Azithromycin and Sudden Cardiac Death: Electrophysiologic Mechanisms
阿奇霉素与心脏性猝死:电生理机制
基本信息
- 批准号:8241465
- 负责人:
- 金额:$ 20.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-12-15 至 2013-11-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdverse effectsAdverse eventAmoxicillinAntibioticsArrhythmiaAzithromycinCalciumCardiacCardiac MyocytesCardiovascular AgentsCardiovascular DiseasesCase StudyCause of DeathCessation of lifeCiprofloxacinClarithromycinCommunitiesCongenital Heart DefectsDataDatabasesDeveloped CountriesElectrocardiogramElectrophysiology (science)ErythromycinEventFluorescenceGoalsHeartHumanInheritedKnowledgeLeadLifeLinkMacrolide AntibioticsMarketingMeasurementMediatingMedicaidMuscle CellsMyocardial IschemiaPatientsPersonsPharmaceutical PreparationsPharmacotherapyPredispositionPropertyPublic HealthRecombinantsReportingRiskRisk FactorsSarcoplasmic ReticulumScreening procedureSudden DeathSyndromeSystemTachyarrhythmiasTennesseeTestingTorsades de PointesVentricularVentricular ArrhythmiaVentricular TachycardiaWithdrawalbasedrug developmentheart rhythmimprovednovelresponsesudden cardiac death
项目摘要
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.
PUBLIC HEALTH RELEVANCE: The studies described in this proposal will improve our understanding of the basic mechanisms that cause a commonly used antibiotic, azithromycin, to increase the risk of sudden death in the general community. We anticipate that we will identify new mechanisms that increase a person's susceptibility to serious heart rhythm disturbances that can cause sudden death. This information can be used to screen and identify other drugs, either before or after they are marketed, that may cause a similar public health problem.
描述(由申请人提供):心源性猝死是工业化国家最常见的死因,占心血管疾病死亡人数的一半以上。大多数心源性猝死是由室性快速心律失常引起的,而此类心律失常的一个重要危险因素是药物治疗。许多非心血管药物已被证明可以改变心脏电生理学,并且在某些情况下,严重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对这一假设提出了挑战。我们利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,证明阿奇霉素会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,但在没有心电图异常的情况下也可能发生多形性室性心动过速,这意味着新的药理作用,我们的初步数据也支持了这一概念。这种不寻常的致心律失常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。该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,从而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 间期正常的情况下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,以检验阿奇霉素改变 hERG 以外的离子电流以延长复极时间并增加心律失常易感性的假设。将在重组人类通道以及天然心室肌细胞的异源表达后研究电流。该提案中概述的研究将增进我们对人类致心律失常机制的理解,特别是对于广泛使用的抗生素阿奇霉素。这些知识将使我们能够在药物开发中筛选和鉴定具有相似特性的其他化合物,这些化合物也可能产生严重的副作用。因此,更好地了解导致阿奇霉素引起的心源性猝死的基本机制应该会导致更安全的药物治疗。
公共卫生相关性:本提案中描述的研究将提高我们对导致常用抗生素阿奇霉素增加普通社区猝死风险的基本机制的理解。我们预计我们将发现新的机制,增加一个人对严重心律紊乱的易感性,从而导致猝死。该信息可用于在其他药物上市之前或之后筛选和识别可能导致类似公共卫生问题的药物。
项目成果
期刊论文数量(0)
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KATHERINE T MURRAY其他文献
KATHERINE T MURRAY的其他文献
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{{ truncateString('KATHERINE T MURRAY', 18)}}的其他基金
Novel Pathophysiological Targets in Atrial Fibrillation Susceptibility
心房颤动易感性的新病理生理学目标
- 批准号:
9921464 - 财政年份:2017
- 资助金额:
$ 20.6万 - 项目类别:
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 - 财政年份:2011
- 资助金额:
$ 20.6万 - 项目类别:
Preamyloid Oligomers and Susceptibility to Atrial Fibrillation
前淀粉样蛋白寡聚物和心房颤动的易感性
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8443864 - 财政年份:2010
- 资助金额:
$ 20.6万 - 项目类别:
Preamyloid Oligomers and Susceptibility to Atrial Fibrillation
前淀粉样蛋白寡聚物和心房颤动的易感性
- 批准号:
7884892 - 财政年份:2010
- 资助金额:
$ 20.6万 - 项目类别:
Preamyloid Oligomers and Susceptibility to Atrial Fibrillation
前淀粉样蛋白寡聚物和心房颤动的易感性
- 批准号:
8063989 - 财政年份:2010
- 资助金额:
$ 20.6万 - 项目类别:
Preamyloid Oligomers and Susceptibility to Atrial Fibrillation
前淀粉样蛋白寡聚物和心房颤动的易感性
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8644853 - 财政年份:2010
- 资助金额:
$ 20.6万 - 项目类别:
Preamyloid Oligomers and Susceptibility to Atrial Fibrillation
前淀粉样蛋白寡聚物和心房颤动的易感性
- 批准号:
8249863 - 财政年份:2010
- 资助金额:
$ 20.6万 - 项目类别:
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