抽象
空气污染颗粒被认为每年导致全世界50万人死亡。风险最大的人群似乎是患有呼吸和心血管疾病的老年人。到目前为止,还没有提出一个普遍接受的机制来解释这些死亡的原因。
Heart rate variability (HRV) was assessed in healthy elderly adults between the ages of 60 and 80 who were exposed twice for 2 h: once to clean air and once to concentrated ambient air pollution particles (CAPS). Changes in HRV were measured immediately before, immediately following, and 24 h after exposure.
老年受试者在暴露后立即在时间域和频率域内经历了HRV的显著降低。其中一些变化至少持续了24小时。这些数据与之前一项研究中从接触cap的年轻健康志愿者中收集的HRV数据进行了比较,在这项研究中没有发现cap导致的HRV变化。
这些集中的环境空气污染颗粒引起的心率变异性的变化,在人类暴露控制研究扩展了类似的发现,在最近的小组研究报告,并提出了颗粒物可能导致不利的心血管事件的潜在机制。
许多流行病学研究已经报道,在过去十年中显著正相关性之间的每日空气污染粒子的浓度以50%的切断空气动力学直径10µm (PM10),以及由呼吸系统和心血管疾病引起的死亡率和发病率上升1-3。A recent analysis of >90 USA cities reported that a 10 µg·m−3增加PM10导致约0.5%的死亡率平均增加4。这些结果的相似性是显着的,因为研究发生在地理气候变化显著许多不同的地点,PM10成分,一年的时间,和气体污染物的数量,如臭氧。观察到的死亡率和发病率的增加虽然具有统计意义,但与职业或其他危险因素的流行病学研究发现的风险相比仍然很小。然而,由于大部分人口可能暴露于空气中的细颗粒物,据估计,全世界每年有50万例额外死亡可能是由PM造成的10五。
总的来说,这些研究报告死亡率较高的归属于呼吸道和心血管疾病比总非偶然死亡率。老年人有心脏或肺部疾病的潜在似乎是风险最大6。这些研究借给可信性的想法,精细的空气污染颗粒造成心肺事件可迅速触发人口的一小部分增加的死亡率或发病率吸入。最近的两项研究支持升高颗粒物(PM)的水平和严重室arrhythymias之间的这种想法报告协会7以及心肌梗塞8。然而,链接PM和心肺死亡病理生理学机制仍然知之甚少。有人认为,PM可能诱发肺部炎症和缺氧,这可能导致心血管窘迫。尽管一些研究在人类已经观察到炎症的低水平暴露在环境空气中的颗粒9目前,在人类中还没有观察到由pm引起的缺氧10。
人们越来越认识到自主神经系统在心血管死亡中的重要性11-14和老年人总死亡率15在那些心肌梗塞的幸存者中16。最近三个小组的研究报告环境PM水平和自主神经系统控制的变化之间的关联在老年志愿者心脏心率变异性(HRV)的评估。HRV反映节奏心脏速率的自主神经调制和改变在时域和频域都通过许多不同的分析技术测定的。An association was reported between particles with a 50% cut-off aerodynamic diameter of 2.5 µm (PM2.5) levels and decreased HRV in the high frequency (HF) range (0.15–0.40 Hz) in a group of 26 elderly residents of a retirement centre in Baltimore who were examined during a 3 week period in the winter of 1997. This association was limited to those participants who had some evidence of pre-existing cardiovascular disease17。通过对鼻腔灌洗获得的细胞和液体进行分析,未发现颗粒与肺功能、心率、收缩压或舒张压、氧饱和度或炎症标志物的变化之间存在关联18。POPEet al。19对7名患有不同程度呼吸和心血管疾病的受试者,在空气污染加重发作之前、期间和之后进行了共计29人日的重复动态心电图监测。提升点10水平与平均增加心脏率相关,降低所有拍心跳的间隔(SDNN),自主神经张力的广泛采用的标准偏差。第三项研究在此期间,研究PM和心血管功能之间的关联在21个高龄活跃波士顿居民中观察到每个人的12倍1997年夏天,据报道PM之间的负相关2.5和SDNN20。由于HRV的下降与不利的心血管事件相关,在这些研究中,与PM增加相关的低变异性可能表明心血管健康状况不佳的老年人发生急性心血管事件的风险增加,通过改变心血管系统的自主调节。
本研究旨在通过以受控的方式人类志愿者暴露于任一清洁的空气或环境空气污染颗粒的相关程度的面板的研究延伸。最近周围粒子集中的发展,使人们有可能通过“真实世界”颗粒吸入进行动物和人类的控制风险。在此研究中使用的设备集中0.1-2.5微米之间的颗粒,而气体和较小的颗粒不会集中21,22。此外,还没有出现是单个颗粒组分,例如金属,硫酸盐,硝酸盐,酸,元素和有机碳的明显损失,和有机物的一般类23。在北卡罗莱纳州的教堂山地区,环境颗粒物质量主要是通过移动源,如汽车驱动,是粒径分布和化学成分,在许多美国东海岸城市发现,尽管在较低浓度相似。颗粒浓度在教堂山空气中发现的6-7倍,让人类控制曝光颗粒相似浓度出现在许多大城市。
In this study healthy elderly volunteers were exposed for 2 h to filtered air or PM2.5从教堂山空气浓缩。Changes in HRV were assessed immediately before, immediately following, and 24 h after exposure. These changes were compared with HRV changes in young healthy volunteers exposed to concentrated ambient air pollution particles (CAPS) in a previous study.
