Relationship between electrocardiographic and biochemical variables in coronary artery disease
☆Wei Yue
a,b, Alexandra Schneider
a, Regina Rückerl
a, Wolfgang Koenig
c, Victor Marder
d, Sheng Wang
b, H.-Erich Wichmann
a,e,f, Annette Peters
a,f,⁎ , Wojciech Zareba
gaInstitute of Epidemiology, GSF-National Research Center for Environment and Health, Neuherberg, Germany
bDepartment of Occupational and Environmental Health, School of Public Health, Peking University, Beijing, China
cDepartment of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
dDivision of Hematology/Medical Oncology, David Geffen School of Medicine, University of California Los Angeles, CA, USA
eIBE Chair of Epidemiology, Ludwig-Maximilians-University of Munich, Munich, Germany
fFocus-Network on Aerosols and Health, GSF-National Research Center for Environment and Health, Neuherberg, Germany
gDepartment of Medicine, School of Medicine, University of Rochester, Rochester, NY, USA Received 24 April 2006; accepted 21 July 2006
Available online 1 December 2006
Abstract
Background: ECG (electrocardiogram) markers reflecting abnormal heart rate variability and abnormal repolarization as well as several biochemical markers reflecting inflammation, endothelial dysfunction, and procoagulation states were reported to show an association with increased cardiovascular mortality. ECG and biochemical markers could operate independently or they could interrelate in pathogenetic pathways of coronary disease. In this study, we aimed to explore the relationship between ECG and biochemical markers in a longitudinal study of coronary patients.
Methods: A total of 499 observations from 52 patients with up to 12 repeated measurements were collected providing data on series of ECG (heart rate variability and repolarization) parameters and biochemical parameters. Generalized estimating equation models adjusting for repeated measurements were used for the analyses.
Results: There was a significant association between ECG parameters reflecting abnormal repolarization (prolonged QT interval, lower T wave amplitude) and elevated levels of C-reactive protein and fibrinogen. Abnormal heart rate variability, increased sympathetic tone (low- frequency power) was associated with increased concentrations of soluble E-selectin, a marker of endothelial cell activation. There was no association between ECG markers and parameters reflecting increased procoagulation states.
Conclusion: These results indicate that there is an association between ECG parameters and blood markers reflecting endothelial function and inflammation in coronary artery disease patients. The pathophysiologic mechanisms of these associations remain to be elucidated.
© 2006 Published by Elsevier Ireland Ltd.
Keywords: Coronary artery disease; Endothelial dysfunction; Epidemiology; Heart rate variability; Inflammation; Repolarization
1. Introduction
In the past decade the use of standard electrocardiogram (ECG) monitoring made a valuable contribution to under- stand different mechanistic factors involved in the increased adverse cardiovascular events[1]. Heart rate variability an- alysis has become an established method to assess autonomic nervous system fluctuations and provides well-defined in- dicators of cardiac autonomic function[2,3]. Reduced heart
☆ Grant support: The study is funded by the US Environmental Protection Agency STAR center grant R-827354 and the GSF Focus-Network of Aerosols and Health, Germany. No conflict of interest was declared.
⁎ Corresponding author. GSF-National Research Center for Environment and Health, Institute of Epidemiology, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany. Tel.: +49 89 3187 4566; fax: +49 89 3187 3380.
E-mail address:peters@gsf.de(A. Peters).
0167-5273/$ - see front matter © 2006 Published by Elsevier Ireland Ltd.
doi:10.1016/j.ijcard.2006.07.129
rate variability and prolonged repolarization measures were associated with cardiovascular morbidity and mortality in patients with coronary artery disease [4–8]. Studies also reported that increased concentrations of inflammatory markers in coronary artery disease patients were associated with progression of the disease [9–11]. Further studies showed that acute phase response, endothelial cell activation and coagulation state interplayed together in the genesis of coronary artery disease[12–14].
Despite the epidemiological evidence for the association between ECG markers and cardiovascular endpoints and biochemical markers and cardiovascular endpoints, there is no data regarding the relationship between these ECG and biochemical markers of interest. There is a possibility that they operate independently in parallel reflecting different mechanistic pathways of cardiovascular disorders, but it is possible that they are interrelated. We hypothesized that there is an association between ECG and blood markers and we investigated these relationships in a cohort of coronary patients enrolled in an epidemiologic air-pollution study. In particular, we hypothesized that changes in the autonomic nervous system (frequently observed in postinfarction patients) might affect endothelial function and inflamma- tion: chronic sympathetic dominance due to sympathetic activation or parasympathetic withdrawal could contribute to endothelial dysfunction and enhanced inflammatory response. We also hypothesized that myocardial involve- ment (damage) in coronary artery disease patients, which could be illustrated by ECG repolarization parameters, might relate to chronic inflammation and increased procoagulant states.
