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Wesley T O’Neal,1 Sanjay Venkatesh,2 Stephen T Broughton,2 William F Griffin,3 Elsayed Z Soliman4,5 1Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA; 2Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 3Department of Internal Medicine, Medical University of South Carolina, Charleston, SC, USA; 4Department of Internal Medicine, Division of Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, USA; 5Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston-Salem, NC, USA Abstract: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, and it places a substantial burden on the health care system. Despite improvements in our understanding of AF pathophysiology, we have yet to develop targeted preventive therapies. Recently, numerous biological markers have been identified to aid in the prediction of future AF events. Subclinical markers of atrial stress, inflammation, endothelial dysfunction, kidney dysfunction, and atherosclerosis have been linked to AF. The connection between these markers and AF is the identification of subclinical states in which AF propagation is likely to occur, as these conditions are associated with abnormal atrial remodeling and fibrosis. Additionally, several risk scores have been developed to aid in the identification of at-risk patients. The practicing clinician should be aware of these subclinical markers, as several of these markers improve the predictive abilities of current AF risk scores. Knowledge of these subclinical markers also provides clinicians with a better understanding of AF risk factors, and the opportunity to reduce the occurrence of AF by incorporating well-known cardiovascular disease risk factor modification strategies. In this review, we highlight several novel biological markers that have improved our understanding of AF pathophysiology and appraise the utility of these markers to improve our ability to predict future AF events. Keywords: biological markers, prediction, atrial fibrillation

Objective: Associations between atrial fibrillation (AF) and heart failure (HF) have been established. We compared the extent to which AF is associated with each primary subtype of HF, with reduced (HFrEF) versus preserved ejection fraction (HFpEF)., Methods: We included 25 787 participants free of baseline HF from the REGARDS (REasons for Geographic And Racial Differences in Stroke) cohort. Baseline AF was ascertained from ECG and self-reported history of physician diagnosis. Incident HF events were determined from physician-adjudicated review of hospitalisation medical records and HF deaths. Based on left ventricular ejection fraction (LVEF) at the time of HF event, HFrEF, HFpEF, and mid-range HF were defined as LVEF <40%, ≥50% and 40%-49%, respectively. Multivariable Cox proportional-hazards models examined the association between AF and HF. The Lunn-McNeil method was used to compare associations of AF with incident HFrEF versus HFpEF., Results: Over a median of 9 years of follow-up, 1109 HF events occurred (356 HFpEF, 388 HFrEF, 77 mid-range and 288 unclassified). In a model adjusted for sociodemographics, cardiovascular risk factors, and incident coronary heart disease, AF was associated with increased risk of all HF events (HR 1.67, 95% CI 1.38 to 2.01). The associations of AF with HFrEF versus HFpEF events did not differ significantly (HR 1.87 (95% CI 1.38 to 2.54) and HR 1.65 (95% CI 1.20 to 2.28), respectively; p value for difference=0.581). These associations were consistent in sex and race subgroups., Conclusions: AF is associated with both HFrEF and HFpEF events, with no significant difference in the strength of association among these subtypes., Competing Interests: Competing interests: EBL: research funding from Amgen and scientific consulting for a research project funded by Novartis., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Upstream therapy of atrial remodeling may decrease atrial fibrillation and associated thromboembolism. We examined the impact of intensive BP lowering on ECG-defined left atrial abnormalities in the SPRINT. SPRINT was a randomized clinical trial comparing outcomes when