Atrial fibrillation (AF) has been suggested as a risk factor for dementia since it may lead to chronic cerebral hypoperfusion and stroke. However, longitudinal studies assessing the association ...between AF and dementia have shown inconsistent results.
To determine the effect of AF on the risk of developing dementia during 20 years of follow-up.
The association of prevalent and incident AF with incident dementia was assessed from July 6, 1989, to February 4, 2010, in 6514 dementia-free participants in the prospective population-based Rotterdam Study. Data analysis was conducted from September 18, 2014, to April 17, 2015. Cox proportional hazards regression models adjusting for age, sex, and cardiovascular risk factors; censored for stroke; and stratified by median age were used. In addition, we investigated whether the association between incident AF and dementia varied according to the duration of exposure, categorized in 6-year time bands.
Prevalent and incident AF.
Incident dementia, determined according to the Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria.
At baseline, 318 of 6514 participants (4.9%) had prevalent AF, and during 81 483 person-years of follow-up, 994 participants (15.3%) developed incident dementia. With findings presented as adjusted hazard ratio (95% CI), prevalent AF was related to an increased risk of dementia (1.33; 1.02-1.73). Among 6196 participants without prevalent AF during 79 003 person-years of follow-up, 723 participants (11.7%) developed incident AF and 932 individuals (15.0%) developed incident dementia. Incident AF was associated with an increased risk of dementia in younger participants (<67 years: 1.81; 1.11-2.94 vs ≥67 years: 1.12; 0.85-1.46; P = .02 for interaction). The risk of dementia was strongly associated with duration of exposure to AF in the younger participants (in the highest stratum: 3.30; 1.16-9.38; P = .003 for trend) but not in the elder participants (0.25; 0.04-1.86; P = .94 for trend).
Atrial fibrillation is associated with an increased risk of dementia, independent of clinical stroke. This association was strongest for younger participants with the longest duration of AF. Future studies should investigate whether optimal treatment of AF can prevent or postpone dementia.
Atherosclerotic cardiovascular disease (ASCVD) is driven by multifaceted contributions of the immune system. However, the dysregulation of immune cells that leads to ASCVD is poorly understood. We ...determined the association of components of innate and adaptive immunity longitudinally with ASCVD, and assessed whether arterial calcifications play a role in this association.
Granulocyte (innate immunity) and lymphocyte (adaptive immunity) counts were determined 3 times (2002-2008, mean age 65.2 years; 2009-2013, mean age 69.0 years; and 2014-2015, mean age 78.5 years) in participants of the population-based Rotterdam Study without ASCVD at baseline. Participants were followed-up for ASCVD or death until 1 January 2015. A random sample of 2,366 underwent computed tomography at baseline to quantify arterial calcification volume in 4 vessel beds. We studied the association between immunity components with risk of ASCVD and assessed whether immunity components were related to arterial calcifications at baseline. Of 7,730 participants (59.4% women), 801 developed ASCVD during a median follow-up of 8.1 years. Having an increased granulocyte count increased ASCVD risk (adjusted hazard ratio for doubled granulocyte count 95% CI = 1.78 1.34-2.37, P < 0.001). Higher granulocyte counts were related to larger calcification volumes in all vessels, most prominently in the coronary arteries (mean difference in calcium volume mm3 per SD increase in granulocyte count 95% CI = 32.3 9.9-54.7, P < 0.001). Respectively, the association between granulocyte count and incident coronary heart disease and stroke was partly mediated by coronary artery calcification (overall proportion mediated 95% CI = 19.0% -10% to 32.3%, P = 0.08) and intracranial artery calcification (14.9% -10.9% to 19.1%, P = 0.05). A limitation of our study is that studying the etiology of ASCVD remains difficult within an epidemiological setting due to the limited availability of surrogates for innate and especially adaptive immunity.
In this study, we found that an increased granulocyte count was associated with a higher risk of ASCVD in the general population. Moreover, higher levels of granulocytes were associated with larger volumes of arterial calcification. Arterial calcifications may explain a proportion of the link between granulocytes and ASCVD.
Selective serotonin reuptake inhibitors (SSRIs) are considered safe and are frequently used during pregnancy. However, two case-control studies suggested an association between prenatal SSRI exposure ...with childhood autism.
To prospectively determine whether intra-uterine SSSRI exposure is associated with childhood autistic symptoms in a population-based study.
A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included. Child pervasive developmental and affective problems were assessed by parental report with the Child Behavior Checklist at ages 1.5, 3 and 6. At age 6, we assessed autistic traits using the Social Responsiveness Scale (n = 4264).
Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07-1.93) and affective problems (OR = 1.44, 95% CI 1.15-1.81). Compared with unexposed children, those prenatally exposed to SSRIs also were at higher risk for developing pervasive developmental problems (OR = 1.91, 95% CI 1.13-3.47), but not for affective problems. Children prenatally exposed to SSRIs also had more autistic traits (B = 0.15, 95% CI 0.08-0.22) compared with those exposed to depressive symptoms only.
