Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results from the MONICA/KORA Augsburg study

Abstract. Karakas M, Koenig W, Zierer A, Herder C, Rottbauer W, Baumert J, Meisinger C, Thorand B (University of Ulm Medical Center, Ulm; German Research Center for Environmental Health, Institute of Epidemiology II, Neuherberg; and Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany). Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results from the MONICA/KORA Augsburg study. J Intern Med 2012; 271 : 43–50. Aims. Oxidative stress plays a critical role in the initiation and progression of atherosclerosis. Myeloperoxidase (MPO) is a marker of oxidative stress. We prospectively investigated whether an increased serum concentration of MPO is associated with an increased risk of incident coronary heart disease (CHD). Methods. We conducted a population‐based case‐cohort study in middle‐aged, healthy men and women within the MONICA/KORA Augsburg studies. Serum levels of MPO were measured in 333 subjects with (cases) and 1727 without (noncases) incident CHD. Mean follow‐up time was 10.8 ± 4.6 years. Results. Baseline concentrations of MPO were higher in cases compared with noncases (P ≤ 0.001 in men; P = 0.131 in women). After adjustment for major cardiovascular risk factors, the hazard ratio (HR) with 95% confidence interval (CI) comparing the top with the two lower tertiles was 1.70 (95% CI, 1.25–2.30). After additional adjustment for markers of inflammation and endothelial dysfunction, the association was attenuated (HR 1.50; 95% CI, 1.08–2.09). There were no significant interactions of MPO with sex or increased weight on CHD risk. Conclusions. Elevated concentrations of the oxidative stress marker MPO were independently associated with increased risk of incident CHD. This finding deserves detailed evaluation in further studies.     

Sex differences in risk factors for incident type 2 diabetes mellitus: the MONICA Augsburg cohort study.

OBJECTIVE: To examine sex-specific associations between cardiovascular risk factors, a parental history of diabetes, and type 2 diabetes mellitus (DM). METHODS: The study is based on 3052 men and 3114 women (aged 35 to 74 years) who participated in one of the 3 MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Augsburg surveys between 1984 and 1995, who were free of DM at baseline and returned a follow-up questionnaire in 1998. Sex-specific hazard ratios (HRs) were estimated from Cox proportional hazard models. RESULTS: A total of 128 cases of incident DM among men and 85 cases among women were registered during the follow-up period. The age-standardized incidence rate was 5.8 per 1000 person-years for men and 4.0 per 1000 person-years for women. In multivariable survival analyses, age, body mass index, and a positive parental history of diabetes were important independent risk factors for DM in both sexes. High-density lipoprotein cholesterol level was inversely associated with DM in men and women. For other risk factors, sex-related differences were observed. Systolic blood pressure (HR per 10 mm Hg increase, 1.16), regular smoking (HR, 1.75), and high daily alcohol intake (HR, 1.95) predicted the development of DM in men only, whereas uric acid (HR per 1 mmol/L increase, 2.05) and physical inactivity during leisure time (HR, 1.80) were associated with diabetes development in women only. CONCLUSIONS: In men and women, most variables predicting future diabetes in the present study are also known to be important risk factors for cardiovascular disease and arteriosclerosis. However, there are sex-related dissimilarities that seem to be involved in disease development.     

Implications of prevalent and incident diabetes mellitus on left ventricular geometry and function in the ageing heart: The MONICA/KORA Augsburg cohort study

Background and Aim

It is unclear to what extent diabetes modulates the ageing-related adaptations of cardiac geometry and function.

Methods and Results

We examined 1005 adults, aged 25-74 years, from a population-based survey at baseline in 1994/5 and at follow-up in 2004/5. We compared persistently non-diabetic individuals (ND; no diabetes at baseline and at follow-up, n = 833) with incident (ID; non-diabetic at baseline and diabetic at follow-up, n = 36) and with prevalent diabetics (PD; diabetes at baseline and follow-up examination, n = 21). Left ventricular (LV) geometry and function were evaluated by echocardiography. Statistical analyses were performed with multivariate linear regression models.Over ten years the PD group displayed a significantly stronger relative increase of LV mass (+9.34% vs. +23.7%) that was mediated by a more pronounced increase of LV end-diastolic diameter (+0% vs. +6.95%) compared to the ND group. In parallel, LA diameter increased (+4.50% vs. +12.7%), whereas ejection fraction decreased (+3.02% vs. −4.92%) more significantly in the PD group. Moreover, at the follow-up examination the PD and ID groups showed a significantly worse diastolic function, indicated by a higher E/EM ratio compared with the ND group (11.6 and 11.8 vs. 9.79, respectively).

