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Background: Stroke risk stratification scores (eg, CHA 2 DS 2 -VASc) are used to tailor therapeutic recommendations for patients with atrial fibrillation (AF) in different risk groups., Objective: The purpose of this study was to develop a tool to estimate stroke risk in patients receiving oral anticoagulants (OACs) and to identify patients who remain at high risk for stroke despite anticoagulation therapy., Methods: Patients with nonvalvular AF initiating OACs were identified in the MarketScan data from 2007 to 2015. Using bootstrapping methods and backward selection of 44 candidate variables, we developed a model that selected variables predicting stroke. The final model was validated in patients with nonvalvular AF in the Optum database in the period 2009-2015. In both databases, the discrimination of existing stroke scores were individually evaluated and compared with our new model termed the AntiCoagulaTion-specific Stroke (ACTS) score., Results: Among 135,523 patients with AF initiating OACs in the MarketScan dataset, 2028 experienced an ischemic stroke after anticoagulant initiation. The stepwise model identified 11 variables (including type of OAC) associated with ischemic stroke. The discrimination (C statistic) of the model was adequate (0.68; 95% confidence interval [CI] 0.66-0.70), showing excellent calibration (χ 2 = 6.1; P = .73). ACTS was then applied to 84,549 AF patients in the Optum dataset (1408 stroke events) and showed similar discrimination (C statistic 0.67; 95% CI 65-0.69). However, previously developed predictive models had similar discriminative ability (CHA 2 DS 2 -VASc 0.67; 95% CI 0.65-0.68)., Conclusion: A novel model to identify AF patients at higher risk of ischemic stroke, using extensive administrative health care data including type of anticoagulant, did not perform better than established simpler models., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

We examined whether the sex differences in atrial fibrillation (AF) is related to difference in risk factors leading to AF or due to a differential impact of the same risk factors in 11,806 participants (55.2 % women) from the REGARDS study. Incident AF was ascertained by electrocardiograms and medical history at a follow-up examination. Backwards elimination logistic regression was used to identify AF risk factors in men and women, separately. Over a median follow-up of 9.0years, 588 (11.1%) men and 428 (6.6%) women (p value <0.001) developed AF. Men had a higher risk of AF than women (age and race adjusted odds ratio [OR] [95% confidence interval (CI)]: 1.61 [1.26, 1.75]). Age, white race, height, weight, use of blood pressure lowering medications and history of cardiovascular disease were identified by backward elimination as AF risk factors shared by both sexes. On the other hand, diabetes was an AF risk factor in women but not in men. Among the shared risk factors between men and women, only age showed a stronger association in women than in men [Interaction p-value = 0.003]. Adjustment for the shared risk factors eliminated the sex difference in AF risk (OR [95% CI]: 0.90 [0.74, 1.09]), which was more noticeable in those younger than the median age (62 years) compared to those who were older (interaction p value 0.003). In conclusion, women and men share several AF risk factors, and these shared risk factors explain the sex differences. However, age association with AF differs by sex, and age modifies the associations between sex and other AF risk factors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In people with atrial fibrillation (AF), periods of sinus rhythm present an opportunity to detect prothrombotic atrial remodeling through measurement of P-wave indices (PWIs)-prolonged P-wave duration, abnormal P-wave axis, advanced interatrial block, and abnormal P-wave terminal force in lead V1. We hypothesized that the addition of PWIs to the CHA 2 DS 2 -VASc score would improve its ability to predict AF-related ischemic stroke., Methods: We included 2229 participants from the ARIC study (Atherosclerosis Risk in Communities) and 700 participants from MESA (Multi-Ethnic Study of Atherosclerosis) with incident AF who were not on anticoagulants within 1 year of AF diagnosis. PWIs were obtained from study visit ECGs before development of AF. AF was ascertained using study visit ECGs and hospital records. Ischemic stroke cases were based on physician adjudication of hospital records. We used Cox proportional hazards models to estimate hazard ratios and 95% CIs of PWIs for ischemic stroke. Improvement in 1-year stroke prediction was assessed by C-statistic, categorical net reclassification improvement, and relative integrated discrimination improvement., Results: Abnormal P-wave axis was the only PWI associated with increased ischemic stroke risk (hazard ratio, 1.84; 95% CI, 1.33-2.55) independent of CHA 2 DS 2 -VASc variables, and that resulted in meaningful improvement in stroke prediction. The β estimate was approximately twice that of the CHA 2 DS 2 -VASc variables, and thus abnormal P-wave axis was assigned 2 points to create the P 2 -CHA 2 DS 2 -VASc score. This improved the C-statistic (95% CI) from 0.60 (0.51-0.69) to 0.67 (0.60-0.75) in ARIC and 0.68 (0.52-0.84) to 0.75 (0.60-0.91) in MESA (validation cohort). In ARIC and MESA, the categorical net reclassification improvements (95% CI) were 0.25 (0.13-0.39) and 0.51 (0.18-0.86), respectively, and the relative integrated discrimination improvement (95% CI) were 1.19 (0.96-1.44) and 0.82 (0.36-1.39), respectively., Conclusions: Abnormal P-wave axis-an ECG correlate of left atrial abnormality- improves ischemic stroke prediction in AF. Compared with CHA 2 DS 2 -VASc, the P 2 -CHA 2 DS 2 -VASc is a better prediction tool for AF-related ischemic stroke.

