium (19). In contrast, Jalife et al. (15) reported that CytoD significantly changed action potentials in isolated mouse hearts.
Because of the growing importance of optical mapping in VF research, we studied the effects of these interventions in swine hearts, which are comparable in size to human hearts, by using algorithms that can detect subtle changes in VF activation patterns (13, 25-27). We recorded VF patterns using electrical mapping, which, unlike optical mapping, can be performed both in vivo and ex vivo and in the presence and absence of dyes and uncoupling agents.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All animals were managed in accordance with guidelines established by the American Heart Association on research animal use (1), and protocols were approved by the Animal Care and Use Committee at the University of Alabama (Birmingham, AL).
Animal preparation.
Sixteen healthy mixed-breed pigs (19-28 kg) of either sex were
anesthetized with intramuscular telazol (4.4 mg/kg), xylazine (2.2 mg/kg), and atropine (0.04 mg/kg) and maintained by isoflurane in 100%
oxygen. An intravenous bolus of succinylcholine (0.25-0.50 mg/kg)
was given several minutes before the first defibrillation attempt
and repeated as needed to suppress muscular contraction in response to
defibrillation shocks. Lactated Ringer solution was continuously
infused intravenously (2-5
ml · kg
1 · min1).
Core body temperature, arterial blood gas values, and serum electrolytes were maintained within normal physiological ranges until
the heart was excised.
VF induction and mapping in vivo. VF was induced by a 9-V battery applied to the right ventricular epicardium and mapped for 30 s before defibrillation. Biphasic defibrillation shocks were delivered from an external defibrillator (Lifepak 7b, Physio-Control). The leading edge voltage of the first phase of the shock was between 300 and 700 V, and if the shock failed, a rescue shock of 600-980 V was delivered. Four VF episodes were mapped in vivo. Electrograms were bandpass filtered between 0.5 and 500 Hz and digitized at 2,000 Hz using a 528-channel mapping system (32). Episodes were separated by 4 min to allow hemodynamics to return to baseline before reinduction.
Heart isolation. After the last in vivo VF episode, 500 IU/kg heparin was given intravenously, followed by a rapid intravenous infusion of 1 liter of cold 0.9% saline. After bradycardia was observed, another liter of cold saline was poured onto the heart with continuous suction of fluid out of the chest cavity. If VF did not occur spontaneously, it was induced with a battery. The aorta was then clamped, and the heart was rapidly excised, with the mapping plaque and defibrillation electrodes still attached, and immersed in 3 liters of cold saline containing 3,000 IU heparin. The aortic root was cannulated. To wash out blood and metabolites, the heart was perfused with 2 liters of modified Tyrode solution, which contained (in mmol/l) 123 NaCl, 11 dextrose, 0.98 MgCl2, 4.50 KCl, 1.01 NaH2PO4, 1.80 CaCl2, and 20.00 NaH2CO3 plus bovine albumin (0.04 g/l) to reduce edema (Sigma; St. Louis, MO). (2) The heart was then connected to a constant-flow (200 ml/min) Langendorff-type apparatus. The valves were disrupted to prevent the heart from working against a load. The perfusate was maintained at 37 ± 1°C and was gassed with 95% O2-5% CO2. Oxygen saturation was maintained above 95%. One liter of perfusate was filtered with a 20-µm filter and recirculated. The pH was maintained in the range of 7.35-7.45. A nearly identical preparation has been used previously (4). The ground reference for the mapping system was attached to the aortic root. To allow the heart to warm up from the isolation procedure, the first postisolation VF episode was not induced until ~5 min after the heart was connected to the perfusion apparatus.
VF induction and mapping ex vivo. Hearts were randomly assigned to three groups: control (n = 4), which did not receive dye or an uncoupling agent; DAM (n = 6), which received dye and the uncoupler DAM (Sigma); and CytoD (n = 6), which received dye and the uncoupler CytoD (Sigma).
In the control hearts, 24 ex vivo VF episodes were induced, mapped, and defibrillated as described above for the in vivo episodes. In all three groups, consecutive VF episodes were separated by ~4 min. In the DAM and CytoD hearts, four VF episodes were mapped before any agents were added to the perfusate. A 20-ml bolus of 10 µmol/l di-4-ANEPPS (Molecular Probes; Eugene, OR) was then injected through the aorta and, 5 min later, four additional VF episodes were mapped (in one animal from the CytoD group, we paused for 20 min instead of the usual 4 min between the second and third postdye VF episodes to replace a faulty defibrillator). In the DAM group, DAM was added to the perfusate at a final concentration of 20 mmol/l. After waiting for ~10 min for cardiac motion to stop, we recorded six more VF episodes. In the CytoD hearts, a bolus of 5 mg CytoD, dissolved in 2 ml DMSO and 50 ml modified Tyrode solution (final concentration of 10 µmol/l), was injected through the aorta. Because, in our experience, CytoD takes longer to take effect than DAM, in these animals we waited ~20 min for motion to stop before mapping six additional VF episodes.Quantification of VF activation patterns.
