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(Circulation. 2002;106:1007.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Intramural Virtual Electrodes During Defibrillation Shocks in Left Ventricular Wall Assessed by Optical Mapping of Membrane Potential

Vladimir G. Fast, PhD; Oleg F. Sharifov, PhD; Eric R. Cheek, MS; Jonathan C. Newton, PhD; Raymond E. Ideker, MD, PhD

From the Department of Biomedical Engineering (V.G.F., O.F.S., E.R.C., R.E.I.) and Department of Medicine (J.C.N., R.E.I.), University of Alabama at Birmingham, Birmingham, Ala.

Correspondence to Vladimir G. Fast, PhD, University of Alabama at Birmingham, 1670 University Blvd, VH B126, Birmingham, AL 35294. E-mail fast{at}crml.uab.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— It is believed that defibrillation is due to shock-induced changes of transmembrane potential (V_m) in the bulk of ventricular myocardium (so-called virtual electrodes), but experimental proof of this hypothesis is absent. Here, intramural shock-induced V_m were measured for the first time in isolated preparations of left ventricle (LV) by an optical mapping technique.

Methods and Results— LV preparations were excised from porcine hearts (n=9) and perfused through a coronary artery. Rectangular shocks (duration 10 ms, field strength E 2 to 50 V/cm) were applied across the wall during the action potential plateau by 2 large electrodes. Shock-induced V_m were measured on the transmural wall surface with a 16x16 photodiode array (resolution 1.2 mm/diode). Whereas weak shocks (E2 V/cm) induced negligible V_m in the wall middle, stronger shocks produced intramural V_m of 2 types. (1) Shocks with E>4 V/cm produced both positive and negative intramural V_m that changed their sign on changing shock polarity, possibly reflecting large-scale nonuniformities in the tissue structure; the V_m patterns were asymmetrical, with V^-_m>V⁺_m. (2) Shocks with E>34 V/cm produced predominantly negative V_m across the whole transmural surface, independent of the shock polarity. These relatively uniform polarizations could be a result of microscopic discontinuities in tissue structure.

Conclusions— Strong defibrillation shocks induce V_m in the intramural layers of LV. During action potential plateau, intramural V_m are typically asymmetrical (V^-_m>V⁺_m) and become globally negative during very strong shocks.

Key Words: arrhythmia • defibrillation • excitation • mapping

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Electrical shocks are commonly used to interrupt ventricular fibrillation, yet key aspects of the interaction between shocks and cardiac tissue are not well understood. In particular, it is not well known how shocks cause changes of transmembrane potential (V_m) that are essential for defibrillation. The classic cable theory predicts that shock-induced V_m decay rapidly with distance from the tissue-bath interface so that no V_m should be present beyond a few electrotonic space constants from the wall surface, leaving the bulk of the left ventricle (LV) unaffected by a shock. To explain defibrillation, it has been suggested that intramural V_m are induced by resistive discontinuities in the tissue structure,^1,2 changing fiber orientation,³ or nonuniformity in the shock electrical field.^4,5 Whether shocks indeed induce intramural V_m remains unknown. Recent optical mapping studies provided important new information about shock-induced V_m in the heart,^6–9 but these studies were limited to measurements from the heart surface. Therefore, the goal of the present study was to measure shock-induced V_m in the intramural layers of the LV. For this purpose, we used isolated coronary-perfused preparations of LV wall¹⁰ excised from pig hearts. Shocks of variable strengths were applied across the wall, and shock-induced V_m were measured optically on the transmural surface.

	Methods

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Preparations of LV Wall
Pigs of either sex weighing 20 to 25 kg (Animal Resource Program, University of Alabama at Birmingham) were anesthetized and operated on in accordance with the American Heart Association guidelines for the care and use of animals, as described elsewhere.¹¹ Hearts were stopped by injection of 10 mmol/L KCl solution, removed, and placed in cold (5°C) Tyrode solution (see below) with 10 mmol/L KCl. The LV was excised, and a branch of the left anterior descending coronary artery was cannulated. To visualize the area of perfusion, a green food-coloring dye was injected into the artery. A preparation containing the perfused area was excised with a sharp razor blade. The approximate location and orientation of the excised tissue are schematically shown in Figure 1A.

