2009 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 T.H. Chan School of Public Health , Harvard University
Current 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, 2008 through July 30,2009
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 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 one 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 this 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 heart rate variability (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:

The NAS cohort has informed us about toxicity of PM2.5, BC, O3 and SO42- on autonomic dysfunction, inflammation, and endothelial dysfunction. We have also gained new insights on individuals at higher risk, such as those with obesity or diabetes. Moreover, we have studied genetic susceptibility factors that inform us about both at-risk groups and possible mechanisms of action of PM. We began exploring multiple pollutants and interactions, and new outcomes including cognition and biomarkers of oxidative stress. We highlight results from our NAS studies below. 

Multiple pollutants and interactions: We have extended beyond our single-pollutant models to investigate multiple-pollutant models and pollutant interactions. We have demonstrated that higher cumulative lead exposures (predominantly from past gasoline lead) modified associations between air pollution and heart rate variability (HRV) among our NAS subjects (Park et al 2008a).  We found graded, significant reductions in both high-frequency and low-frequency powers of HRV in relation to O3 and SO42- across quartiles of tibia lead (Park et al 2006). We also found that polymorphisms of the hemochromatosis (HFE) gene protected against the effects of PM2.5 on HRV (Park et al 2006). Two polymorphisms in the HFE gene (C282Y and H63D) are associated with increased uptake of Fe and other transition metals into cells as compared to the wild type genotype, hence our results suggest a role of transition metals in this PM2.5 effect. Concerning air pollution sources and mixtures, we have examined the differences in impact of PM2.5 on HRV by air mass origin using “backtrajectories” (Park et al 2007). We found that the effects of BC on all HRV measures were strongest on days with southwest trajectories, while the strongest associations of HRV with O3 occurred on days when air parcels came from the west. PM2.5, BC, and SO42- were associated with increased LF/HF ratio on days related to local, slow moving air masses.

Black Carbon Spatio-temporal model: We developed a GIS-based spatial smoothing model to predict 24-hr BC levels as part of our current Center. We used this model to predict address-specific exposures for NAS subjects and for subjects in other Boston-area cohorts. We generated address-specific exposures for more than 100,000 subjects within eastern Massachusetts using our BC model, and we examined the impact of BC on mortality (Maynard et al 2007). We also identified an inverse association between address-specific annual BC and telomere length in NAS subjects, using predicted BC from this model (under review, McCracken et al 2010). 

Inflammation, Endothelial Function, and Oxidative Stress: We observed positive associations between traffic-related PM (PN and BC) and inflammatory markers (CRP, WBC count, sediment rate, and fibrinogen) among subjects in the NAS cohort (Zeka et al 2006). A follow-up study looking at repeated measures of CRP and Fibrinogen is now under review (Bind et al 2010). We also found that exposures to traffic-related PM (BC and organic carbon) were associated with elevated plasma total homocysteine (Park et al 2008b). A follow-up in press shows effect modification by genes related to oxidative stress (Ren et al 2010a). PM2.5 and Black Carbon were associated with increased vascular cell adhesion in subjects, this association was modified by obesity, and by genes (Wilker et al 2009). We report associations between 8-OHdG and both PM2.5 and SO42-, but not BC in a cross-sectional study in review (Ren et al 2010b). Our continuing measurements of 8-OHdG in NAS subjects will improve our estimates of oxidative stress effects.  

Autonomic Dysfunction: We reported an association between short-term PM2.5 exposure and decreased HRV (Park et al 2005).  We found that subjects with wild type endothelial related genes (APOE, LPL and VEGF) showed stronger effects of PM2.5 on HRV compared to those with hetero- or homozygous genotypes (Ren et al 2010c). We found a negative association between PM2.5 and HRV in subjects with lower dietary intakes of methyl nutrients (folate, vitamins B(6) and B(12), methionine), but not in subjects with higher intakes, and the association was also modified by methyl-related gene polymorphisms in MTHFR and cSHMT genes. In addition, we found that genes related to oxidative stress modify this association (Chahine et al 2007).

Telomere Length: We recently reported that exposure to traffic was associated with shortened telomere length in blood leukocytes in a study comparing traffic officers to controls (Hoxha et al 2009). Preliminary results among nonsmokers in the NAS show an association between shorter telomere length and address-specific annual BC (under review). Our continuing collection of telomere data will allow us to follow-up this association in a more powerful longitudinal analysis.

