Diabetes Enhances Vulnerability to Particulate Air Pollution–Associated Impairment in Vascular Reactivity and Endothelial Function
http://www.100md.com
《循环学杂志》
the Department of Environmental Health, Harvard School of Public Health (M.S.O., A.Z., J.A.S., D.R.G., J.S.)
Channing Laboratory, Harvard Medical School (D.R.G., J.S.)
Beth Israel Deaconess Medical Center (A.V.)
Joslin Diabetes Center (P.A.E, E.S.H.), Boston, Mass.
Abstract
Background— Epidemiological studies suggest that people with diabetes are vulnerable to cardiovascular health effects associated with exposure to particle air pollution. Endothelial and vascular function is impaired in diabetes and may be related to increased cardiovascular risk. We examined whether endothelium-dependent and -independent vascular reactivity was associated with particle exposure in individuals with and without diabetes.
Methods and Results— Study subjects were 270 greater-Boston residents. We measured 24-hour average ambient levels of air pollution (fine particles [PM2.5], particle number, black carbon, and sulfates [SO42–]) 500 m from the patient examination site. Pollutant concentrations were evaluated for associations with vascular reactivity. Linear regressions were fit to the percent change in brachial artery diameter (flow mediated and nitroglycerin mediated), with the particulate pollutant index, apparent temperature, season, age, race, sex, smoking history, and body mass index as predictors. Models were fit to all subjects and then stratified by diagnosed diabetes versus at risk for diabetes. Six-day moving averages of all 4 particle metrics were associated with decreased vascular reactivity among patients with diabetes but not those at risk. Interquartile range increases in SO42– were associated with decreased flow-mediated (–10.7%; 95% CI, –17.3 to –3.5) and nitroglycerin-mediated (–5.4%; 95% CI, –10.5 to –0.1) vascular reactivity among those with diabetes. Black carbon increases were associated with decreased flow-mediated vascular reactivity (–12.6%; 95% CI, –21.7 to –2.4), and PM2.5 was associated with nitroglycerin-mediated reactivity (–7.6%; 95% CI, –12.8 to –2.1). Effects were stronger in type II than type I diabetes.
Conclusions— Diabetes confers vulnerability to particles associated with coal-burning power plants and traffic.
Key Words: diabetes mellitus ; endothelium ; epidemiology ; pollution ; vasculature
Introduction
Particulate air pollution has been associated with daily deaths from cardiovascular disease,1 hospital admissions for cardiovascular and respiratory conditions,2 and adverse effects on cardiovascular function.3,4 People with diabetes were especially sensitive to effects of ambient airborne particles on daily mortality5 and heart disease hospitalizations.6 Endothelial function is impaired in diabetes7 and may be related to increased cardiovascular risk.8 Recent epidemiological evidence links impaired endothelium-dependent vascular reactivity and cardiac events, including cardiovascular death, myocardial infarction, ischemic stroke, and unstable angina, among others.9,10 Results are inconsistent with respect to endothelium-independent reactivity.11
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Given the high prevalence of diabetes in the population,12 research on mechanisms behind the epidemiological observations has substantial public health significance. We hypothesized that particulate air pollution would be associated with endothelial dysfunction and impaired vascular reactivity and that different metrics of particulate air pollution might differ in the strength of the association, providing insights into components or sources of ambient particles most relevant to health effects. This article examines whether people with diabetes are at increased risk from airborne particles through the use of data on 270 individuals residing in metropolitan Boston, Mass.
Methods
Data Sources
Study Participants
Baseline data (before randomization to therapy) from 4 clinical trials conducted at the Joslin Diabetes Center and Beth Israel Deaconess Medical Center in Boston were pooled for this analysis. The 4 trials were designed to evaluate effects of medications and vitamin E supplementation but provided an opportunity to examine air pollution effects in existing data sources. Results from all 4 trials have been published.13–16 Baseline data were collected from May 1998 to January 2000 for one trial. The remaining 3 occurred during calendar years 2000 through 2002. Study participants either had diabetes (type I or type II) or were at risk for diabetes (having impaired glucose tolerance and/or history of diabetes in a first-degree relative). Diabetes and impaired glucose tolerance were defined by American Diabetes Association criteria.16 Data use for this study and the original protocols were approved by the ethics committee or institutional review board at participating institutions. All participants had been recruited through local advertisement and had given written informed consent for the original trial protocol. Procedures followed institutional guidelines.
Participant exclusion criteria were developed for the purposes of the clinical trials. We excluded subjects with overt diabetic complications that might lead to difficulty in measuring or interpreting the vascular outcomes. These complications include severe peripheral somatic neuropathy by screening examination or macroalbuminuria (albumin-to-creatinine ratio >300 μg/mg).7 Additionally, we excluded those who had smoked during the last 6 weeks and those with congestive heart failure, atrial fibrillation, atrial flutter, ventricular tachycardia or fibrillation, stroke or transient ischemic attack, uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >105 mm Hg), severe dyslipidemia (triglycerides >600 mg/dL or cholesterol >350 mg/dL), bypass surgery as a result of peripheral vascular disease, and seizure disorder; those on nonsteroidal antiinflammatory medications or aspirin also were excluded. To avoid influence on brachial artery diameter by antihypertensive14 or lipid-lowering medications,13 we selected subjects not on those medications or those on a stable dose for 6 months, with documented blood pressure and lipid control.
Clinical Measurements
Clinical evaluations occurred in the morning at the Clinical Research Center at the Joslin Diabetes Center. A questionnaire on medical history, medication use, and vital statistics was administered. Weight, height, and body mass index (BMI) were obtained with standard procedures. A physician performed a general physical examination on all subjects after an overnight fast. Volunteers were requested not to take diabetes medications (sulfonylureas or metformin) for the previous 12 hours; those on insulin were asked to omit rapid-acting insulin that morning.
