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Background: Abnormalities in intracellular calcium (Ca) cycling during Ca overload can cause triggered activity because spontaneous calcium release (SCR) activates sufficient Ca-sensitive inward currents to induce delayed afterdepolarizations (DADs). However, little is known about the mechanisms relating SCR and triggered activity on the tissue scale. Methods and Results: Laser scanning confocal microscopy was used to measure the spatiotemporal properties of SCR within large myocyte populations in intact rat heart. Computer simulations were used to predict how these properties of SCR determine DAD magnitude. We measured the average and standard deviation of the latency distribution of SCR within a large population of myocytes in intact tissue. We found that as external [Ca] is increased, and with faster pacing rates, the average and SD of the latency distribution decreases substantially. This result demonstrates that the timing of SCR occurs with less variability as the sarcoplasmic reticulum (SR) Ca load is increased, causing more sites to release Ca within each cell. We then applied a mathematical model of subcellular Ca cycling to show that a decrease in SCR variability leads to a higher DAD amplitude and is dictated by the rate of SR Ca refilling following an action potential. Conclusions: Our results demonstrate that the variability of the timing of SCR in a population of cells in tissue decreases with SR load and is dictated by the time course of the SR Ca content.

Abstract-Optical mapping studies have suggested that intracellular Ca 2ϩ and T-wave alternans are linked through underlying alternations in Ca 2ϩ cycling-inducing oscillations in action potential duration through Ca 2ϩ -sensitive conductances. However, these studies cannot measure single-cell behavior; therefore, the Ca 2ϩ cycling heterogeneities within microscopic ventricular regions are unknown. The goal of this study was to measure cellular activity in intact myocardium during rapid pacing and arrhythmias. We used single-photon laser-scanning confocal microscopy to measure Ca 2ϩ signaling in individual myocytes of intact rat myocardium during rapid pacing and during pacing-induced ventricular arrhythmias. At low rates, all myocytes demonstrate Ca 2ϩ alternans that is synchronized but whose magnitude varies depending on recovery kinetics of Ca 2ϩ cycling for each individual myocyte. As rate increases, some cells reverse alternans phase, giving a dyssynchronous activation pattern, even in adjoining myocytes. Increased pacing rate also induces subcellular alternans where Ca 2ϩ alternates out of phase with different regions within the same cell. These forms of heterogeneous Ca 2ϩ signaling also occurred during pacing-induced ventricular tachycardia. Our results demonstrate highly nonuniform Ca 2ϩ signaling among and within individual myocytes in intact heart during rapid pacing and arrhythmias. Thus, certain pathophysiological conditions that alter Ca 2ϩ cycling kinetics, such as heart failure, might promote ventricular arrhythmias by exaggerating these cellular heterogeneities in Ca 2ϩ signaling. (Circ Res. 2006;99:e65-e73.) Key Words: calcium transients Ⅲ calcium alternans Ⅲ subcellular alternans Ⅲ arrhythmias O ne of the most important clues to the mechanisms responsible for repolarization alternans was derived from the fact that action potential duration (APD) alternans occurs at the cellular level in intact heart. 1-3 It is now widely accepted that T-wave alternans (TWA) on the surface ECG reflects tissue repolarization alternans at the level of the whole heart. In contrast to a purely electrophysiological explanation involving ion channel kinetics, 4,5 evidence suggests that APD and T-wave alternans are in fact associated with changes in intracellular Ca 2ϩ dynamics. 2,[5][6][7] The link between alternations in intracellular Ca 2ϩ dynamics and TWA has recently been summarized 2 as possibly arising from underlying alternans in Ca 2ϩ cycling. Intracellular Ca 2ϩ release enters into an alternating pattern based on the balance between the dynamics of Ca 2ϩ release, reuptake, and recovery rates that induce oscillations in APD as a result of Ca 2ϩ -sensitive conductances. Theoretically, a large contraction occurs as the result of a large release of Ca 2ϩ from stores in the sarcoplasmic reticulum (SR), which would in turn cause a large inward Na/Ca exchange current (I NCX ) and a long APD. Because the large SR Ca 2ϩ release would have the effect of temporary depletion of SR Ca 2ϩ content, the next beat would activ...

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