VF activation patterns were quantified using the pattern analysis
algorithms we have previously described (13, 25-27).
Briefly, all 504 electrograms in a VF mapping dataset were digitally
differentiated. A sample (the datum corresponding to a single temporal
sample at a single site) was deemed active if the temporal derivative of the electrogram (dV/dt) was less than 
0.25
V/s. This threshold is less negative than the typically used
value of 0.5 V/s (13, 25) and was chosen to avoid
missing activations in the ex vivo VF episodes, which had a less steep
dV/dt than the in vivo episodes. Individual
wavefronts were identified by grouping active samples adjacent in time
and space. VF wavefronts frequently fragment into multiple new
wavefronts or collide with other wavefronts. In our definition of a
wavefront, a wavefront ends when it fragments, at which time two or
more new wavefronts begin. Conversely, when two or more wavefronts
collide, the original wavefronts end and the resulting wavefront
begins. From this decomposition of the overall activation pattern, we
computed nine descriptors as follows: 1) the total number of
wavefronts in the VF dataset (Nwaves)
(26); 2) the mean area swept out by wavefronts
(Swept; in mm2) (26); 3) the
fraction of wavefronts that terminate (without fragmenting or
colliding) within the mapped region (Block) (26); 4) the fraction of wavefronts that arise de novo within the
mapped region (Breakthru) (26) (such wavefronts might be
the result of true intramural breakthrough propagation or of focal
activity on the epicardium); 5) the fraction of wavefronts
that fragment into multiple new wavefronts (Fragment)
(26); 6) the fraction of wavefronts that
collide and coalesce with one or more other wavefronts (Collide)
(26); 7) the mean speed of the spatial centroid
of wavefronts (Speed; in m/s) (13); and 8) the
multiplicity of the activation pattern (Mult) [This measures the
number of distinct activation pathways within the overall pattern.
Smaller numbers indicate a more organized pattern (27)];
and 9) the incidence of reentry (Inc). For this analysis, we
found sequences of wavefronts connected by fragmentation and collision
events that activated tissue regions more than once. Such sequences
were deemed reentrant. Reentry incidence is the number of reentrant sequences normalized by the total number of sequences
(25). With the use of a network optimization algorithm, we
found the trajectory traced by the tip of each reentrant sequence. By
finding the closed loops in the trajectories, we also computed
additional descriptors: 10) the mean perimeter of the closed
loops in a VF dataset (Perimeter; in mm) (25) and
11) the mean number of cycles for which reentrant sequences
persisted (Ncycles) (25).
1) approximates the global activation rate. It was
computed using the same 5-s duration epochs as descriptors
9-11. Welch's method (31) with segments 4,096 samples long overlapping by 2,048 samples was used to compute the power
spectrum of each electrogram. The frequency with maximum power between
3 and 50 Hz was found and averaged over all electrodes.
Statistical model.
Because isolated heart preparations gradually run down, the above VF
descriptors are functions of time as well as of the various agents
whose effects we are testing. To compensate for the effects of time, we
constructed a piecewise linear regression model for each descriptor
(17). If Y is a descriptor, its model,
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(1) |
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tdye)]; 4) a line fitting data in
the presence of dye and DAM [ tDAM)]; and 5) a line-fitting data
in the presence of dye and CytoD
[ tCytoD)]. We also computed the averages of
tdye, tDAM, and
tCytoD over all animals
(
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(2) |
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Aex). To evaluate the effect of dye, we found
the temporal centroid of all observations in the presence of dye but
not uncoupling agents. We then evaluated the difference between
Dual site recording. Our epicardial electrode array prevented light from reaching the mapped region. Therefore, to test for the effects of light in combination with di-4-ANEPPS and DAM, we performed dual site recording in one additional heart. The heart was isolated and perfused as described above. Two silver wires acting as unipolar electrodes were hooked into the subepicardium of the left and right ventricular free walls. The wires were on opposite sides of the heart. A silver reference electrode was attached to the aortic root. The two signals were acquired simultaneously with a direct current-coupled amplifier and digitally recorded at 2 kHz.