Background: It is unknown whether early cardiology involvement shortly after atrial fibrillation (AF) diagnosis is associated with favorable outcomes in AF patients who have cancer., Objectives: The purpose of this study was to examine the relationship between early cardiology involvement after AF diagnosis in patients with history of cancer., Methods: This study examined associations of early cardiology involvement with oral anticoagulation use, stroke, and bleeding among nonvalvular AF patients (n = 388,045; mean age 68 ± 15 years; 59% male) with a history of cancer (past or active) from the MarketScan database (2009 to 2014). International Classification of Disease-9th Revision-Clinical Modification codes in any position were used to identify cancer diagnosis prior to AF diagnosis. Provider specialty and filled anticoagulant prescriptions 3 months prior to and 6 months after AF diagnosis were obtained. Poisson regression models were used to compute the probability of an oral anticoagulant prescription fill, and Cox regression was used to estimate the risks of stroke and major bleeding., Results: A total of 64,016 (17%) AF patients had a history of cancer. Cardiology involvement was less likely to occur among patients with a history of cancer than those without (relative risk [RR]: 0.92 [95% confidence interval (CI): 0.91 to 0.93]). Patients with history of cancer were less likely to fill prescriptions for anticoagulants (RR: 0.89 [95% CI: 0.88 to 0.90]) than those without cancer, and similar results were observed across cancer types. Patients with cancer were more likely to fill prescriptions for anticoagulants (RR: 1.48 [95% CI: 1.45 to 1.52]) if seen by a cardiologist. A reduced risk of stroke (hazard ratio: 0.89 [95% CI: 0.81 to 0.99]) was observed among all cancer patients who were seen by a cardiology provider, without an increased risk of bleeding (hazard ratio: 1.04 [95% CI: 0.95 to 1.13]). Similar results were observed when the analysis was stratified by active versus remote history of cancer., Conclusions: Although AF patients with cancer were less likely to see a cardiologist, or fill anticoagulant prescriptions, cardiology involvement was associated with increased anticoagulant prescription fills and favorable AF-related outcomes in AF patients with cancer., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Differences in anticoagulation rates and direct oral anticoagulant use by provider specialty may identify an area of practice improvement to reduce future stroke events in patients with atrial fibrillation (AF)., Methods and Results: We examined anticoagulant prescription fills in 388 045 (mean age, 68±15 years; 59% male) patients with incident AF from the MarketScan databases between 2009 and 2014. Provider specialty and filled anticoagulant prescriptions around the time of AF diagnosis (3 months before through 6 months after) were obtained from outpatient services and pharmacy claims. We estimated the association of provider specialty (cardiology versus primary care) with filling oral anticoagulant prescriptions, adjusting for patient characteristics. The risk of stroke and bleeding events also was explored. A total of 235 739 patients (61%) had a cardiology provider claim, whereas 152 306 (39%) were exclusively managed by primary care. Patients seen by cardiology providers were more likely to fill anticoagulant prescriptions than those seen by primary care (39% versus 27%; relative risk, 1.39; 95% confidence interval [CI], 1.37-1.40). Differences were observed for direct oral anticoagulants (relative risk, 1.74; 95% CI, 1.71-1.78) and warfarin (relative risk, 1.24; 95% CI, 1.22-1.26). A reduced risk of stroke events was observed among those seen by cardiology providers (hazard ratio, 0.90; 95% CI, 0.86-0.94) compared with primary care, without an increased bleeding risk (hazard ratio, 1.03; 95% CI, 0.98-1.07)., Conclusions: Patients seen by an outpatient cardiology provider shortly after AF diagnosis were more likely to initiate oral anticoagulation and were at lower risk of future stroke events without a higher rate of bleeding. Early referral to cardiology specialists may increase initiation of anticoagulant therapies and improve outcomes in AF., (© 2018 The Authors and Mayo Clinic. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background and Purpose: Abnormal P-wave axis (aPWA) has been linked to incident atrial fibrillation and mortality; however, the relationship between aPWA and stroke has not been reported. We hypothesized that aPWA is associated with ischemic stroke independent of atrial fibrillation and other stroke risk factors and tested our hypothesis in the ARIC study (Atherosclerosis Risk In Communities), a community-based prospective cohort study., Methods: We included 15 102 participants (aged 54.2±5.7 years; 55.2% women; 26.5% blacks) who attended the baseline examination (1987-1989) and without prevalent stroke. We defined aPWA as any value outside 0 to 75° using 12-lead ECGs obtained during study visits. Each case of incident ischemic stroke was classified in accordance with criteria from the National Survey of Stroke by a computer algorithm and adjudicated by physician review. Multivariable Cox regression was used to estimate hazard ratios and 95% confidence intervals for the association of aPWA with stroke., Results: During a mean follow-up of 20.2 years, there were 657 incident ischemic stroke cases. aPWA was independently associated with a 1.50-fold (95% confidence interval, 1.22-1.85) increased risk of ischemic stroke in the multivariable model that included atrial fibrillation. When subtyped, aPWA was associated with a 2.04-fold (95% confidence interval, 1.42-2.95) increased risk of cardioembolic stroke and a 1.32-fold (95% confidence interval, 1.03-1.71) increased risk of thrombotic stroke., Conclusions: aPWA is independently associated with ischemic stroke. This association seems to be stronger for cardioembolic strokes. Collectively, our findings suggest that alterations in atrial electric activation may predispose to cardiac thromboembolism independent of atrial fibrillation., (© 2017 American Heart Association, Inc.)

