Carol A. Trenga

Diesel Exhaust Inhalation Elicits Acute Vasoconstriction in Vivo

Background Traffic-related air pollution is consistently associated with cardiovascular morbidity and mortality. Recent human and animal studies suggest that exposure to air pollutants affects vascular function. Diesel exhaust (DE) is a major source of traffic-related air pollution. Objectives Our goal was to study the effects of short-term exposure to DE on vascular reactivity and on mediators of vascular tone. Methods In a double-blind, crossover, controlled exposure study, 27 adult volunteers (10 healthy and 17 with metabolic syndrome) were exposed in randomized order to filtered air (FA) and each of two levels of diluted DE (100 or 200 μg/m3 of fine particulate matter) in 2-hr sessions. Before and after each exposure, we assessed the brachial artery diameter (BAd) by B-mode ultrasound and collected blood samples for endothelin-1 (ET-1) and catecholamines. Postexposure we also assessed endothelium-dependent flow-mediated dilation (FMD). Results Compared with FA, DE at 200 μg/m3 elicited a decrease in BAd (0.11 mm; 95% confidence interval, 0.02–0.18), and the effect appeared linearly dose related with a smaller effect at 100 μg/m3. Plasma levels of ET-1 increased after 200 μg/m3 DE but not after FA (p = 0.01). There was no consistent impact of DE on plasma catecholamines or FMD. Conclusions These results demonstrate that short-term exposure to DE is associated with acute endothelial response and vasoconstriction of a conductance artery. Elucidation of the signaling pathways controlling vascular tone that underlie this observation requires further study.

Pulmonary Effects of Indoor- and Outdoor-Generated Particles in Children with Asthma

Most particulate matter (PM) health effects studies use outdoor (ambient) PM as a surrogate for personal exposure. However, people spend most of their time indoors exposed to a combination of indoor-generated particles and ambient particles that have infiltrated. Thus, it is important to investigate the differential health effects of indoor- and ambient-generated particles. We combined our recently adapted recursive model and a predictive model for estimating infiltration efficiency to separate personal exposure (E) to PM2.5 (PM with aerodynamic diameter ≤2.5 μm) into its indoor-generated (Eig) and ambient-generated (Eag) components for 19 children with asthma. We then compared Eig and Eag to changes in exhaled nitric oxide (eNO), a marker of airway inflammation. Based on the recursive model with a sample size of eight children, Eag was marginally associated with increases in eNO [5.6 ppb per 10-μg/m3 increase in PM2.5; 95% confidence interval (CI), −0.6 to 11.9; p = 0.08]. Eig was not associated with eNO (−0.19 ppb change per 10μg/m3). Our predictive model allowed us to estimate Eag and Eig for all 19 children. For those combined estimates, only Eag was significantly associated with an increase in eNO (Eag: 5.0 ppb per 10-μg/m3 increase in PM2.5; 95% CI, 0.3 to 9.7; p = 0.04; Eig: 3.3 ppb per 10-μg/m3 increase in PM2.5; 95% CI, −1.1 to 7.7; p = 0.15). Effects were seen only in children who were not using corticosteroid therapy. We conclude that the ambient-generated component of PM2.5 exposure is consistently associated with increases in eNO and the indoor-generated component is less strongly associated with eNO.

Dietary Antioxidants and Ozone-Induced Bronchial Hyperresponsiveness in Adults with Asthma

Abstract Ozone exposure aggravates asthma, as has been demonstrated in both controlled exposures and epidemiologic studies. In the current double-blind crossover study, the authors evaluated the effects of dietary antioxidants (i.e., 400 IU vitamin E/500 mg vitamin C) on ozone-induced bronchial hyperresponsiveness in adult subjects with asthma. Seventeen subjects were exposed to 0.12 ppm of ozone or to air for 45 min during intermittent moderate exercise. Bronchial hyperresponsiveness was assessed with 10-min sulfur dioxide (i.e., 0.10 ppm and 0.25 ppm) inhalation challenges. Subjects who were given dietary antioxidants responded less severely to sulfur dioxide challenge than subjects given a placebo (i.e., forced expiratory volume in the 1st sec: -1.2% vs. 4.4%, respectively; peak flow: +2.2% vs. -3.0%, respectively; and mid-forced expiratory flow: +2.0% vs. -4.3%, respectively). Effects were more pronounced when subjects were grouped by response to sulfur dioxide at the screening visit. The results suggest that dietary supplementation with vitamins E and C benefits asthmatic adults who are exposed to air pollutants.

