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Am J Physiol Heart Circ Physiol 279: H2665-H2672, 2000;
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Vol. 279, Issue 6, H2665-H2672, December 2000

Effects of [K+]o on electrical restitution and activation dynamics during ventricular fibrillation

Marcus L. Koller1,2, Mark L. Riccio1, and Robert F. Gilmour Jr1

1 Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853-6401; and 2 Department of Medicine, University of Würzburg, D-97074 Würzburg, Germany


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

To test whether hyperkalemia suppresses ventricular fibrillation (VF) by reducing the slope of the action potential duration (APD) restitution relation, we determined the effects of the extracellular K+ concentration ([K+]o) ([KCl] = 2.7-12 mM) on the restitution of APD and maximum upstroke velocity (Vmax) the magnitude of APD alternans and spatiotemporal organization during VF in isolated canine ventricle. As [KCl] was increased incrementally from 2.7 to 12 mM, Vmax was reduced progressively. Increasing [KCl] from 2.7 to 10 mM decreased the slope of the APD restitution relation at long, but not short, diastolic intervals (DI), decreased the range of DI over which the slope was >= 1, and reduced the maximum amplitude of APD alternans. At [KCl] = 12 mM, the range of DI over which the APD restitution slope was >= 1 increased, and the maximum amplitude of APD alternans increased. For [KCl] = 4-8 mM, the persistence of APD alternans at short DI was associated with maintenance of VF. For [KCl] = 10-12 mM, the spontaneous frequency during VF was reduced, and activation occurred predominantly at longer DI. The lack of APD alternans at longer DI was associated with conversion of VF to a periodic rhythm. These results provide additional evidence for the importance of APD restitution kinetics in the development of VF.

action potential duration; extracellular potassium concentration


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE SLOPE OF THE RESTITUTION RELATION for action potential (AP) duration (APD), i.e., the relation between APD and the preceding diastolic interval (DI), is an important determinant of APD dynamics (1, 8, 10, 12, 16, 27). In particular, if the slope of the APD restitution relation is >= 1, alternans of APD occurs during pacing at short cycle lengths, whereas if the slope is <1, alternans does not occur (8, 16). The mechanism for APD alternans may be of some interest, in that repolarization alternans has been linked to the development of ventricular tachyarrhythmias, including ventricular fibrillation (VF) (19, 22-24, 26). The exact connection between APD alternans and VF has not been established, but there is evidence to suggest that alternans precipitates the breakup of single spiral waves of reentrant excitation into multiple smaller spirals (6, 11, 18, 20, 29), which may account for the transition from ventricular tachycardia to VF (5, 6, 30).

Previous studies have indicated that hyperkalemia suppresses VF (2, 28) and reduces the slope of the APD restitution relation (15). To determine whether a causal relationship exists between these two actions of hyperkalemia, we determined the effects of [KCl] on the restitution of APD, the magnitude of APD alternans during rapid pacing, and the degree of spatiotemporal organization during VF in isolated canine myocardium. Our expectation was that hyperkalemia-induced changes in APD alternans and spatiotemporal organization during VF could be attributed to alterations of the APD restitution relation. If so, such a result would provide additional evidence for the importance of APD restitution kinetics in the development of VF.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

All experiments were approved by the Institutional Animal Care and Use Committee of the Center for Research Animal Resources at Cornell University.

Two-dimensional preparations: data acquisition. Adult mongrel dogs of either sex, weighing 10-30 kg, were anesthetized with Fatal-Plus (390 mg/ml pentobarbital sodium, 86 mg/kg iv; Vortech Pharmaceuticals), and their hearts were rapidly excised and placed in cool Tyrode solution. Thin (~2-mm thick) sections of the endocardium measuring 10 × 20 mm were excised from either ventricle and pinned to the bottom of a Plexiglas chamber. The preparations were superfused with oxygenated Tyrode solution at a rate of 15 ml/min. The composition of the Tyrode solution was (in mmol/l) 0.5 MgCl2, 0.9 NaH2PO4, 2.0 CaCl2, 137.0 NaCl, 24.0 NaHCO3, 4.0 KCl, and 5.5 glucose. The Tyrode solution was bubbled with 95% O2-5% CO2. The PO2 was 400-600 mmHg, the pH was 7.35 ± 0.05, and the temperature was 37.0 ± 0.5°C.

