© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
The fine-scale architecture of defibrillation
Computational Biology Laboratory, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom
* Tel.: +44 113 343 4251; fax: +44 113 343 4230. Email address: arun{at}cbiol.leeds.ac.uk
Received 12 September 2004; accepted 20 September 2004
See article by Sharifov et al. (pages 448–456) in this issue
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1. Introduction |
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 Top 1. Introduction References |
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Ventricular fibrillation is fatal, unless it self-terminates or is terminated by an intervention. It probably is partially responsible for most non-violent deaths and is the immediate cause of death in most sudden cardiac deaths, which form up to a fifth of adult premature deaths in the developed world [1]. The only effective treatment is prompt defibrillation by a brief, large-amplitude electrical shock that produces a field of more than 5 V/cm in the myocardium. Since DC cardiac defibrillation/cardioversion was pioneered by Lown [2] in the 1960s, there have been substantial improvements in the engineering of defibrillators, leading to implantable devices for high-risk patients and public access automatic defibrillators in public areas [1,3]. However, the cellular and tissue electrophysiological mechanisms that underlie defibrillation remain poorly understood and controversial. Improvement in the spatial resolution of optical recording of the spatio-temporal pattern of activity across the ventricular wall produced by electrical shocks has helped to clarify these mechanisms.
Fibrillation is produced by irregular, self-sustained propagation of activation wave fronts through the ventricle. The wave front will propagate into tissue that has recovered its excitability (the excitable gap), with a velocity that depends on both its local curvature and the relative refractoriness of the tissue (determined by the time since the previous activation, or the rate of activity). During normal sinus rhythm, the ventricular activation wave front forms a continuous surface, propagating from the sub-endocardial Purkinje fibers towards the epicardium. At a line break in the activation surface, produced by some heterogeneity, propagation may curl back on itself and re-enter tissue that has recovered its excitability, forming a scroll wave. A single re-entrant scroll wave rotates around a filament, and the voltage field at an instant in time can be mapped into phase, with phase changing 360° around the filament, forming a singularity in the phase field. The filament is a writhing, worm-like volume of tissue, a few millimeters across and several centimeters long, either beginning and ending on the ventricular surface or forming a closed ring. The spatio-temporal irregularity of ventricular fibrillation is due to multiple re-entrant waves. Whether fibrillation is produced by a few "mother rotors", with conduction block due to heterogeneity producing the irregularity, or by multiple wavelets, is actively debated [4]. Fibrillation will cease if all re-entrant propagation is eliminated by removing the filaments that are the source or by making most of the tissue refractory so there is nowhere for the re-entry to propagate.
A steady sub-threshold potential applied intracellularly via a microelectrode decays rapidly with distance, with a space constant of a millimeter or so (
10 times larger than the length of a cell). In quasi one-dimensional preparations, such as Purkinje fiber, the decay is exponential, and in three dimensions, the decay with distance is faster than exponential. A defibrillating shock must spread at least 10 cm, throughout the heart, and alter cellular activity. A proposed mechanism for how the external field influences cardiac cells is the sawtooth hypothesis, in which the cell-to-cell coupling via gap junctions provides a resistive periodic heterogeneity at the scale of the cell (100 µm) [5]. This would produce depolarization and hyperpolarization at opposite ends of the cell, and the membrane nonlinearity would lead to the dominance of depolarization, producing large-scale (spatially uniform) depolarization. Such shock-induced tissue depolarization would excite recovered tissue (eliminating the excitable gap) and prolong action potential depolarization, leading to all the tissue becoming refractory, with no space for re-entry, and the tissue can then recover to be excited by the sinus rhythm. However, although these ideas have been developed quantitatively [6], such cellular scale sawtooth heterogeneities have not been observed, even in tissue culture.
The extracellular voltage gradient produced by an external shock can itself induce re-entrant sources; thus, for defibrillation to be successful, it must eliminate all re-entrant sources and not initiate any new ones. The threshold for defibrillation must be above the upper limit of vulnerability so new re-entry is initiated [7].
