Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: a computational analysis.
Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: a computational analysis.
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DOI：
10.1016/j.hrthm.2011.05.023
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发表时间：
2011-11
期刊：
影响因子：
5.5
通讯作者：
Sobie, Eric A.
中科院分区：
文献类型：
--
作者：
Sarkar, Amrita X.;Sobie, Eric A.
“复极储备”经常被用来解释为什么潜在的促心律失常药物会在人群中引起心脏动作电位（AP）的一系列变化。然而，这种个体间差异背后的机制尚不清楚。我们对心室肌细胞的数学模型进行了新颖的分析，以量化复极储备并深入了解导致心律失常药物反应变异的因素。在人类或犬类心室肌细胞的几种模型中，通过随机化模型参数并运行重复模拟来模拟变异性。使用每组随机选择的参数，计算模拟 75% 快速延迟整流器电流 (IKr) 块之前和之后的 AP。进行多变量回归以确定每个模型参数在多大程度上减弱或加剧了 IKr 阻断药物引起的 AP 延长。人类心室肌细胞模型的模拟表明，药物反应受以下因素影响最大：1）IKr 的密度； 2）慢延时整流电流IKs的密度； 3）IKr失活的电压依赖性； 4) L 型 Ca2+ 电流密度和 5) IK 激活动力学。该分析还确定了非直觉行为的潜在机制，例如延长基线 AP 但减少药物引起的 AP 延长的离子电流。最后，模拟提供了对加剧药物反应的条件的定量洞察，例如沉默离子通道突变和心力衰竭。这些建模结果首次全面量化了复极储备，并提高了我们对药物不良反应个体间差异的理解。
"Repolarization reserve" is frequently invoked to explain why potentially pro-arrhythmic drugs cause, across a population, a range of changes to cardiac action potentials (APs). The mechanisms underlying this inter-individual variability, however, are not understood quantitatively. We performed a novel analysis of mathematical models of ventricular myocytes to quantify repolarization reserve and gain insight into the factors responsible for variability in the response to pro-arrhythmic drugs. In several models of human or canine ventricular myocytes, variability was simulated by randomizing model parameters and running repeated simulations. With each randomly-selected set of parameters, APs before and after simulated 75% block of the rapid delayed rectifier current (IKr) were calculated. Multivariable regression was performed to determine how much each model parameter attenuated or exacerbated the AP prolongation caused by the IKr-blocking drug. Simulations with a human ventricular myocyte model suggest that drug response is influenced most strongly by: 1) the density of IKr; 2) the density of slow delayed rectifier current IKs; 3) the voltage-dependence of IKr inactivation; 4) the density of L-type Ca2+ current and 5) the kinetics of IKs activation. The analysis also identified mechanisms underlying non-intuitive behavior, such as ionic currents that prolong baseline APs but decrease drug-induced AP prolongation. Finally, the simulations provided quantitative insight into conditions that aggravate the drug response, such as silent ion channel mutations and heart failure. These modeling results provide the first thorough quantification of repolarization reserve and improve our understanding of inter-individual variability in adverse drug reactions.
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影响因子：
4.3
作者：
Sarkar AX;Sobie EA
通讯作者：
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影响因子：
8.4
作者：
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影响因子：
10.8
作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1152/ajpheart.00612.2001
发表时间：
2002-02-01
影响因子：
4.8
作者：
Fox, JJ;McHarg, JL;Gilmour, RF
通讯作者：
Gilmour, RF