Initially, the fibers were stimulated during a recovery period of at least 60 min at a basic cycle length (BCL) of 500 ms. Rectangular pulses of 2-ms duration and two to three times the diastolic threshold voltage were delivered through Teflon-coated bipolar silver electrodes using a computer-controlled stimulator. Transmembrane recordings were obtained using standard microelectrode techniques (12). The recordings were sampled at 5,000 Hz with 12-bit resolution using custom-written data acquisition programs. Off-line data analysis was performed using programs written in MATLAB 5.2.

Two-dimensional preparations: dynamic restitution protocols. The relationships between APD and DI and between maximum upstroke velocity (Vmax) and DI were determined using a dynamic restitution protocol, as described in detail previously (12). Briefly, the preparations were paced at a constant BCL, which was shortened from 400 to 200 ms in steps of 50 ms and from 200 ms to the effective refractory period in steps of 5-10 ms. The APD restitution relation was determined by plotting APD [measured at 95% of repolarization (APD95)] as a function of DI. In addition, the range of DI over which the slope of the restitution relation was >= 1 (corresponding to the range of DI over which APD alternans occurred, see Refs. 8 and 16) and the magnitude of the APD alternans were determined. The magnitude of APD alternans was defined as the difference between APD95 of consecutive AP during 2:2 stimulus:response locking. Differences in APD >2 ms were considered significant. The Vmax restitution relation was determined by plotting Vmax (determined by differentiating the upstroke of the action potential signal) as a function of DI.

After equilibration in normal Tyrode solution ([KCl] = 4 mM), we changed the [KCl] of the Tyrode solution to 2.7 mM. After a 30-min equilibration period at the new [KCl], we determined the dynamic restitution relation. The [KCl] was then changed sequentially to 6, 8, 10, 12 mM and back to 4 mM, and the procedure was repeated at each [KCl] in each preparation (n = 8). The range of DI over which APD alternans occurred and the magnitude of the APD alternans before and after exposure to each [KCl] were compared using an ANOVA, followed by Scheffé's F-test, to determine statistical significance. P < 0.05 was considered significant.

Three-dimensional preparations: data acquisition. Adult dogs were anesthetized as described above, and their hearts were excised rapidly and placed in cool Tyrode solution. The circumflex coronary artery or the left anterior descending coronary artery was cannulated using polyethylene tubing (21). Tyrode solution was infused into the coronary artery, and the approximate area of perfusion was identified by blanching of the epicardial surface. A transmural section of tissue 3-5 mm larger than the perfused area was then excised. The preparation was suspended in a Plexiglas chamber with the epicardial surface facing up, where it was both perfused via the coronary artery and superfused with normal Tyrode solution. The flow rates of the perfusate and superfusate were constant at 35 ml/min. Perfusion pressure was 50-80 mmHg, and the temperature was 37.0-38.0°C.

Epicardial electrical activity was mapped using an array of 16 monophasic AP-type recording electrodes (21). The monophasic AP-type electrodes consisted of a silver wire insulated with Teflon except at the tip, which was threaded through a 15-mm long sheath of <FR><NU>1</NU><DE>8</DE></FR> in. diameter heat shrink wrap. The electrode array was arranged linearly with a 1.5-mm spacing between the electrodes using the concept of a contour gauge (7). The tension on the electrodes was such that they could be moved up and down individually. The monophasic AP arrays were lowered onto the epicardial surface of the preparation using a micromanipulator. The electrodes were then adjusted as necessary until a stable monophasic AP signal was obtained. The signals from each of the recording sites were referenced to a pellet electrode in the superfusate.

