http://repub.eur.nl/res/aut/6942/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/28357/ 2010-04-01T00:00:00Z http://repub.eur.nl/res/pub/24581/ 2009-08-01T00:00:00Z We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 × 10-7). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 × 10-11; combined RR = 1.25; combined P = 1.8 × 10-15). http://repub.eur.nl/res/pub/17987/ 2009-07-24T00:00:00Z http://repub.eur.nl/res/pub/20468/ 2009-06-17T00:00:00Z Atrial fibrillation is a common disease of the heart, characterized by an irregular and, if not treated, mostly fast heart rhythm. The origin of the disease is the atrial part of the heart. It is a rare disease before the age of 55, but the prevalence is sharply increasing with age. In many cases patients do not even notice that they have a rhythm disorder. But if they have complaints, they mention dyspnoea, chest pain, palpitations, dizziness, and sometimes syncope. For many years, atrial fibrillation has been considered as an innocent bystander of old age, but it is nowadays generally accepted that atrial fibrillation is associated with impaired quality of life and increased morbidity and mortality. Treatment regimens evolved as a consequence, unfortunately sometimes introducing new potential harms to the patients with this disease. Atrial fibrillation is involved in pathological processes through the whole body and has through that inspired numerous investigators in internal medicine, cardiology, neurology, pathology, pharmacology, physiology and epidemiology. The disease concept has evolved as science evolved and often has been in the centre of intense dispute. http://repub.eur.nl/res/pub/24645/ 2009-04-01T00:00:00Z Aims: A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts.Methods and resultsThe Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 ± 10 vs. 71 ± 13 years; Rotterdam 73 ± 8 vs. 69 ± 9 years; Vanderbilt 54 ± 14 vs. 57 ± 14 years; AFNet 62 ± 12 vs. 49 ± 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95 confidence interval (CI) 1.18-1.59; P = 3.1 × 10-5] to 2.52 in AFNet (95 CI 2.22-2.8; P = 1.8 × 10-49). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95 CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95 CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95 CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95 CI 1.60-2.26; P = 3.3 × 10-13) for rs2200733 and of 1.36 (95 CI 1.26-1.47; P = 6.7 × 10-15) for rs10033464.ConclusionThe non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4. http://repub.eur.nl/res/pub/18249/ 2009-01-24T00:00:00Z Objective: To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia. Design: Cohort study with a mean follow-up of 8.5 years. Setting: 27 outpatient lipid clinics. Subjects: 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990. Main outcome measures: Risk of coronary heart disease in treated and "untreated" (delay in starting statin treatment) patients compared with a Cox regression model in which statin use was a time dependent variable. Results: In January 1990, 413 (21%) of the patients had started statin treatment, and during follow-up another 1294 patients (66%) started after a mean delay of 4.3 years. Most patients received simvastatin (n=1167, 33 mg daily) or atorvastatin (n=211, 49 mg daily). We observed an overall risk reduction of 76% (hazard ratio 0.24 (95% confidence interval 0.18 to 0.30), P<0.001). In fact, the risk of myocardial infarction in these statin treated patients was not significantly greater than that in an age-matched sample from the general population (hazard ration 1.44 (0.80 to 2.60), P=0.23). Conclusion: Lower statin doses than those currently advised reduced the risk of coronary heart disease to a greater extent than anticipated in patients with familial hypercholesterolaemia. With statin treatment, such patients no longer have a risk of myocardial infarction significantly different from that of the general population. http://repub.eur.nl/res/pub/28806/ 2008-12-01T00:00:00Z Background: Cigarette smoking is an important risk factor for cardiovascular disease, but it is unknown whether it also contributes to the risk of atrial fibrillation. Methods and results: The study is part of the Rotterdam Study, a population-based cohort study among subjects aged ≥55 years. The association between cigarette smoking and the risk of atrial fibrillation was examined in 5,668 subjects without atrial fibrillation at baseline. During a median follow-up of 7.2 years, 371 cases of atrial fibrillation were identified. Relative risks (RR) were calculated with 95% CIs using