2010 Progress Report: Cardiovascular Responses in the Normative Aging Study: Exploring the Pathways of Particle Toxicity

EPA Grant Number: R832416C001
Subproject: this is subproject number 001 , established and managed by the Center Director under grant R832416
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Harvard Particle Center
Center Director: Koutrakis, Petros
Title: Cardiovascular Responses in the Normative Aging Study: Exploring the Pathways of Particle Toxicity
Investigators: Schwartz, Joel , Sparrow, David , Suh, Helen H. , Vokonas, Pantel
Institution: Harvard University
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2011)
Project Period Covered by this Report: August 1, 2009 through July 31,2010
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

In our original EPA-funded Particle Center, we examined air pollution mediated responses of individuals participating in the Normative Aging Study (NAS), a large prospective cohort living in Eastern Massachusetts. As part of this effort, we collected ECGs and blood samples from each study participant and analyzed these samples for heart rate variability (HRV) and CRP, respectively. In analyses of these data, we found ambient PM2.5 and ambient black carbon (BC) concentrations to be associated with decrements in HRV, with these decrements greatest for hypertensive individuals. Ambient BC concentrations were further found to be associated with increased CRP and fibrinogen levels. These results suggest that the PM-mediated autonomic changes may be brought about through pathways involving the autonomic nervous system and systemic inflammation. Definitive identification of PM-mediated biological mechanisms was limited, however, by the lack of other intermediate cardiac and inflammation endpoints, the use of central site monitoring to characterize exposures for the entire cohort, and by the traditional epidemiologic approaches used to examine exposure-effect associations.  

In Project 1 of our current Center, we are continuing our analysis of the NAS cohort, with continued ECG, CRP and fibrinogen measurements and importantly with additional exposure and health measurements for each NAS participant to enhance our ability to identify important biological pathways. These additional measurements include ECG, blood inflammatory markers, medication, genotypic, food frequency, and particle exposure measurements for each of the current NAS participants. ECG and blood samples are being analyzed for a variety of measures (HRV, ST segments, QT intervals, CRP, sICAM-1, sVCAM-1, and homocysteine); these measures will be used as intermediate markers of the inflammatory, endothelial, and autonomic pathways. In addition, they will be related to individual-specific indoor PM2.5, SO42-, and BC exposures that are being measured for 1 week prior to the clinic visit and to ambient air pollution (PM2.5, PM10, PM2.5-10, SO42‑, NO3-, BC, EC, OC, and PC) concentrations that are being measured at our stationary ambient monitoring (SAM) site. The study will use these data to test three primary hypotheses:

Hypothesis 1:  Cardiovascular effects of particles (PM) will differ by source and by different source-related components.  Specifically, short-term exposures to sulfate and traffic particles will be associated with increases in:

  • acute inflammation and/or endothelial dysfunction, as measured by increases in CRP, soluble intercellular adhesion molecule 1 (sICAM-1),  and soluble vascular cell adhesion molecule 1 (sVCAM-1);
  • autonomic dysfunction, as measured by reduced HRV; and
  • general cardiovascular responses, as measured by increases in blood pressure and ECG changes including ST-segment level and QT-interval.

Hypothesis 2:  Effects of PM on these outcomes will be modified by subject characteristics (genetic, dietary, or pharmacological) that influence susceptibility to:

  • oxidative stress, endothelial dysfunction, and/or acute inflammation, specifically Glutathione-s-trasferase (GSTM1) null or the long repeat Hemeoxygenase-1 (HO-1) genotypes; statin, beta blocker, or calcium channel blocker use; dietary intake of Vitamin C or omega-3 (Ω-3) fatty acids;
  • autonomic dysfunction, specifically beta blocker use, calcium channel blocker use or dietary intake of Ω-3 fatty acids;
  • general cardiovascular disease, specifically hypertension; and
  • reactive airways disease, specifically methacholine reactivity.

Hypothesis 3:  Long-term exposure to PM from traffic is associated with increased risk of inflammation (e.g., CRP, sICAM-1, sVCAM-1, and homocysteine); autonomic dysfunction (e.g., reduced HRV), and impaired cardiovascular outcomes (e.g., elevated blood pressure). This association is modified by the same factors that modify acute responses.

Progress Summary:

We have continued to make progress on a number of fronts in our epidemiologic studies.  A major focus of our recent research has been the role of epigenetics as a pathway and modifier of the effects of air pollution on health. In that regard we made considerable progress. In Baccarelli, et al., we showed that traffic particles are associated with changes in DNA methylation. We subsequently showed that DNA methylation was predictive of concentrations of endothelial and inflammatory markers (Baccarelli, et al.). Other papers are in review.

