Final 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 , 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)
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air

Objective:

The aim of the Rochester PM Center epidemiological studies was to assess short-term health effects of fine and ultrafine particles (UFP) on vascular and cardiac function. It was hypothesized that patients with coronary artery disease (CAD) as well as chronic obstructive pulmonary disease (COPD) would be susceptible to ambient fine and ultrafine particles.

Summary/Accomplishments (Outputs/Outcomes):

Two epidemiological studies were conducted in 61 patients with CAD and in 39 patients with COPD in Erfurt, Germany as part of the Rochester Particle Center. Twelve clinical visits including ECG measurements and blood withdrawals were scheduled for each panel. Intermediate phenotypes such as measurements of clinical parameters like blood inflammation, coagulability, and heart rate variability (HRV) were analyzed based on linear and logistic regression models considering repeated measurements for the subjects adjusting for time trend, season, and meteorological parameters. The lag structure of the association between the air pollutants and the outcomes was analyzed to evaluate the time lags between exposure and response. Additional information on source contributions was obtained to help elucidate the role of different particle properties responsible for cardiovascular disease exacerbation via different mechanisms.

Vascular Function. For CAD patients C-reactive protein (CRP), prothrombin fragments 1+2, soluble CD40 Ligand, and von Willebrand factor (vWF) showed positive associations with UFP, while Factor VII (FVII) decreased significantly. Intercellular adhesion molecule-1 (ICAM-1), serum amyloid A (SAA), and CRP increased in association with increased PM10 levels, while Factor VII, again, was negatively associated. No associations were found for fibrinogen in this study setting. Platelets and leukocytes were negatively associated with UFP (Ruckerl, et al., 2006; Ruckerl, et al., 2007). In contrast to our initial hypothesis, some markers of the clotting cascade decreased in association with air pollution. 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. However, this activation was not associated with increased formation of fibrin, as would be detected by elevated D-dimer levels, which we did not observe.

For the COPD panel, results do not support the concept of an overall increased systemic inflammatory response as no changes in CRP, SAA, and ICAM-1 were seen. However, an increase of fibrinogen and the endothelial adhesion molecule E-selectin was observed. In the differential hemograms preliminary results suggest no effect of particulate matter on all leukocytes combined. However, an increase in neutrophilic bandform granulocytes was observed in association with PM10. Other leukocytic cell types were either unaffected or showed small decreases. These results may provide evidence for a stimulation of the bone marrow by particulate matter (Socher, et al., 2005).

Cardiac Function. In the CAD panel, the autonomic control of the heart was altered in association with PM2.5 and organic (OC) and elementary carbon (EC) concentrations of PM2.5 (Ibald-Mulli, et al., 2005). These findings highlight the importance of the carbonaceous component in particles. Furthermore, we were able to detect for the first time changes in the repolarization of the heart in association with PM2.5 (Henneberger, et al., 2005). Regarding arrhythmia, the number of supraventricular and ventricular runs showed strong effects correlated to UFP (Berger, et al., 2006). Thereby, we found the first evidence that particles also might increase cardiac vulnerability and might modify the cardiac substrate.

In patients suffering from COPD, low frequency (LF) and the ratio of low to high frequency (LF/HF) increased in association with an increase in PM10, OC, and EC during the 24 hours before the ECG measurement. Consistently, there was a significant decrease in heart rate. The analysis also showed a significant delayed increase in root mean square successive difference (RMSSD) in response to an increase in all particle concentrations. These results are contradictory to prior findings in CAD patients and our initial hypothesis. Taking both findings into account, it is conceivable that the air pollution reaction depends on the disease status of the patient and that elevated concentrations of ambient particles are associated with a disturbance of the autonomic heart control manifested by an increased HRV in patients with COPD (Bero Bedada, et al., 2005).

Interdependence of Vascular and Cardiac Function. Between ECG recordings and blood markers, repolarization parameters and acute phase response proteins showed moderate but significant associations. HRV parameters and endothelial cell activation markers were significantly but only weakly associated. The results indicate the interplay between the autonomic nervous system and myocardial substrate as well as interactions of the acute phase response with endothelial cell activation and coagulation state. While ECG parameters and blood markers seem to vary independently, there was the suggestion for a link between systemic inflammation and repolarization as well as endothelial dysfunction and HRV (Yue, et al., 2006).