The monophasic AP recordings were displayed on a storage oscilloscope and a thermal array recorder and were sampled at 1,250 Hz with 12-bit resolution. The electrogram and monophasic AP signals were high-pass (cutoff = 0.15 Hz) and low-pass (cutoff = 600 Hz) filtered. Records of 4-7 s duration were obtained every 20-40 s during the course of the experiment. On-line and off-line data analyses were performed using programs written in MATLAB 4.2C.

Three-dimensional preparations: experimental protocols. The preparations were paced initially at a BCL of 800 ms. After a 15-min equilibration period, we progressively shortened the pacing cycle length until VF was induced. Ten to thirty minutes after VF had been induced, the [KCl] of the perfusate and superfusate were changed to 6 (n = 2), 8 (n = 5), 10 (n = 5), or 12 mM (n = 5).

To assess the degree of temporal organization during VF, the monophasic AP data were analyzed using frequency spectral analysis. For each record, eight monophasic AP recordings were selected for analysis. Frequency power spectra for each recording were estimated using the average absolute value (i.e., squared magnitude) of the fast Fourier transforms (FFT) of four Hanning-windowed, 35%-overlapped data segments of 1,024 samples each. The results were subsequently averaged for all leads to generate a composite spectrum. To examine temporal changes quantitatively, the average frequency and variance were calculated for the composite spectrum of each record. For these calculations, frequencies <2 Hz and >35 Hz were excluded from the analysis. The variance was calculated as the square root of the standard deviation of the composite spectrum normalized by the maximum power of that spectrum.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effects of extracellular K+ concentration on electrical restitution. Examples of the effects of [KCl] on APD restitution are shown in Figs. 1 and 2. Increasing [KCl] from 2.7 to 12 mM produced progressive shortening of APD at all cycle lengths tested and shifted the APD restitution relation to shorter APD and longer DI. As [KCl] was increased, the slope of the APD restitution relation at long DI (>100 ms) was reduced, but a region of steep slope (>= 1) persisted at short DI for all [KCl] studied.


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  		Fig. 1.   Effects of varying [KCl] on action potential (AP) duration (APD) in canine endocardial muscle. AP are shown during pacing at basic cycle lengths (BCL) of 300, 200, 150, and 120 ms after exposure to [KCl] = 4 (left), 8 (middle), and 12 mM (right). The dashed line indicates the resting membrane potential for [KCl] = 4 mM. Pacing at BCL = 120 ms during exposure to [KCl] = 12 mM produced 2:1 block (results not shown). Note the decrease in the magnitude of APD alternans at BCL = 150 ms as [KCl] was increased from 4 to 8 mM and the subsequent increase in the magnitude of APD alternans as [KCl] was increased from 8 to 12 mM. The effects of hyperkalemia were completely reversed after a return to [KCl] = 4 mM (results not shown).



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  		Fig. 2.   Example of the effects of varying [KCl] on the relationship between APD and diastolic interval (DI) in canine endocardial muscle. A: effects of 2.7, 4, 6, and 8 mM [KCl]. B: effects of 10 and 12 mM [KCl], which are shown separately to avoid overlap with the results at lower [KCl].

The shifts in the APD restitution relation induced by changing [KCl] from 2.7 to 8 mM were associated with a reduction of the maximum amplitude of APD alternans at all BCL, as shown by the examples in Figs. 1 and Fig. 3A. The amplitude of APD alternans was reduced further at longer BCL when [KCl] was elevated to 10 or 12 mM, but the amplitude of APD alternans was increased at shorter BCL (Fig. 1 and Fig. 3B).


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  		Fig. 3.   Example of the relationship between the magnitude of APD alternans magnitude (AM) and BCL at different [KCl] [2.7-8 mM (A) and 10-12 mM (B)] in canine endocardial muscle. Same preparation and presentation format as in Fig. 2.

