2002 Progress Report: Inflammatory Responses and Cardiovascular Risk Factors in Susceptible PopulationsEPA 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)
Project Period Covered by this Report: June 1, 2002 through May 31, 2003
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) and 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.
To identify the mechanisms that lead from the deposition of particles in the lung to cardiovascular disease exacerbation, it is crucial to show that the proposed mechanism is at play in diseased patients. The analyses will address the following specific questions with respect to the function of the heart:
- Do fine particles and ultrafine particles (UFP) affect heart rate variability (HRV)?
- Are signs of heart rate-corrected QT (QTc) reduction observed as in the human exposure studies of the Rochester Particle Center?
- Are ventricular ectopic beats and arrhythmia more prevalent on days with high concentrations of fine particles and UFP?
- Are signs of ischemia present in 24 electrocardiogram (ECG) readings during exercise periods in association with fine particles and UFP? Furthermore, blood biomarkers will be used to address the following questions:
- Do acute phase reactants increase in association with fine particles and UFP?
- Do clotting factors also increase in association with fine particles and UFP?
- Do blood cell counts change in association with fine particles and UFP?
Summary of Progress for Years 1 to 3 of the Project
Two panel studies were conducted to assess the health effects of fine and UFP
on patients with cardiopulmonary disease. A panel of CAD patients was studied
during the winter of 2000/2001, and a second panel of COPD patients was recruited
for the winter of 2001/2002.
The study protocol and outcome measures were designed to be as similar as possible to that of the clinical studies (R827354C003). Blood biomarkers are analyzed by the vascular research group under the lead of Victor Marder, and ECG recordings are analyzed by the cardiac research group (led by Wojciech Zareba). Table 1 shows a summary of the panel studies on cardiac patients and patients with COPD. Fifty-eight CAD patients were recruited who performed 98 percent of the scheduled clinic visits. Similarly, 98 percent of the scheduled clinic visits were during the second study with COPD patients.
Table 1. Summary Statistics of the Panel Studies
|CAD-Panel (10/00 – 04/01)||COPD-Panel (10/01 – 04/02)|
|Clinical Examinations (n)||683 (98%)§||460 (98%)|
|20 min-ECG (n)||678 (97%)||460* (98%)|
|24-h ECG (n)||279 (80%)||181 (77%)|
|Blood samples (n)||659 (95%)||439 (94%)|
|Lung function tests (n)||not in the protocol||459 (98%)|
|Patient Characteristics and Disease History|
|Age range (yrs)||51 - 76||36 - 79|
|History of (n)Myocardial infarctionBypass surgery/Ballon dilatationChronic bronchitisCOPDAsthma||
Current Smoker (n)
* 89 had a 20-minute ECG without exercise challenge
The field study with the CAD patients was conducted during the winter of 2000/2001. Concentrations during the field phase are given in Table 2. Missing aerosol spectrometer data were imputed by calculating the UFP fraction based on total number counts measured with the condensation particle counter (CPC) during the same period. The UFP number concentrations are dominated by the very fine particles with diameters between 10 and 30 nm. The correlation coefficient between UFP (NC0.01-0.1) and NC0.01-0.03 was 0.96. UFP are correlated with accumulation mode particles (NC0.1-1.0) with a correlation coefficient of 0.67.
|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.|
|Total number concentrations [cm-3]2)||196||100||20,290||19,310||36,800||47,000|
|1) MAS data, UFP = NC0.01-0.1 [cm-3]
2) CPC data
3) Harvard impactor data
CAD Panel Study
For the CAD panel, all questionnaire-based data were entered and checked for plausibility. The potential role of ECG parameters in air pollution epidemiology was established (Zareba, et al., 2001), and based on these concepts, ECGs obtained in Erfurt during the first field phase were analyzed by the cardiac research project. The ECG-data were transferred and partly analyzed in association with the air pollution data. Analyses of the blood parameters by the vascular research project were delayed because of the September 11th terrorist attacks.
