2003 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, 2003 through May 31, 2004
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 the airways and the blood of patients with stable coronary artery disease (CAD) as well as of patients with chronic obstructive pulmonary disease (COPD). Monitoring of the autonomic function of the heart will investigate how these changes in the inflammatory state relate to alterations in the autonomic control.

This is one of the projects of the Rochester PM Center. The progress for the other projects is reported separately (see reports for R827354C001 and R827352C003 through R827352C005).

Progress Summary:

Panel Study Participants

Two panel studies were conducted to assess the health effects of fine and ultrafine particles on patients with cardiopulmonary disease. A panel of CAD patients was studied during the winter 2000/01 (October to April) and a second panel of COPD patients during the winter 2001/02 (October to May). The study protocol and outcome measures were designed to be as similar as possible to that of the clinical studies (core 3). Blood biomarkers were analysed by the vascular core, and ECG recordings were analysed by the cardiac core. Table 2-1 shows a summary of the panel studies on cardiac patients and patients with COPD. Sixty CAD patients were recruited who performed 96 percent of the scheduled clinic visits. Similarly, 98 percent of the scheduled clinic visits were performed during the second study with 39 COPD patients.

Table 2-1. Summary Statistics of the Panel Studies



Participants (n)



Clinical Examinations (n)

693 (96%)§

460 (98%)

20 minute-ECG (n)

656 (91%)

460* (98%)

24-hour ECG (n)

278 (77%)

181 (77%)

Blood samples (n)

669 (93%)

439 (94%)

Lung function tests: Impulse oscillometry (n)

not in the protocol

459 (98%)

Patient characteristics and disease history

Age range (years)

52 - 76

35 – 78

History of (n)

Coronary heart disease

60 (100%)

11 (28%)

Myocardial infarction

45 (75%)

8 (21%)

By-pass surgery/Ballon dilatation

52 (87%)

4 (10%)

Chronic bronchitis

2 (3%)

29 (74%)



21 (54%)


5 (8%)

39 (100%)

class 0


23 (59%)

class I


2 (1%)

class II


7 (18%)

class III


5 (13%)

Current Smoker (n)


7 (18%)

Non-Smoker (n)

60 (100%)

32 (82%)

§ percent of scheduled examinations
* 89 had a 20-min ECG without exercise challenge

Particle Measurements

Concentrations during the two field phases (CAD and COPD) are given in Table 2-2. UFP were not strongly but more correlated with the accumulation mode ACP (r = 0.64 and r = 0.75) than with PM2.5 (r = 0.41 and r = 0.56). ACP and PM2.5 were highly correlated (both r = 0.91). EC and OC were both highly correlated with ACP and PM2.5 (r > 0.76).

Table 2-2. Distribution of the Measured 24 Hour Average Particle (number and mass) Concentrations During Winter 2000/2001 (CAD) and Winter 2001/2002 (COPD)



Mean (±SD)







Winter 2000/01 (CAD)



12,602 (±6,455)









1,593 (±1,034)







PM2.5 ‡[µg/m³]


20.0 (±15.0)







PM10 ‡[µg/m³]


20.0 (±13.0)









1.5 (±0.6)
















Winter 2001/02 (COPD)



6,618 (±3,231)









1,087 (±768)







PM2.5 ‡[µg/m³]


15.3 (±10.8)







PM10 ‡[µg/m³]


17.5 (±10.4)









1.0 (±0.4)
















*UFP: number concentration of particles between 0.01 and 0.1 µm diameter [n/cm3]: 13 percent and 27 percent of the hourly measurements were imputed in CAD and COPD respectively; †ACP: number concentration of particles between 0.1 and 1.0 µm diameter [n/cm3]; ‡PM2.5 (PM10): mass concentration of particles < 2.5 µm (< 10 µm) diameter [µg/m3]: 15 percent of the hourly measurements were imputed in CAD for PM2.5 and 1 percent of the hourly measurements were imputed in COPD for PM10; §OC, EC: organic and elemental carbon measurements started December 18th, 2000.

Effects of Particulate Air Pollution

Objective (1): Do Fine and Ultrafine Particles Affect Heart Rate Variability(HRV)? For the 24 hour recordings the results show a decrease in overall HRV measured as SDNN concurrent to the recording period (-2.8% CI [-6.6%; 1.0%]) in association with PM2.5. The effects were strongest for the subgroup of patients with an average SDNN below the overall mean SDNN (-6.0% CI [-10.0; -2.0]). A decrease in RMSSD was associated with ambient concentrations of PM2.5 concurrent (-5.3% CI[-11.7%; 1.7%]) and 24 hours prior (-7.3% CI[-13.4%; -0.8%]) to the 24 hour recordings.