a systolic BP of <120 mmHg (standard treatment) was the target. We included SPRINT participants without baseline atrial fibrillation who had a technically interpretable baseline ECG and at least one follow-up ECG. The primary outcome was incident left atrial abnormality, defined as P-wave terminal force in V 1 (PTFV 1 ) > 4000 μV × ms. Secondary outcomes were regression of the left atrial abnormality and the change in PTFV 1 from baseline across follow-up ECGs. Cox regression was used to examine the associations between treatment assignment and incident left atrial abnormality and its regression. We used linear mixed models to examine the changes in PTFV 1 . Of 9361 SPRINT participants, 7738 qualified for this analysis, of whom 5544 did not have baseline left atrial abnormalities. Intensive BP management was not associated with incident left atrial abnormality (HR, 0.96; 95% CI, 0.87-1.07) or regression of the baseline left atrial abnormality (HR, 1.09; 95% CI, 0.98-1.21). The change in PTFV 1 from baseline through follow-up did not differ significantly between treatment groups (difference in μV × ms per year, 6; 95% CI, -67 to 79). Thus, among patients in a randomized clinical trial, we found no difference in the progression or regression of ECG-defined left atrial abnormalities with intensive BP management compared to standard BP management., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Social determinants of health are relevant to cardiovascular outcomes but have had limited examination in atrial fibrillation (AF)., Objectives: The purpose of this study was to examine the association of annual household income and cardiovascular outcomes in individuals with AF., Methods: We analysed administrative claims for individuals with AF from 2009 to 2015 captured by a health claims database. We categorised estimates of annual household income as <$40 000; $40-$59 999; $60-$74 999; $75-$99 999; and ≥$100 000. Covariates included demographics, education, cardiovascular disease risk factors, comorbid conditions and anticoagulation. We examined event rates by income category and in multivariable-adjusted models in reference to the highest income category (≥$100 000)., Results: Our analysis included 336 736 individuals (age 72.7±11.9 years; 44.5% women; 82.6% white, 8.4% black, 7.0% Hispanic and 2.1% Asian) with AF followed for median (25th and 75th percentile) of 1.5 (95% CI 0.6 to 3.0) years. We observed an inverse association between income and heart failure and myocardial infarction (MI) with evidence of progressive risk across decreased income categories. Individuals with household income <$40 000 had the greatest risk for heart failure (HR 1.17; 95% CI 1.05 to 1.30) and MI (HR 1.18; 95% CI 0.98 to 1.41) compared with those with income ≥$100 000., Conclusions: We identified an association between lower household income and adverse outcomes in a large cohort of individuals with AF. Our findings support consideration of income in the evaluation of cardiovascular risk in individuals with AF., Competing Interests: Competing interests: Disclosures: LB is an employee of Optum. There are no other author disclosures., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The association between objectively measured physical activity and atrial fibrillation (AF) has not been examined. Therefore, we examined the association between moderate and vigorous physical activity (MVPA) with incident AF in 5,147 participants who completed accelerometer assessment for 4 to 7 consecutive days in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. MVPA was defined as >1,065 counts/minute, and daily mean time spent in MVPA was computed. Incident AF was identified during follow-up by a study-scheduled electrocardiogram and also from self-reported medical history of a physician diagnosis. Logistic regression was used to assess the relation between daily time in MVPA and incident AF. A total of 429 (8.3%) incident AF cases were detected after a median follow-up of 3.5 years following accelerometer assessment. Participants with higher daily time spent in MVPA were less likely to develop AF than those with lower MVPA achievement (Quartile 1 = 12.4%; Quartile 2 = 8.3%; Quartile 3 = 7.1%; Quartile 4 = 5.4%; p-trend <0.001). In a multivariable model adjusted for AF risk factors, the risk of AF decreased with higher levels of daily MVPA (Quartile 1: Ref; Quartile 2: hazard ratio [HR] = 0.77, 95% confidence interval [CI] 0.58 to 1.01; Quartile 3: HR = 0.72, 95% CI 0.53 to 0.98; Quartile 4: HR = 0.62, 95% CI 0.44 to 0.87; p-trend = 0.0056). In conclusion, higher levels of objectively measured daily MVPA are protective against the development of AF suggesting that promotion of MVPA should be encouraged to reduce the risk of AF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Aims: Evaluating associations of circulating electrolytes with atrial fibrillation (AF) and burden of supraventricular arrhythmias can give insights into arrhythmia pathogenesis., Methods and Results: We conducted a cross-sectional analysis of 6398 participants of the Atherosclerosis Risk in Communities (ARIC) study, ages 71-90, with data on serum electrolytes (magnesium, calcium, potassium, phosphorus, chloride, sodium). Prevalence of AF was determined from electrocardiograms and history of AF hospitalizations. A subset of 317 participants also underwent electrocardiographic recordings for up to 14 days using the Zio® patch. Burden of other supraventricular arrhythmias [premature atrial contractions (PACs), supraventricular tachycardia] was determined with the Zio® patch. We used logistic and linear regression adjusting for potential confounders to determine associations of electrolytes with arrhythmia prevalence and burden. Among 6394 eligible participants, 614 (10%) had AF. Participants in the top quintiles of magnesium [odds ratio (OR) 0.82, 95% confidence interval (CI) 0.62, 1.08], potassium (OR 0.82, 95%CI 0.68, 1.00), and phosphorus (OR 0.73, 95%CI 0.59, 0.89) had lower AF prevalence compared to those in the bottom quintiles. No clear association was found for circulating chloride, calcium or sodium. Higher concentrations of circulating calcium were associated with lower prevalence of PACs in the 12-lead electrocardiogram, while higher concentrations of potassium, chloride and sodium were associated with higher PAC prevalence. Circulating electrolytes were not significantly associated with burden of PACs or supraventricular tachycardia among 317 participants with extended electrocardiographic monitoring., Conclusion: Concentrations of circulating electrolytes present complex associations with selected supraventricular arrhythmias. Future studies should evaluate underlying mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background Atrial fibrillation (AF) is associated with a 5-fold increased stroke risk. While most patients with AF warrant anticoagulation, optimal treatment remains uncertain for patients with AF without cardiovascular comorbidities because the risk of stroke in this population has not been well-characterized. Methods and Results Participants (N=28 253; 55% women, mean age 64.6±9.4 years), from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study (2003-present) were classified into 1 of 4 groups based on the presence or absence of AF and the presence or absence of cardiovascular comorbidities. Cox proportional hazards analysis was used to compare the risk of stroke between groups. During 244 560 person-years of follow-up (median 8.7 years), 1206 strokes occurred. Compared with patients with neither AF nor cardiovascular comorbidities, we did not find an increased stroke risk (hazard ratio [HR], 1.23; 95% CI, 0.62-2.18 [ P =0.511]) among participants with AF alone. Participants without AF but with cardiovascular comorbidities had both an elevated stroke risk (HR, 1.77; 95% CI, 1.48-2.18 [ P <0.0001]) and an increased risk of cardioembolic stroke (HR, 2.34; 95% CI, 1.48-3.90 [ P =0.0002]). Conclusions In this large cohort of participants with AF without cardiovascular comorbidities, we found that AF itself, without cardiovascular comorbidities, did not confer increased risk of stroke. Cardiovascular comorbidities, however, were associated with an increased risk of both stroke of any type and cardioembolic stroke, even in the absence of AF.

