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Chronic Air Pollution Exposure and Endothelial Dysfunction
 
 
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This is the first epidemiological study to suggest that long-term exposure to PM2.5 is associated with decreased endothelial function in a conduit artery independent of cardiovascular risk factors. This finding provides a clue that long-term perturbations of the endothelium-smooth muscle complex from PM2.5 exposure lead to chronic functional changes. These functional changes may partly explain the risk of cardiovascular events previously associated with these environmental exposures

Editorial comment | October 2012

Chronic Air Pollution Exposure and Endothelial Dysfunction What You Can't See-Can Harm You
ONLINE FIRST

Robert D. Brook, MD; Sanjay Rajagopalan, MD

J Am Coll Cardiol. 2012;():. doi:10.1016/j.jacc.2012.08.974

Fine particulate matter air pollution <2.5 μm in diameter (PM2.5), a pervasive and often "invisible" component of modern-day atmospheres, has been linked to numerous adverse outcomes, including increased cardiovascular (CV) morbidity and mortality. Indeed, an American Heart Association scientific statement recently concluded that the overall evidence is consistent with PM2.5 being causally related to CV diseases (1). There remains little doubt that higher ambient PM2.5 levels over a few days can promote acute CV events ((1),2). Although the short-term risks for a single individual are small, due to the vast number of individuals affected worldwide, the public health burden of air pollution is enormous. It has been estimated that up to 4.8% of acute myocardial infarctions are potentially attributable to recent exposures (2). Although alarming, these figures (limited to the acute impact of pollution) in actuality represent an underestimation of the totality of PM2.5-related CV health effects.

Accumulating evidence supports the reasoning that the CV risks posed by PM2.5 mirror those of other classical risk factors (1). The health risks posed by brief perturbations in any factor (e.g., an acute elevation in blood pressure) are markedly outweighed by those induced by the cumulative actions of pervasive long-term abnormalities (e.g., chronic hypertension). Hence, not only the magnitude but also the duration of exposure to a risk factor is important when considering the sum totality of ensuing health risks. In the context of air pollution, prospective cohort studies generally report an order of magnitude greater increase in CV risk induced by several years of PM2.5 exposure compared with that associated with inhaling similar levels over only a few days ((1),3). One hypothesis put forth to explain these observations has been that repetitive exposures have cumulative and pernicious effects on the CV system, both amplifying the adverse effects of other CV risk factors and increasing the detrimental impact of later PM2.5 exposures (i.e., increasing future susceptibility) ((1),4). Emerging data also support a role for chronic air pollution exposures in promoting the genesis of overt disease states, such as atherosclerosis, hypertension, and diabetes mellitus ((1),5).

Using data from the MESA (Multi-Ethnic Study of Atherosclerosis) cohort, the study by Krishnan et al. (6) in this issue of the Journal provides new insights into the adverse CV actions of long-term air pollution exposure. Leveraging off of the numerous inherent strengths of the MESA, the authors performed the first assessment of the chronic effects of long-term PM2.5 exposure on vascular endothelial function as assessed by using flow-mediated dilation (FMD) of the brachial artery. FMD is a marker of nitric oxide-dependent vasodilation and is a validated metric of overall vascular endothelial health as well as an independent predictor of CV prognosis (7). However, a limitation of the MESA study design was that nitroglycerin-mediated vasodilation was not evaluated; hence, the differential impact of air pollution on the endothelium versus smooth muscle function could not be deciphered ((6),7).

The principal finding of this current MESA Air report was that a 3 μg/m3 higher annual average PM2.5 exposure was associated with a significant 0.3% reduction in FMD (6). This magnitude of vascular dysfunction, although seemingly small, was analogous to the adverse effects of smoking or 5 years of aging. This finding suggests that individuals living in regions affected by even modestly higher air pollution levels are at risk for experiencing a clinically pertinent chronic impairment in vascular function. This novel observation should re-awaken us to the fact that even "invisible" elements, such as chronic exposure to low levels of air pollution commonly encountered in the United States, can have significant adverse effects on CV health.