View larger version (35K): [in this window] [in a new window]   Figure 1. A, Schematic illustrating excision of preparation. LAD indicates left anterior descending coronary artery; C, perfusion cannula. Gray area depicts region perfused by branch of LAD artery. Dashed line shows line of transmural cut. B, Schematic of tissue chamber, preparation, and shock electrodes. Dashed square indicates mapping area. Shock field (E), was measured above mapping area with bipolar electrode. C, Schematics of optical mapping setup. LS indicates light source; Ex, excitation filter; DM, dichroic mirror; Em, emission filter; L, objective lens; and PDA, photodiode array. D, Optical measurements of shock-induced Vm. stim. indicates stimulation; E, strength of shock field.

The preparation length and width were 4 and 2 cm, respectively. On one side of the preparation, a straight cut was made through the ventricular wall at the edge of the perfused area. Only those preparations that exhibited uniform perfusion across the transmural section were used for experiments. The preparations were placed into a tissue bath with a glass window for optical mapping (Figure 1B) and arterially perfused with Tyrode solution (in mmol/L: 129 NaCl, 4.5 KCl, 1.3 CaCl₂, 1 MgCl₂, 1 NaH₂PO₄, 25 NaHCO₃, 5 glucose) that was gassed with a mixture of 95% O₂ and 5% CO₂ (36°C). To avoid motion artifacts, solution was supplemented with 15 mmol/L of an electromechanical uncoupler, 2,3-butanedione monoxime (BDM). The solution was delivered to the preparations by a roller pump at a pressure of 40 to 50 mm Hg. The preparations were immersed in the solution. Two types of boundary conditions (BCs) for electrical current flow at the transmural surface were used: impermeable BCs when preparations were brought into contact with the glass window by a piston (Figure 1C) and permeable BCs when preparations were shifted 2 mm away from the glass.

Preparations were paced at a cycle length of 500 ms via an electrode placed at a preparation edge. Rectangular shocks (duration 10 ms) were applied via 2 large mesh electrodes (dimensions 5x2.5 cm²) located at opposite ends of the tissue bath. In the absence of preparations, such electrodes produced a uniform electrical field. Shock strength in the bath was measured by a bipolar electrode (wire diameter 50 µm, interelectrode distance 1 mm) glued to the glass window near the mapping area (Figure 1B).

Optical Mapping of Shock-Induced V_m
Preparations were stained by the V_m-sensitive dye di-4-anepps (Molecular Probes). As shown in Figure 1C, tissue fluorescence was excited at 540±10 nm with a 250-W tungsten-halogen lamp (Oriel). The emitted fluorescence was measured at >610 nm with a photographic lens (Nikon, 50 mm), a 16x16 photodiode array (Hamamatsu), and a data acquisition system described previously.^12,13 Measurements were performed at a sampling rate of 5 kHz/channel and a spatial resolution of 1.2 mm/diode.

Shocks with a strength of 2 to 50 V/cm were applied during the action potential (AP) plateau, at which shock-induced V_m are not masked by the flow of sodium current. V_m were measured as the difference between a linear-regression fit of the plateau before shock application and the V_m level at the shock end (Figure 1D); V_m were normalized by the AP amplitude (APA). The AP duration (APD₅₀) was measured as a time interval between 50% levels of AP upstroke and the repolarization phase. Data were expressed as mean±SD. Tissue structure was examined in 5-µm-thick transmural slices of formalin-fixed myocardium that were stained for collagen by the picrosirius red technique.¹⁴

	Results

Top Abstract Introduction Methods Results Discussion References

 
Experiments were performed in 5 preparations with impermeable BCs and 4 preparations with permeable BCs. Wall thickness measured in the preparation center was 1.6±0.3 cm (n=9). Figure 2A illustrates an outline of a preparation, the mapping area, and stimulation and shock electrodes. Shocks were applied 50±6 ms after AP upstrokes measured at the preparation center. Optical mapping revealed that depending on the shock strength, 3 different types of shock-induced V_m patterns were produced.

View larger version (47K): [in this window] [in a new window]   Figure 2. Effects of weak shocks on intramural Vm (impermeable BCs). A, Outline of preparation and shock electrodes. stim indicates stimulation; epi, epicardium; and endo, endocardium. B, Isochronal map of activation spread. C, Optical recordings of Vm and shock (E) in control and with 2.0- and -1.9-V/cm shocks. Numbers correspond to photodiodes indicated in Figure 2D. D, Isopotential maps of Vm distribution for 2 shocks at t=9 ms after shock onset. E, Spatial profiles of shock-induced Vm and APD50.