Exposure to psychological stress has been associated with the development of sustained arrhythmias. Acute changes in atrial electrophysiology may serve as intermediate phenotypes for stress-induced atrial arrhythmia such as atrial fibrillation. We examined if acute mental stress was associated with the development of abnormal P-wave axis (aPWA) and the role played by stress-induced myocardial ischemia. A total of 359 patients (mean age = 56 ± 9.9 years; 62% men; 43% white) with stable coronary heart disease and normal baseline P-wave axis (between 0° and 75°) were studied. All patients underwent mental stress testing (speech task). A total of 46 (13%) patients developed abnormal P-wave axis during either stress or recovery (stress: n = 43, 12%; recovery: n = 12, 3%). A rise in heart rate during mental stress was associated with an increased risk of an abnormal P-wave axis (per 5-unit increase: OR = 1.37, 95%CI = 1.03, 1.30). Myocardial ischemia induced by mental stress was associated with an increased risk of aPWA in women (OR = 5.2, 95%CI = 1.7, 15.6) and not in men (OR = 0.1, 95%CI = 0.01, 1.01), p-interaction = 0.004). In conclusion, in a sizable proportion of patients, acute mental stress results in the development of an abnormal P-wave axis, and this phenomenon is related to increases in heart rate and, among women, mental stress-induced ischemia. Our data suggest that acute psychological stress can promote adverse transient electrical changes in the atria that may predispose to AF., Competing Interests: Declaration of competing interest None of the other authors report conflict of interest relevant to this article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Resting heart rate (RHR), which may be modifiable through lifestyle changes, has been shown to be associated with cardiovascular disease risk and with inflammatory markers that have been predictive of VTE incidence., Methods: We examined whether RHR is also associated with VTE incidence independent of these risk factors. We studied 6479 Multi-Ethnic Study of Atherosclerosis participants free from clinical VTE at baseline who had baseline RHR ascertained by 12-lead ECG. VTE events were recorded from hospital records and death certificates using International Classification of Diseases (ICD)-9 and ICD-10 codes. We categorised RHR as <60, 60-69, 70-79 and ≥80 bpm. We used Cox hazard models to determine the association of incident VTE by RHR., Results: Participants had mean (SD) age of 62 (10) years and RHR of 63 (10) bpm. RHR was cross-sectionally correlated with multiple inflammatory and coagulation factors. There were 236 VTE cases after a median follow-up of 14 years. Compared with those with RHR<60 bpm, the HR (95% CI) for incident VTE for RHR≥80 bpm was 2.08 (1.31 to 3.30), after adjusting for demographics, physical activity, smoking, diabetes and use of atrioventricular (AV)-nodal blockers, aspirin and anticoagulants, and remained significant after further adjustment for inflammatory markers (2.05 (1.29 to 3.26)). Results were similar after excluding those taking AV-nodal blocker medications. There was no effect modification of these associations by sex or age., Conclusion: Elevated RHR was positively associated with VTE incidence after a median of 14 years; this association was independent of several traditional VTE and inflammatory markers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background and Aims: Individuals with low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are considered high-risk and current guidelines recommend initiating high-intensity statin therapy in this group. We sought to examine the predictive ability of zero CAC in this high-risk group., Methods: Multi-Ethnic Study of Atherosclerosis participants without clinical cardiovascular disease and baseline LDL-C ≥190 mg/dL were identified. Cardiovascular risk factors were compared between those with CAC = 0 and CAC >0. Multivariable Poisson regression was used to identify predictors of CAC = 0. Association of CAC = 0 with incident cardiovascular events over a median follow-up of 13.2 years was examined using multivariable-adjusted Cox regression., Results: 246 individuals (mean age = 63 ± 9.4 years; 42% male; 31% white; 37% CAC = 0) with LDL-C ≥190 mg/dL were identified (mean LDL-C = 215 ± 27 mg/dL). Age <65 years (RR = 2.17, 95%CI = 1.49-3.23), female sex (RR = 2.10, 95%CI = 1.42-3.10), and no diabetes (RR = 2.22, 95%CI = 1.18-4.17) were associated with CAC = 0. Individuals with CAC = 0 had