2. Methods
2.1. Study population
This analysis was performed in a cohort of 52 coronary artery disease patients who were enrolled in the study evaluating the effect of air pollution on cardiovascular risk factors [15,16]. Details of the study were described before [15,16]. Briefly, 61 males with coronary artery disease older than 50 years were scheduled to participate in 12 clinical visits 2 weeks apart over 6 months period between October 16th 2000 and April 27th 2001 in Erfurt, Germany. Ac- cording to the enrollment criteria, patients with pacemakers, recent (b3 months) myocardial infarction, stroke, coronary artery bypass-surgery or coronary angioplasty, bundle- branch blocks, type 1 diabetes or on anti-coagulation therapy (except for acetylsalicylic acid) were excluded from the study. During each visit, ECG recordings and blood drawing were preformed to obtain data on ECG and biochemical parameters described below. The clinical visits were scheduled on the same weekday (Monday to Friday) and time (8:00 a.m. to 5:00 p.m.) every 2 weeks, and all methods were conducted according to standard operating procedures (SOP). Among 61 subjects, 52 patients had complete data
enabling the analysis of correlation between ECG and bio- chemical markers of risk. A written informed consent was obtained from each subject and the study protocol was approved by the German Ethics committee of the “Bayer- ische Landesaerztekammer”, Munich.
2.2. ECG parameters
The ECGs were obtained from continuous 5-min supine resting recordings (Mortara Instruments H-12 recorders, Milwaukee, WI) with spontaneous breathing[15]. All ECG recordings were analyzed blindly at the ECG Core Lab at the University of Rochester Medical Center.
Heart rate variability analyses were focused on the frequency-domain parameters HF_nu (high-frequency nor- malized units), LF_nu (low-frequency normalized units) and LF/HF ratio [2]. The frequency-domain parameters were calculated based on power spectral density analysis and normalized units of parameters were selected to describe contribution of parasympathetic and sympathetic modulation of the heart.
Repolarization parameters included manually measured QT interval corrected for heart rate with Bazett's formula and automatically measured T wave amplitude. QT interval was measured manually in lead II. For T wave amplitude, leads I, II, V1 to V6 were used and the median value from these 8 original leads was taken for each cardiac cycle and averaged over 5 min.
2.3. Blood markers
At each clinical visit after ECG recordings blood samples were drawn from each patient. Samples were centrifuged and aliquots were immediately stored at−20 °C until analysis.
The CRP (acute phase protein) and fibrinogen were measured as markers of inflammation. Intercellular adhesion molecule 1 (ICAM-1), E-selectin and von Willebrand factor (vWF) were regarded as makers of endothelial cell activation, while D-dimer and factor VII reflected blood coagulation state. The blood samples were analyzed by immunonephelometry for CRP and fibrinogen (Dade Behr- ing, Marburg, Germany). ICAM-1 and E-selectin (R&D Systems, Wiesbaden, Germany) were measured by means of a commercial ELISA. D-dimer and vWF were analyzed using an immuno turbidimetric method and factor VII by clotting time measurement (Stago, France).
Originally 599 blood samples were collected from 52 patients. Among them, 46 blood samples of 19 patients reporting an acute infection and/or surgery during 2 weeks prior to the examination were excluded. And 18 blood samples of 15 patients showing implausible low fibrinogen values (b1.0 g/l) were also excluded assuming that the plasma had clotted before centrifugation. Besides, we deleted 31 observations with only blood or ECG results and 5 observations with extreme values. Therefore, a total of 499 observations remained for this analysis.
2.4. Statistical analyses
Generalized estimating equation (GEE) models adjusting for repeated measurements were used to analyze associations between variables. To model the intra-correlation between the responses of each subject, the working correlation matrix type“compound symmetry” was selected. Normal distribu- tion and identity link function were used in each univariate model for all analyzed parameters. Response variables were logarithmically transformed if the model residuals showed skewed distribution (CRP, D-dimer and factor VII).
