DÄ internationalArchive1-2/2008Cardiovascular Risk Factors and Signs of Subclinical Atherosclerosis in the Heinz Nixdorf Recall Study

Original article

Cardiovascular Risk Factors and Signs of Subclinical Atherosclerosis in the Heinz Nixdorf Recall Study

Dtsch Arztebl Int 2008; 105(1-2): 1-8. DOI: 10.3238/arztebl.2008.0001

Erbel, R; Möhlenkamp, S; Lehmann, N; Schmermund, A; Moebus, S; Stang, A; Dragano, N; Hoffmann, B; Grönemeyer, D; Seibel, R; Mann, K; Kröger, K; Bröcker-Preuss, M; Volbracht, L; Siegrist, J; Jöckel, K

Introduction: Modern investigation modalities allow markers of atherosclerosis to be detected at a subclinical stage. The aim of the study was to analyze the prevalence of these markers in relation to traditional risk factors.
Methods: The population based study included 4814 participants, aged 45 to 75 years, with a response rate of 55.8% of those contacted. The patients' history, psychosocial and environmental risk factors were assessed.
Results: The prevalence of obesity was 26.2% in men and 28.1% in women, 26% of men and 21% of women were smokers. Hypertension was found in 46% of men and 31% of women, diabetes in 9.3% of men and 6.3% of women. Markers of subclinical peripheral arterial disease were found in 6.4% of men and 5.1% of women, of subclinical carotid artery disease in 43.2% and 30.7%, and of subclinical coronary artery calcification in 82.3% and 55.2%, respectively. The prevalence of coronary calcification measured using an Agatston Score >100 was in 40% in men and 15% in women, using a score >400, 16.8% and 4.5%, respectively.
Discussion: A high prevalence of subclinical atherosclerosis was found in the older population. The follow-up period will demonstrate whether the detection of markers of subclinical atherosclerosis will improve risk stratification beyond that offered by traditional risk factors.
Dtsch Arztebl Int 2008; 105(1–2): 1–8
DOI: 10.3238/arztebl.2008.0001

Key words: cardiovascular risk, atherosclerosis, peripheral arterial disease, carotid stenosis, ultrasound, CT, EBCT
LNSLNS Diabetes, hypertension, hypercholesterolemia, and smoking are the primary risk factors for cardiovascular events (15). Other contributory factors include lifestyle aspects such as physical activity, overweight, alcohol consumption (6), as well as inflammatory markers such as C-reactive protein, and psychosocial and environmental factors (7, 8, e1e6).

These risk factors promote the development of arterial atherosclerosis, which begins as early as childhood or adolescence and manifests itself clinically decades later as acute myocardial infarction or stroke, or chronic coronary artery disease (CAD) or peripheral artery disease (PAD).

Today, imaging and other diagnostic techniques allow the markers of atherosclerosis to be identified at the subclinical stage (e7, e8). Subclinical PAD, for example, is diagnosed with the aid of the ankle-brachial index (ABI) (10, e9e11), subclinical atherosclerosis of the carotid arteries by measuring intima-media thickness (IMT), plaque formation with the aid of ultrasound (11, e12e15), and subclinical atherosclerosis of the coronary arteries by means of electron-beam computed tomography (EBCT) (12, e16e21). EBCT can be used, without the need for contrast agents, to detect the arterial calcification that accompanies the development of atheromas and fibroatheromas, which become larger and thicker with advancing age. Detecting and quantifying calcification in this manner is reliable and precise, and radiation exposure is low (13, 14).

Concurrent to the Multi-Ethnic Study of Atherosclerosis (MESA) in the United States, the Heinz Nixdorf Recall Study is the first population-based study in Europe to use the above-mentioned diagnostic techniques to analyze the predictive value of subclinical markers of atherosclerosis compared to traditional risk factors (15, 16, e22, e23). The baseline examination of the cohort study has been completed. This paper will present the most important prevalence data on cardiovascular risk factors and subclinical atherosclerosis. The findings provide a picture of the distribution of risk factors in middle-aged and older individuals in the general urban population in Germany.

