PDF(Pubmed)
Abstract：
Amiodarone (AM) is an antiarrhythmic drug whose chronic use has proved effective in preventing ventricular arrhythmias in a variety of patient populations, including those with heart failure (HF). AM has both class III [i.e., it prolongs the action potential duration (APD) via blocking potassium channels) and class I (i.e., it affects the rapid sodium channel) properties; however, the specific mechanism(s) by which it prevents reentry formation in patients with HF remains unknown. We tested the hypothesis that AM prevents reentry induction in HF during programmed electrical stimulation (PES) via its ability to induce postrepolarization refractoriness (PRR) via its class I effects on sodium channels. Here we extend our previous human action potential model to represent the effects of both HF and AM separately by calibrating to human tissue and clinical PES data, respectively. We then combine these models (HF + AM) to test our hypothesis. Results from simulations in cells and cables suggest that AM acts to increase PRR and decrease the elevation of takeoff potential. The ability of AM to prevent reentry was studied in silico in two-dimensional sheets in which a variety of APD gradients (ΔAPD) were imposed. Reentrant activity was induced in all HF simulations but was prevented in 23 of 24 HF + AM models. Eliminating the AM-induced slowing of the recovery of inactivation of the sodium channel restored the ability to induce reentry. In conclusion, in silico testing suggests that chronic AM treatment prevents reentry induction in patients with HF during PES via its class I effect to induce PRR.NEW & NOTEWORTHY This work presents a new model of the action potential of the human, which reproduces the complex dynamics during premature stimulation in heart failure patients with and without amiodarone. A specific mechanism of the ability of amiodarone to prevent reentrant arrhythmias is presented.
摘要：
背景：胺碘酮（AM）是一种抗心律失常药物，其长期使用已被证明可有效预防各种患者人群的室性心律失常，包括心力衰竭患者.AM同时具有III类(即，它延长了动作电位的持续时间，APD,通过阻断钾通道)和I类(即，它影响快速钠通道)特性；然而，它防止HF患者折返形成的具体机制尚不清楚。目的：检验以下假设：AM通过其对钠通道的I类作用诱导再极化后难治性（PRR）的能力，从而在程序电刺激（PES）期间阻止HF的再入诱导。结果：在这里，我们扩展了我们以前的人类动作电位模型，分别通过校准人体组织和临床PES数据来分别表示HF和AM的影响。然后，我们结合这些模型（HF+AM）来检验我们的假设。细胞和电缆中的模拟结果表明，AM可以增加PRR并降低起飞电位的升高。在施加了各种APD梯度（ΔAPD）的二维薄片中，在计算机中研究了AM防止折返的能力。在所有HF模拟中均诱导了折返活性，但在24个HFAM模型中的23个模型中却被阻止。消除AM诱导的钠通道失活恢复的减慢恢复了诱导折返的能力。结论：计算机测试表明，慢性AM治疗可通过其I类诱导PRR的作用防止PES期间HF患者的折返诱导。
