Kardys, I.

Microsimulation for Clinical Decision-Making in Individual Patients With Established Coronary Artery Disease (Article)

2012-11-29T00:00:00Z

Background: In cardiovascular disease, numerous evidence-based prognostic models have been created, usually based on regression analyses of isolated patient datasets. They tend to focus on one outcome event, based on just one baseline evaluation of the patient, and fail to take the disease process in its dynamic nature into account. We present so-called microsimulation as an attractive alternative for clinical decision-making in individual patients. We aim to further familiarize clinicians with the concept of microsimulation and to inform them about the modeling process. Methods and Results: We describe the modeling process, advantages and disadvantages of microsimulation. We illustrate the concept using a hypothetical 60-year-old patient, with several cardiac risk factors, who is hospitalized for myocardial infarction. By using microsimulation, we calculate this patient’s probability of death. In our example, this particular patient’s estimated life expectancy turns out to be 8.9 years. While calculating this life expectancy, we were able to account for multiple outcome events and changing patient characteristics. Conclusions: Microsimulation takes into account the dynamic nature of coronary artery disease by estimating most likely outcomes regarding a broad range of clinical events. Moreover, microsimulation can be used to evaluate treatment effects by estimating the event-free life expectancy with and without treatment. Hence, microsimulation has several advantages compared to modeling techniques such as regression.

Distribution of echocardiographic parameters and their associations with cardiovascular risk factors in the Rotterdam Study (Article)

2010-07-01T00:00:00Z

Insight into echocardiographic parameters in the general population may facilitate early recognition of ventricular dysfunction, reducing the population morbidity and mortality of heart failure. We examined the distribution of structural, systolic and diastolic echocardiographic parameters and their associations with cardiovascular risk factors in the Rotterdam Study, a population-based cohort study in men and women aged ≥55 years. Participants with prevalent heart failure, myocardial infarction and atrial fibrillation and flutter were excluded. Echocardiographic parameters were assessed using two-dimensional, M-mode and Doppler echocardiography. Echocardiograms were available in 4,425 participants. Structural parameters were generally larger in men, and most consistently associated with age, body mass index and blood pressure in both sexes. Prevalence of moderate or poor left ventricular systolic function was 3.9% in men and 2.1% in women. Age, body mass index and blood pressure were most consistently associated with systolic function. E/A ratio was lower in women than in men. Age and diastolic blood pressure were most consistently associated with E/A ratio in both sexes. In conclusion, ventricular systolic and diastolic dysfunction is present in asymptomatic individuals. Selected established cardiovascular risk factors are associated with structural, systolic and diastolic parameters.

Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables (Article)

2010-05-30T00:00:00Z

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes. Copyright

Genetic variation in the fibrinogen-α and fibrinogen-γ genes in relation to arterial stiffness: The Rotterdam Study (Article)

2009-07-01T00:00:00Z

Objective: Arterial stiffness increases with age and predicts cardiovascular disease. Fibrinogen is an acute-phase protein and some studies showed an association with arterial stiffness. We studied genetic variation in the fibrinogen-α (FGA) and fibrinogen-γ (FGG) genes, by means of single nucleotide polymorphisms (FGA: -58 G/A, 1374 G/A, 1526 T/C, 312 Thr/Ala, and FGG: 4288 G/A, 6326 G/A, 7792 T/C) and resultant haplotypes in relation to arterial stiffness. Methods: The present study (n = 3891) was embedded in the Rotterdam Study. Associations of the fibrinogen level, genotypes and haplotypes with aortic stiffness (pulse wave velocity), carotid stiffness (distensibility coefficient) and pulse pressure were investigated in men and women by analyses of variance, linear regression and by haplotype analyses. Analyses were adjusted for age, mean arterial pressure, heart rate, known cardiovascular risk factors and atherosclerosis. Results: Genotype analyses yielded associations of FGA-58 G/A (P = 0.040, for trend) and FGA-1526 T/C (P = 0.004, for trend) with the fibrinogen levels, but no consistent associations with arterial stiffness, in women. FGA-haplotype 4 was associated with the fibrinogen level (P = 0.02) in women. FGA-haplotype 3 and FGG-haplotype 2 were associated with aortic stiffness (P = 0.05) in women. No associations were found in men. Conclusion: Findings indicate that the fibrinogen level and genetic variation in the FGA and FGG genes may influence arterial stiffness in women.

