Ambient air pollution and daily mortality among survivors of myocardial infarction.

BACKGROUND: Certain subgroups in the general population, such as persons with existing cardiovascular or respiratory disease, may be more likely to experience adverse health effects from air pollution. METHODS: In this European multicenter study, 25,006 myocardial infarction (MI) survivors in 5 cities were recruited from 1992 to 2002 via registers, and daily mortality was followed for 6 to 12 years in relation to ambient particulate and gaseous air pollution exposure. Daily air pollution levels were obtained from central monitor sites, and particle number concentrations were measured in 2001 and estimated retrospectively based on measured pollutants and meteorology. City-specific effect estimates from time-series analyses with Poisson regression were pooled over all 5 cities. RESULTS: Particle number concentrations and PM10 averaged over 2 days (lag 0-1) were associated with increased total nontrauma mortality for patients of age 35 to 74 (5.6% [95% confidence interval, 2.8%-8.5%] per 10,000/cm and 5.1% [1.6%-9.3%] per 10 microg/m, respectively). For longer averaging times (5 and 15 days), carbon monoxide and nitrogen dioxide were also associated with mortality. There were no clear associations with ozone or sulfur dioxide. CONCLUSION: Exposure to traffic-related air pollution was associated with daily mortality in MI survivors. Point estimates suggest a stronger effect of air pollution in MI survivors than among the general population.

Air temperature and inflammatory responses in myocardial infarction survivors.

BACKGROUND: Temperature changes have been associated with increased cardiovascular risk, but the role of inflammatory markers in this relationship is not well understood. The objective of this study was to analyze the association between air temperature and C-reactive protein, interleukin-6 and fibrinogen in postmyocardial infarction patients. METHODS: In a multicenter panel study, the 3 inflammatory blood markers were measured repeatedly. In total, 5813 blood samples in 1003 subjects were collected in 6 European cities representing different climates. Data on patient characteristics and disease history were gathered at the baseline visit. Meteorologic data were obtained from the city-specific network stations. The association was analyzed using a semiparametric model with random patient effects. RESULTS: A 10 degrees C decrease in the 5-day-average of air temperature before the blood withdrawal was associated with a 4% increase in C-reactive protein (4.3% [95% confidence interval = 0.2% to 8.1%]). Correspondingly, an increase of interleukin-6 was observed for the same time window (3.3% [0.1% to 6.3%]) whereas fibrinogen showed an increase of 1.3% (0.2% to 2.4%) with a lag of 3 days. CONCLUSION: A decrease in air temperature, particularly the average temperature of the last 5 days, was associated with an increase in both C-reactive protein and interleukin-6, whereas fibrinogen seemed to react to temperature changes after 3 days. In susceptible patients this might lead to an additional risk for cardiovascular events and suggests a biologic mechanism for the observed seasonal variation in death from ischemic heart disease and stroke in the elderly.

Characterization of the GNAQ promoter and association of increased Gq expression with cardiac hypertrophy in humans.

AIMS: Transgenic mice with cardiac overexpression of Gq develop cardiac hypertrophy, apoptosis, and heart failure. Similar mechanisms may contribute to human left ventricular hypertrophy (LVH). However, mechanisms regulating transcription of the human GNAQ gene encoding the Gq protein are unknown and single-nucleotide polymorphisms have not been reported. METHODS AND RESULTS: We delineated essential elements for transcription in the human GNAQ promoter using reporter assays and showed promoter induction by serum and angiotensin II. Sequencing of the whole promoter revealed a common (minor allele frequency 0.48) dinucleotide polymorphism at position -694/-695, resulting in an exchange of two adjacent nucleotides (TT > GC). The GC allele had increased transcription factor binding and was associated with enhanced transcriptional activation by serum or angiotensin II, resulting in enhanced Gq expression and intracellular signalling. Genotyping a population-based survey (n = 1204) revealed a higher prevalence of LVH in individuals with the GC/GC genotype [odds ratio (OR) 4.07; 95% CI 1.63-10.16; P = 0.003], this effect being more pronounced in women (OR 5.52; P = 0.005). CONCLUSION: A novel polymorphism in the Gq promoter region is associated with enhanced promoter activity, Gq expression, intracellular signal transduction, and increased prevalence of LVH, particularly in women.

