Ultrafine Particle Exposure in Humans

描述(由申请人提供)：假设：暴露在环境空气颗粒物中会增加心血管死亡、心律失常和心肌梗死的风险，但机制尚不清楚。血管内皮功能障碍与动脉粥样硬化性血管疾病的发病密切相关，而影响心肌复极的因素影响心律失常的易感性。我们将测试假设：1)吸入超细颗粒改变非吸烟者和吸烟者的内皮功能，以及2)吸入超细颗粒改变心室复极。具体目标：1)确定非吸烟者吸入清洁空气和50pg/rn3碳UFP对内皮功能、白细胞激活和白细胞氧化剂产生的影响。2)测定当前吸烟者吸入清洁空气和50pg/rn3碳UFP对内皮功能、白细胞活化和白细胞氧化剂产生的影响。3)确定吸入清洁空气和50pg/rn3碳UFP对非吸烟者和吸烟者心脏复极的影响。方法：48名健康的非吸烟者采用双盲、随机、两期交叉研究设计，接受空气和50pg/rn3碳质UFP暴露2小时，并进行间歇运动。研究对象组将按年龄和性别进行分层。在暴露前和暴露后每隔一段时间，将进行静脉采血，并使用血流介导的前臂血管扩张(FMD)来评估内皮功能。每次接触都将获得连续的24小时12导联心电监测，并分析心室复极、心率和心率变异性的变化。主要结果将是FMD的变化和通过心电图上校正的QT间期测量的心室复极持续时间。次要结果将包括血液白细胞激活和黏附分子表达的标志物、血浆内皮素和一氧化氮、心率和心率变异性，以及心脏复极的额外测量。在非吸烟者中完成这些研究后，将在当前吸烟者中进行相同的研究方案。在这两项研究中，我们将通过相关性分析来确定全身炎症的血液标记物或基线水平的血液维生素E水平是否影响UFP对心血管的反应。这些研究将确定暴露在环境空气颗粒物中对心血管的影响的关键机制。

DESCRIPTION (provided by applicant): Hypotheses: Exposure to ambient air particles is associated with increased risk for cardiovascular mortality, cardiac arrhythmias, and myocardial infarction, but the mechanisms are unknown. Dysfunction of the vascular endothelium is critically linked to the pathogenesis of atherosclerotic vascular disease, and factors affecting myocardial repolarization influence the susceptibility to arrhythmias. We will test the hypotheses that: 1) inhalation of ultrafine particles alters endothelial function in nonsmokers and smokers, and 2) inhalation of ultrafine particles alters ventricular repolarization. Specific Aims: 1) Determine in nonsmokers the effects of inhalation of clean air and 50 pg/rn3 carbon UFP on endothelial function, leukocyte activation, and leukocyte oxidant production. 2) Determine in current smokers the effects of inhalation of clean air and 50 pg/rn3 carbon UFP on endothelial function, leukocyte activation, and leukocyte oxidant production. 3) Identify effects of inhalation of clean air and 50 pg/rn3 carbon UFP on cardiac repolarization in nonsmokers and smokers. Methods: Forty-eight healthy nonsmokers will undergo exposures to air and 50 pg/rn3 carbonaceous UFP for 2 hours with intermittent exercise, in a double-blind, randomized, two period crossover study design. Subject groups will be stratified by both age and gender. Before and at intervals after exposure, phlebotomy will be performed and endothelial function will be assessed using flow mediated vascular dilatation of the forearm (FMD). Continuous 24-hour 12-lead ECG monitoring will be obtained with each exposure, and analyzed for changes in ventricular repolarization, heart rate, and heart rate variability. Primary outcomes will be changes in FMD and the duration of ventricular repolarization as measured by the corrected QT interval on the ECG. Secondary outcomes will include markers of blood leukocyte activation and expression of adhesion molecules, plasma endothelins and nitric oxide, heart rate and heart rate variability, and additional measures of cardiac repolarization. Following completion of these studies in nonsmokers, an identical study protocol will be undertaken in current smokers. In both studies we will determine by correlation analysis whether blood markers of systemic inflammation or blood vitamin E levels at baseline influence the cardiovascular responses to UFP. These studies will identify key mechanisms for the cardiovascular effects of exposure to ambient air particles.