We also made considerable progress on our examination of genetic polymorphisms as modifiers of the relation between air pollution and health. In Ren, et al., we showed that genes related to endothelial function and lipid metabolism modified the association with HRV. In Wilker, et al., we showed that genes related to the inflammation system modified the association of pollution with markers of inflammation and endothelial function, and in another paper that genes related to inflammation and the rennin-angiotensin system modify the association with postural changes in blood pressure. In Ren, et al., we showed that oxidative stress genes modified the effects of particles, while in Mordukhovitch, et al., we showed that black carbon particles were associated with increased blood pressure, but the association was not modified by oxidative stress genes. On the other hand, in Wilker, et al., we showed that genes related to micro RNA processing modify the association of particles with blood pressure.

Our GIS modeled BC data are important for our ongoing research. In Gryparis, et al., we analyzed all live births in Eastern Massachusetts using our geospatial model, and looked at different approaches for controlling for measurement error induced by using modeled Vs measured air pollution data. We showed that the induced error is predominantly Berkson, and that a common recommended approach, often mislabeled multiple imputation, gives biased results, whereas a naïve plug in approach ignoring the issue has little bias. Less bias and better confidence intervals can be obtained using regression calibration. We applied this to our birthweight data, and showed that the effect sizes increased as well as the significance of the results.  In Chen, et al., we examined neurobehavioral effects of air pollution and found some associations, but also confounding by SES.

An important focus of our research has been on the role of particle components in the association with health. To that end, using mortality data, we examined the association between fine and coarse particles and daily mortality in 112 cities (Zanobetti and Schwartz) and showed there were independent associations. In Baccarelli, et al., we showed that independent of PM10 concentrations, exposure to traffic was a risk factor for deep vein thrombosis. In Zanobetti, et al., we showed that traffic pollution was associated with T-Wave alternans. In another paper, Zanobetti, et al., showed that sulfur and nickel were associated with higher than average toxicity for hospital admissions. In Baja, et al., we showed it was traffic pollution and not secondary pollution that was associated with prolonged QT interval.

In several other areas, Park, et al., showed that dietary factors are associated with HRV. We also have begun studies of the effects of temperature on health to help understand the implications of climate change. In Halonen, et al., we reported associations between temperature and inflammatory markers.