Methods
The Heinz Nixdorf Recall Study is a population-based, prospective cohort study of a random sample of 45- to 74-year-old subjects living the Ruhr-area cities of Bochum, Essen, or Mülheim/Ruhr (e23). Between the years 2000 and 2003, a total of 4814 out of 8400 eligible subjects took part in the study (participation rate: 55.8%) (e26) and were examined in a study center established by the medical school especially for the purposes of this investigation. Anamnestic data related, in particular, to cardiovascular risk factors were recorded by means of computer-aided personal interviews (CAPI) (22, e27, e28). In addition, anthropomet- ric data such as height and weight were collected, and blood pressure was measured using the oscillometric method and size-adjusted cuffs on the right arm (17). Hypertension was defined according to the JNC-7 guidelines as systolic blood pressure >140/90 mm Hg and/or use of blood pressure medication. Laboratory blood tests were performed to determine lipid metabolism parameters and other risk factors. Diabetes was defined as a fasting blood glucose level of >126 mg/dL, a postprandial blood glucose level of >200 mg/dL, or use of diabetes medication. The modified Framingham risk score was calculated based on these measurements (e8, e29). All subjects underwent resting ECG (MAC 5000, GE Health Care, Freiburg, Germany) (19).

To determine the presence of PAD, the ankle brachial index (ABI) was calculated; PAD was defined as a ratio <0.9 (10, 20, e9e11, e30e33). Duplex carotid ultrasound was used to measure IMT and detect plaque formation (Vivid FiVe, GE-Health Care, Freiburg) (11, e24).

EBCT (C-150, GE Imatron, San Francisco, USA) was performed in university radiology departments in Bochum and Mühlheim/Ruhr, and was the only diagnostic procedure to be conducted outside of the study center. To assess coronary artery calcification, 3-mm-thick slices were obtained with an image acquisition time of 100 ms; a calcified lesion was defined as a minimum of 4 adjacent pixels with a density of >130 Hounsfield units (13). Coronary artery calcification was quantified by means of Agatston score. The latter is calculated by multiplying the area of each lesion by a density factor and then summing the individual lesion scores (13, 15, 16, e22, e23). Based on a consensus recommendation, calcium scores were categorized as follows: 0 through 99, >100 through 399, and >400 (21, e34). The 75th percentile for age- and gender-adjusted Agatston score was also calculated. Alongside the absolute Agatston score, this cut-off is an established measure of increased myocardial infarction risk (18, e7, e8).

Psychosocial factors associated with cardiovascular disease were assessed by means of interviews and a questionnaire filled out by the participating subjects (22, e1, e2). These included, above all, aspects related to the social and economic backgrounds of the subjects, known stress factors (e.g. work stress), or psychological factors (e.g. depression). To measure potential environmental risk factors, the distance between place of residence and major roads was calculated, and median concentrations of ultrafine particles at each residential address were derived using a dispersion model (EURAD) (23, e3e6, e25, e35). A distinction was drawn between subjects with CAD (n = 327) and those without it (n = 4487). CAD was defined as myocardial infarction or interventional/operative revascularization.

After the German Federal Office for Radiation Protection in Munich authorized use of the EBCT, the medical school's ethics committee gave approval for the study. In addition, the study was monitored by an external agency and certified on more than one occasion according to DIN EN ISO 9001:2000 by TÜV Med Rheinland. The study was financed by the Heinz Nixdorf Foundation (chairman: Dr. G. Schmidt), and scientific review and oversight were provided on behalf of the foundation by a scientific advisory committee from the German Aerospace Center (under the auspices of the German Federal Ministry of Education and Research).

Statistics
Demographic data and risk factors are expressed as mean ± standard deviation, median, or as percentages. Gender differences were evaluated using the Wilcoxon rank-sum or chi-square test. Age-specific trends in ECG findings were analyzed (e-table gif ppt) using the Mantel-Haenszel chi-square test (alternative hypothesis: non-vanishing correlation). The association between ECG findings and Agatston score was analyzed using multiple linear regression analysis with calcium score (logarithmized: log [calcium score + 1]) as dependent variable adjusted for age, gender, smoking status, systolic blood pressure, BMI, and LDL cholesterol.

Population-based Agatston-score percentiles were calculated separately for men and for women between 45 and 75 years of age and in 5-year increments. IMT percentiles were also calculated in this manner for male subjects. The association between chronic exposure to high traffic levels near a subject's place of residence and an Agatston score >75th age- and gender-specific percentile was assessed using multiple logistic regression analysis. Odds ratios (OR) and their 95% confidence intervals (CI) based on Wald's test were adjusted for age, gender, city, residential area, educational attainment, smoking status, exposure to passive smoke, physical activity, waist-hip ratio, diabetes, blood pressure, and lipid status. The bivariate association between IMT and Agatston score was assessed using Spearman's rank correlation coefficient. Please see e-supplement for a more detailed description of the study methods and statistics.