Effect estimates are presented as percent changes of the mean of response variables together with 95% confidence intervals (95% CI) based on an increase of the explanatory variables from the first to the third quartile (interquartile range, IQR). The associations between ECG parameters and
blood markers were analyzed by using each ECG parameter as the explanatory variable. Subgroup analyses were carried out for patients with and without use of beta-blockers or lipid-lowering drugs. All data were analyzed using the sta- tistical package SAS Version 9.1 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Clinical characteristics and measured parameters The basic characteristics of 52 study subjects are summarized in Table 1. The age ranged between 52 and 76 years and the body mass index between 22 and 38 kg/m2. About three-fourths had a history of myocardial infarction and two-thirds had angina pectoris as well as hypertension.
The majority of patients had a history of coronary artery bypass surgery/balloon dilatation. All patients were current non-smokers (N1 year) but more than two-thirds were ex- smokers. Treatment mainly consisted of beta-blockers, angiotensin-converting enzyme inhibitors, acetylsalicylic acid, and lipid-lowering drugs. The number of repeated clinic visits ranged from 9 to 12 visits per patient. Values of ECG parameters and blood markers are shown inTable 2.
3.2. Associations between ECG parameters and blood markers
Table 3shows the association between ECG parameters and blood markers expressed as the effects of changes in ECG parameters on levels of blood markers. Acute phase proteins CRP and fibrinogen showed significant associations with repolarization parameters QT interval and T wave amplitude. Endothelial cell activation marker E-selectin showed significant associations with low-frequency power of heart rate variability (Fig. 1). Higher E-selectin activation was seen in patients with higher levels of low-frequency
Table 1
Basic characteristics of 52 male patients with coronary artery disease Clinical characteristics Mean (S.D.) or total (%)
Age (years) 66 (6)
Body mass index (kg/m2) 28 (4)
History of
Myocardial infarction 40 (77%)
Angina pectoris 36 (69%)
Coronary artery bypass surgery/PTCAa 45 (87%)
Hypertension 37 (71%)
Diabetes mellitus type 2 11 (21%)
Heart failure 5 (10%)
Ever smokers 37 (71%)
Medication use
Beta-blockers 40 (77%)
ACE-inhibitorsb 29 (56%)
Calcium channel-blockers 15 (29%)
Nitrate 21 (40%)
Acetylsalicylic acid 49 (94%)
Lipid-lowering drugs (statins, fibrates) 27 (52%)
a PTCA = percutaneous transluminal coronary angioplasty.
b ACE-inhibitors = angiotensin-converting enzyme-inhibitors.
Table 2
Basic descriptions of ECG parameters and blood markers of 52 male patients with coronary artery disease
Category Variable (unit) N Mean (S.D.) Min Median Max IQR
ECG parameters
Heart rate variability HF_nu (nu) 499 0.2 (0.2) 0.0 0.1 0.9 0.3
LF_nu (nu) 499 0.4 (0.2) 0.0 0.4 0.9 0.3
LF/HF 499 4.2 (4.7) 0.1 2.5 38.9 4.4
Repolarization QT interval (ms) 472 427.3 (35.7) 346.0 424.0 582.0 39.5
T wave amplitude (μV) 498 252.2 (117.1) 77.8 220.3 663.1 160.5
Blood markers
Inflammation CRP (mg/l) 499 3.3 (3.8) 0.2 1.9 42.0 2.7
Fibrinogen (g/l) 499 2.9 (0.7) 1.2 2.9 4.9 0.8
Endothelial function ICAM-1 (ng/ml) 499 268.8 (65.7) 106.0 262.5 572.0 77.0
E-selectin (ng/ml) 499 53.9 (24.5) 1.7 49.3 179.3 31.0
vWF (% activity) 472 133.1 (57.0) 21.0 133.0 393.0 75.5
Coagulation D-dimer (μg/ml) 472 0.6 (0.5) 0.2 0.4 3.7 0.4
Factor VII (% activity) 468 121.2 (35.3) 42.0 118.0 382.0 38.0
Abbreviations (alphabetical order): CRP = C-reactive protein; HF_nu = high-frequency normalized unit; ICAM-1 = intercellular adhesion molecule 1;
IQR = interquartile range; LF/HF = ratio of LF and HF; LF_nu = low-frequency normalized unit; Max = maximum value; Min = minimum value; S.D. = standard deviation; vWF = von Willebrand factor.
power, reflecting enhanced sympathetic modulation. The ICAM-1, another marker of endothelial function showed significance with LF/HF ratio. There was no association between coagulation markers and ECG parameters.
