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

摘要 电子烟（e-cigs）已经越来越受欢迎，但其急性和慢性健康影响是 大部分是未知的。传统的吸烟会增加心律失常的风险， 心室复极化并诱导心电图（ECG）上的QT间期延长。电子烟 产生在香烟烟雾中发现的几种有害和潜在有害成分（HPHC）。 当雾化时，电子烟溶剂丙二醇（PG）和植物甘油（VG）可类似地 影响复极。我们的初步数据表明，暴露于等比例PG的电子烟溶剂气溶胶 和VG（PG：VG）延长QT并改变对复极化至关重要的离子通道的基因表达 小鼠心脏，表明吸入电子烟溶剂气溶胶可能会将心脏转化为致炎性疾病， 衬底然而，电子烟产生的HPHC水平因设备而异 特性、操作条件和使用模式。因此，其对健康的全面影响 仍不清楚该项目旨在识别特定的设备特性和电子烟成分 与心脏毒性有关。它将应用ECG和程控刺激电生理学（EP） 研究测试假设，电子烟诱导心脏的电干扰，这些影响， 取决于电子烟的特性和成分。研究将1：确定设备如何 特征影响小鼠中电子烟的急性电生理效应，以及2：评估 慢性电子烟暴露对心脏电生理和血液动力学的影响。实时 在急性暴露于PG：VG期间和之后，将通过ECG遥测监测心脏生理学 电子烟的各种特征（设备类型，用户设置，尼古丁水平）的气溶胶，以描述如何 它们影响HPHC的产生和心功能障碍的ECG测量。器件特性 然后，将选择急性心脏影响最大和最轻微的物质进行慢性接触研究， 将通过遥测技术全面评估心脏EP和血流动力学， 超声心动图，心脏的程序电刺激，分子和组织学测定， HPHC的气溶胶评估和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的研究重点，特别是毒性的兴趣领域。我们预计 我们的研究结果将阐明不同电子烟装置、成分和设置的相对毒性， 提供了新的和重要的见解如何影响电子烟的致癌潜力 气溶胶我们相信，我们的项目成果将提供全面和严格的数据，以指导 电子烟产品标准的政策，并告知监管机构与电子烟相关的心脏风险 具体的电子烟成分和特性。

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.