Lipoprotein-associated phospholipase A2 and coronary calcification. The Rotterdam Coronary Calcification Study.

OBJECTIVES: Although several studies have recently suggested that lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent predictor of coronary events, only one study has examined the association between Lp-PLA2 and coronary calcification, using young adults. We investigated the association between Lp-PLA2 activity and coronary calcification assessed by electron-beam computed tomography (EBT) in a population of older participants. METHODS AND RESULTS: The Rotterdam Coronary Calcification Study is a population-based study in men and women aged >/=55 years. Coronary calcification assessed by EBT was quantified in a calcium score according to Agatston's method. Lp-PLA2 activity measured in samples collected 7 years before scanning (n=520) was associated with coronary calcification in men after adjustment for age. The odds ratio per standard deviation of Lp-PLA2 activity of having a total calcium score >1000 was 1.6 (95% confidence interval: 1.1-2.4), as compared to a total calcium score

Soluble Fas, a mediator of apoptosis, C-reactive protein, and coronary and extracoronary atherosclerosis. The Rotterdam Coronary Calcification Study.

RATIONALE: Findings from laboratory studies strongly suggest a role for apoptosis, the process of programmed cell death, in cardiovascular disease. No population-based study has yet investigated whether serum levels of soluble forms of Fas, a receptor capable of inducing the apoptosis cascade, are associated with coronary and extracoronary atherosclerosis. METHODS: Within the Rotterdam Coronary Calcification Study, a population-based cohort study, we measured coronary calcification using electron-beam computed tomography, abdominal aortic calcification by abdominal X-ray, carotid plaques and common carotid intima-media thickness (IMT) by ultrasonography, and lower extremity atherosclerosis by computation of the ankle-arm index. Levels of sFas and of the inflammatory mediator C-reactive protein (CRP) were measured in 1036 participants. RESULTS: Levels of sFas were not related to coronary or extracoronary atherosclerosis. CRP showed strong associations with measures of atherosclerosis, including coronary atherosclerosis, which largely remained after adjustment for traditional cardiovascular risk factors. CONCLUSION: The results of this study do not support a role for sFas in the identification of subjects with atherosclerosis.

Lipoprotein-associated phospholipase A2 and measures of extracoronary atherosclerosis: the Rotterdam Study.

OBJECTIVE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) may be a new and independent predictor of cardiovascular events. The effect of Lp-PLA2 may be exerted through effects of the enzyme on the development of atherosclerosis. Therefore, we investigated the association between Lp-PLA2 activity and measures of extracoronary atherosclerosis. METHODS AND RESULTS: Lp-PLA2 activity was determined in a random sample of 1820 participants from the Rotterdam Study, a population-based cohort study in men and women > or =55 years. Common carotid intima-media thickness, carotid plaques, ankle-arm index, and aortic calcification were examined. Atherosclerosis status could be assigned in 1609 participants. The age-adjusted odds ratio of having atherosclerosis at any site for the highest versus the lowest tertile of Lp-PLA2 activity was 1.86 (95% CI, 1.01 to 3.43) in men and 1.60 (95% CI, 1.08 to 2.37) in women. After additional adjustment for cholesterol, these associations attenuated or even disappeared. The odds ratios of having atherosclerosis at specific sites (carotid arteries and aortic-iliac-femoral tract) followed a similar pattern. CONCLUSIONS: Although Lp-PLA2 has been found to be independently associated with cardiovascular events, the association with measures of subclinical extracoronary atherosclerosis found in this study strongly attenuated or even disappeared after adjustment for cholesterol.

Interleukin 6 -174 g/c promoter polymorphism and risk of coronary heart disease: results from the rotterdam study and a meta-analysis.

OBJECTIVE: Inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Interleukin (IL) 6 has many inflammatory functions, and the IL-6 -174 G/C promoter polymorphism appears to influence IL-6 levels. Findings of previous studies on the relation between this polymorphism and risk of cardiovascular diseases are inconsistent. We investigated this polymorphism in relation to risk of coronary heart disease (CHD) in a population-based study and meta-analysis. METHODS AND RESULTS: Participants (6434) of the Rotterdam Study were genotyped. Analyses on the relation between genotype and CHD were performed using Cox proportional hazards tests, and the association between genotype and plasma levels of IL-6 and C-reactive protein was investigated. All of the analyses were adjusted for age, sex, and common cardiovascular risk factors. A meta-analysis was performed, using a random effects model. No association between genotype and risk of CHD was observed. The polymorphism was not associated with IL-6 levels, but the C-allele was associated with higher C-reactive protein levels (P<0.01). Our meta-analysis did not show a significant association between the genotype and risk of CHD. CONCLUSIONS: We conclude that the polymorphism is not a suitable genetic marker for increased risk of CHD in subjects > or =55 years of age.

