Final Report: Relating Changes in Blood Viscosity, Other Clotting Parameters, Heart Rate, and Heart Rate Variability to Particulate and Criteria Gas Exposures

EPA Grant Number: R827353C010
Subproject: this is subproject number 010 , established and managed by the Center Director under grant R827353
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: EPA Harvard Center for Ambient Particle Health Effects
Center Director: Koutrakis, Petros
Title: Relating Changes in Blood Viscosity, Other Clotting Parameters, Heart Rate, and Heart Rate Variability to Particulate and Criteria Gas Exposures
Investigators: Speizer, Frank E. , Park, S.
Institution: Harvard T.H. Chan School of Public Health , Harvard University
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
Project Amount: Refer to main center abstract for funding details.
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air


Theme III: Biological Mechanisms/Dosimetry: Theme III focused upon mechanisms of cardiac vulnerability as a result of air pollution exposure. Many of our concentrated ambient particles (CAPs) animal toxicology and human panel studies have linked pulmonary and cardiovascular health outcomes to different particulate matter (PM) components such as trace metals, elemental carbon, sulfates and silicon (Batalha, et al., 2002; Clarke, et al., 2000; Saldiva, et al., 2002). Reanalysis of the Harvard Six Cities study provided strong evidence of increased toxicity associated with combustion-related PM from traffic and power plants compared to soil dust (Laden, et al., 2000).

The objectives of Theme III were to identify the particulate and gaseous air pollutants responsible for increased cardiac vulnerability as an adverse health effect and to define the biological mechanisms that lead to this outcome. As part of this theme, we specifically worked to: (1) identify the physical and chemical properties of particulate matter responsible for the observed adverse health effects; (2) determine whether gaseous co-pollutants exacerbate the effects of particles; (3) investigate the biological mechanisms by which particulate matter produces mortality and acute or chronic morbidity; and (4) examine particle deposition patterns and fate in the respiratory tract. These objectives were addressed in several areas of research that explored the components of air pollution that cause adverse health effects and the biological mechanisms that may lead to fatal outcomes. The projects under this theme built upon the findings from a number of our previous animal studies, which made it possible to explore and define both cardiac and pulmonary responses to inhaled fly ash and concentrated ambient particles (Killingsworth, et al., 1997).

For another major project under Theme III of the Center, we monitored the health of approximately 700 Normative Aging Study (NAS) participants, who were examined between 2000 and 2003. The NAS is a longitudinal study of aging in Eastern Massachusetts established in 1963 by the Veterans Administration (VA). Community-dwelling men from the greater Boston metropolitan area were screened at entry and accepted into the study if they had no history of heart disease, hypertension, diabetes mellitus, cancer, peptic ulcer, gout, recurrent asthma, bronchitis, or sinusitis. Between 1963 and 1968, a total of 2,280 men were enrolled, ranging in age from 21 to 80 years (mean = 42 years) at entry. As of April 2004, 757 (mean age = 76+7 years) of the 2,280 men continue to participate in the study. 17% of these men are diabetic; 24% have coronary heart disease; 22% have chronic obstructive pulmonary disease (COPD); and 58% are hypertensive. Correspondingly, beta-blockers are used by 33% of the subjects and calcium channel blockers by 14%; and 45% of the men are GSTM1 null.

As part of the original NAS study, physical examinations of each study participant occur every three years at the Boston VA Hospital. At each of these visits, extensive physical examination, laboratory, anthropometric, and questionnaire data are collected, including height and weight, a complete medical history, and sitting heart rate, and dietary intake using the Willet semi-quantitative Food Frequency Questionnaire. In addition, sitting systolic (SBP) and diastolic blood pressures (DBP) are measured as the means of the left and right arm measurements. Blood samples are collected and analyzed for total serum cholesterol, high-density lipoprotein cholesterol, fasting blood glucose (FBG) levels, white cell counts with differentials, and other standard parameters. Information about cigarette smoking, alcohol consumption, medical history (including respiratory and cardiac symptoms), and medication use are obtained by self–administered questionnaire. Each subject is interviewed by a physician to confirm the identity and purpose of medications used. Incidence of new disease is also noted. For all reported coronary diseases, hospital records are obtained and reviewed by a board certified cardiologist. Criteria used to confirm coronary diseases follow the established protocols used in the Framingham Heart Study and are classified using the 10th edition of the International Classification of Disease. Subjects are recorded as having diabetes if they meet American Diabetes Association criteria (FBG levels greater than 126 mg/dL and/or physician-diagnosed diabetes).

