NS5806 partially restores action potential duration but fails to ameliorate calcium transient dysfunction in a computational model of canine heart failure.
NS5806 partially restores action potential duration but fails to ameliorate calcium transient dysfunction in a computational model of canine heart failure.
复制标题
NS5806 部分恢复了动作电位持续时间，但未能改善犬心力衰竭计算模型中的钙瞬时功能障碍。
DOI：
10.1093/europace/euu252
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
K. Calloe
中科院分区：
文献类型：
--
作者：
M. Maleckar;G. Lines;Jussi T. Koivumäki;J. Cordeiro;K. Calloe
旨在
这项研究调查了如何增加Ito，由激活剂NS 5806介导，影响慢性心力衰竭（HF）的兴奋-收缩偶联。我们假设，由于HF诱导的Ca（2+）处理重塑，将动作电位（AP）的尖峰和圆顶形态恢复到健康表型不足以恢复细胞内Ca（2）（+）瞬变（CaT）。
方法和结果
对犬心室肌细胞的现有数学模型进行了修改，以纳入健康和衰竭肌细胞的最新实验数据，从而得到健康和HF心外膜、心肌中层和内皮细胞变体的模型。NS 5806的影响也通过其与Kv4.3和Kv1.4的直接相互作用被包括在HF模型中。在所有模型（对照、HF和HF +药物）和变体（epi、mid和endo）中进行的单细胞模拟评估了AP形态和潜在的离子过程，重点关注钙瞬变（CaT），这些在HF中如何改变心室壁，以及HF中不同化合物浓度的后续影响。心力衰竭模型变体概括了疾病中AP持续时间（APD）的特征性增加。应用NS 5806的半数最大有效浓度（EC 50）对AP和CaT的定性影响是异质性和非线性的。药物加深AP切迹是Ito激活的直接效应; Ito和随后IK 1动力学的改变均导致AP平台电位降低。APD 50和APD 90的降低均是由于IK 1的改变。分析表明，药物作用取决于透壁性。Ito激活后，钙离子的瞬时形态学改变（幅度增加，达峰时间缩短）是由于伊卡，L的直接增加和间接的SR钙离子释放增加所致。
结论
仅作用于肌膜离子通道的化合物的下游效应难以预测。将APD修复至失败前状态并不能改善CaT功能障碍;然而，切迹深度的恢复似乎在调节早期复极方面具有适度的获益和治疗价值的可能性。
AIMS
The study investigates how increased Ito, as mediated by the activator NS5806, affects excitation-contraction coupling in chronic heart failure (HF). We hypothesized that restoring spike-and-dome morphology of the action potential (AP) to a healthy phenotype would be insufficient to restore the intracellular Ca(2) (+) transient (CaT), due to HF-induced remodelling of Ca(2+) handling.
METHODS AND RESULTS
An existing mathematical model of the canine ventricular myocyte was modified to incorporate recent experimental data from healthy and failing myocytes, resulting in models of both healthy and HF epicardial, midmyocardial, and endocardial cell variants. Affects of NS5806 were also included in HF models through its direct interaction with Kv4.3 and Kv1.4. Single-cell simulations performed in all models (control, HF, and HF + drug) and variants (epi, mid, and endo) assessed AP morphology and underlying ionic processes with a focus on calcium transients (CaT), how these were altered in HF across the ventricular wall, and the subsequent effects of varying compound concentration in HF. Heart failure model variants recapitulated a characteristic increase in AP duration (APD) in the disease. The qualitative effects of application of half-maximal effective concentration (EC50) of NS5806 on APs and CaT are heterogeneous and non-linear. Deepening in the AP notch with drug is a direct effect of the activation of Ito; both Ito and consequent alteration of IK1 kinetics cause decrease in AP plateau potential. Decreased APD50 and APD90 are both due to altered IK1. Analysis revealed that drug effects depend on transmurality. Ca(2+) transient morphology changes-increased amplitude and shorter time to peak-are due to direct increase in ICa,L and indirect larger SR Ca(2+) release subsequent to Ito activation.
CONCLUSIONS
Downstream effects of a compound acting exclusively on sarcolemmal ion channels are difficult to predict. Remediation of APD to pre-failing state does not ameliorate dysfunction in CaT; however, restoration of notch depth appears to impart modest benefit and a likelihood of therapeutic value in modulating early repolarization.
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影响因子：
20.1
作者：
O'Rourke, B;Kass, DA;Marbán, E
通讯作者：
Marbán, E
DOI：
10.1152/ajpheart.00748.2003
发表时间：
2004-04-01
影响因子：
4.8
作者：
Cordeiro, JM;Greene, L;Antzelevitch, C
通讯作者：
Antzelevitch, C
瞬时外向钾电流激活剂概括了布鲁格达综合征的心电图表现。
影响因子：
10.8
作者：
Calloe K;Cordeiro JM;Di Diego JM;Hansen RS;Grunnet M;Olesen SP;Antzelevitch C
通讯作者：
Antzelevitch C
影响因子：
20.1
作者：
Winslow, RL;Rice, J;O'Rourke, B
通讯作者：
O'Rourke, B
影响因子：
5
作者：
Calloe K;Soltysinska E;Jespersen T;Lundby A;Antzelevitch C;Olesen SP;Cordeiro JM
通讯作者：
Cordeiro JM