We used a 450-W Xe arc lamp (Instruments SA; Edison, NJ) to illuminate the heart. The output of the lamp was heat and bandpass filtered (520 ± 60 nm) and focused onto the input of a quadruple fiber-optic light guide. The output of two of the guide arms was directed to the left ventricular site. This is about twice the light intensity we have previously used for optical mapping in swine hearts (4). The right ventricular site was protected from this light. We recorded 20 s of VF from both sites after dye and DAM were given but before light exposure. We then recorded four additional 20-s VF segments with the light turned on. The recording episodes were separated by 4-8 min. The light was turned off between episodes. To characterize the signals, we divided them into nonoverlapping 1-s segments, zero padded each segment to 16,384 samples, and then computed its power spectrum with a fast Fourier transfer. This allowed us to find the frequency with peak power in each segment to within 0.12 Hz. We used this frequency as an estimate of the local activation rate.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The mean body weights for the control, DAM, and CytoD pigs were 24.8 ± 1.4, 22.7 ± 2.4, and 22.9 ± 2.8 kg, respectively [P = not significant (NS)]. The mean heart weights were 188 ± 27, 199 ± 23, and 208 ± 20 g, respectively (P = NS).
The raw data and regression model for the Nwaves
descriptor are shown in Fig. 2. There is
substantial variability; nevertheless, modeling the time effect as a
linear trend appears justified.
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The regression coefficients and R2 values for
all models are shown in Table 2. No
epicardial reentry was observed in the presence of CytoD; thus we did
not compute ACytoD or
MCytoD for the Inc, Ncycles, or Perimeter descriptors. Slope
coefficients that are significantly different from zero are indicated.
Table 3 lists the times at which the
various agents were injected into each animal as well as the mean times
over all animals. The temporal centroids for the dye, DAM + dye,
and CytoD + dye treatments were 45.92, 70.92, and 82.66 min,
respectively. Table 4 lists the variances
with respect to each component (Eq. 2) for each model.
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The time-corrected effects of each intervention (heart
isolation, dye, DAM + dye, and CytoD + dye) on each VF
descriptor are shown in Fig. 3. Each plot
shows the gap due to the intervention (see Fig. 1 for description of
gaps) as well as the gap normalized by its control value. Significant
gaps are indicated. Because no reentry was detected in the
presence of CytoD, the gap plotted for Inc is simply
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With the use of RMSgap to estimate the overall effect of each intervention on VF, we found that heart isolation had the largest overall effect (RMSgap = 0.326) and the dye had the smallest (RMSgap = 0.047). CytoD + dye (RMSgap = 0.241) had a larger effect than DAM + dye (RMSgap = 0.069).
Heart isolation changed all VF descriptors except for Perimeter. Postisolation VF was more organized, with fewer, smaller wavefronts that were less likely to fragment or collide with other wavefronts but more likely to undergo conduction block or breakthrough onto the epicardium. The activation rate was slower and dV/dt was less steep; however, propagation velocity was increased. This inconsistency may be explained by a shift in the mean propagation axis to a more endo-epicardial orientation. Such a shift would increase the apparent epicardial velocity of wavefronts that activate large regions of the epicardium nearly simultaneously. This notion is supported by the increase in the fraction of breakthrough waves and the decrease in the incidence of reentry; decreased epicardial reentry might indicate that the central filaments of reentrant wavefronts had shifted to become more parallel to the epicardium.
Injecting dye significantly increased Mult and decreased Swept. All other descriptors were unchanged. Thus dye disorganized the VF pattern by shrinking wavefronts and causing them to propagate over more diverse pathways.
The combination of DAM + dye made dV/dtpeak slightly more negative, slowed Rate slightly, and decreased Swept. All other descriptors were unchanged. The combination of CytoD + dye had more pronounced effects, increasing organization of VF by decreasing Mult, Nwaves, Fragment, and Collide. The Rate descriptor was also slowed.
Mex was significantly different from zero for all descriptors except Block and Speed (Table 2), indicating a significant time effect on most descriptors in the control VF episodes. Significant agent-induced deviations from the control slope (Mdye, MDAM, and MCytoD in Table 2) were present for the Block, Break, dV/dtpeak, Rate, and Swept descriptors. For Block, Break, and dV/dtpeak, the deviations increased a positive slope; for Rate, the deviations decreased a negative slope. In contrast, for Swept, the agents reversed the slope from positive to negative.
With the use of RMSslope to estimate the overall effect of
the agents on the control time effect, we found that dye had the least
effect (RMSslope = 0.0072 min1),
CytoD + dye had the most effect (RMSslope = 0.0181 min1), and the DAM + dye effect was
intermediate (RMSslope = 0.0172 min1).