Estimated cardiorespiratory fitness (e-CRF) based on readily available clinical and self-reported data is a promising alternative to the costly traditional assessment of CRF using exercise equipment, but its role as a predictor for incident atrial fibrillation (AF) is unclear. This study included 10,126 participants (54.5% women, 35% African-American, mean age 63.2 years) from the Reasons for Geographic and Racial Differences in Stroke study who were free of AF at baseline. Baseline (2003 to 2007) e-CRF was determined using a previously validated nonexercise algorithm. Incident AF cases were identified at a follow-up examination by electrocardiogram and self-reported medical history of previous physician diagnosis. After a median follow-up of 9.4 years, 906 participants (8.9%) developed AF. In a multivariable logistic regression model adjusted for sociodemographics and baseline cardiovascular disease risk factors as well as incident coronary heart disease, heart failure, and stroke, each 1-metabolic equivalent of task increase in e-CRF was associated with a 5% lower risk of AF development (odds ratio [95% CI] 0.95 [0.92 to 0.99]; p = 0.0129). This association was stronger in women (OR [95% CI] 0.85 (0.79, 0.92) than in men (OR (95% CI) 0.88 (0.84, 0.93), interaction p value = 0.05. No significant interactions by age, race, history of cardiovascular disease, or physical limitations were observed. In conclusion, e-CRF using a nonexercise algorithm is a useful predictor of incident AF, which is consistent with previous reports using traditional CRF. This suggests that e-CRF using nonexercise algorithms may serve as a useful alternative to CRF measured by costly and time-consuming exercise testing., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Prior studies have not examined which cardiovascular outcomes most frequently develop in participants with atrial fibrillation (AF) from population-based cohorts of the elderly., Methods: This analysis included 4,304 (85% white; 61% women) participants from the Cardiovascular Health Study who were free of baseline cardiovascular disease. AF cases were identified at baseline and as time-updated events during follow-up. Kaplan-Meier estimates were used to compute the 1-, 5-, 10-, and 15-year cumulative incidence rates of the following outcomes: coronary heart disease (CHD), myocardial infarction (MI), heart failure, and ischemic stroke. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between AF and each outcome., Results: For all time periods, the cumulative incidence estimates of CHD, MI, heart failure, and ischemic stroke were higher for those with AF compared with those without AF. Heart failure was the most frequent outcome in those with AF, while CHD events were the most frequently detected outcome in participants without AF. Compared with persons who did not have AF, the risk of heart failure was higher in those with AF (HR = 3.18, 95% CI = 2.78-3.64), and the magnitude of this association was greater than the other outcomes of interest (CHD: HR = 1.76, 95% CI = 1.54-2.03; MI: 1.40, 95% CI = 1.14-1.71; ischemic stroke: HR = 1.98, 95% CI = 1.63-2.39)., Conclusions: AF is associated with several adverse cardiovascular outcomes and heart failure is the most frequently detected event. Potentially, risk factor modification strategies for the primary prevention of heart failure will reduce the morbidity and mortality associated with AF., (© 2016 Wiley Periodicals, Inc.)

Pulse pressure (PP) has been associated with atrial fibrillation (AF) independent of other measures of arterial pressure and other AF risk factors. However, the impact of gender, race, age, and geographic region on the association between PP and AF is unclear. A cross-sectional study of data from 25,109 participants (65 ± 9 years, 54% women, 40% black) from the Reasons for Geographic and Racial Differences in Stroke study recruited between 2003 and 2007 were analyzed. AF was defined as a self-reported history of a previous physician diagnosis or presence of AF on ECG. Multivariable logistic regression models were used to calculate the odds ratio for AF. Interactions for age (<75 years and ≥75 years), gender, race, and region were examined in the multivariable adjusted model. The prevalence of AF increased with widening PP (7.9%, 7.9%, 8.4%, and 11.6%, for PP < 45, 45-54.9, 55-64.9, and ≥65 mm Hg, respectively, [P for trend <.001]) but attenuated with adjustment. No differences by gender, race, and region were observed. However, there was evidence of significant effect modification by age (interaction P = .0002). For those <75 years, PP ≥ 65 mm Hg compared to PP < 45 mm Hg was significantly associated with higher risk of AF in both the unadjusted and multivariable adjusted models (odds ratio = 1.66 [95% CI = 1.42-1.94] and 1.32 [95% CI = 1.03-1.70], respectively). In contrast, higher PP (55-64.9 mm Hg) among those ≥75 years was significantly associated with a lower risk of AF. The relationship between PP and AF may differ for older versus younger individuals., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Objective: Given that recent reports have suggested left atrial disease to be an independent risk factor for ischemic stroke, we sought to examine if advanced interatrial block (aIAB) is an independent stroke risk factor., Methods: We examined the association between aIAB and incident ischemic stroke in 14,716 participants (mean age 54 ± 5.8 years; 55% female; 26% black) from the Atherosclerosis Risk in Communities Study (ARIC). Cases of aIAB were identified from digital ECGs recorded during the baseline ARIC visit (1987-1989) and the first 3 follow-up study visits (1990-1992, 1993-1995, and 1996-1998). Adjudicated ischemic stroke events were ascertained through December 31, 2010., Results: There were 266 (1.8%) participants who had evidence of aIAB. Over a median follow-up of 22 years, 916 (6.2%) ischemic stroke events were detected. The incidence rate (per 1,000 person-years) of ischemic stroke among those with aIAB (incidence rate 8.05, 95% confidence interval [CI] 5.7, 11.4) was more than twice the rate in those without aIAB (incidence rate 3.14, 95% CI 2.94, 3.35). In a multivariable Cox regression analysis adjusted for stroke risk factors and potential confounders, aIAB was associated with an increased risk of ischemic stroke (hazard ratio 1.63, 95% CI 1.13, 2.34). The results were consistent across subgroups of participants stratified by age, sex, and race., Conclusions: In the ARIC, aIAB was associated with incident ischemic stroke, which strengthens the hypothesis that left atrial disease should be considered an independent stroke risk factor., (© 2016 American Academy of Neurology.)