All brachial artery reactivity evaluations were performed at the Beth Israel Deaconess Medical Center under supervision of the same investigator (A.V.) according to published methods.7 High-resolution brachial artery ultrasound was performed with a 10.0-MHz linear-array transducer and an HDI Ultramark 9 system (Advanced Technology Laboratories) following recent guidelines17 with longitudinal images.18 Flow-mediated reactivity was assessed by comparing baseline brachial artery diameter with diameter after reactive hyperemia produced by inflating a pneumatic tourniquet proximal to the brachial artery to 50 mm Hg above systolic pressure for 5 minutes and then deflating it. Pulsed Doppler tracing was recorded for the first 15 seconds after cuff release, followed by a repeated 2D scan for 90 seconds after deflation. Nitroglycerin-mediated reactivity was assessed by studying brachial artery diameter changes 5 minutes after administration of 400 μg sublingual glyceryl trinitrate spray. This test was performed 15 minutes after the reactive hyperemia test and after a new baseline reading was obtained. Previous research showed satisfactory reliability and repeatability of this technique.19
Air Pollution and Meteorology
Air pollution concentrations were measured at a site established by the Harvard School of Public Health, located near (0.5 km) the site where patients were examined. We assessed associations with 4 measures of particulate air pollution: particles with aerodynamic diameter <2.5 μm (PM2.5), particle number (PN), black carbon (BC), and sulfate (SO42–). PM2.5 concentrations were available for the entire study period. PN and SO42– concentrations were available after October 1999; BC concentrations were available after February 1999. Measurements were made following standard techniques and quality control.
PN reflects ultrafine combustion-related particles and indexes fresh, locally generated traffic particles.20 BC is also emitted primarily from traffic-related sources, weighted toward diesel,21 but can reflect both local and aged, transported traffic particles. SO42– concentrations indicate particles from coal-burning power plants, often transported over long distances.22,23
Meteorological data (daily mean temperature, relative humidity, barometric pressure) were obtained from hourly surface observations of the National Weather Service Station at Logan Airport (East Boston) (Earth-Info, Inc).
Statistical Analysis
We merged the clinical and environmental data by date and evaluated associations with each index of airborne particles (one at a time in 1-pollutant models) on the day on which the vascular reactivity measures were taken, controlling for patient characteristics and weather. Additionally, we modeled pollutant exposure from the previous day and lagged moving averages of days 0 through 2, 3, 4, and 5, respectively, for a total of 6 different exposure periods for each of the 4 indexes. We averaged exposures up to 6 days before the examination day on the basis of research showing that multiple day average exposures better predicted cardiovascular outcomes.24 Vascular reactivity outcomes were log transformed to achieve normal distributions. We used linear regression, controlling for patient characteristics selected a priori as likely predictors of vascular reactivity: age, sex, BMI, and race. We tested baseline brachial artery diameter and HbA1c as covariates, but because they were not important confounders, we did not include them in the final models. Because BC and SO42– represent particles from different sources, we repeated the regressions with both these pollutants entered together to ascertain whether independent effects were distinguishable.
In some but not all the clinical trials, patients reported use of alcohol; aspirin; insulin-control, hypertension, diabetes, and lipid-control medications; multivitamins; and hormone replacement therapy or birth control pills. Similarly, not all the trials measured clinical outcomes (blood pressure, fasting blood glucose, cholesterol) simultaneously with brachial artery scans. These covariates could confound the association between air pollution and vascular reactivity if they predicted vascular reactivity and were more or less prevalent among patients seen on higher-pollution days. We did not select them as a priori covariates because they were not measured on all subjects. Instead, we added them to the regressions, one at a time. We compared the association between air pollution (6-day moving average) and vascular reactivity with and without these covariates to assess confounding.
To control for potential impacts of weather, we included apparent temperature (AT), an index of thermal comfort calculated from dew point and temperature, in the models.25 AT is calculated as follows: AT=–2.653+(0.994xTa)+(0.0153xTd2), where Ta is air temperature and Td is dew point temperature. Dummy variables for 4 seasons were also included because vascular reactivity may be affected by season.
Initially, we analyzed all subjects in one model, using an indicator variable for disease status. Then, we fit models stratified by diabetes, at risk for diabetes by virtue of having impaired glucose tolerance and/or a family history of diabetes, and then diabetes type.
Results
A total of 270 subjects had complete information on the outcomes and covariates (Table 1). Most self-classified as white and had been diagnosed with type I or type II diabetes at the time of examination. About 58% were male, and most were >50 years of age. Those with type II diabetes were more likely to be male and older and to have a history of smoking and higher BMI than those with type I diabetes.
Consistent with previous studies, subjects with diabetes showed less vascular reactivity, both flow and nitroglycerin mediated, than did those at risk for the condition (Table 2). Reactivity was lower for type II than type I diabetes.
Air pollution levels in Boston are relatively low; the maximum PM2.5 level (40 μg/m3) was well within the US national standard of 65 μg/m3 (24-hour average)26 (Table 3). Only PM2.5 and weather data were available for every day the patients were seen; a smaller sample was available for the 3 other pollutants as described previously. The strongest significant Pearson’s correlations were among BC, PM2.5, and SO42– (range, 0.55 to 0.80). Other particle metrics were weakly correlated with PN (–0.11 to 0.19), although PN was significantly negatively correlated with apparent temperature (0.77).