a lower risk for future cardiovascular events (incidence rate per 1000 person-years = 4.7; 10-year risk = 3.7%; risk/year = 0.4%) than those with CAC >0 (incidence rate per 1000 person-years = 26.4; 10-year risk = 20%; risk/year = 2.0%), adjusted HR 0.25 (95%CI = 0.10-0.66)., Conclusions: Among persons with LDL-C ≥190 mg/dL, younger age, female sex, and the absence of diabetes were associated with CAC = 0. CAC = 0 was associated with a low risk of cardiovascular events, suggesting the utility of CAC assessment for stratifying risk in this high-risk group., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Lung cancer survivors are at risk for physical fitness and autonomic function impairments. In a cross-sectional study of consecutive lung cancer survivors post-curative intent therapy, we assessed and identified predictors of resting heart rate variability (HRV) and heart rate recovery (HRR), defined as standard deviation of normal-to-normal-R-to-R intervals (SDNN) and root-mean-square-of-successive-differences (rMSSD) from routine outpatient single 10-s electrocardiographs (ECGs) and difference in heart rate (HR) at 1-minute following and the end of the six-minute-walk-test (6MWT), respectively. In 69 participants, the mean (SD) HRR was -10.6 (6.7) beats. Significant independent predictors of HRR were age and HR change associated with the 6MWT. In a subset of 41 participants with available ECGs, the mean (SD) SDNN and rMSSD were 19.1 (15.6) and rMSSD 18.2 (14.6) ms, respectively. Significant independent predictors of HRV were supine HR, HRR, and total lung capacity. HRV/HRR may be useful physiological measures in studies aimed at improving physical fitness and/or autonomic function in lung cancer survivors., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background Circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, a well-known indicator of atrial wall stress and remodeling, inversely correlate with body mass index. Both are strongly predictive of atrial fibrillation (AF). Their potential interaction in relation to incident AF, however, has not been explored. Methods and Results In total, 9556 participants of the ARIC (Atherosclerosis Risk in Communities) study who had 2 measurements of NT-proBNP and no baseline AF or heart failure were followed from 1996 to 1998 through 2016 for the occurrence of incident AF. Participants were categorized as obese (body mass index ≥30) and nonobese (body mass index <30) and by NT-proBNP levels (using the median of 68.2 pg/mL as the cutoff). Over a median follow-up of 18.3 years, we identified 1806 incident cases of AF. Analysis using multivariable Cox regression models showed that obese participants with high NT-proBNP levels at visit 4 had a higher adjusted risk of incident AF (hazard ratio: 3.64; 95% CI, 3.15-4.22) compared with nonobese individuals with low NT-proBNP levels. The association of obesity with AF risk was not modified by NT-proBNP levels ( P =0.46 for interaction). Increasing BNP among participants from 1990-1992 to 1996-1998 was associated with increased AF risk. After further adjustment for clinical risk factors and medications, results were similar. Conclusions Individuals who had both elevated body mass index and NT-proBNP and were free of clinically recognized heart failure were at higher risk of AF development. Those who experienced an increase in NT-proBNP levels between visits 2 and 4 were at higher risk of AF.

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., Competing Interests: LGSB is employed by Optum, but neither they nor the rest of the authors have had special access or privileges to the Optum data that others would not have. This does not alter our adherence to PLOS ONE policies on sharing data and materials, with the restrictions stated above. Authors do not have any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products.

