AP and Ca2+ alternans: An inseparable couple.
AP and Ca2+ alternans: An inseparable couple.
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AP 和 Ca2 交替：不可分割的一对。
DOI：
10.1080/19336950.2017.1330094
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Blatter,LotharA
中科院分区：
文献类型：
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作者：
Kanaporis,Giedrius;Blatter,LotharA
心脏动作电位（AP）复极交替是危及生命的心律失常的危险因素。在细胞水平上，心脏交替被定义为在恒定刺激速率下收缩力、AP持续时间（APD）和细胞内Ca 2+释放的周期性、搏动间交替。心脏交替现象在一个多世纪前首次被描述。我们目前的理解几乎没有疑问，胞质Ca 2+浓度（[Ca 2 +] i）和膜电位（Vm）之间的双向关系在交替糖的产生中起着关键作用。Vm和[Ca2 +] i的双向耦合由以下事实定义：Vm直接决定电压依赖性Ca2+处理机制的活性，而[Ca2 +] i动力学通过Ca2+依赖性离子电流和转运蛋白影响Vm调节。然而，交替发生的确切机制，以及Vm或[Ca2 +] i调节的紊乱是否是交替发生的主要原因仍然没有解决，并被称为"鸡和蛋"的难题。1其原因是Vm和细胞内Ca 2+处理之间双向耦合的复杂性以及难以分离Ca 2+和Vm的实验效应。最初，Nolasco和Dahlen 2认为，搏动-搏动Vm交替由APD恢复决定。APD恢复是指APD依赖于前一舒张间期。在高起搏频率下，AP的恢复不完全，因此可能发生AP交替。这一假设得到了计算研究的有力支持，然而实验结果不太一致，实际上揭示了实验确定的APD恢复动力学和交替的诱导之间的相关性较差。最近，随着[Ca2 +] i成像的进展，出现了另一种假设，即细胞内Ca2+处理的干扰是交替的主要原因，并获得了越来越多的实验支持。Ca2+交替的潜在机制的一个流行的候选者是肌浆网（SR）Ca2+含量（[Ca2 +] SR）的搏动-搏动波动，3然而，其他人已经证明，在舒张[Ca2 +] SR中可以观察到Ca2+交替而没有交替。4作为SR Ca2+负荷假说的替代，提出了SR Ca2+释放的不应性的搏动-搏动差异。[5]最有力的证据表明，在电压钳位的心肌细胞中，在Vm中没有搏动间交替的情况下，可以诱发Ca2+交替。6目前，"Ca2+假说"在该领域占主导地位，Vm在心脏交替产生中的作用越来越被忽视。在最近的一项研究中，我们证明了AP形态中的逐拍交替不能被忽视，并且是交替产生的关键因素。为了克服上述的困难和限制的实验区别的影响Ca 2+和Vm，我们监测AP和Ca 2+交替动态电流钳兔心房肌细胞。我们证明了起搏诱导的Ca 2+和AP交替强烈相关，并且细胞在大和小Ca 2+瞬变（CaTs）期间表现出独特的AP波形，我们分别将其称为APCaT_Large和APCaT_Small。然后，我们使用这些特征AP形态在不同的组合作为电压钳位的电压命令
Cardiac action potential (AP) repolarization alternans is a risk factor for life threatening cardiac arrhythmias. At the cellular level cardiac alternans is defined as cyclic, beat-to-beat alternations in contraction force, AP duration (APD) and intracellular Ca2+ release at constant stimulation rate. The phenomenon of cardiac alternans was first described more than a century ago. Our current understanding leaves little doubt that the bi-directional relationship between cytosolic Ca2+ concentration ([Ca2+] i) and membrane potential (Vm) plays a key role in the generation of alternans. Bi-directional coupling of Vm and [Ca2+] i is defined by the facts that Vm directly determines the activity of Ca2+ handling mechanisms that are voltage-dependent, whereas [Ca2+] i dynamics affect Vm regulation through Ca2+-dependent ion currents and transporters. However, the precise mechanisms how alternans develops, and whether disturbances of Vm or [Ca2+] i regulation is the primary cause of alternans have still remained unresolved, and has been referred to as a “chicken and egg” conundrum. 1 A reason for this is the complexity of the bi-directional coupling between Vm and intracellular Ca2+ handling and the difficulty to separate experimentally effects of Ca2+ and Vm. Initially, Nolasco and Dahlen 2 suggested that beatto-beat Vm alternation is determined by APD restitution. APD restitution refers to the APD dependence on the preceding diastolic interval. At high pacing rates recovery of the AP is incomplete, and consequently AP alternans can occur. This hypothesis received strong support from computational studies, however experimental findings were less consistent and actually revealed poor correlation between experimentally determined APD restitution kinetics and inducibility of alternans. More recently, with the advances in [Ca2+] i imaging, the alternative hypothesis that disturbances of intracellular Ca2+ handling is the primary cause of alternans emerged and gained increasing experimental support. A popular candidate for the underlying mechanism for Ca2+ alternans were beat-to-beat fluctuations in sarcoplasmic reticulum (SR) Ca2+ content ([Ca2+] SR), 3 however others have demonstrated that Ca2+ alternans could be observed without alternans in diastolic [Ca2+] SR. 4 As an alternative to the SR Ca2+ load hypothesis, beat-to-beat differences in refractoriness of SR Ca2+ release was proposed. 5 Strongest support for disturbances in Ca2+ handling as the main cause of alternans came from studies demonstrating that Ca2+ alternans can be elicited in voltage-clamped myocytes in the absence of beat-to-beat alternations in Vm. 6 Currently, the “Ca2+ hypothesis” dominates the field and the role of Vm in the generation of cardiac alternans became increasingly overlooked. In a recent study we demonstrated 7 that beat-to-beat alternations in AP morphology cannot be ignored and is a critical element in alternans generation. To overcome the aforementioned difficulties and limitations of experimental distinction between effects of Ca2+ and Vm, we monitored AP and Ca2+ alternans dynamics in current-clamped rabbit atrial myocytes. We demonstrated that pacinginduced Ca2+ and AP alternans are strongly correlated and cells exhibit distinctive AP waveforms during large and small Ca2+ transients (CaTs), which we refer to as APCaT_Large and APCaT_Small, respectively. We then used these characteristic AP morphologies in different combinations as voltage commands for voltage clamp