Association of sports activities in leisure time and incident myocardial infarction in middle-aged men and women from the general population: the MONICA/KORA Augsburg cohort study.

BACKGROUND: To examine sex-specific associations between sports activities in leisure time and incident myocardial infarction (MI) in a representative population sample in Germany. DESIGN: Cohort study. METHODS: The study was based on 3501 men and 3475 women (aged 45-74 years) who participated in one of the three MONICA Augsburg surveys between 1984 and 1995 and were followed up until 2002. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. RESULTS: A total of 295 cases of incident MIs among men and 91 among women were registered during a median follow-up period of 8.6 years. In both sexes, moderate and high level of sports activities in leisure time were associated with a reduced risk of incident MI after age and survey adjustment; the HRs of MIs associated with a moderate and high level of sports activities in leisure time were 0.68 (0.49-0.96), and 0.71 (0.50-0.99) for men and 0.42 (0.21-0.84), and 0.18 (0.04-0.74) for women. Further adjustment for other major coronary heart disease risk factors attenuated the HRs: in moderately and highly active men, the HRs were not significant anymore (HRs 0.78 and 0.84, respectively), but the HRs remained significantly reduced in moderately and highly active women (HR 0.49; 95% CI, 0.24-1.00 and HR 0.21; 95% CI, 0.05-0.87, respectively). CONCLUSION: Moderate or high levels of sports activities in leisure time are associated with a significantly reduced risk of MI in women, but not men from the general population.

Head-to-head comparison of BNP and IL-6 as markers of clinical and experimental heart failure: Superiority of BNP.

Activation of BNP and IL-6 are hallmarks of left ventricular (LV) dysfunction and congestive heart failure (CHF). To assess the relative activation of BNP and IL-6 in clinical and experimental heart failure, we performed a human study in which plasma N-terminal proBNP (NT-proBNP) and IL-6 were measured in a large group of patients in the chronic phase after myocardial infarction (MI) and an animal study in which LV gene expression of BNP and IL-6 was assessed in rapid ventricular pacing-induced heart failure. In the human study, NT-proBNP and IL-6 were measured by non-extracted, enzyme-linked immunoassay in 845 subjects (n=468 outpatients after MI, MONICA MI register Augsburg; and 377 siblings without MI, control). NT-proBNP (295+/-23pg/mL vs. CTRL 84+/-8, P<0.05) and IL-6 (2.7+/-0.1pg/mL vs. CTRL 2.1+/-0.1, P<0.05) were both elevated in subjects with MI. These increases were particularly pronounced in the presence of concomitant CHF (both P<0.01 vs. CTRL) and LV dysfunction (EF<45%, both P<0.05 vs. CTRL). However, NT-proBNP was significantly correlated with several cardiac structural and functional parameters (EF, LVMI, history of MI, CHF symptoms; all P<0.05) upon regression analysis whereas IL-6 was only correlated with history of MI (P<0.001). Accordingly, MI subjects with symptomatic LV dysfunction were detected by NT-proBNP with a greater sensitivity, specificity, and ROC-area (85%, 88%, and 0.87, respectively) as compared to IL-6 (69%, 53%, and 0.67, respectively). In the animal study, IL-6 and BNP expression were both significantly elevated in CHF (both P<0.05) but with a much greater absolute activation of BNP. In addition, BNP mRNA expression displayed a stronger inverse correlation with LV function (r=-0.74; P<0.001) than IL-6 (r=-0.53; P=0.001) and was a markedly more sensitive and specific molecular marker of LV dysfunction (sensitivity 91%, specificity 100%, ROC-area 0.94) than IL-6 (sensitivity 74%, specificity 83%, ROC-area 0.87). Our animal study provides evidence that IL-6 expression is activated in heart failure but to a significantly lesser degree than that of BNP. Both the stronger expression of BNP and the better correlation with LV function provide the molecular basis for a diagnostic superiority of NT-proBNP in clinical LV dysfunction and heart failure.

Sleep duration and sleep complaints and risk of myocardial infarction in middle-aged men and women from the general population: the MONICA/KORA Augsburg cohort study.