Results
In the 4487 subjects (93.2%) without CAD, 46.3% of men and 30.8% of women had hypertension (stage 1 or 2), 26% of men and 21.3% of women were smokers, 9.3% of men and 6.3% of women had diabetes, and 50.5% of men and 49.5% of women had hypercholesterolemia. A high Framingham risk score (>20% over 10 years) was found in 26.2% of men and 1.4% of women (table 1 gif ppt).

Like these risk factors, the prevalence of detectable arrhythmias and pathological ECG findings were age- and gender-specific (table 2 gif ppt). ECG abnormalities indicative of a past myocardial infarction were found in 13.3% of men and 8.3% of women >65 years of age. Adjusted for age, gender, and risk factors, a normal ECG was independently predictive of low coronary calcification in subjects without CAD and with no treated risk factors. In contrast, left-ventricular hypertrophy, prolonged QTc interval, and major ECG abnormalities were associated with pronounced coronary calcification.

A total of 1.8% of men and 0.4% of women without CAD indicated that they had PAD; among men and women with CAD, however, these numbers rose to 24% and 18.2%, respectively. The age- and gender-specific prevalences of an ABI <0.9 are given in diagram 1 (gif ppt). Medial arterial calcification, defined as an ABI >1.3, was observed in 1.7% of men and 0.7% of women.

The prevalence of plaque formation in the carotid arteries was 43.2% in men and 30.7% in women. However, 23% of the 1526 men without any coronary calcification also showed plaque formation in the carotid arteries. IMT (diagram 2 gif ppt) was highly age-dependent, and the percentiles allow for an individual assessment of results.

Coronary artery calcification, defined as a positive EBCT result (Agatston score >0), was found in 82.3% of men and 55.2% of women (table 1). Women had a considerably lower degree of calcification than men (diagram 3 gif ppt). All men and 92% of women with CAD had coronary artery calcification. If the Agatston score was >10, 65% of the participants had carotid plaque formation; 34%, if the Agatston score was >100. Twenty percent of male subjects had both a calcium score >100 and plaques in the carotid arteries. Only 3% of men had an ABI <0.9, plaques in the carotid arteries, and a coronary calcium score >100.

Various analyses demonstrated that the majority of established cardiovascular risk factors occurred more frequently in subjects from lower socioeconomic groups, as defined in terms of income, education, and occupation. Because the results cannot be presented here in detail, diagram 4 (gif ppt) shows an example of this kind of social gradient – i.e., the median coronary calcium score according to income group. As can be seen in the diagram, the median calcification score increases as income decreases. This finding was statistically significant, even after adjusting for age in multivariate analysis (not shown).

Of the 4494 subjects for whom coded data on place of residence, coronary calcium score, and all documented risk factors were available, a total of 351 (7.8%) were living within 100 m of an expressway or federal highway with an average traffic flow of between 10 000 and 130 000 motor vehicles per day. A total of 8.0% (n = 28) of the subjects in this group had CAD compared to only 6.5% (n = 270) of the 4143 subjects who were not exposed to these levels of traffic. Among all subjects, the adjusted odds ratio for the association between living close (<100 m) to a major road or highway and having a coronary calcium score >75th percentile was 1.45 (95% CI: 1.15 to 1.82), with strong effects in men (OR: 1.65; 95% CI: 1.19 to 2.28) and in subjects with low educational attainment (OR: 1.64; 95% CI: 1.22 to 2.20). However, this association was weaker in women (OR: 1.26; 95% CI: 0.90 to 1.76), smokers (OR: 1.35; 95% CI: 0.86 to 2.14), and individuals with high levels of educational attainment (OR: 1.36; 95% CI: 0.69 to 2.68). As can be seen in diagram 5 (gif ppt), there was a clear exposure-effect relationship between increasing proximity to a major road and having an Agatston score >75th percentile.