Our results suggest an association between prenatal SSRI exposure and autistic traits in children. Prenatal depressive symptoms without SSRI use were also associated with autistic traits, albeit this was weaker and less specific. Long-term drug safety trials are needed before evidence-based recommendations are possible.
Data are scarce for the lifetime risk of developing impaired glucose metabolism, including prediabetes, as are data for the risk of eventual progression from prediabetes to diabetes and for ...initiation of insulin treatment in previously untreated patients with diabetes. We aimed to calculate the lifetime risk of the full range of glucose impairments, from normoglycaemia to prediabetes, type 2 diabetes, and eventual insulin use.
In this prospective population-based cohort analysis, we used data from the population-based Rotterdam Study. We identified diagnostic events by use of general practitioners' records, hospital discharge letters, pharmacy dispensing data, and serum fasting glucose measurements taken at the study centre (Rotterdam, Netherlands) visits. Normoglycaemia, prediabetes, and diabetes were defined on the basis of WHO criteria for fasting glucose (normoglycaemia: ≤6·0 mmol/L; prediabetes: >6·0 mmol/L and <7·0 mmol/L; and diabetes ≥7·0 mmol/L or use of glucose-lowering drug). We calculated lifetime risk using a modified version of survival analysis adjusted for the competing risk of death. We also estimated the lifetime risk of progression from prediabetes to overt diabetes and from diabetes free of insulin treatment to insulin use. Additionally, we calculated years lived with healthy glucose metabolism.
We used data from 10 050 participants from the Rotterdam Study. During a follow-up of up to 14·7 years (between April 1, 1997, and Jan 1, 2012), 1148 participants developed prediabetes, 828 developed diabetes, and 237 started insulin treatment. At age 45 years, the remaining lifetime risk was 48·7% (95% CI 46·2-51·3) for prediabetes, 31·3% (29·3-33·3) for diabetes, and 9·1% (7·8-10·3) for insulin use. In individuals aged 45 years, the lifetime risk to progress from prediabetes to diabetes was 74·0% (95% CI 67·6-80·5), and 49·1% (38·2-60·0) of the individuals with overt diabetes at this age started insulin treatment. The lifetime risks attenuated with advancing age, but increased with increasing BMI and waist circumference. On average, individuals with severe obesity lived 10 fewer years without glucose impairment compared with normal-weight individuals.
Impaired glucose metabolism is a substantial burden on population health, and our findings emphasise the need for more effective prevention strategies, which should be implemented as soon in a person's life as possible. The substantial lifetime risk of prediabetes and diabetes in lean individuals also supports risk factor control in non-obese individuals.
Erasmus MC and Erasmus University Rotterdam; Netherlands Organisation for Scientific Research; Netherlands Organisation for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Netherlands Ministry of Education, Culture and Science; Netherlands Ministry of Health, Welfare and Sports; European Commission; and Municipality of Rotterdam.
Context:
In vitro and in vivo experiments have assigned both oncosuppressive and oncogenic properties to thyroid hormones. Population-based studies have found inconclusive results.
Objective:
We ...aimed to prospectively assess the relation between thyroid function and incident cancer in a population-based setting.
Design, Setting, and Participants:
The current study is a prospective population-based cohort study including 10 318 participants for whom baseline measurements of free T4 (FT4) and/or TSH were available.
Main Outcome Measures:
Cox proportional hazards models were used to assess hazard ratios (HRs) of any solid non-skin cancer, as well as lung, breast, prostate, and gastrointestinal cancer specifically.
Results:
Higher FT4 levels were associated with a higher risk of any solid cancer (HR, 1.42; 95% confidence interval CI, 1.12–1.79), lung cancer (HR, 2.33; 95% CI, 1.39–3.92) and breast (HR, 1.77; 95% CI, 1.10–2.84) cancer. The risk estimates were similar after exclusion of thyroid-altering medication, but the association lost significance for breast cancer. Compared with the lowest FT4 tertile, the highest tertile was associated with a 1.13-fold increased risk of any solid, 1.79-fold increased risk of lung, and 1.14-fold increased risk of breast cancer (P for trend <.05 for all). For TSH levels we found no associations with cancer risk. There was no differential effect of sex or age on the association between thyroid function and cancer risk.
Conclusions:
Higher FT4 levels are significantly associated with an increased risk of any solid, lung, and breast cancer. Further research should elucidate the underlying pathophysiological mechanisms.
In this prospective population-based cohort study, higher serum FT4 levels were associated with an increased risk of any solid cancer, lung cancer and breast cancer.
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.
Reduction of gastric acid secretion by acid-suppressive therapy allows pathogen colonization from the upper gastrointestinal tract. The bacteria and viruses in the contaminated stomach have been ...identified as species from the oral cavity.
To examine the association between the use of acid-suppressive drugs and occurrence of community-acquired pneumonia.