Echocardiographic parameters and all-cause mortality: The Rotterdam Study (Article)

2009-04-03T00:00:00Z

Background: Even when heart failure has not yet become clinically manifest, preclinical ventricular dysfunction may be present, and therapeutic interventions introduced at this time may reduce morbidity and mortality. However, data on the predictive value of echocardiographic characteristics in the general population remain relatively scarce. Methods: The Rotterdam Study is a population-based cohort study in men and women aged ≥ 55 years. Participants with prevalent heart failure, myocardial infarction and atrial fibrillation and flutter at the time of echocardiography were excluded. Structural, systolic and diastolic parameters were assessed using two-dimensional, M-mode and Doppler echocardiography. Echocardiograms were available in 4425 participants. Results: During a mean follow-up of 3.0 years, 226 participants died. Increased left ventricular mass was an independent risk factor for all-cause mortality, particularly in men (hazard ratio per standard deviation of natural log transformed left ventricular mass, 1.20 (95% CI, 1.01-1.43)). Fractional shortening and left ventricular systolic function did not show a clear association with mortality. E/A ratio < 0.75 was an independent risk factor in men (age-adjusted hazard ratio 1.82 (95% CI 1.23-2.69)). This was further reflected by diastolic function: impaired relaxation was a risk factor in men, but not in women. Conclusions: Structural and diastolic echocardiographic parameters are associated with all-cause mortality in an asymptomatic population. However, the evidence is still inadequate to support the usefulness of echocardiography for screening to identify asymptomatic individuals with preclinical ventricular dysfunction.

Haplotypes of the NR4A2/NURR1 gene and cardiovascular disease: The Rotterdam study (Article)

2009-03-01T00:00:00Z

Nuclear receptor subfamily 4, group A, member 2 (NR4A2, also called Nurr1) has lately become of interest with regard to atherogenesis. We examined the association between common variation in the NR4A2 gene and cardiovascular disease in the Rotterdam Study, a prospective population-based study among persons aged ≥55 years. Three SNPs that tag common haplotypes across a 36-kb region surrounding the NR4A2 gene were determined. Four haplotypes with frequencies 41% covered 96% of the genetic variation. In 5,650 participants without history of coronary heart disease, 729 coronary heart disease events occurred during a median follow-up time of 11.9 years. NR4A2 haplotypes were neither associated with coronary events nor with intima-media thickness (IMT), carotid plaques, or ankle-arm index (AAI). NR4A2 haplotypes showed a tendency toward associations with aortic and coronary calcification (haplo.score global simulation P values 0.076 and 0.075, respectively), which seemed to be based on haplotype 2 (individual P values were both P = 0.015). Furthermore, NR4A2 haplotype 3 was associated with higher high-density lipoprotein (HDL) cholesterol and haplotype 4 with lower systolic blood pressure. In conclusion, NR4A2/NURR1 haplotypes were not associated with coronary events, carotid IMT, carotid plaques, or AAI. There was a tendency toward associations with aortic calcification and coronary calcification. Associations for NR4A2 were found with both HDL levels and blood pressure. It remains to be investigated which pathophysiological mechanisms pertain to NR4A2 function in cardiovascular disease.

Genetic variation in the C-reactive protein gene and arterial stiffness: The Rotterdam Study (Article)

2008-11-01T00:00:00Z

Background and aim: Arterial stiffness increases with age and has been found to predict cardiovascular disease. C-reactive protein (CRP) is an inflammation marker and has been found to be associated with arterial stiffness and risk of cardiovascular disease. Genetic factors account for part of the variance in CRP level. We studied the association of the total common variation in the CRP gene by polymorphisms 1184 C/T, 2042 C/T, 2911 C/G and haplotypes with arterial stiffness within the Rotterdam study. Methods: The study (n = 3615) was embedded in the Rotterdam Study, a prospective, population-based study among subjects aged 55 years and older. Associations of genotypes and haplotypes with CRP level and measures of arterial stiffness were examined using linear regression and analyses of variance. Measures of arterial stiffness included aortic pulse wave velocity, carotid distensibility and pulse pressure. Analyses were adjusted for age, sex, mean arterial pressure, heart rate, known cardiovascular risk factors and measures of atherosclerosis. Results: CRP level was significantly associated with pulse wave velocity (p < 0.001) and pulse pressure (p < 0.05), also after adjusting for cardiovascular risk factors. CRP level was also associated with the 1184 C/T (T-allele: higher level), the 2042 C/T (T-allele: lower level) and 2911 C/G (G-allele: higher level) polymorphisms (all p < 0.001). Genotype and haplotype analyses showed no consistent associations of genetic variation with pulse wave velocity, carotid distensibility and pulse pressure. Conclusions: No consistent associations of the CRP polymorphisms 1184 C/T, 2042 C/T, 2911 C/G and corresponding haplotypes were found with measures of arterial stiffness.

