doi: 10.1161/01.RES.0000177922.62341.f2
© 2005 American Heart Association, Inc.
Editorials |
The Shape of the Electrical Action-Potential Upstroke
A New Aspect From Optical Measurements on the Surface of the Heart
From the Department of Physiology, University of Bern, Switzerland
Correspondence to Dr André G. Kléber, Department of Physiology, University of Bern, Bühlplatz5, CH-3012 Bern, Switzerland. E-mail KLEBER{at}PYL.UNIBE.CH
See related article, pages 277–284
Key Words: action potential • optical measurements • excitation • propagation • upstroke
Since the first measurement of an action potential from cardiac tissue by Coraboeuf and Weidmann in 1948,1 the biological information contained in its shape has been the subject of many theoretical and experimental studies.
In the context of the article published by Hyatt et al2 in the current issue of Circulation Research, describing the role of the shape of an optical action-potential upstroke, it seems important to define the action potential of a cardiac cell. An action potential, in the classical sense of the term, is caused by the change in transmembrane potential of a cardiac cell during excitation. It is usually measured from a very small site with a microelectrode (diameter <1 mm) or with a voltage-sensitive dye (smallest membrane area 6x6 mm).1,3 It is not disputed that the upstroke of the normal cardiac action potential is caused by the flow of ions through channels specific for Na+.4 In the sinoatrial node and the inner zone of the atrioventricular node, ionic current through the L-type Ca2+ channel may play an additional role (see Kléber et al5). In the setting of isopotentiality of the cell membrane (created artificially by voltage clamp) the ionic current during a subsequent action potential will change the charge distribution at the lipid membrane bilayer. Expressed in terms of a simple biophysical model, the change in membrane potential, dV/dt, is proportional to ion current flow and the steepest portion of the action-potential upstroke, dV/dtmax, occurs at maximal Na+ flow.4
In the case of a propagated action potential, the situation is more complex. Here, the net ionic charge flowing through channels and exchangers incorporates 2 components, a first component changing the membrane capacity and producing the action-potential upstroke and a second component providing charge for excitation of downstream elements. The match between these 2 electrical charges and the charge needed for excitation of a given cell (initial portion or "foot" of the action potential) determines whether there is successful propagation or conduction block.6 The fact that ionic inward current provides the charge for excitation of still-resting neighbor cells is not only the key to successful propagation; it also means that downstream current flow affects the shape of the action-potential upstroke. Thus in plane wave propagation in a continuous medium, the maximal upstroke velocity occurs late during the upstroke and is no longer a direct measure of Na+ inward current flow.7,8 As long as the downstream impedance load remains constant (so-called "continuous conduction"), the shape of the cardiac action potential remains constant during propagation and the change of membrane voltage as a function of time is directly coupled to the spatial change through propagation velocity.9
However, real heart tissue is different from a continuous electrical medium. Thus, structural and functional discontinuities are present at several levels. At the cellular level, discontinuities are attributable to the presence of cell borders and intercellular connections formed by connexin proteins; at the tissue level structural discontinuities are formed by connective tissue septa (increasing with age) and the intrinsic myocardial architecture is characterized by laminar and trabecular structures.10,11 The biophysical rules explaining the changes in shape of propagating action potential attributable to current-to-load mismatch are independent of the scale at which the discontinuities occur. Thus, partial collision of a propagation wave with a resistive obstacle leads to an increase in action-potential upstroke velocity, whereas dispersion of local current at a site of a convex wavefront leads to a decrease of action-potential upstroke velocity and to a concomitant increase of the duration of the action-potential upstroke.7,12–14
The first portion or "foot" of the action-potential upstroke is caused by electrotonic current flowing into the membrane capacitance from excited upstream elements. Several experimental and theoretical studies have shown that the shape of the action-potential "foot", like the later portion of the upstroke, is affected by variables other than the local membrane properties. Thus, the action-potential foot is changed by propagation in tissue layers adjacent to a bulk conductor (subendocardial and subepicardial layers) and by the presence of the dense microvasculature that can alter the action-potential foot by acting as a direction-dependent reservoir for electrical charge provided by local current flow in the wavefront of excitation.15–18 In summary, the upstroke of a propagating action potential in a cardiac cell is determined in a complex way by the depolarizing ion current as well as by the changing downstream resistive and capacitive load that is dependent on the underlying (anisotropic) cardiac structure.
Measurement of intracellular potential, ie, the action-potential upstroke in the proper sense of the term, has been mostly confined to single cells, 2D tissue cultures, or the immediate subsurface layer of cardiac tissue. Intramural information about the moment of local depolarization has been derived from unipolar or bipolar extracellular electrograms. In seminal studies multiterminal "needle electrodes" were used to define the excitation of the total human heart by isochrone mapping19 and the potential distribution during excitation and repolarization in the dog heart.20 A further step in the analysis of transmural electrical activity was made with the development of the so-called arterially-perfused "wedge" preparation.21 This preparation enables recording from an intramural surface layer exposed by cutting the ventricular wall and preserving its perfusion. Although this preparation is very useful to analyze radially-oriented electrical gradients, the cut surface represents a reflection boundary for tangentially-oriented electrical currents and wavefronts. Only recently, optical measurements of transmembrane action potentials were obtained from so-called "optrodes", ie, optical fibers introduced into the depth of the myocardium.22,23 However, the shape of the action-potential upstroke was not specifically analyzed in these experiments.
