Aistrup Gary L, Kelly James E, Kapur Sunil, Kowalczyk Michael, Sysman-Wolpin Inbal, Kadish Alan H, Wasserstrom J Andrew
Department of Molecular Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Ill, USA.
Circ Res. 2006 Sep 29;99(7):e65-73. doi: 10.1161/01.RES.0000244087.36230.bf. Epub 2006 Sep 7.
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.
光学映射研究表明，细胞内Ca2+与T波交替现象通过Ca2+循环的潜在交替相联系，这种交替通过Ca2+敏感电导诱导动作电位持续时间的振荡。然而，这些研究无法测量单细胞行为；因此，微观心室区域内的Ca2+循环异质性尚不清楚。本研究的目的是测量完整心肌在快速起搏和心律失常期间的细胞活性。我们使用单光子激光扫描共聚焦显微镜来测量完整大鼠心肌单个心肌细胞在快速起搏和起搏诱导的室性心律失常期间的Ca2+信号。在低频率时，所有心肌细胞都表现出同步的Ca2+交替现象，但其幅度因每个心肌细胞Ca2+循环的恢复动力学而异。随着频率增加，一些细胞会反转交替相，即使在相邻的心肌细胞中也会出现不同步的激活模式。起搏频率增加还会诱导亚细胞交替现象，即同一细胞内不同区域的Ca2+出现不同步。这些异质性Ca2+信号形式在起搏诱导的室性心动过速期间也会出现。我们的结果表明，在快速起搏和心律失常期间，完整心脏中单个心肌细胞之间以及细胞内的Ca2+信号高度不均匀。因此，某些改变Ca2+循环动力学的病理生理条件，如心力衰竭，可能通过夸大Ca2+信号中的这些细胞异质性来促进室性心律失常。
