Tri-Institutional MD-PhD Program, Weill Cornell Medical College/The Rockefeller University/Sloan-Kettering Cancer Institute, New York, NY 10021, USA.
Sci Transl Med. 2011 Aug 31;3(98):98ra83. doi: 10.1126/scitranslmed.3002588.
A long-sought, and thus far elusive, goal has been to develop drugs to manage diseases of excitability. One such disease that affects millions each year is cardiac arrhythmia, which occurs when electrical impulses in the heart become disordered, sometimes causing sudden death. Pharmacological management of cardiac arrhythmia has failed because it is not possible to predict how drugs that target cardiac ion channels, and have intrinsically complex dynamic interactions with ion channels, will alter the emergent electrical behavior generated in the heart. Here, we applied a computational model, which was informed and validated by experimental data, that defined key measurable parameters necessary to simulate the interaction kinetics of the anti-arrhythmic drugs flecainide and lidocaine with cardiac sodium channels. We then used the model to predict the effects of these drugs on normal human ventricular cellular and tissue electrical activity in the setting of a common arrhythmia trigger, spontaneous ventricular ectopy. The model forecasts the clinically relevant concentrations at which flecainide and lidocaine exacerbate, rather than ameliorate, arrhythmia. Experiments in rabbit hearts and simulations in human ventricles based on magnetic resonance images validated the model predictions. This computational framework initiates the first steps toward development of a virtual drug-screening system that models drug-channel interactions and predicts the effects of drugs on emergent electrical activity in the heart.
长期以来，人们一直致力于开发能够治疗兴奋性疾病的药物，但目前仍未实现这一目标。每年都有数百万人受到心律失常的影响，这种疾病是由于心脏中的电脉冲紊乱引起的，有时会导致突然死亡。心律失常的药物治疗之所以失败，是因为无法预测靶向心脏离子通道的药物，以及与离子通道具有内在复杂动态相互作用的药物，将如何改变心脏中产生的突发电行为。在这里，我们应用了一种计算模型，该模型得到了实验数据的指导和验证，该模型定义了模拟抗心律失常药物氟卡尼和利多卡因与心脏钠离子通道相互作用动力学所需的关键可测量参数。然后，我们使用该模型预测了这些药物在常见心律失常触发因素，自发性室性早搏的情况下，对正常人心室细胞和组织电活动的影响。该模型预测了氟卡尼和利多卡因在临床上相关浓度下，会加剧而不是改善心律失常。基于磁共振图像的兔心实验和人类心室模拟验证了该模型的预测。该计算框架为开发虚拟药物筛选系统迈出了第一步，该系统可以模拟药物-通道相互作用，并预测药物对心脏突发电活动的影响。