Several strengths of the current study (6) merit highlighting. It is among the largest investigations linking air pollution exposure with CV imaging endpoints (1). Although not involving the entire MESA cohort, 3,040 patients is an enviable sample size for an FMD-based study. This size is likely why the authors were able to find significant adverse vascular effects despite the small interquartile range (3 μg/m3) in PM2.5 exposure levels. The richness of the acquired covariates and patient-related information also allowed for numerous explorations of effect modification and sensitivity analyses. In this regard, their findings support previous suppositions that women might be more susceptible (1) and provide new insights into other potential at-risk groups. The quality and standardization of ultrasound methods, critically important for FMD protocols, were also previously well established for this study. Finally, enormous efforts were paid to developing and validating estimates of "chronic" residence-level PM2.5 exposures using advanced spatiotemporal models. This experimental strength likely reduced the occurrences of significant exposure misclassifications capable of obfuscating true air pollution-mediated health effects.

How do the current findings of Krishnan et al. (6) compare with previous studies? A number of controlled experiments and panel studies have evaluated the effects of air pollutants on vascular function; however, these studies were conducted only after short-term periods of exposure (1). Previous findings have been mixed, with some reports demonstrating reduced endothelial-dependent vasodilation (with or without concomitant blunted nitroglycerin-mediated dilation), whereas others have observed acute arterial vasoconstriction. How does one reconcile this variability and place it into context given these new study findings? Differences in populations, patient susceptibilities, underling CV diseases, and risk factors, as well as the known intrinsic variability of endothelial function testing as an outcome (e.g., biological aspects and technical limitations) (7), are undoubtedly contributing explanations. It is moreover possible that the air pollutants evaluated across the published studies may also be partially to blame. PM2.5 is not a homogeneous entity but is composed of numerous chemical compounds (1). Differing pollution sources, characteristics, and mixtures could in theory elicit discordant vascular responses. Unfortunately, because only PM2.5 mass was evaluated in the current MESA Air report (6), the specific components (e.g., metals, organic carbon) and pollution sources (e.g., traffic, regional) most responsible for perturbing vascular function continue to be obscure. In this regard, it is interesting to note that the reported FMD responses differed somewhat among the 5 cities. Perhaps future analyses of this cohort will provide much-needed insights into the responsible or most harmful airborne compounds as well as the impact of multiple co-pollutants together (e.g., ozone, nitrogen oxides).

The most novel aspect of the current study (6) was the exploration of the effects of "long-term" PM2.5 exposure on vascular function. However, deciphering the temporal associations between exposures and health outcomes is a complicated issue that cannot be completely elucidated by any single experiment. It is important to note that the current results cannot rule out the possibility that only "subacute" periods of PM2.5 exposure (e.g., a few weeks) are all that is biologically required to cause most (or all) of the PM2.5-induced vascular dysfunction attributed to their year-long exposure metric (4). There is a large missing time window between 3 days and 1 year (the acute versus chronic exposure metrics in their study [6]). This possibility is supported by a previous publication from MESA (8). Although blood pressure was not found to be associated with PM2.5 levels during the previous 1 to 7 days, it was significantly elevated in relation to the levels during the previous 30 to 60 days. A significant relation would have been missed if the health effect was evaluated solely in regard to the preceding few days' concentrations. In the current MESA Air report, although trends toward reductions in brachial artery diameter and FMD were indeed seen in relation to short-term PM2.5 exposure levels, some degree of exposure misclassifications may have obscured the investigators' ability to observe significant acute impairments in vascular function. Their estimations of short-term PM2.5 levels were acknowledged to be inferior to those used for the annual values. Less sophisticated models coupled with greater variations in subject time-activity, indoor particle penetration, and the dominant pollutant sources over the short-term may be contributing factors. Based on these considerations, the current findings should not be interpreted as a refutation of previous publications showing that PM2.5 can be capable of impairing vascular function within days (1). Rather, the results are illustrative of the concept that cumulative exposures (of a yet to be precisely determined duration) likely have more discernible and/or harmful effects on the CV system.