Similar results were observed in the other seven preparations tested, as illustrated by the summary data in Fig. 4. The maximum amplitude of APD alternans decreased as [KCl] was increased from 2.7 to 6 mM and then increased as [KCl] was increased further to 8, 10, and 12 mM. In addition, the range of DI over which APD alternans occurred decreased as [KCl] was increased from 2.7 to 10 mM and then increased as [KCl] was increased to 12 mM.


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  		Fig. 4.   Summary data (n = 8) for the effects of different [KCl] on the peak AM (open circle ) and the range of DI over which APD alternans occurred (DI Range; ).

The restitution of Vmax also was shifted to lower Vmax and longer DI as [KCl] was increased from 2.7 to 12 mM (Fig. 5A). Steady-state Vmax at a pacing cycle length of 300 ms (the shortest cycle length at which no APD alternans occurred in any of the cells at any [KCl]) was similar at [KCl] = 2.7, 4, and 6 mM (P = not significant) but was reduced progressively (P < 0.05) as [KCl] was increased to 8, 10, and 12 mM (Fig. 5B).


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  		Fig. 5.   Effects of [KCl] on maximum upstroke velocity (Vmax) in canine endocardium. A: example of the restitution relation for Vmax at different [KCl]. B: mean steady-state Vmax measured at a pacing cycle length of 300 ms (n = 6).

Effects of extracellular K+ concentration on spatiotemporal organization during VF. Elevation of [KCl] from 4 to 6 mM during VF did not significantly alter mean VF frequency or variance of the FFT spectra in the two preparations studied (results not shown). Additional elevation of [KCl] to 8 mM reduced mean VF frequency from 10.1 ± 2.1 to 7.8 ± 0.7 Hz (means ± SE) but did not significantly alter the variance (Figs. 6 and 7). Local activation, as assessed by monophasic AP recordings, remained disorganized and aperiodic (Fig. 6).


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  		Fig. 6.   Examples of epicardial monophasic AP recordings obtained from isolated perfused canine left ventricle during ventricular fibrillation (VF) at [KCl] = 4 mM (A), after 15-min exposure to [KCl] = 8 mM (B), and after 4- and 7-min exposure to [KCl] = 10 mM (C and D, respectively).



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  		Fig. 7.   Examples of epicardial monophasic AP recordings obtained from isolated perfused canine left ventricle during VF at [KCl] = 4 mM (A) and after exposure to [KCl] = 12 mM (B) for 3 min.

At [KCl] = 10 mM, marked reduction of mean VF frequency (to 5.1 ± 0.4 Hz) was associated with increased spatiotemporal organization, as reflected by decreased variance (Figs. 8 and 9), and the conversion of VF into a single periodic rhythm in four of five preparations (Figs. 6 and 8). In those preparations that converted to a periodic rhythm, the mean frequency of the periodic rhythm was not different from the mean frequency during VF, as determined 1 min before the onset of the periodic rhythm (Fig. 9). However, the variance during the periodic rhythm was significantly lower than during VF (Fig. 9).


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  		Fig. 8.   Composite fast Fourier transform (FFT) (top), mean frequency (middle) and variance of the composite FFT (bottom) during VF at different [KCl]. Increasing [KCl] from 4 to 8 mM (A) reduced the mean frequency but did not significantly affect the variance. Increasing [KCl] further to 10 mM decreased both the mean frequency and the variance, ultimately resulting in the conversion of VF to a periodic rhythm (B). On return to [KCl] = 4 mM, VF was reinduced using rapid pacing (C). Subsequent exposure to [KCl] = 12 mM suppressed VF (D).



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  		Fig. 9.   Effects of [KCl] on the mean frequency (open bars) and variance (solid bars) of the composite FFT spectrum during VF in isolated perfused canine left ventricle (n = 5). For [KCl] = 10 mM, values are shown after the emergence of a periodic (p) rhythm in the 4 preparations that developed such a rhythm (10p) and either 1 min before the emergence of the periodic rhythm, when the rhythm was still aperiodic (a) or after 15-min exposure in the 1 preparation that did not develop a periodic rhythm (10a).