STUDY OBJECTIVES: To examine gender-specific associations between sleep duration and sleep complaints and incident myocardial infarction (MI). DESIGN: Cohort study. SETTING: A representative population sample of middle-aged subjects in Germany. PARTICIPANTS: The study was based on 3508 men and 3388 women (aged 45 to 74 years) who participated in one of the 3 MONICA (Monitoring trends and determinants on cardiovascular diseases) Augsburg surveys between 1984 and 1995, who were free of MI and angina pectoris at baseline and were followed up until 2002. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A total of 295 cases of incident MI among men and 85 among women occurred during a mean follow-up period of 10.1 years. Compared with women sleeping 8 hours, the multivariable adjusted hazard ratio (HR) of MI among women sleeping < or =5 hours was 2.98 (95% CI, 1.48-6.03), and among women sleeping > or =9 hours 1.40 (95% CI, 0.74-2.64); the corresponding HRs among men were 1.13 (95% CI, 0.66-1.92) and 1.07 (95% CI, 0.75-1.53). In multivariable analysis the relative risk of an incident MI for men and women with difficulties maintaining sleep was 1.12 (95% CI, 0.84-1.48) and 1.53 (95% CI, 0.99-2.37), respectively, and for men and women with difficulties initiating sleep the relative risk was 1.16 (95% CI, 0.82-1.63) and 1.30 (95% CI, 0.81-2.06), respectively. CONCLUSIONS: Modest associations between short sleep duration and difficulties maintaining sleep and incident MI were seen in middle-aged women but not men from the general population.

Asymmetric dimethylarginine, smoking, and risk of coronary heart disease in apparently healthy men: prospective analysis from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg study and experimental data.

BACKGROUND: An increased plasma concentration of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predicts adverse clinical outcome in patients with coronary heart disease. We investigated the association between plasma concentrations of ADMA and risk in initially healthy smoking and nonsmoking men. METHODS: Participants for this nested case-control study came from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg study. ADMA was measured by liquid chromatography-tandem mass spectrometry in 88 men with incident coronary events (fatal and nonfatal myocardial infarction and sudden cardiac death) and 254 age-matched controls, with a median (interquartile range) follow-up of 6.2 (3.3-7.9) years. RESULTS: After adjustment for potential confounders, the relative risk for a future coronary event was 2.00 [95% confidence interval (CI) 1.27-3.16; P = 0.003] for smokers compared with nonsmokers and 1.35 (95% CI 0.78-2.33; P = 0.282) for the top vs the bottom tertile of the ADMA distribution. In cases and controls, lower ADMA plasma concentrations were observed in smokers. Analysis of ADMA-associated risk in smokers and nonsmokers separately revealed substantial differences: the adjusted relative risk for future coronary events (top vs bottom tertile of the ADMA distribution) was 0.48 (95% CI 0.16-1.46; P = 0.198) in smokers and 2.40 (95% CI 1.14-5.08; P = 0.021) in nonsmokers. Exposure of human endothelium-derived EAhy 926 cells to tobacco smoke enhanced expression of the ADMA metabolizing enzyme dimethylarginine dimethylaminohydrolase 2 and reduced ADMA concentration. CONCLUSIONS: In apparently healthy men, increased ADMA predicts the risk for coronary events in nonsmokers, but not in smokers. This may be explained in part by an alteration of ADMA metabolism by tobacco smoke.

Gene variants of monocyte chemoattractant protein 1 and components of metabolic syndrome in KORA S4, Augsburg.

OBJECTIVE: Monocyte chemoattractant protein 1 (MCP-1) has been suggested to be involved in the development of several components of metabolic syndrome (MetS). The present study investigated the association of nine MCP-1 single nucleotide polymorphisms (SNPs) with MetS, type 2 diabetes mellitus and metabolic risk factors. SUBJECTS AND METHODS: The population-based study sample comprised 1630 subjects aged 55-74 years from KORA S4 (Cooperative Health Research in the Region of Augsburg Survey 4). Genotyping was carried out by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis of allele-dependent primer extension products. RESULTS: The MCP-1 SNP c.-3813C>T exhibited trends for differences between the genotype groups in triglycerides, 2-h glucose and uric acid (P = 0.0084, 0.014, 0.027). Other trends were observed for c.-928G>C associated with height and fasting glucose (P = 0.0024, 0.033), for c.105T>C with height and leukocytes (P = 0.0095, 0.047), for c.*65C>T and c.*3879C>T with MCP-1 levels (both P = 0.012) and for c.-2138A>T with interleukin-6 levels. After correction for multiple testing, none of the analysed SNPs, except c.-928G>C in men showed a significant association with MetS, T2DM or other analysed parameters. Haplotype MCP-1*1 and c.-928G>C in men (P = 0.0002, 0.0004) were significantly associated with an increase in height. CONCLUSIONS: This is the first study to investigate the associations of MCP-1 SNPs with MetS. We found trends for several components of MetS. These parameters were hyperlipidaemia, fasting and 2-h glucose, and uric acid. A new finding is that MCP-1*1 haplotype is associated with height. Further investigation in larger populations is needed to clarify the involvement of MCP-1 in MetS.