What are the broader implications of the findings by Krishnan et al. (6)? The fact that year-long PM2.5 exposures were related to a decrease in FMD provides an important mechanistic foundation that supports the plausibility of prior studies linking air pollutants with the presence and/or progression of atherosclerosis (1). Their findings also support the growing number of studies associating PM2.5 with other facets of the cardiometabolic syndrome (e.g., diabetes and hypertension) that are also biologically linked to underlying endothelial dysfunction ((1),5). Considering that endothelial dysfunction is an independent predictor for future events (7), these findings corroborate the contention that air pollution is as an insidious and omnipresent CV risk factor (1). Moreover, the harmful vascular effects induced by PM2.5 occurred among cities in the United States with comparatively low air pollution concentrations that were near or within existing annual National Ambient Air Quality Standards (1) (<15 μg/m3). When one considers the fact that PM2.5 levels often average 5- to 10-fold higher across numerous regions populated by billions of people worldwide (9), the grave global public health consequences of air pollution corroborated by the findings of this important study deserve serious and immediate attention.

*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology

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Vascular Responses to Long- and Short-Term Exposure to Fine Particulate MatterThe MESA Air (Multi-Ethnic Study of Atherosclerosis and Air Pollution) ONLINE FIRST

Ranjini M. Krishnan, MD, MS; Sara D. Adar, ScD; Adam A. Szpiro, PhD; Neal W. Jorgensen, MS; Victor C. Van Hee, MD, MPH; R. Graham Barr, MD, DrPH; Marie S. O'Neill, PhD; David M. Herrington, MD; Joseph F. Polak, MD, MPH; Joel D. Kaufman, MD, MPH

J Am Coll Cardiol. 2012;():. doi:10.1016/j.jacc.2012.08.973

Abstract

Objectives
This study evaluated the association of long- and short-term air pollutant exposures with flow-mediated dilation (FMD) and baseline arterial diameter (BAD) of the brachial artery using ultrasound in a large multicity cohort.

Background Exposures to ambient air pollution, especially long-term exposure to particulate matter <2.5 μm in aerodynamic diameter (PM2.5), are linked with cardiovascular mortality. Short-term exposure to PM2.5 has been associated with decreased FMD and vasoconstriction, suggesting that adverse effects of PM2.5 may involve endothelial dysfunction. However, long-term effects of PM2.5 on endothelial dysfunction have not been investigated.

Methods FMD and BAD were measured by brachial artery ultrasound at the initial examination of the Multi-Ethnic Study of Atherosclerosis. Long-term PM2.5 concentrations were estimated for the year 2000 at each participant's residence (n = 3,040) using a spatio-temporal model informed by cohort-specific monitoring. Short-term PM2.5 concentrations were based on daily central-site monitoring in each of the 6 cities.

Results An interquartile increase in long-term PM2.5 concentration (3 μg/m3) was associated with a 0.3% decrease in FMD (95% confidence interval [CI] of difference: -0.6 to -0.03; p = 0.03), adjusting for demographic characteristics, traditional risk factors, sonographers, and 1/BAD. Women, nonsmokers, younger participants, and those with hypertension seemed to show a greater association of PM2.5 with FMD. FMD was not significantly associated with short-term variation in PM2.5 (-0.1% per 12 μg/m3 daily increase [95% CI: -0.2 to 0.04] on the day before examination).

Conclusions Long-term PM2.5 exposure was significantly associated with decreased endothelial function according to brachial ultrasound results. These findings may elucidate an important pathway linking air pollution and cardiovascular mortality. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487.