Exposure to [KCl] = 12 mM initially reduced mean VF frequency and variance (Fig. 8). Subsequently, VF terminated spontaneously in all five preparations studied (Figs. 7 and 8). Summary data for mean VF frequency and variance were not tabulated for [KCl] = 12 mM because both of these variables changed rapidly and continuously up to the point where VF ceased. The suppressant effects of [KCl] = 10 and 12 mM on VF were reversible; VF could be reinduced after washout of [KCl] = 10 or 12 mM and a return to [KCl] = 4 mM (Fig. 8).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

New findings. The purpose of this study was to determine whether the suppressant effects of hyperkalemia on VF could be attributed to a reduction in the slope of the APD restitution relation and the resulting inhibition of APD alternans. Hyperkalemia reduced the slope of the APD restitution relation at long DI, but the slope of the restitution relation remained >= 1 at short DI. Consequently, APD alternans still occurred during rapid pacing. For [KCl] = 4-8 mM, the persistence of APD alternans at short DI was associated with the induction and maintenance of VF. As [KCl] was elevated further to 10-12 mM, the spontaneous frequency during VF was reduced, and activation occurred predominantly at longer DI. The lack of APD alternans at longer DI was associated with increased spatiotemporal organization, evident in [KCl] = 10 mM as a conversion of VF into a periodic rhythm. At [KCl] = 12 mM, further reduction of the VF frequency was associated with cessation of VF. These results suggest that hyperkalemia suppressed VF by reducing the slope of APD restitution relation and the magnitude of APD alternans at long DI and by shifting the cycle lengths during VF to those at which APD alternans no longer occurred.

Effects of [KCl] on electrical restitution. The observation that hyperkalemia reduced the slope of the APD restitution relation at long DI is in agreement with a previous study (15), in which APD restitution was determined using a standard S1S2 protocol. However, we also observed that a region of steep slope persisted at short DI during hyperkalemia. Detection of the steeply sloped region can be attributed to our use of a dynamic restitution protocol, as opposed to a standard S1S2 protocol, in that the standard S1S2 protocol tends to underestimate the slope of the APD restitution relation at short DI (12). The identification of a steeply sloped region of APD restitution has important implications for APD dynamics, in that a restitution slope >= 1 is a prerequisite for the development of beat-to-beat oscillations of APD (16).

The hyperkalemia-induced reduction in the slope of the APD restitution relation at long DI may account, at least in part, for the flattening of APD restitution that occurs during acute myocardial ischemia (3). Such a reduction in the slope of the restitution relation would be expected to suppress APD alternans, for the reasons discussed above. However, APD alternans occurs commonly during acute ischemia (3). Our results suggest that APD alternans occurs during ischemia because a region of steep slope persists in the APD restitution relation. Such a region is more likely to be detected using a dynamic restitution protocol, as in the present study, than a standard protocol, as employed by Dilly and Lab (3). Moreover, the region of steep restitution slope is shifted to longer DI by hyperkalemia (Fig. 2), resulting in the development of marked APD alternans at longer DI during exposure to [KCl] = 12 mM than during exposure to [KCl] = 4 mM (Fig. 3). The latter effect may account for the emergence of APD alternans during ischemia at cycle lengths that do not provoke alternans during normal perfusion (3).

Our finding that hypokalemia ([KCl] = 2.7 mM) steepened APD restitution also may be relevant to arrhythmia development. The hypokalemia-induced increase in the slope of the restitution relation was associated with an increase in the magnitude of APD alternans. Such an effect would be expected to facilitate the induction of VF, although this hypothesis was not tested in the present study. If confirmed, facilitation of VF induction by hypokalemia might account for the strong relationship between low serum K+ levels and the occurrence of ventricular tachyarrhythmias, as demonstrated by both experimental (9) and clinical (17) studies.

