Lifetime risk of common neurological diseases in the elderly population.

OBJECTIVE: To quantify the burden of common neurological disease in older adults in terms of lifetime risks, including their co-occurrence and preventive potential, within a competing risk framework. METHODS: Within the prospective population-based Rotterdam Study, we studied lifetime risk of dementia, stroke and parkinsonism between 1990 and 2016. Among 12 102 individuals (57.7% women) aged ≥45 years free from these diseases at baseline, we studied co-occurrence, and quantified the combined, and disease-specific remaining lifetime risk of these diseases at various ages for men and women separately. We also projected effects on lifetime risk of hypothetical preventive strategies that delay disease onset by 1, 2 and 3 years, respectively. RESULTS: During follow-up of up to 26 years (156 088 person-years of follow-up), 1489 individuals were diagnosed with dementia, 1285 with stroke and 263 with parkinsonism. Of these individuals, 438 (14.6%) were diagnosed with multiple diseases. Women were almost twice as likely as men to be diagnosed with both stroke and dementia during their lifetime. The lifetime risk for any of these diseases at age 45 was 48.2% (95% CI 47.1% to 51.5%) in women and 36.2% (35.1% to 39.3%) in men. This difference was driven by a higher risk of dementia as the first manifesting disease in women than in men (25.9% vs 13.7%; p<0.001), while this was similar for stroke (19.0%vs18.9% in men) and parkinsonism (3.3% vs 3.6% in men). Preventive strategies that delay disease onset with 1 to 3 years could theoretically reduce lifetime risk for developing any of these diseases by 20%-50%. CONCLUSION: One in two women and one in three men will develop dementia, stroke or parkinsonism during their life. These findings strengthen the call for prioritising the focus on preventive interventions at population level which could substantially reduce the burden of common neurological diseases in the ageing population.

Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization.

BACKGROUND: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. METHODS: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis. RESULTS: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32-0.54] kg/m2 per A-allele, P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90-1.20] kg/m2 per 1-U increase, P<0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02-1.11] per A-allele, P=0.004; BMI gene score, hazard ratio, 1.11 [1.05-1.18] per 1-U increase, P<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04-1.26) per kg/m2, P=0.005 (FTO) and 1.11 (1.05-1.17) per kg/m2, P<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04-1.06] per kg/m2, P<0.001). Multivariable adjustment did not significantly change findings. CONCLUSIONS: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.

Thyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF. METHODS: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF. RESULTS: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease. CONCLUSIONS: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.

Role of Prestroke Vascular Pathology in Long-Term Prognosis After Stroke: The Rotterdam Study.

BACKGROUND AND PURPOSE: Mortality after stroke remains high for years, mostly because of cardiovascular causes. Given that cardiovascular pathology plays an important role in causing the initial stroke, such prestroke pathology might also influence the prognosis after stroke. Within the population-based Rotterdam Study, we examined the proportion of deaths after stroke that are attributable to pre-existent cardiovascular risk factors before stroke (the population attributable risk). METHODS: We examined 1237 patients with first-ever stroke and 4928 stroke-free participants (between 1990 and 2012), matched on age, sex, examination round, and stroke date (index date). Cardiovascular risk factors measured on ≈4 years before index date were used as determinants. Participants were continuously followed up for mortality (≈6 years) after the index date. We calculated separate and combined population attributable risk of hypertension, total cholesterol, high-density lipoprotein-cholesterol, body mass index, diabetes mellitus, smoking, transient ischemic attack, and atrial fibrillation. RESULTS: Nine hundred and nineteen patients with stroke and 2654 stroke-free participants died. The combined population attributable risk in patients with stroke was 27% (95% confidence interval, 14%-45%) and in stroke-free participants was 19% (95% confidence interval, 12%-29%). Population attributable risks of diabetes mellitus, smoking, and atrial fibrillation were higher in patients with stroke than in the reference group because of a higher prevalence of risk factors. In addition, people with atrial fibrillation and stroke had a higher hazard ratio for death than those with only atrial fibrillation. CONCLUSIONS: One quarter of deaths after stroke could theoretically be prevented with rigorous cardiovascular prevention and treatment, but this should preferably start before stroke occurrence. In addition, research into factors explaining the remaining deaths needs to be encouraged.