Susceptibility: In addition to looking at genetic and dietary susceptibility factors, we have investigated obesity and diabetes as susceptibility factors for increased risk to air pollution responsiveness. We found obesity to be a significant susceptibility factor for O3 acute effects on lung function, with twice the estimated decrease in FEV1 due to O3 in obese subjects compared to non-obese subjects (Alexeev et al 2007). In addition, we found a greater effect of traffic-related PM on inflammatory markers in obese individuals (Zeka et al 2006).

Future Activities:

Our continuing measurements of 8-OHdG in NAS subjects will improve our estimates of oxidative stress effects.  We are processing our second set of measurements of augmentation index, telomere length, and 8-OHdG, and we continue to collect more data. With repeated measurements on each subject, we will have the power to examine effect modification by multiple sources of susceptibility and vulnerability. We have recently expanded our suite of inflammatory markers to include IL6, TNFα, and several others.

We have just begun analysis of the sub-clinical effects of temperature, to better understand the mechanisms underlying the effects of temperature on mortality. We have used our spatio-temporal model of BC to identify associations between long-term exposure to BC and decreased telomere length as well as increased blood pressure. We are starting to analyze many of our other outcomes in relation to our modeled BC exposures.

We are using epigenetics to study the effects of genes both directly, and as modifiers of responses to pollution, where certain subpopulations have genetic profiles that put them at increased risk to the health effects of air pollution. We also continue to study gene methylation, an important indicator of gene activation. We are also starting our novel analyses of MicroRNAs, examining whether they mediate the effects of environmental pollutants on human health, since certain miRNA profiles have been associated with cardiovascular disorders as well as vascular inflammation.