材料和方法
研究人群
对报纸广告作出反应的年轻和年老的志愿者都在电话中预先进行了筛选。老年人口的选择标准如下:年龄在60-80岁之间;身体健康;没有心血管或慢性肺部疾病的诊断。具体的排除标准:表明糖尿病、哮喘、慢性阻塞性肺疾病(COPD),使用β肾上腺素能阻止应承担的药物,失代偿性心力衰竭或左心室射血分数< 40%,心绞痛、心房纤颤、历史nonsustained或持续室性心动过速,起搏器,内部心脏除颤器,肥厚性心肌病,渗透心肌病(例如sarcoidosis, amyloidosis), long QT interval, second or higher degree heart block, ventricular or atrial bigeminy or left ventricular hypertrophy, uncontrolled hypertension (blood pressure >160/90 mmHg), myocardial infarction or coronary bypass surgery in the past 12 months, episodes of syncope within the past 12 months, dementia, dialysis treatment, need for supplemental oxygen, use of digoxin. The elderly subjects were also required to have visited their personal physician within the past 2 yrs and be willing to have their records reviewed to confirm self-reported diagnoses and use of medications.
The young healthy population was selected using the following criteria: between the ages of 18–40 yrs; nonsmokers for at least 5 yrs prior to study; no history of allergies or respiratory diseases (food allergy, hay fever, dust allergies, rhinitis, asthma, chronic bronchitis, COPD, tuberculosis, haemoptysis or recurrent pneumonia); and not presently on any medication prescribed by a physician (except birth control pills). A urine pregnancy test was performed on all female subjects and a positive result excluded the subject from further participation in this study.
此前参与这项研究中,受试者被告知的程序和潜在的风险和各签署知情同意书的声明。该协议和知情同意书是关于保护人类受试者的权利批准的医学专业委员会的北卡罗来纳州大学医学院。每个主题的筛选程序包括了明尼苏达多项人格问卷,病史,体格检查,胸部X线片,和常规血液学和生化检查。
暴露于浓环境微粒
Particles between the sizes of 0.1–2.5 µm present in the Chapel Hill air were concentrated 6–10 fold using a Harvard/Environmental Protection Agency Ambient Fine Particle Concentrator. The principles by which this device works have been previously described21,22及其在人类PM暴露研究使用进行了详细的描述9。在腔室内部的PM的浓度改变取决于PM的浓度2.5in the Chapel Hill air (which usually ranges from 5–30 µg·m−3)。通过将受试者暴露在没有颗粒物的清洁空气中进行虚假暴露。每位老年志愿者都接触了两次:一次接触过滤过的空气,另一次接触帽子。曝光时间为2小时,受试者安静地坐着。在暴露2小时期间,使用锥形元件振动微天平(TEOM,系列1400a;Rupprecht & Patashnick, Inc.,纽约州奥尔巴尼)。在早期的一项研究中,年轻的志愿者只接触一次过滤过的空气或帽子。采用遥测法和氧饱和度法对受试者进行连续监测。总暴露时间为2小时。受试者在暴露期间交替进行15分钟的休息和15分钟的适度锻炼。 Workload was adjusted so that these subjects breathed at a ventilatory rate, normalised for body surface area, of 25 L·m−2每分钟。
颗粒表征
对于CAPS的物理和化学特性的方法已如前所述9。
心脏心率变异性分析
所有的潜在受试者都用24‐h动态心电图(ECG)进行筛选,以评估其对HRV分析的适用性。如果动态心电图显示有房颤或频繁心律失常的证据,则排除受试者。排除标准还包括同时使用已知对自主神经系统和HRV有影响的药物,如肾上腺素能受体激动剂或拮抗剂、钙通道拮抗剂和中枢作用的降压药。分别于暴露前、暴露后即刻和暴露后24小时测定HRV。受试者躺在黑暗安静的房间里。在每一种情况下,这25分钟的最后10分钟可用于HRV分析。这些录音在Zymed holter系统上进行分析,该系统使用标准Zymed软件算法进行初始QRS标记和编辑。一名心电研究技术人员对随机治疗方法不知情,然后编辑心电复合物的序列,以确保每个QRS复合物的正确标记。选择7‐min的时间进行进一步分析,以最小化噪声并插入节拍。确定并标记异常的室性早搏和房性早搏,排除含有干扰噪声的节段。 The remaining normal-to-normal (N‐N) QRS intervals were then transferred to a second software program that downloaded the N‐N files for HRV analysis. Excluded intervals were replaced using an interpolation method. Because of the stringent exclusion criteria related to arrhythmia and low noise levels, arrhythmias were rare in this population and few interpolated beats are included in the study. Nevertheless, the results of one subject were excluded because of numerous premature atrial beats.
