Azithromycin and Sudden Cardiac Death: Electrophysiologic Mechanisms

阿奇霉素与心脏性猝死：电生理机制

• 批准号: 8399036
• 负责人: KATHERINE T MURRAY
• 金额: $ 18.56万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399036
• 关键词: Accounting; Adverse effects; Adverse event; Amoxicillin; Antibiotics; Arrhythmia; Azithromycin; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Agents; Cardiovascular Diseases; Case Study; Cause of Death; Cessation of life; Ciprofloxacin; Clarithromycin; Communities; Congenital Heart Defects; Data; Databases; Developed Countries; Electrocardiogram; Electrophysiology (science); Erythromycin; Event; Fluorescence; Goals; Heart; Human; Inherited; Knowledge; Lead; Life; Link; Macrolide Antibiotics; Marketing; Measurement; Mediating; Medicaid; Muscle Cells; Myocardial Ischemia; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Property; Public Health; Recombinants; Reporting; Risk; Risk Factors; Sarcoplasmic Reticulum; Sudden Death; Syndrome; System; Tachyarrhythmias; Tennessee; Testing; Torsades de Pointes; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; Withdrawal; base; drug development; heart rhythm; improved; novel; response; screening; sudden cardiac death

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.

描述(申请人提供)：心源性猝死是工业化国家最常见的单一死亡原因，占心血管疾病死亡的一半以上。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危险因素是药物。一些非心血管药物已被证明可以改变心脏电生理，在某些情况下，严重的室性心律失常的发生导致它们退出市场。大环内酯类抗生素红霉素和克拉霉素被认为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最小。然而，最近关于严重室性心律失常的病例报告，以及FDA不良事件报告系统的数据，挑战了这一假设。我们使用田纳西州医疗补助数据库进行了一项大规模的药物流行病学研究，表明阿奇霉素使心脏性猝死的风险增加数倍。此外，病例报告表明，虽然QT延长很少引起，但在没有心电图异常的情况下，多形性室性心动过速可能会发生，这意味着新的药理效应，这一概念也得到了我们初步数据的支持。这种不寻常的前心律失常综合征的机制目前尚不清楚，阿奇霉素的电生理效应仍未得到充分研究。这项建议的目的是验证阿奇霉素在心脏引起新的电生理效应，增加对严重室性心律失常的易感性的假设。在具体目标1中，我们将获得完整心肌细胞内钙荧光的测量，以验证阿奇霉素通过促进肌浆网异常自发钙释放而增加心源性猝死风险的假设。这种机制与遗传性心律失常综合征中QT间期正常的多形性室性心动过速有关。在具体目标2中，我们将进行电生理学研究，以验证阿奇霉素改变HERG以外的离子电流以延长复极和增加心律失常易感性的假说。将研究重组人通道异源表达后的电流，以及在天然心室肌细胞中的电流。这项提案中概述的研究将提高我们对人类心律失常诱发机制的理解，特别是对广泛使用的抗生素阿奇霉素的理解。这一知识将使人们能够在药物开发中筛选和识别具有类似性质的其他化合物，这些化合物也可能具有严重的不良影响。因此，对阿奇霉素所致心源性猝死的基本机制有了更深入的了解，应该会带来更安全的药物治疗。