Systematic identification of cardiotoxic e-cigarette flavorants

系统鉴定心脏毒性电子烟香料

基本信息

批准号：
10610732
负责人：
Alex Perrow Carll
金额：
$ 71.43万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-22 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610732
关键词：
Action Potentials Acute Adult Adverse effects Aerosols Affect Aldehydes Arrhythmia Biological Biological Assay Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiotoxicity Cardiovascular Physiology Cardiovascular system Cessation of life Chemicals Chronic Circulation Conscious Consumption Data Dependence Devices Dose Electrocardiogram Electronic cigarette Electrophysiology (science)Emerging Tobacco Products Equilibrium Evaluation Exposure to Flavoring Food Additives Functional disorder Future Heart Heart Rate Heating Human In Vitro Incidence Individual Ingestion Inhalation Knowledge Link Long-Term Effects Lung Malignant Neoplasms Marketing Modeling Monitor Mus Negative Finding Nicotine Oral Ingestion Outcome Pathologic Pathway interactions Performance Periodicity Policies Prevalence Propylene Glycols Regulation Research Priority Risk Safety Serum Smoker Smoking Solvents Structure Sum Testing Tissues Toxic effect Toxicology Toxin Ventricular Ventricular Arrhythmia Work Youth aerosolized air filter clinical predictors e-cigarette aerosols electronic cigarette use electronic cigarette user electronic liquid experimental study heart cell heart function high risk in vivo manufacture nicotine exposure respiratory response stem sudden cardiac death tobacco products tobacco regulatory science vegetable glycerin

项目摘要

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.

抽象的自 2003 年首次推出以来，电子烟 (e-cigs) 的使用量大幅增加。设备雾化电子液体，通常由尼古丁和调味剂含量不同的保湿剂组成化学品。尽管市售风味混合物有数千种，但它们在功能上通常是重叠的单独的风味化学品（香料），其数量要少得多。许多这些调味剂属于常见的化学类别，通常被认为可以安全摄入。然而，他们的直接和间接加热和吸入后对心脏的影响，特别是与尼古丁联合使用时，仍然大多未知。单独直接接触尼古丁会明显影响心脏动作电位波形，可能有助于吸烟者心律失常和心源性猝死的高发生率。最近的证据还表明电子烟中的尼古丁同样可能会导致不良的心脏后果。然而，调味剂对电子烟气雾剂对心脏的影响尚未经过测试。在我们正在进行的工作中，我们发现接触尼古丁- 含有各种口味的电子烟气溶胶会急剧且差异性地改变小鼠的心电图（ECG），不同程度地诱发 QT 间期延长、心率加快并诱发心律失常。同样，两个独立的具有相同特征香料的电子液体持续增加室性心律失常。此外，我们在心肌细胞中观察到，用电子烟常见的几种香料进行处理会直接改变收缩性，节律性和动作电位持续时间。尽管如此，目前尚不清楚电子烟中的个别香料如何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和由于迫切需要研究这些产品中成分的体内毒理学特征，我们建议进行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电生理学，导致心律失常和心脏功能重塑。为了测试这一点，我们将使用以下方法系统地确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、体外和离体方法的结合。具体来说，我们将： 1) 确定调味电子烟气雾吸入对体内心脏电生理学的急性影响，2) 检查食用香料对体外和离体心脏电生理学的直接影响，以及，3) 阐明有害物质急性和慢性食用香料气溶胶暴露对心脏电生理学、结构和功能的影响功能。这些研究响应 FDA/CTP 的研究重点，将提供新数据显示不同风味化学物质如何影响心脏兴奋性并可能促进心律失常发生。这些结果将有助于制定监管调味品生产、分销和营销的政策。电子烟。