Host polymorphisms in interleukin 4, complement factor H, and C-reactive protein associated with nasal carriage of Staphylococcus aureus and occurrence of boils (Article)

2008-05-01T00:00:00Z

Background. Staphylococcus aureus is capable of persistently colonizing the vestibulum nasi. We hypothesized that polymorphisms in host inflammatory response genes and genetic variation in S. aureus contribute to susceptibility to S. aureus carriage and infection. Methods. The prevalence of persistent nasal carriage of S. aureus in 3851 participants aged 61-101 years was 18% (678 of 3851 participants), whereas 73% of volunteers (2804 of 3851) were not colonized. A total of 1270 individuals had boils. Polymorphisms in TNFA (C -863T), IL4 (C -542T), CFH (Tyr402His), and CRP (C1184T, C2042T, and C2911G) were determined. Genetic similarity among 428 S. aureus isolates was determined by use of amplified fragment length polymorphism analysis (AFLP)-mediated genotyping. Results. The IL4 -524 C/C host genotype was associated with an increased risk of persistent S. aureus carriage, irrespective of S. aureus AFLP genotype. The CRP haplotype 1184C; 2042C; 2911C was overrepresented in individuals who were not colonized . In individuals with boils, carriers of the CFH Tyr402 variant, and the CRP 2911 C/C genotype were overrepresented. Conclusion. Persistent carriage of S. aureus is influenced by genetic variation in host inflammatory response genes. As would be expected in multifactorial host-microbe interactions, these effects are limited. Interestingly, host genotype was associated with the carriage of certain S. aureus genotypes. Apparently, a close interaction between host and bacterial determinants are prerequisites for long-term colonization.

Plasma concentration of heat shock protein 27 and risk of cardiovascular disease: A prospective, nested case-control study (Article)

2008-01-01T00:00:00Z

BACKGROUND: Heat shock protein 27 (HSP27) has been hypothesized to be a potential biomarker of atherothrombosis. However, no prospective studies have yet been performed to investigate the association between HSP27 plasma concentration and incident cardiovascular events among initially healthy individuals. METHODS: We evaluated plasma concentrations of HSP27 at baseline among 255 initially healthy participants in the Women's Health Study who subsequently developed myocardial infarction, ischemic stroke, or cardiovascular death during a follow-up period of up to 5.9 years and among an equal number of women matched for age and smoking but who remained free of cardiovascular disease over the same time period. RESULTS: Overall, HSP27 plasma concentrations were inversely associated with age (Spearman correlation coefficient r = -0.258, P <0.001), but not with other established cardiovascular risk factors. Conditional logistic regression analysis showed no significant association of baseline HSP27 plasma concentration with future cardiovascular disease; the odds ratio for upper vs lower tertile of HSP27 concentration at baseline was 0.99 (95% CI 0.62-1.57, P for trend = 0.99). CONCLUSION: In this prospective study of initially healthy women, baseline HSP27 plasma concentration was not associated with incident cardiovascular events.

Inflammatory Markers and Genes: Epidemiologic Studies on their Roles in Cardiovascular Disease (Doctoral Thesis)

