Resting heart rate (RHR) is independently associated with cardiovascular disease (CVD) risk. We determined whether RHR, measured in mid-life, is also associated with cognitive decline. We studied 13,720 middle-aged white and black ARIC participants without a history of stroke or atrial fibrillation. RHR was obtained from a 12-lead resting electrocardiogram at the baseline visit (1990 to 1992) and categorized into groups as <60 (reference), 60 to 69, 70 to 79 and ≥80 beats/min. Cognitive scores were obtained at baseline and at up to 2 additional visits (1996 to 1998 and 2011 to 2013). The primary outcome was a global composite cognitive score (Z-score) derived from 3 tests: delayed word recall, digit symbol substitution, and word fluency. The associations of RHR with cognitive decline and incident dementia were examined using linear mixed-effects and Cox hazard models, respectively, adjusting for sociodemographics, CVD risk factors, and AV-nodal blockade use. Multiple imputation methods were used to account for attrition over follow-up. Participants had mean ± SD age of 58 ± 6 years; 56% were women, 24% black. Average RHR was 66 ± 10 beats/min. Over a mean follow-up of 20 years, those with RHR ≥80 beats/min had greater global cognitive decline (average adjusted Z-score difference −0.12 [95% confidence interval −0.21, −0.03]) and increased risk for incident dementia (hazard ratio 1.28 (1.04, 1.57), compared with those with RHR <60 beats/min. In conclusion, elevated RHR is independently associated with greater cognitive decline and incident dementia over 20 years. Further studies are needed to determine whether the associations are causal or secondary to another underlying process, and whether modification of RHR can affect cognitive decline.

Background: Abnormal P-wave indices (PWIs)-reflecting underlying left atrial abnormality-are associated with increased risk of stroke independent of atrial fibrillation. We assessed whether abnormal PWIs are associated with incident dementia and greater cognitive decline, independent of atrial fibrillation and ischemic stroke. Methods and Results: We included 13 714 participants (mean age, 57±6 years; 56% women; 23% black) who were followed for dementia through the end of 2015. (Abnormal P-wave terminal force in lead V1, ≥4000 μV×ms), abnormal P-wave axis (>75° or <0°), prolonged P-wave duration (>120 ms), and advanced interatrial block were determined from ECGs at visits 2 to 4. Dementia was adjudicated by an expert panel using data from cognitive tests and hospitalization International Classification of Diseases codes. Cognitive function was measured longitudinally using 3 neuropsychological tests. Cox proportional hazards models were used to assess the association between time-dependent abnormal PWIs with incident dementia. Linear regression models were used to evaluate PWIs with cognitive function over time. At the conclusion of the study, 19%, 16%, 28%, and 1.9% of participants had abnormal P-wave terminal force in lead V1, abnormal P-wave axis, prolonged P-wave duration, and advanced interatrial block, respectively. During mean follow-up of 18 years, there were 1390 (10%) dementia cases. All abnormal PWIs except advanced interatrial block were associated with an increased risk of dementia even after adjustment for incident atrial fibrillation and stroke: multivariable hazard ratio of abnormal P wave terminal force in lead V1=1.60, 95% CI, 1.41 to 2.83; abnormal P-wave axis, hazard ratio =1.36, 95% CI, 1.17 to 2.57; prolonged P-wave duration, hazard ratio=1.60, 95% CI, 1.42 to 1.80. Only abnormal P-wave terminal force in lead V1 was associated with greater decline in global cognition. Conclusions: Abnormal PWIs are independently associated with an increased risk of dementia. This novel finding should be replicated in other cohorts and the underlying mechanisms should be evaluated.

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.

Animal and human laboratory studies suggest that the pathogenesis of abdominal aortic aneurysms (AAAs) involves inflammation and degradation and remodeling of the extracellular matrix. This study prospectively assessed the association between biomarkers for these mechanisms and the presence of AAA during 24 years of follow-up in the Atherosclerosis Risk in Communities (ARIC) study. The ARIC prospectively identified clinically diagnosed AAAs in 15 792 men and women from baseline in 1987 to 1989 to 2011 using hospital discharge codes and death records. Additional asymptomatic AAAs were detected by an abdominal ultrasound scan in 2011 to 2013. Matrix metalloproteinase (MMP)-3, MMP-9, interleukin 6 (IL-6), N-terminal propeptide of Type III procollagen (PIIINP), and osteopontin were measured in blood samples collected between 1987 and 1992 in participants with AAA (544 clinically diagnosed AAAs and 72 ultrasound-detected AAAs) and a random sample of 723 participants selected from baseline and matched with AAAs by age, race and sex. Higher concentrations of MMP-9 and IL-6 were associated with future risk of clinically diagnosed AAA (hazard ratios [95% confidence intervals]: 1.55 [1.22-1.97] and 1.87 [1.48-2.35], respectively, comparing highest versus lowest tertiles) after multivariable adjustment (P for trend <.001). Matrix metalloproteinase-9 was also associated with ultrasound-detected AAA. In conclusion, blood concentrations of MMP-9 and IL-6 measured in middle age predicted the risk of AAA during 24 years of follow-up.