When all participants were examined together, negative associations were seen between all particle measures and flow-mediated vascular reactivity and all but one measure and nitroglycerin-mediated reactivity (Table 4). However, the only significant associations were between SO42– particles and flow-mediated reactivity and between nitroglycerin-mediated reactivity and PM2.5. When data were stratified by diabetes status, a more complex pattern appeared. In people at risk of developing diabetes, all associations with flow-mediated reactivity were positive but nonsignificant. Nitroglycerin-mediated reactivity was positively and significantly associated with PN. For people with diabetes, negative associations were seen between all particle measures and both measures of vascular reactivity. The associations were significant for SO42– and both forms of reactivity. In addition, significant associations were seen for BC and flow-mediated reactivity and for PM2.5 and nitroglycerin-mediated reactivity. The association for type II diabetes drove these results (Table 5). Although precision dropped, associations remained significant and sometimes greater for SO42–, BC, and PM2.5 among patients with type II diabetes.
Although the strongest associations were with the 6-day moving average, similar patterns and quantitatively similar results appeared with other lags (Table 6). We also analyzed associations using only days when all 4 particle metrics were available (equal n for the regressions). The magnitude of the associations was not sensitive to missing days, so we report effects and sample size for the complete data available.
In models including both SO42– and BC, for subjects with diabetes, effects of SO42– on flow-mediated dilation remained negative but were slightly diminished by inclusion of BC; they remained significant for all exposure periods except lag 0 and the 6-day moving average. For the 6-day moving average, the effect dropped from a –10.7% change in diameter (95% CI, –17.3 to –3.5) to –8.3% (95% CI, –16.4 to 0.6). For nitroglycerin-mediated dilation, associations with SO42–, controlling for BC, remained negative for all but one lag, and all were nonsignificant. The pattern of change for BC effects, controlling for SO42–, was similar but with somewhat greater reductions.
In analyses of confounding by medications, clinical covariates, supplements, or behaviors reported by patients with diabetes, few estimates changed substantially. When hormone replacement therapy or birth control pill use was controlled for in the 51 women with data, BC, SO42–, and PM2.5 had stronger associations with reduced vascular reactivity. Adjusting for alcohol use also strengthened the inverse association between both forms of vascular reactivity and BC and PM2.5. For the results shown in Table 4, the point estimates of effect remained approximately the same when controlling for HbA1c, and the precision of the estimates was not affected, except for the estimate of the effect of PM2.5 on flow-mediated dilation among those with diabetes, which became slightly stronger and significant with HbA1c included (–8.24%; 95% CI, –15.53 to –0.34) compared with the unadjusted estimate of –7.6% (95% CI, –14.9 to 0.4). No other covariates analyzed had substantial or consistent confounding effects on the associations.
Discussion
We observed an inverse relationship between air pollution and both flow- and nitroglycerin-mediated reactivity for people with type II diabetes. These results provide evidence that endothelium-dependent and -independent mechanisms may contribute to systemic vascular and perhaps cardiovascular effects of pollution in people with type II diabetes. To the best of our knowledge, this is the first evidence showing that ambient levels of particulate matter can alter vasomotor function in humans.
Relatively few studies on air pollution and cardiovascular end points have evaluated effects of particles from different sources. Our strongest and most robust finding was the association between reduced flow-mediated dilation and SO42– particles, which represent primarily long-range transport from coal-burning power plants in the Boston area.23 Although epidemiological results examining health impacts of SO42– are not yet conclusive, the present findings provide additional support to studies showing associations between cardiovascular morbidity and mortality in areas with higher SO42– concentrations.27,28
Our study contrasts with results of a recent chamber exposure study of healthy adults that found particle-associated reduction of basal brachial artery diameter, but not flow-mediated and nitroglycerin-mediated dilation, after inhalation of 150 μg/m3 of concentrated ambient fine particles and ozone (120 ppb) for 2 hours compared with inhalation of filtered air.4 Our findings may differ from those of the chamber study because of the sensitivity of the subjects with diabetes in our study. Additionally, our exposure period ranged from a 24-hour average to a moving average of 6 days; longer exposures may be required to elicit changes in vascular reactivity.
Because particle pollution exposure was associated with reductions in both flow-mediated and nitroglycerin-mediated dilation among the individuals with diabetes, the mechanism for its effect could lie in endothelial dysfunction, smooth muscle dysfunction, or (more likely) both. Flow-mediated response depends on both the endothelium and smooth muscle. The acute response to an environmental exposure can be reduced because of endothelial factors, including less endothelial production of nitric oxide (NO) or more quenching of NO by an excess of oxidative radicals (superoxide anions) resulting from particle-associated inflammation and subsequent oxidative stress.29–31 Both the flow-mediated and nitroglycerin-mediated responses may be attenuated if the smooth muscle response to NO is reduced. This may occur, for example, with changes in responsiveness to guanylate cyclase activation or increases in angiotensin II formation.32
People with type II diabetes may be more vulnerable to the acute effects of particles for many reasons, including chronic inflammation/oxidative stress quenching NO,33,34 imbalances in vasoactive mediators in the arterial tissue,35 or vascular remodeling that can result in impaired flow-mediated dilation.36–38
Circulating angiotensin II and endothelin-1 may already be elevated in type II diabetes,39,40 and a further particle-associated increase in superoxide flux on the endothelium may overwhelm the system, quench NO, and reduce the flow-mediated response. Hyperglycemia itself can induce oxidative stress and result in reduced NO availability.41 Chronic inflammation and oxidative stress are more prominent in type II diabetes compared with type I diabetes. These mechanisms may be involved in increasing individual sensitivity to air pollution, so the higher associations with vascular reactivity among those with type II, but not type I, diabetes in this study are consistent with that mechanistic theory. Those who were "at risk" also did not respond to pollution, which is consistent with the observation that the number of years since diagnosis of overt diabetes predicts the risk of finding systemic and coronary vascular effects of the disease42,43; glucose intolerance alone may not confer sufficient risk to be sensitive to air pollution.7
Environmental tobacco smoke exposure, which includes fine particles, is also associated with inflammation, oxidative stress, and impaired vascular function.44 Epidemiological studies can look at particle-associated physiological outcomes that may reflect certain mechanisms for vascular effects of particles, giving direction to animal experiments that allow isolation of the various compartments that may be involved in the particle response. Data from animal and epidemiological studies support the association of particle pollution with inflammatory processes leading to oxidative stress45 and with autonomic dysfunction.46 Our epidemiological study suggests that both these mechanisms may be at work in the particle effect on the vasculature and informs us as to what experiments might be relevant in the animal laboratory. Animal models that isolate the endothelial response from the smooth muscle response to particles are required to evaluate which pathways in the production and quenching of NO or the response of the smooth muscle to NO are being influenced.