Effects of Traffic on Myocardial Infarction. A complete series of 691 myocardial infarction (MI) survivors registered between 1999 and mid 2001 was interviewed to collect information on activities during the four days before MI onset. Time spent in traffic was associated with MI onset 1 hour later (OR= 2.9 (95% CI: 2.2 to 3.8). These associations were seen for times spent in cars, in public transport, and on bicycles (Peters, et al., 2004). Ambient PM2.5 concentrations at the urban background site also suggested an association with MI onset 2 days later (Peters, et al., 2005).

Source Apportionment. Sources of fine and ultrafine particles were analyzed by positive matrix factorization. Analyses were conducted in collaboration with Core 1. Five factors representing particles from airborne soil, UFP from local traffic, secondary aerosols from local fuel combustion, particles from remote traffic, and secondary aerosols from multiple sources were identified (Yue, et al., 2007a). The associations of the contributing particle fractions and gaseous pollutants with the ECG and blood biomarkers were compared to the health effects of the different sources. The results suggest that traffic-related and combustion-generated particles show stronger adverse health impact with regard to cardiac function measured by QT interval and T wave amplitude, and that different source particles may have the potential to cause an acute phase response indicated by CRP and vWF in these patients (Yue, et al., 2007b).

References:

Berger A, Zareba W, Schneider A, Ruckerl R, Ibald-Mulli A, Cyrys J, Wichmann HE, Peters A. Runs of ventricular and supraventricular tachycardia triggered by air pollution in patients with coronary heart disease. Journal of Occupational and Environmental Medicine 2006;48(11):1149-1158.

Bero Bedada G, Henneberger A, Zareba W, Ruckerl R, Cyrys J, Wichmann HE, Peters A. Ambient air pollution and heart rate variability in patients with chronic obstructive pulmonary disease (COPD). Masters Thesis (not peer review published yet, 2005).

Henneberger A, Zareba W, Ibald-Mulli A, Ruckerl R, Cyrys J, Couderc JP, Mykins B, Woelke G, Wichmann HE, Peters A. Repolarization changes induced by air pollution in ischemic heart disease patients. Environmental Health Perspectives 2005;113(4):440-446.

Ibald-Mulli A, Zareba W, Ruckerl R, Couderc JP, Mykins B, Woelke G, Pitz M, Wichmann HE, Peters A. Heart rate variability changes induced by ambient air pollution in patients with ischemic heart disease. Ph.D. Thesis (not peer review published yet, 2005).

Peters A, von Klot S, Heier M, Trentinaglia I, Hormann A, Wichmann HE, Lowel H. Exposure to traffic and the onset of myocardial infarction. New England Journal of Medicine 2004;351:1721-1730.

Peters A. Particulate matter and heart disease: evidence from epidemiological studies. Toxicology and Applied Pharmacology 2005;207(2 Suppl):477-82.

Phipps RP. Atherosclerosis: the emerging role of inflammation and the CD40-CD40 ligand system. Proceedings of the National Academy of Sciences of the United States of America 2000;97(13):6930-6932.

Ruckerl R, Ibald-Mulli A, Koenig W, Schneider A, Woelke G, Cyrys 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):432-41.

Ruckerl R, Phipps RP, Schneider A, Frampton M, Cyrys J, Oberdorster G, Wichmann HE, Peters
A. Ultrafine particles and platelet activation in patients with coronary heart disease–results from a prospective panel study. Particle and Fibre Toxicology 2007;4(1):1

Socher M, Ruckerl R, Henneberger A, Berger A, Heinrich J, Wichmann HE, Peters A. Impact of ambient air pollution and the white blood cell count in patients with chronic obstructive pulmonary disease (COPD). Masters Thesis (not peer review published yet, 2005).

Yue W, Schneider A, Ruckerl R, Koenig W, Marder V, Wang S, Wichmann HE, Peters A, Zareba W. Relationship between electrocardiographic and biochemical variables in coronary artery disease. International Journal of Cardiology 2006; online.