The association between angiotensin-converting enzyme gene polymorphism and coronary calcification. The Rotterdam Coronary Calcification Study.

BACKGROUND: An insertion/deletion (I/D) polymorphism in the gene encoding angiotensin-converting enzyme (ACE) has been associated with serum ACE levels. The association between the ACE I/D polymorphism and coronary heart disease is unclear. Electron-beam-computed tomography (EBT) is a technique to non-invasively quantify the amount of coronary calcification. We investigated the association between the ACE I/D polymorphism and coronary calcification. METHODS AND RESULTS: The Rotterdam Coronary Calcification Study is a population-based study in subjects aged 55 years and over. EBT scanning was performed in 2013 participants. Coronary calcification was quantified according to the Agatston score. The ACE I/D polymorphism was available for 1976 subjects. Geometric mean calcium scores in men with the II, ID and DD genotype were 167, 207 and 219, respectively. However, the difference in calcium score (p=0.19 for ID versus II; p=0.15 for DD versus II) and the trend (ptrend=0.17) were not significant. Calcium scores in women with the II, ID and DD genotype were 44, 42 and 36, respectively. There were no significant differences in calcium score (p=0.78 for ID versus II; p=0.29 for DD versus II), neither was the trend (ptrend=0.27). After we stratified on cardiovascular risk factors, no associations were present. CONCLUSION: The present study failed to show an association between the ACE I/D polymorphism and coronary calcification in the general population. Also, no significant associations were present between the ACE I/D polymorphism and coronary calcification in strata of cardiovascular risk factors.

Coronary calcification improves cardiovascular risk prediction in the elderly.

BACKGROUND: Coronary calcification detected by electron beam tomography may improve cardiovascular risk prediction. The technique is particularly promising in the elderly because the predictive power of cardiovascular risk factors weakens with age. We investigated the prognostic value of coronary calcification for cardiovascular events and mortality in a general, asymptomatic population of elderly subjects. METHODS AND RESULTS: From 1997 to 2000, electron beam tomography scanning to assess coronary calcification was performed in subjects of the population-based Rotterdam Study. Risk factors were measured by standardized procedures. Coronary calcium scores were available for 1795 asymptomatic participants (mean age, 71 years; range, 62 to 85 years). During a mean follow-up of 3.3 years, 88 cardiovascular events, including 50 coronary events, occurred. The risk of coronary heart disease increased with increasing calcium score. The multivariate-adjusted relative risk of coronary events was 3.1 (95% CI, 1.2 to 7.9) for calcium scores of 101 to 400, 4.6 (95% CI, 1.8 to 11.8) for calcium scores of 401 to 1000, and 8.3 (95% CI, 3.3 to 21.1) for calcium scores >1000 compared with calcium scores of 0 to 100. The predictive value in subjects >70 years of age was similar. Risk prediction based on the cardiovascular risk factors improved when coronary calcification was added. CONCLUSIONS: Coronary calcification is a strong and independent predictor of coronary heart disease, also in the elderly. Coronary calcification improves prediction of coronary events based on cardiovascular risk factors. Risk stratification by assessment of coronary calcification may have an important role in the primary prevention of coronary heart disease events in the elderly.

Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been proposed as an inflammatory marker of cardiovascular disease. In the present study, we investigated whether Lp-PLA2 is an independent predictor of coronary heart disease and ischemic stroke. METHODS AND RESULTS: The Rotterdam Study is a population-based follow-up study in 7983 subjects > or =55 years of age. We performed a case-cohort study, including 308 coronary heart disease cases, 110 ischemic stroke cases, and a random sample of 1820 subjects. We used Cox proportional-hazard models with modification of the standard errors based on robust variance estimates to compute hazard ratios adjusted for age, sex, body mass index, systolic blood pressure, non-HDL cholesterol, HDL cholesterol, diabetes, smoking, alcohol consumption, cholesterol-lowering medication, white blood cell count, and C-reactive protein. Compared with the first quartile of Lp-PLA2 activity, multivariate-adjusted hazard ratios for coronary heart disease for the second, third, and fourth quartiles were 1.39 (95% CI, 0.92 to 2.10), 1.99 (95% CI, 1.32 to 3.00), and 1.97 (95% CI, 1.28 to 3.02), respectively (P for trend=0.01). Corresponding multivariate-adjusted hazard ratios for ischemic stroke were 1.08 (95% CI, 0.55 to 2.11), 1.58 (95% CI, 0.82 to 3.04), and 1.97 (95% CI, 1.03 to 3.79) (P for trend=0.03). The relation between Lp-PLA2 and coronary heart disease was present in both subjects with non-HDL cholesterol levels below the median and those with non-HDL cholesterol levels above the median. CONCLUSIONS: This study shows that Lp-PLA2 activity is an independent predictor of coronary heart disease and ischemic stroke in the general population.