2007-12-19T00:00:00Z

Established cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus and smoking do not fully explain the occurrence of cardiovascular disease; although the majority of patients have at least one of these risk factors, a substantial proportion of cases occurs in individuals that have none.1 As such, further insight is required into the pathophysiology of cardiovascular disease and in factors that may identify individuals at high risk. One of the most relevant insights in atherosclerosis of the past years is the recognition of the role of inflammation.2 Research on inflammatory markers, both experimental and epidemiological, has taken flight, and several of these markers have been implicated in cardiovascular disease.3 This development was accompanied by an expansion of research on genetic variation that may influence inflammatory processes. The field of genetics has rapidly evolved over the last years because of improved technology and methodology in combination with the emergence of large, publicly available genetic databases.4 The purpose of this thesis was to expand the knowledge on inflammatory markers and inflammatory genes that may play a part in the pathophysiology of cardiovascular disease. We focused on factors that have drawn increased attention in the recent years, such as C-reactive protein (CRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2), and examined their roles in both atherothrombotic disease and in heart failure. Most studies were conducted within the Rotterdam Study, a population- based cohort study among 7983 men and women aged 55 years and over living in a well-defined suburb of Rotterdam, the Netherlands.5 During a visit of the participants to the research center, blood was drawn in order to assess inflammatory markers and genetic variation. Several measures of atherosclerosis were assessed at the research center, and furthermore, participants were followed-up for the occurrence of coronary events and heart failure. Specifically, the main research questions we examined were as follows. With regard to inflammation, atherosclerosis and coronary events: - Is CRP serum level associated with atherosclerosis and coronary events? - Is variation in the CRP gene and variation in the complement factor H gene associated with coronary events, and do these genes interact to predict disease? - Is Lp-PLA2 activity associated with atherosclerosis? With regard to inflammation and heart failure: - What is the distribution of echocardiographic parameters in an asymptomatic population, and do these parameters predict mortality? - Are the inflammatory markers CRP and Lp-PLA2 associated with the occurrence of heart failure?

C-reactive protein is related to extent and progression of coronary and extra-coronary atherosclerosis; results from the Rotterdam study (Article)

2007-12-01T00:00:00Z

Aims: Although prospective studies have unequivocally shown that C-reactive protein (CRP) is an independent predictor of future cardiovascular events, studies on the association between CRP and atherosclerosis have provided inconsistent results. We investigated the association of CRP with extent and progression of atherosclerosis in multiple vessel beds in a large, population-based cohort study. Methods: In the Rotterdam Study, standardized measurements of coronary and extra-coronary atherosclerosis were performed in 1962 persons and 6582 persons, respectively. Progression of extra-coronary atherosclerosis during a mean follow-up period of 6.4 years was assessed in 3757 persons. Results: Independent and graded associations were found of CRP with the number of carotid plaques and carotid plaque progression ((OR 1.72; 95% CI 1.14-2.59) for severe progression in participants with CRP > 3 mg/dl versus participants with CRP < 1 mg/dl). Similarly, CRP was independently and graded related to ankle-brachial-index (ABI) and worsening ABI over the years ((OR 1.99; 95% CI 1.37-2.88) for severe progression in participants with CRP > 3 mg/dl versus participants with CRP < 1 mg/dl). Although CRP was independently related to the highest level of carotid intima-media thickness (IMT), the association with change in IMT was not significant. Furthermore, there was an independent, graded relation between CRP and aortic calcification, but no independent association was observed with progression of aortic calcification, nor with the amount of coronary calcification. Conclusion: In this population-based study, independent and graded associations were present of CRP with extent and progression of carotid plaques and ABI, while associations with carotid IMT and aortic and coronary calcification were less pronounced.

Polymorphisms and haplotypes in the C-reactive protein gene and risk of dementia (Article)

2007-09-01T00:00:00Z

Objective: Inflammation plays a role in the pathogenesis of dementia and Alzheimer's disease (AD). Studies examining serum levels of C-reactive protein in relation to dementia yielded conflicting results. Since serum levels of C-reactive protein are partly determined by genetic factors, we examined the association between genetic variation in the C-reactive protein gene with dementia and AD. Methods: This study was performed in the Rotterdam Study, a population-based prospective cohort study among elderly. Polymorphisms in the C-reactive protein gene (1184C > T, 2042C > T and 2911C > G) tagging the common haplotypes were genotyped and haplotypes were constructed. During follow-up (mean 9.2 years) 607 dementia cases were identified. We estimated the association between polymorphisms and haplotypes with dementia and AD with Cox' proportional hazard models. Results: The T allele of the C-reactive protein 2042C > T polymorphism, related to lower serum levels of C-reactive protein, was associated with a lower risk of dementia and AD. This association was strongest in APOE ε4 allele carriers. Conclusion: These findings suggest that C-reactive protein plays a role in development of dementia.