With respect to the short term recordings, effects on HRV were observed for the period of 5 minutes spontaneous breathing at rest. The strongest effects of particles were seen in association with a decrease in normalized units of high frequency power (HF [n.u.]) which mainly reflects a withdrawal in parasympathetic tone. Significant effects were seen with exposure to EC and OC in association with high frequency power and RMSSD 0-23 hours prior to the recording. However, PM2.5 particles also show a borderline significant decrease in high frequency power. Overall the findings suggest a decrease in HRV measured as SDNN and RMSSD as well as HF associated with particulate air pollution in healthy elderly subjects. Our results support the hypothesis that exposure to particulate air pollution can alter the autonomic function of the heart, a potential risk factor for cardiac morbidity and mortality.

Objective (2): Are Signs of QTc Reduction Observed as in the Human Exposure Studies of the Rochester Particle Centre? Novel measures of repolarization (T wave complexity [analysed by principal component analysis], T wave amplitude and Bazett-corrected QT interval [QTc]) characterizing myocardial substrate and vulnerability were used to investigate the underlying pathophysiological mechanisms leading to adverse reactions of the heart in response to air pollution. Although the measured particulate pollutants were highly correlated, the analysed repolarization parameters showed different pollutant-specific responses. In association with ACP, PM2.5,and OC concentrations for the whole 0-23 hours period before the recording, an increase in QTc could be seen, being significant especially for OC. T wave amplitude showed a significant decrease with UFP, ACP, PM2.5,and EC concentrations measured during 0-5 hours (only borderline for EC) and during 0-23 hours before the recording (significant only for UFP and ACP). Consistently with this finding, T wave complexity increased significantly in association with PM2.5 concentrations in the same time interval. The observed inhomogeneous reaction to the air pollution mix for the analyzed repolarization parameters might point towards different action of air pollution components on the complex repolarization process. In contrast to the results from of the human controlled exposure experiments, an increase in QTc was observed. As the ECG equipment and the procedures for ECG parameter generation were the same in both studies, the diverging results might be due to the subjects studied or the particle exposures considered. In the epidemiological study we investigated the repolarization changes in the patients with coronary artery disease. Therefore, their response might be quite different from the effects observed in healthy or mild asthmatics.

Objective (3): Are Ventricular Ectopic Beats and Arrhythmia More Prevalent on Days With High Concentrations of Fine and Ultrafine Particles? The number of supraventricular runs (SVESruns) was positively associated with all particulate pollutants for all lag structures. All particulate pollutants showed the clearest effect for the number of SVESruns at lag 1, 2 and 5 day average. In addition, UFP and ACP were significantly associated with the number of SVESruns concurrent respectively at lag 0. Similar to SVESruns the ventricular runs (VESruns) showed a positive association with all particulate pollutants for all lag structures, but there were less significant results. All particulate pollutants were significantly associated with the number of VESruns at lag 2. In addition, the association between VESruns and UFP and ACP was borderline significant at 5 day average. The estimated effects for the association between the number of sporadic or two successional ventricular/supraventricular extrasystoles per 24-hour ECG with all particulate pollutants showed no clear pattern.

Objective (4): Are Signs of Ischemia Present in 24-hour ECG Readings During Exercise Periods in Association With Fine and Ultrafine Particles? The descriptive analysis of the ST-segment in the 24-hour ECG data showed that the CAD patients only rarely had ST-segment depression or elevation and thus no regression analysis could be done.

Objective (5): Do Acute Phase Reactants Increase in Association With Fine and Ultrafine Particles? The odds of observing levels of C-reactive protein (CRP) above the 90th percentile were significantly increased in association with ACP and PM2.5 for lag 2 and the 5-day average. For PM2.5, lag 1 and 4 showed additional significant increases. For UFP the effects for lag 2 were only borderline significant. Serum amyloid A (SAA) increased significantly in association with PM10 and PM2.5 showing an immediate effect for both particle sizes and significant lag 2, lag 4 and 5-day-average effects for PM10 only. In addition, SAA increase was statistically significant in association with UFP concentrations, with the largest effect for lag 3. SAA is closely related to CRP, and it is assumed that SAA is a comparably sensitive marker to an acute phase reaction, but it does not react identically to CRP in all subjects. More specifically, we observed positive associations between PM2.5 and CRP but not between traffic related pollutants such as EC, OC and UFP. In contrast, the response of SAA was seen in association with traffic related pollutants.