Effects of [KCl] on spatiotemporal organization during VF. Recent evidence suggests that a steeply sloped APD restitution relation underlies the development of VF (6, 11, 18, 20, 21). Interventions that reduce the slope of the restitution relation prevent the induction of VF and convert existing VF into a periodic rhythm, presumably by suppressing the development of APD alternans and the destabilization of spiral waves induced by such alternans. These observations support the idea that the initiation and maintenance of VF depend on the development of APD alternans. Furthermore, they confirm earlier predictions (8, 16) that the development of APD alternans requires 1) an APD restitution relation that contains a region of slope >= 1 (typically at short DI) and 2) activation at short DI, i.e., pacing at short cycle lengths.

In the present study, the effects of different [KCl] on spatiotemporal organization during VF could be attributed to their relative effects on the magnitude of APD alternans, the range of DI over which APD alternans occurred, and the mean VF cycle length. Increasing [KCl] from 4 to 8 mM reduced the magnitude of APD alternans and decreased VF frequency, but the mean cycle length during VF (~130 ms) was still within the range of cycle lengths that produced APD alternans (Fig. 3). These results suggest that, although [KCl] = 8 mM reduced the magnitude of APD alternans, sufficient alternans persisted to destabilize spiral waves. Furthermore, the shift in VF cycle length to longer cycle lengths, which ordinarily would reduce APD alternans, was offset by a parallel shift in the range of DI over which alternans occurred to longer DI.

Elevation of [KCl] to 10 mM produced a more marked reduction of APD alternans and a further shift of the range of DI over which alternans occurred to longer DI. [KCl] = 10 mM also produced a more marked reduction in mean VF frequency as well as a reduced variance; the latter being reflected in the development of a periodic rhythm. Apparently, the shift of VF cycle lengths to longer cycle lengths (to ~200 ms) was more marked than the shift of the range of DI over which alternans occurred. Consequently, activation occurred primarily at longer DI than those required to produce APD alternans (Fig. 3). The same mechanism could be proposed for the regularization of VF, before its cessation, during exposure to [KCl] = 12 mM.

The mechanism for the reduction of VF frequency by hyperkalemia is not obvious from our studies, in that we did not directly measure wave propagation during VF. However, the results of previous studies (13, 14, 24) would suggest that changes of VF frequency may be precipitated by changes in spiral wave core size. In particular, reduction of VF frequency has been observed during acute ischemia in association with an increase in the core size of epicardial spiral waves (14). The increase in core size and the resulting increase in circulation time of the spiral wave were attributed to decreased excitability and an accompanying increase in the critical radius of wavefront curvature. A similar phenomenon may have occurred in the present study, given the known effects of hyperkalemia to reduce excitability (4). Expansion of the core size also might be implicated in the increased spatiotemporal organization during [KCl] = 10 mM, secondary to a reduction in the number of spiral wave cores (and, therefore, in the number of spiral waves) that could be supported by tissue of a given size. Further expansion of the core size upon exposure to [KCl] = 12 mM may have exceeded the capacity of the preparations to support even a single spiral wave. Consequently, reentrant activity was terminated.

In summary, as [KCl] is increased, the slope of the APD restitution relation is progressively reduced at long DI. However, a region of steep slope persists at short DI. Activation at short DI induces APD alternans, which may contribute to the initiation and maintenance of VF at [KCl] = 2.7-8 mM. At higher [KCl], marked prolongation of the mean VF cycle length prevents activation at short DI, an effect that is associated with increased spatiotemporal organization. These results support the hypothesis that a steep slope of APD restitution is a prerequisite for the development of VF. As such, they may be relevant to clinical circumstances in which the extracellular K+ concentraton is abnormal.


    ACKNOWLEDGEMENTS

These studies were supported in part by a grant-in-aid from the American Heart Association, New York State Affiliate. M. L. Koller is currently supported by the Interdisciplinary Center for Clinical Research at the University of Würzburg.