the Cox proportional hazards model, adjusted for age, gender, body mass index, hypertension, systolic blood pressure, serum cholesterol level, diabetes mellitus, left ventricular hypertrophy on the electrocardiogram, prevalent and incident myocardial infarction, prevalent heart failure, and the use of pulmonary medication. After multivariate adjustment, current smokers and former smokers had increased risks of atrial fibrillation as compared to never smokers (RR 1.51, 95% CI 1.07-2.12; and RR 1.49, 95% CI 1.14-1.97, respectively). No differences were found between men and women. Conclusions: The results of this prospective, population-based study show that current and former smoking of cigarettes are associated with increased risk of atrial fibrillation. http://repub.eur.nl/res/pub/32401/ 2008-11-10T00:00:00Z Background: Overt and subclinical hyperthyroidism are both well-known independent risk factors for atrial fibrillation. We aimed to investigate the association of high-normal thyroid function with the development of atrial fibrillation in a prospective population-based study in the elderly. Methods: The association between thyroid-stimulating hormone (TSH) levels and atrial fibrillation was examined in 1426 subjects with TSH levels in the normal range (0.4-4.0 mU/L) and without atrial fibrillation at baseline. In 1177 of the 1426 persons in this group, we also examined the association between free thyroxine levels within the normal range (0.86-1.94 ng/dL [to convert to picomoles per liter, multiply by 12.871]) and atrial fibrillation. During a median follow-up of 8 years, 105 new cases of atrial fibrillation were identified. Hazard ratios (HRs) were calculated with 95% confidence intervals (CIs) using Cox proportional hazards models after adjustment for age, sex, current smoking, former smoking, body mass index, systolic blood pressure, hypertension, history of myocardial infarction, presence of heart failure, left ventricular hypertrophy on the electrocardiogram, diabetes mellitus, total cholesterol level, and time of the drawing of blood samples. Results: The risk of atrial fibrillation was associated with the TSH level. The multivariate adjusted HR was 1.94 (95% CI, 1.13-3.34, lowest vs highest quartile; P for trend, .02). The multivariate adjusted level of free thyroxine showed a graded association with risk of atrial fibrillation (HR, 1.62; 95% CI, 0.84-3.14, highest vs lowest quartile; P for trend, .06). Conclusion: Within the normal range of thyroid parameters, persons with high-normal thyroid function are at an increased risk of atrial fibrillation. http://repub.eur.nl/res/pub/29851/ 2008-11-01T00:00:00Z Objective: The aim of the study was to investigate how settings and registry characteristics affect the prevalence and nature of multimorbidity in elderly individuals. Study Design and Setting: We used data from three population-based studies, two general practitioner registries, one hospital discharge register, and one nursing home registry to estimate the prevalence of multimorbidity. Individuals aged 55 years and over were included. Results: Multimorbidity was most prevalent in nursing homes (82%), followed by the general population and general practitioner registries (56%-72%) and the hospital setting (22%). There were large differences in the nature of multimorbidity between settings. Combinations of hypertension, heart disease, and osteoarthritis were dominant in the population-based setting, whereas hypertension in combination with osteoarthritis, obesity, disorders of lipid metabolism, and diabetes dominated in the general practitioner setting. In the hospital setting, combinations of heart diseases had the highest prevalence. Combinations of dementia, hypertension, and stroke were dominant within the nursing home setting. Conclusion: This study shows that setting and registry characteristics have an important influence on the outcome of multimorbidity studies. We recommend provision of at least information about the setting, the (list of) conditions included, the data collection method, and the time frame used, when reporting about the size and nature of multimorbidity. http://repub.eur.nl/res/pub/14708/ 2008-10-01T00:00:00Z OBJECTIVES: To determine the prognostic role of orthostatic hypotension for cardiovascular disease (CVD) and all-cause mortality in elderly people. DESIGN: Prospective study. SETTING: Community based. PARTICIPANTS: Five thousand sixty-four subjects from the Rotterdam study aged 55 and older. MEASUREMENTS: Orthostatic hypotension was measured using a Dinamap automatic blood