Air pollution is a complex mixture of particulate matter, volatile organic compounds, and gaseous pollutants such as oxides of nitrogen. Epidemiological analyses have demonstrated an association between short- and long-term exposures to air pollution, especially particulate matter <2.5 μm in aerodynamic diameter (PM2.5) and increased cardiovascular morbidity and mortality ((1),2). It is postulated that this adverse cardiovascular effect is related to systemic inflammation, oxidative stress, or autonomic nervous system imbalance effects in the artery wall (3). Hence, one of the intermediate steps by which PM2.5exposure increases cardiovascular morbidity and mortality may be via functional changes in the endothelium-smooth muscle complex.

Previous studies have shown associations between short-term exposure to PM2.5 and nitric oxide (NO)-mediated endothelial dysfunction measured by using forearm plethysmography (4) or flow-mediated dilation (FMD) using brachial ultrasound ((5),6). In a study of healthy volunteers situated for 2 h at different urban bus stops, a 30-μg/m3 increase in PM2.5 exposure corresponded to a 0.5% reduction in FMD (7). In contrast, other experimental studies have shown associations with vasoconstriction measured as a decrease in baseline arterial diameter (BAD) but not FMD ((8),9). These studies provide different conclusions: PM2.5 exposure may primarily affect NO-mediated endothelial dysfunction or it may alter elaboration of vasoconstrictors.

Observations from short-term exposure studies provide only limited insight into effects of pollutants and mechanisms. Are the vascular responses transient or do lasting effects accrue after long-term exposure? We hypothesized that repeated short-term insults to the vasculature result in persistent endothelial dysfunction related to long-term exposures. To test this hypothesis, we investigated the relationship between PM2.5 exposures and changes in the brachial artery in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. Leveraging the detailed exposure assignment of the MESA Air Pollution (MESA Air) study, we examined whether long- and short-term exposure to PM2.5 is associated with decreased FMD and/or decreased BAD in this cohort.

Discussion

In this large, multisite, multiethnic cohort, a significant association was observed between long-term residential PM2.5 concentrations and NO-mediated endothelial dysfunction as assessed by FMD, independent of major cardiovascular risk factors. Although previous studies ((5),(6),21) have assessed the relation between short-term exposure to PM2.5 and endothelial function, this is the first investigation of the relation between long-term PM2.5 exposure and endothelial function. Our study provides unique insights into the mechanisms of long-term PM2.5 exposure and increased cardiovascular mortality.

Increasing age, SBP, BMI, and smoking are inversely related to FMD (19). The magnitude of the long-term effect of an IQR (difference between the 25th and 75th percentile) increase in PM2.5 on FMD% is comparable to the effect of 5 years' increase in age, or of active tobacco smoking, in this population. A 3-μg/m3 increase in PM2.5 concentration occurs as a contrast in residential exposure between less polluted and more polluted areas in most major U.S. metropolitan areas. Taken together, these data suggest that PM2.5 exerts a clinically relevant degree of effect on endothelial dysfunction.

Endothelial dysfunction measured by using FMD is a precursor for atherogenesis (22) and is associated with hypertension (23), passive smoking (24), and cardiovascular events ((11),25). Although the role of FMD as a predictor is still controversial, it is consistently associated with future cardiovascular events (26). In a nested case-cohort study using MESA data, abnormal FMD was predictive of incident cardiovascular events independent of other major cardiovascular risk factors (11). Furthermore, a recent meta-analysis using pooled data from 14 studies (including 5,447 participants) found that a 1% decrease in FMD% was associated with an 8% increase in cardiovascular mortality independent of risk factors (26). In our study, a 10 μg/m3 annual increase in PM2.5 concentration was associated with a 1% decrease in FMD% (regardless of the adjustment for 1/BAD). Although we report our outcomes for an IQR increase in the PM2.5 contrast, the equivalent of a 10-μg/m3 exposure contrast has previously been associated with a 9% increase in cardiopulmonary mortality in the American Cancer Society Cancer Prevention Study II (27) and a 24% increase in cardiovascular events in the Women's Health Initiative Observational Study (28).