As to the clinical import of our findings, flow-mediated dilation has been strongly correlated (r=0.78, P<0.001) with flow-mediated coronary artery responses,47,48 even without adjustment for nitroglycerin-mediated responses. Reduced flow-mediated dilation has been associated with increased C-reactive protein concentrations.49 Thus, if particle exposure reduces flow-mediated dilation, it may also reduce flow-mediated coronary artery responses and increase the risk of coronary occlusion in vulnerable patients.
We did not see pollution-associated impairment in reactivity in those at-risk for diabetes, except for PN. Although it is possible that the isolated positive association of PN with increased reactivity suggests different responses rather than no response for those without overt diabetes, it is more likely that the limited sample size of at-risk subjects resulted in a chance finding. A larger sample would be necessary to confirm the observed associations among this group. Another limitation of our study is potential error from the use of ambient air pollution measurements to represent personal exposures. PM2.5 and SO42– are fairly homogenously distributed in the eastern United States,50 specifically in south Boston,51 so it is reasonable that a single stationary ambient monitoring site will characterize PM2.5 and SO42– exposures of individuals living in the area. A 1995 study found "remarkable" similarities in SO42– concentrations in rural western Massachusetts and in Boston 2 km from the Harvard site.52 Hence, SO42– should be a good indicator of exposure to ambient-origin particles even for subjects living outside Boston. The consistent levels of SO42– across New England support the observation that these particles represent long-range transported "background" particles not generated in Massachusetts. However, PN and carbonaceous particle concentrations are more spatially variable and concentrated near roadways and urban areas.52,53 Measurement error may be greater for these particle measures compared with PM2.5 and SO42–, given likely variation in time-activity patterns of study participants. Thus, the lack of associations between vascular reactivity and PN may be more attributable to exposure misclassification than lack of biological activity of these particles. To date, few studies have evaluated health responses to PN exposures, and the present effort contributes to this relatively limited database of knowledge.54
Although recent research has validated use of ambient monitors for representing day-to-day exposures to particles,55,56 we had data on only 1 day per person. Air pollution levels were measured on numerous days during the study period and represent a range of exposure, but home characteristics and activities affecting personal exposure to particles may vary between study participants. The relative importance of between-subject and between-day exposure variability is unknown for this study. However, for exposure misclassification to have biased our results, home characteristics and/or activity patterns of subjects with diabetes versus those at risk would have had to differ substantially and systematically. We think it is unlikely that differential misclassification of exposure would be great enough to explain the observed effect modification by diabetes status. Because subjects lived at different distances from the monitor, we reran the regressions, restricting to individuals from ZIP codes within 40 km; results remained unchanged. We also evaluated whether the fact that only people with diabetes were enrolled in the studies before 2001 might have biased the results because of some systematic difference in air pollution exposure by period. Again, we found the patterns of association to be unchanged when we ran regressions for only subjects examined during the same time period.
We analyzed only 1 day’s observation for each subject, and daily fluctuations in vascular reactivity may vary significantly within a person. Additionally, we had a limited sample size of at-risk subjects and subjects with type I diabetes, so future studies with greater power are needed to validate our results. The model covariates may not capture all individual characteristics that influence vascular reactivity. An analysis of repeated reactivity measures, including measurement of additional clinical covariates simultaneous with brachial artery scans, will enable better control of within-individual variation in response and will increase confidence in the observed associations.
Although patients with diabetes are at overall increased risk for cardiovascular morbidity34 and for pollution-related cardiovascular morbidity,57 the relationship between air pollution and vascular reactivity in diabetes has not previously been examined, nor has effect modification by type of diabetes been studied. Although we measured vascular reactivity in the brachial arteries, these responses correlate well with those of the coronary arteries,47,58 suggesting they are a valid marker of cardiovascular risk.8 Our results link pollution exposure and physiological responses known to be along the pathway of adverse cardiovascular outcomes. We saw significant associations between vascular reactivity and exposure to particulate pollution, especially SO42–, and greater responses among people with diabetes. Higher rates of cardiac hospitalization and mortality on high-particulate-pollution days among people with diabetes may be partially explained by impairments in endothelial function, vascular smooth muscle function, and subsequent coronary artery vascular responses.
Acknowledgments
This work was supported in part by grant 2 T32 ES07069-24 from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIEHS, NIH. Additional funding sources include grants NIEHS ES00002, NIEHS P01 ES009825, and EPAR827353 and the Robert Wood Johnson Foundation Health & Society Scholars Program. Support for the clinical trials includes grants to Dr Horton from Pfizer Inc. and the American Diabetes Association; grants to Dr Veves from Parke Davis Inc, Pfizer, Inc, and the Juvenile Diabetes Foundation International; NIH grant 2P30-DK-36836; NIH grant RR 01032 to the Beth Israel Deaconess Medical Center General Clinical Research Center; a William Randolph Hearst Fellowship (William Randolph Hearst Foundation); and a Mary K. Iacocca Fellowship (Iacocca Foundation). We thank Tania Kotlov, Steven J. Melly, Sung Kyun Park, Caitlin Sparks, and Elizabeth Tiani for their contributions.