To determine whether exposing di-4-ANEPPS-stained myocardium to strong light altered VF more than dye without light, in the dual site recording heart, we estimated the activation rate at the illuminated (left ventricular) and unilluminated (right ventricular) sites for each second of the five 20-s VF records. To determine if the mean difference in activation rate varied among the recordings taken before and after light exposure, we performed one-way ANOVA on the five groups. There was no difference (P > 0.24), indicating that light exposure had no effect on VF rate.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Major findings. The major results of the present study are as follows: 1) the interventions typically used to prepare a heart for optical mapping (heart isolation, injection of voltage-sensitive dye, and treatment with electromechanical uncoupling agents) all affected VF activation patterns; 2) heart isolation had the largest effect, followed by the uncoupler CytoD (in combination with the dye di-4-ANEPPS), the uncoupler DAM (also in combination with dye), and, finally, di-4-ANEPPS by itself; and 3) VF patterns changed slowly with time. The addition of agents accelerated this effect; CytoD + dye had the largest accelerating effect, followed by DAM + dye and dye alone.
Effects of interventions. Heart isolation caused a step change in almost all VF descriptors. Broadly speaking, VF became slower and more organized with a possible shift in the mean direction of propagation to an endo-epicardial axis. These changes are similar to those we observed in a canine model of heart failure (14) and are consistent with a decrease in excitability, much of which may be explained by depressed sympathetic activity (11) due to denervation of the heart and perfusion with a solution free of endogenous catecholamines. The contrast between in vivo and ex vivo VF episodes was likely increased because sympathetic tone in vivo was elevated from surgery and early ischemia from loss of coronary perfusion.
The addition of the voltage-sensitive dye di-4-ANEPPS changed VF patterns much less than did heart isolation. Only two descriptors were changed (Swept and Mult), and our overall measure of VF change, RMSgap, was only 0.047 versus 0.326 for heart isolation. This mild effect is not surprising given the low reported toxicity of di-4-ANEPPS (21) and the paucity of reports of significant phototoxic effects in whole heart optical mapping studies (10). However, in isolated myocytes, di-4-ANEPPS in combination with strong light has been shown to prolong the action potential, cause early afterdepolarizations, reduce the resting potential, and eventually lead to inexcitability (28). We were unable to test for any additional effects of strong light on spatiotemporal VF patterns in our preparation because the mapped region was protected from light by the electrode array. However, we reasoned that the dramatic changes found in isolated myocytes would, if present in whole hearts, be manifested by a change in VF activation rate. We therefore studied an additional dye-stained heart in which we recorded VF from two electrodes located on opposite sides of the heart. One of the sites was exposed to strong green light suitable for optical mapping, whereas the other site was not. We found that, although there was a difference in VF activation rate between the two sites before light exposure, the difference did not change with repeated light exposures. This finding is consistent with the report of Girouard et al. (10) showing that phototoxicity was significant in isolated myocytes exposed to high concentrations of dye but not in intact hearts and isolated tissue. An interesting feature of our data is that, although most of the descriptor changes due to dye were not significant, in 10 of 13 descriptors, the change was in the opposite direction as the change due to heart isolation. In other words, dye may have slightly increased excitability. The mechanisms for such a change are unclear, although the recent finding of Cheng et al. (6) that the voltage-sensitive dye RH421 increases the contractility of cardiac muscle suggests that calcium cycling may be involved. The electromechanical uncoupler DAM has been shown to reduce APD and propagation velocity (12, 20). In isolated perfused slabs of the canine ventricle, Riccio et al. (24) showed that DAM prevented the induction of VF and converted existing VF to a stable periodic rhythm. Lee et al. (19) had very similar results in the isolated swine right ventricle and additionally found that DAM reduced the number of VF wavefronts. In isolated rabbit hearts, Evans et al. (8) used DAM to create a model of monomorphic ventricular tachycardia. Although the concentration of DAM we used was similar to that used in these studies, we did not see a strong regularizing effect. Although DAM + dye slowed the rate of VF by 8%, decreased dV/dtpeak by 7%, and decreased Swept by 22%, Nwaves and Mult, both sensitive indicators of organization, and all other VF descriptors were unchanged. The RMSgap value for DAM + dye was larger than that for dye alone (0.069 vs. 0.047) but less than that for heart isolation (0.326). A possible explanation for the difference in results is in the fibrillating mass of the different preparations. It has been shown that progressive tissue mass reduction can convert VF to a stable periodic rhythm (16). The above three preparations in which DAM had a strong regularizing effect were much smaller than the whole pig hearts we used and hence may have required a smaller change to the substrate for