A severe problem in experimental investigation into the mechanism of defibrillation is that the shock artifacts obscure intracellular recordings during the application of the shock; thus, it is reasonable to assume that the shock extracellular voltage field produces a proportionate membrane depolarization. Optical monitoring of electrical activity via voltage-sensitive dyes, with motion suppressed by excitation–contraction uncoupling agents, allows membrane depolarization to be monitored during and following defibrillating shocks.
The bidomain model offers an idealized computational model for cardiac tissue in which the tissue voltage is represented as two co-extensive domains, the intracellular and the extracellular, that differ in their anisotropy. The intracellular anisotropy is due to fiber orientation, the cylindrical cell shape, and the longitudinal cell-to-cell coupling via gap junctions being stronger than the transverse cell-to-cell coupling. The extracellular anisotropy is due to the thin (100 nm thick) layer of extracellular fluid around and between cell. In cardiac tissue, the extra- and intracellular anisotropies are unequal. Computations with bidomain models with unequal anisotropy have shown that a unipolar cathodal electrode does not lead to a depolarization that decays smoothly with distance, but to spatial changes in the polarity of membrane potential: regions of de- and hyperpolarization that extend over several space constants. These shock-induced areas of opposite polarity act as virtual electrodes, and are enhanced by tissue heterogeneities [8]. They have been observed on the cardiac surface in optical experiments [9]. The major cause of surface virtual electrodes is secondary sources (of current entrance and exit) at the boundary of the heart.
Ventricular fibrillation is three dimensional—filaments are intramural as well as transmural, and spiral wave patterns are only occasionally seen on the cardiac surface. We need to visualize the electrical activity within the ventricular wall during fibrillation and observe the intramural effects of defibrillation. Although intramural filaments have been inferred [10], observing transmural behavior in the isolated, perfused ventricular wedge preparation provides insight into intramural behaviors.
The results of virtual electrode theory developed from bidomain simulation predicts that shock-induced intramural virtual electrode polarizations will be both positive and negative in different parts of the wall, but large shocks produce only positive virtual electrode polarization during diastole and only negative during the plateau [10,11]. These experimental measurements used a 16x16 photodiode array, with a spatial resolution of 1.2 mm/diode. The failure to visualize virtual electrodes of opposite polarity could be due to the limited spatial resolution [12]: Sharifov et al. [13] in this issue compare both high (0.11 mm/diode) and low (1.2 mm/diode) optical maps of transmural polarization produced by large-amplitude shocks. The high-resolution recordings showed both positive and negative virtual electrode polarizations, during the plateau and during diastole, in agreement with the theory. Thus, the intramural virtual electrode polarization produced by large shocks has a small-scale, fine structure that is apparent at 0.1-mm resolution, and the areas of polarization extend over a few millimeters, i.e., approximately the standard space constant.
Their important paper validates the predictions of the virtual electrode theory for intramural effects of defibrillating shocks. The methods of optical recording (voltage-sensitive dyes and, in particular, the use of excitation–contraction uncouplers) do introduce artifacts since membrane channel kinetics and cell-to-cell coupling can be altered. However, the space scale on which defibrillation acts is not the cell, nor the whole ventricle, but is of a few millimeters, where heterogeneities in muscle structure due to fiber orientation, branching, and the sheet structure of the ventricular muscle are important [14]. Although for propagation cardiac muscle behaves as a continuous system or functional syncytium, for understanding defibrillation, the grainy, stratified structure appears to be essential. It would be useful to compare high-resolution images of experimental transmural virtual electrode polarization with the results of bidomain computations using tissue geometry reconstructed from the same preparations to determine the relative contributions of the different heterogeneities.
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Acknowledgements |
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Research on cardiac virtual tissue engineering in the Computational Biology Laboratory is supported by grants from the British Heart Foundation, Engineering and Physical Sciences Research Council, and the Medical Research Council.
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References |
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