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Zanobetti A, Schwartz J. Are diabetics more susceptible to the health effects of airborne particles;. Am J Resp Crit Care. 2001; 164: 831–833.
Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995; 26: 1235–1241.(Marie S. O’Neill, PhD; Ar)
Channing Laboratory, Harvard Medical School (D.R.G., J.S.)
Beth Israel Deaconess Medical Center (A.V.)
Joslin Diabetes Center (P.A.E, E.S.H.), Boston, Mass.
Abstract
Background— Epidemiological studies suggest that people with diabetes are vulnerable to cardiovascular health effects associated with exposure to particle air pollution. Endothelial and vascular function is impaired in diabetes and may be related to increased cardiovascular risk. We examined whether endothelium-dependent and -independent vascular reactivity was associated with particle exposure in individuals with and without diabetes.
Methods and Results— Study subjects were 270 greater-Boston residents. We measured 24-hour average ambient levels of air pollution (fine particles [PM2.5], particle number, black carbon, and sulfates [SO42–]) 500 m from the patient examination site. Pollutant concentrations were evaluated for associations with vascular reactivity. Linear regressions were fit to the percent change in brachial artery diameter (flow mediated and nitroglycerin mediated), with the particulate pollutant index, apparent temperature, season, age, race, sex, smoking history, and body mass index as predictors. Models were fit to all subjects and then stratified by diagnosed diabetes versus at risk for diabetes. Six-day moving averages of all 4 particle metrics were associated with decreased vascular reactivity among patients with diabetes but not those at risk. Interquartile range increases in SO42– were associated with decreased flow-mediated (–10.7%; 95% CI, –17.3 to –3.5) and nitroglycerin-mediated (–5.4%; 95% CI, –10.5 to –0.1) vascular reactivity among those with diabetes. Black carbon increases were associated with decreased flow-mediated vascular reactivity (–12.6%; 95% CI, –21.7 to –2.4), and PM2.5 was associated with nitroglycerin-mediated reactivity (–7.6%; 95% CI, –12.8 to –2.1). Effects were stronger in type II than type I diabetes.
Conclusions— Diabetes confers vulnerability to particles associated with coal-burning power plants and traffic.
Key Words: diabetes mellitus ; endothelium ; epidemiology ; pollution ; vasculature
Introduction
Particulate air pollution has been associated with daily deaths from cardiovascular disease,1 hospital admissions for cardiovascular and respiratory conditions,2 and adverse effects on cardiovascular function.3,4 People with diabetes were especially sensitive to effects of ambient airborne particles on daily mortality5 and heart disease hospitalizations.6 Endothelial function is impaired in diabetes7 and may be related to increased cardiovascular risk.8 Recent epidemiological evidence links impaired endothelium-dependent vascular reactivity and cardiac events, including cardiovascular death, myocardial infarction, ischemic stroke, and unstable angina, among others.9,10 Results are inconsistent with respect to endothelium-independent reactivity.11
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Given the high prevalence of diabetes in the population,12 research on mechanisms behind the epidemiological observations has substantial public health significance. We hypothesized that particulate air pollution would be associated with endothelial dysfunction and impaired vascular reactivity and that different metrics of particulate air pollution might differ in the strength of the association, providing insights into components or sources of ambient particles most relevant to health effects. This article examines whether people with diabetes are at increased risk from airborne particles through the use of data on 270 individuals residing in metropolitan Boston, Mass.
Methods
Data Sources
Study Participants
Baseline data (before randomization to therapy) from 4 clinical trials conducted at the Joslin Diabetes Center and Beth Israel Deaconess Medical Center in Boston were pooled for this analysis. The 4 trials were designed to evaluate effects of medications and vitamin E supplementation but provided an opportunity to examine air pollution effects in existing data sources. Results from all 4 trials have been published.13–16 Baseline data were collected from May 1998 to January 2000 for one trial. The remaining 3 occurred during calendar years 2000 through 2002. Study participants either had diabetes (type I or type II) or were at risk for diabetes (having impaired glucose tolerance and/or history of diabetes in a first-degree relative). Diabetes and impaired glucose tolerance were defined by American Diabetes Association criteria.16 Data use for this study and the original protocols were approved by the ethics committee or institutional review board at participating institutions. All participants had been recruited through local advertisement and had given written informed consent for the original trial protocol. Procedures followed institutional guidelines.
Participant exclusion criteria were developed for the purposes of the clinical trials. We excluded subjects with overt diabetic complications that might lead to difficulty in measuring or interpreting the vascular outcomes. These complications include severe peripheral somatic neuropathy by screening examination or macroalbuminuria (albumin-to-creatinine ratio >300 μg/mg).7 Additionally, we excluded those who had smoked during the last 6 weeks and those with congestive heart failure, atrial fibrillation, atrial flutter, ventricular tachycardia or fibrillation, stroke or transient ischemic attack, uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >105 mm Hg), severe dyslipidemia (triglycerides >600 mg/dL or cholesterol >350 mg/dL), bypass surgery as a result of peripheral vascular disease, and seizure disorder; those on nonsteroidal antiinflammatory medications or aspirin also were excluded. To avoid influence on brachial artery diameter by antihypertensive14 or lipid-lowering medications,13 we selected subjects not on those medications or those on a stable dose for 6 months, with documented blood pressure and lipid control.
Clinical Measurements
Clinical evaluations occurred in the morning at the Clinical Research Center at the Joslin Diabetes Center. A questionnaire on medical history, medication use, and vital statistics was administered. Weight, height, and body mass index (BMI) were obtained with standard procedures. A physician performed a general physical examination on all subjects after an overnight fast. Volunteers were requested not to take diabetes medications (sulfonylureas or metformin) for the previous 12 hours; those on insulin were asked to omit rapid-acting insulin that morning.