Left ventricular hypertrophy (LVH) diagnosed by electrocardiography (ECG-LVH) and echocardiography (echo-LVH) are independently associated with an increased risk of cardiovascular disease (CVD) events. However, it is unknown if ECG-LVH retains its predictive properties independent of LV anatomy. We compared the risk of CVD associated with ECG-LVH and echo-LVH in 4,076 participants (41% men, 86% white) from the Cardiovascular Health Study, who were free of baseline CVD. ECG-LVH was defined with Minnesota ECG Classification criteria from baseline ECG data. Echo-LVH was defined by gender-specific LV mass values normalized to body surface area (male: >102 g/m(2); female: >88 g/m(2)). ECG-LVH was detected in 144 participants (3.5%) and echo-LVH in 430 participants (11%). Over a median follow-up of 10.6 years, 2,274 CVD events occurred. In a multivariate Cox regression analysis adjusted for common CVD risk factors, ECG-LVH (hazard ratio [HR] 1.84, 95% CI 1.51 to 2.24) and echo-LVH (HR 1.35, 95% CI 1.19 to 1.54) were associated with an increased risk for CVD events. The association between ECG-LVH and CVD events was not substantively altered with further adjustment for echo-LVH (HR 1.76, 95% CI 1.45 to 2.15). In conclusion, the association of ECG-LVH with CVD events is not dependent on echo-LVH. This finding provides support to the concept that ECG-LVH is an electrophysiological marker with predictive properties independent of LV anatomy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Left atrial enlargement (LAE) is independently associated with an increased risk of stroke and atrial fibrillation (AF). The combination of both LAE and AF possibly increases the risk of stroke beyond that observed with AF., Methods: This analysis included 4572 (43% men, 95% white) participants from the Cardiovascular Health Study. LAE was defined using transthoracic echocardiographic 2-dimensional M-mode measurements of the left atrial diameter using sex-specific cut-points (men: ≥4.1 cm, women: ≥3.9 cm). AF cases were identified during the initial study electrocardiogram or by self-reported history. We examined the association between baseline AF and incident ischemic stroke stratified by the presence of LAE. Incident cases of ischemic stroke were identified by adjudication of medical records, including hospitalization data, through December 31, 2010., Results: At baseline, a total of 253 (5.5%) participants had AF and 1947 (43%) had LAE. Participants with AF (n = 163, 64%) were more likely to have LAE than those without AF (n = 1784, 41%; P < .001). Over a median follow-up of 13 years, 739 (16%) ischemic stroke events were identified. Both AF (hazard ratio [HR] = 2.12, 95% confidence interval [CI] = 1.64-2.74) and left atrial diameter (per 1-cm increase: HR = 1.14, 95% CI = 1.01-1.28) were associated with an increased risk for ischemic stroke. The association between AF and ischemic stroke was not modified by the presence of LAE (LAE: HR = 2.13, 95% CI = 1.42-3.19; no LAE: HR = 1.91, 95% CI = 1.36-2.68; P interaction = .86)., Conclusion: Our results suggest that echocardiographic LAE does not modify the stroke risk observed with AF., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Aims: To determine if the association between electrocardiographic left ventricular hypertrophy (ECG-LVH) and ischaemic stroke is partially explained by the concomitant presence of QT prolongation., Methods and Results: A total of 24 948 (mean age = 65 ± 9.4 years; 40% black; 55% women) participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. Electrocardiographic left ventricular hypertrophy was defined by the Sokolow-Lyon criteria. Heart rate-adjusted QT (QTa) was computed using a linear regression model. Adjudicated ischaemic stroke events were the outcome of interest. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between ECG-LVH and prolonged QTa, in isolation and combined, with ischaemic stroke. There were 2422 (9.7%) participants with ECG-LVH, 820 (3.3%) with prolonged QTa, and 161 (0.6%) with both. Over a median follow-up of 7.6 years, 714 (2.9%) ischaemic stroke events occurred. After adjustment for stroke risk factors and potential confounders, an increased risk of ischaemic stroke was observed among participants with ECG-LVH and prolonged QTa (HR = 1.85, 95% CI = 1.04-3.30), isolated ECG-LVH (HR = 1.40, 95% CI = 1.13-1.75), and isolated prolonged QTa (HR = 1.45, 95% CI = 1.04-2.03) compared with participants without either condition. When ECG-LVH and prolonged QTa were examined as separate variables, the risk of ischaemic stroke for each condition remained statistically significant., Conclusion: The combination of ECG-LVH and prolonged QT is associated with a higher risk of ischaemic stroke compared with either condition in isolation, and the stroke risk for each condition does not depend on the presence of the other., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Although mortality associated with atrial fibrillation (AF) has been reported to decrease over prior decades, the mortality risk of asymptomatic, nonhospitalized AF has not been examined., Hypothesis: Asymptomatic, nonhospitalized AF is associated with an increased risk of death., Methods: This analysis included 25,976 participants (mean age, 65 ± 9.4 years; 55% female; 38% black) from the Reasons for Geographic And Racial Differences (REGARDS) study. Atrial fibrillation was detected on the baseline electrocardiogram (ECG AF) or by self-reported history. Atrial fibrillation unawareness was defined as present if ECG evidence of the arrhythmia was detected but no self-reported history was reported. All-cause mortality was confirmed during follow-up through March 31, 2014., Results: A total of 2208 (8.5%) participants had AF at baseline (ECG: n = 371/17%; self-reported: n = 1837/83%). Over a median follow-up of 7.6 years, 3481 deaths occurred. In a multivariable Cox regression model, AF was associated with a 32% increased risk of mortality (95% confidence interval [CI]: 1.19-1.46). Risk of death was higher among those with ECG AF (hazard ratio: 1.71, 95% CI: 1.42-2.07) compared with self-reported cases (hazard ratio: 1.15, 95% CI: 1.03-1.29). Those who were unaware of their AF diagnosis had a 94% increased risk of death (95% CI: 1.50-2.52) compared with AF participants who were aware of their diagnosis., Conclusions: Asymptomatic, nonhospitalized AF is associated with an increased risk of mortality in the general population. Mortality is higher in those with ECG-confirmed cases and among those who are unaware of their diagnosis., (© 2016 Wiley Periodicals, Inc.)