Flow mediated dilation of the brachial artery: an investigation of methods requiring further standardization

BackgroundIn order to establish a consistent method for brachial artery reactivity assessment, we analyzed commonly used approaches to the test and their effects on the magnitude and time-course of flow mediated dilation (FMD), and on test variability and repeatability. As a popular and noninvasive assessment of endothelial function, several different approaches have been employed to measure brachial artery reactivity with B-mode ultrasound. Despite some efforts, there remains a lack of defined normal values and large variability in measurement technique.MethodsTwenty-six healthy volunteers underwent repeated brachial artery diameter measurements by B-mode ultrasound. Following baseline diameter recordings we assessed endothelium-dependent flow mediated dilation by inflating a blood pressure cuff either on the upper arm (proximal) or on the forearm (distal).ResultsThirty-seven measures were performed using proximal occlusion and 25 with distal occlusion. Following proximal occlusion relative to distal occlusion, FMD was larger (16.2 ± 1.2% vs. 7.3 ± 0.9%, p < 0.0001) and elongated (107.2 s vs. 67.8 s, p = 0.0001). Measurement of the test repeatability showed that differences between the repeated measures were greater on average when the measurements were done using the proximal method as compared to the distal method (2.4%; 95% CI 0.5–4.3; p = 0.013).ConclusionThese findings suggest that forearm compression holds statistical advantages over upper arm compression. Added to documented physiological and practical reasons, we propose that future studies should use forearm compression in the assessment of endothelial function.

Effects of diesel exhaust inhalation on heart rate variability in human volunteers.

OBJECTIVES Particulate matter (PM) air pollution is associated with alterations in cardiac conductance and sudden cardiac death in epidemiological studies. Traffic-related air pollutants, including diesel exhaust (DE) may be at least partly responsible for these effects. In this experimental study we assessed whether short-term exposure to DE would result in alterations in heart rate variability (HRV), a non-invasive measure of autonomic control of the heart. METHODS In a double-blind, crossover, controlled-exposure study, 16 adult volunteers were exposed (at rest) in randomized order to filtered air (FA) and two levels of diluted DE (100 or 200 microg/m(3) of fine particulate matter) in 2-h sessions. Before, and at four time points after each exposure we assessed HRV. HRV parameters assessed included both time domain statistics (standard deviation of N-N intervals (SDNN), and the square root of the mean of the sum of squared differences between successive N-N intervals (RMSSD)) and frequency domain statistics (high-frequency (HF) power, low-frequency (LF) power, and the LF/HF ratio). RESULTS We observed an effect at 3-h after initiation of DE inhalation on the frequency domain statistics of HRV. DE at 200 microg/m(3) elicited an increase in HF power compared to FA (Delta=0.33; 95% CI: 0.01-0.7) and a decrease in LF/HF ratio (Delta=-0.74; 95% CI: -1.2 to -0.2). The effect of DE on HF power was not consistent among study participants. There was no DE effect on time domain statistics and no significant DE effect on HRV in later time points. CONCLUSIONS We did not observe a consistent DE effect on the autonomic control of the heart in a controlled-exposure experiment in young participants. Efforts are warranted to understand discrepancies between epidemiological and experimental studies of air pollutions impact on HRV.

