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Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes

Lothar A. Blatter, Jens Kockskämper, Katherine A. Sheehan, Aleksey V. Zima, Jörg Hüser and Stephen L. Lipsius

Subcellular Ca²⁺ signalling during normal excitation-contraction (E-C) coupling and during Ca²⁺ alternans was studied in atrial myocytes using fast confocal microscopy and measurement of Ca²⁺ currents (I_Ca). Ca²⁺ alternans, a beat-to-beat alternation in the amplitude of the [Ca²⁺]_i transient, causes electromechanical alternans, which has been implicated in the generation of cardiac fibrillation and sudden cardiac death. Cat atrial myocytes lack transverse tubules and contain sarcoplasmic reticulum (SR) of the junctional (j-SR) and non-junctional (nj-SR) types, both of which have ryanodine-receptor calcium release channels. During E-C coupling, Ca²⁺ entering through voltage-gated membrane Ca²⁺ channels (I_Ca) triggers Ca²⁺ release at discrete peripheral j-SR release sites. The discrete Ca²⁺ spark-like increases of [Ca²⁺]_i then fuse into a peripheral 'ring' of elevated [Ca²⁺]_i, followed by propagation (via calcium-induced Ca²⁺ release, CICR) to the cell centre, resulting in contraction. Interrupting I_Ca instantaneously terminates j-SR Ca²⁺ release, whereas nj-SR Ca²⁺ release continues. Increasing the stimulation frequency or inhibition of glycolysis elicits Ca²⁺ alternans. The spatiotemporal [Ca²⁺]_i pattern during alternans shows marked subcellular heterogeneities including longitudinal and transverse gradients of [Ca²⁺]_i and neighbouring subcellular regions alternating out of phase. Moreover, focal inhibition of glycolysis causes spatially restricted Ca²⁺ alternans, further emphasising the local character of this phenomenon. When two adjacent regions within a myocyte alternate out of phase, delayed propagating Ca²⁺ waves develop at their border. In conclusion, the results demonstrate that (1) during normal E-C coupling the atrial [Ca²⁺]_i transient is the result of the spatiotemporal summation of Ca²⁺ release from individual release sites of the peripheral j-SR and the central nj-SR, activated in a centripetal fashion by CICR via I_Ca and Ca²⁺ release from j-SR, respectively, (2) Ca²⁺ alternans is caused by subcellular alterations of SR Ca²⁺ release mediated, at least in part, by local inhibition of energy metabolism, and (3) the generation of arrhythmogenic Ca²⁺ waves resulting from heterogeneities in subcellular Ca²⁺ alternans may constitute a novel mechanism for the development of cardiac dysrhythmias.

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