Our finding regarding short-term exposures, although not statistically significant, is still notable given the prior association with endothelial dysfunction in both experimental ((8),9) and observational ((5),21) studies. Our results of larger associations with long-term compared with short-term associations (one-tenth of the effect estimate for short-term compared with long-term) parallel the larger magnitude of effect on cardiovascular mortality noted in previous population-based studies ((27),(28),29). For example, a 10-μg/m3 increase in short-term exposure to particulate matter is typically associated with a 0.1% to 0.5% mortality increase in the large multicity studies (30) compared with 10% or greater mortality increases in long-term exposure cohort studies ((1),(27),28). The lack of more robust findings for short-term analysis may be due to limited statistical power or the simplified approach to short-term exposure estimation compared with long-term exposures.

Several mechanisms have been proposed to explain the potential cardiovascular risk associated with pollutants, involving oxidative stress, inflammation, and autonomic imbalance, each of which can affect the endothelium directly or indirectly. A recent study found an association between arterial stiffness and annual average concentrations of nitrogen dioxide and sulfur dioxide but not PM2.5 (31). Reduced production and efficacy of NO in the vasculature is a hallmark of endothelial dysfunction. Previous studies in humans ((8),9) have shown vasoconstriction and altered FMD with PM2.5 but typically on an acute time scale. Stimulation of the angiotensin-1 receptor (32) or uncoupling of endothelial NO synthase (33) or generation of highly reactive oxygen species via nicotinamide adenine dinucleotide phosphate (reduced) oxidase and Toll-like receptor pathways (34) and Rho kinase activation (35) have been proposed as the relevant vascular mechanisms of PM2.5. We found that long-term exposure to PM2.5 might produce chronic changes in the brachial artery that negatively affects its ability to react to shear stress, primarily from NO-mediated endothelial dysfunction.

Insights into potential mechanisms of PM2.5 exposure on endothelial function are further suggested by a subgroup analysis analyzing antihypertensive medication use. Although limited by subgroup sizes, we found that the use of ACE inhibitors, but not other classes of antihypertensive agents (including angiotensin receptor blockers) or lipid-lowering drugs, seemed to abrogate the association between long-term PM2.5 concentrations and FMD%. Elevated endothelial kinins and NO from ACE inhibition could play a role in mitigating PM2.5-induced endothelial dysfunction ((36),37). Recently, we found that the genetic variation in the renin-angiotensin-aldosterone pathway seemed to modify the effect of traffic-related air pollution on increased left ventricular mass in the MESA cohort (38).

Study strengths and limitations

Major strengths of our study include availability of vascular functional measurements in a large multiethnic cohort with high-quality control standards and excellent data on covariates. We took advantage of the specialized monitoring and sophisticated exposure models from MESA Air to predict spatially resolved, individual-specific estimates at each participant's home (15).

Our study has several limitations. Most importantly, this is a cross-sectional evaluation of images collected on 1 occasion; important information might be gained by a longitudinal study of vascular function. Our findings also may not be generalizable to either normal younger individuals or those with recognized clinical disease. It should be noted that although our long-term exposure estimates are derived from sophisticated exposure modeling methods, they are subject to measurement error and may not fully reflect an individual's long-term exposure because information on specific microenvironments, time-activity patterns, or periods of exposure >1 year before testing is lacking. Future MESA Air exposure metrics will be able to incorporate individual-level data on pollutant infiltration efficiencies and time spent indoors, which will improve these estimates.

FMD is a commonly applied marker for NO-mediated endothelial dysfunction (39). We found consistent associations between PM2.5 and reduced NO-mediated endothelial dysfunction, whether expressed as FMD% (with or without adjustment for 1/BAD) or the simple change in FMDmm. Because MESA did not include nitroglycerin administration, we could not rule out NO-independent endothelial dysfunction in this analysis.

Conclusions

This is the first epidemiological study to suggest that long-term exposure to PM2.5 is associated with decreased endothelial function in a conduit artery independent of cardiovascular risk factors. This finding provides a clue that long-term perturbations of the endothelium-smooth muscle complex from PM2.5 exposure lead to chronic functional changes. These functional changes may partly explain the risk of cardiovascular events previously associated with these environmental exposures.

