Grantee Research Project Results
2007 Progress Report: Cardiovascular Responses in the Normative Aging Study: Exploring the Pathways of Particle Toxicity
EPA Grant Number: R832416C001Subproject: 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: Health Effects Institute (2015 - 2020)
Center Director: Greenbaum, Daniel S.
Title: Cardiovascular Responses in the Normative Aging Study: Exploring the Pathways of Particle Toxicity
Investigators: Schwartz, Joel , Suh, Helen H. , Sparrow, David , 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: October 1, 2006 through September 30, 2007
RFA: Particulate Matter Research Centers (2004) RFA Text | Recipients Lists
Research Category: Human Health , Air
Objective:
The EPA Particle Center at HSPH now includes four projects (the 2nd of the original 5 was eliminated, as discussed in the 1st year progress report, and the projects were re-numbered accordingly): Project 1, with a focus on exploring the pathways of particle toxicity for cardiovascular responses in the Normative Aging Study is being conducted for Years One through Three. Project 2, with a focus on cardiovascular toxicity of concentrated ambient fine, ultrafine and coarse particles in controlled human exposures, is being conducted for Years One through Five. Project 3, with a focus on assessing toxicity of local and transported ambient particles using animal models exposed to CAPs, is being conducted for Years One through Three. Project 4, with a focus on assessing toxicity of vehicular emissions, using animal models, will be conducted for Years Three through Five. This 2nd year progress report includes preliminary results for (re-numbered) Projects 1, 2, and 3.
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 new 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. As proposed, these additional measurements will include ECG, blood inflammatory marker, medication, genotypic, food frequency, and particle exposure measurements for each of the current NAS participants, with measurements of urine oxidative stress markers added to the study in the past year. ECG, blood and urine samples are being analyzed for a variety of measures (HRV, ST segments, QT intervals, CRP, sICAM-1, sVCAM-1, homocysteine, 8-OHdG and creatinine); these measures will be used as intermediate markers of the inflammatory, endothelial, oxidative stress and autonomic pathways. In addition, these measures 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 PN) concentrations that are being measured at our stationary ambient monitoring (SAM) site. The study will use this data to test three primary hypotheses (with amendments to these hypotheses in italics):
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 increased arrhythmias;
- oxidative stress, as measured by increases in 8-OHdG and creatinine and;
- general cardiovascular responses,as measured by increases in blood pressure and ECG changes including ST-segment level and QT-length.
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-transferase (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 made substantial progress in our NAS study, both in the analysis of data previously collected as part of our original Harvard-EPA Particle Center and in the collection of new data for our current Harvard-EPA Particle Center. This progress is discussed briefly below.
Analysis of Previously Collected Data: In Year Two, we continued our analysis and interpretation of data collected on the NAS participants as part of our original Harvard-EPA Particle Center. These analyses have focused on the relation between ambient pollution and intermediate cardiac (HRV) and pulmonary (pulmonary function), and inflammatory (white blood count, C-reactive protein (CRP), fibrinogen) outcomes and on how these relationships vary with individual-specific factors, such as genetic polymorphisms, diet, and weight. Results from these analyses have helped to identify important biological pathways by which ambient particles may impact health and important susceptible populations. Findings from these analyses have been presented at conferences and have been submitted or published in peer-reviewed journals, with representative papers discussed briefly below.
- In a paper by Park et al. (2006), we investigated the relation between ambient particles and HRV in our NAS subjects and examined whether this relation was mediated by transition metals, such as iron, which have been shown to produce reactive oxygen species when present in high concentrations in humans. The importance of transition metals to particle toxicity was examined using polymorphisms in the hemochromatosis (HFE) gene, two of which (C282Y and H63D) are associated with increased uptake of iron and other transition metals as compared to the wild type genotype. Polymorphisms in the HFE gene were hypothesized to be important, as it was possible that differences in transition metal uptake would lead to corresponding differences in the effects of particle-bound transition metals on cardiac function, as was found with blood and bone levels of the transition metal lead. Results from our analysis showed that the impact of PM2.5 on HRV was indeed modified by HFE variants, with ambient PM2.5 negatively associated with the high frequency (HF) component of HRV in individuals with the wild type genotype, but having no association in individuals with the C282Y or H63D variant. These results suggest that the effect of PM2.5 on cardiac autonomic function is shielded in individuals with greater iron uptake and that PM-associated iron and other transition metals may be important to particle toxicity. Further, results suggest that the oxidative stress and/or inflammatory pathways may be important to PM-mediated toxicity.
