Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes
Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes
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DOI：
10.1113/jphysiol.2002.025502
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发表时间：
2002-11-15
影响因子：
5.5
通讯作者：
Blatter, LA
中科院分区：
文献类型：
--
作者：
Kockskämper, J;Blatter, LA
Ca 2+交替是心肌细胞中动作电位诱导的[Ca 2 +]（i）瞬变幅度的潜在致心律失常性搏动-搏动交替。尽管其病理生理意义的细胞机制的Ca 2+交替知之甚少。然而，最近的证据表明，从肌浆网的钙离子诱导的钙释放（CICR）的调制。(SR)能量代谢的局部改变是Ca 2+交替的重要决定因素。因此，我们研究了场刺激猫心房肌细胞采用快速二维荧光共聚焦显微镜的亚细胞特性的钙交替。Ca 2+交替引起的刺激频率的增加或代谢干预靶向糖酵解。观察到交替发生的时间、幅度和阶段存在显着的亚细胞变化。纵向和横向梯度的Ca 2+交替被发现，以及相邻的亚细胞区域交替异相。此外，局灶性抑制糖酵解导致空间限制的Ca 2+交替。当肌细胞内两个相邻区域交替异相时，在它们的边界处形成陡峭的[Ca 2 +]（i）梯度，引起延迟传播的Ca 2+波。结果表明，Ca 2+交替是一种亚细胞现象引起的调制SR Ca 2+释放，这是介导的，至少部分，通过局部抑制能量代谢。由Ca 2+交替时相的亚细胞变化产生的致心律失常性Ca 2+波代表了房性心律失常发展的一种新机制。
Ca2+ alternans is a potentially arrhythmogenic beat-to-beat alternation of the amplitude of the action potential-induced [Ca2+](i) transient in cardiac myocytes. Despite its pathophysiological significance the cellular mechanisms underlying Ca2+ alternans are poorly understood. Recent evidence, however, points to the modulation of Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum. (SR) by localized alterations in energy metabolism as an important determinant of Ca2+ alternans. We therefore studied the subcellular properties of Ca2+ alternans in field-stimulated cat atrial myocytes employing fast two-dimensional fluorescence confocal microscopy. Ca2+ alternans was elicited by an increase in stimulation frequency or by metabolic interventions targeting glycolysis. Marked subcellular variations in the time of onset, the magnitude, and the phase of alternans were observed. Longitudinal and transverse gradients of Ca2+ alternans were found as well as neighbouring subcellular regions alternating out-of-phase. Moreover, focal inhibition of glycolysis resulted in spatially restricted Ca2+ alternans. When two adjacent regions within a myocyte alternated out-of-phase, steep [Ca2+](i) gradients developed at their border giving rise to delayed propagating Ca2+ waves. The results demonstrate that Ca2+ alternans is a subcellular phenomenon caused by modulation of SR Ca2+ release, which is mediated, at least in part, by local inhibition of energy metabolism. The generation of arrhythmogenic Ca2+ waves by subcellular variations in the phase of Ca2+ alternans represents a novel mechanism for the development of atrial disrhythmias.