    FOOTNOTES

Address for reprint requests and other correspondence: R. F. Gilmour, Jr., Dept. of Biomedical Sciences, T7 012C VRT, Cornell Univ., Ithaca, NY 14853-6401 (E-mail: rfg2{at}cornell.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.

Received 27 January 2000; accepted in final form 27 June 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Chialvo, DR, Gilmour RF, Jr, and Jalife J. Low dimensional chaos in cardiac tissue. Nature 343: 653-657, 1990[Medline].

2.   Coronel, R, Fiolet JWT, Wilms-Schopman FJG, Schaapherder AFM, Johnson TA, Gettes LS, and Janse MJ. Distribution of extracellular potassium and its relation to electrophysiologic changes during acute myocardial ischemia in the isolated perfused porcine heart. Circulation 77: 1125-1138, 1988[Abstract/Free Full Text].

3.   Dilly, SG, and Lab MJ. Electrophysiological alternans and restitution during acute regional ischaemia in myocardium of anaesthetized pig. J Physiol (Lond) 402: 315-333, 1988[Abstract/Free Full Text].

4.   Dominguez, G, and Fozzard HA. Influence of extracellular K+ concentration on cable properties and excitability in sheep cardiac Purkinje fibers. Circ Res 26: 656-574, 1970[Free Full Text].

5.   Frazier, DW, Wolf PD, Wharton JM, Tang ASL, Smith WM, and Ideker RE. Stimulus-induced critical point. A mechanism for electrical initiation of re-entry in normal canine myocardium. J Clin Invest 83: 1039-1052, 1989.

6.   Garfinkel, A, Kim YH, Voroshilovsky O, Qu Z, Kil JR, Lee MH, Karagueuzian HS, Weiss JN, and Chen PS. Preventing ventricular fibrillation by flattening cardiac restitution. Proc Natl Acad Sci USA 97: 6061-6066, 2000[Abstract/Free Full Text].

7.   Gilmour, RF, Jr, and Watanabe M. Dynamics of circus movement reentry across canine Purkinje fibre-muscle junctions. J Physiol (Lond) 476: 473-485, 1994[Abstract/Free Full Text].

8.  Guevara MR, Ward G, Shrier A, and Glass L. Electrical alternans and period doubling bifurcations. IEEE Computers in Cardiology Conference 1984, p. 167-170.

9.   Hohnloser, SH, Verrier RL, Lown B, and Raeder EA. Effect of hypokalemia on susceptibility to ventricular fibrillation in the normal and ischemic canine heart. Am Heart J 112: 32-35, 1986[Web of Science][Medline].

10.   Karagueuzian, HS, Khan SS, Hong K, Kobayashi Y, Denton T, Mandel WJ, and Diamond GA. Action potential alternans and irregular dynamics in quinidine-intoxicated ventricular muscle cells: implications for ventricular proarrhythmia. Circulation 87: 1661-1672, 1993[Abstract/Free Full Text].

11.   Karma, A. Electrical alternans and spiral wave breakup in cardiac tissue. Chaos 4: 461-472, 1994[Web of Science][Medline].

12.   Koller, ML, Riccio ML, and Gilmour RF, Jr. Dynamic restitution of action potential duration during electrical alternans and ventricular fibrillation. Am J Physiol Heart Circ Physiol 275: H1635-H1642, 1998[Abstract/Free Full Text].

13.   Kwan, YY, Fan W, Kamjoo K, Hough D, Lee JJ, Fishbein MC, Karagueuzian HS, and Chen PS. The effects of procainamide on the characteristics of functional reentry in canine ventricular fibrillation. Circulation 97: 1828-1836, 1998[Abstract/Free Full Text].