Effects of Weak Shocks on Intramural V_m and APD
Figures 2C through 2E illustrate the effects of the weakest shocks (E2 V/cm) on intramural V_m with impermeable BCs. Figure 2C displays optical recordings obtained in control and with 2.0 and -1.9 V/cm shocks; Figure 2D displays corresponding isopotential V_m maps. The 2-V/cm shock induced positive V_m at the tissue edge facing the cathode and negative V_m at the edge facing the anode. With the -1.9-V/cm shock, the polarization pattern was reversed. In both cases, maximal V⁺_m and V^-_m were achieved at the wall edges, and there was a relatively gradual transition in V_m magnitude between the edges. A local V_m increase in the wall middle at distance (x) 7 mm (Figure 2E) was too small (<6% APA) to be considered a virtual electrode.

The lower plot in Figure 2E illustrates shock-induced changes in APD₅₀ (APD₅₀) at different locations across the wall. APD₅₀ was prolonged at sites of maximal V⁺_m, whereas at sites of maximal V^-_m, APD₅₀ was either not changed or was slightly prolonged.

Effects of Intermediate Shocks
Figure 3 shows the effects of 9-V/cm shocks, which differed from the effects of the weaker shocks in 4 main aspects. (1) The stronger shocks produced localized increases of V⁺_m and V^-_m inside the wall. One such region with V_m 30% APA was created just under the epicardium in the lower left part of the mapping area (site 13). With the -8.8-V/cm shock (Figure 3B, bottom map), this area was positively polarized, and it was surrounded by an area of negative polarization. Such isolated polarization, as well as the overall nonuniform distribution of V_m across the wall, clearly indicated the presence of intramural virtual electrodes. (2) The V_m induced by the stronger shocks were asymmetrical. Thus, V^-_m was larger than V⁺_m at the same sites (Figure 3A, traces 1 and 11), and the area occupied by V^-_m was larger than the area of V⁺_m (Figure 3B). (3) Quite unexpectedly, negative V_m extended toward the cathode side of the preparation, such as in the lower part of the top map in Figure 3B. Close inspection of the V_m recordings from this area (Figure 3A, site 12) revealed that there was an initial positive deflection of V_m at the edge of the wall (red trace), but V_m became negative toward the end of the shock, likely because of electrotonic interaction with the adjacent area of large negative V_m (site 13). (4) Stronger shocks prolonged APD at all sites across the wall for both V⁺_m and V^-_m.

View larger version (70K): [in this window] [in a new window]   Figure 3. Effects of intermediate shocks on intramural Vm. A, Vm recordings in control and with 9.1- and -8.8-V/cm shocks. B, Isopotential maps of shock-induced Vm.

Effects of Strong Shocks
Increasing the shock strength further produced V_m patterns of the third type illustrated in Figure 4. Shocks with E28 V/cm produced predominantly negative V_m across the wall where either minor V⁺_m (<10% APA) were present (Figure 4B, top map) or the whole transmural surface was negatively polarized (bottom map). The degree of APD prolongation was similar for shocks of both polarities and was not dependent on the local value of V_m (Figure 4C).

View larger version (60K): [in this window] [in a new window]   Figure 4. Effects of strong shocks on intramural Vm. A, Vm recordings in control and with 28.9- and -26.0-V/cm shocks. B, Isopotential maps of shock-induced Vm. C, Spatial profiles of shock-induced Vm and APD50.

Intramural virtual electrodes were observed in all 5 LV preparations with impermeable BCs. The specific V_m patterns differed between preparations, but all of them exhibited intramural V_m of the 2 types described above. The transition between different V_m patterns on increasing shock strength is illustrated in Figure 5, with panel A depicting maximal and minimal V_m, panel B showing areas occupied by V⁺_m and V^-_m, and panel C showing profiles of V_m across preparations (n=5). Plots in panels A and B can be separated into 3 areas. Shocks with E2 V/cm produced both V⁺_m and V^-_m of similar magnitudes. Shocks stronger than 4 V/cm induced asymmetrical V_m with V^-_m>V⁺_m. Shocks with E>34 V/cm induced predominantly negative polarizations.

View larger version (38K): [in this window] [in a new window]   Figure 5. Dependence of shock-induced polarization on shock strength (impermeable BCs). A, Maximal (max) and minimal (min) Vm. B, Proportion of tissue area polarized by shocks above 5% APA () or below -5% APA (). C, Profiles of Vm across preparations (n=5) at different shock strengths.

Figure 6 shows the effects of shocks on APD₅₀ averaged across mapping area (A) and relative standard deviation of APD₅₀ (B) in 5 preparations. Application of shocks caused prolongation of average APD₅₀ in a dose-dependent manner, whereas the variability of APD₅₀ was slightly decreased. This decrease in the APD standard deviation reflects increased uniformity of APD₅₀ distribution illustrated in Figure 4C.