pressure recorder. Orthostatic hypotension is defined as a decline in systolic blood pressure of 20 mmHg or more or a decline in diastolic blood pressure of 10 mmHg or more from supine to standing position at any of three measurements taken 1, 2, and 3 minutes after standing. RESULTS: At baseline, 901 subjects had orthostatic hypotension. During follow-up, 668 subjects had coronary heart disease (CHD) (mean follow-up 6.0 ± 3.5 years), and 1,835 subjects died (mean follow-up period 7.8 ± 3.8 years). Orthostatic hypotension increased the risk of CHD (hazard ratio (HR)=1.31, 95% confidence interval (CI)=1.08-1.57) and all-cause mortality (HR=1.22, 95% CI=1.09-1.36), in models adjusted for age and sex. The risk was slightly lower after additional adjustment for cardiovascular risk factors. In analyses stratified for age, the HRs for all-cause mortality were 1.80 (95% CI 1.25-2.60), 1.13 (0.89-1.42), and 1.27 (95% CI=1.11-1.44), in the first, second, and third tertile of age, respectively. CONCLUSION: Orthostatic hypotension increases the risk of CHD and all-cause mortality in elderly people. The risk of CVD and mortality is strongest in younger and very old subjects. http://repub.eur.nl/res/pub/29606/ 2008-04-01T00:00:00Z AIMS: The risk of adverse events due to chronic benzodiazepine use is high in the elderly. Clinicians need to be able to identify those persons who are at risk of chronic benzodiazepine use, but little is known about the determinants. This study determined social and health related factors that predict new-onset chronic benzodiazepine use in community-dwelling elderly. METHODS: This study was embedded in an ongoing cohort study among 5364 persons aged ≥57 years. Drug-dispensing medication records were available for the period between 1991 and 2003. We defined chronic benzodiazepine use as use during at least 180 days in a period of 365 consecutive days. The association of various social, psychiatric and somatic variables with new-onset chronic benzodiazepine use was studied with a Cox proportional hazards analysis. RESULTS: Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new-onset chronic use. In the subsample of participants who had filled at least one prescription in the follow-up period, of these variables only pain related joint complaints increased the risk of new-onset chronic use. Living alone protected against chronic benzodiazepine use. CONCLUSIONS: The elderly with poor mental and physical health are at an increased risk of chronic benzodiazepine use. Living alone was found to decrease the risk of chronic use, which suggests that social factors may determine drug usage patterns. Very few characteristics predicted chronic benzodiazepine use once patients had received their first prescription. For clinicians, identification of patients at high risk is therefore not straightforward. http://repub.eur.nl/res/pub/5936/ 2003-03-01T00:00:00Z The C282Y and H63D mutations in the HFE gene are important causes of hemochromatosis. In the elderly, these mutations might be associated with increased morbidity because of the lifelong accumulation of iron. In a population-based sample of the elderly, we determined the value of genotyping for HFE mutations to screen for subclinical hemochromatosis. HFE genotype frequencies were determined in a random group of 2095 subjects (55 years and over). In this random group, we selected within the six genotype groups a total of 342 individuals and measured their serum transferrin saturation, iron and ferritin levels. We also estimated the heritability and parameters needed to evaluate screening, including the sensitivity, specificity, positive and negative predictive values (PPV, NPV) of HFE genotypes. Iron parameters were significantly increased in subjects homozygous, heterozygous or compound heterozygous. The effect of the mutations was more pronounced in men than in women. For the H63D mutation, an allele dose effect was observed. The HFE gene explained about 5% of the variability in serum iron indices. The PPV for hemochromatosis for the C282Y homozygous was 100% in men and 67% in women. The NPV of the wild-type allele was 97% for both men and women. The sensitivity of both mutations was 70% for men and 52% for women and the specificity was 62% for men and 64% for women. Our study shows that the HFE C282Y and H63D are determinants of iron parameters in the elderly and will be effective in detecting individuals at high risk of hemochromatosis. However, when screening based on these two mutations, some individuals with subclinical hemochromatosis will be missed.