Jeffrey H. Sullivan

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.

Relation between short-term fine-particulate matter exposure and onset of myocardial infarction.

Background: Epidemiologic studies have reported increases in the incidence of cardiovascular morbidity and myocardial infarction (MI) associated with increases in short-term and daily levels of fine-particulate matter air pollution, suggesting a role for particulate matter in triggering an MI. Methods: We studied the association between onset time of MI and preceding hourly measures of fine-particulate matter using a case-crossover study of 5793 confirmed cases of acute MI. We linked data from a community-wide database on acute MI from 1988–1994 in King County, Washington, with central site air pollution monitoring data on fine-particulate matter determined by nephelometry. We compared air pollution exposure levels averaged 1 hour, 2 hours, 4 hours, and 24 hours before MI onset to a set of time-stratified referent exposures from the same day of the week in the month of the case event. Results: The estimated relative risk for a 10-μg/m3 increase in fine-particulate matter the hour before MI onset was 1.01 (95% CI = 0.98–1.05). Analyses of pollutant levels at the other time points demonstrated a similar lack of association. No increased risk was found in all cases with preexisting cardiac disease (odds ratio = 1.05; 0.95–1.16). Stratification by known cardiovascular risk factors (hypertension, diabetes, and smoking status) also did not modify the relation between fine-particulate matter and MI onset. Conclusion: Although a very small effect cannot be excluded, there was no consistent association between ambient levels of fine-particulate matter and risk of MI onset.

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.

Association between particulate matter and emergency room visits, hospital admissions and mortality in Spokane, Washington.

There is conflicting evidence regarding the association between different size fractions of particulate matter (PM) and cardiac and respiratory morbidity and mortality. We investigated the short-term associations of four size fractions of particulate matter (PM1, PM2.5, PM10, and PM10–2.5) and carbon monoxide with hospital admissions and emergency room (ER) visits for respiratory and cardiac conditions and mortality in Spokane, Washington. We used a log-linear generalized linear model to compare daily averages of PM and carbon monoxide with daily counts of the morbidity and mortality outcomes from January 1995 to June 2001. We examined pollution lags ranging from 0 to 3 days and compared our results to a similar log-linear generalized additive model. Effect estimates tended to be smaller and have larger standard errors for the generalized linear model. Overall, we saw no association with respiratory ER visits and any size fraction of PM. However, there was a suggestion of greater respiratory effect from fine PM when compared to coarse fraction. Carbon monoxide was associated with both all respiratory ER visits and visits for asthma at the 3-day lag. We feel that carbon monoxide may be serving as a marker for combustion-derived pollutants, which is one large component of the diverse air pollutant mixture. We also found no association with any size fraction of PM or CO with cardiac hospital admissions or mortality at the 0- to 3-day lag. We found no consistent associations between any size fraction of PM and cardiac or respiratory ER visits or hospital admissions.

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.

Blood Pressure Response to Controlled Diesel Exhaust Exposure in Human Subjects

Exposure to traffic-related air pollution is associated with risk of cardiovascular disease and mortality. We examined whether exposure to diesel exhaust increased blood pressure (BP) in human subjects. We analyzed data from 45 nonsmoking subjects, 18 to 49 years of age in double-blinded, crossover exposure studies, randomized to order. Each subject was exposed to diesel exhaust, maintained at 200 &mgr;g/m3 of fine particulate matter, and filtered air for 120 minutes on days separated by ≥2 weeks. We measured BP pre-exposure, at 30-minute intervals during exposure, and 3, 5, 7, and 24 hours from exposure initiation and analyzed changes from pre-exposure values. Compared with filtered air, systolic BP increased at all of the points measured during and after diesel exhaust exposure; the mean effect peaked between 30 and 60 minutes after exposure initiation (3.8 mm Hg [95% CI: −0.4 to 8.0 mm Hg] and 5.1 mm Hg [95% CI: 0.7–9.5 mm Hg], respectively). Sex and metabolic syndrome did not modify this effect. Combining readings between 30 and 90 minutes, diesel exhaust exposure resulted in a 4.4-mm Hg increase in systolic BP, adjusted for participant characteristics and exposure perception (95% CI: 1.1–7.7 mm Hg; P=0.0009). There was no significant effect on heart rate or diastolic pressure. Diesel exhaust inhalation was associated with a rapid, measurable increase in systolic but not diastolic BP in young nonsmokers, independent of perception of exposure. This controlled trial in humans confirms findings from observational studies. The effect may be important on a population basis given the worldwide prevalence of exposure to traffic-related air pollution.

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.