View larger version (17K): [in this window] [in a new window]   Figure 6. Effects of shocks on APD. A, Dependence of average APD50 on shock strength. B, Dependence of APD50 dispersion on shock strength.

Role of BCs
To evaluate the role of BCs in formation of virtual electrodes, V_m were measured in 4 preparations with permeable BCs. In 2 of these preparations, measurements were subsequently repeated with impermeable BCs. Figure 7 compares V_m maps measured with 2 BCs in the same preparation at different shock strengths. It demonstrates that both localized virtual electrodes (A and B) and globally negative V_m (C) were observed with both BCs. Moreover, V_m patterns and shock dependence of maximal and minimal V_m (D) were qualitatively similar to those observed with impermeable BCs.

View larger version (58K): [in this window] [in a new window]   Figure 7. Effect of BCs on intramural Vm. A through C, Maps of Vm distributions with permeable and impermeable BCs. D, Maximal (max) and minimal (min) Vm with permeable BCs.

Tissue structure was examined in 2 pig hearts. Figure 8 illustrates the gross morphology (A) and microscopic structure (B) of thin transmural slices stained with picrosirius red. These images demonstrate the existence of both macroscopic structural nonuniformities related to blood vessels and changing orientation of fiber bundles (Figure 8A) as well as microscopic discontinuities related to collagen septa (bright lines in Figure 8B). The large blood vessels such as shown in Figure 8A were not present on the transmural surface during optical mapping, but they could be located close enough beneath the surface to produce subepicardial V_m such as exemplified in Figure 3B.

View larger version (102K): [in this window] [in a new window]   Figure 8. A, Macroscopic transmitted-light image of transmural LV slice. B, Microscopic fluorescent image of picrosirius red-stained tissue.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This work presents the first optical measurements of shock-induced intramural V_m in the LV wall. The most important findings of this work are as follows: (1) shocks of sufficient strength produced intramural V_m; (2) V_m were of 2 types: weaker shocks produced isolated areas of V_m that changed their sign on changing the shock polarity, whereas stronger shocks produced globally negative V_m across the whole transmural surface; and (3) strong shocks induced APD prolongation for both positive and negative V_m.

Intramural Virtual Electrodes
It has long been believed that successful defibrillation of the heart depends on V_m changes in a "critical mass" of cardiac tissue,¹⁵ which postulates the presence of intramural V_m in the bulk of ventricular muscle. However, the experimental evidence supporting this hypothesis was lacking. Moreover, there is contradictory evidence from the classic linear cable model that indicates that no intramural V_m should be induced by shocks in the bulk of the LV,¹ which makes experimental verification especially important. The present study presents the first experimental evidence that defibrillation shocks indeed induce V_m in the deep layers of LV wall.

Two types of V_m were observed. Intramural V_m induced by shocks of moderate strength were strongly nonuniform. Both positive and negative V_m were observed, and their sign was changed on changing the shock polarity (Figure 3). V_m induced by stronger shocks were predominantly negative, independent of shock polarity (Figure 4). This is an unexpected finding that is in apparent contradiction to the concept that shocks should produce polarizations of both signs, reflecting inflow of current into the intracellular space at some locations and outflow at other locations.

There are 2 main mechanisms by which the electrical field can change V_m far from shock electrodes or the tissue-bath interface. One mechanism relates V_m to a nonuniform electrical field ("activating function").^4,16 The other explains V_m by nonuniform tissue structure, eg, resistive discontinuities^1,2 or fiber rotation.³ Separating these 2 mechanisms in a tissue with restricted extracellular space can be difficult, because V_m caused by tissue nonuniformities will inevitably lead to nonuniformities in the extracellular field. Therefore, the existence of field nonuniformities does not necessarily mean that they are the cause of V_m. This would be the case if the field nonuniformity was not related to the tissue structure, eg, if it were due to electrode geometry and/or BCs. This was not the case in the present study, because the bath electrical field was uniform without preparations. Therefore, it is more likely that intramural V_m were due to nonuniform tissue structure.

