Grantee Research Project Results
Final Report: Air Pollution and Human Vascular Dysfunction: Mechanism and Mediators
EPA Grant Number: CR830837Title: Air Pollution and Human Vascular Dysfunction: Mechanism and Mediators
Investigators: Brook, Robert D. , Keeler, Gerald J. , Brook, Jeffrey R. , Dvonch, Joseph T. , Silverman, Frances , Vincent, Renaud , Rajagopalan, Sanjay
Institution: University of Michigan , Health Canada - Ottawa , University of Toronto
EPA Project Officer: Chung, Serena
Project Period: May 1, 2003 through April 30, 2006 (Extended to April 30, 2008)
Project Amount: $1,050,000
RFA: Airborne Particulate Matter Health Effects: Cardiovascular Mechanisms (2002) RFA Text | Recipients Lists
Research Category: Human Health , Particulate Matter , Air
Objective:
We have shown that short-term 2-hour exposure to concentrated ambient fine particulate (PM2.5) air pollution (CAP) + ozone (O3) causes acute conduit artery vasoconstriction and raises arterial blood pressure. Some studies have shown that PM and/or different air pollutants (e.g. gases) cause endothelial dysfunction in humans and animals in both in vivo and ex vivo models. These biological changes may be important mechanisms whereby PM2.5 can trigger a host of acute cardiovascular (CV) events such as myocardial infarctions and stroke following short-term exposure in vulnerable people. The objectives of this current proposal were threefold. First, to elucidate the underlying patho-physiological mechanisms linking air pollution with impaired arterial reactivity. Specifically, the roles of CAP-induced oxidative stress and increased vascular activity of endothelins were investigated by determining the ability of vitamin C and bosentan to mitigate any air pollution-mediated adverse vascular health effects, respectively. Second, we sought to determine the significance of the air pollution-mediated arterial vasoconstriction on systemic hemodynamics by evaluating the blood pressure (BP) response during and after exposures. Third, we aimed to identify the specific air pollution components responsible for any adverse impact on human vascular function, foremost to determine the role(s) of CAP (particulates) versus O3.
Fifty subjects (ages18-50), who were healthy non-smokers without CV disease or risk factors and on no medications underwent protocol #1 in Ann Arbor. Thirty-one similar subjects participated in protocol #2 in Toronto. In protocol #1, subjects were exposed to CAP (150 μg/m3) plus O3 (120 ppb) during all exposures in the AirCARE-1 mobile exposure facility (Harvard 3-stage concentrator system) on 3 separate visits (1 week between exposures). Subjects were randomly given 1 of 3 pre-exposure treatments prior to each study (Bosentan 250 mg [non-specific endothelin antagonist], Vitamin C 2000 mg [anti-oxidant], or placebo). Vascular outcomes [arterial tone, brachial endothelial-dependent and independent vasomotion], blood biomarkers, and BP were measured by non-invasive standardized methodologies before, after, and 24 hours after each exposure. Protocol #2 was identical except that subjects were not given a pre-exposure treatment and subjects were randomly exposed to 4 different conditions (1 week apart at the Gage Institute Downtown Toronto using a Harvard 2-stage concentrator system). The exposures were (CAP + O3), (CAP alone), (O3 alone), and (filtered air – placebo) at the same concentrations in protocol #1. The same vascular, BP, and blood biomarkers were measured in a similar standardized fashion.
Approach:
We plan to undertake two separate double-blind, cross-over studies using controlled human exposures to concentrated ambient PM2.5 (CAP) ± O3. A new mobile human exposure facility (AirCARE 1) will be employed at the University of Michigan to focus on the underlying biological mechanisms. AirCARE 1 is the result of a joint collaboration between the University of Michigan and Michigan State University. The effects of pre-exposure treatments with anti-oxidants and endothelin receptor blockade on the vascular responses to air pollution exposure will be investigated compared to placebo. The exposure facility located at the University of Toronto will be used to investigate the importance of CAP versus O, as well as specific particle constituents, in the etiology of the vascular dysfunction following air pollution exposure.
Summary/Accomplishments (Outputs/Outcomes):
All participants met each inclusion/exclusion criteria in both protocols. BP, all fasting serum lipids, and fasting glucose were within normal limits for all subjects.