Serum liver enzymes are associated with all-cause mortality in an elderly population.

BACKGROUND & AIMS: Little is known about the association of serum liver enzymes with long-term outcome in the elderly. We sought to clarify the association of serum gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with all-cause and cause-specific mortality in an elderly population. METHODS: This study was embedded in the Rotterdam Study, a large population-based cohort of persons aged 55 years or older. Cox-regression analyses were performed to examine the association of baseline serum GGT, ALP, and aminotransferase levels with mortality, adjusted for age, sex, education, smoking status, alcohol intake, hypertension, diabetes mellitus, body mass index and total cholesterol levels. Liver enzyme levels were categorized according to sample percentiles; levels <25th percentile were taken as a reference. RESULTS: During a follow-up of up to 19.5 years, 2997 of 5186(57.8%) participants died: 672 participants died of causes related to cardiovascular diseases (CVD) and 703 participants died of cancer. All serum liver enzymes were associated with all-cause mortality (all P < 0.001). Moreover, GGT was associated with increased CVD mortality (P < 0.001), and ALP and AST with increased cancer-related mortality (P = 0.03 and P = 0.005 respectively). Participants with GGT and ALP in the top 5% had the highest risk for all-cause mortality (HR1.55; 95%CI 1.30-1.85 and HR1.49; 95%CI 1.25-1.78 respectively). AST and ALT <25th percentile were also associated with a higher risk of all-cause mortality. CONCLUSIONS: All serum liver enzymes were positively associated with long-term mortality in this elderly population. Why participants with low ALT and AST levels have higher risk of mortality remains to be elucidated.

Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060.

AIMS: Since atrial fibrillation (AF) is associated with increased risks of cardiovascular and cerebrovascular complications, estimations on the number of individuals with AF are relevant to healthcare planning. We aimed to project the number of individuals with AF in the Netherlands and in the European Union from 2000 to 2060. METHODS AND RESULTS: Age- and sex-specific AF prevalence estimates were obtained from the prospective community-based Rotterdam Study. Population projections for the Netherlands and the European Union were obtained from the European Union's statistics office. In the age stratum of 55-59 years, the prevalence of AF was 1.3% in men (95% CI: 0.4-3.6%) and 1.7% in women (95% CI: 0.7-4.0%). The prevalence of AF increased to 24.2% in men (95% CI: 18.5-30.7%), and 16.1% in women (95% CI: 13.1-19.4%), for those >85 years of age. This age- and sex-specific prevalence remained stable during the years of follow-up. Furthermore, we estimate that in the European Union, 8.8 million adults over 55 years had AF in 2010 (95% CI: 6.5-12.3 million). We project that this number will double by 2060 to 17.9 million (95% CI: 13.6-23.7 million) if the age- and sex-specific prevalence remains stable. CONCLUSION: We estimate that from 2010 to 2060, the number of adults 55 years and over with AF in the European Union will more than double. As AF is associated with significant morbidities and mortality, this increasing number of individuals with AF may have major public health implications.

Personalized prediction of lifetime benefits with statin therapy for asymptomatic individuals: a modeling study.

BACKGROUND: Physicians need to inform asymptomatic individuals about personalized outcomes of statin therapy for primary prevention of cardiovascular disease (CVD). However, current prediction models focus on short-term outcomes and ignore the competing risk of death due to other causes. We aimed to predict the potential lifetime benefits with statin therapy, taking into account competing risks. METHODS AND FINDINGS: A microsimulation model based on 5-y follow-up data from the Rotterdam Study, a population-based cohort of individuals aged 55 y and older living in the Ommoord district of Rotterdam, the Netherlands, was used to estimate lifetime outcomes with and without statin therapy. The model was validated in-sample using 10-y follow-up data. We used baseline variables and model output to construct (1) a web-based calculator for gains in total and CVD-free life expectancy and (2) color charts for comparing these gains to the Systematic Coronary Risk Evaluation (SCORE) charts. In 2,428 participants (mean age 67.7 y, 35.5% men), statin therapy increased total life expectancy by 0.3 y (SD 0.2) and CVD-free life expectancy by 0.7 y (SD 0.4). Age, sex, smoking, blood pressure, hypertension, lipids, diabetes, glucose, body mass index, waist-to-hip ratio, and creatinine were included in the calculator. Gains in total and CVD-free life expectancy increased with blood pressure, unfavorable lipid levels, and body mass index after multivariable adjustment. Gains decreased considerably with advancing age, while SCORE 10-y CVD mortality risk increased with age. Twenty-five percent of participants with a low SCORE risk achieved equal or larger gains in CVD-free life expectancy than the median gain in participants with a high SCORE risk. CONCLUSIONS: We developed tools to predict personalized increases in total and CVD-free life expectancy with statin therapy. The predicted gains we found are small. If the underlying model is validated in an independent cohort, the tools may be useful in discussing with patients their individual outcomes with statin therapy.