In addition to the regularly collected data, we collected additional electrocardiograph (ECG) measurements for each NAS participant at his/her clinic visit. Also, we analyzed collected blood samples for C-reactive protein (CRP), a marker of systemic inflammation. ECG recordings were analyzed for heart rate variability (HRV). HRV measures included the standard deviation of NN intervals (SDNN), the square root of the mean of the squared differences between adjacent NN intervals (r-MSSD), total power (TP) (< 0.4 Hz), high frequency (HF) (0.15 to 0.4 Hz), low frequency (LF) (0.04 to 0.15 Hz), and LF/HF ratio using software complying with European Society of Cardiology and North American Society of Pacing and Electrophysiology guidelines. Subjects with atrial fibrillation, atrial bigeminy and trigeminy, pacemakers, irregular rhythm, irregular sinus rhythm, frequent ventricular ectopic activity, ventricular bigeminy, multifocal atrial tachycardia, or measurement time less than 3.5 minutes were not included in the analysis.

Summary/Accomplishments (Outputs/Outcomes):

In this study, we found an association between reduced HRV and both PM2.5 and ozone, after controlling for age, diastolic blood pressure, fasting blood glucose level, cigarette smoking, angiotensin converting enzyme (ACE) inhibitor use, room temperature, season, and outdoor temperature (Park, et al., 2005). Associations with black carbon (BC) were slightly weaker than those for PM2.5, while other pollutants showed little association with HRV. The pollution associations were strongest for participants with hypertension (defined as either taking hypertension medication or having an SBP >140 or DBP > 90). The effects of PM2.5 and ozone on LF were muted or blocked in those taking either calcium channel blockers or β-blockers, while the HF response was not affected. Effect modification was not observed for participants on ACE inhibitors, which reduce blood pressure via different cardiac pathways.

Air Pollution, HRV, and Genes Related to Oxidative Stress

We have reanalyzed the association between air pollution and HRV using a subset of NAS participants for whom genotyping was performed as part of a separate study. In the subset analysis, no effect of particles was seen in subjects with GSTM1 present, and a substantially greater effect was seen in those with the GSTM1 deletion. In addition, three-way interactions were also seen, whereby the effect of PM was modified by both GSTM1 and either obesity or elevated neutrophils (suggesting a role for systemic inflammation), or statins (which in addition to lowering cholesterol and CRP, have antioxidant properties, specifically enhanced NO synthase and reduced endothelin-1). Table 1 shows these results.

Table 1. Effect of 10 μg/m3 PM2.5 on HF by GSTM1 Status and Other Modifier



% Change

95% CI

GSTM1 Null, No Statin
GSTM1 Null, Statin
GSTM1 Present, No Statin
GSTM1 Present, Statin



-53.0, -7.20
-66.5, 161.9
-40.5, 56.2
-50.0, 87.2

GSTM1 Null, High Neutrophils*
GSTM1 Null, Normal Neutrophils‡
GSTM1 Present, High Neutrophils*
GSTM1 Present, Normal Neutrophils‡



-88.0, 63.1
-55.2, -8.7
-86.4, 86.1
-20.0, 73.0

GSTM1 Null, Obeseº
GSTM1 Null, not Obeseº
GSTM1 Present, Obeseº
GSTM1 Present, not Obeseº



-88.0, 52.0
-50.6, -3.6
-77.9, 96.5
-29.7, 64.3

* Upper 25th percentile of the distribution in the study population
‡ Lower 75 percent of the distribution in the study population
º Obesity—Body Mass Index (BMI) of 30 (kg/m2) or greater

Air Pollution, HRV, and Genes Related to Metal Metabolism

We also examined whether HFE modified the association between PM2.5 and HRV in the NAS (Park, et al., 2006). We found a 32.4% (95% confidence interval, 11.1% to 48.5%) decrease in HF component of HRV in persons with wild-type, whereas no relationship was observed in persons with either HFE variant. The difference in effect of PM2.5 on HF between persons with and without HFE variants was significant (p for interaction = 0.02). We also found an association with LF, but only in the HFE variant carriers (19% reduction).