Results

Characteristics of the study population


Of the 6,814 MESA participants, only a subset of images from the brachial ultrasound examinations was analyzed due to quality control and funding reasons and also only in 5 of the 6 MESA study sites. Similar to the main cohort, our study population of 3,040 subjects included 50% female patients and 18% with less than a high school education. The exclusion of 1 site resulted in a lower proportion of African Americans and higher proportion of Chinese Americans than in the overall MESA cohort. Fifteen percent of the study population used lipid-lowering drugs, and 34% were treated for hypertension (Table 1). Approximately 21% of the participants had moved residential location within 5 years before their brachial examination. Estimated long-term PM2.5 concentrations ranged from 10.6 to 24.7 μg/m3, with an IQR of 3 μg/m3. Short-term PM2.5 concentrations ranged from 1 to 74 μg/m3, with an IQR of 12 μg/m3 (Figure 73_gr1). The mean BAD and FMD% in this cohort were 4.3 ± 0.8 mm and 4.4 ± 2.8%, respectively (Table 2).

Long-term exposure to PM2.5 and its association with reduced NO-mediated endothelial function

We found a significant inverse association between long-term PM2.5 concentrations and FMD% but not with BAD. For every 3-μg/m3 increase in the annual average of PM2.5, FMD% decreased by 0.3% (95% CI: -0.6 to -0.03; p = 0.03) independent of cardiovascular risk factors ((Table 3);Figure 73_gr2). A weaker but highly statistically significant relationship was observed between long-term PM2.5 concentrations and FMD% (-0.1% [95% CI: -0.2 to -0.04]; p = 0.005) without adjustment for sonographer or city (6). Exclusion of sonographers who performed 1 to 2 examinations did not affect these estimates. Restricting analysis to those with a stable residential address for ≥5 years did not affect the association (6). In sensitivity analyses using the FMD% without adjustment for 1/BAD (-0.3% [95% CI: -0.5 to 0.01]; p = 0.06) or the simple FMDmm (-0.01 mm [95% CI: -0.02 to 0.001]; p = 0.07), this negative association persisted.

Short-term PM2.5 concentrations were associated with a small but not statistically significant reduction in FMD% (-0.1% [95% CI: -0.2 to 0.04]; p = 0.4) and BAD (-0.01 mm [95% CI: -0.05 to 0.01]; p = 0.4) for the day 1 before examination when adjusted for risk factors, seasonality, and meteorology (Table 4). Associations with long-term PM2.5 exposure did not significantly change when short-term exposure estimates or temperature or season were included in the model (6).

City-specific differences for vascular outcomes and PM2.5 association

Models stratified according to city demonstrated that the relationship between long-term PM2.5 concentration and reduced FMD% was consistently negative across the 5 communities, except for St. Paul, which had the lowest mean PM2.5 concentrations. Chicago participants showed the largest decrease in FMD% per IQR increase in PM2.5 (Table 3). Similar effect estimates were noted when sonographer was not included as a covariate.

Assessing effect modification of association between long-term PM2.5 exposure and NO-mediated endothelial dysfunction

A significant interaction was found between age and the association between long-term PM2.5 and the FMD% (p < 0.001) but not for BMI or blood pressure. Younger age was associated with a larger magnitude of effect of PM2.5 on reduced endothelial function (FMD% -0.5% [95% CI: -0.8 to -0.2%]; p = 0.001). Stratified analyses suggest that women, never smokers, participants with stages 1 and 2 hypertension, and those not taking antihypertensive medications tend to have a slightly greater negative association of PM2.5 with FMD% (6). Although no category of medication usage demonstrated statistically significant effect modification, the association between long-term PM2.5 and FMD% seemed to be ameliorated by ACE inhibitor use (n = 163); there was a 0.3% increase (95% CI: -1.04 to 1.6) in FMD% per 3-μg/m3 annual increase in PM2.5 (6).

 
 
 
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