在犬心力衰竭的计算模型中，NS5806 部分恢复了动作电位持续时间，但未能改善钙瞬变功能障碍。
NS5806 partially restores action potential duration but fails to ameliorate calcium transient dysfunction in a computational model of canine heart failure.
机构信息
Simula Research Laboratory, Center for Cardiological Innovation and Center for Biomedical Computing, PO Box 134, Lysaker 1325, Norway
Simula Research Laboratory, Center for Cardiological Innovation and Center for Biomedical Computing, PO Box 134, Lysaker 1325, Norway Department of Informatics, University of Oslo, PO Box 1072, Oslo 0316, Norway.
出版信息
Europace. 2014 Nov;16 Suppl 4:iv46-iv55. doi: 10.1093/europace/euu252.
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.
目的
本研究旨在探讨 Ito 的增加（由激活剂 NS5806 介导）如何影响慢性心力衰竭（HF）中的兴奋-收缩偶联。我们假设，由于 HF 引起的 Ca（2+）处理重构，恢复动作电位（AP）的尖峰和穹顶形态到健康表型将不足以恢复细胞内 Ca（2+）（CaT），因为 HF 引起的 Ca（2+）处理重构。
方法和结果
对犬心室肌细胞的现有数学模型进行了修改，纳入了来自健康和衰竭心肌细胞的最新实验数据，从而产生了健康和 HF 心外膜、中层和心内膜细胞变体的模型。HF 模型还通过其与 Kv4.3 和 Kv1.4 的直接相互作用纳入了 NS5806 的影响。在所有模型（对照、HF 和 HF+药物）和变体（心外膜、中层和心内膜）中进行的单细胞模拟评估了 AP 形态和潜在的离子过程，重点是 CaT，HF 如何在心室壁中改变 CaT，以及随后在 HF 中改变化合物浓度的影响。HF 模型变体再现了疾病中 AP 持续时间（APD）的特征性增加。应用 NS5806 的半最大有效浓度（EC50）对 AP 和 CaT 的定性影响是异质和非线性的。随着药物的应用，AP 切迹的加深是 Ito 激活的直接作用； Ito 的激活和随之而来的 IK1 动力学改变都会导致 AP 平台电位降低。APD50 和 APD90 的降低均归因于 IK1 的改变。分析表明，药物的作用取决于跨壁性。Ca（2+）瞬变形态的变化-增加的幅度和达到峰值的时间缩短-是由于 ICa，L 的直接增加和随后 Ito 激活导致的 SR Ca（2+）释放增加所致。
结论
专门作用于肌膜离子通道的化合物的下游效应难以预测。将 APD 恢复到衰竭前状态并不能改善 CaT 的功能障碍；然而，恢复切迹深度似乎会适度获益，并有可能在调节早期复极方面具有治疗价值。
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