Methods of data collection and definitions of cardiac outcomes in the Rotterdam Study.

The prevalence of cardiovascular diseases is rising. Therefore, adequate risk prediction and identification of its determinants is increasingly important. The Rotterdam Study is a prospective population-based cohort study ongoing since 1990 in the city of Rotterdam, The Netherlands. One of the main targets of the Rotterdam Study is to identify the determinants and prognosis of cardiovascular diseases. Case finding in epidemiological studies is strongly depending on various sources of follow-up and clear outcome definitions. The sources used for collection of data in the Rotterdam Study are diverse and the definitions of outcomes in the Rotterdam Study have changed due to the introduction of novel diagnostics and therapeutic interventions. This article gives the methods for data collection and the up-to-date definitions of the cardiac outcomes based on international guidelines, including the recently adopted cardiovascular disease mortality definitions. In all, detailed description of cardiac outcome definitions enhances the possibility to make comparisons with other studies in the field of cardiovascular research and may increase the strength of collaborations.

Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation.

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 RESULTS: The 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 x 10(-5)] to 2.52 in AFNet (95% CI 2.22-2.8; P = 1.8 x 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 x 10(-13)) for rs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464. CONCLUSION: The 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.

Chronic obstructive pulmonary disease and the development of atrial fibrillation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been associated with atrial fibrillation (AF). More insight into the epidemiology and underlying mechanisms is required to optimize management. METHODS: The Rotterdam Study is a large, population-based cohort study with long-term follow-up. Time dependent Cox proportional hazard models were constructed to study the effect of COPD on incident AF, adjusted for age, sex and pack years of cigarette smoking, and additionally stratified according to exacerbation frequency, left atrial size and baseline systemic inflammatory levels. RESULTS: 1369 of 10,943 subjects had COPD, of whom 804 developed AF. The AF incidence rate was 14 per 1000 person years in COPD and 8 per 1000 person years in subjects without COPD. The adjusted hazard ratio (HR) for COPD subjects to develop AF as compared to subjects without COPD was 1.28 (95%CI [1.04, 1.57]). COPD subjects with frequent exacerbations had a twofold increased AF risk (HR 1.99 [1.42, 2.79]) and COPD subjects with a left atrial size ≥40 mm also had an elevated AF risk (HR 1.77 [1.07, 2.94]). COPD subjects with baseline systemic inflammatory levels above the median had significantly increased AF risks (hsCRP≥1.83 mg/L: HR 1.51 [1.13, 2.03] and IL6 ≥ 1.91 ng/L: HR 2.49 [1.18, 5.28]), whereas COPD subjects below the median had in both analyses no significantly increased AF risk. CONCLUSIONS: COPD subjects had a 28% increased AF risk, which further increased with frequent exacerbations and an enlarged left atrium. The risk was driven by COPD subjects having elevated systemic inflammatory levels.

Development and Validation of a Dementia Risk Prediction Model in the General Population: An Analysis of Three Longitudinal Studies.