计算并报告为自主神经张力的措施标准时域和频域措施。Time-domain parameters included the SDNN and the percentage of N‐N intervals >50 ms (PNN50). Frequency domain analysis was limited to 7‐min intervals as noted. The frequency spectrum is divided into low frequency (LF) power (0.03–0.15 Hz) and HF power (0.15–0.40 Hz). The HF component and PNN50 are believed to respond to changes in vagal input to the heart, while LF represents a mixture of both sympathetic and parasympathic input.
统计分析
数据表示为平均值±SE。在HRV差异空气和CAPS-曝光之间的老人受试者使用配对t检验。显着性假定为p <0.05。使用的独立装置中的配对t检验,而那些多个组之间使用单因子变异数分析比较了年轻受试者空气和CAPS之间的HRV的变化进行了测试。采用的事后检验为薛费的测试。意义的双尾测试使用。
结果
研究人口和曝光
老年人10名,男7名,女3名,平均年龄66.9±1.0岁。帽有相当大范围曝光反映外面的变化,个人风险敞口从21.2 - -80.3µg·m−3。The average for all CAPS exposures was 40.5±8.6 µg·m−3和平均浓度因子为6.5。The average for air exposures was 1.1±0.4 µg·m−3。曝光气溶胶的粒度分布没有改变下列浓度,并大约数正态与质量中值空气动力学直径和几何标准偏差的类似于之前报道的值9。
在心脏心率变异的变化
图1a⇓显示老年受试者在接触清洁空气或CAPS 2小时后HRV的变化。条形图表示接触后的值除以接触前立即记录的基线值。与暴露于洁净空气相比,暴露于CAPS后时间域和频率域均显著降低。在CAPS暴露后,HF区域的HRV下降了35.7%,PNN50下降了59.6%。cap暴露后SDNN也下降了16.5%,接近但未达到统计学显著性。其他测量值的变化没有变化。在暴露24小时后,cap导致的PNN50下降仍然明显,高频模式下HRV也有下降趋势(图1b)⇓)。Abnormal beats recorded during the 24 h period the subjects wore the Holter monitor were also assessed. Although there were no statistically significant changes induced by CAPS for the group as a whole, several subjects experienced significant increases in abnormal beats following CAPS exposure. For example, two subjects experienced a >3‐fold increase in premature atrial contractions following CAPS exposure, and three subjects experienced a >5‐fold increase in bradycardia. It is not clear if these individuals represent a population that may be especially susceptible to PM or a statistical anomaly.
在心脏心率变异的变化(HRV) in elderly volunteers a) immediately following and b) 24 h after exposure to concentrated ambient air pollution particles (CAPS) and clean air. Subjects were exposed to air or CAPS on two separate occasions. HRV was assessed immediately before and then a) immediately after, and b) 24 h after exposure. Bars labelled standard deviation of all beat-to-beat intervals (SDNN) and the percentage of N‐N intervals >50 ms (PNN50) refer to changes in time domain variables and bars labelled low frequency (LF), high frequency (HF), total, and ratio refer to changes in frequency domain variables. □: clean air; └: CAPS. *: p<0.05;+:P <0.08。
在早先的研究中,年轻健康的成年人暴露于CAPS或清洁的空气,其次是支气管肺泡灌洗9以评估因接触CAPS炎症的程度。HRV也在这些受试者的一个子集进行测量。Twenty-two subjects (17 male, five female, average age 28.8±0.9) were exposed to varying concentrations of CAPS (range 24.8–216.6 µg·m−3and average 105.8±12.6 µg·m−3)。11名受试者(只雄性,4只雌性,平均年龄29.6±1.1)暴露于清洁空气。要么立即有任何HRV参数没有显著CAPS引起的变化在这一人群中(图2a⇓) or 24 h (fig. 2b⇓)暴露。
在心脏心率变异的变化(HRV) in young volunteers a) immediately following and b) 24 h after exposure to concentrated ambient air pollution particles (CAPS) and clean air. One group of subjects was exposed to air and one to CAPS. HRV was assessed immediately before and then a) immediately after, and b) 24 h after exposure. Bars labelled standard deviation of all beat-to-beat intervals (SDNN) and the percentage of N‐N intervals >50 ms (PNN50) refer to changes in time domain variables and bars labelled low frequency (LF), high frequency (HF), total, and ratio refer to changes in frequency domain variables. □: clean air; └: CAPS.