Conclusions

Long-standing diabetes was associated with an acceleration of age-related changes of left ventricular geometry accumulating in an eccentric remodelling of the left ventricle. Likewise, echocardiographic measures of systolic and diastolic ventricular function deteriorated more rapidly in individuals with diabetes.     

Myeloperoxidase, but not oxidized LDL, is associated with leisure-time physical activity: results from the MONICA/KORA Augsburg Studies 1984-1995

Objective

Oxidative stress-induced cell damage contributes to several chronic conditions such as cardiovascular disease, but only very few population-based studies have examined the influence of regular physical activity (PA) on oxidative stress.

Methods

1820 men and women aged 35–74 years were randomly drawn from three population-based MONICA/KORA Augsburg Studies conducted between 1984 and 1995. Geometric means of the oxidative stress markers myeloperoxidase (MPO) and oxidized LDL (ox-LDL) were calculated and multiple linear regression was performed to assess their associations with three self-reported PA domains, namely work, leisure-time or walking.

Results

Mean MPO concentrations were lower for participants engaged in high leisure-time PA (124.2 μg/ml; 95%-CI, 116.8–132.0) compared to the inactive reference group (133.5 μg/ml; 95%-CI, 127.6–139.6) (P_trend across PA levels: 0.007). No significant association between ox-LDL and PA domains was observed (P_trend between 0.162 and 0.803).

Conclusion

These data indicate that regular leisure-time PA may reduce MPO concentrations.     

Association of cigarette smoking and tar and nicotine intake with development of type 2 diabetes mellitus in men and women from the general population: the MONICA/KORA Augsburg Cohort Study

Aims/hypothesis We examined sex-specific associations between cigarette smoking and incident type 2 diabetes mellitus in Germany.Subjects, materials and methods The study was based on 5,470 men and 5,422 women (aged 25–74 years) without diabetes who participated in one of the three population-based MONICA Augsburg surveys between 1984 and 1995. Incident cases of type 2 diabetes were assessed using follow-up questionnaires. Hazard ratios (HRs) were estimated from Cox proportional hazard models.Results Up to 31 December 2002 a total of 409 cases of incident type 2 diabetes among men and 263 among women were registered. The number of cigarettes and the nicotine and tar consumption per day were associated with a significantly increased risk of type 2 diabetes among men, but not among women; this could be due to the low power of the study in women. After multivariable adjustment, the HRs for type 2 diabetes compared with never-smokers were 1.48, 2.03 and 2.10 for men smoking 1 to 14, 15 to 19 and ≥20 cigarettes/day (p for trend <0.0001) and 1.25, 1.34 and 1.37 for women smoking 1 to 9, 10 to 19 and ≥20 cigarettes/day (p for trend 0.0985). Compared with never-smokers, the HRs for increasing tar intake in men (1–167, 168–259 and ≥260 mg/day) were 1.45, 2.32 and 2.07 (p for trend <0.0001); the respective HRs in women (1–89, 90–194 and ≥195 mg/day) were 1.18, 1.57 and 1.24 (p for trend 0.1159).Conclusions/interpretation Cigarette smoking is an important modifiable risk factor of type 2 diabetes particularly in men from the general population.     

A high linear growth is associated with an increased risk of childhood diabetes mellitus

