This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. We previously reported that incident atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. We now aimed to identify predictors of SCD in persons with AF from the Atherosclerosis Risk in Communities (ARIC) study, a community-based cohort study. We included all participants who attended visit 1 (1987–89) and had no prior AF (n = 14,836). Incident AF was identified from study electrocardiograms and hospitalization discharge codes through 2012. SCD was physician-adjudicated. We used cause-specific Cox proportional hazards models, followed by stepwise selection (backwards elimination, removing all variables with p > 0.10) to identify predictors of SCD in participants with AF. AF occurred in 2321 (15.6%) participants (age 45–64 years, 58% male, 18% black). Over a median of 3.3 years, SCD occurred in 110 of those with AF (4.7%). Predictors of SCD in AF included higher age, body mass index (BMI), coronary heart disease, hypertension, diabetes, current smoker, left ventricular hypertrophy, increased heart rate, and decreased albumin. Predictors associated only with SCD and not other cardiovascular (CV) death included increased BMI (HR per 5-unit increase, 1.15, 95% CI, 0.97–1.36, p = 0.10), increased heart rate (HR per SD increase, 1.18, 95% CI 0.99–1.41, p = 0.07), and low albumin (HR per SD decrease 1.23, 95% CI 1.02–1.48, p = 0.03). In the ARIC study, predictors of SCD in AF that are not associated with non-sudden CV death included increased BMI, increased heart rate, and low albumin. Further research to confirm these findings in larger community-based cohorts and to elucidate the underlying mechanisms to facilitate prevention is warranted.

BACKGROUND/OBJECTIVE: The 2020 Strategic Impact Goal introduced by the American Heart Association (AHA) aims at improving cardiovascular health (CVH) of all Americans by 20%. AHA defined ideal CVH across seven established modifiable risk factors for cardiovascular diseases. Prior studies have indicated that ideal CVH also benefits brain health and cognitive aging, but it is possible that this association is explained by familial factors. METHODS: We examined 272 male monozygotic and dizygotic twin pairs (total 544 subjects) free of overt cardiovascular disease and dementia from the Vietnam Era Twin Registry. Memory and learning were measured by Trail Making tests and Wechsler Memory Scale (Immediate and Delayed Memory tests and Visual Reproductive Test). Each of the seven CVH components (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and blood glucose) was scored per established criterion. RESULTS: The mean age of the twins was 55 years, 96% were whites, and 61% monozygotic. When considering twins as individuals, for every unit increase in CVH score (indicating better cardiovascular health), twins demonstrated faster cognitive processing speed (Trail B: - 5.6 s, 95% CI - 10.3, - 0.9; p = 0.03) and better story recall, both immediate (0.35, 95% CI 0.06, 0.62; p = 0.02) and delayed (0.39, 95% CI 0.08, 0.70; p = 0.01). CONCLUSIONS: Better CVH is associated with better cognitive health in several domains. As suggested by within-pair analysis, this association is largely explained by familial factors, implying that early life exposures are shared determinants of both brain health and cardiovascular health.

Background: Ceruloplasmin (CP) may promote structural changes in the atrium making it more arrhythmogenic. We assessed the associations between CP, CP-associated genetic variants, and incident atrial fibrillation (AF) in the Atherosclerosis Risk in Communities (ARIC) study. Methods and results We studied 10,059 men and women without prevalent AF aged 53 to 75 years in 1996–1998 and followed through 2012. Circulating CP was measured in stored blood samples obtained in 1996–1998. Polymorphisms rs11708215 and rs13072552, previously associated with CP concentrations, were measured in 10,059 and 8829 participants respectively. AF was ascertained from study electrocardiograms, hospital discharge codes, and death certificates. Multivariable Cox models were run to study the association between circulating CP, CP-associated polymorphisms, and the incidence of AF. Over 10.5 years of mean follow-up, 1357 cases of AF were identified. After adjusting for traditional risk factors and biomarkers, higher levels of circulating CP were associated with incident AF (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.11, 1.61 comparing top to bottom quartiles). Both rs11708215 and rs13072552 were significantly associated with CP levels. Presence of the CP-increasing alleles in rs11708215 and rs13072552, however, were significantly associated with lower risk of AF in whites (HR 0.84, 95%CI 0.76, 0.94, p = 0.002 and HR 0.83; 95%CI 0.69, 0.99, p = 0.043 respectively per CP-increasing allele in the final adjusted model) but not in African Americans. Conclusions Even though higher CP concentrations were associated with increased AF risk, genetic variants associated with higher CP decreased the risk of AF in whites. Our results suggest that circulating CP levels may not be causally related to risk of incident AF.

