Roden Dan M
Department of Medicine, and Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, 532 Medical Research Building I, Nashville, TN 37232, United States.
Cardiovasc Res. 2005 Aug 15;67(3):419-25. doi: 10.1016/j.cardiores.2005.04.022.
Proarrhythmia represents an extreme example of the phenomenon that drug effects vary widely among individuals. Studies of mechanisms leading to proarrhythmia have had important implications for understanding arrhythmogenesis, rational use of antiarrhythmic therapies, selection of patients for specific therapies, and drug development. In addition, because proarrhythmia often seems to develop in the absence of clear risk predictors, a role for genetics in predisposing to this adverse drug reaction has been postulated. This review presents mechanisms whereby genetic factors may contribute to variable drug responses and describes our current understanding of how these mechanisms play a role in proarrhythmia. A unifying hypothesis is presented: physiologic processes (such as drug elimination or cardiac repolarization) include multiple redundancies, and congenital or acquired absence of such redundancies--due to disease, interacting drugs, or genetic makeup--may confer no baseline phenotype, but nevertheless enhance susceptibility to unusual drug responses.
致心律失常作用是个体间药物效应差异极大这一现象的极端例子。对导致致心律失常作用机制的研究，对于理解心律失常的发生机制、合理使用抗心律失常疗法、选择特定疗法的患者以及药物研发都具有重要意义。此外，由于致心律失常作用似乎常常在缺乏明确风险预测因素的情况下发生，因此推测遗传学在易患这种药物不良反应方面发挥了作用。本综述介绍了遗传因素可能导致药物反应差异的机制，并描述了我们目前对这些机制如何在致心律失常作用中发挥作用的理解。本文提出了一个统一的假说：生理过程（如药物消除或心脏复极）包含多个冗余环节，而由于疾病、相互作用的药物或基因组成导致的这些冗余环节的先天性或后天性缺失，可能不会产生基线表型，但却会增加对异常药物反应的易感性。