Summary Insulin release and growth are intimately connected. The aim of the present study was to investigate height and weight in diabetic children from birth to onset of Type 1 (insulin-dependent) diabetes mellitus compared to that in referent children. Data on height and weight were collected from mailed questionnaires and from growth records obtained from the child health clinics and schools in 337 recentonset diabetic children, 0–14 years old, and from 517 age-, sex-, and geographically matched referent children. A total of 9002 paired height and weight observations were collected. The anthropometric development of the children was expressed as standard deviation scores using the National Center for Health Statistics/Centers for Disease Control (NCHS/CDC) growth reference material. On the average, the diabetic children were consistently taller than the referent children, a finding more pronounced among the boys. The diabetic boys were significantly taller from 7 to 1 years before the clinical onset of the disease, regardless of age at onset. A similar tendency was found for the girls. When mean height from 5 to 1 years before onset was used as a possible risk factor for diabetes, a linearly increasing trend in the odds ratio was found for diabetes in boys (odds ratio = 1.0; 1.57; 2.46 for height standard deviation score values <0; 0–1 and > 1, respectively; p=0.002 for trend). A similar, but statistically not significant, tendency was found for girls (odds ratio = 1.0; 1.44; 1.43). As regards height increment from birth similar trends in odds ratios were found. Weight-for-height was similar among diabetic and referent children of both sexes. We conclude that diabetic boys tend to be taller and grow faster than referent boys for several years preceding the disease. A similar, but not statistically significant tendency was found among diabetic girls. Our findings indicate that rapid linear growth is a risk factor for Type 1 diabetes in childhood, and may be either a promoter of Type 1 diabetes or else a marker of a physiological mechanism that affects both growth and the pathogenesis of Type 1 diabetes.     

C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984-1998

BACKGROUND: Previous studies have suggested that low-grade systemic inflammation is involved in the pathogenesis of type 2 diabetes mellitus. OBJECTIVE: To investigate the association between C-reactive protein (CRP), the classic acute-phase protein, and incident type 2 diabetes mellitus among middle-aged men. METHODS: A total of 2052 initially nondiabetic men aged 45 to 74 years who participated in 1 of the 3 MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Augsburg surveys between 1984 and 1995 were followed up for an average of 7.2 years. Incidence of diabetes was assessed by questionnaire mailed to participants in 1998. High-sensitive CRP was measured by an immunoradiometric assay. RESULTS: A total of 101 cases of incident diabetes occurred during the follow-up period. The age-standardized incidence rate was 6.9 per 1000 person-years. Men with CRP levels in the highest quartile (CRP > or = 2.91 mg/L) had a 2.7 times higher risk of developing diabetes (95% confidence interval, 1.4-5.2) compared with men in the lowest quartile (CRP < or = 0.67 mg/L) in a Cox proportional hazards model adjusted for age and survey. After further adjustment for body mass index, smoking, and systolic blood pressure, the observed association was significantly reduced and became nonsignificant. CONCLUSIONS: Low-grade systemic inflammation is associated with an increased risk of type 2 diabetes mellitus in middle-aged men. Inflammation could be one mechanism by which known risk factors for diabetes mellitus, such as obesity, smoking, and hypertension, promote the development of diabetes mellitus.     

Implications of persistent prehypertension for ageing-related changes in left ventricular geometry and function: the MONICA/KORA Augsburg study

BACKGROUND: It is unclear whether persistent prehypertension causes structural or functional alterations of the heart. METHODS: We examined echocardiographic data of 1005 adults from a population-based survey at baseline in 1994/1995 and at follow-up in 2004/2005. We compared individuals who had either persistently normal (<120 mmHg systolic and <80 mmHg diastolic, n = 142) or prehypertensive blood pressure (120-139 mmHg or 80-89 mmHg, n = 119) at both examinations using multivariate regression modeling. RESULTS: Over 10 years, left ventricular end-diastolic diameters were stable and did not differ between the two groups. However, the prehypertensive blood pressure group displayed more pronounced ageing-related increases of left ventricular wall thickness (+4.7 versus +11.9%, P < 0.001) and left ventricular mass (+8.6 versus +15.7%, P = 0.006). Prehypertension was associated with a raised incidence of left ventricular concentric remodeling (adjusted odds ratio 10.7, 95% confidence interval 2.82-40.4) and left ventricular hypertrophy (adjusted odds ratio 5.33, 1.58-17.9). The ratio of early and late diastolic peak transmitral flow velocities (E/A) decreased by 7.7% in the normal blood pressure versus 15.7% in the prehypertensive blood pressure group (P = 0.003) and at follow-up the ratio of early diastolic peak transmitral flow and early diastolic peak myocardial relaxation velocities (E/EM) was higher (9.1 versus 8.5, P = 0.031) and left atrial size was larger (36.5 versus 35.3 mm, P = 0.024) in the prehypertensive blood pressure group. Finally, the adjusted odds ratio for incident diastolic dysfunction was 2.52 (1.01-6.31) for the prehypertensive blood pressure group. CONCLUSIONS: Persistent prehypertension accelerates the development of hypertrophy and diastolic dysfunction of the heart.     