Low magnesium may increase the risk of atrial fibrillation. We conducted a double-blind pilot randomized trial to assess adherence to oral magnesium supplementation (400 mg of magnesium oxide daily) and a matching placebo, estimate the effect on circulating magnesium concentrations, and evaluate the feasibility of using an ambulatory heart rhythm monitoring device (ZioPatch) for assessing premature atrial contractions. A total of 59 participants were randomized; 73% were women, and the mean age was 62 years. A total of 98% of the participants completed the follow-up. In the magnesium supplement group, 75% of pills were taken, and in the placebo group, 83% were taken. The change in magnesium concentrations was significantly greater for those given the magnesium supplements than for those given the placebo (0.07; 95% confidence interval: 0.03, 0.12 mEq/L; p = 0.002). The ZioPatch wear time was approximately 13 of the requested 14 days at baseline and follow-up. There was no difference by intervention assignment in the change in log premature atrial contractions burden, glucose, or blood pressure. Gastrointestinal changes were more common among the participants assigned magnesium (50%) than among those assigned the placebo (7%), but only one person discontinued participation. In sum, compliance with the oral magnesium supplementation was very good, and acceptance of the ZioPatch monitoring was excellent. These findings support the feasibility of a larger trial for atrial fibrillation (AF) prevention with oral magnesium supplementation.

Atrial fibrillation (AF) may increase risk of venous thromboembolism (VTE), and vice versa. Bidirectionality was assessed prospectively via data from 15 129 black and white individuals. AF was associated with greater risk of developing VTE, and VTE with greater risk of AF. Associations were strongest among blacks and in the first 6 months after initial diagnosis. Summary: Background Atrial fibrillation (AF) and venous thromboembolism (VTE) frequently co-occur. These conditions have shared risk factors and are accompanied by coagulation abnormalities. Furthermore, mechanistic pathways may directly link the disorders. Objectives To test the hypothesis that individuals with incident AF are at greater risk of developing VTE, and those with VTE are at elevated risk of AF. We also tested whether associations were stronger in the first 6 months after the initial diagnosis, and explored race differences. Patients/Methods A total of 15 129 ARIC study participants (45–64 years, 55% female, 26% Black) were followed from 1987 to 2011 for incident AF and VTE (median follow-up 19.8 years). Multivariable-adjusted Cox regression was used, with AF and VTE modeled as time-dependent exposures. Results Incident AF was associated with greater risk of subsequent incident VTE (hazard ratio [95% CI], 1.71 [1.32–2.22]); the association was stronger in Black people (2.30 [1.48–3.58]) and during the first 6 months after AF diagnosis (5.08 [3.08–8.38]). Similarly, incident VTE was associated with increased risk of incident AF (1.73 [1.34–2.24]), especially in Black people (2.40 [1.55–3.74]) and in the first 6 months after VTE diagnosis (4.50 [2.61–7.77]). Conclusions The occurrence of AF was associated with increased risk of incident VTE, and occurrence of VTE was associated with greater risk of incident AF. Associations were particularly strong among Black people and during the first 6 months after the initial diagnosis, although they remained elevated even after 6 months. These findings highlight patient populations that may be at increased risk of AF and VTE, and perhaps should be targeted with preventive strategies.

Background-—Current literature examining the prospective relationship between depression and other measures of negative affect with atrial fibrillation (AF) are limited. We determined the relationships of depression, anger, anxiety, and chronic stress with incident AF in a multiethnic cohort of middle-and older-aged adults. Methods and Results-—This analysis included 6644 MESA (Multi-Ethnic Study of Atherosclerosis) study participants who were free of AF at baseline. Depressive symptoms were assessed at baseline and defined as either a 20-item Center for Epidemiologic Studies Depression Scale score ≥16 or use of antidepressant medications. The Spielberger Trait Anger Scale, Spielberger Trait Anxiety Scale, and Chronic Burden Scale were also administered at baseline to assess anger, anxiety, and chronic stress, respectively. The primary outcome was incident AF, identified by follow-up study visit ECGs, hospital discharge diagnoses, or Medicare claims data. A total of 875 (13%) incident AF cases were detected over a median follow-up of nearly 13 years. A Center for Epidemiologic Studies Depression Scale score ≥16 (referent, Center for Epidemiologic Studies Depression Scale score <2) and antidepressant use were associated with a 34% and 36% higher risk of AF, respectively, in separate adjusted Cox proportional hazards analyses (hazard ratio, 1.34; 95% CI 1.04–1.74 for Center for Epidemiologic Studies Depression Scale ≥16; hazard ratio, 1.36; 95% CI, 1.04–1.77 for antidepressant use). No significant associations were observed for anger, anxiety, or chronic stress with development of AF. Conclusions-—Depressive symptoms are associated with an increased risk of incident AF. Further study into whether improving depressive symptoms reduces AF incidence is important.