Usefulness of Combining Complement Factor H and C-Reactive Protein Genetic Profiles for Predicting Myocardial Infarction (from the Rotterdam Study) (Article)

2007-08-15T00:00:00Z

Complement factor H (CFH) is an important regulator of the complement cascade. Binding of C-reactive protein (CRP) to CFH augments the ability of CFH to downregulate the effect of complement in atherosclerotic lesions. The CFH Tyr402His polymorphism has been suggested to influence the ability of CFH to bind CRP. We hypothesized that the combined presence of unfavorable CRP and CFH genetic profiles is associated with risk of myocardial infarction (MI). The Rotterdam Study is a population-based cohort study in 7,983 men and women aged ≥55 years. The CFH Tyr402His (rs1061170) polymorphism was determined (His402allele 37%), and using 3 tagging polymorphisms (rs1130864, rs1205, and rs3093068), CRP haplotypes were inferred (1 = CTC, 2 = TCC, 3 = CCC, 4 = CCG; frequencies of 33%, 32%, 30%, and 6%, respectively). Participants were grouped by CFH genotype (TyrTyr [reference], TyrHis, and HisHis) and CRP haplotype (haplotype 1 homozygotes [reference], haplotype 2 carriers, haplotype 3 carriers, and haplotype 4 carriers), which resulted in a total of 12 groups. CFH His402homozygotes who were also CRP haplotype 3 carriers had an age- and gender-adjusted hazard ratio of 5.9 (95% confidence interval 2.1 to 16.5) to develop MI compared with the reference group. In conclusion, this population-based study suggests that the combined presence of unfavorable CFH and CRP genetic profiles is associated with risk of MI.

CRP gene haplotypes, serum CRP, and cerebral small-vessel disease: The Rotterdam Scan Study and the MEMO Study (Article)

2007-08-01T00:00:00Z

BACKGROUND AND PURPOSE - It remains unclear whether C-reactive protein (CRP) is a serum marker for atherothrombotic disease or a causal factor in the pathogenesis of atherosclerosis. We explored the association between CRP gene variations and cerebral small-vessel disease (SVD) in the Rotterdam Scan Study (N=1035) and the MEMO Study (N=268). METHODS - Common haplotypes within the CRP gene were determined by genotype-tagging single-nucleotide polymorphisms. Then their relation with periventricular and subcortical white matter lesions and the prevalence of lacunar brain infarcts was explored by regression analyses. RESULTS - There was no association between CRP haplotypes and measures of cerebral SVD in either study. There was no effect modification of the association between serum CRP levels and measures of SVD by CRP haplotypes. CONCLUSIONS - Our observations suggest that CRP is not causally involved in the pathogenesis of SVD.

The female advantage in cardiovascular disease: Do vascular beds contribute equally? (Article)

2007-07-01T00:00:00Z

The female advantage in coronary heart disease occurrence is not completely understood. To characterize gender differences in cardiovascular disease by vascular site, the authors compared degrees of coronary, carotid, peripheral, and aortic atherosclerosis in men and women aged ≥55 years from the population-based Rotterdam Study (Rotterdam, the Netherlands). Data were collected between 1997 and 2000. A subset of 2,013 participants had data on both coronary calcification and one or more measures of extracoronary atherosclerosis, including intima-media thickness (IMT), carotid plaques, ankle-arm index (AAI), and aortic calcification. The multivariable-adjusted male:female odds ratios for calcium score > 1,000 were 7.8 (95% confidence interval (CI): 3.2, 19.3), 5.4 (95% CI: 2.8, 10.2), and 3.0 (95% CI: 1.7, 5.2) in the lowest, middle, and highest age tertiles, respectively. For IMT > 1.0 mm, severe carotid plaques, AAI < 0.90, and severe aortic calcification, ratios did not decline with age. Overall multivariable-adjusted male:female odds ratios for these measures were 2.9 (95% CI: 2.0, 4.1), 2.0 (95% CI: 1.4, 2.8), 0.9 (95% CI: 0.7, 1.3), and 1.0 (95% CI: 0.8, 1.5), respectively. The authors conclude that the gender difference in atherosclerosis is larger in the coronary vessels than in other vascular beds. Remarkably, it is absent in the aorta and the lower-extremity vessels. Factors causing this site-specific gender difference require further investigation.

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

2007-04-01T00:00:00Z

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 ≤100. After adjustment for non-HDL and HDL-cholesterol, this association disappeared. In women, the association was less consistent. For Lp-PLA2 measured concurrently to scanning (n = 703), no association was found with coronary calcification. Conclusions: Lp-PLA2 activity is moderately associated with coronary calcification after adjustment for age. The effect of Lp-PLA2 on coronary calcification may be exerted through its effect on LDL-cholesterol.