Living alone is a risk factor for mortality in men but not women from the general population: a prospective cohort study.

BACKGROUND: During the past decades a rising trend of living alone can be observed in the population especially in urban areas. Living alone is considered a psychosocial risk factor. We studied the relationship between living alone, cardiovascular risk factors and mortality. METHODS: We analysed data from the population-based MONICA/KORA cohort study including 3596 men and 3420 women of at least one of three surveys carried out between 1984 and 1995 in the region of Augsburg, Germany. They were between 45 and 74 years old and were followed-up until 31 December 2002. During follow-up 811 men and 388 women died. Cox proportional hazards analysis was used to examine the association between living alone and mortality. RESULTS: Altogether 260 men (7%) and 620 women (18%) were living alone at baseline. Men, who lived alone, were less well educated, had fewer children and friends, and they smoked significantly more than other men. Women, living alone, were also significantly more often current smokers and had less children and friends, but they were more often better educated than cohabitating women. The latter group showed a higher proportion of obese and hypertensive women. Men living alone had a twofold risk to die after multivariable adjustment (hazard ratio = 1.96; p < 0.0001; 95% confidence interval 1.56-2.46). This was not the case for women. CONCLUSION: Living alone is an independent risk factor for mortality in men. It is unclear whether living alone causes an increased mortality or whether predisposition for increased mortality is responsible for men living alone.

Calpain-10 variants and haplotypes are associated with polycystic ovary syndrome in Caucasians.

PCOS is known to be associated with an increased risk of T2DM and has been proposed to share a common genetic background with T2DM. Recent studies suggest that the Calpain-10 gene (CAPN10) is an interesting candidate gene for PCOS susceptibility. However, contradictory results were reported concerning the contribution of certain CAPN10 variants, especially of UCSNP-44, to genetic predisposition to T2DM, hirsutism, and PCOS. By means of MALDI-TOF MS technique, we genotyped an expanded single nucleotide polymorphism panel, including the CAPN10 UCSNP-44, -43, -56, ins/del-19, -110, -58, -63, and -22 in a sample of 146 German PCOS women and 606 population-based controls. Statistical analysis revealed an association between UCSNP-56 and susceptibility to PCOS with an odds ratio (OR) of 2.91 (95% CI=1.51-5.61) for women carrying an AA genotype compared with GG. As expected, the 22-genotype of the ins/del-19 variant, which is in high linkage disequilibrium (r2=0.98) with UCSNP-56, was also significantly associated (OR=2.98, 95% CI=1.55-5.73). None of the additionally tested variants alone showed any significant association with PCOS. A meta-analysis including our study (altogether 623 PCOS cases and 1,224 controls) also showed significant association only with ins/del-19. The most common haplotype TGG3AGCA was significantly associated with a lower risk for PCOS (OR=0.487, P=0.0057). In contrast, the TGA2AGCA haplotype was associated with an increased risk for PCOS (OR=3.557, P=0.0011). By investigating a broad panel of CAPN10 variants, our results pointed to an allele dose-dependent association of UCSNP-56 and ins/del-19 with PCOS.

[Epidemiology and demographic evolution exemplified for cardiovascular diseases in Germany]. / Epidemiologie und demographische Entwicklung am Beispiel kardiovaskulärer Erkrankungen in Deutschland.