Journal Articles on this Report : 14 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 Alexeeff SE, Litonjua AA, Suh H, Sparrow D, Vokonas PS, Schwartz J. Ozone exposure and lung function: effect modified by obesity and airways hyperresponsiveness in the VA Normative Aging Study. Chest 2007;132(6):1890-1897. R832416 (2006)
R832416 (2009)
R832416 (Final)
R832416C001 (2008)
R832416C001 (2009)
R832416C001 (Final)
R827353 (Final)
  • Abstract from PubMed
  • Full-text: ScienceDirect-Full Text-HTML
    Exit
  • Abstract: ScienceDirectt-Abstract
    Exit
  • Other: ScienceDirect-Full Text-PDF
    Exit
  • Journal Article Chahine T, Baccarelli A, Litonjua A, Wright RO, Suh H, Gold DR, Sparrow D, Vokonas P, Schwartz J. Particulate air pollution, oxidative stress genes, and heart rate variability in an elderly cohort. Environmental Health Perspectives 2007;115(11):1617-1622. R832416 (2006)
    R832416 (2008)
    R832416 (2009)
    R832416 (Final)
    R832416C001 (2008)
    R832416C001 (2009)
    R832416C001 (Final)
    R827353 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ResearchGate-Full Text PDF
    Exit
  • Other: Harvard University-Full Text PDF
    Exit
  • Journal Article Hoxha M, Dioni L, Bonzini M, Pesatori AC, Fustinoni S, Cavallo D, Carugno M, Albetti B, Marinelli B, Schwartz J, Bertazzi PA, Baccarelli A. Association between leukocyte telomere shortening and exposure to traffic pollution:a cross-sectional study on traffic officers and indoor office workers. Environmental Health 2009;8:41. R832416 (2009)
    R832416C001 (2009)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: BioMed Central-Full Text HTML
    Exit
  • Other: BioMed Central-PDF
    Exit
  • Journal Article Maynard D, Coull BA, Gryparis A, Schwartz J. Mortality risk associated with short-term exposure to traffic particles and sulfates. Environmental Health Perspectives 2007;115(5):751-755. R832416 (2008)
    R832416 (2009)
    R832416C001 (2009)
    R827353 (Final)
    R827355 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Journal Article Park SK, O'Neill MS, Vokonas PS, Sparrow D, Schwartz J. Effects of air pollution on heart rate variability: the VA Normative Aging Study. Environmental Health Perspectives 2005;113(3):304-309. R832416 (2009)
    R832416C001 (2009)
    R827353 (Final)
    R827353C010 (Final)
    R831076 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Journal Article Park SK, O'Neill MS, Wright RO, Hu H, Vokonas PS, Sparrow D, Suh H, Schwartz J. HFE genotype, particulate air pollution, and heart rate variability: a gene-environment interaction. Circulation 2006;114(25):2798-2805. R832416 (2009)
    R832416C001 (2009)
    R827353 (Final)
    R827353C010 (Final)
    R831076 (Final)
  • Abstract from PubMed
  • Full-text: Circulation-Full Text PDF
    Exit
  • Abstract: Circulation-Abstract
    Exit
  • Journal Article Park SK, O'Neill MS, Stunder BJ, Vokonas PS, Sparrow D, Koutrakis P, Schwartz J. Source location of air pollution and cardiac autonomic function: trajectory cluster analysis for exposure assessment. Journal of Exposure Science & Environmental Epidemiology 2007;17(5):488-497. R832416 (2008)
    R832416 (2009)
    R832416C001 (2009)
    R827353 (Final)
    R827353C010 (Final)
    R831076 (Final)
  • Abstract from PubMed
  • Full-text: Nature-Full Text HTML
    Exit
  • Abstract: Nature-Abstract
    Exit
  • Other: Nature-Full Text PDF
    Exit
  • Journal Article Park SK, O’Neill MS, Vokonas PS, Sparrow D, Spiro III A, Tucker KL, Suh H, Hu H, Schwartz J. Traffic-related particles are associated with elevated homocysteine: the VA Normative Aging Study. American Journal of Respiratory and Critical Care Medicine 2008;178(3):283-289. R832416 (2006)
    R832416 (2009)
    R832416 (Final)
    R832416C001 (2008)
    R832416C001 (2009)
    R832416C001 (Final)
    R827353 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: AJRCCM-Full Text HTML
    Exit
  • Abstract: AJRCCM-Abstract
    Exit
  • Other: AJRCCM-Full Text PDF
    Exit
  • Journal Article Park SK, O’Neill MS, Vokonas PS, Sparrow D, Wright RO, Coull B, Nie H, Hu H, Schwartz J. Air pollution and heart rate variability: effect modification by chronic lead exposure. Epidemiology 2008;19(1):111-120. R832416 (2006)
    R832416 (2009)
    R832416 (Final)
    R832416C001 (2008)
    R832416C001 (2009)
    R832416C001 (Final)
    R827353 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Epidemiology-Full Text HTML
    Exit
  • Abstract: Epidemiology-Abstract
    Exit
  • Other: Epidemiology-Full Text PDF
    Exit
  • 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)
    R832416 (Final)
    R832416C001 (2009)
    R832416C001 (2010)
    R832416C001 (Final)
    R827353 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: JECH-Abstract
    Exit
  • 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)
    R832416 (Final)
    R832416C001 (2009)
    R832416C001 (2010)
    R832416C001 (Final)
    R827353 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: Epidemiology-Abstract
    Exit
  • Journal Article Ren C, Fang S, Wright RO, Suh H, Schwartz J. Urinary 8-hydroxy-2'-deoxyguanosine as a biomarker of oxidative DNA damage induced by ambient pollution in the Normative Aging Study. Occupational and Environmental Medicine 2011;68(8):562-569. R832416 (2009)
    R832416C001 (2009)
  • Abstract from PubMed
  • Abstract: Occupational and Environmental Medicine-Abstract
    Exit
  • 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)
    R832416 (Final)
    R832416C001 (2009)
    R832416C001 (2010)
    R832416C001 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ResearchGate-Abstract
    Exit
  • Abstract: Atherosclerosis-Abstract
    Exit
  • Journal Article Zeka A, Sullivan JR, Vokonas PS, Sparrow D, Schwartz J. Inflammatory markers and particulate air pollution:characterizing the pathway to disease. International Journal of Epidemiology 2006;35(5):1347-1354. R832416 (2008)
    R832416 (2009)
    R832416C001 (2009)
    R827353 (Final)
    R827353C004 (Final)
    R827353C010 (Final)
  • Abstract from PubMed
  • Full-text: Oxford Journals-Full Text HTML
    Exit
  • Abstract: Oxford Journals-Abstract
    Exit
  • Other: Oxford Journals-Full Text PDF
    Exit
  • 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
  • 2010 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