Genetic variation, C-reactive protein levels, and incidence of diabetes (Article)

2007-03-01T00:00:00Z

C-reactive protein (CRP) has been shown to be associated with type 2 diabetes, but whether CRP has a causal role is not yet clear. We examined the association in the Rotterdam Study, a population-based prospective cohort study. The association of baseline serum CRP and incident diabetes during follow-up was investigated, and a meta-analysis was conducted on the BMI-adjusted relation of CRP and diabetes. Furthermore, the association of CRP haplotypes with serum CRP and risk of diabetes was assessed. The age-and sex-adjusted hazard ratio for diabetes was 1.41 (95% CI 1.29-1.54) per 1 SD increase in natural logarithm of CRP, and it was 1.88, 2.16, and 2.83 for the second, third, and fourth quartiles of CRP, respectively, compared with the first quartile. The risk estimates attenuated but remained statistically significant after additional adjustment for obesity indexes, which agreed with the results of the meta-analysis. The most common genetic haplotype was associated with a significantly lower CRP level compared with the three other haplotypes. The risk of diabetes was significantly higher in the haplotype with the highest serum CRP level compared with the most common haplotype (OR 1.45, 95% CI 1.08-1.96). These findings support the hypothesis that serum CRP enhances the development of diabetes.

Fibrinogen gene haplotypes in relation to risk of coronary events and coronary and extracoronary atherosclerosis: The Rotterdam Study (Article)

2007-02-01T00:00:00Z

Fibrin network structure has been correlated with coronary disease. Fibrinogen γ and α (FGG and FGA) gene haplotypes (chromosome 4q28) may be associated with fibrin network structure, and thereby with rigidity of the fibrin clot and sensitivity of the fibrin clot to the fibrinolytic system.Through these mechanisms they may influence risk of cardiovascular disease. We set out to investigate the relation between combined fibrinogen FGG and FGA gene haplotypes, representing the common variation of the fibrinogen FGG and FGA genes, coronary events and measures of coronary and extracoronary atherosclerosis. The study was embedded in the Rotterdam Study, a prospective population-based study among men and women aged ≥55 years. Common haplotypes were studied using seven tagging SNPs across a 30-kb region with the FGG and FGA genes. Incident coronary events were registered, and carotid intima-media thickness, carotid plaques, ankle-arm index, aortic calcification and coronary calcification were assessed. Seven haplotypes with frequencies >1% covered 97.5% of the genetic variation. In 5,667 participants without history of coronary heart disease (CHID), 733 CHID cases occurred during a median follow-up time of 11.9 years. Fibrinogen gene haplotypes were not associated with coronary events. Fibrinogen gene haplotypes did not show a consistent association with measures of coronary and extracoronary atherosclerosis. In conclusion, fibrinogen FGG and FGA gene haplotypes are not associated with coronary events, coronary atherosclerosis or extracoronary atherosclerosis. Confirmation of these findings by future population-based studies is warranted.

Spatial QRS-T angle predicts cardiac death in a general population (Article)

2003-01-01T00:00:00Z

AIMS: The aim of this study was to assess the prognostic importance of the spatial QRS-T angle for fatal and non-fatal cardiac events. METHODS AND RESULTS: Electrocardiograms (ECGs) were recorded in 6134 men and women aged 55 years and over from the prospective population-based Rotterdam Study. Spatial QRS-T angles were categorized as normal, borderline or abnormal. Using Cox's proportional hazards model, abnormal angles showed increased hazard ratios of cardiac death (age-and sex-adjusted hazard ratio 5.2 (95% CI 4.0-6.8)), non-fatal cardiac events (2.2 (1.5-3.1)), sudden death (5.6 (3.7-8.5)) and total mortality (2.3 (2.0-2.7)). None of the classical cardiovascular and ECG predictors provided larger hazard ratios. After adjustment for these predictors, the association of abnormal spatial QRS-T angles with all fatal study endpoints remained strong, but the association with non-fatal cardiac events disappeared. Computation of Akaike's information criterion showed that the angle contributed significantly to the prediction of all fatal endpoints by classical cardiovascular and ECG predictors. CONCLUSION: The spatial QRS-T angle is a strong and independent predictor of cardiac mortality in the elderly. It is stronger than any of the classical cardiovascular risk factors and ECG risk indicators and provides additional value to them in predicting fatal cardiac events.