Objective: Whether endogenous testosterone concentrations are associated with atrial fibrillation (AF) development is not well established. We assessed the association between plasma total testosterone concentrations and incident AF in a population-based longitudinal study., Study Design: Using data from the prospective Atherosclerosis Risk in Communities (ARIC) study, we identified incident AF among 9282 participants who had plasma total testosterone measured by liquid chromatography tandem mass spectrometry at Visit 4 (1996-1998)., Main Outcome Measures: AF cases were identified by electrocardiograms performed during study visits, hospital records/discharge codes, and death certificates through 2013. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident AF across quartiles of plasma total testosterone, stratified by sex, with multivariable Cox models., Results: The mean age of the participant sample at ARIC Visit 4 was 63 years (range 52-75); 54.5% were women. Mean (SD) plasma total testosterone levels were 537 ng/dL (213) for men and 27.6 ng/dL (34.7) for women. Over a mean of 13.7 years of follow-up, 1664 incident cases of AF were identified. Comparing those in the highest quartile of plasma total testosterone concentration to those in the lowest quartile and after adjustment for potential confounding variables, there was a positive association between plasma total testosterone and incident AF in men (HR 1.33, 95% CI 1.07, 1.66), but no such association in women (HR 0.99, 95% CI 0.80, 1.22). Conclusion A higher plasma total testosterone concentration was associated with a modestly greater incidence rate of AF in men., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We have previously identified associations of 2 circulating secondary bile acids (glycocholenate and glycolithocolate sulfate) with atrial fibrillation (AF) risk in 1,919 blacks in the Atherosclerosis Risk in Communities cohort. We aimed to replicate these findings in an independent sample of 2,003 white and black Atherosclerosis Risk in Communities participants, and performed a new metabolomic analysis in the combined sample of 3,922 participants, followed between 1987 and 2013. Metabolomic profiling was done in baseline serum samples using gas and liquid chromatography mass spectrometry. AF was ascertained from electrocardiograms, hospitalizations, and death certificates. We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of AF by 1 standard deviation difference of metabolite levels. Over a mean follow-up of 20 years, 608 participants developed AF. Glycocholenate sulfate was associated with AF in the replication and combined samples (HR 1.10, 95% CI 1.00, 1.21 and HR 1.13, 95% CI 1.04, 1.22, respectively). Glycolithocolate sulfate was not related to AF risk in the replication sample (HR 1.02, 95% CI 0.92, 1.13). An analysis of 245 metabolites in the combined cohort identified 3 additional metabolites associated with AF after multiple-comparison correction: pseudouridine (HR 1.18, 95% CI 1.10, 1.28), uridine (HR 0.86, 95% CI 0.79, 0.93) and acisoga (HR 1.17, 95% CI 1.09, 1.26). In conclusion, we replicated a prospective association among a previously identified secondary bile acid, glycocholenate sulfate, and AF incidence, and identified new metabolites involved in nucleoside and polyamine metabolism as markers of AF risk., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background The association of antidepressant medication type with the risk of cardiovascular disease ( CVD ) is unclear. We hypothesized that selective serotonin reuptake inhibitors ( SSRI s) are associated with lower risks of CVD events relative to tricyclics and other non- SSRI antidepressants. Methods and Results We studied 2027 participants from the ARIC (Atherosclerosis Risk in Communities) study (mean age 63±10 years; 29% men; 78% white) treated with antidepressants at some time between 1987 and 2013. Antidepressant usage was confirmed by participants bringing pill bottles to study visits. CVD events in the study sample were identified, including atrial fibrillation, heart failure, myocardial infarction, and ischemic stroke. Hazard ratios were used to compare CVD events adjusted for sociodemographic and clinical risk factors in SSRI s users (47%) versus non- SSRI users. Participants were followed from antidepressant initiation up to 2016 for a median of 13.5 years. We identified 332 atrial fibrillation, 365 heart failure, 174 myocardial infarction and 119 ischemic stroke events. CVD risk was similar for SSRI s and non- SSRI antidepressant users (hazard ratio, 1.10; 95% CI , 0.86-1.41 for atrial fibrillation; hazard ratio, 0.98; 95% CI, 0.77-1.25 for heart failure; hazard ratio, 0.91; 95% CI , 0.64-1.29 for myocardial infarction; and hazard ratio, 1.07; 95% CI , 0.70-1.63 for ischemic stroke). Conclusions SSRI use was not associated with reduced risk of incident CVD compared with non- SSRI antidepressant use. These results do not provide evidence supporting the use of SSRI s compared with tricyclics and other non- SSRI antidepressants in relation to CVD risk.

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.)

