Comprehensive analyses of ventricular myocyte models identify targets exhibiting favorable rate dependence.
Comprehensive analyses of ventricular myocyte models identify targets exhibiting favorable rate dependence.
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DOI：
10.1371/journal.pcbi.1003543
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发表时间：
2014-03
影响因子：
4.3
通讯作者：
Sobie EA
中科院分区：
文献类型：
--
作者：
Cummins MA;Dalal PJ;Bugana M;Severi S;Sobie EA
反向速率依赖性是抗心律失常药物延长心脏动作电位（AP）的一个有问题的性质。反向速率依赖性药物引起的延长在慢心率时更大，导致快心率时心律失常抑制降低，慢心率时心律失常风险增加。相反的性质，前向速率依赖，理论上可以克服这些平行问题，但前向速率依赖（FRD）抗心律失常药物仍然难以捉摸。此外，有证据表明反向速率依赖是AP扰动的内在特性。我们通过对13个心室肌细胞模型进行全面分析，解决了正向速率依赖的可能性。通过模拟具有不同性质的肌细胞群体并统计分析群体结果，我们同时预测了多个模型参数变化的速率依赖效应。在每个模型中平均测试40个参数，并以慢（0.2 Hz）和快（2 Hz）速率评估对AP持续时间的影响。该分析确定了各种FRD离子电流扰动，并对其机制产生了具体的预测。例如，当l型钙电流的增加伴随着缓慢延迟整流钾电流的间接、速率相关的变化时，则为FRD。跨模型预测的比较确定了内向整流钾电流和钠钾泵是最有可能产生FRD AP延长的两个目标。最后，对13个模型结果的统计分析表明，AP形状具有最小速率依赖变化的模型对FRD扰动的能力很小，而形状变化较大的模型具有相当大的FRD潜力。这可以解释物种之间和心室细胞类型之间的差异。总的来说，这项研究为AP持续时间依赖性的决定因素提供了新的见解，无论是具体的还是一般的，并阐明了设计潜在有益的抗心律失常药物的策略。一些治疗心律失常的药物由于其不利的速率依赖特性而失败。也就是说，药物不能改变心率快时的电活动，这是有益的，但它们会影响心率慢时的电活动，这是不需要的。在有针对性的研究中，一些药物显示出这些不利的特性，表明这些速率依赖性反应可能是心室肌固有的。为了确定是否可以合理设计具有理想速率依赖特性的药物，我们对几种心脏细胞模型进行了全面和系统的分析。这些分析计算了任何模型参数变化的速率依赖特性，从而同时产生大量的模型预测。分析表明，具有有利速率依赖特性的靶标确实可以被识别，进一步的模拟揭示了这些行为背后的机制。此外，在不同模型中获得的定量比较结果提供了新的见解，为什么给定的药物应用于不同的物种，或不同的组织类型，可能产生不同的速率依赖行为。总的来说，这项研究表明，对心脏细胞模型的全面和系统的方法如何既能识别新的靶点，又能对心脏电活动的速率依赖性改变产生更全面的了解。
Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP). The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD) antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz) and fast (2 Hz) rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, rate-dependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal rate-dependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of AP duration rate dependence, and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs. Several drugs intended to treat cardiac arrhythmias have failed because of unfavorable rate-dependent properties. That is, the drugs fail to alter electrical activity at fast heart rates, where this would be beneficial, but they do affect electrical activity at slow rates, where this is unwanted. In targeted studies, several agents have been shown to exhibit these unfavorable properties, suggesting that these rate-dependent responses may be intrinsic to ventricular muscle. To determine whether drugs with desirable rate-dependent properties could be rationally designed, we performed comprehensive and systematic analyses of several heart cell models. These analyses calculated the rate-dependent properties of changes in any model parameter, thereby generating simultaneously a large number of model predictions. The analyses showed that targets with favorable rate-dependent properties could indeed be identified, and further simulations uncovered the mechanisms underlying these behaviors. Moreover, a quantitative comparison of results obtained in different models provided new insight in why a given drug applied to different species, or to different tissue types, might produce different rate-dependent behaviors. Overall this study shows how a comprehensive and systematic approach to heart cell models can both identify novel targets and produce more general insight into rate-dependent alterations to cardiac electrical activity.