- As discussed in Park et al. (2007), we investigated whether the impact of ambient particles on HRV in our NAS subjects differs by air mass origin, as an indicator of important pollution sources. To do so, the paths traveled by the air masses (“back-trajectories”) before arriving in Boston were identified, classified into six clusters and subsequently related to pollution and several HRV measures.
We found that the effects of black carbon (BC) on all HRV measures were strongest on days with southwest trajectories. Subjects who were examined on days when air parcels came from the west had the strongest associations of HRV with ozone. PM2.5, BC, and sulfates were associated with increased LF/HF ratio on days related to local, slow moving air masses. Also significant increases in LF/HF were associated with days when air came from the northwest and west compared to north trajectory days. Results suggest that the effects of ambient particles on HRV differs by the origin of pollutant air masses, providing further evidence that the impacts of ambient particles on autonomic function differs for different particle sources.
- As shown in Zeka et al. (2006), we used the NAS cohort to investigate particle-mediated impacts on several markers of inflammation and thrombotic activity, which may play key roles in the physio-pathological processes leading to cardiovascular disease and mortality. We examined the impacts of ambient particles on inflammation and thrombotic activity using white blood cell counts (WBC), CRP, sediment rate, and fibrinogen and investigated whether these impacts were modified by age, health status, polymorphisms in glutathione-S-transferases (GSTM1: a key factor in cellular defenses against reactive oxygen species), and statin medications. Further, we examined whether these impacts varied with particle component, with specific emphasis on the traffic related components, BC and particle number (PN).
We found both BC and PN to be related to increased inflammation, with associations most consistent for the thrombotic factor fibrinogen and strongest when exposures were averaged over the 4-weeks prior to the measurement. Although no statistically important difference was found for any category of effect modifiers, results suggested that older individuals (>78 years of age) increased the effect of PN on fibrinogen and CRP levels. Similarly, the association between fibrinogen and PN and between BC and CRP was approximately two- and four-fold higher among the obese, respectively. Results also suggested the GSTM1-null subjects and non-statin users had a greater BC-mediated inflammatory effect; however, these differences were not statistically significant. These findings are consistent with an adverse effect of ambient particles on inflammation and thrombotic activity, with these effects strongest for traffic-related particles and possibly in individuals older than 78 years, individuals with chronic pro-inflammatory states (as shown for obese individuals), and individuals with reduced defenses to reactive oxygen species (as shown for people with the GSTM1-null genetic polymorphism or in non-statin users).
- In Gyparis et al. (2007), we presented our GIS-based spatial smoothing model that was developed to predict 24-hr outdoor black carbon concentrations across eastern Massachusetts. This model is based on repeated observations from roughly 100 different locations, derived from State and Federal monitoring networks and from our previous exposure studies funded by our original Harvard-EPA Center. This model extends previous work by including both a regression approach (prediction by variables such as distance to road, etc.) as well as a geospatial smoothing term. In addition, by combining several surrogates of traffic particles (EC, BC, NO2), it allows us to obtain an estimate of traffic particle exposure using structural equation modeling that incorporates a measurement error correction. We showed that this model predicts 24-hr BC concentrations extremely well, resulting in an R2 of 0.81 when 24-hr estimates were regressed on measured concentrations. Model performance is even higher when used to predict annual average BC levels.
This model has subsequently been used to examine the impact of participant specific outdoor BC exposures on mortality within eastern Massachusetts (Maynard et al., 2007) and will also be used to examine the relation between outdoor BC exposures and HRV, inflammatory, oxidative stress, and endothelial function outcomes for our NAS subjects. Prior to this application, however, the model will be revised to include a daily interaction between planetary boundary layer (PBL) and spatial terms to allow for greater temporal-spatial resolution. This revised model will be used to impute more precise short and long term particle exposures for the NAS participants.