Background: It is currently unknown if premature atrial contractions (PACs) detected on the routine screening electrocardiogram are associated with an increased risk of ischemic stroke., Methods: We examined the association between PACs and ischemic stroke in 22,975 (mean age 64 ± 9.2; 56% women; 40% black) participants from the Reasons for Geographic and Racial Differences in Stroke study. Participants who were free of stroke at baseline were included. PACs were detected from centrally read electrocardiograms at baseline. Cox regression was used to examine the association between PACs and ischemic stroke events through March 31, 2014., Results: PACs were present in 1,687 (7.3%) participants at baseline. In a Cox regression model adjusted for stroke risk factors and potential confounders, PACs were associated with an increased risk of ischemic stroke (hazards ratio (HR) 1.34, 95% CI 1.04-1.74). The relationship was limited to non-lacunar infarcts (HR 1.42, 95% CI 1.08-1.87), and not lacunar strokes (HR 1.01, 95% CI 0.51-2.03). An interaction by sex was detected, with the association between PACs and ischemic stroke being stronger among women (HR 1.82, 95% CI 1.29-2.56) than men (HR 1.03, 95% CI 0.69-1.52; p-interaction = 0.0095)., Conclusion: PACs detected on the routine electrocardiogram are associated with an increased risk for non-lacunar ischemic strokes, especially in women., Competing Interests: The authors declare no conflicts of interest., (© 2016 S. Karger AG, Basel.)

Background: The association between resting heart rate and ischemic stroke remains unclear., Aim: To examine the association between resting heart rate and ischemic stroke., Methods: A total of 24 730 participants (mean age: 64 ± 9·3 years; 59% women; 41% blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who were free of stroke at the time of enrollment (2003-2007) were included in this analysis. Resting heart rate was determined from baseline electrocardiogram data. Heart rate was examined as a continuous variable per 10 bpm increase and also as a categorical variable using tertiles ( <61 bpm, 61 to 70 bpm, and >70 bpm). First-time ischemic stroke events were identified during follow-up and adjudicated by physician review., Results: Over a median follow-up of 7·6 years, a total of 646 ischemic strokes occurred. In a Cox regression model adjusted for socio-demographics, cardiovascular risk factors, and potential confounders, each 10 bpm increase in heart rate was associated with a 10% increase in the risk of ischemic stroke (hazard ratio = 1·10, 95% confidence interval = 1·02, 1·18). In the categorical model, an increased risk of ischemic stroke was observed for heart rates in the middle (hazard ratio = 1·29, 95% confidence interval = 1·06, 1·57) and upper (hazard ratio = 1·37, 95% confidence interval = 1·12, 1·67) tertiles compared with the lower tertile. The results were consistent when the analysis was stratified by age, gender, race, exercise habits, hypertension, and coronary heart disease., Conclusion: In REGARDS, high resting heart rates were associated with an increased risk of ischemic stroke compared with low heart rates. Further research is needed to examine whether interventions aimed to reduce heart rate decrease stroke risk., (© 2015 World Stroke Organization.)

Background: The association between perceived stress and atrial fibrillation (AF) remains unclear., Purpose: The aim of this study was to examine the association between perceived stress and AF., Methods: A total of 25,530 participants (mean age 65 ± 9.4 years; 54 % women; 41 % blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. Logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for the association between the short version of the Cohen Perceived Stress Scale and AF., Results: In a multivariable analysis adjusted for demographics, cardiovascular risk factors, and potential confounders, the prevalence of AF was found to increase with higher levels of stress (none: OR = 1.0, referent; low stress: OR = 1.12, 95 % CI = 0.98, 1.27; moderate stress OR = 1.27, 95 % CI = 1.11, 1.47; high stress: OR = 1.60, 95 % CI = 1.39, 1.84)., Conclusion: Increasing levels of perceived stress are associated with prevalent AF in REGARDS.

Background: Recent studies suggest atrial fibrillation (AF) is an independent risk factor for coronary heart disease (CHD)., Aims: To determine if alterations in hemostasis or inflammation explain the association between AF and CHD., Methods: C-reactive protein (CRP), D-dimer, factor VIII, and fibrinogen were measured in incident CHD cases (n = 647) and a stratified cohort random sample (CRS, n = 1104) between 2003 and 2007 from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Using a case-cohort approach, Cox models examined whether inflammation or hemostasis biomarkers explained the association between AF and CHD., Results: In participants free of CHD at baseline, 12.2% of CHD cases and 7.1% of the CRS had AF. Over a median follow-up of 4.4 years, all biomarkers were associated with an increased risk of CHD in those with and those without AF after adjusting for CHD risk factors. The association of D-dimer with CHD was greater in those with AF (HR 2.52, 95% CI = 1.49, 4.26) than those without AF (HR 1.34, 95% CI = 1.12, 1.61) (p-interaction = 0.02). Similar interactions were not observed for the other biomarkers., Conclusions: Our results suggest that alterations in D-dimer, a marker of hemostasis, explain the association between AF and CHD. Potentially, D-dimer is a useful biomarker to assess CHD risk in persons with AF., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of this study was to assess the relationship between abnormally increased P-wave terminal force in lead V1 , an electrocardiographic (ECG) marker of left atrial abnormality, and incident ischemic stroke subtypes. We hypothesized that associations would be stronger with nonlacunar stroke, given that we expected left atrial abnormality to reflect the risk of thromboembolism rather than in situ cerebral small-vessel occlusion., Methods: Our cohort comprised 14,542 participants 45 to 64 years of age prospectively enrolled in the Atherosclerosis Risk in Communities study and free of clinically apparent atrial fibrillation (AF) at baseline. Left atrial abnormality was defined as PTFV1 >4,000μV*ms. Outcomes were adjudicated ischemic stroke, nonlacunar (including cardioembolic) ischemic stroke, and lacunar stroke., Results: During a median follow-up period of 22 years (interquartile range, 19-23 years), 904 participants (6.2%) experienced a definite or probable ischemic stroke. A higher incidence of stroke occurred in those with baseline left atrial abnormality (incidence rate per 1,000 person-years, 6.3; 95% confidence interval [CI]: 5.4-7.4) than in those without (incidence rate per 1,000 person-years, 2.9; 95% CI: 2.7-3.1; p < 0.001). In Cox regression models adjusted for potential confounders and incident AF, left atrial abnormality was associated with incident ischemic stroke (hazard ratio [HR]: 1.33; 95% CI: 1.11-1.59). This association was limited to nonlacunar stroke (HR, 1.49; 95% CI: 1.07-2.07) as opposed to lacunar stroke (HR, 0.89; 95% CI: 0.57-1.40)., Interpretation: We found an association between ECG-defined left atrial abnormality and subsequent nonlacunar ischemic stroke. Our findings suggest that an underlying atrial cardiopathy may cause left atrial thromboembolism in the absence of recognized AF., (© 2015 American Neurological Association.)