Discussion
The Heinz Nixdorf Recall Study is the first study to determine the prevalence in Germany not only of known and new candidate cardiovascular risk factors, but also of subclinical atherosclerosis in the carotid arteries, the arteries of the lower limbs, and coronary vessels. The study sample is representative of the population of the Ruhr area, which is home to approximately 6 million people with a higher percentage of female smokers than elsewhere in Germany (4). Concurrent to the present study, the similarly designed MESA study in the United States examined, among other ethnic groups, 2619 white subjects aged 45 to 84 years (15, 24, e36). Gender distribution and BMI (at 28 ± 5 kg/m²) were comparable in both studies. However, participants in the Heinz Nixdorf Recall Study had cholesterol levels that were 35 mg/dL higher, LDL cholesterol levels that were 30 mg/dL higher, and triglyceride levels that were 15 mg/dL higher on average; they were also less likely to be taking cholesterol-lowering drugs (9.6% versus 18%). The prevalence of diabetes and hypertension in the present study were 7.7% and 35%, respectively, and were thus virtually identical to the prevalences observed among white subjects in the MESA study (7.8% and 36%, respectively). At 124 ± 20 and 70 ± 10 mm Hg, blood pressure in the cohorts of the present study was higher than in the MESA study. Moreover, in the German study there were twice as many smokers (24% versus 12%). The median Framingham score (risk of experiencing a cardiovascular event within the next 10 years) was 10.6 ± 7.6% in the present study versus 9.3 ± 7.1% in the MESA study. The follow-up data will show whether, as is to be expected (e37), the Framingham score overestimates the actual risk in Germany.

Peripheral artery disease
In the present study, PAD was present in almost 1 out of every 20 participants, a figure that rose to 1 out of every 5 men and 1 out of every 7 women among patients with CAD (20, e9). In the getABI study, which examined a German cohort of 6880 patients over 65 years of age, PAD was detected in 19.8% of men and 16.8% of women (25). The ABI is simple to perform and should be considered standard of care in the older population, because of therapeutic consequences (10, e9, e10), and because 20% to 50% of patients over 50 years of age have no symptoms and only 10% to 35% have classic claudication (10). Moreover, nonfatal myocardial infarction or stroke occurs in 20% to 40% of cases and is associated with a mortality of 10% to 30% over the following 5 years (10, e9). In the MESA study, the prevalence of PAD was considerably lower than in the present study (in men: 2.7%; in women: 3.4%) (20, e9).

Carotid artery disease
When evaluating IMT, age and gender need to be taken into account to ensure reliable risk stratification of individual patients. In general, an IMT of >0.9 mm to >1 mm is considered to be a cut-off value for identifying high-risk patients (5, 11, 18, e32, e33). Patients with evidence of plaque formation in the carotid artery are also to be considered at high risk (e24). However, according to the results of the present study, the current IMT cut-off values appear to be too high, thus leading to underestimates of cardiovascular risk. Analyses of data from the prospective study will demonstrate whether the cut-off values need to be modified.

Our data show that there was only a weak association between the degree of coronary calcification and IMT in male subjects (Spearman's rank correlation coefficient of 0.26), which means that IMT measurements alone are insufficient to predict the presence of subclinical atherosclerosis of the coronary arteries.

Coronary artery calcification
The prevalence of coronary artery calcification in men was 82.3%, which was significantly higher than the 55.2% detected in women. The age- and gender-adjusted percentiles allow for an individual assessment of results, which are available on the internet (www.recall-studie.uni-essen.de). Previous analyses of data from selected patient collectives have demonstrated that the actual risk has been considerably underestimated (diagram 6 gif ppt) (16, e16e19).

The analyses of the population-based studies thus confirmed the criticism directed at earlier publications in which selected patient collectives were investigated (e37). In comparison to the MESA study a very good agreement was found (24). In addition, the MESA study shows considerable differences between ethnicities (e-diagram gif ppt).

EBCT has recently given way to multislice computed tomography (MSCT), also known as multidetector computed tomography (MDCT); the results, however, are comparable (e38). By using correction factors, different CT systems can be compared to one another (e36).

Psychosocial risk factors
The cross-sectional data alone show a clear relationship between socioeconomic status and risk of disease (e39), as demonstrated by the association between income and degree of coronary calcification presented above (22). This example is confirmed by further analyses (not presented here), which reveal an association between educational attainment or occupation and coronary calcification, as well as between socioeconomic indicators and PAD. In addition, the cross-sectional data provide preliminary insight into the socioeconomic inequalities affecting disease risk. In lower socioeconomic groups, an unhealthy lifestyle (7, e27, e28) and increased exposure to illness-causing psychosocial and physical environmental factors appear to play a very important role. These initial findings suggest that socioeconomic characteristics should be taken more strongly into consideration when evaluating risk profiles, and that preventive measures are needed to help reduce socioeconomic inequalities.

Environmental risk factors
It is well-known that chronic exposure to high concentrations of ultrafine particles leads to increased cardiovascular morbidity and mortality (e3e6, e40, e41) The present study shows that long-term exposure to high levels of traffic near an individual's place of residence is associated with increased cardiovascular morbidity and subclinical atherosclerosis, independent of background concentrations of ultrafine particles (23, e35). The ultrafine particle fraction (<100 nm) or specific chemical components such as transition metals and traffic noise have been variously hypothesized to be responsible for the pathogenic effects of traffic emissions (e25).

