Re-entry comprises the most severe form of cardiac arrhythmia and generally involves self-sustained activity supported by circus movement. However, in 1972, Wit, Hoffman and Cranefield suggested that a specialized form of one-dimensional re-entry, which they termed reflection, might be possible (Wit et al. 1972). Later, in 1980, Antzelevitch, Jalife and Moe showedthat reflection was feasible in an isolated bundle of Purkinje tissue (Antzelevitch et al. 1980). Two excitable regions were separated by a short segment of suppressed activity. Following stimulation of one region (the proximal side), electrical activity electrotonically traversed the inexcitable segment with a substantial delay and brought the distal region to excitation threshold to fire an action potential, which in turn generated electrotonic currents in the retrograde direction. Following further delay, the proximal region of the fibre could then re-excite, completing the reflection event as a return extrasystole (Fig. 1A). A delicate balance in terms of conduction delay and regional excitability of the cell membrane was necessary to achieve this effect. The total delay had to be long enough to allow the proximal region time to recover from refractoriness and regain its excitability, while the inexcitable segment had to be short enough to provide sufficient electrotonic coupling from one side to the other to enable both distal and proximal activation. In the next dozen years, conditions for reflected re-entry were explored in numerous experimental (cf. Antzelevitch, 1990) and computational (Cabo & Barr, 1992) studies and shown to apply also to isolated ventricular and atrial tissue. In general, depression of cellular properties of the segment in the form of reduced excitability and/or reduced electrical coupling was required. Such conditions may be especially prevalent in ischaemic or fibrotic regions of tissue in which regions of cardiomyocytes are separated by zones of depressed conduction or collagenous septa. Figure 1 Two types of reflection In an elegant and detailed study that combined experiments and computational simulations, Auerbach and co-workers provide a new account of reflection in this issue of The Journal of Physiology (Auerbach et al. 2011). Cell cultures are a contemporary experimental platform that is amenable to geometric patterning, control of cell types, and genetic manipulation for the study of tissue-level forms of cardiac arrhythmia and are a biological analogue to computational models (Tung & Zhang, 2006). Using optical mapping to visualize action potentials and propagated activity, Auerbach et al. show that in patterned cultures of neonatal rat ventricular myocytes (NRVMs), heterogeneous cell properties are not essential for reflection, unlike the case described above for what one might call ‘segment-type reflection’. Instead, a simple structural heterogeneity (a geometric expansion) produces conditions that support what might be called ‘expansion-type reflection’ (Fig. 1B), an idea that was studied previously for a nerve fibre having a step increase in diameter (Goldstein & Rall, 1974). Although the experimental model consists of proximal and distal expansion regions connected by a narrow isthmus, the proximal expansion region does not really play a functional role, and the process of reflection occurs entirely where the isthmus meets the distal expansion. The expansion has the property that electrical load is asymmetric – propagation from isthmus to distal expansion faces an increased electrical load (owing to increased wavefront curvature), whereas propagation in the opposite direction faces a decreased electrical load. As it turns out, these conditions facilitate reflection. Importantly, the source-load mismatch at the isthmus exit site attenuates repolarizing currents and assists with the formation of an early afterdepolarization (EAD), which provides a delayed, retrograde current that can re-excite the isthmus. The incidence of EADs and reflection could be greatly augmented by a genetic or pharmacological increase of persistent sodium current. To analyse the dependence of expansion-type reflection on sodium current, wavefront curvature and EAD formation, the authors utilized a novel form of a one-dimensional cable model as well as two-dimensional computer simulations. As with all insightful studies, the work by Auerbach et al. raises additional, intriguing questions. First, can reflected re-entry occur between proximal and distal regions in a to-and-fro manner, giving rise to repetitive activity? Second, do conditions that facilitate EADs, apart from persistent sodium current, generally facilitate expansion-type reflection? Finally, what might be the proarrhythmic or antiarrhythmic consequences of modulation of ion channel function at different pacing rates, as was revealed in previous pharmacological studies of segment-type reflection (Antzelevitch, 1990)? One limitation of NRVMs is their short action potential duration compared with other mammalian (including human) cardiac cells. Future studies may require the development of new cultured cell types with more pronounced action potential plateaus. Time will tell whether yet more types of reflection are possible.
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Jul 31, 2019
Xueqing Wu + 5