Ambient Pollution and Blood Markers of Inflammation/Endothelial Function

We examined the effects of several pollutants (BC, total particle count, and PM2.5) on inflammatory markers and blood parameters for the 710 NAS subjects between 2000 and 2003. Fibrinogen was elevated in association with BC and particle count concentrations, and CRP was marginally significantly elevated in association with those particle measures in the entire cohort, and significantly elevated in association with particles in the subset with BMI over 30. A paper with these results is in press.


Results from this study suggest that short-term exposures to PM2.5 and O3 are predictors of alterations in cardiac autonomic function as measured by HRV among older adults. Persons with ischemic heart disease (IHD), hypertension, and diabetes appear to be more susceptible to autonomic dysfunction related to PM2.5 exposure. The consistency of the effect modification observed in this and other studies strengthens the evidence that these conditions mark susceptibility to air pollution exposure and provides new information to guide research on underlying biological mechanisms.


Batalha JRF, Saldiva PHN, Clarke RW, Coull BA, Stearns RC, Lawrence J, Krishna Murthy GG, Koutrakis P, Godleski JJ. Concentrated ambient air particles induce vasoconstriction of small pulmonary arteries in rats. Environmental Health Perspectives 2002;110(12):1191-1197.

Clarke RW, Coull BA, Reinisch U, Catalano P, Killingsworth CR, Koutrakis P, Kavouras I, Krishna Murthy GG, Lawrence J, Lovett EG, Wolfson JM, Verrier RL, Godleski JJ. Inhaled concentrated ambient particles are associated with hematologic and bronchoalveolar lavage changes in canines. Environmental Health Perspectives 2000;108(12):1179-1187.

Killingsworth C, Alessandrini F, Murthy G, Catalano P, Paulauskis J, Godleski J. Inflammation, chemokine expression, and death in monocrotaline-treated rats following fuel oil fly ash inhalation. Inhalation Toxicology 1997;9:541-565.

Laden F, Neas L, Dockery D, Schwartz J. Association of fine particulate matter from different sources with daily mortality in six U.S. cities. Environmental Health Perspectives 2000;108(10):941-947.

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.

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.

Saldiva PH, Clarke RW, Coull BA, Stearns RC, Lawrence J, Koutrakis P, Suh H, Tsuda A, Godleski JJ. Acute pulmonary inflammation induced by concentrated ambient air particles is related to particle composition. American Journal of Respiratory and Critical Care Medicine 2002;165(12):1610-1617.