Results for protocol #2
PM2.5 Mass Concentration and Ozone levels during 2-hr Exposures in Toronto
|
Exposure Measure |
Filtered Air |
Ozone |
CAP |
CAP+Ozone |
|
PM2.5 (µg/m3)a |
1.3 ± 8.0 |
2.8 ± 11.7 |
148.5 ± 54.4 |
132.4 ± 38.7 |
|
Ozone (ppb)b |
10.9 ± 7.2 |
111.3 ± 6.5 |
9.7 ± 6.1 |
109.0 ± 5.6 |
Values are mean ± SD, n=31. PM2.5: Gravimetric measure (post - pre exposure conditioned filter delta weight) over 2-hr exposure. Ozone: Dasibi UV photometric ozone analyzer, mean of 15-sec readings over 2-hr exposure. ANOVA, post-hoc test (SAS Contrast statement):
ap<0.0001: FA versus CAP; O3 versus CAP; FA versus CAP+O3; O3 versus CAP+O3.
bp<0.0001: FA versus O3; CAP versus O3; FA versus CAP+O3; CAP versus CAP+O3.
Vascular function: Brachial artery diameter (BAD) [arterial tone], brachial flow-mediated dilatation (FMD) [endothelial-dependent vasodilatation and function], and nitroglycrine-mediated dilatation (NMD) [endothelial-independent vasodilation and smooth muscle function] were normal in all sujects at baseline. No vascular parameter was significantly altered by any exposure except brachial FMD was significantly decreased 24 hours post CAP and combined CAP+ O3 exposures vs pre-exposure levels. For CAP + O3, FMD decreased from 10.7 ± 6.5% to 8.5 ± 4.2% [p=0.013 for the 24 hr post - pre-exposure Δ: FA Δ + O3 Δ versus CAP Δ + CAP+O3 Δ (Mixed Model)].
Blood pressure: Although BP was not changed following any exposure type (post vs pre-exposure levels), the diastolic BP was significantly increased during the CAP and the CAP+O3 exposures. The intra-exposure diastolic BP increase during CAP+O3 and CAP alone were similar. There was a significant effect of the presence of CAP, but not O3, on diastolic BP change. Heart rate and systolic BP were not altered.
Biomarkers: There were no biologically meaningful or significant alterations by any exposure type on blood biomarkers in protocol #2 (C-reactive protein, inflammatory cytokines [panel], white blood cells). Modest significant increases in venous neutrophil levels were seen immediately following only CAP and CAP + O3 exposures.
Pending Results: On-going secondary outcome analyses will investigate the effect of exposures on endothelin levels and heart rate variability (HRV) changes. Further analyses will provide detailed characterizations of the CAP exposure chemistry (nitrates, sulfates, metals, ions, organic/elemental carbon) and compare exposures to specific constituents to the biological responses in order to investigate their role in the etiology of the health effects. Post hoc analyses will investigate the effect of exposures on HDL-C sub-classes, HDL anti-oxidant and anti-inflammatory functional status.
Results for protocol #1
PM2.5 Mass Concentration and Ozone levels during 2-hr Exposures in Ann Arbor
During all exposures (CAP + O3) there was no statistically significant difference in PM2.5 or O3 levels among the 3 exposure days (mean PM2.5 range 126 -142 ± 48-55 μg/m3 and O3 = 120 ± 8 ppb)
Vascular function: BAD, FMD, NMD, and measures of small and large arterial compliance (C1, C2), along with cardiac output, and systemic vascular resistance (measured by computerized arterial waveform analyses by radial tonometry) were not significantly altered post or 24-hours-post any exposure (all 3 pre-exposure treatments).
Biomarkers: There was no significant increase in hsCRP, catecholamines, cortisol, insulin, or glucose.
Pending Results: On-going secondary outcome analyses will investigate the effect of exposures on endothelin levels and oxidant stress markers (e.g. serum F2 isoprostanes). Further analyses will provide detailed characterizations of the CAP exposure chemistry (nitrates, sulfates, metals, ions, organic/elemental carbon) and compare exposures to specific constituents to the biological responses in order to investigate their role in the etiology of the health effects.
Blood pressure: BP and heart rate levels were not changed following any exposure type (post vs pre-exposure levels), nor were they raised for the 24 hour period after any exposure vs. the period before exposures by ambulatory monitoring. However, diastolic BP was significantly increased during all exposures types (i.e. following each pre-treatment) to a similar degree (not statistically significantly different). Heart rate was significantly increased during all exposures types (i.e. following each pre-treatment) to a similar degree (not statistically significantly different). There was no change in systolic BP.