Background: American Indians (AIs) have high stroke morbidity and mortality. We compared stroke incidence and mortality in AIs, blacks, and whites. Methods and Results: Pooled data from 2 cardiovascular disease cohort studies included 3182 AIs from the SHS (Strong Heart Study), aged 45 to 74 years at baseline (1988–1990) and 3765 blacks and 10 413 whites from the ARIC (Atherosclerosis Risk in Communities) Study, aged 45 to 64 years at baseline (1987–1989). Stroke surveillance was based on self-report, hospital records, and death certificates. We estimated hazard ratios for incident stroke (ischemic and hemorrhagic combined) through 2008, stratified by sex and birth-year tertile, and relative risk for poststroke mortality. Incident strokes numbered 282 for AIs, 416 for blacks, and 613 for whites. For women and men, stroke incidence among AIs was similar to or lower than blacks and higher than whites. Covariate adjustment resulted in lower hazard ratios for most comparisons, but results for these models were not always statistically significant. After covariate adjustment, AI women and men had higher 30-day poststroke mortality than blacks (relative risk=2.1 [95% CI=1.0, 3.2] and 2.2 [95% CI=1.3, 3.1], respectively), and whites (relative risk=1.6 [95% CI=0.8, 2.5] and 1.7 [95% CI=1.1, 2.4]), and higher 1-year mortality (relative risk range=1.3–1.5 for all comparisons). Conclusions: Stroke incidence in AIs was lower than for blacks and higher than for whites; differences were larger for blacks and smaller for whites after covariate adjustment. Poststroke mortality was higher in AIs than blacks and whites.

Background: Direct oral anticoagulants (DOACs), namely rivaroxaban, apixaban, dabigatran, and edoxaban, are now included together with warfarin as standards of care for the primary treatment of venous thromboembolism (VTE). The extent to which the DOACs have been adopted since receiving US Food and Drug Administration (FDA) approval is unknown. Objective: To document temporal trends in oral anticoagulant (OAC) prescriptions among anticoagulant-naïve patients initiating OACs for VTE primary treatment in the United States and to report participant characteristics by OAC prescribed for the year 2017. Methods: MarketScan databases for years 2012 through 2017 were used to identify VTE cases and comorbidities using International Classification of Diseases codes and prescriptions for OACs via outpatient pharmaceutical claims data. Results: The 137 203 VTE cases were on average (± standard deviation) 56.7 ± 16.0 years old and 49.9% female. Warfarin was prescribed to 98.7% of VTE patients receiving an OAC in quarter 1 (January through March) of 2012. By quarter 4 (October through December) of 2017, warfarin was prescribed to 17.5%, while rivaroxaban was prescribed to 42.7%, apixaban to 38.6%, dabigatran to 1.3%, and edoxaban to <0.1%. In 2017, the comorbidity burden was highest among patients prescribed warfarin, intermediate among patients prescribed apixaban, and lowest among patients prescribed rivaroxaban. Conclusions: Rivaroxaban and apixaban use to treat VTE has increased dramatically since receiving FDA approval, whereas warfarin use has plummeted. Dabigatran and edoxaban are infrequently prescribed. Given widespread usage of rivaroxaban and apixaban, there is a need for continued monitoring of the comparative effectiveness of these OAC therapies in real-world settings.

Introduction: The interplay between midlife vascular risk factors and midlife cognitive function with later life mild cognitive impairment (MCI) and dementia (DEM) is not well understood. Methods: In the Atherosclerosis Risk in Communities Study, cardiovascular risk factors and cognition were assessed in midlife, ages 45–64 years. In 2011–2013, 20–25 years later, all consenting Atherosclerosis Risk in Communities participants underwent a cognitive and neurological evaluation and were given adjudicated diagnoses of cognitively normal, MCI, or DEM. Results: In 5995 participants with complete covariate data, midlife diabetes, hypertension, obesity, and hypercholesterolemia were associated with late-life MCI and DEM. Low midlife cognition function was also associated with greater likelihood of late-life MCI or DEM. Both midlife vascular risk factors and midlife cognitive function remained associated with later life MCI or DEM when both were in the model. Discussion: Later life MCI and DEM were independently associated with midlife vascular risk factors and midlife cognition.