Alcohol consumption and coronary calcification in a general population.

BACKGROUND: A U- or J-shaped association exists between alcohol consumption and coronary heart disease. One of the proposed mechanisms for this association involves atherogenesis, but there are no data on the association between alcohol consumption and coronary atherosclerosis in asymptomatic subjects. Coronary calcification, a measure of coronary atherosclerosis, allows for the study of the association. METHODS: This cross-sectional study was performed using data from the population-based Rotterdam Coronary Calcification Study. Data on alcohol consumption were available for 1795 individuals without coronary heart disease. Mean +/- SD age of the participants was 71 +/- 5.7 years. Coronary calcification was detected on electron beam computed tomographic scans and quantified as a calcium score by the Agatston method. Extensive coronary calcification was defined as a calcium score above 400. RESULTS: In this population, 15.8% of individuals consumed no alcohol; 46.5% consumed 1 alcoholic drink or less per day; 16.9% consumed 1 to 2 drinks per day; and 20.9% consumed more than 2 drinks per day. A U-shaped association was found between alcohol consumption and coronary calcification. Compared with nondrinkers, the odds ratio of extensive coronary calcification was 0.60 (95% confidence interval [CI], 0.44-0.82) for those who consumed 1 drink or less daily; 0.51 (95% CI, 0.35-0.76) for those who consumed 1 to 2 drinks daily; and 0.90 (95% CI, 0.62-1.29) for those who consumed more than 2 drinks. The association remained after multivariate adjustment. CONCLUSIONS: The consumption of 2 alcoholic drinks or fewer per day was inversely associated with extensive coronary calcification. The risk of extensive coronary calcification was 50% lower in individuals who consumed 1 to 2 alcoholic drinks per day than in nondrinkers.

The association of Rose questionnaire angina pectoris and coronary calcification in a general population: the Rotterdam Coronary Calcification Study.

PURPOSE: The Rose questionnaire is a standardized method of measuring angina pectoris in general populations. Electron-beam computed tomography (CT) is a non-invasive technique to quantify the amount of coronary calcification. In a population-based study, we investigated the association between Rose questionnaire angina pectoris and coronary calcification. METHODS: The Rotterdam Coronary Calcification Study is embedded in the Rotterdam Study, a population-based study in subjects aged > or = 55 years. Participants of the Rotterdam Coronary Calcification Study underwent an electron-beam CT scan between 1997 and 2000. Coronary calcification was quantified in a calcium score according to Agatston's method. Rose questionnaire angina pectoris was assessed during a home interview. The first 2013 participants were included in the present analyses. RESULTS: In men, the presence of Rose questionnaire angina pectoris was associated with a 12.9-fold (95% confidence interval: 3.8-43.7) increased risk of a calcium score >1000 (reference: calcium score 0-100). The corresponding relative risk in women was 4.8 (2.0-11.3). Similar results were found when we computed sex-specific quartiles of the calcium score. CONCLUSIONS: Rose questionnaire angina pectoris is strongly associated with the amount of coronary calcification. Rose questionnaire angina pectoris corresponds better with the amount of coronary calcification in men than in women.

Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction.