The weaker association between traffic and coronary calcification in smokers is potentially due to the dominating effect of smoking, since the cardiovascular effects of smoking and those of ultrafine particles presumably involve the same pathophysiological mechanisms (e41).

Perspectives
Both the Heinz Nixdorf Recall Study and the MESA study aim to assess markers of subclinical atherosclerosis in relation to traditional and new candidate risk factors, as well as to the Framingham, PROCAM, and European Society of Cardiology (ESC) Score algorithms. A particularly important observation is that risk estimates based on established risk factors frequently underestimate the actual extent of subclinical atherosclerosis by considerable margins (e42).

Data from the follow-up period will demonstrate whether this difference is also reflected in a different rate of cardiovascular events.

Conflict of interest statement
Prof. Dr. Raimund Erbel declares that he received support from Siemens to organize a congress.
PD Möhlenkamp receives research support and fees from GE Medical Systems and Merck.
PD Schmermund received fees from GE Medical Systems and Siemens, as well as research support from Siemens.
Prof. Jöckel conducts a variety of externally funded projects at his institute, including some that are funded by the (pharmaceutical) industry.
Dr. Lehmann, Dr. Moebus, Prof. Stang, Dr. Dragano, Dr. Hoffmann, Prof. Grönemeyer, Prof. Seibel, Prof. Siegrist, Prof. Mann, PD Kröger, Dr. Broecker-Preuss, and Dr. Volbracht declare that no conflict of interest exists according to the guidelines of the International Committee of Medical Journal Editors.
Manuscript received on 11 January 2007; revised version accepted on 7 August 2007.

Translated from the original German by Matthew D. Gaskins.