Background: QRS duration (QRSd), a measure of ventricular conduction, has been associated with adverse cardiovascular outcomes, but its relationship with incident atrial fibrillation (AF) is poorly understood. Methods and results: This study included 15,314 participants from the Atherosclerosis Risk in Communities (ARIC) study who were free of AF at baseline. QRSd was automatically measured from resting 12-lead electrocardiograms (ECGs) at baseline. Incident AF cases were systematically ascertained using ECGs, hospital discharge diagnoses and death certificates. Multivariable adjusted Cox regression analyses were performed to investigate the relationship between QRSd and incident AF. Mean age of our population was 54 ± 6 years (55% females). During a median follow-up of 21.2 years, 2041 confirmed incident AF cases occurred. In multivariable adjusted Cox models, a 1-SD increase in QRSd was associated with a hazard ratio (HR) (95% CI) for AF of 1.05 (1.01; 1.10), p = 0.01. This relationship was significant among women (HR per 1-SD increase in QRSd (95% CI) 1.13 (1.06; 1.20), p < 0.001), but not among men (1.00 (0.95; 1.06), p = 0.97) (p for interaction 0.005). Compared to individuals with a QRSd <100 ms, the HRs for incident AF in individuals with a QRSd of 100–119 and ≥120 ms were 1.13 (1.02; 1.26) and 1.35 (1.08; 1.68), respectively (p for trend 0.002). Again, this relationship was significant among women (p for trend <0.001) but not among men (p for trend 0.23). Conclusion: In this large population-based study, QRSd was an independent predictor of incident AF among women, but not in men. Further studies are needed to better understand the underlying mechanisms.

Early cardiology involvement after atrial fibrillation (AF) diagnosis is associated with increased oral anticoagulant prescription fills and reduced stroke risk. It is unknown if this association varies by race, sex, or education. We examined anticoagulant fills in 223,891 patients with incident nonvalvular AF (mean age = 71 years; 44% women; 84% white; 9% black; 5% Hispanic; 2% Asian) from the Optum Clinformatics database (2009 to 2014). Provider specialty and filled anticoagulant prescriptions 3 months before and 6 months after AF diagnosis were obtained. Poisson regression was used to compute the probability of oral anticoagulant prescription fill and Cox regression was used to estimate the risk of stroke and major bleeding. Cardiology involvement was less likely among nonwhites (white = Referent; black = relative risk = 0.96, 95% confidence interval (0.95 to 0.97); Hispanic = 0.99 (0.98 to 1.00); Asian = 0.95 (0.93 to 0.97)) and women (0.92 (0.91 to 0.93)), but more likely with higher education level (high school or less = Referent; some college = 1.03 (1.02 to 1.04); college or more = 1.08 (1.07 to 1.09)). Patients seen by cardiology providers were more likely to fill anticoagulant prescriptions (Any = 1.67 (1.64 to 1.69); direct oral anticoagulants = 2.59 (2.49 to 2.68); warfarin = 1.38 (1.35 to 1.41)) compared with patients not seen by a cardiology provider. Patients seen by a cardiologist had a reduced stroke risk (hazard ratio = 0.84 (0.79 to 0.88)) and similar bleeding risk (1.01 (0.96 to 1.06)). Outcomes did not vary by race, sex, or education level. In conclusion, although race, sex, and education differences exist in early cardiology involvement after AF diagnosis, the influence of cardiology involvement on anticoagulant prescription fills and AF-related outcomes does not vary by these factors. Initiatives to improve early cardiology referral in nonwhites, women, and those with lower educational attainment may improve AF outcomes.

Introduction: The objective of this study was to investigate whether 10 phospholipids/metabolites previously identified as prospectively predictive of mild cognitive impairment (MCI) or dementia in whites would also be predictive in a mostly African-American cohort. Methods: We repeatedly measured 188 phospholipids/metabolites in plasma samples of 221 participants of the Atherosclerosis Risk in Communities study, 97% African American, who were followed between 2004–2006 and 2011–2013. Results: After a mean follow-up of 7.3 years, 77 were classified as having MCI and 18 as having dementia. Our study failed to replicate previous findings in this mostly African American cohort, in that the 10 phospholipids/metabolites only achieved a C statistic/AUC of 0.609 in predicting development of MCI or dementia (compared to 0.96) and 0.607 in distinguishing normal from MCI or dementia at the follow-up visit. Conclusion: A panel of 10 phospholipids/metabolites previously associated with incident dementia was not predictive of MCI or dementia in an independent cohort.