It is unclear if patients who have atrial fibrillation (AF) have a greater fall risk compared with those in the general population and if falls increase mortality beyond that observed in AF. A total of 24,117 (mean age 65 ± 9.3 years; 55% women; 38% black) participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included. AF was identified from baseline electrocardiogram data and by self-reported history. Falls were considered present if participants reported ≥2 falls within the year before the baseline examination. Logistic regression was used to examine the relationship between prevalent AF and falls. Cox regression was used to examine the risk of death in those with AF and falls, separately and in combination, compared with those without either condition. A total of 2,007 participants (8.3%) had baseline AF and 1,655 (6.7%) reported falls. A higher prevalence of falls was reported in those with AF (n = 209; 10%) than those without AF (n = 1,446; 6.5%; p <0.0001). After adjustment for fall risk factors, AF was significantly associated with falls (odds ratio 1.22, 95% confidence interval [CI] 1.04 to 1.44). Compared with no history of AF or falls, the concomitant presence of AF and falls (hazard ratio [HR] 2.12, 95% CI 1.64 to 2.74) was associated with a greater risk of death than AF (HR 1.44, 95% CI 1.28 to 1.62) or falls (HR 1.61, 95% CI 1.42 to 1.82). In conclusion, patients with AF are more likely to report a history of falls in REGARDS. Additionally, participants with AF who report falls have an increased risk of death than those with either condition in isolation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: It is unclear whether left ventricular hypertrophy (LVH) detected by electrocardiography (ECG-LVH) is equally predictive of heart failure as LVH detected by echocardiography (echo-LVH)., Methods: This analysis included 4,008 white participants (41% men) aged 65 years or older from the Cardiovascular Health Study who were free of stroke and major intraventricular conduction defects. ECG-LVH was defined by the Cornell criteria from baseline ECG data and echo-LVH was calculated from baseline echocardiography measurements. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ECG-LVH and echo-LVH and adjudicated incident stroke events, separately. Harrell's concordance indices (C-index) were calculated for the Framingham Stroke Risk Score with inclusion of ECG-LVH and echo-LVH, separately., Results: ECG-LVH was detected in 136 (3.4%) participants and echo-LVH was present in 208 (5.2%) participants. Over a median follow-up of 13 years, a total of 769 (19%; incidence rate = 15.4 per 1000 person-years) strokes occurred. In a multivariable Cox regression analysis adjusted for stroke risk factors and potential confounders, ECG-LVH (HR = 1.68; 95% CI = 1.23, 2.28) and echo-LVH (HR = 1.58; 95% CI = 1.17, 2.14) were associated with an increased risk of stroke. Similar values were obtained for the C-index when either ECG-LVH (C-index = .786) or echo-LVH (C-index = .786) were included in the Framingham Stroke Risk Score., Conclusion: ECG-LVH and echo-LVH are able to be used interchangeably in stroke risk scores., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Prolongation of the QT interval is associated with an increased risk of atrial fibrillation (AF) and stroke., Objectives: The purpose of this analysis was to determine if AF explains the association between prolonged QT and stroke., Methods: A total of 6305 participants (mean age 62 ± 10 years; 54% women; 38% whites; 27% blacks; 23% Hispanics; 12% Chinese-Americans) from the Multi-Ethnic Study of Atherosclerosis (MESA) were included in this analysis. A linear scale was used to compute heart rate-adjusted QT (QT(a)). Prolonged QT(a) was defined as ≥ 460 ms in women and ≥ 450 ms in men. Incident AF cases were identified using hospital discharge records and Medicare claims data. Vascular neurologists adjudicated stroke events by medical record review. Cox regression was used to examine the association between prolonged QT(a) and stroke with and without AF., Results: A total of 216 (3.4%) of study participants had prolonged QT(a). Over a median follow-up of 8.5 years, 280 (4.4%) participants developed AF and 128 (2.0%) participants developed stroke. In a multivariable Cox regression analysis adjusted for socio-demographics, cardiovascular risk factors, and potential confounders, prolonged QT(a) was associated with an increased risk of AF (HR = 1.7, 95% CI 1.1, 2.6) and stroke (HR = 2.3, 95% CI 1.3, 4.1). When AF was included as a time-dependent covariate, the association between prolonged QT(a) and stroke was not substantively altered (HR = 2.4, 95% CI 1.3, 4.3)., Conclusion: The increased risk of stroke in those with prolonged QT potentially is not explained by documented AF. Further research is needed to determine if subclinical AF explains the association between the QT interval and stroke.