3.3. Subgroup analyses
For subgroup analyses, the moderate effects of repolar- ization parameters on acute phase protein in the group using beta-blockers were consistent with original effect estimates, but tended to disappear in the group without using beta- blockers. The effect of LF_nu on E-selectin was seen in the beta-blockers using group but not in the group who did not use it (Fig. 2). In the group without using lipid-lowering drugs, all these observed significant associations turned insignificant (results not shown).
4. Discussion
There is a known interplay among acute phase response, endothelial cell activation, and coagulation parameters, and known relationship between heart rate variability and repolarization parameters (Fig. 3). However, there is no comprehensive data regarding the relationship between ECG parameters and biochemical markers reflecting increased risk of cardiovascular morbidity and mortality. In our study of 52 coronary artery disease patients undergoing several mea- surements of studied parameters, we observed a significant association between heart rate variability parameters reflect- ing sympathetic activation and endothelial activation blood markers and between repolarization parameters and inflam- matory markers. These findings indicate that there is a link between ECG parameters and blood variables. It is difficult to determine the direction and causative nature of the relationship.
It is important to realize that this analysis was embedded in a study assessing associations between ambient air pollution exposure and changes of ECG parameters and blood markers in male coronary artery disease patients. Here, the relations among heart rate variability, repolarization and blood marker levels were analyzed to guide the interpretation of the associations between air pollution and heart rate variability[17], repolarization[15]and blood marker levels [16].
We hypothesized that sympathetic activation might affect endothelial function since increased levels of circulating catecholamines influence vascular response. Among mea- sured parameters of endothelial activation, only E-selectin showed the association with low frequency levels. E-selectin is a cell-surface-bound leukocyte adhesion molecule specific to endothelial cell. It mediates the interaction between leukocytes, platelets, and the endothelium. A recent study in cocaine-treated mice demonstrated that catecholamines induce upregulation of adhesion molecules including E- selectin [18]. There are no clinical data illustrating this association and our study contributes with indirect
Table3 Effectestimates(%)and95%CI(inparenthesis)ofECGparametersonbloodmarkersperIQRincrement InflammationEndothelialfunctionCoagulation CRPaFibrinogenICAM-1E-selectinvWFD-dimeraFactorVIIa HeartratevariabilityHF_nu3.4(−6.1,13.8)0.1(−3.1,3.1)−1.2(−3.0,0.6)−0.3(−2.6,1.9)−0.9(−4.5,2.7)1.9(−2.3,6.3)0.8(−2.4,4.0) LF_nu−0.2(−11.9,13.1)−0.2(−3.1,2.8)0.2(−1.5,2.0)3.2(0.5,5.9)⁎0.1(−4.1,4.3)0.4(−4.1,5.1)−0.3(−3.9,3.4) LF/HF−0.7(−6.6,5.7)1.0(−1.6,3.6)1.6(0.3,2.9)⁎0.9(−0.6,2.4)−0.6(−4.3,3.0)0.2(−2.7,3.2)0.0(−2.7,2.7) RepolarizationQTinterval7.4(0.8,14.4)⁎2.9(0.4,5.5)⁎0.6(−1.0,2.2)0.7(−1.1,2.6)3.0(−2.1,8.1)−0.4(−3.9,3.2)2.0(−0.4,4.4) Twave amplitude−12.1(−21.4,0.0)⁎−5.0(−8.9,−1.1)⁎−0.5(−3.8,2.8)−1.8(−6.0,2.4)−1.1(−9.2,7.1)1.6(−4.7,8.4)−3.2(−7.7,1.6) Abbreviations(alphabeticalorder):CRP=C-reactiveprotein;HF_nu=high-frequencynormalizedunit;ICAM-1=intercellularadhesionmolecule1;IQR=interquartilerange;LF/HF=ratioofLFandHF; LF_nu=low-frequencynormalizedunit;vWF=vonWillebrandfactor. aResponsevariablewaslogarithmicallytransformed. ⁎pb0.05.
(throughout heart rate variability analysis) evidence for such clinical effects.
