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(Circulation Research. 2006;99:E65.)
© 2006 American Heart Association, Inc.

UltraRapid Communications

Pacing-induced Heterogeneities in Intracellular Ca²⁺ Signaling, Cardiac Alternans, and Ventricular Arrhythmias in Intact Rat Heart

Gary L. Aistrup, James E. Kelly, Sunil Kapur, Michael Kowalczyk, Inbal Sysman-Wolpin, Alan H. Kadish, J. Andrew Wasserstrom

From the Departments of Molecular Pharmacology (G.L.A., J.A.W.), Biological Chemistry (G.L.A., J.A.W.), and Medicine (Division of Cardiology) (J.E.K., S.K., M.K., I.S.-W., A.H.K., J.A.W.) and The Feinberg Cardiovascular Research Institute (A.H.K., J.A.W.), Northwestern University Feinberg School of Medicine, Chicago, Ill.

Correspondence to J. Andrew Wasserstrom, Division of Cardiology (S203) Ward 3-105, 303 E Chicago Ave, Chicago, IL 60611. E-mail ja-wasserstrom{at}northwestern.edu

Optical mapping studies have suggested that intracellular Ca²⁺ and T-wave alternans are linked through underlying alternations in Ca²⁺ cycling-inducing oscillations in action potential duration through Ca²⁺-sensitive conductances. However, these studies cannot measure single-cell behavior; therefore, the Ca²⁺ 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 Ca²⁺ signaling in individual myocytes of intact rat myocardium during rapid pacing and during pacing-induced ventricular arrhythmias. At low rates, all myocytes demonstrate Ca²⁺ alternans that is synchronized but whose magnitude varies depending on recovery kinetics of Ca²⁺ 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 Ca²⁺ alternates out of phase with different regions within the same cell. These forms of heterogeneous Ca²⁺ signaling also occurred during pacing-induced ventricular tachycardia. Our results demonstrate highly nonuniform Ca²⁺ signaling among and within individual myocytes in intact heart during rapid pacing and arrhythmias. Thus, certain pathophysiological conditions that alter Ca²⁺ cycling kinetics, such as heart failure, might promote ventricular arrhythmias by exaggerating these cellular heterogeneities in Ca²⁺ signaling.

Key Words: calcium transients • calcium alternans • subcellular alternans • arrhythmias