title: Pacing-induced heterogeneities in intracellular Ca2+ signaling, cardiac alternans, and ventricular arrhythmias in intact rat heart.
abstract: 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.
authors.affiliation: Department of Molecular Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Ill, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Aistrup
authors.forename: James E
authors.initials: JE
authors.lastname: Kelly
authors.forename: Sunil
authors.initials: S
authors.lastname: Kapur
authors.forename: Michael
authors.initials: M
authors.lastname: Kowalczyk
authors.forename: Inbal
authors.initials: I
authors.lastname: Sysman-Wolpin
authors.forename: Alan H
authors.initials: AH
authors.lastname: Kadish
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Wasserstrom
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002304:Cardiac Pacing, Artificial; D006321:Heart / Q000503:physiopathology*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism*; D007700:Kinetics; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac; D010496:Pericardium / Q000503:physiopathology; D051381:Rats; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology*; D013696:Temperature
chemical_list: D002118:Calcium