2001 Progress Report: Inflammatory Responses and Cardiovascular Risk Factors in Susceptible Populations

EPA Grant Number: R827354C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R827354
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Airborne PM - Rochester PM Center
Center Director: Oberdörster, Günter
Title: Inflammatory Responses and Cardiovascular Risk Factors in Susceptible Populations
Investigators: Wichmann, Heinz-Erich , Heyder, Joachim , Peters, Annette
Current Investigators: Wichmann, Heinz-Erich , Peters, Annette
Institution: GSF - Forschungszentrum fur Umwelt und Gesundheitand Ludwig Maximilian University, Neuherberg, Germany
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
Project Period Covered by this Report: June 1, 2001 through May 31, 2002
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air


The objective of this research project is to characterize the association between ambient particle exposures and changes in biomarkers of inflammation in both the airways and blood of patients with stable coronary artery disease (CAD), as well as of patients with chronic obstructive pulmonary disease (COPD). By monitoring the autonomic function of the heart, we will be able to investigate how changes in the inflammatory state relate to alterations in the autonomic control.

Progress Summary:

Thus far, all published evidence on the effects of particulate air pollution on the autonomic nervous system function is based on panels of healthy elderly subjects (Pope, et al. 1999a, Pope, et al. 1999b, Liao, et al. 1999, Gold, et al. 2000, Creason, et al. 2001), population based samples (Peters, et al. 1999), or occupational cohorts (Magari, et al. 2001). A European multicenter study on patients with CAD, the Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air (ULTRA) study, did not observe an association between ambient air pollution and autonomic nervous system function (Timonen, et al. 2001, Ibald-Mulli, et al. 2001b). Nevertheless, particulate air pollution was associated with ST-segment depression as a sign for ischemia (Pekkanen, et al. 2001). It might therefore be that ischemic events, rather than altered autonomic control, might be the main mechanism in patients with CAD. Recent work on the role of particles as a trigger of myocardial infarctions (Peters, et al. 2001b) support the effects seen in the ULTRA study. Therefore, the first set of analyses will address the following questions:

· Do fine and ultrafine particles not affect blood pressure, heart rate, and heart rate variability as seen in the ULTRA study?

· Are signs of QTc reduction observed as in the human exposure studies of the University of Rochester–Environmental Protection Agency Particulate Matter (PM) Center (referred to as “the Center”)?
· Are ventricular ectopic beats and arrhythmia more prevalent on days with high concentrations of fine and ultrafine particles, as in the ULTRA study?

· Are signs of ischemia present in 24 electrocardiogram (ECG) readings during exercise periods in association with fine and ultrafine particles ?

So far, evidence on an association between ambient concentrations of particulate matter and markers of blood coagulability were only obtained in cross-sectional settings (Peters, et al. 1997, Pekkanen, et al. 2000, Schwartz 2001, Peters, et al. 2001a). Only one study assessed this association in healthy elderly subjects, and no effect was observed (Seaton, et al. 2000). Therefore, the second set of analyses will investigate systemic effects of fine and ultrafine particles in subjects with preexisting disease, based on changes in blood parameters of inflammation and coagulability. The following questions will be addressed:

· Do white blood cell counts increase in association with fine and ultrafine particles reflecting the recruitment of leukocytes to the lung?

· Do red blood cells decrease based on the process of sequestration?

· Do acute phase reactants increase in association with fine and ultrafine particles?

· Will plasma viscosity increase in association with fine and ultrafine particles?

· Do clotting factors also increase in association with fine and ultrafine particles?

The first time-series study on mortality that considers ultrafine particles in addition to particles showed relative risk estimates of comparable sizes in association with cumulated particle concentrations over the last 4 days (Wichmann, et al., 2000). In addition, the data suggests that respiratory mortality increased immediately after elevated concentrations of particles, while cardiovascular disease mortality showed a delay of up to 4 days. Therefore, we will investigate the lag-structure carefully in all analyses.

Two panel studies are being conducted to assess the health effects of fine and ultrafine particles on patients with cardiopulmonary disease. A panel of CAD patients was studied during winter 2000/2001, and a second panel of COPD patients was recruited for winter 2001/2002.

