Published online before print January 10, 2002, doi: 10.1161/hh0302.104723
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Spatiotemporal Transition to Conduction Block in Canine Ventricle
From the Departments of Biomedical Sciences (J.J.F., M.L.R., F.H., R.F.G.) and Physics (J.J.F., E.B.), Cornell University, Ithaca, NY.
Correspondence to Robert F. Gilmour, Jr, Department of Biomedical Sciences, T7 012C VRT, Cornell University, Ithaca, NY 14853-6401. E-mail rfg2{at}cornell.edu
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Abstract |
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Interruption of periodic wave propagation by the nucleation and subsequent disintegration of spiral waves is thought to mediate the transition from normal sinus rhythm to ventricular fibrillation. This sequence of events may be precipitated by a period doubling bifurcation, manifest as a beat-to-beat alternation, or alternans, of cardiac action potential duration and conduction velocity. How alternans causes the local conduction block required for initiation of spiral wave reentry remains unclear, however. In the present study, a mechanism for conduction block was derived from experimental studies in linear strands of cardiac tissue and from computer simulations in ionic and coupled maps models of homogeneous one-dimensional fibers. In both the experiments and the computer models, rapid periodic pacing induced marked spatiotemporal heterogeneity of cellular electrical properties, culminating in paroxysmal conduction block. These behaviors resulted from a nonuniform distribution of action potential duration alternans, secondary to alternans of conduction velocity. This link between period doubling bifurcations of cellular electrical properties and conduction block may provide a generic mechanism for the onset of tachycardia and fibrillation.
Key Words: ventricular fibrillation • alternans • conduction block
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Introduction |
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Our current understanding of the mechanism for ventricular fibrillation is incomplete, as reflected by the statistic that sudden death continues to be the leading cause of mortality in the Western world. One candidate mechanism for fibrillation is the nucleation of a pair of counterrotating spiral waves, which subsequently disintegrate into multiple wavelets,1,2 in association with a period doubling bifurcation of cellular electrical properties.3–6 However, the mechanism by which a period doubling bifurcation may precipitate the local conduction block necessary for the initiation of spiral wave reentry is unknown.
Previous studies have shown that the induction and propagation of period doubling bifurcations in cardiac tissue depend on the recovery properties for action potential duration (D) and conduction velocity (V), where D or V for a given action potential (Dn+1 or Vn+1, respectively) is a function of the preceding interval (In) between action potentials.7–10 If the function Dn+1=f(In) has a maximum slope 
1, 1:1 stimulus:response locking during pacing at long cycle lengths is replaced by 2:2 locking at short cycle lengths, with 2:2 locking being characterized by beat-to-beat, long-short alternations of D and I.
During 2:2 locking, alternation of I also causes an alternation of V, where Vn+1=c(In). Alternation of V influences action potential propagation and the spatial distribution of D along a cardiac fiber.11,12 If the fiber is sufficiently long, the long-short D pattern at one end of the fiber reverses phase and becomes a short-long pattern at the other end. This phenomenon, known as discordant alternans, has been observed in computer simulations of homogeneous one-dimensional cables11,12 and in experimental studies in isolated hearts.13,14 However, in the experimental studies, discordant alternans was attributed to intrinsic heterogeneity of cellular electrical properties, with little or no role assigned to dynamical heterogeneity or to conduction velocity alternans.13,14
The objectives of the present study were to determine whether dynamical heterogeneity is sufficient for the induction of discordant alternans and conduction block. Studies were conducted in unbranched Purkinje fibers, to approximate as closely as possible a homogeneous linear strand of cardiac tissue, and in ionic and coupled maps models of homogeneous one-dimensional fibers. After verifying that the experimental results and the results generated by the ionic and coupled maps models were in agreement, the coupled maps model was used to identify the dynamical mechanism for the spatiotemporal transition to conduction block.