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 particle mass (PM2.5) and UFP counts. 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 strongest for the UFP at lag 4. Total white blood cell counts also decreased in association with ambient particle concentrations. For UFP, a significant decrease is observed for lag 1 and lag 4, and fine particle mass shows a significant effect for lag 4 and 5. The lag structure observed in these analyses are partly consistent with those found by Wichmann and colleagues analyzing the impact of ambient particle number concentrations on mortality (Wichmann, et al., 2000). Platelet counts also decreased in association with ambient particle concentrations. The consistency and plausibility of these effects need to be evaluated further.
COPD Panel Study
The COPD panel study took place between October 2001 and April 2002. All data from the COPD panel study was entered in the database and is currently being checked for plausibility. All ECGs have been analyzed by the cardiac research project. Blood samples will be shipped in the near future. Because of 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 UFP counts from a scanning mobility particle sizer (TSI, Inc.) 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 TSI Inc. CPC, which can be used to impute the missing DMPS data at the beginning of the study period.
Summary of Progress Year 4 of the Project
For the CAD Panel Study, statistical analyses considering Questions 1-3 as well as 5-7 have been conducted. Here we report in detail on the results addressing the first two questions.
1. Do Fine and UFP Affect HRV?
Analysis of HRV. The ECG recordings were analyzed with the H-Scribe 12-Lead Digital Holter System at the University of Rochester Medical Center. For the calculation of HRV parameters, only normal QRS intervals were used. Artifacts and ectopic beats were excluded after the scanning and manual editing of the QRS complexes standard deviation normal-normal (SDNN) and root mean square of successive differences (RMSSD) were used to assess HRV in the 24-hour recordings. In the short-term recordings, only RMSSD was used in addition to the frequency domain parameters. For the analyses of frequency domain, HRV-normalized units of low frequency (LF), high frequency (HF), and the log-transformed LF/HF ratio were used. LF and HF components were only applied to the short-term recordings.
Statistical Analyses. Data were analyzed using the statistical package SAS Version 8 (SAS Institute Inc., Cary, NC) and S-Plus 2000 Professional Release 1 (Math Soft, Inc.). A descriptive analysis of the characteristics of the study participants was based on data obtained through the baseline questionnaire. Linear mixed models were used (PROC MIXED in SAS). Parametric functions of the confounding variables based on lowest akaike information criterion (AIC) were included as fixed effects in the final linear mixed model, and a random effect was used for each subject.
Results. For the 24-hour recordings, the results show a decrease in
overall HRV measured as SDNN (-2.8% confidence interval [CI] [-6.6% to 1.0%])
in association with PM2.5. The effects were strongest for exposure
concurrent to the recording period and significant in patients with an average
SDNN below the overall mean SDNN (-6.0% CI [-10.0% to -2.0%). A decrease in
RMSSD was associated with ambient concentrations of PM2.5 concurrent
(7.0% CI [-13.7% to -0.2%]) and 24-hours prior (-8.0% CI [-14.3% to -1.3%])
to the 24-hour recordings. Short-term recording 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
HF power, which mainly reflects a withdrawal in parasympathetic tone (see Figure
1a). Significant effects were seen in association with average exposure to elemental
and organic carbon for 0-24 hours before the recording. However, PM2.5
particles also show a borderline significant decrease in HF power.
|Figure 1a. SDNN and HF.NN in Association with Elemental Carbon in Patients with CAD Figure||1b. RMSSD and LF/HF in Association with Elemental Carbon in Patients with CAD|
Significant effects with exposure to elemental carbon (as shown in Figures 1b) also were seen in association with RMSSD.
Overall, the previously published 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 Center?
Analysis of Repolarization. The objective of this study was to assess associations between daily variations in particulate air pollution and repolarization ECG parameters, representing abnormalities in the myocardial substrate and increased vulnerability of myocardium to arrhythmias. Mortara’s automated algorithms provided measurements of QT interval, T wave amplitude, and T wave complexity. QT was adjusted for heart rate with Bazett’s formula (QTca). The measurements of Bazzett corrected QTc also were performed manually. T wave complexity was measured in each beat by principal component analysis. T wave complexity describes global shape of the T wave with the advantage of not having the need for T wave end determination. The first component (eigenvector) accounts for most of the energy in repolarization in a normal T wave, whereas the second indicates a relevant contribution to the inhomogeneous repolarization. The average ratio between the second and the first component—expressed in percent—represents a measure of complexity and heterogeneity of repolarization, and provides an estimate of the fatness of the T wave loop relative to its amplitude.
