In cat atrial myocytes, Ca(2+) alternans is caused by subcellular alterations of SR Ca(2+) release mediated by local inhibition of energy metabolism, generating arrhythmogenic Ca(2+) waves.
Subcellular heterogeneities in calcium alternans, driven by local metabolic inhibition, can generate arrhythmogenic calcium waves, providing a novel mechanism for cardiac dysrhythmias.
Subcellular Ca(2+) signalling during normal excitation-contraction (E-C) coupling and during Ca(2+) alternans was studied in atrial myocytes using fast confocal microscopy and measurement of Ca(2+) currents (I(Ca)). Ca(2+) alternans, a beat-to-beat alternation in the amplitude of the Ca(2+)(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, Ca(2+) entering through voltage-gated membrane Ca(2+) channels (I(Ca)) triggers Ca(2+) release at discrete peripheral j-SR release sites. The discrete Ca(2+) spark-like increases of Ca(2+)(i) then fuse into a peripheral 'ring' of elevated Ca(2+)(i), followed by propagation (via calcium-induced Ca(2+) release, CICR) to the cell centre, resulting in contraction. Interrupting I(Ca) instantaneously terminates j-SR Ca(2+) release, whereas nj-SR Ca(2+) release continues. Increasing the stimulation frequency or inhibition of glycolysis elicits Ca(2+) alternans. The spatiotemporal Ca(2+)(i) pattern during alternans shows marked subcellular heterogeneities including longitudinal and transverse gradients of Ca(2+)(i) and neighbouring subcellular regions alternating out of phase. Moreover, focal inhibition of glycolysis causes spatially restricted Ca(2+) alternans, further emphasising the local character of this phenomenon. When two adjacent regions within a myocyte alternate out of phase, delayed propagating Ca(2+) waves develop at their border. In conclusion, the results demonstrate that (1) during normal E-C coupling the atrial Ca(2+)(i) transient is the result of the spatiotemporal summation of Ca(2+) 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 Ca(2+) release from j-SR, respectively, (2) Ca(2+) alternans is caused by subcellular alterations of SR Ca(2+) release mediated, at least in part, by local inhibition of energy metabolism, and (3) the generation of arrhythmogenic Ca(2+) waves resulting from heterogeneities in subcellular Ca(2+) alternans may constitute a novel mechanism for the development of cardiac dysrhythmias.
Blatter et al. (Wed,) conducted a other in Cardiac dysrhythmias (experimental model). Increased stimulation frequency or inhibition of glycolysis vs. Normal excitation-contraction coupling was evaluated on Subcellular Ca(2+) signalling and spatiotemporal [Ca(2+)](i) patterns. In cat atrial myocytes, Ca(2+) alternans is caused by subcellular alterations of SR Ca(2+) release mediated by local inhibition of energy metabolism, generating arrhythmogenic Ca(2+) waves.