Azithromycin and Sudden Cardiac Death: Electrophysiologic Mechanisms

描述（由申请人提供）：心源性猝死是工业化国家最常见的单一死因，占心血管疾病死亡人数的一半以上。大多数心脏性猝死是由室性快速性心律失常引起的，而这种心律失常的一个重要风险因素是药物。许多非心血管药物已被证明会改变心脏电生理学，在某些情况下，严重室性心律失常的发生导致其退出市场。大环内酯类抗生素红霉素和克拉霉素与危及生命的心律失常有关，而阿奇霉素被认为对心脏的不良影响很小。然而，最近严重室性心律失常的病例报告以及来自FDA不良事件报告系统的数据沿着，对这一假设提出了挑战。我们使用田纳西州医疗补助数据库进行了一项大型药物流行病学研究，证明阿奇霉素可使心源性猝死的风险增加数倍。此外，病例报告表明，虽然QT间期延长很少是病因，但在没有ECG异常的情况下可能发生多形性室性心动过速，这意味着新的药理学作用，这一概念也得到了我们的初步数据的支持。这种不寻常的促肾上腺皮质激素综合征的机制目前尚不清楚，阿奇霉素的电生理作用仍有待研究。本提案的目的是检验阿奇霉素在心脏中引起新的电生理效应，增加严重室性心律失常的易感性的假设。在特定目标1中，我们将获得完整心肌细胞的细胞内钙荧光测量值，以检验阿奇霉素通过促进肌浆网异常自发钙释放增加心脏性猝死风险的假设。这种机制与遗传性心律失常综合征中正常QT间期的多态性室性心动过速有关。在特定目标2中，我们将进行电生理学研究，以检验阿奇霉素改变离子电流而不是hERG以延长复极和增加心律失常易感性的假设。电流将在重组人通道的异源表达后以及在天然心室肌细胞中进行研究。本提案中概述的研究将提高我们对人类预防机制的理解，特别是广泛使用的抗生素阿奇霉素。这些知识将使药物开发中筛选和鉴定具有相似性质的其他化合物成为可能，这些化合物也可能产生严重的不良反应。因此，对阿奇霉素引起的心脏性猝死的基本机制的进一步了解应该会导致更安全的药物治疗。

DESCRIPTION (provided by applicant): Sudden cardiac death is the single most common cause of death in industrialized countries, accounting for more than half of deaths from cardiovascular diseases. Most sudden cardiac deaths are caused by ventricular tachyarrhythmias, and an important risk factor for such arrhythmias is medications. A number of non- cardiovascular drugs have been shown to alter cardiac electrophysiology, and in some cases, the occurrence of serious ventricular arrhythmias has led to their withdrawal from the market. The macrolide antibiotics erythromycin and clarithromycin have been linked to life-threatening arrhythmias, while azithromycin is considered to have minimal adverse cardiac effects. However, recent case reports of serious ventricular arrhythmias, along with data from the FDA's Adverse Events Reporting System, have challenged this assumption. We have performed a large pharmacoepidemiologic study using the Tennessee Medicaid database, demonstrating that azithromycin increases the risk of sudden cardiac death by several fold. Moreover, case reports indicate that while QT prolongation is rarely causative, polymorphic ventricular tachycardia can occur in the absence of ECG abnormalities, implying novel pharmacologic effects, a concept also supported by our preliminary data. The mechanism of this unusual proarrhythmic syndrome is currently not known, and the electrophysiologic effects of azithromycin remain understudied. The goal of this proposal is to test the hypothesis that azithromycin causes novel electrophysiologic effects in the heart that increase susceptibility to serious ventricular arrhythmias. In Specific Aim 1, we will obtain intracellular calcium fluorescence measurements in intact cardiomyocytes to test the hypothesis that azithromycin increases the risk of sudden cardiac death by promoting abnormal spontaneous calcium release from the sarcoplasmic reticulum. This mechanism has been linked to polymorphic ventricular tachycardia in the setting of a normal QT interval in inherited arrhythmia syndromes. In Specific Aim 2, we will perform electrophysiologic studies to test the hypothesis that azithromycin alters ionic currents other than hERG to prolong repolarization and increase arrhythmia susceptibility. Currents will be studied following heterologous expression of recombinant human channels, as well as in native ventricular myocytes. The studies outlined in this proposal will improve our understanding of proarrhythmic mechanisms in humans, and specifically for the widely-prescribed antibiotic azithromycin. This knowledge would enable the screening and identification of additional compounds in drug development with similar properties that could also have the potential for serious adverse effects. Thus, an improved understanding of the basic mechanisms causing azithromycin-induced sudden cardiac death should lead to safer pharmacotherapy.