The study protocol and outcome measures were designed to be as similar as possible to that of the clinical studies of the Center. Blood biomarkers are analyzed by the vascular core under the lead of Victor Marder, and ECG recordings are analyzed by the cardiac core lead by Wojciech Zareba. For the CAD patients, it comprised a maximum of 12 bimonthly clinical examinations, with an interview, resting ECG, blood pressure measurement, urine sample, and blood sample. Further, 6 monthly 24-hour holter recordings and daily blood pressure measurements for a period of 1 month, were taken. Throughout the whole study period, subjects were recording symptoms and medication use in a diary. For the COPD patients, additional baseline characterization of the health status by bodyplethysmogaphy and spirometry before and after bronchodilater use was added to the initial baseline examination. Further pulseoximetry and an exercise challenge during the ECG recording, as well as lung function testing by Impulse-Oscillation-Spirometry, was added to the clinical protocol. The selection criteria were based on the recommendations of the scientific advisory board in collaboration with researchers from Rochester, NY. Local expertise from the German National Research Center for Environmental and Health (GSF)-Aerosol Research Program was provided to implement the additional measurements for the COPD panel.

Table 1 shows the summary statistics of the panel studies on CAD and COPD patients. The study recruited 58 CAD patients who performed 98 percent of the scheduled clinic visits. Similarly, the 98 COPD patients performed 98 percent of the sheduled clinics. Compliance with 24 ECG recordings and exercise tests were lower (around 80 percent) for the two groups of patients. The CAD patients had little evidence for COPD, but nearly half of the COPD patients also had CAD. We recruited only non-smoking CAD patients, but we decided to include 18 percent smokers into our COPD panel. The amount of cigarettes smoked were recorded both in the protocol at the clinic visit and in the diary.

Table 1. Summary Statistics of the Panel Studies.

Study period
10/00 to 04/01
10/01 to 04/02
Participants (n)
Clinical Examinations (n)
683 (98%)§
460 (98%)
20-min ECG (n)
678 (97%)
460* (98%)
24-hr. ECG(n)
279 (80%)
181 (77%)
Blood samples (n)
659 (95%)
439 (94%)
Lung funcion tests (n)
not in protocol
459 (98%)
51 to 76
36 to 79
History of Angina pectoris (n)
38 (66%)#
15 (38%)
Myocardial infarction
43 (74%)
8 (21%)
By-pass surgery/Ballon dilation
50 (86%)
4 (10%)
Chronic bronchitis
2 (3%)
29 (74%)
4 (7%)
39 (100%)
Asthma Emphysema
1 (2%)
21 (54%)
Hay fever
2 (3%)
11 (28%)
Current Smoker (n)
7 (18%)
Non-Smoker (n)
58 (100%)
32 (82%)
    Range (kg/m2)
22 to 38
18 to 36
    Mean (kg/m2)
§ = percent of scheduled examinations
* = 89 had a 20-minute ECG without exercise challenge
# = percent of participants

CAD Panel Study. For the CAD panel, all questionnaire based data was entered and has been checked for plausibility. The ECGs obtained in Erfurt, Germany during the first field phase have been analyzed by the cardiac core. The ECG-data have been transferred and will be analyzed in association with the air pollution data. Analyses of the blood parameters by the vascular core are ongoing because shipment of blood samples from Germany was postponed after September 11th. The same blood parameter and ECG parameter will be determined by the same core facilities for the epidemiological studies and the human exposure studies. Therefore, the results will be directly comparable to those of the human exposure studies.

The CAD patients field study was conducted during winter 2000/2001 (see Table 2). Unfortunately, no aerosol spectrometer data are available between January 20th and February 13th due to a technical defect of the measuring device. Data will be imputed by calculating the ultrafine particle fraction based on total number counts measured with the condensation particle counter during the same period. The ultrafine particle number concentrations are dominated by the very fine particles with diameters between 10 and 30 nanometers (nm). The correlation coefficient between ultrafine particle (NC0.01-0.1) and NC0.01-0.03 was 0.96. Ultrafine particles are correlated with accumulation mode particles (NC0.1-1.0), with a correlation coefficient of 0.67. However, the two different fractions of the ultrafine particles show different correlation coefficients with the accumulation mode particles (0.90 for NC0.03-0.1 and 0.47 with NC0.01-0.03). The variation in exposure to particle number concentrations seems to be sufficient for epidemiological data analyses.