In the current issue of Circulation Research, Hyatt et al2 present a new method for obtaining information about the direction of wave front propagation in subepicardial tissue layers. The term optical-action-potential upstroke, as used by Hyatt et al, stands for the weighted spatio-temporal convolution of action-potential upstrokes from a multicellular volume of tissue emitting light from the subepicardial muscle layers (Figure). The authors use the analysis of the shape of the optical-action-potential upstroke, computed from a monodomain model and measured on the epicardial surface of a pig heart, to define the angle between the intramural wavefront and the epicardial surface. In this way, the authors show that it is possible to gain information about intramural 3D propagation from 2D epicardial measurements.
|
F/F) from the same membrane site. Note that the 2 signals fully superimpose. B, Sketch of the optical action-potential upstroke as measured from the epicardium of a porcine heart. The spatio-temporal convolution of single action-potential upstrokes is recognized from the duration of the signal, which is >25-fold the duration of the signal from the single cell. (Redrawn from references It is important to note that there is no essential difference between the direct electrical measurement of membrane potential (microelectrode) and the measurement with voltage-sensitive dyes, with the exception that the latter provide a relative measure and may require calibration (Figure).3,24 The duration of the optical-action-potential upstroke, as defined by Hyatt et al, is more than 1 order of magnitude longer than the duration of a "classical" local action-potential upstroke (Figure). To validate their method, the authors use a comparison with computer simulations. The information about the wavefront angle stems from the averaging process that masks the classical action-potential shape produced by the individual cells contributing to the signal. The mechanism underlying the shape change, although not explained in detail by the authors, seems to be intuitively clear. In the case of a wavefront propagating away from the epicardium, the early component of the signal is dominated by excitation of the cells closest to the light sensor (steep component), although the later component will be slurred by the superimposition of action potential excited deeper and later. This is expected to produce initially a steeper voltage change than in the later phase of the optical-action-potential upstroke. Conversely, a wave front approaching the epicardium will produce proximal steep local components on collision with the epicardium, ie, in the end phase of the process. One of the experiments that the authors use to validate the method also suggests a useful application. On centrifugal spread from a central stimulus, the angle of the wavefront changes. The zero-angle, as derived from the action-potential shape, will indicate propagation parallel to the epicardium. Measurement of propagation velocity at that site will minimize the error that may be caused by the changing axis of anisotropy or by the inclusion of sites within the area of the virtual stimulus electrode.25 The applicability to further situations of epicardial and subepicardial propagation remains to be demonstrated. An interesting case will be the investigation of epicardial and intramural activation during the spread of intramural scroll waves occurring during ventricular tachyarrhythmias and fibrillation.26 However, one caveat remains. The method is not suited to localize wavefront angles in case of wavefront collision. Especially during normal cardiac excitation, with preferential endocardial-to-epicardial propagation, collision is expected to occur between epicardial waves emerging from epicardial breakthrough sites.19 Moreover, propagation on the endocardial surface is characterized by discontinuous propagation because of trabeculation and the presence of the Purkinje fiber network that is expected to produce sites of wavefront dispersion and partial collision.14,27 Therefore, it will be interesting to validate the usefulness of this method on the endocardial surface of the heart.
 |
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
1. Coraboeuf E, Weidmann S. Potentiel de repos et potentiel d’action du muscle cardiaque, mesures a l’aide d’electrodes intracellulaire. C R Seances Soc Biol Fil. 1949; 143: 1329–1331.
2. Hyatt C, Mironov S, Vetter F, Zemlin C, Pertsov A Optical action potential upstroke morphology reveals near-surface transmural propagation direction. Circ Res. 2005; 97: 277–284.
3. Fast VG, Kléber AG. Microscopic conduction in cultured strands of neonatal rat heart cells measured with voltage-sensitive dyes. Circ Res. 1993; 73: 914–925.
4. Weidmann S. The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system. J Physiol. 1955; 127: 213–224.
5. Kléber AG, Janse MJ, Fast VG. Normal and abnomal conduction in the heart. In: Page E, Fozzard H, Solaro R, eds. The Handbook of Physiology. Vol 1:The Heart. New York: Oxford University Press; 2002: 455–530.