Introduction: Atrial fibrillation (AF) is an independent risk factor for end-stage renal disease (ESRD) among persons with chronic kidney disease (CKD), however, the association between AF and incident ESRD has not been examined in the general United States population., Methods: A total of 24,953 participants (mean age 65 ± 9.0 years; 54% women; 40% blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. AF was identified at baseline (2003-2007) from electrocardiogram data and self-reported history. Incident cases of ESRD were identified through linkage with the United States Renal Data System. Cox proportional-hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between AF and incident ESRD., Results: A total of 2,155 (8.6%) participants had AF at baseline. Over a median follow-up of 7.4 years, 295 (1.2%) persons developed ESRD. In a model adjusted for demographics and potential confounders, AF was associated with an increased risk of incident ESRD (HR=1.51, 95% CI=1.08, 2.11). The association between AF and ESRD became non-significant after further adjustment for CKD markers (eGFR <60 mL/min/1.73 m(2) and urine albumin-to-creatinine ratio ≥ 30 mg/dL) (HR=1.24, 95% CI=0.89, 1.73)., Conclusion: AF is associated with an increased risk of ESRD in the general United States population and this association potentially is explained by underlying CKD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Peripheral arterial disease (PAD) shares several risk factors with atrial fibrillation (AF), and persons with PAD have an increased risk of stroke. It is unclear if PAD is associated with an increased risk for AF and whether this potential association explains the increased risk of stroke observed in those with PAD., Methods and Results: We examined the association between PAD, measured by ankle-brachial index (ABI), and incident AF and incident stroke, separately, in 6568 participants (mean age 62±10 years, 53% women, 62% nonwhite) from the Multi-Ethnic Study of Atherosclerosis (MESA). ABI values <1.0 or >1.4 defined PAD. AF was ascertained through review of hospital discharge records and from Medicare claims data until December 31, 2010. An independent adjudication committee ascertained stroke events. Cox regression was used to estimate hazard ratios and 95% CIs for the association between PAD and AF and stroke. Over a median follow-up of 8.5 years, 301 (4.6%) participants developed AF and 140 (2.1%) developed stroke. In a model adjusted for sociodemographics, cardiovascular risk factors, and potential confounders, PAD was associated with an increased risk of AF (hazard ratio 1.5, 95% CI 1.1 to 2.0). In a similar model, PAD was associated with incident stroke (hazard ratio 1.7, 95% CI 1.1 to 2.5), and the magnitude of risk was not different after inclusion of AF as a time-dependent covariate (hazard ratio 1.7, 95% CI 1.1 to 2.5)., Conclusions: PAD is associated with an increased risk of AF and stroke in MESA. Potentially, the relationship between PAD and stroke is not mediated by AF., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Outcomes among atrial fibrillation (AF) patients may differ according to race/ethnicity and sex due to differences in biology, the prevalence of cardiovascular risk factors, and the use and effectiveness of AF treatments. We aimed to characterize patterns of cardiovascular risk across subgroups of AF patients by sex and race/ethnicity, since doing so may provide opportunities to identify interventions. We also evaluated whether these patterns changed over time. Methods: We utilized administrative claims data from the Optum Clinformatics® Datamart database from 2009 to 2015. Patients with AF with ≥6 months of enrollment prior to the first non-valvular AF diagnosis were included in the analysis. Final analysis utilized Cox proportional hazard models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for cardiovascular outcomes stratified by sex and race/ethnicity. An additional analysis stratified outcomes by calendar year of AF diagnosis to evaluate changes in outcomes over time. Results: In a cohort of 380,636 AF patients, women had a higher risk of ischemic stroke [HR (95% CI): 1.25 (1.19, 1.31)] and lower risk of heart failure and myocardial infarction [HR (95% CI): 0.91 (0.88, 0.94) and 0.81 (0.77, 0.86), respectively)] compared to men. Black patients had elevated risk across all endpoints compared to whites, while Hispanics and Asian Americans showed no significant differences in any outcome compared to white patients. These sex and race/ethnic differences did not change over time. Conclusions: We found sex and race/ethnic differences in risk of cardiovascular outcomes among AF patients, without evidence of improvement over time. [ABSTRACT FROM AUTHOR]

Background It is unknown if higher levels of ambient particulate matter (PM) exposure increase the risk for premature ventricular contractions (PVC) in a population-based study of men and women, and if this relationship varies by race or sex. Methods We examined the association of PM <2.5 µm in diameter (PM 2.5 ) concentration with PVCs in 26,121 (mean age=64±9.3 years; 55% female; 41% black) participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Estimates of short- (2-week) and long-term (1-year) PM 2.5 exposures were computed prior to the baseline visit using geographic information system data on the individual level at the coordinates of study participants’ residences. PVCs were identified from baseline electrocardiograms. Results PVCs were detected in 1719 (6.6%) study participants. Short- (OR=1.08, 95%CI=1.03, 1.14) and long- (OR=1.06, 95%CI=1.01, 1.12) term PM 2.5 exposures were associated with PVCs. Interactions were not detected by race or sex. An interaction between short-term PM 2.5 exposure and PVCs was detected for those with cardiovascular disease (OR=1.16, 95%CI=1.06, 1.27) compared with those without cardiovascular disease (OR=1.05, 95%CI=0.99, 1.12; p-interaction=0.027). Conclusion Our findings suggest that PM 2.5 exposure is associated with an increased risk for PVCs in a biracial population-based study of men and women. We also have identified persons with cardiovascular disease as an at-risk population for PVCs when increases in short-term PM 2.5 concentration occur. [ABSTRACT FROM AUTHOR]

Aims: To determine if the association between electrocardiographic left ventricular hypertrophy (ECG-LVH) and ischaemic stroke is partially explained by the concomitant presence of QT prolongation.Methods and Results: A total of 24 948 (mean age = 65 ± 9.4 years; 40% black; 55% women) participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. Electrocardiographic left ventricular hypertrophy was defined by the Sokolow-Lyon criteria. Heart rate-adjusted QT (QTa) was computed using a linear regression model. Adjudicated ischaemic stroke events were the outcome of interest. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between ECG-LVH and prolonged QTa, in isolation and combined, with ischaemic stroke. There were 2422 (9.7%) participants with ECG-LVH, 820 (3.3%) with prolonged QTa, and 161 (0.6%) with both. Over a median follow-up of 7.6 years, 714 (2.9%) ischaemic stroke events occurred. After adjustment for stroke risk factors and potential confounders, an increased risk of ischaemic stroke was observed among participants with ECG-LVH and prolonged QTa (HR = 1.85, 95% CI = 1.04-3.30), isolated ECG-LVH (HR = 1.40, 95% CI = 1.13-1.75), and isolated prolonged QTa (HR = 1.45, 95% CI = 1.04-2.03) compared with participants without either condition. When ECG-LVH and prolonged QTa were examined as separate variables, the risk of ischaemic stroke for each condition remained statistically significant.Conclusion: The combination of ECG-LVH and prolonged QT is associated with a higher risk of ischaemic stroke compared with either condition in isolation, and the stroke risk for each condition does not depend on the presence of the other. [ABSTRACT FROM AUTHOR]

