From particles to patients: oxidative stress and the cardiovascular effects of air pollution

Air pollution, especially airborne particulate matter (PM), is associated with an increase in both morbidity and mortality from cardiovascular disease, although the underlying mechanisms remain incompletely established. The one consistent observation that links the pulmonary and cardiovascular effects of inhaled PM is oxidative stress. This article examines the evidence for the role of oxidative stress in the cardiovascular effects of air pollution, beginning with observations from epidemiological and controlled exposure studies and then exploring potential mechanistic pathways involving free radical generation from PM itself, to effects of PM on cell cultures, isolated organs, healthy animals and animal models of disease. Particular emphasis is placed on the vascular and atherosclerotic effects of urban air pollution and diesel exhaust emissions as rich sources of environmental ultrafine particles.     

空气污染与心律失常的相关性研究

常见的空气污染物主要包括颗粒物、臭氧、二氧化氮和二氧化硫、一氧化碳等.吸入污染的空气不仅诱发呼吸系统疾病,同时还会诱发心血管疾病.流行病学调查发现人体暴露于污染物中可促进缺血性心脏病、心力衰竭、心律失常和心脏骤停在内的心脏事件的发生,增加心血管病发病率和病死率.现对国内外空气污染与心律失常的相关文献进行综述.     

Impact of Particulate Air Pollution on Cardiovascular Health

Purpose of Review

Air pollution is established as an independent risk factor for cardiovascular diseases (CVDs). Ambient particulate matter (PM), a principal component of air pollutant, has been considered as a main culprit of the adverse effects of air pollution on human health.

Recent Findings

Extensive epidemiological and toxicological studies have demonstrated particulate air pollution is positively associated with the development of CVDs. Short-term PM exposure can trigger acute cardiovascular events while long-term exposure over years augments cardiovascular risk to an even greater extent and can reduce life expectancy by a few years. Inhalation of PM affects heart rate variability, blood pressure, vascular tone, blood coagulability, and the progression of atherosclerosis. The potential molecular mechanisms of PM-caused CVDs include direct toxicity to the cardiovascular system or indirect injury by inducing systemic inflammation and oxidative stress in circulation.

Summary

This review mainly focuses on the acute and chronic effects of ambient PM exposure on the development of cardiovascular diseases and the possible mechanisms for PM-induced increases in cardiovascular morbidity and mortality. Additionally, we summarized some appropriate interventions to attenuate PM air pollution-induced cardiovascular adverse effects, which may promote great benefits to public health.

     

PM2．5与肺癌

流行病学研究显示,PM2．5对呼吸、心血管、生殖系统疾病的发病和死亡有着重要影响。近期国际癌症研究机构把大气污染确认定为致癌物,其重要组成部分大气细颗粒物（PM2．5）对人群健康致癌性研究日益受到关注,综述介绍有关国内外对大气中细颗粒物PM2．5与肺癌的研究状况。     

You are what you breathe: Evidence linking air pollution and blood pressure

Exposure to particulate matter (PM) air pollution increases the risk for myocardial infarctions, strokes, and cardiovascular mortality. A variety of responsible mechanisms have been described, including PM-induced elevations in blood pressure. Observational studies and controlled experiments have provided evidence that PM is capable of acutely increasing blood pressure in certain scenarios. Enhanced sympathetic tone and vascular dysfunction due to PM-induced systemic oxidative stress/inflammation are leading explanations. The hemodynamic responses to air pollution may be altered by underlying cardiovascular risk factors and the chemical composition of the PM. However, even the small elevations in blood pressure observed following certain exposures to PM have tremendous public health implications, due to the ubiquitous nature of air pollution.     