All brachial artery reactivity evaluations were performed at the Beth Israel Deaconess Medical Center under supervision of the same investigator (A.V.) according to published methods.7 High-resolution brachial artery ultrasound was performed with a 10.0-MHz linear-array transducer and an HDI Ultramark 9 system (Advanced Technology Laboratories) following recent guidelines17 with longitudinal images.18 Flow-mediated reactivity was assessed by comparing baseline brachial artery diameter with diameter after reactive hyperemia produced by inflating a pneumatic tourniquet proximal to the brachial artery to 50 mm Hg above systolic pressure for 5 minutes and then deflating it. Pulsed Doppler tracing was recorded for the first 15 seconds after cuff release, followed by a repeated 2D scan for 90 seconds after deflation. Nitroglycerin-mediated reactivity was assessed by studying brachial artery diameter changes 5 minutes after administration of 400 μg sublingual glyceryl trinitrate spray. This test was performed 15 minutes after the reactive hyperemia test and after a new baseline reading was obtained. Previous research showed satisfactory reliability and repeatability of this technique.19
Air Pollution and Meteorology
Air pollution concentrations were measured at a site established by the Harvard School of Public Health, located near (0.5 km) the site where patients were examined. We assessed associations with 4 measures of particulate air pollution: particles with aerodynamic diameter <2.5 μm (PM2.5), particle number (PN), black carbon (BC), and sulfate (SO42–). PM2.5 concentrations were available for the entire study period. PN and SO42– concentrations were available after October 1999; BC concentrations were available after February 1999. Measurements were made following standard techniques and quality control.
PN reflects ultrafine combustion-related particles and indexes fresh, locally generated traffic particles.20 BC is also emitted primarily from traffic-related sources, weighted toward diesel,21 but can reflect both local and aged, transported traffic particles. SO42– concentrations indicate particles from coal-burning power plants, often transported over long distances.22,23
Meteorological data (daily mean temperature, relative humidity, barometric pressure) were obtained from hourly surface observations of the National Weather Service Station at Logan Airport (East Boston) (Earth-Info, Inc).
Statistical Analysis
We merged the clinical and environmental data by date and evaluated associations with each index of airborne particles (one at a time in 1-pollutant models) on the day on which the vascular reactivity measures were taken, controlling for patient characteristics and weather. Additionally, we modeled pollutant exposure from the previous day and lagged moving averages of days 0 through 2, 3, 4, and 5, respectively, for a total of 6 different exposure periods for each of the 4 indexes. We averaged exposures up to 6 days before the examination day on the basis of research showing that multiple day average exposures better predicted cardiovascular outcomes.24 Vascular reactivity outcomes were log transformed to achieve normal distributions. We used linear regression, controlling for patient characteristics selected a priori as likely predictors of vascular reactivity: age, sex, BMI, and race. We tested baseline brachial artery diameter and HbA1c as covariates, but because they were not important confounders, we did not include them in the final models. Because BC and SO42– represent particles from different sources, we repeated the regressions with both these pollutants entered together to ascertain whether independent effects were distinguishable.
In some but not all the clinical trials, patients reported use of alcohol; aspirin; insulin-control, hypertension, diabetes, and lipid-control medications; multivitamins; and hormone replacement therapy or birth control pills. Similarly, not all the trials measured clinical outcomes (blood pressure, fasting blood glucose, cholesterol) simultaneously with brachial artery scans. These covariates could confound the association between air pollution and vascular reactivity if they predicted vascular reactivity and were more or less prevalent among patients seen on higher-pollution days. We did not select them as a priori covariates because they were not measured on all subjects. Instead, we added them to the regressions, one at a time. We compared the association between air pollution (6-day moving average) and vascular reactivity with and without these covariates to assess confounding.
To control for potential impacts of weather, we included apparent temperature (AT), an index of thermal comfort calculated from dew point and temperature, in the models.25 AT is calculated as follows: AT=–2.653+(0.994xTa)+(0.0153xTd2), where Ta is air temperature and Td is dew point temperature. Dummy variables for 4 seasons were also included because vascular reactivity may be affected by season.
Initially, we analyzed all subjects in one model, using an indicator variable for disease status. Then, we fit models stratified by diabetes, at risk for diabetes by virtue of having impaired glucose tolerance and/or a family history of diabetes, and then diabetes type.
Results
A total of 270 subjects had complete information on the outcomes and covariates (Table 1). Most self-classified as white and had been diagnosed with type I or type II diabetes at the time of examination. About 58% were male, and most were >50 years of age. Those with type II diabetes were more likely to be male and older and to have a history of smoking and higher BMI than those with type I diabetes.
Consistent with previous studies, subjects with diabetes showed less vascular reactivity, both flow and nitroglycerin mediated, than did those at risk for the condition (Table 2). Reactivity was lower for type II than type I diabetes.
Air pollution levels in Boston are relatively low; the maximum PM2.5 level (40 μg/m3) was well within the US national standard of 65 μg/m3 (24-hour average)26 (Table 3). Only PM2.5 and weather data were available for every day the patients were seen; a smaller sample was available for the 3 other pollutants as described previously. The strongest significant Pearson’s correlations were among BC, PM2.5, and SO42– (range, 0.55 to 0.80). Other particle metrics were weakly correlated with PN (–0.11 to 0.19), although PN was significantly negatively correlated with apparent temperature (0.77).