14.   Mandapati, R, Asano Y, Baxter WT, Gray R, Davidenko J, and Jalife J. Quantification of effects of global ischemia on dynamics of ventricular fibrillation in isolated rabbit heart. Circulation 98: 1688-1696, 1999[Abstract/Free Full Text].

15.   Moore, EN, Preston JB, and Moe GK. Durations of transmembrane action potentials and functional refractory periods of canine false tendon and ventricular myocardium: comparisons in single fibers. Circ Res 17: 259-273, 1965[Abstract/Free Full Text].

16.   Nolasco, JB, and Dahlen RW. A graphic method for the study of alternation in cardiac action potentials. J Appl Physiol 25: 191-196, 1968[Free Full Text].

17.   Nordrehaug, JE. Malignant arrhythmia in relation to serum potassium in acute myocardial infarction. Am J Cardiol 56: 20D-23D, 1985[Medline].

18.   Panfilov, AV. Spiral breakup as a model of ventricular fibrillation. Chaos 8: 57-64, 1998[Web of Science][Medline].

19.   Pastore, JM, Girouard SD, Laurita KR, Akar FG, and Rosenbaum DS. Mechanism linking T-wave alternans to the genesis of cardiac fibrillation. Circulation 99: 1385-1394, 1999[Abstract/Free Full Text].

20.   Qu, Z, Weiss JN, and Garfinkel A. Cardiac electrical restitution properties and stability of reentrant spiral waves: a simulation study. Am J Physiol Heart Circ Physiol 276: H269-H283, 1999[Abstract/Free Full Text].

21.   Riccio, ML, Koller ML, and Gilmour RF, Jr. Electrical restitution and spatiotemporal organization during ventricular fibrillation. Circ Res 84: 955-963, 1999[Abstract/Free Full Text].

22.   Rosenbaum, DS, Jackson LE, Smith JM, Garan H, Ruskin JN, and Cohen RJ. Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med 330: 235-241, 1994[Abstract/Free Full Text].

23.   Shimizu, W, and Antzelevitch C. Cellular and ionic basis for T-wave alternans under long-QT conditions. Circulation 99: 1499-1507, 1999[Abstract/Free Full Text].

24.   Smith, JM, Clancy EA, Valeri CR, Ruskin JN, and Cohen RJ. Electrical alternans and cardiac electrical instability. Circulation 77: 110-121, 1988[Abstract/Free Full Text].

25.   Uchida, T, Yashima M, Gotoh M, Qu Z, Garfinkel A, Weiss JN, Fishbein MC, Mandel WJ, Chen PS, and Karagueuzian HS. Mechanism of acceleration of functional reentry in the ventricle: effects of ATP-sensitive potassium channel opener. Circulation 99: 704-712, 1999[Abstract/Free Full Text].

26.   Verrier, RL, and Nearing BD. Electrophysiologic basis for T wave alternans as an index of vulnerability to ventricular fibrillation. J Cardiovasc Electrophysiol 5: 445-461, 1994[Web of Science][Medline].

27.   Watanabe, M, Otani NF, and Gilmour RF, Jr. Biphasic restitution of action potential duration and complex dynamics in ventricular myocardium. Circ Res 76: 915-921, 1995[Abstract/Free Full Text].

28.   Watanabe, Y, Toda H, and Uchida H. Electrophysiological mechanisms for the initiation and maintenance of ventricular fibrillation in nonischemic rabbit hearts. Heart Vessels Suppl 2: 69-87, 1987[Medline].

29.   Winfree, AT. Electrical turbulence in 3-dimensional heart muscle. Science 266: 1003-1006, 1994[Abstract/Free Full Text].

30.   Witkowski, FX, Leon LJ, Penkoske PA, Giles WR, Spano ML, Ditto WL, and Winfree AT. Spatiotemporal evolution of ventricular fibrillation. Nature 392: 78-82, 1998[Medline].

Am J Physiol Heart Circ Physiol 279(6):H2665-H2672
0363-6135/00 $5.00 Copyright © 2000 the American Physiological Society


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