Statistical Analyses. Generalized additive models, including pollutant and confounder variables, were used for linear fixed effects regression with individual intercepts for each patient. Data were analyzed using SAS Version 8.2 and S-Plus Version 6.0. To adjust for confounders, model building was conducted for each ECG variable separately using nonparametric smooth functions based on locally weighted least squares. Model fit was based on the AIC.
Results. T wave complexity, a computerized measure of repolarization morphology, increased significantly in association with mean PM2.5 concentrations of 6 hours before the recording. Consistent with this finding, the T wave amplitude showed a significant decrease with UFP, accumulation mode particles, and PM2.5 in the same time interval. A rather immediate increase in manually measured QTc also could be seen in association with accumulation mode particles and PM2.5 for exposure within 24 hours before the recording, but results were only borderline significant for particles in the accumulation mode and not significant for PM2.5.
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 because of the subjects studied or the particle exposures considered. In the epidemiological study, we investigated the repolarization changes in the patients with CAD. Therefore, their response might be quite different from the effects observed in healthy or mild asthmatics.
COPD Panel Study
All epidemiological data were entered in the database and checked for plausibility. All ECGs were processed by the cardiac. Blood samples have been analyzed for acute phase reactants and have been shipped for coagulation factors analyses. Additional analyses will be conducted after the analyses of the CAD study have been completed and the observed associations understood. The air pollution data have been cleaned and are available for analyses.
Ibald-Mulli A, Wichmann H-E, Kreyling W, Peters A. Epidemiological evidence on health effects of ultrafine particles. Journal of Aerosol Medicine 2002;15(2):189-201.
Cyrys J, Heinrich J, Peters A, Kreyling WG, Wichmann H-E. Emissionen, immission und messungen feiner und ultrafeiner partikel. Umweltmedizin in Forschung und Praxis 2002;7(2):67-77.
Pekkanen J, Peters A, Hoek G, Tiittanen P, Brunekreef B, Hartwig A, 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.
Peters A, Heinrich J, Wichmann H-E. Gesundheitliche Wirkungen von Feinstaub: epidemiologie der Kurzzeiteffekte. Umweltmedizin in Forschung und Praxis 2002;7(2):101-115.
Wichmann HE, Cyrys J, Stölzel M, Spix C, Wittmaack K, Tuch T, Peters A, Wölke G, Menzel N, Hietel B, Schulz F, Heinrich J, Kreyling W, Heyder J. Sources and elemental composition of ambient particles in Erfurt, Germany. Ecomed Verlag Landsberg (Monograph, 2002).
Henneberger A, Ibald-Mulli A, Zareba W, Rückerl R, Cyrys J, Gouderc JP, Mykins B, Woelke G, Wichmann HE, Peters A. Effects of particulate air pollution on repolarization parameters in coronary artery disease patients. American Journal of Respiratory and Critical Care Medicine 2003;A332 (abstract).
Ibald-Mulli A, Zareba W, Rückerl R, Gouderc JP, Mykins B, Pitz M, Wichmann HE, Peters A. Effects of particulate air pollution on heart rate variability in patients with coronary artery disease. American Journal of Respiratory and Critical Care Medicine 2003;A333 (abstract).
Future activities include the completion of the statistical analyses for the CAD and COPD panel. 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 to understanding the results with respect to air pollution. The CAD and the COPD panel first will be summarized in terms of internal consistency and plausibility and then compared with one another. 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 observed results.
Journal Articles on this Report : 3 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|
||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.||
||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.||
||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.||
Supplemental Keywords:pollution prevention, urban air pollution, atmosphere, biomarkers, airway inflammation, ambient particles, air, health, atmospheric sciences, biochemistry, environmental chemistry, epidemiology, molecular biology, health risk assessment, risk assessments, air toxics, tropospheric ozone, PM2.5, particulates, ultrafine particles, particulate matter, particle exposure, particle size, aerosol, ambient air, ambient air monitoring, ambient air quality, 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, lung, lung inflammation, morbidity, mortality, pathophysiological mechanisms, pulmonary, pulmonary disease, stratospheric ozone,, 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
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