Air particulate matter and cardiovascular disease: A narrative review

Consistent evidences from both epidemiological and experimental studies have demonstrated that short- and long-term exposure to particulate matter (PM), in particular to the finest particles (i.e. airborne PM with aerodynamic diameter less than 2.5 μm, PM_2.5), is associated with cardiovascular morbidity and mortality. PM concentration has been linked with several clinical manifestations of cardiovascular diseases (CVD), including myocardial infarction, stroke, heart failure, arrhythmias, and venous thromboembolism. Noteworthy, some groups of subjects, like elderly, diabetics, or those with known coronary artery disease, appear specifically susceptible to the harmful effects triggered by PM exposure. Although the PM-related risk for a single individual appears relatively low, the PM-related population attributable risk is impressive. Recent studies indicate that the PM-CVD relationship is likely more complex than a mere quantitative association between overall PM concentration and disease risk. Indeed, the biological effects of PM may vary in function of both the aerodynamic diameter and the chemical composition. Moreover, it has been shown that the influence of air pollution on health is not limited to PM. Indeed, other gaseous pollutants may play an independent role in CVD, suggesting the need to develop multi-pollutant preventive approaches. Causality has been recently strongly supported by observations showing reduced CVD mortality after coordinated community policies resulting in lowering PM exposure at population level. An in-depth knowledge on the heterogeneous sources, chemical compounds, and biological effects of PM may help to propose more accurate and clinically effective recommendations for this important and modifiable factor contributing to CVD burden.     

Respiratory health effects of diesel particulate matter

Particulate matter (PM) emissions involve a complex mixture of solid and liquid particles suspended in a gas, where it is noted that PM emissions from diesel engines are a major contributor to the ambient air pollution problem. While epidemiological studies have shown a link between increased ambient PM emissions and respiratory morbidity and mortality, studies of this design are not able to identify the PM constituents responsible for driving adverse respiratory health effects. This review explores in detail the physico-chemical properties of diesel PM (DPM) and identifies the constituents of this pollution source that are responsible for the development of respiratory disease. In particular, this review shows that the DPM surface area and adsorbed organic compounds play a significant role in manifesting chemical and cellular processes that if sustained can lead to the development of adverse respiratory health effects. The mechanisms of injury involved included inflammation, innate and acquired immunity, and oxidative stress. Understanding the mechanisms of lung injury from DPM will enhance efforts to protect at-risk individuals from the harmful respiratory effects of air pollutants.     

Cardiovascular effects of particulate air pollution exposure: time course and underlying mechanisms

OBJECTIVE: Air pollution is now recognized as an important independent risk factor for cardiovascular morbidity and mortality and may be responsible for up to 3?million premature deaths each year worldwide. The mechanisms underlying the observed effects are poorly understood but are likely to be multifactorial. Here, we review the acute and chronic effects of air pollution exposure on the cardiovascular system and discuss how these effects may explain the observed increases in cardiovascular morbidity and mortality.     

Inflammation, edema, and peripheral blood changes in lung-compromised rats after instillation with combustion-derived and manufactured nanoparticles

Increased exposure to pollution has been implicated in cardiovascular malfunction, and although studies show a relationship between PM10 and mortality, the exact biological causes are unclear. This study investigated how compromised lungs respond to instillation of nanoparticles, and the links between exposure to nanoparticles and the subsequent effects on the blood. Instillation of diesel exhaust particles and Cabosil caused significant permeability and inflammatory changes in both bleomycin-treated and control lungs, as shown by increased lung surface protein and lung:body weight ratio. This was true in edematous and maximally repairing lungs, but without significant hematological alterations. Plasma viscosity, a renowned marker for cardiovascular disease, correlated strongly statistically with free cell numbers, type I cell marker rT140, and lung acellular protein. These correlations are a new and novel insight into the mechanisms linking air pollution to cardiovascular mortality.     

空气污染与心血管疾病发病及预后的研究进展

近年来以细颗粒物（PM2.5）为代表的可吸入颗粒物（PM）日益被视为全球空气污染相关死亡率升高的主要原因。有确凿的证据支持炎症、氧化应激、动脉粥样硬化、血栓形成以及自主调节异常等多种机制的相互作用,最终可增加短期及长期接触污染空气人群心血管疾病发病率与死亡率。空气污染带来的心血管风险是可以部分规避的。     

Impact of urban atmospheric pollution on coronary disease.