讨论
本次调查的结果表明,健康老年人的2小时暴露至中度的HRV改变的颗粒物污染的结果水平。对这些个体暴露污染物的水平可媲美世界各地的许多大城市看到的。Furthermore, the elderly subjects were only exposed for 2 h while quietly sitting, in contrast to most people who would be exposed to particles for a longer period of time while ambulatory (and thus with higher respiratory rates). The physiological importance of the observed changes in HRV is not fully known. Lower HRV has been associated with increased risk for developing coronary heart disease and to sudden cardiac death. Although there is a rich literature demonstrating a link between decreased HRV and high risk of cardiovascular disease and sudden death in population-based studies, it is not yet known whether day-to-day changes in HRV (such as those found following an acute exposure to PM) is associated with day-to-day risk for sudden cardiac death.
在反映在心脏速率高的频率变化的变化分量中观察到的影响,这表明暴露于PM可能导致心脏速率的副交感控制的损失。这些结果与显示PM之间的关联面板研究协议,并在一个退休在家的老年居民减少HF HRV17和老年波士顿居民表示PM和之间的关联的面板研究平均的相邻正常心跳到搏动(RR)时间间隔(R-MSSD)之间的平方差,这一措施,其与相关因素的HRV HF分量20。其他小组的研究有PM和SDNN之间的关联报道;在这项研究中也有使用外盖降低SDNN的倾向,但这些水平没有达到统计学意义。These differences may reflect differences in sampling intervals (5 min in the present study与24 h in some of the panel studies), differences in the nature of the particles to which subjects were exposed (for example, CAPS do not contain significant amounts of ultrafine particles), or the fact that subjects were exposed only a single time in the present study.
这些结果与最近几毒理学研究报告,其暴露于PM人或动物心脏不良事件是一致的。在心电图的模式,包括ST段的海拔变化,据报道在狗接触到CAPS24。暴露于残油飞灰大鼠中观察到的心电图模式类似的模式改变25或CAPS26。增加心律失常也出现在暴露于油飞灰或CAPS大鼠27。暴露于超细碳颗粒的人类志愿者遇到改变心脏复极化通过在心电图上在校正的QT间隔的变化所指示的28。
在心脏心率变异的集中环境空气污染颗粒诱导递减在健康老年志愿者发现,在对比的是缺乏反应在早先的研究中曝露于汇聚环境空气中的污染颗粒的健康年轻成人观察到的本作者。虽然这两个基团暴露于浓缩环境空气污染的颗粒的可比较的水平,青年志愿者间歇行使整个曝光,而老年受试者保持静止整个曝光。当前作者估计,青年组的通气量增加导致了〜3浓缩环境空气污染颗粒的折叠增加的沉积到他们的肺。Nevertheless, there were no concentrated ambient air pollution particle-induced changes in heart rate variability in these subjects either immediately following exposure or 24 h later. This could indicate that elderly people are more responsive to particulate matter than young individuals. However, the young subject study, which was designed to primarily measure changes in lung inflammation, was not a paired study with each person serving as their own control, but rather a cohort study in which some subjects were exposed to CAPS and others to clean air. Each elderly subject was exposed to both air and concentrated ambient air pollution particles. Thus the difference in results seen between the two studies could also be related to design differences.
致谢
作者要感谢J. Stonehuerner和J. Scott提供的技术支持,以及M.A. Bassett、D. Levin和S. Derrenbacher提供的护理支持。免责声明:本报告已由美国环境保护署国家健康与环境影响研究实验室审核并批准出版。批准并不表示内容必须反映该机构的观点和政策,亦不表示提及商号或商业产品即构成认可或建议使用。
- 收到了2002年4月12日。
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