CONTEXT: The role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor alpha (ESR1) gene may influence IHD risk, but the role of common sequence variations in the ESR1 gene is unclear. OBJECTIVE: To determine whether the ESR1 haplotype created by the c.454-397T>C (PvuII) and c.454-351A>G (XbaI) polymorphisms is associated with myocardial infarction (MI) and IHD risk. DESIGN, SETTING, AND PARTICIPANTS: In 2617 men and 3791 postmenopausal women from The Rotterdam Study (enrollment between 1989-1993 and follow-up to January 2000), a population-based, prospective cohort study of participants aged 55 years and older, ESR1 c.454-397T>C and c.454-351A>G haplotypes were determined. Detailed interviews and physical examinations were performed, blood samples were obtained, and cardiovascular risk factors were assessed. MAIN OUTCOME MEASURE: The primary outcome was MI and IHD defined as MIs, revascularization procedures, and IHD mortality. RESULTS: Approximately 29% of women and 28.2% of men were homozygous carriers of the ESR1 haplotype 1 (-397 T and -351 A) allele, 49% of women and 50% of men were heterozygous carriers, and 22% of women and 21.4% of men were noncarriers. During a mean follow-up of 7.0 years, 285 participants (115 women; 170 men) had MI, and 440 (168 women; 272 men) had an IHD event, of which 97 were fatal. After adjustment for known cardiovascular risk factors, female heterozygous carriers of haplotype 1 had an increased risk of MI (event rate, 2.8%; relative risk [RR], 2.23; 95% confidence interval [CI], 1.13-4.43) compared with noncarriers (event rate, 1.3%), whereas homozygous carriers had an increased risk (event rate, 3.2%; RR, 2.48; 95% CI, 1.22-5.03). For IHD events, we observed a similar association. In women, the effect of haplotype 1 on fatal IHD was larger than on nonfatal IHD. In men, the ESR1 haplotypes were not associated with an increased risk of MI (event rate, 5.7%; RR, 0.93; 95% CI, 0.59-1.46 for heterozygous carriers; and event rate, 5.1%; RR, 0.82; 95% CI, 0.49-1.38 for homozygous carriers) compared with noncarriers (event rate, 5.8%) and were not associated with an increased risk of IHD. CONCLUSIONS: In this population-based, prospective cohort study, postmenopausal women who carry ESR1 haplotype 1 (c.454-397 T allele and c.454-351 A allele) have an increased risk of MI and IHD, independent of known cardiovascular risk factors. In men, no association was observed.

Risk factors for coronary calcification in older subjects. The Rotterdam Coronary Calcification Study.

AIMS: We examined associations between cardiovascular risk factors and coronary calcification assessed by electron-beam tomography (EBT) in an unselected population of older subjects. METHODS AND RESULTS: The Rotterdam Coronary Calcification Study is a population-based study in subjects > =55 years. Participants underwent EBT scanning. Coronary calcification was quantified according to the Agatston score. Cardiovascular risk factors were assessed 7 years before and concurrently to scanning. We used the first 2013 participants for the present analyses. Risk factors assessed 7 years before scanning were strongly associated with calcium score. Associations with blood pressure and cholesterol attenuated when measured concurrently to scanning. Although the number of risk factors was strongly associated with a high calcium score in asymptomatic subjects, 29% of the men and 15% of the women without risk factors had a high calcium score. CONCLUSIONS: This population-based study in older subjects shows that cardiovascular risk factors are associated with coronary calcification. Associations were stronger for risk factors measured at earlier age. Almost 30% of the men and 15% of the women without risk factors had extensive coronary calcification.

The association between coronary calcification assessed by electron beam computed tomography and measures of extracoronary atherosclerosis: the Rotterdam Coronary Calcification Study.

OBJECTIVES: The present study was designed to examine the associations of coronary calcification assessed by electron beam computed tomography (CT) with measures of extracoronary atherosclerosis. BACKGROUND: Although measures of extracoronary atherosclerosis have been used to predict coronary events, it is not yet known to what extent those measures reflect coronary atherosclerosis. METHODS: The Rotterdam Coronary Calcification Study is a population-based study in subjects age 55 years and over. Participants of the study underwent an electron beam CT scan. Coronary calcification was quantified according to the Agatston calcium score. Measures of extracoronary atherosclerosis included common carotid intima media thickness (IMT), carotid plaques, ankle-arm index (AAI) and aortic calcification. We used the first 2,013 participants for the present analyses. Age-adjusted geometric mean calcium scores were computed for categories of extracoronary measures using analyses of variance. RESULTS: Graded associations with coronary calcification were found for the carotid and aortic measures. Associations were strongest for carotid plaques and aortic calcification; coronary calcification increased from the lowest category (no plaques) to the highest category 9-fold and 11-fold in men and 10-fold and 20-fold in women, respectively. A nonlinear association was found for AAI with an increase in coronary calcification only at lower levels of AAI. CONCLUSIONS: In this population-based study, graded associations were found between coronary calcification and common carotid IMT, carotid plaques and aortic calcification. A nonlinear association was found between coronary calcification and the AAI.