It is also likely that 2 different types of V_m were due to different structural factors. The isolated areas of positive or negative V_m induced by shocks of moderate strength were probably caused by relatively large-scale nonuniformities such as fiber rotation,³ variation in the surface-to-volume ratio,¹⁷ or blood vessels. Owing to light integration from some depth, both surface and subsurface tissue nonuniformities could contribute to V_m. With impermeable BCs, uneven tissue surface could lead to current flow across the transmural surface at some locations, which could also cause V_m. This factor, however, should not play the primary role, because qualitatively similar results were obtained with permeable BCs. As expected from V_m produced by large nonuniformities, they changed their sign with changing shock polarity.

The nature of the second type of intramural V_m is more difficult to explain. We suggest that uniformly negative V_m are due to microscopic discontinuities in the tissue structure. Myocardium contains discontinuities of multiple types, including blood vessels, collagen septa (Figure 8B), and intercellular clefts.¹⁸ Intramural cells are organized into relatively sparsely interconnected bundles¹⁹ and layers.²⁰ The basic features of V_m in such structures can be inferred from the shock response of a cell strand or an intercellular cleft. Optical measurements indicate that shocks invariably induce both positive and negative V_m at the opposite sides of such structures.^12,21 However, if these polarizations are measured on a macroscopic scale (1.2 mm in the present study) that exceeds structure dimensions and the electrotonic space constant (0.3 to 0.5 mm²²), then the negative and positive polarizations should be averaged out. Signal averaging is likely to be augmented by light contributions from deeper cell layers. In a system with a linear V_m response, the net result would be a zero or negligible macroscopic polarization. This can explain the absence of detectable virtual electrodes during weak shocks when V_m were nearly symmetrical. Stronger shocks, however, induce nonlinear V_m with a strong negative bias (V^-_m>V⁺_m) during AP plateau.^12,23,24 Because of this asymmetry, macroscopic measurements of V_m produced by small discontinuities should yield only negative V_m. This can explain the present observations of globally negative polarizations and the fact that the maximal magnitude of hyperpolarization was much smaller than that measured at microscopic resolution in cell cultures.¹²

Effects of Shocks on APD
Shock-induced APD prolongation⁶ or shortening⁹ have been reported previously, and both are considered important factors in defibrillation. In the present work, APD shortening was observed only rarely at sites of V^-_m during the weakest shocks. More typically, APD was prolonged at sites of both V⁺_m and V^-_m, and this effect became more prominent with increasing shock strength and V_m becoming more negative. This finding appears counterintuitive, because negative polarization reflects a withdrawal of positive charge from the intracellular space, and therefore, it should be followed by faster repolarization. The explanation for this paradox might be related to the same factor that we think is responsible for the globally negative V_m, ie, microscopically discontinuous tissue structure. Indeed, if shock-induced V_m are due to microscopic structures such as cell bundles and layers, then the areas of V^-_m and V⁺_m at the edges of these structures are in close proximity to each other. Strong negative polarization is expected to reactivate ionic channels in cardiac membrane and reset these myocytes to their resting states. After a shock, these cells will become excited by depolarization spreading from the areas of V⁺_m and generate new action potentials. During macroscopic measurements, the combined duration of new and preceding action potentials will be interpreted as APD prolongation. Thus, the observed characteristics of both shock-induced V_m patterns and APD changes indicate that microscopic discontinuities in the tissue structure could play an important role in intramural shock-induced V_m.

Study Limitations
A limitation of this study is that BCs (both permeable and impermeable) might not exactly represent the conditions in intact LV. Impermeable BCs are most similar to intact LV, because such a preparation is equivalent to a whole wall, which is symmetrical across the transmural plane. It is possible that because of wall asymmetry, some current can flow across the transmural plane in the intact wall. This current, however, should be much smaller than the current flowing along the transmural plane, and therefore, the associated V_m should be negligible.

Another limitation is related to the use of the electromechanical uncoupler BDM to suppress the motion artifact. Whereas BDM is routinely used in optical mapping studies,^8,25,26 it is known to affect ionic currents,²⁷ and therefore, it can potentially affect shock-induced V_m. Similar to other channel blockers,²⁸ however, the effect of BDM is expected to be only quantitative, without radical changes in V_m patterns.

Finally, the present study was limited to V_m measurements during the AP plateau. Because V_m responses are different during repolarization and diastole,²⁹ the magnitude and pattern of intramural V_m induced by shocks during these AP phases will be different, but this effect will not change the existence of intramural virtual electrodes.

	Acknowledgments

 
This work was supported by NIH grant HL-67748, a grant from the Whitaker Foundation (both to Dr Fast), and NIH grant HL-42760 (to Dr Ideker).

Received February 12, 2002; revision received May 22, 2002; accepted May 23, 2002.

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