OBJECTIVE: Identification of individuals at high risk of dementia is essential for development of prevention strategies, but reliable tools are lacking for risk stratification in the population. The authors developed and validated a prediction model to calculate the 10-year absolute risk of developing dementia in an aging population. METHODS: In a large, prospective population-based cohort, data were collected on demographic, clinical, neuropsychological, genetic, and neuroimaging parameters from 2,710 nondemented individuals age 60 or older, examined between 1995 and 2011. A basic and an extended model were derived to predict 10-year risk of dementia while taking into account competing risks from death due to other causes. Model performance was assessed using optimism-corrected C-statistics and calibration plots, and the models were externally validated in the Dutch population-based Epidemiological Prevention Study of Zoetermeer and in the Alzheimer's Disease Neuroimaging Initiative cohort 1 (ADNI-1). RESULTS: During a follow-up of 20,324 person-years, 181 participants developed dementia. A basic dementia risk model using age, history of stroke, subjective memory decline, and need for assistance with finances or medication yielded a C-statistic of 0.78 (95% CI=0.75, 0.81). Subsequently, an extended model incorporating the basic model and additional cognitive, genetic, and imaging predictors yielded a C-statistic of 0.86 (95% CI=0.83, 0.88). The models performed well in external validation cohorts from Europe and the United States. CONCLUSIONS: In community-dwelling individuals, 10-year dementia risk can be accurately predicted by combining information on readily available predictors in the primary care setting. Dementia prediction can be further improved by using data on cognitive performance, genotyping, and brain imaging. These models can be used to identify individuals at high risk of dementia in the population and are able to inform trial design.

Cigarette smoking and risk of atrial fibrillation: the Rotterdam Study.

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 > or =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.

Determinants of chronic benzodiazepine use in the elderly: a longitudinal study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * The risk of adverse events due to chronic benzodiazepine use is high in the elderly. * Cross-sectional studies have shown that increasing age, female gender and poor physical and mental health are associated with benzodiazepine use. * When users were re-examined some years later, chronic somatic disease, pain and stress seemed to contribute to the continuation of benzodiazepine use. WHAT THIS STUDY ADDS: * This is the first longitudinal study that analyzed the determinants of new-onset chronic benzodiazepine use in community-dwelling elderly. * Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new-onset chronic use. Living alone was found to decrease the risk of chronic use. 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 >or=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.

Subclinical atherosclerosis and risk of atrial fibrillation: the rotterdam study.

BACKGROUND: Myocardial infarction is an important risk factor for atrial fibrillation, but the role of subclinical atherosclerosis is unknown. This longitudinal study evaluates whether atherosclerosis affects the risk of atrial fibrillation in persons without overt coronary disease. METHODS: This investigation was part of the Rotterdam Study, a population-based cohort study among persons 55 years or older. Participants with atrial fibrillation at baseline, with a history of myocardial infarction, or with angina pectoris and those who had undergone cardiac operative procedures were excluded, leaving 4407 subjects for the analyses. Baseline intima-media thickness of the common carotid artery and the presence of carotid plaques were used as indices of generalized atherosclerosis. During a median follow-up of 7.5 years, 269 cases of incident atrial fibrillation were identified. Relative risks were calculated with 95% confidence intervals, adjusted for age and sex, using the Cox proportional hazards model. Additional adjustments were made for body mass index, hypertension, systolic blood pressure, serum cholesterol level, smoking, diabetes mellitus, left ventricular hypertrophy on the electrocardiogram, and the use of cardiac medication. RESULTS: The risk of atrial fibrillation was associated with carotid intima-media thickness (relative risk, 1.90; 95% confidence interval, 1.20-3.00, highest vs lowest quartile) and severity of carotid plaques (relative risk, 1.49; 95% confidence interval, 1.06-2.10, severe vs absence). Risk estimates were stronger in women than in men. CONCLUSIONS: Atherosclerosis in participants without manifest atherosclerotic disease is an independent risk factor for atrial fibrillation. These results suggest that aggressive treatment of asymptomatic atherosclerosis may help to prevent atrial fibrillation.

Corticosteroids and the risk of atrial fibrillation.