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Materials and Methods |
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Purkinje Fiber Experiments
Adult dogs of either sex weighing 10 to 30 kg were anesthetized with Fatal-Plus (390 mg/mL pentobarbital sodium; Vortex Pharmaceuticals; 86 mg/kg IV) and their hearts were excised rapidly.15 Free-running unbranched Purkinje fibers (n=10), 13 to 24 mm in length and 1 to 2 mm in width, were excised from either ventricle, mounted in a Plexiglas chamber and superfused with Tyrode’s solution at 15 mL/min. The Tyrode’s solution was bubbled with 95% O2 and 5% CO2. The PO2 was 400 to 600 mm Hg, the pH was 7.35±0.05, and the temperature was 37.0±0.5°C. The composition of the Tyrode’s (in mmol/L) was MgCl2 0.5, NaH2PO4 0.9, CaCl2 2.0, NaCl 137.0, NaHCO3 24.0, KCl 4.0, and glucose 5.5. The fibers were stimulated using rectangular pulses of 2 ms in duration and 2 to 3 times the diastolic threshold (0.1 to 0.3 mA), delivered through Teflon-coated bipolar silver electrodes. Transmembrane action potentials recordings were obtained simultaneously from 3 to 4 sites along the fiber using glass capillary electrodes filled with 3 mol/L KCl. The recordings were sampled at 2000 Hz with 12-bit resolution using custom-written data acquisition programs. Online data display and offline data analysis were performed using programs written in Matlab 4.2c run on an Apple Macintosh PowerPC. All experiments were approved by the Institutional Animal Care and Use Committee of the Center for Research Animal Resources at Cornell University. Animals were obtained from a colony of dogs maintained by Cornell University.
One-Dimensional Ionic Models
Cellular action potentials and wave propagation were simulated using a modified version of the Winslow ionic model,16 as described in detail elsewhere.17 The model is based largely on data obtained from canine mid-myocardial myocytes (M cells). Briefly, compared with the native Winslow model, IK1 was decreased at depolarized potentials, to agree with Freeman et al.18 The maximum conductance and rectification of IKr were increased and activation kinetics were slowed, to agree with Gintant.19 IKs was increased in magnitude and activation shifted to less positive voltages, to agree with Varro et al.20 L-type calcium current was modified to produce a smaller, more rapidly inactivating current. Finally, a simplified form of intracellular calcium dynamics was adapted from Chudin et al.21
The partial differential equation for a one-dimensional piece of tissue was solved numerically, as described by Qu et al.22 The length of the one-dimensional cable was set to 220 cells (30 cells longer than the minimum length required for the development of at least one node), with the length of each cell as 200 µm and a diffusion coefficient of 0.001 cm2/ms.
One-Dimensional Coupled Maps Model
The key determinants of the spatiotemporal dynamics observed experimentally and in the computer simulations were studied in more detail using a coupled maps model of a one-dimensional cardiac fiber.3,23,24 See the Appendix for details of the model. The defining equation for the model was a summation over space and a difference equation in time:
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was the period delivered to the pacing site and 
x was the length of a single cell. Tn+1(xi), the period between activations n+1 and n+2, was determined by including the time delays required for an action potential to propagate from the pacing site to site xi. Conduction velocity Vn+1(xi) depended only on the diastolic interval I through the function Vn+1=c(In). Action potential duration Dn+1(xi) depended on the diastolic interval I through the function Dn+1=f(In).
An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org.
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Results |
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Purkinje Fiber Experiments
To determine whether discordant alternans could be induced in homogenous cable-like cardiac tissue, 10 Purkinje fibers were stimulated at one end at progressively shorter
and action potentials were recorded along the length of the fiber. The electrophysiological properties of cells at the four recording sites were similar, as shown in Figure 1. Although action potential duration varied between preparations, there was no significant difference in action potential duration at 50% and 90% of repolarization (APD50 and APD90, respectively) across the four recording sites (Figure 1a), indicating that within a given preparation, action potential duration was relatively uniform.
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To further characterize the ranges of action potential duration, the differences between the longest and shortest action potentials during pacing at a cycle length of 400 ms were calculated for each fiber. As shown in Figure 1b, the difference in action potential duration was less than 22 ms for all preparations, with a mean difference of 11.6±1.8 ms for APD50 and 12.3±2.0 ms for APD90 (mean±SE). Resting membrane potential and action potential amplitude also were similar within a given fiber, with maximum differences of 2.1±0.5 mV and 3.2±0.7 mV (mean±SE), respectively, and no significant differences across the four recording sites (data not shown).
Pacing the fibers at =120 to 220 ms induced concordant D alternans, whereas pacing at shorter induced discordant D alternans (Figure 2a). The latter progressed to 2:1 conduction block at the distal recording site (Figure 2b). In 5 of the 10 fibers, the 2:1 conduction block was paroxysmal: over time during pacing at the same , a pattern of 2:1
2:22:1 locking occurred (Figure 2c). In the remaining 5 fibers, 2:1 conduction block was stable (nonparoxysmal) and was limited to the 2 distal recording sites in 3 fibers and migrated to the site of stimulation in 2 fibers (Figure 3).