Diesel Exhaust Inhalation and Assessment of Peripheral Blood Mononuclear Cell Gene Transcription Effects: An Exploratory Study of Healthy Human Volunteers

Ambient fine particulate matter has been associated with cardiovascular and other diseases in epidemiological studies, and diesel exhaust (DE) is a major source of urban fine particulate matter. Air pollutions cardiovascular effects have been attributed to oxidative stress and systemic inflammation, with resulting perturbation of vascular homeostasis. Peripheral leukocytes are involved in both inflammation and control of vascular homeostasis. We conducted a pilot study using microarray techniques to analyze whether global gene expression profiles in peripheral blood mononuclear cells (PBMCs) can elucidate effects of DE inhalation, for further investigation of mechanisms underlying vascular effects. In a double-blind, crossover, controlled exposure study, healthy adult volunteers were exposed in randomized order to filtered air (FA) and diluted DE in 2-h sessions. We isolated RNA (Trizol/Qiagen method) from PBMCs before and two times after each exposure. RNA samples were arrayed using the Affymetrix U133 Plus 2.0 arrays. Microarray analyses were conducted on five subjects with available RNA samples from exposures to FA and to the highest DE inhalation (200 μg/m3 of fine particulate matter). Following data normalization and statistical analysis, a total of 1290 out of 54,675 probe sets evidenced differential expression (more than 1.5-fold up- or downregulated with p < .05) between FA and DE exposure. These genes demonstrated a clear distinction between the FA and DE groups and an indication of a time-dependent effect on biological processes such as inflammation and oxidative stress. This study addresses the value of using PBMC gene expression to assess pathways relevant to cardiovascular effect in healthy individuals.

Association between short term exposure to fine particulate matter and heart rate variability in older subjects with and without heart disease

Background: Short term increases in exposure to particulate matter (PM) air pollution are associated with increased cardiovascular morbidity and mortality. The mechanism behind this effect is unclear, although changes in autonomic control have been observed. It was hypothesised that increases in fine PM measured at the subjects’ home in the preceding hour would be associated with decreased high frequency heart rate variability (HF-HRV) in individuals with pre-existing cardiac disease. Methods: Two hundred and eighty five daily 20 minute measures of HRV (including a paced breathing protocol) were made in the homes of 34 elderly individuals with (n = 21) and without (n = 13) cardiovascular disease (CVD) over a 10 day period in Seattle between February 2000 and March 2002. Fine PM was continuously measured by nephelometry at the individuals’ homes. Results: The median age of the study population was 77 years (range 57–87) and 44% were male. Models that adjusted for health status, relative humidity, temperature, mean heart rate, and medication use did not find a significant association between a 10 μg/m3 increase in 1 hour mean outdoor PM2.5 before the HRV measurement and a change in HF-HRV power in individuals with CVD (3% increase in median HF-HRV (95% CI −19 to 32)) or without CVD (5% decrease in median HF-HRV (95% CI −34 to 36)). Similarly, no association was evident using 4 hour and 24 hour mean outdoor PM2.5 exposures before the HRV measurement. Conclusion: No association was found between increased residence levels of fine PM and frequency domain measures of HRV in elderly individuals.

Fine particulate air pollution and cardiorespiratory effects in the elderly.

Background: Past studies of air pollution effects among sensitive subgroups have produced inconsistent results. Our objective was to determine relationships between various measures of air pollution and cardiorespiratory effects in older subjects. Methods: We conducted a study that included repeated measurements of pulmonary function (arterial oxygen saturation) and cardiac function (heart rate and blood pressure) in a panel of 88 subjects (>57 years of age) in Seattle during the years 1999 to 2001. Subjects were healthy or had lung or heart disease. Each subject participated in sessions of 10 consecutive days of exposure monitoring and collection of health outcomes for up to 2 sessions. Associations between health outcomes and indoor, outdoor, and personal measures of particulate matter ≤2.5 micrometers (PM2.5) or particulate matter ≤10 micrometers (PM10) were evaluated using generalized estimating equations with an exchangeable working correlation matrix and robust standard errors. The model included terms for the within-subject, within-session effect; the within- subject, between-session effect; and an interaction term for medication usage. The model controlled for temperature, relative humidity, body mass index, and age. Results: Associations between air pollution and health measurements were found primarily in healthy subjects. Healthy subjects taking no medications had decreases in heart rate associated with indoor and outdoor PM2.5 and PM10. Healthy subjects on medication had small increases in systolic blood pressure associated with indoor PM2.5 and outdoor PM10. Heterogeneity analysis found differences among the health groups for associations with particulate air pollution in heart rate but not in blood pressure. Conclusion: Modest concentrations of air pollutants were associated with small changes in cardiac function.