Corresponding author
Prof. Dr. med. Raimund Erbel
Klinik für Kardiologie
Universitätsklinikum Essen
Westdeutsches Herzzentrum Essen
Universität Duisburg-Essen
Hufelandstr. 55
45122 Essen, Germany
erbel@uk-essen.de
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Schmermund A, Möhlenkamp S, Stang A et al.: Assessment of clinically silent atherosclerotic disease and established and novel risk factors for predicting myocardial infarction and cardiac death in healthy middle-aged subjects: Rationale and design of the Heinz Nixdorf RECALL Study. Am Heart J 2002; 144: 212–8. MEDLINE
e24.
Kitamura A, Iso H, Imano H et al.: Carotid intima-media thickness and plaque characteristics as a risk factor for stroke in Japanese elderly men. Stroke 2004; 35: 2788–94. MEDLINE
e25.
Babisch WF, Beule B, Schust M, Kersten N, Ising H: Traffic noise and risk of myocardial infarction. Epidemiology 2005; 16: 33–40. MEDLINE
e26.
Stang A, Moebus S, Dragano N et al.: Baseline recruitment and analyses of nonresponse of the Heinz Nixdorf Recall Study: Identifiability of phone numbers as the major determinant of response. Eur J Epidemiol 2005; 20: 489–96. MEDLINE
e27.
Dragano N, Bobak M, Wege N et al.: Neighbourhood socioeconomic status and cardiovascular risk factors: a multilevel analysis of nine cities in the Czech Republic and Germany. BMC Public Health 2007; 7: 255 MEDLINE
e28.
Wege N, Dragano N, Moebus S et al.: When does work stress hurt? Testing the interaction with socioeconomic position in the Heinz Nixdorf Recall Study. J Epidemiol Commun Health 2007 (im Druck/in press).
e29.
Wilson PW, D´Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB: Prediction of coronary heart disease using rist factor categories. Circulation 1998; 97: 1837–47. MEDLINE
e30.
Criqui MH, Fronek A, Klauber MR, Barrett-Connor E, Gabriel S: The sensitivity, specifity, and predictive value of traditional clinical evaluation of peripheral arterial disease: results from non-invasive testing in a defined population. Circulation 1985; 71: 516–22. MEDLINE
e31.
Heald CL, Fowkes FG, Murray GD, Price JF: Risk of mortality and cardiovascular disease associated with the ankle-brachial index: Systematic review. Atherosclerosis 2006; 189: 61–9. MEDLINE
e32.
Taylor A, Shaw LJ, Fayad Z et al.: Tracking atherosclerosis regression: a clinical tool in preventive cardiology. Atherosclerosis 2005; 180: 1–10. MEDLINE
e33.
Meijer R, Grobee DE, Bots ML: Mannnheim consensus on carotid intima-media thickness: opposite and complementary points of view. Cerebrovasc Dis 2006; 21: 415–6. MEDLINE
e34.
Budhoff MJ, Achenbach S, Blumenthal RS et al.: Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on cardiovascular imaging and intervention, Council on Cardiovacular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 2006; 114: 1761–91. MEDLINE
e35.
Hoffmann B, Moebus S, Stang A et al. on behalf of the Heinz Nixdorf Recall Study Investigation Group: Residence close to high traffic and prevalence of coronary heart disease. Eur Heart J 2006; 27: 2696–702. MEDLINE
e36.
Carr JJ, Nelson JC, Wong ND et al.: Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of multi-ethnic study of atherosclerosis (MESA) and coronary artery risk development in young adults (CARDIA) study. Radiology 2005; 234: 35–43. MEDLINE
e37.
Redberg RF: Coronary artery calcium: should we rely on this surrogate marker? Circulation 2006; 113: 336–7. MEDLINE
e38.
Schmermund A, Erbel R, Silber S: Age and gender distribution of coronary artery calcium measured by four-slice computed tomography in 2,030 persons with no symptoms of coronary artery disease. Am J Cardiol 2002; 90: 168–73. MEDLINE
e39.
Lynch JW, Kaplan GA, Cohen RD, Tuomilehto J, Salonen JT: Do cardiovascular risk factors explain the relation between socioeconomic status, risk of all-cause mortality, cardiovascular mortality, and acute myocardial infarction? Am J Epidemiol 1996; 144: 934–42. MEDLINE
e40.
Oberdörster G: Pulmonary effects of inhaled ultrafine particles. Int Arch Occup Environ Health 2001; 74: 1–8. MEDLINE
e41.
Kim JY, Chen JC, Boyce PD, Christiani DC: Exposure to welding fumes is associated with acute systemic inflammatory responses. Occup Environ Med 2005; 62: 157–63. MEDLINE
e42.
Erbel R, Möhlenkamp S, Lehmann N et al. on behalf of the Heinz Nixdorf Recall Study Investigative Group: Sex related cardiovascular risk stratification based on quantification of atherosclerosis and inflammation. Atherosclerosis. 2007 [Epub ahead of print]. MEDLINE
Klinik für Kardiologie, Westdeutsches Herzzentrum, Universitätsklinikum Essen, Universität Duisburg-Essen: Prof. Dr. med. Erbel, PD Dr. med. Möhlenkamp; Institut für Medizinische Informatik, Biometrie und Epidemiologie, Universitätsklinikum Essen, Universität Duisburg-Essen: Prof. Dr. rer. nat. Jöckel, Dr. rer. nat. Moebus MPH, Dr. rer. nat. Lehmann, Dr. med. Hoffmann MPH; Cardioangiologisches Centrum Bethanien (CCB), Frankfurt: PD Dr. med. Schmermund; Institut für Medizinische Epidemiologie, Biometrie und Informatik, Universitätsklinikum Halle-Wittenberg: Prof. Dr. med. Stang; Institut für Medizinische Soziologie, Universitätsklinikum Düsseldorf: Prof. Dr. phil. Siegrist, Dr. phil. Dragano; Institut für Mikrotherapie im Lehrstuhl für Radiologie und Mikrotherapie an der Privaten Universität Witten-Herdecke: Prof. Dr. med. Grönemeyer; Institut für Diagnostische und Interventionelle Radiologie, Mülheim, Universität Witten-Herdecke: Prof. Dr. med. Seibel; Klinik für Endokrinologie, Zentrallabor Bereich Forschung und Lehre, Universitätsklinikum Essen, Universität Duisburg-Essen: Prof. Dr. med. Mann, Dr. rer. nat. Bröcker-Preuss; Klinik für Angiologie, Universitätsklinikum Essen, Universität Duisburg-Essen: PD Dr. med. Kröger; Zentrallabor des Universitätsklinikums Essen, Universität Duisburg-Essen: Dr. med. Volbracht
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e39. Lynch JW, Kaplan GA, Cohen RD, Tuomilehto J, Salonen JT: Do cardiovascular risk factors explain the relation between socioeconomic status, risk of all-cause mortality, cardiovascular mortality, and acute myocardial infarction? Am J Epidemiol 1996; 144: 934–42. MEDLINE
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