Our hypothesis regarding the relationship between heart rate variability and inflammatory markers was not confirmed in our cohort. Our study is the first to examine associations between ECG parameters and blood markers in coronary artery disease patients using repeated measurements. Previous studies relied on one measurement of these highly variable parameters. One study in 643 middle-aged and elderly subjects (average age of 64 ± 6.8 years) without apparent heart disease found that increased heart rate and reduced heart rate variability were associated with subclinical inflammation[19]. In the multivar- iate logistic regression models, a negative association was found between 24-h SDNN (standard deviation of normal to normal intervals) and CRP as well as a CRP odds ratio (OR = 0.990, 95% CI: 0.984, 0.997) associated with 24-h SDNN comparing the upper third to the lower two-thirds. Both the point value and confidence interval of the CRP odds ratio close to 1 indicate that this negative association is very weak. Another cross-sectional study conducted in 121 women (average age of 64 ± 8.6 years)
with coronary artery disease using 24-h ECG recordings found that the relationships between heart rate variability parameters (SDNN, TP, HF, LF, VLF) and CRP levels were weak and insignificant[20]. Controlling for potential confounding factors and adjusting for medication such as beta-blockers and statins yielded similar results. The authors concluded that no significant relationship existed between heart rate variability and CRP levels in these female coronary artery disease patients.
Moderate associations between repolarization parameters and acute phase proteins, found in our analysis, suggested that deterioration of myocardial substrate and the increase in a systemic inflammatory response coincided. Inflammation triggered by air pollution might lead to changes in the cardiac ion channel function reflected by repolarization abnormal- ities [21]. It is difficult to determine causative relationship, since it could be a parallel phenomenon. We hypothesize it to have an inflammation–repolarization ion channel link.
Alternatively, one could argue that the autonomic nervous system could be affected by inflammation and that the observed repolarization abnormalities were in response to heart rate variability changes. However, these moderate associations tended to disappear in the subgroup without using beta-blockers or lipid-lowering drugs. Beta-blockers can block the action of epinephrine and norepinephrine on the beta-adrenergic receptors in the myocardium and have an effect on the repolarization process by decreasing QT in- terval and QT dispersion[22]. Lipid-lowering drugs such as statins and fibrates are used to improve blood cholesterol and can influence blood marker levels, especially the acute phase
Fig. 2. Subgroup analyses by beta-blockers, comparison of effect estimates of repolarization parameters on C-reactive protein (CRP), and low frequency power on E-selectin levels in total, using and not using group.
Fig. 3. Associations between ECG parameters and blood markers. Abbrevia- tions (alphabetical order): CRP = C-reactive protein; HF_nu = high-frequency normalized unit; ICAM-1 = intercellular adhesion molecule 1; LF/HF = ratio of LF and HF; LF_nu = low-frequency normalized unit; vWF = von Willebrand factor.
Fig. 1. Mean E-selectin concentrations by low-frequency quartiles.
proteins such as CRP[23,24]. We speculate that using either or both of these two drug classes might be an indicator for a more severe disease, rendering patients more vulnerable.
Subgroup analyses indicate that medication represents an effect modifier and that potentially the associations were only moderate between repolarization parameters and acute phase proteins because they were damped by medication. It may further imply that these associations still do exist but are too weak to detect in healthy people, whereas in documented coronary artery disease patients on medication, the associa- tions are detectable.
It has been hypothesized that air pollution-induced changes in ECG contribute to the increased cardiovascular mortality[21,25]. This supports the concept of the“cardiac death triangle theory” [1]. Reduced heart rate variability parameters reflect an imbalance between sympathetic and parasympathetic tones modulating the cardiovascular sys- tem, known risk factor for cardiac death [4–6]. Abnormal repolarization, reflecting changes in myocardial substrate, also indicates elevated risk in coronary patients [7,8]. Air pollution was shown to affect these parameters but the mechanisms of these effects are unknown. It is possible that air pollution triggers inflammatory and endothelial response or abnormal autonomic modulation and/or myocardial substrate make coronary artery disease patients vulnerable to air pollution.
A major strength of this study is the availability of 12 repeated measurements in most participants during 6 months with each subject being his own control. In contrast to a cross-sectional study, this design avoids the instability of a single measurement point and can reduce the influence of other factors on the measurement process.
In conclusion, our results indicate that there is an as- sociation between ECG parameters and blood markers re- flecting endothelial function and inflammation in coronary artery disease patients.
Acknowledgments
The study is funded by the US Environmental Protection Agency STAR center grant R-827354 and the Focus-Network of Aerosols and Health, GSF. The Focus-Network of Aerosols and Health coordinates and focuses all GSF research on health effects and the characterization of aerosols. It comprises research projects of the GSF Institutes of Ecological Chemistry, Epidemiology, Inhalation Biology, Radiation Protection, and Toxicology. No conflict of interest was declared.