Journal Articles on this Report : 6 Displayed | Download in RIS Format

Other subproject views: All 6 publications 6 publications in selected types All 6 journal articles
Other center views: All 200 publications 198 publications in selected types All 197 journal articles
Type Citation Sub Project Document Sources
Journal Article Baccarelli A, Zanobetti A, Martinelli I, Grillo P, Hou L, Giacomini S, Bonzini M, Lanzani G, Mannucci PM, Bertazzi PA, Schwartz J. Effects of exposure to air pollution on blood coagulation. Journal of Thrombosis and Haemostasis 2007;5(2):252-260. R827353 (Final)
R827353C010 (Final)
  • Abstract from PubMed
  • Full-text: Wiley Online-Full Text HTML
  • Abstract: Wiley Online-Abstract
  • Other: Wiley Online-Full Text PDF
  • 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. R827353 (Final)
    R827353C010 (Final)
    R831076 (Final)
    R832416 (2009)
    R832416C001 (2009)
  • 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. R827353 (Final)
    R827353C010 (Final)
    R831076 (Final)
    R832416 (2009)
    R832416C001 (2009)
  • Abstract from PubMed
  • Full-text: Circulation-Full Text PDF
  • Abstract: Circulation-Abstract
  • 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. R827353 (Final)
    R827353C010 (Final)
    R831076 (Final)
    R832416 (2008)
    R832416 (2009)
    R832416C001 (2009)
  • Abstract from PubMed
  • Full-text: Nature-Full Text HTML
  • Abstract: Nature-Abstract
  • Other: Nature-Full Text PDF
  • Journal Article Schwartz J, Park SK, O'Neill MS, Vokonas PS, Sparrow D, Weiss S, Kelsey K. Glutathione-S-transferase M1, obesity, statins, and autonomic effects of particles:gene-by-drug-by-environment interaction. American Journal of Respiratory and Critical Care Medicine 2005;172(12):1529-1533. R827353 (Final)
    R827353C010 (Final)
    R832416 (2008)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ATS Journals-Full Text HTML
  • Abstract: ATS Journals-Abstract
  • Other: ATS Journals-Full Text PDF
  • 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. R827353 (Final)
    R827353C004 (Final)
    R827353C010 (Final)
    R832416 (2008)
    R832416 (2009)
    R832416C001 (2009)
  • Abstract from PubMed
  • Full-text: Oxford Journals-Full Text HTML
  • Abstract: Oxford Journals-Abstract
  • Other: Oxford Journals-Full Text PDF
  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, Air, Geographic Area, particulate matter, Toxicology, air toxics, Environmental Chemistry, Epidemiology, State, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Disease & Cumulative Effects, Environmental Monitoring, Atmospheric Sciences, Molecular Biology/Genetics, Biology, Environmental Engineering, ambient air quality, health effects, interindividual variability, molecular epidemiology, monitoring, particle size, particulates, risk assessment, sensitive populations, cardiac arrhythmia, chemical exposure, atmospheric particulate matter, air pollutants, cardiopulmonary responses, health risks, human health effects, ambient air monitoring, exposure and effects, ambient air, ambient measurement methods, exposure, pulmonary disease, developmental effects, epidemelogy, respiratory disease, automotive emissions, air pollution, children, Human Health Risk Assessment, Massachusetts (MA), particle exposure, lung cancer, biological mechanism , cardiopulmonary response, chronic effects, human exposure, inhalation, pulmonary, particulate exposure, ambient particle health effects, blood viscosity, heart rate, elderly, inhaled, PM, human susceptibility, inhalation toxicology, gaseous co-polutants, cardiopulmonary, indoor air quality, inhaled particles, human health, cardiac ischemia, traffic related air pollution, air quality, cardiovascular disease, dosimetry, human health risk, metals, respiratory, genetic susceptibility, cardiopulmonery responses, toxics

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    Progress and Final Reports:

    Original Abstract
  • 1999
  • 2000 Progress Report
  • 2001 Progress Report
  • 2002 Progress Report
  • 2003 Progress Report
  • 2004

  • Main Center Abstract and Reports:

    R827353    EPA Harvard Center for Ambient Particle Health Effects

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R827353C001 Assessing Human Exposures to Particulate and Gaseous Air Pollutants
    R827353C002 Quantifying Exposure Error and its Effect on Epidemiological Studies
    R827353C003 St. Louis Bus, Steubenville and Atlanta Studies
    R827353C004 Examining Conditions That Predispose Towards Acute Adverse Effects of Particulate Exposures
    R827353C005 Assessing Life-Shortening Associated with Exposure to Particulate Matter
    R827353C006 Investigating Chronic Effects of Exposure to Particulate Matter
    R827353C007 Determining the Effects of Particle Characteristics on Respiratory Health of Children
    R827353C008 Differentiating the Roles of Particle Size, Particle Composition, and Gaseous Co-Pollutants on Cardiac Ischemia
    R827353C009 Assessing Deposition of Ambient Particles in the Lung
    R827353C010 Relating Changes in Blood Viscosity, Other Clotting Parameters, Heart Rate, and Heart Rate Variability to Particulate and Criteria Gas Exposures
    R827353C011 Studies of Oxidant Mechanisms
    R827353C012 Modeling Relationships Between Mobile Source Particle Emissions and Population Exposures
    R827353C013 Toxicological Evaluation of Realistic Emissions of Source Aerosols (TERESA) Study
    R827353C014 Identifying the Physical and Chemical Properties of Particulate Matter Responsible for the Observed Adverse Health Effects
    R827353C015 Research Coordination Core
    R827353C016 Analytical and Facilities Core
    R827353C017 Technology Development and Transfer Core