Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA.
Heart Rhythm. 2011 Nov;8(11):1749-55. doi: 10.1016/j.hrthm.2011.05.023. Epub 2011 Jun 7.
"Repolarization reserve" is frequently invoked to explain why potentially proarrhythmic drugs cause, across a population, a range of changes to cardiac action potentials (APs). However, the mechanisms underlying this interindividual variability are not understood quantitatively.
The purpose of this study was to perform 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 proarrhythmic drugs.
METHODS/RESULTS: In several models of human or canine ventricular myocytes, variability was simulated by randomizing model parameters and running repeated simulations. With each randomly generated set of parameters, APs before and after simulated 75% block of the rapid delayed rectifier current (I(Kr)) were calculated. Multivariable regression was performed to determine how much each model parameter attenuated or exacerbated the AP prolongation caused by the I(Kr)-blocking drug. Simulations with a human ventricular myocyte model suggest that drug response is influenced most strongly by (1) the density of I(Kr), (2) the density of slow delayed rectifier current I(Ks), (3) the voltage dependence of I(Kr) inactivation, (4) the density of L-type Ca2+ current, and (5) the kinetics of I(Ks) activation. The analysis also identified mechanisms underlying nonintuitive 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 interindividual variability in adverse drug reactions.
“复极储备”经常被用来解释为什么在人群中，潜在的致心律失常药物会引起心脏动作电位（AP）的一系列变化。然而，这种个体间变异性的机制尚未得到定量理解。
本研究的目的是对心室肌细胞的数学模型进行新的分析，以量化复极储备，并深入了解致心律失常药物反应变异性的原因。
方法/结果：在几种人类或犬类心室肌细胞模型中，通过随机化模型参数并重复模拟来模拟变异性。对于每个随机生成的参数集，计算模拟快速延迟整流电流（I（Kr））阻断 75%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 I（Kr）阻断药物引起的 AP 延长。使用人类心室肌细胞模型的模拟表明，药物反应受以下因素的强烈影响：（1）I（Kr）的密度，（2）缓慢延迟整流电流 I（Ks）的密度，（3）I（Kr）失活的电压依赖性，（4）L-型 Ca2+电流的密度，以及（5）I（Ks）激活的动力学。该分析还确定了导致非直观行为的机制，例如延长基线 AP 但降低药物引起的 AP 延长的离子电流。最后，模拟为恶化药物反应的条件提供了定量的见解，例如沉默的离子通道突变和心力衰竭。
这些建模结果首次对复极储备进行了全面的量化，并提高了我们对不良反应个体间变异性的理解。