Conclusions:
We have confirmed in 2 separate protocols (Toronto and Ann Arbor) that CAP + O3 rapidly raises diastolic BP in healthy humans (~4 mmHg). The response occurs only actually during the exposure period to particles, resolves within minutes, and does not persist or recur for any time in a 24 hour period post-exposure. Our results demonstrate that it is fine particles, and not O3, that causes the pro-hypertensive hemodynamic response. Conduit artery endothelial dysfunction occurred only in a delayed fashion (24 hours later) only after exposures that contained particles (CAP and CAP + ozone) and solely in Toronto. These responses suggest that endothelial dysfunction requires several hours to be instigated following fine particle exposure. Moreover, the difference between responses in Ann Arbor and Toronto suggest that the particle chemistry or composition may be a significant determinant of the impact on endothelial function. On the other hand, the almost identical hemodynamic responses that occurred at both sites suggests that the inhalation of particles per se (regardless of composition) may be adequate to stimulate a hyper-acute pro-hypertensive response. Further studies of the chemical composition and components of the CAP mixture at both sites and linkages to the health response will provide insight. The hyper-acute and transient nature of the pro-hypertensive response, which was not associated with impaired vascular endothelial function or compliance at the time point of occurrence and not mitigated by endothelin antagonism or an anti-oxidant, suggests that air pollution-mediated autonomic imbalance is the most likely biological mechanism responsible. Further analyses linking the degree of change in HRV with the BP change in Toronto subjects may provide more insight. We did not identify any air pollution mediated acute effects on systemic inflammation or changes in smooth muscle function, or arterial compliance. On-going studies will investigate if there is an effect upon HDL anti-atherosclerotic functions.
Expected Results:
It is anticipated that CAP (PM2.5) will be primarily implicated in mediating the adverse effects on the vasculature and that both pre-exposure treatments with anti-oxidants and ET-blockade will prevent or significantly blunt the air pollution-mediated vasoconstriction. The results of this study will provide important insights into the biological mechanism linking air pollution with cardiovascular disease, supporting a crucial role of oxidative stress and heightened vascular expression of ETs.
Journal Articles on this Report : 3 Displayed | Download in RIS Format
| Other project views: | All 5 publications | 3 publications in selected types | All 3 journal articles |
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Brook RD, Urch B, Dvonch JT, Bard RL, Speck M, Keeler G, Morishita M, Marsik FJ, Kamal AS, Kaciroti N, Harkema J, Corey P, Silverman F, Gold DR, Wellenius G, Mittleman MA, Rajagopalan S, Brook JR. Insights into the mechanisms and mediators of the effects of air pollution exposure on blood pressure and vascular function in healthy humans. Hypertension 2009;54(3):659-667. |
CR830837 (Final) R832416 (2009) R832416C002 (2009) R832416C002 (2010) |
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Sivagangabalan G, Spears D, Masse S, Urch B, Brook RD, Silverman F, Gold DR, Lukic KZ, Speck M, Kusha M, Farid T, Poku K, Shi E, Floras J, Nanthakumar K. The effect of air pollution on spatial dispersion of myocardial repolarization in healthy human volunteers. Journal of the American College of Cardiology 2011;57(2):198-206. |
CR830837 (Final) R832416 (Final) R832416C002 (2010) R832416C002 (Final) R834798 (2012) R834798 (2014) R834798 (Final) R834798C002 (2014) R834798C002 (Final) R834798C004 (2012) R834798C004 (2014) R834798C004 (Final) |
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Thompson AM, Zanobetti A, Silverman F, Schwartz J, Coull B, Urch B, Speck M, Brook JR, Manno M, Gold DR. Baseline repeated measures from controlled human exposure studies: associations between ambient air pollution exposure and the systemic inflammatory biomarkers IL-6 and fibrinogen. Environmental Health Perspectives 2010;118(1):120-124. |
CR830837 (Final) R832416 (2009) R832416 (Final) R832416C002 (2009) R832416C002 (2010) R832416C002 (Final) |
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Supplemental Keywords:
concentrated ambient air, ozone, health effects, endothelium, atherosclerosis, concentrated ambient air pollution,, RFA, Scientific Discipline, Health, Air, particulate matter, Health Risk Assessment, Risk Assessments, Biochemistry, particulates, atmospheric particulate matter, human health effects, PM 2.5, airway disease, cardiovascular vulnerability, ozone, airborne particulate matter, air pollution, human exposure, vascular dysfunction, cardiovascular diseaseRelevant Websites:
http://www.med.umich.edu/endothelial/index.htm Exit
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.