doi: 10.1161/hh0801.090538
© 2001 American Heart Association, Inc.
Editorials |
Mechanisms of the Dynamics of Reentry in a Fibrillating Myocardium
Developing a Genes-to-Rotors Paradigm
From the Departments of Pediatrics and Cell Biology, Duke University Medical Center, Durham, NC.
Correspondence to Madison S. Spach, MD, Box 3475, Duke University Medical Center, Durham, NC 27710. E-mail cspach{at}duke.edu
Key Words: reentry • ventricular fibrillation • anisotropic discontinuities • wavefront curvature • electrical heterogeneity
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Introduction |
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 Top Introduction Advances and Problems in...ImplicationsReferences |
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Because the myocardium was considered to behave structurally as a continuous medium, for many years attention focused on spatial variations in the membrane properties, which allow some cells to recover excitability faster as the mechanism for reentry.1 This mechanism still holds its place as a major underlying cause of many arrhythmias; eg, the long-QT syndrome.2 In the early 1980s, a second general mechanism was introduced with evidence that propagation in the myocardium is discontinuous because of the discrete nature of cells, which results in anisotropic differences in conduction attributable to the anisotropic distribution of the intercellular connections.3 4 Additional evidence quickly accumulated that resistive discontinuities at a larger size scale delay wavefront movement at locations where there is an abrupt change in fiber orientation.5 6 The underlying mechanism of anisotropic resistive discontinuities is that they alter electrical loading of the active membrane.3 4 5
During the last decade, a third type of reentrant mechanism produced by the geometrical shape of excitation waves has received considerable attention. These mechanisms do not "depend on any peculiarities of the cardiac muscle and may be demonstrated in any excitable medium" (page 631). Previously, cardiac electrical events were described for a reentrant path2 8 9 10 or the vortex of reentrant wavefronts (leading circle theory).11 Presently, reentrant wavefront dynamics are described in terms of wavefront curvature, rotors, spiral waves, and scroll waves.12 13 14 15 16 These studies demonstrated that an intrinsic heterogeneity of the myocardium is not necessarily required for reentry to be maintained. For example, if a small area is stimulated within the tail of the broad wavefront of repolarization, a critical point is established that forms the vortex of reentrant wavefront movement. This cardiac phenomenon was initially predicted in the computer simulations of van Capelle and Durrer,17 and their predictions were subsequently confirmed experimentally by Frazier et al.18
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Advances and Problems in Mapping Wavefront Movement |
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TopIntroductionAdvances and Problems in...ImplicationsReferences |
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During the last decade, study of the complex dynamics of excitation waves has been significantly influenced by newer mapping capabilities from two new types of recording systems: large electrode arrays applied to the surfaces of the atria and ventricles,18 19 with plunge electrodes monitoring intramural events,8 9 and imaging systems that monitor fluorescent dye changes as a reflection of the transmembrane potential on the endocardial and epicardial surfaces. However, Baxter et al20 recently showed that this technique may allow monitoring action potentials within preparations that are several millimeters thick.
During ventricular tachycardia (VT), plunge electrode studies have traced the movement of single wavefronts that produce intramural reentry.2 8 9 During the more complex ventricular fibrillation (VF), however, intramural reentry has defied experimental documentation. Furthermore, epicardial and endocardial reentry has been shown to be relatively uncommon during VF.21 22 Because intramural reentrant circuits have been demonstrated during VT, VF may be driven by organized intramural reentry not evident from surface measurements.21 Experimental limitations have prevented solving this issue. However, Berenfeld and Pertsov16 modeled the ventricular wall, incorporating twisted anisotropy attributable to the rotation of layers of fibers within the wall. Their computer model results showed that 3-dimensional scroll waves occur within the wall (intramural reentry) with little manifestation of reentry on the ventricular surfaces.16
In this issue of Circulation Research, Valderrábano et al23 cleverly use the perfused ventricular wedge technique24 to produce the first convincing experimental demonstration that intramural reentrant circuits occur prominently during ventricular fibrillation, thereby confirming the Berenfeld-Pertsov computer model predictions.16 Valderrábano et al23 also report important histological correlations that demonstrate that abrupt changes in fiber orientation occur at sites of reentry and wave splitting.