References
[1] Zareba W, Nomura A, Couderc JP. Cardiovascular effects of air pollution: what to measure in ECG? Environ Health Perspect 2001;109 (Suppl 4):533–8.
[2] Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrocardiography. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996;93:1043–65.
[3] Kara T, Nykodym J, Somers VK. Heart rate variability: back to the beginning. J Cardiovasc Electrophysiol 2003;14:800–2.
[4] van Boven AJ, Jukema JW, Haaksma J, et al. Depressed heart rate variability is associated with events in patients with stable coronary artery disease and preserved left ventricular function. Am Heart J 1998;135:571–6.
[5] Wennerblom B, Lurje L, Tygesen H, Vahisalo R, Hjalmarson A.
Patients with uncomplicated coronary artery disease have reduced heart rate variability mainly affecting vagal tone. Heart 2000;83:290–4.
[6] Janszky I, Ericson M, Mittleman MA, et al. Heart rate variability in long-term risk assessment in middle-aged women with coronary heart disease: The Stockholm Female Coronary Risk Study. J Intern Med 2004;255:13–21.
[7] Zareba W, Moss AJ, le Cessie S. Dispersion of ventricular repolarization and arrhythmic cardiac death in coronary artery disease. Am J Cardiol 1994;74:550–3.
[8] Lee KW, Kligfield P, Dower GE, Okin PM. QT dispersion, T-wave projection, and heterogeneity of repolarization in patients with coronary artery disease. Am J Cardiol 2001;87:148–51.
[9] Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000;343:1139–47.
[10] Zouridakis E, Avanzas P, Arroyo-Espliguero R, Fredericks S, Kaski JC.
Markers of inflammation and rapid coronary artery disease progression in patients with stable angina pectoris. Circulation 2004;110:1747–53.
[11] Hoffmeister A, Rothenbacher D, Kunze M, Brenner H, Koenig W.
Prognostic value of inflammatory markers alone and in combination with blood lipids in patients with stable coronary artery disease. Eur J Intern Med 2005;16:47–52.
[12] Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease.
Circulation 2000;102:1000–6.
[13] Anderson R, Dart AM, Starr J, Shaw J, Chin-Dusting JP. Plasma C- reactive protein, but not protein S, VCAM-1, von Willebrand factor or P-selectin, is associated with endothelium dysfunction in coronary artery disease. Atherosclerosis 2004;172:345–51.
[14] Lindmark E, Wallentin L, Siegbahn A. Blood cell activation, coagulation, and inflammation in men and women with coronary artery disease. Thromb Res 2001;103:249–59.
[15] Henneberger A, Zareba W, Ibald-Mulli A, et al. Repolarization changes induced by air pollution in ischemic heart disease patients. Environ Health Perspect 2005;113:440–6.
[16] Ruckerl R, Ibald-Mulli A, Koenig W, et al. Air pollution and markers of inflammation and coagulation in patients with coronary heart disease. Am J Respir Crit Care Med 2006;173:432–41.
[17] Ibald-Mulli A, Zareba W, Rückerl R, et al. Effects of particulate air pollution on heart rate variability in patients with coronary artery disease (Abstract). 2003 International Conference of American Thoracic Society. Am J Respir Crit Care Med 2003;167(Suppl 7):A333.
[18] Chen Y, Ke Q, Xiao YF, et al. Cocaine and catecholamines enhance inflammatory cell retention in the coronary circulation of mice by upregulation of adhesion molecules. Am J Physiol Heart Circ Physiol 2005;288(5):H2323–31.
[19] Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF. Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J 2004;25:363–70.
[20] Janszky I, Ericson M, Lekander M, et al. Inflammatory markers and heart rate variability in women with coronary heart disease. J Intern Med 2004;256:421–8.
[21] Schulz H, Harder V, Ibald-Mulli A, et al. Cardiovascular effects of fine and ultrafine particles. J Aerosol Med 2005;18:1–22.
[22] Yoshiga Y, Shimizu A, Yamagata T, et al. Beta-blocker decreases the increase in QT dispersion and transmural dispersion of repolarization induced by bepridil. Circ J 2002;66:1024–8.
[23] Bickel C, Rupprecht HJ, Blankenberg S, et al. Relation of markers of inflammation (C-reactive protein, fibrinogen, von Willebrand factor, and leukocyte count) and statin therapy to long-term mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 2002;89:901–8.
[24] Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29–38.
[25] Brook RD, Franklin B, Cascio W, et al. Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association.
Circulation 2004;109(21):2655–71.