Journal Articles on this Report : 17 Displayed | Download in RIS Format

Other subproject views: All 68 publications 67 publications in selected types All 67 journal articles
Other center views: All 200 publications 194 publications in selected types All 194 journal articles
Type Citation Sub Project Document Sources
Journal Article Baccarelli A, Wright RO, Bollati V, Tarantini L, Litonjua AA, Suh HH, Zanobetti A, Sparrow D, Vokonas PS, Schwartz J. Rapid DNA methylation changes after exposure to traffic particles. American Journal of Respiratory and Critical Care Medicine 2009;179(7):572-578. R832416 (Final)
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  • Journal Article Baccarelli A, Martinelli I, Pegoraro V, Melly S, Grillo P, Zanobetti A, Hou L, Bertazzi PA, Mannucci PM, Schwartz J. Living near major traffic roads and risk of deep vein thrombosis. Circulation 2009;119(24):3118-3124. R832416C001 (2010)
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  • Journal Article Baccarelli A, Tarantini L, Wright RO, Bollati V, Litonjua AA, Zanobetti A, Sparrow D, Vokonas PS, Schwartz J. Repetitive element DNA methylation and circulating endothelial and inflammation markers in the VA Normative Aging Study. Epigenetics 2010;5(3):222-228. R832416 (Final)
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  • Journal Article Baja ES, Schwartz JD, Wellenius GA, Coull BA, Zanobetti A, Vokonas PS, Suh HH. Traffic-related air pollution and QT interval: modification by diabetes, obesity, and oxidative stress gene polymorphisms in the Normative Aging Study. Environmental Health Perspectives 2010;118(6):840-846. R832416 (Final)
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  • Journal Article Chen J-C, Schwartz J. Neurobehavioral effects of ambient air pollution on cognitive performance in US adults. NeuroToxicology 2009;30(2):231-239. R832416 (Final)
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  • Journal Article Gryparis A, Paciorek CJ, Zeka A, Schwartz J, Coull BA. Measurement error caused by spatial misalignment in environmental epidemiology. Biostatistics 2009;10(2):258-274. R832416 (2008)
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  • Journal Article Halonen JI, Zanobetti A, Sparrow D, Vokonas PS, Schwartz J. Associations between outdoor temperature and markers of inflammation:a cohort study. Environmental Health 2010;9:42 (9 pp.). R832416 (Final)
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  • Journal Article Mordukhovich I, Wilker E, Suh H, Wright R, Sparrow D, Vokonas PS, Schwartz J. Black carbon exposure, oxidative stress genes, and blood pressure in a repeated-measures study. Environmental Health Perspectives 2009;117(11):1767-1772. R832416 (Final)
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  • Journal Article Park SK, Tucker KL, O'Neill MS, Sparrow D, Vokonas PS, Hu H, Schwartz J. Fruit, vegetable, and fish consumption and heart rate variability: the Veterans Administration Normative Aging Study. American Journal of Clinical Nutrition 2009;89(3):778-786. R832416 (Final)
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  • Journal Article Ren C, Baccarelli A, Wilker E, Suh H, Sparrow D, Vokonas P, Wright R, Schwartz J. Lipid and endothelium-related genes, ambient particulate matter, and heart rate variability—the VA Normative Aging Study. Journal of Epidemiology and Community Health 2010;64(1):49-56. R832416 (2009)
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  • Journal Article Ren C, Park SK, Vokonas PS, Sparrow D, Wilker E, Baccarelli A, Suh HH, Tucker KL, Wright RO, Schwartz J. Air pollution and homocysteine: more evidence that oxidative stress-related genes modify effects of particulate air pollution. Epidemiology 2010;21(2):198-206. R832416 (2009)
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  • Journal Article Wilker EH, Alexeeff SE, Poon A, Litonjua AA, Sparrow D, Vokonas PS, Mittleman MA, Schwartz J. Candidate genes for respiratory disease associated with markers of inflammation and endothelial dysfunction in elderly men. Atherosclerosis 2009;206(2):480-485. R832416 (2009)
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  • Journal Article Wilker EH, Baccarelli A, Suh H, Vokonas P, Wright RO, Schwartz J. Black carbon exposures, blood pressure, and interactions with single nucleotide polymorphisms in microRNA processing genes. Environmental Health Perspectives 2010;118(7):943-948. R832416 (Final)
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  • Journal Article Wilker E, Mittleman MA, Litonjua AA, Poon A, Baccarelli A, Suh H, Wright RO, Sparrow D, Vokonas P, Schwartz J. Postural changes in blood pressure associated with interactions between candidate genes for chronic respiratory diseases and exposure to particulate matter. Environmental Health Perspectives 2009;117(6):935-940. R832416 (Final)
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  • Journal Article Zanobetti A, Franklin M, Koutrakis P, Schwartz J. Fine particulate air pollution and its components in association with cause-specific emergency admissions. Environmental Health 2009;8:58 (12 pp.). R832416 (Final)
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  • Journal Article Zanobetti A, Schwartz J. The effect of fine and coarse particulate air pollution on mortality: a national analysis. Environmental Health Perspectives 2009;117(6):898-903. R832416 (Final)
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  • Journal Article Zanobetti A, Stone PH, Speizer FE, Schwartz JD, Coull BA, Suh HH, Nearing BD, Mittleman MA, Verrier RL, Gold DR. T-wave alternans, air pollution and traffic in high-risk subjects. American Journal of Cardiology 2009;104(5):665-670. R832416 (Final)
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  • Supplemental Keywords:

      Normative Aging Study, inflammation, autonomic function, oxidative stress, RFA, Health, Scientific Discipline, Air, particulate matter, Environmental Chemistry, Health Risk Assessment, Epidemiology, Risk Assessments, ambient air quality, atmospheric particulate matter, biological pathways, chemical characteristics, human health effects, toxicology, cardiovascular vulnerability, automobile exhaust, airborne particulate matter, chemical composition, biological mechanisms, biological mechanism , traffic related particulate matter, human exposure, ambient particle health effects, autonomic dysfunction, human health risk

    Relevant Websites:

    http://www.hsph.harvard.edu/epacenter/ Exit

    Progress and Final Reports:

    Original Abstract
  • 2006 Progress Report
  • 2007 Progress Report
  • 2008 Progress Report
  • 2009 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R832416    Harvard Particle Center

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R832416C001 Cardiovascular Responses in the Normative Aging Study: Exploring the Pathways of Particle Toxicity
    R832416C002 Cardiovascular Toxicity of Concentrated Ambient Fine, Ultrafine and Coarse Particles in Controlled Human Exposures
    R832416C003 Assessing Toxicity of Local and Transported Particles Using Animal Models Exposed to CAPs
    R832416C004 Cardiovascular Effects of Mobile Source Exposures: Effects of Particles and Gaseous Co-pollutants
    R832416C005 Toxicological Evaluation of Realistic Emission Source Aerosol (TERESA): Investigation of Vehicular Emissions