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：
10451184
负责人：
Alex Perrow Carll
金额：
$ 71.37万
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/10451184
关键词：
Action Potentials Acute Adult Adverse effects Aerosols Affect Aldehydes Arrhythmia Biological Biological Assay Blood Circulation Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiotoxicity Cardiovascular Physiology Cardiovascular system Cessation of life Chemicals Chronic 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 air filter base clinical predictors e-cigarette aerosols electronic cigarette use electronic cigarette user electronic liquid experimental study heart cell heart function high risk in vivo nicotine exposure nicotine inhalation respiratory response stem sudden cardiac death tobacco products tobacco regulatory science vegetable glycerin young adult

Action Potentials Acute Adult Adverse effects Aerosols Affect Aldehydes Arrhythmia Biological Biological Assay Blood Circulation Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiotoxicity Cardiovascular Physiology Cardiovascular system Cessation of life Chemicals Chronic 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 air filter base clinical predictors e-cigarette aerosols electronic cigarette use electronic cigarette user electronic liquid experimental study heart cell heart function high risk in vivo nicotine exposure nicotine inhalation respiratory response stem sudden cardiac death tobacco products tobacco regulatory science vegetable glycerin young adult

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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年首次引入电子烟（电子烟）以来，电子烟（电子烟）的使用已大大增加。设备雾化的电子液体，通常由具有变化水平的尼古丁和调味料的湿润剂组成化学物质。尽管有成千上万的市售风味混合物，但它们通常重叠单个风味化学品（味道），数量少得多。这些调味剂中有许多属于常见的化学类别，通常被认为是安全摄入的安全。但是，他们的直接和间接加热和吸入后的心脏效应，尤其是与尼古丁联合使用，仍然尚不清楚。直接暴露于尼古丁会明显影响心脏动作电位波形，并有可能导致吸烟者的心律不齐和心脏猝死的高发病率。最近的证据也表明电子烟中的尼古丁可能会类似地促进心脏不良后果。然而，调味剂对电子烟气溶胶的心脏影响未经测试。在我们正在进行的工作中，我们发现暴露于尼古丁 - 包含各种口味的E-CIG气溶胶急性和差异改变了小鼠的心电图（ECG），可变诱导QT间隔延长，心率增加并引起心律不齐。同样，两个分开具有相同特征风味剂的电子液体始终增加心室心律不齐。此外，我们在心肌细胞中观察到，用电子烟的几种调味剂直接改变收缩力，节奏性和动作潜在持续时间。尽管如此，尚不清楚e-cig中的个体味道如何气溶胶在体内发挥直接或间接心脏作用。考虑到电子烟和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味剂修改了电子烟气暴露对心脏的影响的假设电生理学，导致心律不齐和功能重塑。为了测试这一点，我们将系统地确定风味剂暴露剂对心脏电生理学的急性和长期影响在体内，体外和体内方法的结合。具体来说，我们将：1）确定调味的E-cig气溶胶吸入对体内心脏生理学的急性影响，2）检查调味剂对体外和体内心脏生理学的直接影响，3）阐明有害急性和慢性风味剂气溶胶暴露对心脏电生理学，结构和功能。这些研究对FDA/CTP的研究优先级有回应的研究将提供新数据表明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。这样的结果将有助于制定规范调味的制造，分销和营销的政策电子烟。