Data Collection: In Year Two, we continued to collect information for NAS participants as they came in for their every three-year health exam. At each health exam, we specifically collected ECG, blood inflammatory marker, and daily diet information on the study participants. We supplemented these measurements with those of 8-OHdG and creatinine in urine, which were added to obtain direct measures of oxidative stress in our participants. This addition was possible through the reallocation of funds originally allocated to the project that was eliminated (The Cardiovascular Effects of Particles and Gaseous Co-pollutants from Mobile Sources – the “old” Project 2). In total, we obtained new data for approximately 150 participants, less than anticipated due to attrition from death (73 subjects), sickness (22 subjects), or dropouts (e.g., could participate but decided to miss their health appointment; 7 subjects). Most of the participants were seen in the non-winter months.
In addition to the health measurements, we also collected one-week long indoor PM2.5 samples inside the homes of 83 NAS participants. These subjects were recruited from the NAS subjects that lived in a non-smoking household and that were going to be at home for the week prior to their health visit. Originally, recruitment also was to be limited to subjects that lived within the greater metropolitan Boston area (defined as within Route 495 highway); however, these criteria were relaxed to allow recruitment of subjects living in southeastern Massachusetts and southern New Hampshire. Of the 53 NAS subjects who did participate in the indoor monitoring portion of the study, fifteen lived outside of our geographic recruitment area, 25 had a health clinic visit prior to the start of indoor monitoring, three lived in a smoking household, five were confused or overwhelmed by the indoor monitoring requirements, and five did not volunteer for the indoor monitoring portion of the study.
Laboratory Analysis: We continued to analyze collected health data, with laboratory analysis of HRV, blood and urine samples conducted in the appropriate laboratories. To obtain ECG measures in addition to HRV, we re-analyzed ECG tapes using software from Forest Medical for ST segments, arrhythmias, and QT length. This additional analysis, however, does not include ECG tapes for individuals seen between mid-March and mid-September 2006, which were lost due to problems with computer backups (Figure 1). This data loss does not affect the HRV measures. Indoor PM2.5 samples have been off-weighed, with concentrations processed. The samples are currently scheduled for BC (by reflectance) and sulfate (by ion chromatography) analysis in our laboratory.
Figure 1. Number of Currently Available ECG tapes by Month
Future Activities:
We are continuing to collect HRV, blood and urine samples at each participant’s health visit and to recruit participants for indoor sampling. For Study Year 3, we anticipate that 140 subjects will be seen at their NAS health appointment, with approximately 60% of these individuals participating in the indoor monitoring component of the study. This number is lower than we had previously anticipated, due to attrition from death, illnesses, and general age-related issues. For participants that have moved since our last address geocoding, we will update residential addresses and geocodes.
In addition, we will continue to analyze data in the laboratory using statistical methods. Laboratory analyses will include analysis of ECG, blood and urine markers discussed above. We plan to begin our statistical analyses of PM exposures and ST, arrhythmias, QT length, 8-OHgD, and ICAM and VCAM data. These analyses will include exposures estimated using our GIS-based spatial model and our measured indoor concentrations.
Journal Articles:
No journal articles submitted with this report: View all 68 publications for this subprojectSupplemental 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, airborne particulate matter, cardiovascular vulnerability, automobile exhaust, biological mechanisms, traffic related particulate matter, chemical composition, biological mechanism , human exposure, ambient particle health effects, autonomic dysfunction, oxidative stressRelevant Websites:
http://www.hsph.harvard.edu/epacenter/ Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R832416 Health Effects Institute (2015 - 2020) 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
The 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.
Project Research Results
- Final Report
- 2010 Progress Report
- 2009 Progress Report
- 2008 Progress Report
- 2006 Progress Report
- Original Abstract
67 journal articles for this subproject
Main Center: R832416
206 publications for this center
199 journal articles for this center