Background: Limited information exists on the lifetime risk of atrial fibrillation (AF) in African Americans and by socioeconomic status.Methods: We studied 15 343 participants without AF at baseline from the ARIC (Atherosclerosis Risk in Communities) cohort recruited in 1987 to 1989 from 4 communities in the United States when they were 45 to 64 years of age. Participants have been followed through 2014. Incidence rates of AF were calculated dividing the number of new cases by person-years of follow-up. Lifetime risk of AF was estimated by a modified Kaplan-Meier method considering death as a competing risk. Participants' family income and education were obtained at baseline.Results: We identified 2760 AF cases during a mean follow-up of 21 years. Lifetime risk of AF was 36% (95% confidence interval, 32%-38%) in white men, 30% (95% confidence interval, 26%-32%) in white women, 21% (95% confidence interval, 13%-24%) in African American men, and 22% (95% confidence interval, 16%-25%) in African American women. Regardless of race and sex, incidence rates of AF decreased from the lowest to the highest categories of income and education. In contrast, lifetime risk of AF increased in individuals with higher income and education in most sex-race groups. Cumulative incidence of AF was lower in those with higher income and education compared with their low socioeconomic status counterparts through earlier life but was reversed after age 80.Conclusions: Lifetime risk of AF in the ARIC cohort was ≈1 in 3 among whites and 1 in 5 among African Americans. Socioeconomic status was inversely associated with cumulative incidence of AF before the last decades of life. [ABSTRACT FROM AUTHOR]

Introduction: Lower neighborhood socioeconomic status (SES) has been associated with several cardiovascular diseases, but its relationship with atrial fibrillation (AF) is unclear. Hypothesis: In a national cohort of black and white adults, lower neighborhood SES will be associated with increased risk of incident AF. Methods: This analysis consisted of 12481 participants (42% black, 58% white), aged 45 and older, enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study between 2003 and 2007. Included participants had geocoded addresses, were free of AF at baseline and completed a 10-year follow-up assessment. Incident AF was defined by electrocardiogram or self-report of physician diagnosis. A neighborhood SES score was constructed using 6 neighborhood-level variables from linked 2000 census data (median household income, median value of owner-occupied units, % of households receiving interest or rental income, % of adults with HS diploma, % of adults with college degree, % of adults employed in professional occupations), and then divided into quartiles. Logistic regression was used to estimate the association of neighborhood SES quartile with incident AF, adjusting for demographics, individual SES measures, AF risk factors, and access to care factors. Results: During follow-up, 1474 incident AF cases were identified (11.7%). In multivariable adjusted models, neighborhood SES was not associated with increased risk of incident AF: (Odds ratio (OR) (95% confidence interval (CI)): Q1: 1.04 (0.87, 1.25); Q2: 0.96 (0.81, 1.13); Q3: 0.87 (0.74, 1.02)) for the lowest three quartiles of neighborhood SES score compared to the highest quartile (Q4). However, individual SES measures, including low household income (<$20K vs. $75K+ OR (95% CI): 1.27 (1.01, 1.61)) and housing instability (lived in 3 or more places during follow-up vs. same residence OR (95% CI): 1.19 (1.04, 1.36)) were each independently associated with increased risk of incident AF. Conclusions: In this analysis from a large geographically diverse biracial cohort of adults, there was no association between neighborhood SES and incident AF, although there was an association between different individual SES variables and risk of AF. [ABSTRACT FROM AUTHOR]

Background: In people with atrial fibrillation (AF), periods of sinus rhythm present an opportunity to detect prothrombotic atrial remodeling through measurement of P-wave indices (PWIs)-prolonged P-wave duration, abnormal P-wave axis, advanced interatrial block, and abnormal P-wave terminal force in lead V1. We hypothesized that the addition of PWIs to the CHA2DS2-VASc score would improve its ability to predict AF-related ischemic stroke.Methods: We included 2229 participants from the ARIC study (Atherosclerosis Risk in Communities) and 700 participants from MESA (Multi-Ethnic Study of Atherosclerosis) with incident AF who were not on anticoagulants within 1 year of AF diagnosis. PWIs were obtained from study visit ECGs before development of AF. AF was ascertained using study visit ECGs and hospital records. Ischemic stroke cases were based on physician adjudication of hospital records. We used Cox proportional hazards models to estimate hazard ratios and 95% CIs of PWIs for ischemic stroke. Improvement in 1-year stroke prediction was assessed by C-statistic, categorical net reclassification improvement, and relative integrated discrimination improvement.Results: Abnormal P-wave axis was the only PWI associated with increased ischemic stroke risk (hazard ratio, 1.84; 95% CI, 1.33-2.55) independent of CHA2DS2-VASc variables, and that resulted in meaningful improvement in stroke prediction. The β estimate was approximately twice that of the CHA2DS2-VASc variables, and thus abnormal P-wave axis was assigned 2 points to create the P2-CHA2DS2-VASc score. This improved the C-statistic (95% CI) from 0.60 (0.51-0.69) to 0.67 (0.60-0.75) in ARIC and 0.68 (0.52-0.84) to 0.75 (0.60-0.91) in MESA (validation cohort). In ARIC and MESA, the categorical net reclassification improvements (95% CI) were 0.25 (0.13-0.39) and 0.51 (0.18-0.86), respectively, and the relative integrated discrimination improvement (95% CI) were 1.19 (0.96-1.44) and 0.82 (0.36-1.39), respectively.Conclusions: Abnormal P-wave axis-an ECG correlate of left atrial abnormality- improves ischemic stroke prediction in AF. Compared with CHA2DS2-VASc, the P2-CHA2DS2-VASc is a better prediction tool for AF-related ischemic stroke. [ABSTRACT FROM AUTHOR]