When all participants were examined together, negative associations were seen between all particle measures and flow-mediated vascular reactivity and all but one measure and nitroglycerin-mediated reactivity (Table 4). However, the only significant associations were between SO42– particles and flow-mediated reactivity and between nitroglycerin-mediated reactivity and PM2.5. When data were stratified by diabetes status, a more complex pattern appeared. In people at risk of developing diabetes, all associations with flow-mediated reactivity were positive but nonsignificant. Nitroglycerin-mediated reactivity was positively and significantly associated with PN. For people with diabetes, negative associations were seen between all particle measures and both measures of vascular reactivity. The associations were significant for SO42– and both forms of reactivity. In addition, significant associations were seen for BC and flow-mediated reactivity and for PM2.5 and nitroglycerin-mediated reactivity. The association for type II diabetes drove these results (Table 5). Although precision dropped, associations remained significant and sometimes greater for SO42–, BC, and PM2.5 among patients with type II diabetes.
Although the strongest associations were with the 6-day moving average, similar patterns and quantitatively similar results appeared with other lags (Table 6). We also analyzed associations using only days when all 4 particle metrics were available (equal n for the regressions). The magnitude of the associations was not sensitive to missing days, so we report effects and sample size for the complete data available.
In models including both SO42– and BC, for subjects with diabetes, effects of SO42– on flow-mediated dilation remained negative but were slightly diminished by inclusion of BC; they remained significant for all exposure periods except lag 0 and the 6-day moving average. For the 6-day moving average, the effect dropped from a –10.7% change in diameter (95% CI, –17.3 to –3.5) to –8.3% (95% CI, –16.4 to 0.6). For nitroglycerin-mediated dilation, associations with SO42–, controlling for BC, remained negative for all but one lag, and all were nonsignificant. The pattern of change for BC effects, controlling for SO42–, was similar but with somewhat greater reductions.
In analyses of confounding by medications, clinical covariates, supplements, or behaviors reported by patients with diabetes, few estimates changed substantially. When hormone replacement therapy or birth control pill use was controlled for in the 51 women with data, BC, SO42–, and PM2.5 had stronger associations with reduced vascular reactivity. Adjusting for alcohol use also strengthened the inverse association between both forms of vascular reactivity and BC and PM2.5. For the results shown in Table 4, the point estimates of effect remained approximately the same when controlling for HbA1c, and the precision of the estimates was not affected, except for the estimate of the effect of PM2.5 on flow-mediated dilation among those with diabetes, which became slightly stronger and significant with HbA1c included (–8.24%; 95% CI, –15.53 to –0.34) compared with the unadjusted estimate of –7.6% (95% CI, –14.9 to 0.4). No other covariates analyzed had substantial or consistent confounding effects on the associations.
Discussion
We observed an inverse relationship between air pollution and both flow- and nitroglycerin-mediated reactivity for people with type II diabetes. These results provide evidence that endothelium-dependent and -independent mechanisms may contribute to systemic vascular and perhaps cardiovascular effects of pollution in people with type II diabetes. To the best of our knowledge, this is the first evidence showing that ambient levels of particulate matter can alter vasomotor function in humans.
Relatively few studies on air pollution and cardiovascular end points have evaluated effects of particles from different sources. Our strongest and most robust finding was the association between reduced flow-mediated dilation and SO42– particles, which represent primarily long-range transport from coal-burning power plants in the Boston area.23 Although epidemiological results examining health impacts of SO42– are not yet conclusive, the present findings provide additional support to studies showing associations between cardiovascular morbidity and mortality in areas with higher SO42– concentrations.27,28
Our study contrasts with results of a recent chamber exposure study of healthy adults that found particle-associated reduction of basal brachial artery diameter, but not flow-mediated and nitroglycerin-mediated dilation, after inhalation of 150 μg/m3 of concentrated ambient fine particles and ozone (120 ppb) for 2 hours compared with inhalation of filtered air.4 Our findings may differ from those of the chamber study because of the sensitivity of the subjects with diabetes in our study. Additionally, our exposure period ranged from a 24-hour average to a moving average of 6 days; longer exposures may be required to elicit changes in vascular reactivity.
Because particle pollution exposure was associated with reductions in both flow-mediated and nitroglycerin-mediated dilation among the individuals with diabetes, the mechanism for its effect could lie in endothelial dysfunction, smooth muscle dysfunction, or (more likely) both. Flow-mediated response depends on both the endothelium and smooth muscle. The acute response to an environmental exposure can be reduced because of endothelial factors, including less endothelial production of nitric oxide (NO) or more quenching of NO by an excess of oxidative radicals (superoxide anions) resulting from particle-associated inflammation and subsequent oxidative stress.29–31 Both the flow-mediated and nitroglycerin-mediated responses may be attenuated if the smooth muscle response to NO is reduced. This may occur, for example, with changes in responsiveness to guanylate cyclase activation or increases in angiotensin II formation.32
People with type II diabetes may be more vulnerable to the acute effects of particles for many reasons, including chronic inflammation/oxidative stress quenching NO,33,34 imbalances in vasoactive mediators in the arterial tissue,35 or vascular remodeling that can result in impaired flow-mediated dilation.36–38
Circulating angiotensin II and endothelin-1 may already be elevated in type II diabetes,39,40 and a further particle-associated increase in superoxide flux on the endothelium may overwhelm the system, quench NO, and reduce the flow-mediated response. Hyperglycemia itself can induce oxidative stress and result in reduced NO availability.41 Chronic inflammation and oxidative stress are more prominent in type II diabetes compared with type I diabetes. These mechanisms may be involved in increasing individual sensitivity to air pollution, so the higher associations with vascular reactivity among those with type II, but not type I, diabetes in this study are consistent with that mechanistic theory. Those who were "at risk" also did not respond to pollution, which is consistent with the observation that the number of years since diagnosis of overt diabetes predicts the risk of finding systemic and coronary vascular effects of the disease42,43; glucose intolerance alone may not confer sufficient risk to be sensitive to air pollution.7
Environmental tobacco smoke exposure, which includes fine particles, is also associated with inflammation, oxidative stress, and impaired vascular function.44 Epidemiological studies can look at particle-associated physiological outcomes that may reflect certain mechanisms for vascular effects of particles, giving direction to animal experiments that allow isolation of the various compartments that may be involved in the particle response. Data from animal and epidemiological studies support the association of particle pollution with inflammatory processes leading to oxidative stress45 and with autonomic dysfunction.46 Our epidemiological study suggests that both these mechanisms may be at work in the particle effect on the vasculature and informs us as to what experiments might be relevant in the animal laboratory. Animal models that isolate the endothelial response from the smooth muscle response to particles are required to evaluate which pathways in the production and quenching of NO or the response of the smooth muscle to NO are being influenced.
