Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes

Ca2+ alternans is a potentially arrhythmogenic beat-to-beat alternation of the amplitude of the action potential-induced [Ca2+](i) transient in cardiac myocytes. Despite its pathophysiological significance the cellular mechanisms underlying Ca2+ alternans are poorly understood. Recent evidence, however, points to the modulation of Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum. (SR) by localized alterations in energy metabolism as an important determinant of Ca2+ alternans. We therefore studied the subcellular properties of Ca2+ alternans in field-stimulated cat atrial myocytes employing fast two-dimensional fluorescence confocal microscopy. Ca2+ alternans was elicited by an increase in stimulation frequency or by metabolic interventions targeting glycolysis. Marked subcellular variations in the time of onset, the magnitude, and the phase of alternans were observed. Longitudinal and transverse gradients of Ca2+ alternans were found as well as neighbouring subcellular regions alternating out-of-phase. Moreover, focal inhibition of glycolysis resulted in spatially restricted Ca2+ alternans. When two adjacent regions within a myocyte alternated out-of-phase, steep [Ca2+](i) gradients developed at their border giving rise to delayed propagating Ca2+ waves. The results demonstrate that Ca2+ alternans is a subcellular phenomenon caused by modulation of SR Ca2+ release, which is mediated, at least in part, by local inhibition of energy metabolism. The generation of arrhythmogenic Ca2+ waves by subcellular variations in the phase of Ca2+ alternans represents a novel mechanism for the development of atrial disrhythmias.