Questions naturally arise as to whether these authors’ results reflect events in a fibrillating intact ventricle. For example, the exposed surface of the wedge preparation produces a boundary effect. However, such boundary effects were the same over the entire surface, within which there were marked variations in wavefront dynamics, many of which correlated with locations of anisotropic discontinuities. Similar boundary conditions were present in the study by Yan et al,24 who demonstrated that at slow rates, M-cell action potentials prolong in the middle of the left ventricular wall.
The results of Valderrábano et al23 raise an interesting question concerning the future use of specific terminology for heterogeneous versus discontinuous cardiac phenomena, the two often overlapping. Webster’s dictionary (1977) defines heterogeneous as "consisting of dissimilar ingredients or constituents: mixed." The definition Webster’s gives for discontinuity is "lack of continuity." When applied to the results of Valderrábano et al,23 heterogeneous seems to cover all of events that occurred at multiple sites, with anisotropic discontinuities at specific locations.
It is worth noting that the widely published single-instant color maps present a problem for the reader. It is very difficult to see localized events in still maps that represent different time instants. A major advance in interpreting (and visualizing) measured wavefront dynamics would be provided if all of the instantaneous maps could be viewed in motion at different speeds. This electronic capability in now available with online presentations.25
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Implications |
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TopIntroductionAdvances and Problems in...ImplicationsReferences |
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Based on the preceding studies from many laboratories, it becomes apparent that one of the most important changes occurring in cardiac electrophysiology is that a new final goal is gradually being put in place. Based on recent transgenic-histological-conduction studies,26 27 28 we now face the task of developing a literal genes-to-rotors paradigm for cardiac tachyarrhythmias. It seems highly likely that only a part of all known and to-be-defined mechanisms will play an important role in any one heart. Furthermore, the induction of genetic alterations may have different effects in the atrium versus the ventricle, as demonstrated by Nakajima et al29 for the effects on collagen deposition (fibrosis, a major proarrhythmic factor30 ) of a mutant transforming growth factor-ß1 transgene.
The
Table
shows some of the already known factors that may
contribute to specific mechanisms at the microscopic and the larger
macroscopic size scales for the three classes of reentrant mechanisms.
A sobering implication of this Table is that it makes one aware that a
major problem in cardiac electrophysiology is our lack of knowledge as
to whether experimental or naturally occurring genetically induced
remodeling of the cellular and interstitial distribution of
proteins (cell size, gap junctions, Na+
channels, and interstitial collagen) alters electrical
events within and between cells. Consequently, as a guide to the future
genetic manipulation of proteins that change cellular
parameters and interstitial collagen, answers
to two questions are of prime importance. First, do changes in cellular
geometric parameters change electrical events within
cardiac myocytes and alter the transfer of the excitatory impulse
between cells? Second, if these changes alter electrical events within
and between individual cells, do the cellular changes affect
anisotropic conduction at the macroscopic tissue level?
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Mapping techniques developed by Kléber et al31 have provided a significant advance in the study of propagation at a small size scale in neonatal cellular culture monolayers. Even with these elegant techniques, experimental limitations in cardiac bundles still prevent measurement of propagation delays across specific gap junctions, much less measurement of the intracellular distributions of dV/dtmax and the Na+ current. However, mathematical models that incorporate a representation of the structure of cardiac bundles provide an important way to gain insight about microscopic electrical changes that occur when several cellular parameters are remodeled simultaneously (eg, cell size and the cellular distribution of gap junctions32 ). The success of the computational models of Moe et al,1 van Capelle and Durrer,17 and Berenfeld and Pertsov16 for continuous media, all of which were developed at a time when experimental limitations prevented measurement of the predicted excitation wave dynamics, have established an important precedent. Thus, mathematical models incorporating a representation of actual microscopic structure should become increasingly important. They provide a way to obtain insight into the microscopic electrical effects of induced and naturally occurring changes in the density and cellular distribution of proteins. Such information about propagation within and between individual cells at different ages and in different disease conditions may become quite important for understanding the generation and maintenance of reentrant arrhythmias and their ultimate prevention.
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Acknowledgments |
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The author would like to thank Dr Roger Barr for his helpful discussions during the preparation of this editorial.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
See related article, pages 839-848
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References |
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TopIntroductionAdvances and Problems in...ImplicationsReferences |
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