As to the clinical import of our findings, flow-mediated dilation has been strongly correlated (r=0.78, P<0.001) with flow-mediated coronary artery responses,47,48 even without adjustment for nitroglycerin-mediated responses. Reduced flow-mediated dilation has been associated with increased C-reactive protein concentrations.49 Thus, if particle exposure reduces flow-mediated dilation, it may also reduce flow-mediated coronary artery responses and increase the risk of coronary occlusion in vulnerable patients.
We did not see pollution-associated impairment in reactivity in those at-risk for diabetes, except for PN. Although it is possible that the isolated positive association of PN with increased reactivity suggests different responses rather than no response for those without overt diabetes, it is more likely that the limited sample size of at-risk subjects resulted in a chance finding. A larger sample would be necessary to confirm the observed associations among this group. Another limitation of our study is potential error from the use of ambient air pollution measurements to represent personal exposures. PM2.5 and SO42– are fairly homogenously distributed in the eastern United States,50 specifically in south Boston,51 so it is reasonable that a single stationary ambient monitoring site will characterize PM2.5 and SO42– exposures of individuals living in the area. A 1995 study found "remarkable" similarities in SO42– concentrations in rural western Massachusetts and in Boston 2 km from the Harvard site.52 Hence, SO42– should be a good indicator of exposure to ambient-origin particles even for subjects living outside Boston. The consistent levels of SO42– across New England support the observation that these particles represent long-range transported "background" particles not generated in Massachusetts. However, PN and carbonaceous particle concentrations are more spatially variable and concentrated near roadways and urban areas.52,53 Measurement error may be greater for these particle measures compared with PM2.5 and SO42–, given likely variation in time-activity patterns of study participants. Thus, the lack of associations between vascular reactivity and PN may be more attributable to exposure misclassification than lack of biological activity of these particles. To date, few studies have evaluated health responses to PN exposures, and the present effort contributes to this relatively limited database of knowledge.54
Although recent research has validated use of ambient monitors for representing day-to-day exposures to particles,55,56 we had data on only 1 day per person. Air pollution levels were measured on numerous days during the study period and represent a range of exposure, but home characteristics and activities affecting personal exposure to particles may vary between study participants. The relative importance of between-subject and between-day exposure variability is unknown for this study. However, for exposure misclassification to have biased our results, home characteristics and/or activity patterns of subjects with diabetes versus those at risk would have had to differ substantially and systematically. We think it is unlikely that differential misclassification of exposure would be great enough to explain the observed effect modification by diabetes status. Because subjects lived at different distances from the monitor, we reran the regressions, restricting to individuals from ZIP codes within 40 km; results remained unchanged. We also evaluated whether the fact that only people with diabetes were enrolled in the studies before 2001 might have biased the results because of some systematic difference in air pollution exposure by period. Again, we found the patterns of association to be unchanged when we ran regressions for only subjects examined during the same time period.
We analyzed only 1 day’s observation for each subject, and daily fluctuations in vascular reactivity may vary significantly within a person. Additionally, we had a limited sample size of at-risk subjects and subjects with type I diabetes, so future studies with greater power are needed to validate our results. The model covariates may not capture all individual characteristics that influence vascular reactivity. An analysis of repeated reactivity measures, including measurement of additional clinical covariates simultaneous with brachial artery scans, will enable better control of within-individual variation in response and will increase confidence in the observed associations.
Although patients with diabetes are at overall increased risk for cardiovascular morbidity34 and for pollution-related cardiovascular morbidity,57 the relationship between air pollution and vascular reactivity in diabetes has not previously been examined, nor has effect modification by type of diabetes been studied. Although we measured vascular reactivity in the brachial arteries, these responses correlate well with those of the coronary arteries,47,58 suggesting they are a valid marker of cardiovascular risk.8 Our results link pollution exposure and physiological responses known to be along the pathway of adverse cardiovascular outcomes. We saw significant associations between vascular reactivity and exposure to particulate pollution, especially SO42–, and greater responses among people with diabetes. Higher rates of cardiac hospitalization and mortality on high-particulate-pollution days among people with diabetes may be partially explained by impairments in endothelial function, vascular smooth muscle function, and subsequent coronary artery vascular responses.
Acknowledgments
This work was supported in part by grant 2 T32 ES07069-24 from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIEHS, NIH. Additional funding sources include grants NIEHS ES00002, NIEHS P01 ES009825, and EPAR827353 and the Robert Wood Johnson Foundation Health & Society Scholars Program. Support for the clinical trials includes grants to Dr Horton from Pfizer Inc. and the American Diabetes Association; grants to Dr Veves from Parke Davis Inc, Pfizer, Inc, and the Juvenile Diabetes Foundation International; NIH grant 2P30-DK-36836; NIH grant RR 01032 to the Beth Israel Deaconess Medical Center General Clinical Research Center; a William Randolph Hearst Fellowship (William Randolph Hearst Foundation); and a Mary K. Iacocca Fellowship (Iacocca Foundation). We thank Tania Kotlov, Steven J. Melly, Sung Kyun Park, Caitlin Sparks, and Elizabeth Tiani for their contributions.
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