6. Shaw RM, Rudy Y. Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. Circ Res. 1997; 81: 727–741.
7. Spach MS, Kootsey JM. Relating the sodium current and conductance to the shape of transmembrane and extracellular potentials by simulation: effects of propagation boundaries. IEEE Trans Biomed Eng. 1985; 32: 743–755.[Medline] [Order article via Infotrieve]
8. Walton MK, Fozzard HA. The conducted action potential: Models and comparison to experiments. Biophys J. 1983; 44: 9–26.[Medline] [Order article via Infotrieve]
9. Hodgkin AL. A note on conduction velocity. J Physiol (Lond). 1954; 125: 221–224.
10. Le Grice IJ, Smaill BH, Chai LZ, Edgar SG, Gavin JB, Hunter PJ. Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog. Am J Physiol. 1995; 38: H571–H582.
11. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res. 1986; 58: 356–371.
12. Fast VG, Darrow BJ, Saffitz JE, Kléber AG. Anisotropic activation spread in heart cell monolayers assessed by high-resolution optical mapping: role of tissue discontinuities. Circ Res. 1996; 79: 115–127.
13. Fast VG, Kléber AG. Cardiac tissue geometry as a determinant of unidirectional conduction block: assessment of microscopic excitation spread by optical mapping in patterned cell cultures and in a computer model. Cardiovasc Res. 1995; 29: 697–707.[CrossRef][Medline] [Order article via Infotrieve]
14. Spach MS, Miller WT3rd, Dolber PC, Kootsey JM, Sommer JR, Mosher CE Jr. The functional role of structural complexities in the propagation of depolarization in the atrium of the dog. Cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res. 1982; 50: 175–191.
15. Henriquez CS, Muzikant AL, Smoak CK. Anisotropy, fiber curvature, and bath loading effects on activation in thin and thick cardiac tissue preparations: Simulations in a three-dimensional bidomain model. J Cardiovasc Electrophysiol. 1996; 7: 424–444.[Medline] [Order article via Infotrieve]
16. Roth BJ. Action potential propagation in a thick strand of cardiac muscle. Circ Res. 1991; 68: 162–173.
17. Spach MS, Heidlage JF, Dolber PC, Barr RC. Extracellular discontinuities in cardiac muscle: evidence for capillary effects on the action potential foot. Circ Res. 1998; 83: 1144–1164.
18. Suenson M. Interaction between ventricular cells during the early part of excitation in the ferret heart. Acta Physiol Scand. 1985; 125: 81–90.[Medline] [Order article via Infotrieve]
19. Durrer D, van Dam RT, Freud GE, Janse MJ, Meijler FL, Arzbaecher RC. Total excitation of the isolated human heart. Circulation. 1970; 41: 899–912.
20. Spach MS, Barr RC. Ventricular intramural and epicardial potential distributions during ventricular activation and repolarization in the intact dog. Circ Res. 1975; 37: 243–257.
21. Yan GX, Shimizu W, Antzelevitch C. Characteristics and distribution of M cells in arterially perfused canine left ventricular wedge preparations. Circulation. 1998; 98: 1921–1927.
22. Byars JL, Smith WM, Ideker RE, Fast VG. Development of an optrode for intramural multisite optical recordings of Vm in the heart. J Cardiovasc Electrophysiol. 2003; 14: 1196–1202.[CrossRef][Medline] [Order article via Infotrieve]
23. Hooks DA, LeGrice IJ, Harvey JD, Smaill BH. Intramural multisite recording of transmembrane potential in the heart. Biophys J. 2001; 81: 2671–2680.[Medline] [Order article via Infotrieve]
24. Windisch H, Ahammer H, Schaffer P, Muller W, Platzer D. Optical multisite monitoring of cell excitation phenomena in isolated cardiomyocytes. Pflugers Arch. 1995; 430: 508–518.[CrossRef][Medline] [Order article via Infotrieve]
25. Wikswo JP Jr, Lin SF, Abbas RA. Virtual electrodes in cardiac tissue: a common mechanism for anodal and cathodal stimulation. Biophys J. 1995; 69: 2195–2210.[Medline] [Order article via Infotrieve]
26. Gray RA, Jalife J, Panfilov AV, Baxter WT, Cabo C, Davidenko JM, Pertsov AM. Mechanisms of cardiac fibrillation. Science. 1995; 270: 1222–1223.
27. Spach MS, Barr RC, Johnson EA, Kootsey JM. Cardiac extracellular potentials. Analysis of complex wave forms about the Purkinje networks in dogs. Circ Res. 1973; 33: 465–473.
Related Article:
Circ. Res. 2005 97: 277-284.
This article has been cited by other articles:
 |
|
 |
|
  G. L. Aistrup, J. E. Kelly, S. Kapur, M. Kowalczyk, I. Sysman-Wolpin, A. H. Kadish, and J. A. Wasserstrom Pacing-induced Heterogeneities in Intracellular Ca2+ Signaling, Cardiac Alternans, and Ventricular Arrhythmias in Intact Rat Heart Circ. Res., September 29, 2006; 99(7): E65 - E73. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||