Yue W, Stolzel M, Cyrys J, Pitz M, Heinrich J, Kreyling WG, Wichmann HE, Peters A. Source apportionment of ambient fine particle size distribution using positive matrix factorization in Erfurt, Germany. Atmospheric Chemistry and Physics. 2007a; online.

Yue W, Schneider A, Stolzel M, Ruckerl R, Cyrys J, Pan X, Zareba W, Koenig W, Wichmann HE, Peters A. Ambient source-specific particles are associated with prolonged repolarizationand increased levels of inflammation in male coronary artery disease patients. Mutation Research 2007b; online.

Technical Report:

Full Final Technical Report (PDF, 8pp., 800KB, about PDF)


Journal Articles on this Report : 10 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)
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  • Abstract: Ecomed Medizin - Abstract (German and English)
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  • 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)
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  • Abstract from PubMed
  • Abstract: Mary Ann Liebert, Inc Publishers - Abstract
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  • 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)
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  • Abstract from PubMed
  • Full-text: Circulation - Full Text HTML
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  • Abstract: Circulation - Abstract
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  • Other: Circulation - Full Text PDF
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  • 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)
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  • Full-text: Schwerpunktthema Feinstäube - Full Text (English and German)
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  • Abstract: Ecomed - Abstract (English and German)
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  • Journal Article Peters A, von Klot S, Heier M, Trentinaglia I, Hormann A, Wichmann HE, Lowel H, Cooperative Health Research in the Region of Augsburg Study Group. Exposure to traffic and the onset of myocardial infarction. New England Journal of Medicine 2004;351(17):1721-1730. R827354 (Final)
    R827354C002 (Final)
    R832415 (2010)
    R832415 (Final)
  • Abstract from PubMed
  • Full-text: NEJM - Full Text HTML
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  • Abstract: NEJM - Abstract
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  • Other: NEJM - Full Text PDF
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  • Journal Article Peters A. Particulate matter and heart disease:evidence from epidemiological studies. Toxicology and Applied Pharmacology 2005;207(2-Suppl):477-482. R827354 (Final)
    R827354C002 (Final)
    R832415 (2010)
    R832415 (Final)
  • Abstract from PubMed
  • Full-text: ScienceDirect - Full Text HTML
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  • Abstract: ScienceDirect - Abstract
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  • Other: ScienceDirect - Full Text PDF
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  • 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
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  • Abstract: ATS Journals - Abstract
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  • Other: ATS Journals - Full Text PDF
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  • Journal Article Stolzel M, Breitner S, Cyrys J, Pitz M, Wolke G, Kreyling W, Heinrich J, Wichmann H-E, Peters A. Daily mortality and particulate matter in different size classes in Erfurt, Germany. Journal of Exposure Science & Environmental Epidemiology 2007;17(5):458-467. R827354 (Final)
    R827354C002 (Final)
    R832415 (2010)
    R832415 (Final)
    R832415C002 (2011)
  • Abstract from PubMed
  • Full-text: Nature Publishing - Full Text HTML
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  • Abstract: Nature Publishing - Abstract
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  • Other: Nature Publishing - Full Text PDF
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  • Journal Article von Klot S, Peters A, Aalto P, Bellander T, Berglind N, D'Ippoliti D, Elosua R, Hormann A, Kulmala M, Lanki T, Lowel H, Pekkanen J, Picciotto S, Sunyer J, Forastiere F. Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities. Circulation 2005;112(20):3073-3079. R827354 (Final)
    R827354C002 (Final)
    R832415 (2010)
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  • Abstract from PubMed
  • Full-text: Circulation - Full Text HTML
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  • Abstract: Circulation - Abstract
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  • Other: Circulation - Full Text PDF
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  • Supplemental Keywords:

    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

    Relevant Websites:

    Full Final Technical Report (PDF, 8pp., 800KB, about PDF)
    http://www2.envmed.rochester.edu/envmed/PMC/indexPMC.html Exit

    Progress and Final Reports:

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