Table 2. Distribution of the Measured 24-Hour Average Particle Number Concentrations and PM2.5 During Winter 2000/2001 When the CAD Panel Study was Conducted. (The indices give the size range of the particles counted in µm).
  N % Mean Median 95% Max
NC0.01-0.1 [cm-3]1) 163 83.2 12,540 10,940 25,190 34,290
NC0.01-0.03 [cm-3]1) 163 83.2 8,740 8,240 17,320 22,530
NC0.03-0.1 [cm-3]1) 163 83.2 3,800 2,810 9,290 12,320
NC0.1-1.0 [cm-3]1) 163 83.2 1,570 1,220 3,920 4,910
Total number concentrations [cm-3]2) 196 100 20,290 19,310 36,800 47,000
PM2.5 [µg/m3]3) 189 96.5 15.2 11.3 38.0 66.3
1) MAS data, UFP = NC0.01-0.1 (cm-3)
2) CPC data
3) Harvard impactor data

Preliminary analyses of the blood cell counts and 24-hour averages of particle mass and number counts were conducted. Results indicate a decrease in red blood cells in association with fine PM2.5 and ultrafine particle counts (see Figure 1). Similar effects of particulate matter on red blood cell counts have been observed by Seaton and colleagues (Seaton et al. 2000). The decrease in red blood cells was most significant for the ultrafine particles at lag 4. The hematocrit showed results consistent with those observed for the red blood cells, however, the results were not statistically significant. Total white blood cell counts also decreased in association with ambient particle concentrations. For ultrafine particles, a significant decrease is observed for lags 1 and 4, and fine particle mass shows a significant effect for lags 4 and 5. The lag structure observed in these analyses are partly consistent with those found by Wichmann and colleagues analysing the impact of ambient particle number concentrations on mortality (Wichmann et al. 2000). Cardiovascular disease mortality showed the strongest evidence of an association with ultrafine particles with a lag of 4 days (relative risk: 1.051, 95 percent confidence interval (CI): 0.990 to 1.115), while respiratory disease mortality also showed an increase in association with ultrafine particles. However, the relative risk was most significant for lag 1 (relative risk: 1.155 (95 percent CI: 1.055 to 1.264). Platelet counts also decreased in association with ambient particle concentrations. The strongest association was observed with the pollutant concentrations delayed by 2 days. For an increase of 10,000 particles, a reduction of 4.6 platelets x 109/l was observed (95 percent CI: -1.33 to -7.87). The consistency and plausibility of these effects need to be further evaluated. In particular It will be assessed whether these results are in accordance with findings from the analyses of more specific biomarkers, such as clotting factors or soluble intercellular adhesion molecule-1 (ICAM-1).

COPD Panel Study. The COPD panel study took place between October 2001 and April 2002. Recruitment of patients proved to be very difficult. Lung specialists and general practitioners were contacted, and newspaper advertisements were issued monthly during the recruitment period. Patients compliance with the protocols seemed to be poorer and more quality assurance efforts were needed to achieve the same overall compliance as with the CAD panel. All data is currently entered in the database and has been checked for plausibility. All ECGs have been shipped to the cardiac core for analysis. Blood samples will be shipped in the near future. Due to an irreparable defect of the LAS-X from the aerosol spectrometer at the beginning of the field phase for the COPD panel study, the aerosol spectrometer was replaced by a differential mobility particle sizer (DMPS), which measures size fractioned particle counts in the size range of 10 to 500 nm. Further ultrafine particle counts from a scanning mobility particle sizer (SMPS, TSI) counting particles in the size range from 3 to 64 nm are available for the whole COPD study period. Total number counts were measured by a condensation particle counter (CPC, TSI) similar to the CAD panel study, and can be used to impute the missing DMPS data at the beginning of the study period (October 15th–November 28th).

Figure 1. Red Blood Cells and White Blood Cells in Association With 24-Hour Average Concentrations of PM2.5 and Ultrafine Particles (UFP) of the CAD Panel During Winter 2000/2001 in Erfurt (Rochester Particle Center).

Future Activities:

The statistical analyses of the CAD and COPD panel will be done based on the concepts outlined in the background section. This is a major task given the large database. Effort will be spent on the relationship between blood biomarkers and ECG parameters, as these relations have not been assessed well in the current medical literature. However, this knowledge will be crucial in order to understand the results with respect to air pollution. The CAD and the COPD panel will first be summarized in terms of internal consistency and plausibility, and then compared between each other. Comparable or additional information obtained by the human studies of the Rochester Particle Center and epidemiological, as well as human studies by the other centers, will be used to substantiate the results observed. Toxicological experiments using particles collected on filters from Erfurt during the winters of 2000/2001 and 2001/2002 are planned. Additional blood analyses, applying recently developed techniques in proteomics, will be conducted through the GSF-EPA collaboration with Robert Devlin and Lucas Neas at the National Health and Environmental Effects Research Lab.