The interplay between demographic and epidemiologic evolutions is presented exemplified for cardiovascular diseases in Germany. The actually 82 million inhabitants of Germany build the frame for disease occurrence; currently, 2.1 million men and 4.4 million women are > or = 75 years old. The ongoing increase of life expectancy to 75.6 years in men and 81.3 years in women was associated with a remarkable decrease of cardiovascular and ischemic heart disease (IHD) mortality and an increasing disease-specific mean age of death. Each third male and each fourth female death from IHD could be prevented, whereas the absolute number of nonfatal acute myocardial infarction (AMI) increased in the younger ages and decreased in the higher age groups. Since 1985, the total number of fatal and nonfatal cases of AMI has decreased by 24% in men and by 22% in women; two thirds of male and one third of female cases occur before the 75th year of age. These positive trends are mainly the result of a more effective acute and long-term therapy after AMI onset. Actually, 35% of all AMI patients do not survive the first day after acute onset and in up to 90% of them classic risk factors (hypertension, dyslipidemia, diabetes, cigarette smoking) were present. Therefore, the theme number 1 for the population must be intensified activities of primary prevention.

Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany.

OBJECTIVES: We sought to assess the association between serum concentrations of adiponectin and long-term risk of type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) in initially healthy middle-aged men within the same representative population in Augsburg, southern Germany. BACKGROUND: It has been postulated that high serum concentrations of adiponectin, an emerging biomarker that is linked to insulin resistance and endothelial dysfunction, may be protective against T2DM and CHD. METHODS: Serum concentrations of adiponectin were determined in apparently healthy middle-aged men, sampled from the general population in 1984/1985 and followed until 2002. During this period, 115 of 887 men had a newly diagnosed T2DM, and 126 of 937 men suffered from a CHD event. RESULTS: In a Cox model, after multivariable adjustment for cardiovascular risk factors, the hazard ratio of incident T2DM, comparing extreme tertiles of the adiponectin distribution, was 0.55 (95% confidence interval [CI], 0.35 to 0.89), and for incident CHD it was 0.62 (95% CI, 0.39 to 0.98). Further adjustment for high-density lipoprotein cholesterol (HDL-C) attenuated the association, which became formally non-significant. In joint analysis, men with low adiponectin and low HDL-C values showed a 2.63 times (95% CI, 1.66 to 4.15) increased incidence of T2DM and a 1.91 times (95% CI, 1.20 to 3.04) increased incidence of CHD after multivariable adjustment in comparison with men with high HDL-C and high adiponectin. CONCLUSIONS: For patients with low HDL-C values, additional measurement of adiponectin may be helpful to identify individuals at very high risk for T2DM and CHD.

Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up.

AIMS: Peripheral arterial occlusive disease is associated with a high risk of cardiovascular morbidity and mortality. We prospectively examined the association of the ankle-brachial index (ABI) and arterial plaques in carotid and femoral arteries with incident myocardial infarctions (MIs) and cardiovascular and total mortality in 1325 participants of the population-based MONICA Augsburg Survey 1989/90. METHODS AND RESULTS: At baseline, 6.1% of men and 2.6% of women had an ABI < or =0.9. At least one plaque in the carotid or femoral arteries was identified in 51.8% of men and 36.3% of women. During a 13-year follow-up, 58 persons (4.4%) suffered a MI before age 75 and 189 persons (14.3%) died, 86 (6.5%) of them from cardiovascular causes. Kaplan-Meier curves confirmed both measurements as strong predictors for all three endpoints (P<0.0001). Cox regression analysis revealed an increase of the risk for MI and cardiovascular and total mortality of 22 (P=0.012), 35, and 32% (P<0.00001), respectively, per 0.1 unit decrease in ABI. Correction for measurement error in ABI increased these estimates. The increase in risk for MI and cardiovascular and total mortality was 52, 70, and 45%, respectively, for each increase in the number of plaque-affected arteries (P<0.0001). CONCLUSION: Both ABI and number of plaque-affected arteries are strong predictors for incident MI and cardiovascular and total mortality.

IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants' data from 21 studies.

Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 -573G>C and type 2 diabetes. The observed association of the IL6 -174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding.

Body fat distribution and risk of type 2 diabetes in the general population: are there differences between men and women? The MONICA/KORA Augsburg cohort study.