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Conduction block always developed initially at the distal end of the fiber and never in the absence of discordant alternans. Moreover, the same sequence of dynamics occurred regardless of which end of the fiber was paced, attesting to the homogeneity of intrinsic cellular electrical properties in the preparations.
One-Dimensional Ionic Model
Rapid pacing also induced concordant and discordant D alternans and paroxysmal 2:1 conduction block in computer simulations of homogeneous one-dimensional fibers (see Figure 4 and online movies). Unlike in the experiments, it was possible in the simulations to monitor action potentials from each cell on the fiber and thereby demonstrate the spatially distributed transition from concordant D alternans to discordant D alternans and paroxysmal 2:1 conduction block. As shown in Figure 4, at longer cycle lengths (eg, 177 ms; Figures 4a through 4c) the node migrated slowly through the fiber, leaving in its wake discordant D alternans (Figure 4b) and 2:1 block (Figure 4c). At a shorter cycle length (170 ms; Figure 4d), the node migrated more rapidly, eventually reaching the site of stimulation. Shortly thereafter, conduction was restored transiently throughout the fiber, until a new node developed and migrated to a point on the fiber where 2:1 block resumed. This sequence of events was then repeated.
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In agreement with our previous studies in a single myocyte model,17 both concordant and discordant D alternans along the one-dimensional fiber were associated with alternans of peak ICa, whereas at the node, D and ICa were constant (Figure 5). Alternation of other ionic currents also accompanied D alternans, but alternations of these currents appeared to result from the D alternans, rather than being the underlying mechanism for them. For example, peak IKr alternated during D alternans, yet the larger peak was associated with the longer action potential, contrary to what would be expected if IKr were the primary determinant of D during alternans (Figure 5).
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Reduction of ICa or elevation of IKr eliminated electrical alternans at the site of stimulation, as expected from our results using the single myocyte model.17 In the absence of D alternans at the site of pacing, rapid pacing did not induce D alternans at other sites on the fiber or a transition to conduction block along the fiber (Figure 6). Instead, 1:1 locking eventually was replaced by stable 2:1 conduction block at all sites (not shown). The link between D alternans at the site of stimulation and the transition to discordant alternans and conduction block is described in detail in the next section.
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One-Dimensional Coupled Maps Model
Iteration of the coupled maps model (Equation 1) produced a spatial distribution of Dn(xi) and Tn(xi) (Figure 7 and online movie) similar to that observed experimentally and in the ionic model. The mechanism for the spatial distribution of D and T is given in Figure 7, which shows iterations of the return map at a different T. During concordant D alternans, D alternans magnitude decreased and local T alternans magnitude increased from the proximal to distal ends of the fiber (Figure 7a). Local T alternans grew because differences in conduction delays increased with increasing distance from the pacing site. During concordant D alternans, the long action potential iterated to a long T, causing a contraction in the magnitude of D alternans (compare Figures 8b and 8c).
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For sufficiently large T alternans, concordant D alternans became unstable and converted to discordant D alternans (Figures 7b and 7c). If I1 and I2 are the two intervals during alternans, this instability occurred when the product of the slopes of the recovery function at those Is was 1 [ie, |f'(I1)f'(I2)|1, where D=f(I)]. Discordant D alternans had a larger magnitude because the pattern of iteration switched, becoming long D to short T (Figure 8d). During discordant D alternans, the transition point (node) between regions of short-long and long-short D migrated over time toward the pacing site. As pacing continued, several nodes accumulated in the fiber, leading to significant dynamic heterogeneity of D (Figures 7d and 7e).
Paroxysmal 2:1 block (Figure 7f) occurred when the magnitude of D and T alternans distal to the node became so large that attempted activation at short T failed (Figure 8e). As the node continued to migrate toward the pacing site, the magnitude of T alternans decreased (became closer to ) and recovery from 2:1 block occurred (Figures 7g and 7h and Figure 8f). As new nodes formed and migrated, this process was repeated. Thus, for any given activation of the cable during sufficiently rapid pacing, regions of long D, short D, and conduction block coexisted, as in the experiments.
