Systematic identification of cardiotoxic e-cigarette flavorants

摘要 自2003年首次推出以来，电子烟（e-cigs）的使用大幅增加。电子烟 这些装置使通常由具有可变水平的尼古丁和香料的湿润剂组成的电子液体雾化 化学品尽管有成千上万种市售的风味混合物，但它们通常会重叠在一起。 单独的香料化学品（香料），其数量少得多。这些调味剂中的许多属于 常见的化学类别，通常被认为是安全的摄入。直接和间接的 加热和吸入后，特别是与尼古丁联合使用后，对心脏的影响仍然是未知的。 单独直接暴露于尼古丁明显影响心脏动作电位波形， 吸烟者心律失常和心脏性猝死的高发率。最近的证据也表明 电子烟中的尼古丁可能同样会导致不良的心脏后果。然而，调味剂对 电子烟气溶胶对心脏的影响尚未得到测试。在我们正在进行的研究中，我们发现接触尼古丁- 含有各种口味的电子烟气雾剂，急性和差异性地改变了小鼠的心电图（ECG）， 引起QT间期延长、心率加快和心律失常。另外，两个独立的 具有相同特征的调味剂的电子液体一致地增加了室性心律失常。而且我们 在心肌细胞中观察到用电子烟常见的几种调味剂处理直接改变了收缩性， 节律性和动作电位持续时间。尽管如此，仍然不清楚电子烟中的个别香料 气溶胶在体内发挥直接或间接的心脏作用。考虑到电子烟的日益普及， 迫切需要研究这些产品中成分的体内毒理学特征，我们建议测试 电子烟香料改变电子烟气溶胶暴露对心脏的影响的假设 这可能会导致心脏电生理学异常，导致心律失常和心脏功能重塑。为了验证这一点，我们 系统地鉴定食用香料暴露对心脏电生理学的急性和长期影响， 最先进的体内、体外和离体方法的组合。具体而言，我们将：1）识别 调味电子烟气雾吸入对体内心脏电生理学的急性影响，2）检查 调味剂对体外和离体心脏电生理学的直接影响，以及，3）阐明有害的 急性和慢性食用香料气溶胶暴露对心脏电生理、结构和 功能这些研究响应了FDA/CTP的研究重点，将提供新的数据 显示了不同的风味化学物质如何影响心脏兴奋性并潜在地促进心脏发生。 这些结果将有助于制定政策，规范调味品的生产，分销和营销 电子烟

Abstract The use of e-cigarettes (e-cigs) has increased substantially since they were first introduced in 2003. E-cig devices aerosolize e-liquids that typically consist of humectants with variable levels of nicotine and flavoring chemicals. Although there are thousands of commercially available flavor mixtures, they routinely overlap in individual flavor chemicals (flavorants), which are far fewer in number. Many of these flavorants belong to common chemical classes and are generally recognized as safe for ingestion. However, their direct and indirect cardiac effects following heating and inhalation, particularly in combination with nicotine, remain mostly unknown. Direct exposure to nicotine alone distinctly affects the cardiac action potential waveform, potentially contributing to the high incidence of arrhythmias and sudden cardiac death among smokers. Recent evidence also suggests that nicotine in e-cigs may similarly promote adverse cardiac outcomes. Yet, the influence of flavorants on the cardiac effects of e-cig aerosols remains untested. In our ongoing work, we found that exposure to nicotine- containing e-cig aerosols of various flavors acutely and differentially altered the electrocardiogram (ECG) in mice, variably inducing QT interval prolongation, increasing heart rate, and evoking arrhythmia. As well, two separate e-liquids with the same characterizing flavorant consistently increased ventricular arrhythmias. Furthermore, we observed in cardiomyocytes that treatment with several flavorants common to e-cigs directly altered contractility, rhythmicity, and action potential duration. Nonetheless, it remains unknown how individual flavorants in e-cig aerosols exert direct or indirect cardiac effects in vivo. Considering the growing popularity of e-cigarettes and the urgent need for studying the in vivo toxicological profile of constituents in these products, we propose to test the hypothesis that e-cigarette flavorants modify the effects of e-cig aerosol exposures on cardiac electrophysiology, leading to arrhythmias and functional remodeling of the heart. To test this, we will systematically identify both acute and long-term effects of flavorant exposure on cardiac electrophysiology using a combination of state-of-the-art in vivo, in vitro, and ex vivo approaches. Specifically, we will: 1) Identify the acute effects of flavored e-cig aerosol inhalation on cardiac electrophysiology in vivo, 2) Examine the direct impact of flavorants on cardiac electrophysiology in vitro and ex vivo, and, 3) Elucidate deleterious impacts of acute and chronic flavorant aerosol exposure on cardiac electrophysiology, structure, and function. These studies, which are responsive to the research priorities of the FDA/CTP, will provide new data showing how different flavor chemicals affect cardiac excitability and potentially promote arrhythmogenesis. Such results would aid in formulating policies regulating the manufacture, distribution and marketing of flavored e-cigarettes.