Background—Oral anticoagulants (OACs) in patients with atrial fibrillation (AF), in addition to reducing stroke risk, could also prevent adverse cognitive outcomes. The purpose of this study was to compare the risk of dementia incidence across patients with AF initiating different OACs. Methods and Results—We identified patients with nonvalvular AF initiating OACs in 2 US healthcare claim databases, MarketScan (2007–2015) and Optum Clinformatics (2009–2015). Dementia, comorbidities, and use of medications were defined on the basis of inpatient and outpatient claims. We performed head-to-head comparisons of warfarin, dabigatran, rivaroxaban, and apixaban in propensity score–matched cohorts. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) of incident dementia for each propensity score–matched cohort and meta-analyzed database-specific results. We analyzed 307 099 patients with AF from the MarketScan database and 161 346 from the Optum database, of which 6572 and 4391, respectively, had a diagnosis of incident dementia. The mean follow-up of each cohort ranged between 0.7 and 2.2 years. Patients initiating direct OACs experienced lower rates of dementia than those initiating warfarin (dabigatran: HR, 0.85; 95% CI, 0.71–1.01; rivaroxaban: HR, 0.85; 95% CI, 0.76–0.94; apixaban: HR, 0.80; 95% CI, 0.65–0.97). There were no differences in rates of dementia comparing direct OAC user groups (dabigatran versus rivaroxaban: HR, 1.02; 95% CI, 0.79–1.32; dabigatran versus apixaban: HR, 0.92; 95% CI, 0.63– 1.36; apixaban versus rivaroxaban: HR, 1.01; 95% CI, 0.86–1.19). Conclusions—Patients with AF initiating direct OACs experienced lower rates of incident dementia than warfarin users. No obvious benefit was observed for any particular direct OAC in relation to dementia rates.

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

Background Polypharmacy is highly prevalent in elderly people with chronic conditions, including atrial fibrillation (AF). The impact of polypharmacy on adverse outcomes and on treatment effectiveness in elderly patients with AF remains unaddressed. Methods and Results We studied 338 810 AF patients ≥75 years of age enrolled in the MarketScan Medicare Supplemental database in 2007–2015. Polypharmacy was defined as ≥5 active prescriptions at AF diagnosis (defined by the presence of International Classification of Diseases, Ninth Revision, Clinical Modification [ICD‐9‐CM] codes) based on outpatient pharmacy claims. AF treatments (oral anticoagulation, rhythm and rate control) and cardiovascular end points (ischemic stroke, bleeding, heart failure) were defined based on inpatient, outpatient, and pharmacy claims. Multivariable Cox models were used to estimate associations of polypharmacy with cardiovascular end points and the interaction between polypharmacy and AF treatments in relation to cardiovascular end points. Prevalence of polypharmacy was 52%. Patients with polypharmacy had increased risk of major bleeding (hazard ratio [HR], 1.16; 95% CI, 1.12–1.20) and heart failure (HR, 1.33; 95% CI, 1.29–1.36) but not ischemic stroke (HR, 0.96; 95% CI, 0.92–1.00), compared with those not receiving polypharmacy. Polypharmacy status did not consistently modify the effectiveness of oral anticoagulants. Rhythm control (versus rate control) was more effective in preventing heart failure hospitalization in patients not receiving polypharmacy (HR, 0.87; 95% CI, 0.76–0.99) than among those with polypharmacy (HR, 0.98; 95% CI, 0.91–1.07; P=0.02 for interaction). Conclusion Polypharmacy is common among patients ≥75 with AF, is associated with adverse outcomes, and may modify the effectiveness of AF treatments. Optimizing management of polypharmacy in AF patients ≥75 may lead to improved outcomes.