Incident acid-suppressive drug users with at least 1 year of valid database history were identified from the Integrated Primary Care Information database between January 1, 1995, and December 31, 2002. Incidence rates for pneumonia were calculated for unexposed and exposed individuals. To reduce confounding by indication, a case-control analysis was conducted nested in a cohort of incident users of acid-suppressive drugs. Cases were all individuals with incident pneumonia during or after stopping use of acid-suppressive drugs. Up to 10 controls were matched to each case for practice, year of birth, sex, and index date. Conditional logistic regression was used to compare the risk of community-acquired pneumonia between use of proton pump inhibitors (PPIs) and H2-receptor antagonists.
Community-acquired pneumonia defined as certain (proven by radiography or sputum culture) or probable (clinical symptoms consistent with pneumonia).
The study population comprised 364,683 individuals who developed 5551 first occurrences of pneumonia during follow-up. The incidence rates of pneumonia in non-acid-suppressive drug users and acid-suppressive drug users were 0.6 and 2.45 per 100 person-years, respectively. The adjusted relative risk for pneumonia among persons currently using PPIs compared with those who stopped using PPIs was 1.89 (95% confidence interval, 1.36-2.62). Current users of H2-receptor antagonists had a 1.63-fold increased risk of pneumonia (95% confidence interval, 1.07-2.48) compared with those who stopped use. For current PPI users, a significant positive dose-response relationship was observed. For H2-receptor antagonist users, the variation in dose was restricted.
Current use of gastric acid-suppressive therapy was associated with an increased risk of community-acquired pneumonia.
The association between thyroid function and cardiovascular disease is well established, but no study to date has assessed whether it is a risk factor for sudden cardiac death (SCD). Therefore, we ...studied the association of thyroid function with SCD in a prospective population-based cohort.
Participants from the Rotterdam Study ≥45 years with thyroid-stimulating hormone or free thyroxine (FT4) measurements and clinical follow-up were eligible. We assessed the association of thyroid-stimulating hormone and FT4 with the risk of SCD by using an age- and sex-adjusted Cox proportional-hazards model, in all participants and also after restricting the analysis to euthyroid participants (defined by thyroid-stimulating hormone 0.4-4.0 mIU/L). Additional adjustment included cardiovascular risk factors, notably hypertension, serum cholesterol, and smoking. We stratified by age and sex and performed sensitivity analyses by excluding participants with abnormal FT4 values (reference range of 0.85-1.95 ng/dL) and including only witnessed SCDs as outcome. Absolute risks were calculated in a competing risk model by taking death by other causes into account.
We included 10 318 participants with 261 incident SCDs (median follow-up, 9.1 years). Higher levels of FT4 were associated with an increased SCD risk, even in the normal range of thyroid function (hazard ratio, 2.28 per 1 ng/dL FT4; 95% confidence interval, 1.31-3.97). Stratification by age or sex and sensitivity analyses did not change the risk estimates substantially. The absolute 10-year risk of SCD increased in euthyroid participants from 1% to 4% with increasing FT4 levels.
Higher FT4 levels are associated with an increased risk of SCD, even in euthyroid participants.
Common variation within the nitric oxide-1 synthase activator protein (NOS1AP) locus is strongly related to QT interval, a sudden cardiac death (SCD) risk factor. A recent report describes common ...variation in NOS1AP associated with SCD in a US population of European ancestry. The objective of the current study was to obtain additional evidence by investigating the association between NOS1AP variants and SCD in the prospective population-based Rotterdam Study. The study population consisted of 5974 European ancestry subjects, aged 55 years and older, genotyped on Illumina arrays. SCD was defined according to European Society of Cardiology guidelines. Smoking, body mass index, diabetes mellitus, hypertension, heart failure and myocardial infarction were used as covariates in Cox proportional hazard models. Results were combined with reported evidence using inverse-variance weighted meta-analysis. Two hundred and eight (109 witnessed) cases of SCD occurred during a mean follow-up of 10.4 years. Within the Rotterdam Study alone, no significant associations were observed. Upon pooling of results with existing data, we observed strengthening of existing evidence for rs16847549 (US data HR = 1.31, P = 0.0024; Rotterdam Study HR = 1.18, P = 0.16; joint HR = 1.26, P = 0.0011). When the case definition in the Rotterdam Study was restricted to witnessed SCD, association of rs16847549 with SCD became stronger (joint P = 0.00019) and additionally the association between rs12567209 and SCD gained significance (US data HR = 0.57, P = 0.0035; Rotterdam Study HR = 0.69, P = 0.23; joint HR = 0.60, P = 0.0018). In conclusion, this study provided additional evidence for association between genetic variation within NOS1AP and SCD. The mechanism by which this effect is exerted remains to be elucidated.
Background & Aims Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of ...idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. Results AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P = 4.8 × 10−14 ), which correlated with rs3135388, a tag SNP of HLA - DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant ( P = 1.1 × 10−4 ). An independent association was observed in the class I region (rs2523822, P = 1.8 × 10−10 ), related to HLA-A*0201 . The most significant class I and II SNPs showed statistical interaction ( P = .0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 ( P = 2 × 10−6 ) and HLA-DQB1*0602 ( P = 5 × 10−10 ) and their interaction ( P = .005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated ( P = 1.3 × 10−4 ). Conclusions Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.
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