Pacing-induced heterogeneities in intracellular Ca2+ signaling, cardiac alternans, and ventricular arrhythmias in intact rat heart.
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.
Aistrup
Gary L
GL
Department of Molecular Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Ill, USA.
Kelly
James E
JE
Kapur
Sunil
S
Kowalczyk
Michael
M
Sysman-Wolpin
Inbal
I
Kadish
Alan H
AH
Wasserstrom
J Andrew
JA
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
D002118:Calcium