Journal Articles on this Report : 4 Displayed | Download in RIS Format

Other subproject views: All 11 publications 11 publications in selected types All 11 journal articles
Other center views: All 104 publications 98 publications in selected types All 90 journal articles
Type Citation Sub Project Document Sources
Journal Article Cyrys J, Heinrich J, Peters A, Kreyling W, Wichmann HE. Emission, immission und messung feiner und ultrafeiner partikel (Emission, immission and measurement of fine and ultrafine particles). Umweltmedizin Forschung Und Praxis 2002;7(2):67-77. R827354 (2004)
R827354 (Final)
R827354C002 (2001)
R827354C002 (2002)
R827354C002 (Final)
R827354C003 (Final)
  • Abstract: Ecomed Medizin - Abstract (German and English)
  • Journal Article Ibald-Mulli A, Wichmann HE, Kreyling W, Peters A. Epidemiological evidence on health effects of ultrafine particles. Journal of Aerosol Medicine 2002;15(2):189-201. R827354 (Final)
    R827354C002 (2001)
    R827354C002 (2003)
    R827354C002 (Final)
    R832415 (2010)
    R832415 (Final)
  • Abstract from PubMed
  • Abstract: Mary Ann Liebert, Inc Publishers - Abstract
  • Journal Article Pekkanen J, Peters A, Hoek G, Tiittanen P, Brunekreef B, de Hartog J, Heinrich J, Ibald-Mulli A, Kreyling WG, Lanki T, Timonen KL, Vanninen E. Particulate air pollution and risk of ST-segment depression during repeated submaximal exercise tests among subjects with coronary heart disease:the Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air (ULTRA) study. Circulation 2002;106(8):933-938. R827354 (Final)
    R827354C002 (2001)
    R827354C002 (2002)
    R827354C002 (2003)
    R827354C002 (Final)
    R832415 (2010)
    R832415 (Final)
  • Abstract from PubMed
  • Full-text: Circulation - Full Text HTML
  • Abstract: Circulation - Abstract
  • Other: Circulation - Full Text PDF
  • Journal Article Peters A, Heinrich J, Wichmann H-E. Gesundheitliche Wirkungen von Feinstaub: Epidemiologie der Kurzzeiteffekte (Health impact of exposure to fine particles: epidemiology of short-term effects). Umweltmedizin in Forschung und Praxis 2002;7(2):101-115. R827354 (Final)
    R827354C002 (2001)
    R827354C002 (2002)
    R827354C002 (2003)
    R827354C002 (Final)
    R832415 (2010)
    R832415 (Final)
  • Full-text: Schwerpunktthema Feinstäube - Full Text (English and German)
  • Abstract: Ecomed - Abstract (English and German)
  • Supplemental Keywords:

    coronary artery disease, CAD, chronic obstructive pulmonary disease, COPD, particulate matter, air pollution, ultrafine particle, electrocardiogram, ECG., RFA, Health, Scientific Discipline, Air, Geographic Area, particulate matter, Virology, Environmental Chemistry, Health Risk Assessment, Epidemiology, Risk Assessments, Biochemistry, Atmospheric Sciences, Molecular Biology/Genetics, International, ambient air quality, cytokine production, particle size, particulates, sensitive populations, cardiopulmonary responses, fine particles, human health effects, morbidity, ambient air monitoring, cardiovascular vulnerability, pulmonary disease, susceptible populations, COPD, epidemelogy, environmental health effects, particle exposure, Germany, human exposure, particulate exposure, lung inflamation, coronary artery disease, inhalation toxicology, PM, mortality, urban environment, aerosols, human health risk, cardiovascular disease, ultrafine particles

    Progress and Final Reports:

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

  • Main Center Abstract and Reports:

    R827354    Airborne PM - Rochester PM Center

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R827354C001 Characterization of the Chemical Composition of Atmospheric Ultrafine Particles
    R827354C002 Inflammatory Responses and Cardiovascular Risk Factors in Susceptible Populations
    R827354C003 Clinical Studies of Ultrafine Particle Exposure in Susceptible Human Subjects
    R827354C004 Animal Models: Dosimetry, and Pulmonary and Cardiovascular Events
    R827354C005 Ultrafine Particle Cell Interactions: Molecular Mechanisms Leading to Altered Gene Expression
    R827354C006 Development of an Electrodynamic Quadrupole Aerosol Concentrator
    R827354C007 Kinetics of Clearance and Relocation of Insoluble Ultrafine Iridium Particles From the Rat Lung Epithelium to Extrapulmonary Organs and Tissues (Pilot Project)
    R827354C008 Ultrafine Oil Aerosol Generation for Inhalation Studies