BACKGROUND: It remains controversial whether body mass index (BMI), waist circumference (WC), or waist-hip ratio (WHR) is a better risk predictor of type 2 diabetes. OBJECTIVE: The objective was to examine the sex-specific relevance of WC, WHR, and BMI to the development of type 2 diabetes. DESIGN: The prospective population-based cohort study was based on 3055 men and 2957 women aged 35-74 y who participated in the second (1989-1990) or third (1994-1995) MONICA (Monitoring Trends and Determinants on Cardiovascular Diseases) Augsburg survey. The subjects were free of diabetes at baseline. Hazard ratios (HRs) were estimated from Cox proportional hazards models. RESULTS: During a mean follow-up of 9.2 y, 243 cases of incident type 2 diabetes occurred in men and 158 occurred in women. Multivariable-adjusted HRs across quartiles of BMI were 1.0, 1.37, 2.08, and 4.15 in men and 1.0, 3.77, 4.95, and 10.58 in women; those of WC were 1.0, 1.15, 1.57, and 3.40 in men and 1.0, 3.21, 3.98, and 10.70 in women; those of WHR were 1.0, 1.14, 1.80, and 2.84 in men and 1.0, 0.82, 2.06, and 3.51 in women. In joint analyses, the highest risk was observed in men and women with a high BMI in combination with a high WC and a high WHR. CONCLUSIONS: Both overall and abdominal adiposity were strongly related to the development of type 2 diabetes. Because there was an additive effect of overall and abdominal obesity on risk prediction, WC should be measured in addition to BMI to assess the risk of type 2 diabetes in both sexes.

Comparison of different methods in analyzing short-term air pollution effects in a cohort study of susceptible individuals.

BACKGROUND: Short-term fluctuations of ambient air pollution have been associated with exacerbation of cardiovascular disease. A multi-city study was designed to assess the probability of recurrent hospitalization in a cohort of incident myocardial infarction survivors in five European cities. The objective of this paper is to discuss the methods for analyzing short-term health effects in a cohort study based on a case-series. METHODS: Three methods were considered for the analyses of the cohort data: Poisson regression approach, case-crossover analyses and extended Cox regression analyses. The major challenge of these analyses is to appropriately consider changes within the cohort over time due to changes in the underlying risk following a myocardial infarction, slow time trends in risk factors within the population, dynamic cohort size and seasonal variation. RESULTS: Poisson regression analyses, case-crossover analyses and Extended Cox regression analyses gave similar results. Application of smoothing methods showed the capability to adequately model the complex time trends. CONCLUSION: From a practical point of view, Poisson regression analyses are less time-consuming, and therefore might be used for confounder selection and most of the analyses. However, replication of the results with Cox models is desirable to assure that the results are independent of the analytical approach used. In addition, extended Cox regression analyses would allow a joint estimation of long-term and short-term health effects of time-varying exposures.

Chemokines and incident coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.

OBJECTIVE: The chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), interleukin-8 (IL-8/CXCL8), and interferon-gamma-inducible protein-10 (IP-10/CXCL10) have been reported to be involved in the development of atherosclerosis and type 2 diabetes. The aim of this study was to assess whether elevated systemic levels of these chemokines precede coronary events. METHODS AND RESULTS: We investigated MCP-1, IL-8, and IP-10 serum levels in a case-cohort design based on data from 381 individuals (294 men, 87 women) with and 1977 individuals (1006 men, 971 women) without incident coronary heart disease (CHD) from the prospective, population-based MONICA/KORA Augsburg study (1984 to 2002). The mean follow-up time was 11.0 years. Baseline concentrations were significantly higher in cases compared with noncases (P < or = 0.001 for all chemokines). MCP-1 and IL-8 remained associated with CHD risk after adjustment for age, sex, and survey with hazard ratios (95% confidence intervals) comparing extreme tertiles of 1.39 (1.05 to 1.84) for MCP-1 and 1.48 (1.10 to 1.99) for IL-8. However, adjustment for further cardiovascular and immunologic risk factors attenuated the observed associations, and they became nonsignificant. CONCLUSIONS: Elevated systemic levels of the chemokines MCP-1, IL-8, and IP-10 precede CHD but do not represent independent risk factors. Thus, the associations are less pronounced than previously shown for type 2 diabetes.

Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989-1998.

