Systematic identification of cardiotoxic e-cigarette flavorants

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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.