Recent epidemiological findings have suggested that urban atmospheric pollution may have adverse effects on the cardiovascular system as well as on the respiratory system. We carried out an exhaustive search of published studies investigating links between coronary heart disease and urban atmospheric pollution. The review was conducted on cited articles published between 1994 and 2005 and whose main objective was to measure the risk of ischaemic heart diseases related to urban pollution. Of the 236 references identified, 46 epidemiological studies were selected for analysis on the basis of pre-defined criteria. The studies were analysed according to short-term effects (time series and case-crossover designs) and long-term effects (case-control and cohort studies). A link between coronary heart disease and at least one of the pollutants studied (PM10, O3, NOx, CO, SO2) emerged in 40 publications. Particulate matter, nitrogen oxides, and carbon monoxide were the pollutants most often linked with coronary heart disease. The association was inconstant for O3. Although the mean mortality or morbidity risk related to urban atmospheric pollution is low compared with that associated with other better-known risk factors, its impact on health is nevertheless major because of the large number of people who are exposed. This exhaustive review supports the possibility that urban pollution is indeed an environmental cardiovascular risk factor and should be considered as such by the cardiologists.     

Are diabetics more susceptible to the health effects of airborne particles?

Convincing evidence now exists that particulate air pollution exacerbates heart and lung disease, leading to increased morbidity and mortality. The populations particularly susceptible to these exposures are still unclear. Recent work on potential mechanisms of action of particulate air pollution point to pathways also influenced by diabetes. We examined whether diabetes modified the effect of airborne particles by looking at the association of PM(10) with hospital admissions for heart and lung disease in persons with or without diabetes as a comorbidity. In addition we stratified by age within persons with and without diabetes. We used Medicare data for Cook County, Illinois for the years 1988-1994, and found that a 10 microg/m(3) increase in PM(10) was associated with a 2.01% (95% CI 1.40-2.62%) increase in admissions for heart disease with diabetes, but only a 0.94% (95% CI 0.61-1.28%) increase in persons without diabetes. Similar effect modification was not seen for lung diseases. When analyzing by age we found twice the PM(10)-associated risk for heart disease in diabetics than nondiabetics in both age groups. We found for pneumonia admissions that diabetes is an effect modifier in the younger age group, and for COPD in the older age group. We conclude that persons with diabetes are a susceptible population.     

空气污染与心血管疾病专家共识

空气污染是全球性的严重公共卫生问题,也是对我国民众健康的严峻挑战。空气污染可增加心血管疾病发病及死亡风险,已成为一项重要且可干预的心血管疾病危险因素。空气污染导致的死亡主要为心血管疾病死亡。本共识汇总了国内外关于空气污染与心血管疾病的最新流行病学及临床研究证据,推荐室内使用清洁能源烹饪及采暖、在重污染天气佩戴符合国家标准的N95防护口罩等措施以降低个体对空气污染物的暴露水平。该共识为进一步加强医疗卫生人员对空气污染危害心血管健康的认识,帮助其开展健康宣教和确定未来科研方向,并为相关部门制定公共卫生政策提供参考。     

Spatial variation in heart failure and air pollution in Warwickshire,UK: an investigation of small scale variation at the ward level

BackgroundAir pollution has been linked to the development and exacerbation of various health problems, including cardiovascular diseases such as heart failure. This project sought to spatially map the morbidity and mortality caused by heart failure within the county of Warwickshire, UK, to characterise and quantify any influence of air pollution on these risks.MethodsData on air pollution, hospital admission for heart failure, and mortality within 105 Warwickshire county wards were collected from 2005 to 2013. Air pollution data included mono-nitrogen oxide (NO_x), sulphur dioxide (SO₂), particulate matter (PM), and benzene, which could then be united into a combined index. We used Bayesian geo-additive mixed models to map the spatial distribution of air pollution and heart failure data at the county level, accounting for county risk factors.FindingsDuring 2005–13 in Warwickshire, heart failure led to 5045 hospital admissions and 479 deaths. In multivariate analyses, presence of NO_x, benzene, and index of multiple deprivation (IMD) score were consistently associated with risk of heart failure morbidity (posterior mean PM 3·35, 95% credible region 1·89–4·99 vs 31·9, 8·36–55·85 vs 0·02, 0·01–0·03). PM was negatively associated with the risk of heart failure morbidity (?12·93, ?20·41 to ?6·54) but no association with SO₂ was seen. Risk of heart failure mortality was higher in wards with a high NO_x (4·30, 1·68–7·37) and in wards with more inhabitants older than 50 years (1·60, 0·47–2·92). PM was negatively associated with heart failure mortality (?14·69, ?23·46 to ?6·50). SO₂, benzene, and IMD score were not associated with heart failure mortality. There was a striking variation in heart failure morbidity and mortality risk across wards, the highest risk being in the regions around Nuneaton and Bedworth (appendix).InterpretationThis study showed distinct spatial patterns in heart failure morbidity and mortality in Warwickshire, suggesting a potential role of air pollution beyond individual-level risk factors. Environmental factors should therefore be taken into account when considering the wider determinants of public health and the effect that changes in air pollution might have on the health of a population.FundingThis paper presents independent research supported by the National Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care West Midlands.     

Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a risk factor for development of cardiovascular events, independent of smoking. The mechanisms are unclear, but systemic inflammation associated with COPD may contribute to this cardiovascular risk. Similar to cigarette smoking, exposure to particulate air pollution is associated with an increase in the mortality and morbidity from respiratory and cardiovascular diseases. The exposure of humans to high levels of ambient particles stimulates the bone marrow and the release of neutrophils, band cells, and monocytes into the circulation. This bone marrow simulation is associated with increased levels of circulating interleukin-1beta and interleukin-6, similar to cigarette smoking. In animals, exposure to particulate matter accelerates the transit of neutrophils and monocytes in bone marrow and expands the leukocyte pool size. This systemic inflammatory response to particle inhalation causes endothelial activation and upregulation adhesion molecules that are critically important in leukocyte recruitment into atherosclerotic plaques. Exposure to particles also causes disease progression and destabilization of atherosclerotic plaques in rabbits that develop atherosclerosis naturally. We suspect, therefore, that the systemic inflammatory responses described activate vascular endothelium and cause progression and instability of atherosclerotic plaques. We speculate that this mechanism may contribute to the cardiovascular morbidity and mortality associated with COPD.     

Reduction in fine particulate air pollution and mortality: Extended follow-up of the Harvard Six Cities study

RATIONALE: A large body of epidemiologic literature has found an association of increased fine particulate air pollution (PM2.5) with acute and chronic mortality. The effect of improvements in particle exposure is less clear. OBJECTIVES: Earlier analysis of the Harvard Six Cities adult cohort study showed an association between long-term ambient PM2.5 and mortality between enrollment in the mid-1970s and follow-up until 1990. We extended mortality follow-up for 8 yr in a period of reduced air pollution concentrations. METHODS: Annual city-specific PM2.5 concentrations were measured between 1979 and 1988, and estimated for later years from publicly available data. Exposure was defined as (1) city-specific mean PM2.5 during the two follow-up periods, (2) mean PM2.5 in the first period and change between these periods, (3) overall mean PM2.5 across the entire follow-up, and (4) year-specific mean PM2.5. Mortality rate ratios were estimated with Cox proportional hazards regression controlling for individual risk factors. MEASUREMENTS AND MAIN RESULTS: We found an increase in overall mortality associated with each 10 microg/m3 increase in PM2.5 modeled either as the overall mean (rate ratio [RR], 1.16; 95% confidence interval [CI], 1.07-1.26) or as exposure in the year of death (RR, 1.14; 95% CI, 1.06-1.22). PM2.5 exposure was associated with lung cancer (RR, 1.27; 95% CI, 0.96-1.69) and cardiovascular deaths (RR, 1.28; 95% CI, 1.13-1.44). Improved overall mortality was associated with decreased mean PM2.5 (10 microg/m3) between periods (RR, 0.73; 95% CI, 0.57-0.95). CONCLUSION: Total, cardiovascular, and lung cancer mortality were each positively associated with ambient PM2.5 concentrations. Reduced PM2.5 concentrations were associated with reduced mortality risk.     

Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress

Air pollution is associated with significant adverse health effects, including increased cardiovascular morbidity and mortality. Exposure to particulate matter with an aerodynamic diameter of <2.5 microm (PM(2.5)) increases ischemic cardiovascular events and promotes atherosclerosis. Moreover, there is increasing evidence that the smallest pollutant particles pose the greatest danger because of their high content of organic chemicals and prooxidative potential. To test this hypothesis, we compared the proatherogenic effects of ambient particles of <0.18 microm (ultrafine particles) with particles of <2.5 microm in genetically susceptible (apolipoprotein E-deficient) mice. These animals were exposed to concentrated ultrafine particles, concentrated particles of <2.5 microm, or filtered air in a mobile animal facility close to a Los Angeles freeway. Ultrafine particle-exposed mice exhibited significantly larger early atherosclerotic lesions than mice exposed to PM(2.5) or filtered air. Exposure to ultrafine particles also resulted in an inhibition of the antiinflammatory capacity of plasma high-density lipoprotein and greater systemic oxidative stress as evidenced by a significant increase in hepatic malondialdehyde levels and upregulation of Nrf2-regulated antioxidant genes. We conclude that ultrafine particles concentrate the proatherogenic effects of ambient PM and may constitute a significant cardiovascular risk factor.     

Air pollution and markers of inflammation and coagulation in patients with coronary heart disease

RATIONALE: Ambient air pollution has been shown to be associated with cardiovascular morbidity and mortality. OBJECTIVES: A prospective panel study was conducted to study the early physiologic reactions characterized by blood biomarkers of inflammation, endothelial dysfunction, and coagulation in response to daily changes in air pollution in Erfurt, Germany. METHODS: Blood parameters were repeatedly measured in 57 male patients with coronary heart disease during the winter of 2000/2001. Fixed-effects linear and logistic regression models were applied, adjusting for trend, weekday, and meteorologic parameters. MEASUREMENTS: Hourly data on ultrafine particles (UFPs; number concentration of particles from 0.01 to 0.1 microm), mass concentration of particles less than 10 (PM(10)) and 2.5 microm in diameter, elemental and organic carbon, gaseous pollutants, and meteorologic data were collected at central monitoring sites. MAIN RESULTS: Increased levels of C-reactive protein above the 90th percentile were observed for an increase in air pollution concentrations of one interquartile range. The effect was strongest for accumulation mode particles, with a delay of 2 d (odds ratio [OR], 3.2; confidence interval [CI], 1.7, 6.0). Results were consistent for UFPs and PM(10), which also showed a 2-d delayed response (OR, 2.3; CI, 1.3, 3.8; and OR, 2.2; CI, 1.2, 3.8, respectively). However, not all of the blood markers of endothelial dysfunction and coagulation increased consistently in association with air pollutants. CONCLUSION: These results suggest that inflammation as well as parts of the coagulation pathway may contribute to the association between particulate air pollution and coronary events.     

Air Pollution Particulate Matter Collected from an Appalachian Mountaintop Mining Site Induces Microvascular Dysfunction

Objective

Air pollution PM is associated with cardiovascular morbidity and mortality. In Appalachia, PM from mining may represent a health burden to this sensitive population that leads the nation in cardiovascular disease, among others. Cardiovascular consequences following inhalation of PM_MTM are unclear, but must be identified to establish causal effects.

Methods

PM was collected within 1 mile of an active MTM site in southern WV. The PM was extracted and was primarily <10 μm in diameter (PM₁₀), consisting largely of sulfur (38%) and silica (24%). Adult male rats were IT with 300 μg PM_MTM. Twenty‐four hours following exposure, rats were prepared for intravital microscopy, or isolated arteriole experiments.

Results

PM_MTM exposure blunted endothelium‐dependent dilation in mesenteric and coronary arterioles by 26%, and 25%, respectively, as well as endothelium‐independent dilation. In vivo, PM_MTM exposure inhibited endothelium‐dependent arteriolar dilation (60% reduction). α‐adrenergic receptor blockade inhibited PVNS‐induced vasoconstriction in exposed animals compared with sham.

Conclusions

These data suggest that PM_MTM exposure impairs microvascular function in disparate microvascular beds, through alterations in NO‐mediated dilation and sympathetic nerve influences. Microvascular dysfunction may contribute to cardiovascular disease in regions with MTM sites.     

Homocysteine and cardiovascular disease: current evidence and future prospects

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Despite the well-known effectiveness of vitamin supplementation in reducing homocysteine levels, it is not known whether lowering of homocysteine levels is associated with a reduction in cardiovascular morbidity and mortality. The aim of this review is to discuss the epidemiologic evidence about the relation between homocysteine and cardiovascular disease, the pathophysiologic mechanisms responsible for the deleterious vascular and hemostatic effects of homocysteine, and studies of the potential benefits of homocysteine-lowering therapy.