The Role of E-cigarette Characteristics and Constituents in Cardiac Dysfunction

摘要 电子烟越来越受欢迎，但它们对健康的急性和慢性影响是 大部分都是未知的。传统的吸烟会减缓患心律失常的风险 并在心电图上引起QT间期延长。电子烟 产生香烟烟雾中发现的几种有害和潜在有害成分(HPHC)。 当雾化时，e-cig溶剂丙二醇(PG)和植物甘油(VG)可以类似地 影响复极。我们的初步数据显示，暴露在等比例PG的e-cig溶剂气雾剂中。 VG(PG：VG)延长QT，改变复极关键离子通道基因表达 小鼠心脏，提示吸入e-cig溶剂气雾剂可能会将心脏转化为致心律失常 底物。然而，电子烟产生的HPHC水平因设备而异。 特点、运行条件和使用模式。因此，它们对健康的全面影响 目前仍不清楚。该项目旨在确定特定的设备特征和e-cig组件。 与心脏毒性有关。它将同时应用于心电图和程序刺激电生理学(EP)。 对电子烟引起心脏电紊乱以及这些影响的假设进行测试的研究 取决于e-cig的特点和构成。研究将1：确定设备如何 特征影响电子烟对小鼠的急性电生理效应，以及2：评估 慢性电子烟暴露对心脏电生理和血流动力学的影响。实时 在急性接触PG：VG期间和之后，将通过心电遥测监测心脏生理 来自不同特征的电子烟的气雾剂(设备类型、用户设置、尼古丁水平)，以描绘如何 它们既影响HPHC的产生，也影响心功能不全的心电指标。设备特性 最严重和最轻微的急性心脏影响将被选为慢性暴露研究，在 哪些心脏EP和血流动力学将通过遥测进行综合评估， 超声心动图，心脏程序性电刺激，分子和组织学分析， HPHC的气溶胶评估，以及HPHC暴露的生物标志物分析。所有暴露组 将同时与香烟烟雾和过滤空气暴露组进行比较。我们的研究计划是 响应FDA/CTP的研究优先事项，特别是感兴趣的毒性领域。我们预计 我们的结果将阐明不同电子烟设备、成分和环境的相对毒性，以及 提供新的和有意义的见解，了解每种方法如何影响e-cig的致心律失常潜力。 气雾剂。我们相信，我们项目的结果将提供全面和严谨的数据来指导 关于电子烟产品标准的政策，并向监管当局通报与以下相关的心脏风险 具体的电子烟的构成和特点。

ABSTRACT E-cigarettes (e-cigs) have become increasingly popular, but their acute and chronic health effects are mostly unknown. Conventional cigarette smoking increases the risk of cardiac arrhythmia by slowing ventricular repolarization and inducing QT interval prolongation on the electrocardiogram (ECG). E-cigs produce several of the harmful and potentially harmful constituents (HPHCs) found in cigarette smoke. When aerosolized, the e-cig solvents propylene glycol (PG) and vegetable glycerin (VG), may similarly affect repolarization. Our preliminary data indicate exposure to e-cig solvent aerosols of equal-ratio PG and VG (PG:VG) prolongs QT and alters gene expression of ion channels key for repolarization in the mouse heart, suggesting inhalation of e-cig solvent aerosols may convert the heart into an arrhythmogenic substrate. However, e-cigs produce HPHCs at levels that vary markedly according to device characteristics, operating conditions, and use patterns. Thus, the full spectrum of their health impacts remains unclear. This project is designed to identify specific device characteristics and e-cig constituents associated with cardiac toxicity. It will apply both ECG and programmed stimulus electrophysiology (EP) studies to test the hypothesis that e-cigs induce electrical disturbances in the heart and that these effects depend upon e-cig characteristics and constituents. The studies will 1: Determine how device characteristics influence the acute electrophysiologic effects of e-cigs in mice, and 2: Assess the impacts of chronic e-cig exposure on cardiac electrophysiology and hemodynamics. Real-time cardiac physiology will be monitored through ECG telemetry during and after acute exposures to PG:VG aerosols from e-cigs of various characteristics (device type, user settings, nicotine levels), to delineate how they affect both HPHC production and ECG measures of cardiac dysfunction. The device characteristics with the greatest and slightest acute cardiac effects will then be selected for chronic exposure studies, in which cardiac EP and hemodynamics will be comprehensively assessed through telemetry, echocardiography, programmed electrical stimulation of the heart, molecular and histologic assays, aerosol assessments of HPHCs, and analyses of biomarkers of HPHC exposures. All exposure groups will be simultaneously compared to cigarette smoke and filtered-air exposure groups. Our research plan is responsive to the research priorities of the FDA/CTP, especially the interest area of toxicity. We expect that our results will elucidate the relative toxicity of different e-cig devices, constituents, and settings, and provide novel and significant insights into how each influences the arrhythmogenic potential of e-cig aerosols. We believe the outcome of our project would provide comprehensive and rigorous data to guide policies on e-cig product standards and to inform regulatory authorities of the cardiac risks associated with specific e-cig constituents and characteristics.