Does ephaptic coupling contribute to propagation in cardiac tissue?

When I was in graduate school, I spent a couple weeks at the University of Cincinnati working in the laboratory of Nicholas Sperelakis. Nick, who passed away a few months ago, was a renowned physiologist and a delightful man. However, his opinion about the mechanism of propagation in cardiac tissue was at odds with the traditional view of electrical coupling between cells through low-resistance channels at the gap junctions (1xAn electric field mechanism for transmission of excitation between myocardial cells. Sperelakis, N. Circ. Res. 2002; 91: 985–987Crossref | PubMed | Scopus (44)See all References1). Instead, he believed in what is often called “ephaptic coupling,” but which he referred to as an electric-field mechanism of propagation (2xEvaluation of electric field changes in the cleft between excitable cells. Sperelakis, N. and Mann, J.E. Jr. J. Theor. Biol. 1977; 64: 71–96Crossref | PubMed | Scopus (49)See all References, 3xGap junction uncoupling and discontinuous propagation in the heart. A comparison of experimental data with computer simulations. Cole, W.C., Picone, J.B., and Sperelakis, N. Biophys. J. 1988; 53: 809–818Abstract | Full Text PDF | PubMedSee all References). I will let him describe this idea in his own words (4xPropagation mechanisms in heart. Sperelakis, N. Annu. Rev. Physiol. 1979; 41: 441–457Crossref | PubMedSee all References4).“Sperelakis & Mann (2xEvaluation of electric field changes in the cleft between excitable cells. Sperelakis, N. and Mann, J.E. Jr. J. Theor. Biol. 1977; 64: 71–96Crossref | PubMed | Scopus (49)See all References2) presented a new model that would allow an electrical transmission process to occur at the IDs [intercalated disks] but that requires neither low-resistance connections between the cells nor a very large capacitance between the cells. They analyzed the electric field that would develop in the narrow cleft between two myocardial cells…. When the pre-membrane fired an action potential, the cleft between the cells became negative with respect to ground (ISF [interstitial fluid]), and this potential acted to depolarize the post-membrane to its threshold.”Recently, James Keener and his colleagues in the Department of Mathematics at the University of Utah have analyzed the idea of ephaptic coupling in a series of elegant computer simulations (5xEphaptic coupling of cardiac cells through the junctional electric potential. Copene, E.D. and Keener, J.P. J. Math. Biol. 2008; 57: 265–284Crossref | PubMed | Scopus (14)See all References, 6xModeling electrical activity of myocardial cells incorporating the effects of ephaptic coupling. Lin, J. and Keener, J.P. Proc. Natl. Acad. Sci. USA. 2010; 107: 20935–20940Crossref | PubMed | Scopus (19)See all References, 7xEphaptic coupling in cardiac myocytes. Lin, J. and Keener, J.P. IEEE Trans. Biomed. Eng. 2013; 60: 576–582Crossref | PubMed | Scopus (15)See all References). In this issue of the Biophysical Journal, Joyce Lin and Keener present additional calculations supporting this hypothesis (8xMicrodomain effects on transverse cardiac propagation. Lin, J. and Keener, J.P. Biophys. J. 2013; 106: 925–931Abstract | Full Text | Full Text PDF | Scopus (10)See all References8). Their study is motivated by recent experiments from Steven Poelzing’s group (9xInterstitial volume modulates the conduction velocity-gap junction relationship. Veeraraghavan, R., Salama, M.E., and Poelzing, S. Am. J. Physiol. Heart Circ. Physiol. 2012; 302: H278–H286Crossref | PubMedSee all References9), which showed—surprisingly—that increased extracellular volume is associated with decreased conduction velocity, especially for propagation in the transverse direction (perpendicular to the myocardial fibers). To explain this behavior, Lin and Keener’s model (8xMicrodomain effects on transverse cardiac propagation. Lin, J. and Keener, J.P. Biophys. J. 2013; 106: 925–931Abstract | Full Text | Full Text PDF | Scopus (10)See all References8) accounts for voltage gradients in the microscopic extracellular clefts between cells (the “microdomains” of their title). They observe ephaptic conduction in their simulations, and predict an inverted extracellular volume/conduction speed relationship like that observed experimentally. Lin and Keener describe