BACKGROUND: High-dose (pulse) corticosteroid therapy has been associated with the development of atrial fibrillation. This association, however, is mainly based on case reports. METHODS: To test the hypothesis that high-dose corticosteroid exposure increases the risk of new-onset atrial fibrillation, we performed a nested case-control study within the Rotterdam Study, a population-based cohort study among 7983 older adults. Cases were defined as persons with incident atrial fibrillation between July 1, 1991, and January 1, 2000. Their date of diagnosis was defined as the index date. All noncases within the Rotterdam Study who were alive and eligible on this index date were used as controls. Subsequently, we compared the proportion of cases and controls that received a corticosteroid prescription within 1 month preceding the index date. Corticosteroid exposure was categorized into high-dose exposure (oral or parenteral steroid at a daily dose > or =7.5 mg of prednisone equivalents) and low-intermediate-dose exposure (<7.5 mg of prednisone equivalents or inhaled corticosteroids). RESULTS: There were 385 eligible cases of new-onset atrial fibrillation during the study period. The risk of new-onset atrial fibrillation was significantly higher for persons who received a corticosteroid prescription within 1 month before the index date than for those without (odds ratio [OR], 3.75; 95% confidence interval [CI], 2.38-5.87). However, only high-dose corticosteroid use was associated with an increased risk (OR, 6.07; 95% CI, 3.90-9.42), whereas low-intermediate-dose use was not (OR, 1.42; 95% CI, 0.72-2.82). The association of atrial fibrillation with high-dose corticosteroid use was largely independent of the indication for corticosteroid therapy, since the risk of new-onset atrial fibrillation was not only increased in patients with asthma or chronic obstructive pulmonary disease (OR, 4.02; 95% CI, 2.07-7.81) but also in patients with rheumatic, allergic, or malignant hematologic diseases (OR, 7.90; 95% CI, 4.47-13.98). CONCLUSION: Our findings strongly suggest that patients receiving high-dose corticosteroid therapy are at increased risk of developing atrial fibrillation.

Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

Intake of very long-chain n-3 fatty acids from fish and incidence of atrial fibrillation. The Rotterdam Study.

BACKGROUND: Atrial fibrillation is the most common sustained cardiac arrhythmia. It is a major cause of morbidity and mortality through an increased risk of thromboembolic stroke. Experimental as well as observational evidence suggests that n-3 polyunsaturated fatty acids may have antiarrhythmic effects. The objective of this study was to examine whether high intakes of fish and its very long-chain n-3 fatty acids eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) are associated with risk of incident atrial fibrillation. METHODS: We used data from the Rotterdam Study, a prospective cohort study. At baseline, dietary intake data were available for 5184 subjects free from atrial fibrillation. Dietary intake was assessed using a semiquantitative food-frequency questionnaire, and incidence of atrial fibrillation was continuously monitored during follow-up. Cox proportional hazards model (adjusted for lifestyle and disease factors) was used to examine the associations between intakes of EPA plus DHA and of fish with atrial fibrillation. RESULTS: After a mean follow-up of 6.4 (+/-1.6) years, 312 subjects developed atrial fibrillation. Intake of EPA and DHA in the third textile compared with first was not associated with risk of atrial fibrillation (relative risk 1.18, 95% CI 0.88-1.57). Furthermore, no association was observed with intake of >20 g/d fish compared with no fish intake (relative risk 1.17, 95% CI 0.87-1.57). CONCLUSIONS: In this study, intakes of EPA and DHA and the consumption of fish were not associated with the onset of atrial fibrillation. This finding does not support that n-3 fatty acids have a general antiarrhythmic effect.

Association of Lipid-Related Genetic Variants with the Incidence of Atrial Fibrillation: The AFGen Consortium.

BACKGROUND: Several studies have shown associations between blood lipid levels and the risk of atrial fibrillation (AF). To test the potential effect of blood lipids with AF risk, we assessed whether previously developed lipid gene scores, used as instrumental variables, are associated with the incidence of AF in 7 large cohorts. METHODS: We analyzed 64,901 individuals of European ancestry without previous AF at baseline and with lipid gene scores. Lipid-specific gene scores, based on loci significantly associated with lipid levels, were calculated. Additionally, non-pleiotropic gene scores for high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc) were calculated using SNPs that were only associated with the specific lipid fraction. Cox models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of AF per 1-standard deviation (SD) increase of each lipid gene score. RESULTS: During a mean follow-up of 12.0 years, 5434 (8.4%) incident AF cases were identified. After meta-analysis, the HDLc, LDLc, total cholesterol, and triglyceride gene scores were not associated with incidence of AF. Multivariable-adjusted HR (95% CI) were 1.01 (0.98-1.03); 0.98 (0.96-1.01); 0.98 (0.95-1.02); 0.99 (0.97-1.02), respectively. Similarly, non-pleiotropic HDLc and LDLc gene scores showed no association with incident AF: HR (95% CI) = 1.00 (0.97-1.03); 1.01 (0.99-1.04). CONCLUSIONS: In this large cohort study of individuals of European ancestry, gene scores for lipid fractions were not associated with incident AF.