VF regularization to be achieved. CytoD stops contraction by disrupting the polymerization of F-actin. Because of this, it can alter ionic currents that are modulated by the cytoskeleton (22, 29, 30), including the voltage-sensitive sodium channel (30). It has been shown to significantly alter the action potential in mice (15). In the present study, we found that CytoD + dye had a larger overall effect on VF descriptors (RMSgap = 0.241) than DAM + dye (RMSgap = 0.069). CytoD + dye slowed and simplified VF patterns as indicated by the decreased Nwaves, Mult, Rate, Collide, and Fragment. These changes are consistent with decreased excitability due to the effects of CytoD on sodium channels. However, others have found that CytoD has little to no effect on electrical function: in superfused canine myocardium (3) and arterial perfused canine ventricular wedge preparations (33), CytoD had no effect on action potential parameters or propagation patterns. In the swine right ventricle, Lee et al. (19) found that CytoD had no effect on APD, the slope of APD restitution, the complexity of VF, or the number of VF wavefronts.Temporal changes in VF descriptors. Almost all of the VF descriptors changed with time as indicated by significant values of Mex. For the most part, the temporal drift was in the same direction as the change due to heart isolation (the exception to this was the Swept descriptor, which increased with time after a drop after isolation), indicating a progressive loss of excitability and increase in VF organization. One possible explanation for this change is hypoxia due to the decreased oxygen carrying capacity of Tyrode solution relative to blood. This was probably not the case because this was a nonworking preparation and oxygen demand in such hearts has been shown to be less than one-half that of working hearts (9). Furthermore, oxygen saturation and flow rates were both maintained at high levels. More likely explanations include edema from small osmotic differences between the myocardium and perfusate [although this should have been minimized by our addition of bovine albumin to the perfusate (2)] and the buildup of waste metabolites due to the lack of normal hepatic and renal filtering mechanisms.
Each of the agents added to the perfusate changed the rate of drift of at least three VF descriptors, indicating that they all decreased the temporal stability of the preparation. CytoD + dye accelerated the drift the most (RMSslope = 0.0181 min1), followed by DAM + dye
(RMSslope = 0.0172 min1) and dye alone
(RMSslope = 0.0072 min1).
In conclusion, much recent attention has been focused on finding the
most appropriate electromechanical uncoupler for optical mapping
studies (3, 15, 19, 33). In contrast to a previous study
(19), our results indicate that during VF mapping, the electromechanical uncoupling agent DAM has less effect on VF patterns and the temporal stability of the preparation than CytoD. This finding,
combined with the time it takes CytoD to take effect (~20 min in our
experience), its high cost, and the health risk it poses for
investigators, suggest that DAM may be the preferable uncoupling agent
for large whole heart preparations. However, we also found that
isolating the heart had a much larger effect on VF patterns than either
uncoupler, making the choice between them less critical. The
significant differences in VF patterns between the in vivo and ex vivo
states indicate that findings from isolated heart and tissue studies of
VF should be interpreted with care and ideally validated in vivo.
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ACKNOWLEDGEMENTS |
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The authors thank Frank L. Vance, Tracy L. Gamblin, Reuben L. Collins, and Dennis L. Rollins for excellent technical assistance.
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FOOTNOTES |
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This study was supported in part by National Heart, Lung, and Blood Institute Grant HL-64184.
Address for reprint requests and other correspondence: J. M. Rogers, 1670 University Blvd., B-140, Volker Hall, Birmingham, AL 35294-0019 (E-mail: jmr{at}crml.uab.edu).
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.
10.1152/ajpheart.00923.2002
Received 1 November 2002; accepted in final form 16 January 2003.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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), are the components of the
regression model. The dashed lines are the global lines for ex vivo
data with dye, DAM + dye, and CytoD + dye computed using
averaged values for the times at which the respective agents were
injected. 
, Values of the descriptor model
(
, time-aligned points on the control line. The
hypotheses that were tested are indicated by the arrows.
H0 is the null hypothesis.
P < 0.001. Swept, mean area swept out by wavefronts
(in mm2); Block, fraction of wavefronts that terminate
within the mapped region; Breakthru, fraction of wavefronts that arise
de novo within the mapped region; Fragment, fraction of wavefronts that
fragment into multiple new wavefronts; Collide, fraction of wavefronts
that collide and coalesce with one or more other wavefronts; Speed,
mean speed of the spatial centroid of wavefronts (in m/s); Mult,
multiplicity of the activation pattern; Inc, incidence of reentry;
Perimeter, mean perimeter of the closed loops in a VF dataset (in mm);
Ncycles, mean number of cycles for which
reentrant sequences persisted;
dV/dtpeak, peak change in voltage
over time; Rate, approximate global activation rate (in
s