Pacing-induced heterogeneities in intracellular Ca2+ signaling, cardiac alternans, and ventricular arrhythmias in intact rat heart

Optical mapping studies have suggested that intracellular Ca and T-wave alternans are linked through underlying alternations in Ca cycling-inducing oscillations in action potential duration through Ca-sensitive conductances. However, these studies cannot measure single-cell behavior; therefore, the Ca 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 signaling in individual myocytes of intact rat myocardium during rapid pacing and during pacing-induced ventricular arrhythmias. At low rates, all myocytes demonstrate Ca alternans that is synchronized but whose magnitude varies depending on recovery kinetics of Ca 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 alternates out of phase with different regions within the same cell. These forms of heterogeneous Ca signaling also occurred during pacing-induced ventricular tachycardia. Our results demonstrate highly nonuniform Ca signaling among and within individual myocytes in intact heart during rapid pacing and arrhythmias. Thus, certain pathophysiological conditions that alter Ca cycling kinetics, such as heart failure, might promote ventricular arrhythmias by exaggerating these cellular heterogeneities in Ca signaling.