Objective (6):Do Clotting Factors Also Increase in Association With Fine and Ultrafine Particles? In contrast to our initial hypothesis, some markers of the clotting cascade decreased in association with air pollution. Fibrinogen showed decreasing mean concentrations with an increase in ambient air pollutants. The clearest effect was observed for UFP with lag 0. A strong association could also be detected for lag 3 with ACP. Consistent and statistically significant results were found for almost all pollutants with FVII, indicating an immediate (lag 0 and 1) decrease in the mean of percent activity as well as a cumulative effect associated with the 5-day average exposures. Overall the strongest association was seen with UFP. For prothrombin fragments 1+2, the logistic regression revealed consistent increases of the odds ratios with lag 1 and 4 and for the 5-day average showing a consistent pattern in all pollutants. The strongest association was seen for UFP for the 5-day-average exposure. The analyses of vWF revealed statistically significant positive associations for almost all particulate pollutants, with the largest effect on the 5-day-average exposure. Apart from the results of FVII and fibrinogen, the significant increase in prothrombin fragments 1+2 indicates an activation of the early steps of blood coagulation. This activation, however, was not associated with increased formation of fibrin, as would be detected by elevated D-dimer levels which we did not see.

Further Analyses.

We assessed symptom prevalence with different methods for analysing individual level data from panel studies. We found good agreement between currently used approaches based on generalized estimating equations and Bayesian approaches allowing for individual confounder adjustment. In addition the analysis showed a positive effect of NO and UFP with a two-day-lag on the probability of experiencing chest pain. For NO, a marker of freshly emitted diesel exhaust, this effect is significant.

Respiratory reactance during lung function measurement by impulse oscillometry decreased in association with an increase in the particle number concentration as well as with particles in the size range of 0.03 to 0.05 nm with a lag of 2 days in the COPD panel. As the reactance reflects the smaller airways, and the largest effect was seen for the smaller size fraction of the particles, the observed effects are small but indicate impairment in the lung function with increasing air pollution. Moreover, a decrease in the tidal volume in association with NO2 with a lag of four days was seen; however, the data of the impulse oscillometry have to be analysed in more detail yet.

Future Activities:

The statistical analyses of the CAD and COPD panel will be completed. 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. 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. In addition, novel biomarkers such as CD40-ligand will be measured in stored blood samples. Source apportionment analyses will be conducted in cooperation with core 1 and used in data analyses of the panel study data.

Journal Articles on this Report : 5 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 Henneberger A, Zareba W, Ibald-Mulli A, Ruckerl R, Cyrys J, Couderc J-P, Mykins B, Woelke G, Wichmann H-E, Peters A. Repolarization changes induced by air pollution in ischemic heart disease patients. Environmental Health Perspectives 2005;113(4):440-446. R827354 (Final)
R827354C002 (2003)
R827354C002 (Final)
R832415 (2010)
R832415 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • 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)
  • Journal Article Ruckerl R, Ibald-Mulli A, Koenig W, Schneider A, Woelke G, Cyrys J, Heinrich J, Marder V, Frampton M, Wichmann HE, Peters A. Air pollution and markers of inflammation and coagulation in patients with coronary heart disease. American Journal of Respiratory and Critical Care Medicine 2006;173(4):432-441. R827354 (Final)
    R827354C002 (2003)
    R827354C002 (Final)
    R827354C003 (Final)
    R827354C004 (Final)
    R832415 (2010)
    R832415 (2011)
    R832415 (Final)
    R832415C003 (2011)
  • Abstract from PubMed
  • Full-text: ATS Journals - Full Text HTML
  • Abstract: ATS Journals - Abstract
  • Other: ATS Journals - Full Text PDF
  • Supplemental Keywords:

    pollution prevention, urban air pollution, atmosphere, atmospheric sciences, biochemistry, children’s health, environmental chemistry, epidemiology, genetics, virology, molecular biology, health risk assessment, risk assessments, incineration, combustion, combustion engines, air toxics, tropospheric ozone, PM2.5, particulates, ultrafine particles, particulate matter, particle exposure, particle size, aerosol, aerosols, ambient air, ambient air monitoring, ambient air quality, animal model, atmospheric, cardiopulmonary, cardiopulmonary responses, cardiovascular disease, cardiovascular vulnerability, coronary artery disease, cytokine production, fine particles, human exposure, human health, human health effects, environmental health effects, inhalation toxicology, lead, lung, lung inflammation, metals, morbidity, mortality, pathophysiological mechanisms, pulmonary, pulmonary disease, stratospheric ozone, sensitive populations, susceptible populations,, RFA, Health, Scientific Discipline, Air, Geographic Area, particulate matter, Environmental Chemistry, Health Risk Assessment, Virology, 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

    Relevant Websites:

    http://www2.envmed.rochester.edu/envmed/PMC/ Exit

    Progress and Final Reports:

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