Macrophage migration inhibitory factor (MIF) and risk for coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002

Objective

Macrophage migration inhibitory factor (MIF), a central cytokine of the innate immunity, has been reported to contribute to the development of cardiovascular disease. MIF is expressed in atherosclerotic lesions in humans, and gene deletion and antibody inhibition studies in animal models indicated that MIF may be cause rather than consequence of atherosclerosis. We sought to assess the triangular association between MIF genotypes, circulating MIF levels and risk for incident coronary heart disease (CHD) in the large, prospective, population-based MONICA/KORA case-cohort study (Augsburg, Southern Germany).

Methods

MIF genotypes, haplotypes and serum concentrations were determined in 363 individuals with incident CHD and 1908 individuals without CHD during follow-up (mean follow-up time 10.3 years).

Results

Circulating MIF concentrations were not associated with the risk for CHD. In women, carriers of the minor alleles rs755622C and rs2070766G had a higher risk for incident CHD, and a haplotype that contained these two minor alleles was significantly associated with increased risk for CHD (HR 2.44, 95%CI 1.30–4.59).

Conclusion

The lack of association between serum levels and incident CHD indicates that MIF may not be a novel biomarker for CHD risk. However, the association of a haplotype containing the rs755622C allele, which has been reported before to increase the susceptibility for various other proinflammatory conditions, with CHD points towards a role for MIF in local vascular inflammation and atherogenesis.     

Prognostic value of apolipoprotein B and A-I in the prediction of myocardial infarction in middle-aged men and women: results from the MONICA/KORA Augsburg cohort study.

AIMS: To investigate the association between apolipoprotein B (apoB), A-I (apoA-I), the apoB/apoA-I ratio, and the incidence of coronary events. METHODS AND RESULTS: Analysis included 1414 men and 1436 women aged 35-64 years without a prior coronary event who participated in the population-based MONICA Augsburg survey 1984-85 (median followed-up period 13 years). Incidence of fatal and non-fatal myocardial infarction, and sudden cardiac death was assessed using data of the MONICA/KORA Augsburg coronary event registry. During follow-up, 114 incident coronary events occurred in men and 31 in women. In multivariable analysis, an increase of 1 standard deviation in the serum concentration of apoB was associated with an increased risk of coronary events in men [hazard ratio (HR)=1.49; 95% confidence interval (CI); 1.25-1.78] and in women (HR=1.73; 95% CI; 1.32-2.27). By contrast, elevated concentrations of apoA-I were not associated with a significantly decreased risk of coronary events in either sex (HR=0.91). Furthermore, the predictive power of the apoB/apoA-I ratio was similar to that of the total cholesterol/HDL cholesterol ratio in men and women. CONCLUSION: ApoB and the apoB/apoA-I ratio were strong predictors of coronary events in middle-aged men and women, whereas apoA-I did not add significantly to the estimation of future coronary risk.     

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.     

Adult asthma is associated with an increased risk of herpes zoster: A population-based cohort study

Objective: The objective of this study was to determine whether a new diagnosis of asthma is associated with a later diagnosis of herpes zoster (HZ) in a nationwide, retrospective, non-age limited, population-based cohort. Methods: We used data from the National Health Insurance Research Database in Taiwan. The asthma group consisted of all 40 069 patients in the database with newly diagnosed asthma and using asthma medications from 2000 through 2005. The nonasthma group comprised 40 069 age- and sex-matched patients without any asthma diagnosis. Cox proportional hazards regression analysis was applied to calculate the hazard ratio of HZ in the patients with asthma relative to those without asthma. Results: During a mean follow-up period of 8.77 years, the risk of HZ was 1.48-fold higher in the asthma group compared with that in the nonasthma group after adjustment for sex, age, comorbidities, inhaled and systemic corticosteroid use, and annual outpatient department visits to dermatologists. Additional stratified analyses revealed that the risk of HZ was significantly higher in patients of both sexes and those aged older than 21 years. Conclusions: Newly diagnosed adult patients with asthma have a significantly higher risk of developing HZ than do those without asthma.