A community study of the effect of particulate matter on blood measures of inflammation and thrombosis in an elderly population.

BackgroundThe mechanism behind the triggering effect of fine particulate matter (PM) air pollution on cardiovascular events remains elusive. We postulated that elevated levels of PM would be associated with increased blood levels of inflammatory and thrombotic markers in elderly individuals. We also hypothesized that elevated PM would increase levels of cytokines in individuals with heart disease.MethodsWe measured these blood markers in 47 elderly individuals with (23) and without (16 COPD and 8 healthy) cardiovascular disease (CVD) on 2 or 3 mornings over a 5 or 10-day period between February 2000 and March 2002. Blood measures were paired with residence level outdoor PM measured by nephelometry. Analyses determined the within-individual effect of 24-hour averaged outdoor PM on blood measures.ResultsAnalyses found no statistically significant effect of a same day 10 ug/m3 increase in fine PM on log transformed levels of CRP 1.21 fold-rise [95% CI: 0.86, 1.70], fibrinogen 1.02 fold-rise [95% CI: 0.98, 1.06], or D-dimer 1.02 fold-rise [95% CI: 0.88, 1.17] in individuals with CVD. One-day lagged analyses in the CVD subgroup found similar null results. These same models found no change in these blood markers at the same-day or 1-day lag in the group without CVD. In 21 individuals with CVD, a 10 μg/m3 increase in same-day PM was associated with a 1.3 fold-rise [95% CI: 1.1, 1.7] in the level of monocyte chemoattractant protein-1.ConclusionWe did not find consistent effects of low ambient levels of PM on blood measures of inflammation or thrombosis in elderly individuals.

Effect of diesel exhaust inhalation on antioxidant and oxidative stress responses in adults with metabolic syndrome

Background: Traffic-related air pollution is associated with cardiovascular morbidity and mortality. Although the biological mechanisms are not well understood, oxidative stress may be a primary pathway. Subpopulations, such as individuals with metabolic syndrome (MeS), may be at increased risk of adverse effects associated with air pollution. Our aim was to assess the relationship between exposure to diesel exhaust (DE) and indicators of systemic antioxidant and oxidative responses in adults with MeS. We hypothesized that DE exposure would result in greater oxidative stress and antioxidant responses compared with filtered air (FA). Methods: Ten adult subjects with MeS were exposed on separate days for two hours to FA or DE (at 200μg/m3), in a double blind, crossover experiment. Urinary 8-isoPGF2α (F2-isoprostanes), and 8-hydroxy-2’-deoxyguanosine (8-OHdG) were assessed as markers of oxidative stress at 3 hrs and 22 hrs, respectively, after exposure initiation. To assess the short-term antioxidant response we analyzed plasma ascorbic acid (AA) 90 minutes after exposure initiation. All outcomes were compared to pre-exposure levels, and mean changes were compared between FA and DE exposures. Results: Mean changes in urinary F2-isoprostanes (ng/mg creatinine), (−0.05 [95% CI = −0.29, 0.15]), and 8-OHdG (μg/g creatinine) (−0.09 [−0.13, 0.31]), were not statistically significant. Mean changes in plasma AA (mg/dl) were also not significant (−0.02 [−0.78, 0.04]). Conclusions: In this carefully controlled experiment, we did not detect significant changes in oxidative stress or systemic antioxidant responses in subjects with MeS exposed to 200μg/m3 DE.