Abstract 21246: Non-Trivial Effects of Intercellular Coupling on Spatiotemporal Intracellular Ca2+ Dynamics in Cardiac Myocytes
Recent evidence from modeling and experiments casts intracellular Ca2+ dynamics as independent pro-arrhythmic factor. However, the detailed mechanism of instabilities progression to arrhythmias at the tissue level is not well understood. Cellular coupling through gap junctions provides low-resistance pathways between cardiac myocytes and hence helps synchrony. We hypothesize that cellular coupling alters the early spatiotemporal evolution of Ca2+ instabilities and can be quantitatively linked to arrhythmic events. We experimentally perturbed cellular coupling bi-directionally (increasing and decreasing) by use of a small molecule, 4-phenylbutyrate (4PB), which we have shown to serve as gap junction agonist, increasing diffusion and conduction velocity (CV) without major side effects, and the use of a gap junction uncoupler — heptanol. Coupling under these conditions was quantified by macroscopic fluorescence recovery after photobleaching (gap-FRAP). Calcium waves were captured by ultra-high resolution optical mapping (allowing subcellular imaging over cm-scale) in conjunction with a recently published algorithm for spatiotemporal detection of subtle fine-scale alternans. Figure 1A illustrates the expected increase of CV and breakpoint frequency with coupling. However, tracking the evolution of Ca2+ alternans with pacing frequency in Figure 1B reveals a non-monotonic dependence of early (<2Hz) alternans area with coupling, as intermediate (not low) coupling results in largest alternating area. This relationship is closely matched by the % of samples exhibiting large-scale alternans as function of coupling. We conclude that although reduced coupling may lead to paradoxically less Ca2+ alternans overall, a better coupling renders anti-arrhythmic benefits by increasing CV and the frequency at which alternans occur. Furthermore, our data indicate that early subtle alternans characteristics may be predictive of later arrhythmia events.
- © 2010 by American Heart Association, Inc.