this type of propagation as being along an inverted cable:“One way to understand this mode of propagation is to view the junctional space as an ‘inverted’ cable, which supports propagation along its length, i.e., transverse to the longitudinal axis of the cell.”Although their conduction speed results are suggestive, what one really wants is a definitive prediction about propagation that could be tested experimentally and that could distinguish unambiguously between the two mechanisms: ephaptic conduction and electrical coupling via gap junctions. For instance, the ephaptic mechanism only works if there are large electric fields in the extracellular cleft. How could such fields be measured? With a cleft width of only 150 A, it is difficult to imagine inserting an electrode into it. Rather, one needs a method analogous to optical mapping of transmembrane potential, but designed to measure extracellular cleft voltages rather than voltages across the membrane. Another way to test for ephaptic conduction might be for Lin and Keener (8xMicrodomain effects on transverse cardiac propagation. Lin, J. and Keener, J.P. Biophys. J. 2013; 106: 925–931Abstract | Full Text | Full Text PDF | Scopus (10)See all References8) to calculate the longitudinal current associated with the action-potential wave front. The sucrose gap technique, as well as biomagnetic methods (10xLongitudinal resistance in cardiac muscle and its effects on propagation. Roth, B.J. and Wikswo, J.P. Jr. : 165–178See all References, 11xMeasurements of transmembrane potential and magnetic field at the apex of the heart. McBride, K.K., Roth, B.J...., and Baudenbacher, F.J. Biophys. J. 2010; 99: 3113–3118Abstract | Full Text | Full Text PDF | PubMed | Scopus (3)See all References), measure current rather than voltage, and if the longitudinal current is significantly affected by the ephaptic mode of propagation, these methods may provide a unique signature. Another interesting test would be to determine how the underlying tissue structure leading to ephaptic conduction might affect four-electrode impedance measurements (12xA biophysical model for cardiac microimpedance measurements. Pollard, A.E. and Barr, R.C. Am. J. Physiol. Heart Circ. Physiol. 2010; 298: H1699–H1709Crossref | PubMed | Scopus (11)See all References12). Yet another is to see how models including a complete three-dimensional microstructure with all its complexity (13xCardiac microstructure: implications for electrical propagation and defibrillation in the heart. Hooks, D.A., Tomlinson, K.A...., and Hunter, P.J. Circ. Res. 2002; 91: 331–338Crossref | PubMed | Scopus (171)See all References13), but extended to include ephaptic behavior, will affect propagation and defibrillation. In general, the most important next step for these simulations is to make additional testable predictions that would give one result if propagation is by electrical coupling through gap junctions and another if by ephaptic coupling via the cleft.What I like most about Lin and Keener’s article is that it has forced me to rethink everything I thought I knew about the electrical behavior of the heart. These days, most articles report incremental advances within an established conceptual framework, so I find a study that proposes a different point of view to be refreshing and fascinating. Have Lin and Keener won me over? Do I now believe in ephaptic coupling between myocardial cells? No, at least not in healthy tissue. Many of the predicted ephaptic effects arise when gap junction coupling is low and sodium channels are restricted to the ends of the cells facing the clefts. Perhaps in certain pathological conditions when gap junctional conductance is compromised ephaptic coupling may play a significant role in propagation, but I doubt it contributes in normal healthy tissue. Still, understanding heart disease means understanding unhealthy tissue, where ephaptic coupling might play a significant role. Maybe.For decades, Nick Sperelakis argued passionately for an electric-field mechanism for propagation in cardiac tissue. I am sure he would have been pleased if he could have read Lin and Keener’s article. The agreement between their simulations and Poelzing’s data is impressive, but I will need a more definitive experimental confirmation before I can embrace the ephaptic hypothesis.