Although changes in the magnitude of T alternans were required for the transitions from concordant to discordant alternans and for the subsequent transition to paroxysmal 2:1 block, the magnitude of T alternans was small, compared with the magnitude of D alternans (Figure 7). At the onset of discordant alternans, T was only ±0.9 ms (Figure 7c), increasing to ±4.6 ms at the onset of 2:1 block (Figure 7f) and decreasing to approximately ±2.1 ms at the resumption of 2:2 locking (Figure 7h). The corresponding values for the experimental data were similar (±1.0, ±1.6, and ±1.2 ms, respectively), as were the values for the ionic model (±4.0, ±3.0, and ±2.0 ms, respectively). Note that the maximum beat-to-beat differences in T occurred in a region of the fibers where the magnitude of D alternans was minimal (Figure 7). Conversely, the minimum values of T occurred where D alternans magnitude was maximal (Figure 7).
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Discussion |
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Spatially Distributed Complex Dynamics
The spatial distribution of complex dynamics observed in the present study depended on three key cellular electrical properties. The first was a D recovery function with slope
1, without which D alternans would not have occurred at the pacing site or at any other site on the fiber. The second was the electrotonic interaction between cells, represented by diffusion in the ionic model and by spatial averaging in the coupled maps models. The role of spatial averaging was identified by removing it from the coupled maps model. In the absence of averaging, concordant and discordant alternans and 2:1 conduction block still occurred (not shown). However, paroxysmal 2:1 block did not occur. Rather, conduction block was stable, as were the steady-state positions of the nodes. Without migration of the nodes toward the pacing site, T differences remained sufficiently large to sustain block.
The third requirement for the development of complex dynamics was a recovery function for conduction velocity. If V were a constant, Dn+1(xi) for any given beat would be the same for each site on the fiber (see Equation 1), precluding the possibility of discordant alternans. However, the magnitude of V alternans and the resultant T alternans during discordant alternans typically were small (
2 ms), particularly in the region of largest D alternans (Figure 7). T alternans of this magnitude is likely to be obscured under most experimental circumstances, which may account for the conclusion reached by Pastore and Rosenbaum that T alternans is not required for the induction of discordant D alternans,13,14 whereas intrinsic spatial heterogeneity of action potential duration is. Although our experiments indicate that discordant D alternans can be induced in the absence of intrinsic heterogeneity, it seems likely that preexisting gradients of repolarization13,25,26 may affect the development of discordant D alternans.
Implications
The results of these experiments demonstrate for the first time a complete transition from planar wave propagation, through alternans to local conduction block, where the spatiotemporal heterogeneity required for the induction of these phenomena developed dynamically. Of clinical interest is the possibility that the mechanism for conduction block developed in the present study may contribute not only to the initiation of spiral wave reentry but also to the subsequent fractionation of wave propagation associated with stable, meandering, or disintegrating spiral waves.2,27,28 This idea remains to be tested. But, if it is found to be valid, interrupting the spatiotemporal transition to conduction block may provide a key to prevention of lethal heart rhythm disorders.5,29
Appendix
To characterize the determinants of the spatiotemporal dynamics observed experimentally, we used a coupled maps model of a one-dimensional cardiac fiber.3,23,24 The model is given by the equation:
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Tn+1(xi) equals the period between activations of site xi. Tn+1(xi) is determined by including the time delays required for an action potential to propagate from the pacing site to site xi. This yields
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where is the period delivered to the pacing site, and x is the length of a single cell. The conduction velocity Vn(xi) depends only on the diastolic interval I through the V restitution function Vn=c(In).
The defining equation for the model is a summation over space and a difference equation in time:
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The coupled maps model used the following functions and parameters. All time units are in ms and all space units are in mm. The duration of the n+1th action potential is a function of the nth rest interval, with Dn+1=f(In):
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as determined by experimental data.15 For In<Imin=2 ms, f(In)=0 (conduction block). The V restitution function Vn=c(In) is given by
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also determined from experimental data (authors’ unpublished data, 2001) and using the fitting function from Karma.3 Coupling is included by a weighted averaging of Dn+1(xi) over a distance 
24:
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with =50 and µ=0.06. We set the length of each cell x to 0.1 mm. If the index falls outside the 150-cell cable, that term is not included in the sums in Equation 7.
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Acknowledgments |
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These studies were supported by NIH grant HL62543 (R.F.G.), by an Integrated Graduate Education and Research Traineeship Program (IGERT) grant from the National Science Foundation (J.J.F.), and by a predoctoral fellowship (F.H.) and grant-in-aid (R.F.G.) from the American Heart Association, New York State Affiliate, Inc. We thank Amanda Werthman for assisting with the data analysis.
Received August 23, 2001; revision received October 16, 2001; accepted December 21, 2001.
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