OBJECTIVES: Immunoglobulin A (IgA) autoantibodies to tissue transglutaminase (tTG) are commonly used for screening and diagnosing of celiac disease. We examined the hypothesis that elevated IgA anti-tTG antibodies were associated with higher all-cause mortality risk. METHODS: The cohort, 2333 men and 2300 women, was based on the follow-up of participants of a representative population-based survey in Southern Germany (KORA/MONICA Augsburg project) conducted in 1989-1990. The endpoint for the vital status with cause of death was the year 1998. The sera drawn at baseline and stored at -80 degrees C, were recently screened with an IgA enzyme-linked immunosorbent assay (ELISA) using human recombinant tTG. Age-standardized mortality rates and age-adjusted hazard ratios were calculated. RESULTS: From the 4633 sera analyzed, 63 had an IgA anti-tTG concentration>or=7 AU/ml. Of these 63 individuals, 15 died between 1989 and 1998. The age-adjusted hazard ratio (HRa) of all-cause mortality was 1.86 (95% CI: 1.01-3.41) and 3.92 (95% CI: 1.44-10.71) for men and women, respectively. The excess of cancer mortality was even higher with an HR(a) of 2.47 (95% CI: 0.89-6.83) in men and of 6.65 (95% CI: 2.04-21.63) in women. CONCLUSIONS: Individuals with elevated IgA anti-tTG antibodies had a highly increased mortality risk, particularly due to cancer. New studies are necessary to clarify if this increased risk is due to undiagnosed celiac disease or/and if this elevated IgA anti-tTG antibodies level is a marker of serious diseases like cancer, chronic liver disease or end-stage heart failure.

Chronic kidney disease and risk of incident myocardial infarction and all-cause and cardiovascular disease mortality in middle-aged men and women from the general population.

AIMS: Chronic kidney disease (CKD) was found to be an independent risk factor for all-cause mortality as well as adverse cardiovascular disease (CVD) events in high-risk populations. Findings from population-based studies are scarce and inconsistent. We investigated the gender-specific association of CKD with all-cause mortality, cardiovascular mortality, and incident myocardial infarction (MI) in a population-based cohort. METHODS AND RESULTS: The study was based on 3860 men and 3674 women (aged 45-74 years) who participated in one of the three MONICA Augsburg surveys between 1984 and 1995. CKD was defined by an estimated glomerular filtration rate between 15 and 59 mL/min/1.73 m(2). Hazard ratios (HRs) were estimated from Cox proportional hazard models. In this study, 890 total deaths, 400 CVD deaths, and 321 incident MIs occurred in men up to 31 December 2002; the corresponding numbers in women were 442, 187, and 102. In multivariable analyses, the HR for women with CKD compared to women with preserved renal function was significant for incident MI [HR 1.67; 95% confidence interval (CI) 1.07-2.61] and CVD mortality (HR 1.60; 95% CI 1.17-2.18). In men, CKD was also significantly associated with incident MI (HR 1.51; 95% CI 1.09-2.10) and CVD mortality (HR 1.48; 95% CI 1.15-1.92) after adjustment for common CVD risk factors. In contrast, men and women with CKD had no significant increased risk of all-cause mortality. CONCLUSION: CKD was strongly associated with an increased risk of incident MI and CVD mortality independent from common cardiovascular risk factors in men and women from the general population.

Association of cardiovascular risk factors with markers of endothelial dysfunction in middle-aged men and women. Results from the MONICA/KORA Augsburg Study.

Endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases and diabetes mellitus. However, the causes underlying endothelial dysfunction are not fully understood. Therefore, the aim of the present study was to investigate associations of cardiovascular risk factors with soluble adhesion molecules (sE-Selectin, sICAM-1), soluble thrombomodulin (sTM) and von Willebrand factor (vWF) as markers of endothelial dysfunction. The study population consisted of a subcohort of 2,168 men and women aged 35 to 74 years randomly drawn from three cross-sectional population-based MONICA/KORA Augsburg surveys conducted between 1984 and 1995. In multivariable linear regression analysis, current smoking, high (versus moderate) alcohol consumption, ratio of total cholesterol/HDL-cholesterol (TC/HDL-C) and C-reactive protein (CRP) were significantly associated with elevated levels of sE-selectin and sICAM-1. Increased levels of sE-selectin were also found in subjects with actual hypertension, high body mass index and prevalent diabetes mellitus. In addition, low physical activity and no (versus moderate) alcohol consumption were significantly associated with elevated concentrations of sICAM-1. Levels of sTM were higher in subjects with actual hypertension, no or high amounts of alcohol intake and a high ratio of TC/HDL-C, but were lower in subjects with a history of myocardial infarction. VWF was significantly associated with CRP only. In conclusion, sE-selectin and sICAM-1 are more strongly associated with traditional cardiovascular risk factors than sTM and vWF.