Background: The autonomic response to acute emotional stress can be highly variable, and pathological responses are associated with increased risk of adverse cardiovascular events. We evaluated the autonomic response to stress reactivity of young healthy subjects and aging subjects with coronary artery disease to understand how the autonomic stress response differs with aging., Methods: Physiologic reactivity to arithmetic stress in a cohort of 25 young, healthy subjects (< 30 years) and another cohort of 25 older subjects (> 55 years) with CAD was evaluated using electrocardiography, impedance cardiography, and arterial pressure recordings. Stress-related changes in the pre-ejection period (PEP), which measures sympathetic activity, and high frequency heart rate variability (HF HRV), which measures parasympathetic activity, were analyzed as primary outcomes., Results: Mental stress reduced PEP in both groups (p<0.01), although the decrease was 50% greater in the healthy group. Mean HF HRV decreased significantly in the aging group only (p = 0.01)., Discussion: PEP decreases with stress regardless of health and age status, implying increased sympathetic function. Its decline with stress may be attenuated in CAD. The HF HRV (parasympathetic) stress reactivity is more variable and attenuated in younger individuals; perhaps this is related to a protective parasympathetic reflex., Trial Registration: ClinicalTrials.gov Identifier: NCT02657382., Competing Interests: The authors have declared that no competing interests exist.

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: Low diastolic blood pressure (DBP) is associated with increased risk of cardiovascular events. In patients with coronary artery disease (CAD), limitations in coronary blood flow and immune activity are implicated mechanisms, but evidence is lacking. We investigated the association between DBP, biomarkers of myocardial injury, inflammation, immune activation and incident events in patients with CAD., Methods: We studied 2448 adults (mean age 65 ± 12 years, 68% male, median follow-up 4.5 years) with CAD. DBP was categorized into 10 mm Hg increments. Biomarkers of myocardial injury (high sensitivity cardiac troponin-I [hs-cTnI]) and immune activity/inflammation (soluble urokinase plasminogen activator receptor [suPAR]) were dichotomized at their median values. DBP 70-79 mm Hg was used as the referent group, and individuals were followed prospectively for adverse outcomes., Results: After adjusting for demographic and clinical covariates, individuals with DBP < 60 mm Hg had increased odds of elevated levels of hs-cTnI (OR = 1.68; 95% CI = 1.07, 2.65) and suPAR (OR = 1.71; 95% CI = 1.10, 2.65) compared to the referent group. Additionally, DBP < 60 mm Hg was associated with increased adjusted risk of cardiovascular death or MI (HR = 2.04; 95% CI = 1.32, 3.16) and all-cause mortality (HR = 2.41; 95% CI = 1.69, 3.45)., Conclusion: In patients with CAD, DBP < 60 mm Hg is associated with subclinical myocardial injury, immune/inflammatory dysregulation and incident events. Aggressive BP control may be harmful in these patients, and further investigation is warranted to determine appropriate BP targets in patients with CAD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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: 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.

An assumption regarding transcatheter aortic valve replacement (TAVR), a minimally invasive procedure for treating aortic stenosis, is that patients remain at, or near baseline and soon return to their presurgical home to resume activities of daily living. However, this does not consistently occur. The purpose of this study was to identify preoperative factors that optimally predict discharge to a skilled nursing facility (SNF) after TAVR. Delineation of these conditions is an important step in developing a risk stratification model to assist in making informed decisions. Data was extracted from the American College of Cardiology (ACC) transcatheter valve therapy (TVT) registry and the Society of Thoracic Surgeons (STS) database on 285 patients discharged from 2012⁻2017 at a tertiary referral heart institute located in the southeastern region of the United States. An analysis of assessment, clinical and demographic variables was used to estimate relative risk (RR) of discharge to a SNF. The majority of participants were female (55%) and white (84%), with a median age of 82 years (interquartile range = 9). Approximately 27% ( n = 77) were discharged to a SNF. Age > 75 years (RR = 2.3, p = 0.0026), female (RR = 1.6, p = 0.019), 5-meter walk test (5MWT) >7 s (RR = 2.0, p = 0.0002) and not using home oxygen (RR = 2.9, p = 0.0084) were identified as independent predictive factors for discharge to a SNF. We report a parsimonious risk-stratification model that estimates the probability of being discharged to a SNF following TAVR. Our findings will facilitate making informed treatment decisions regarding this older patient population.

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 OAC s. Methods and Results We identified patients with nonvalvular AF initiating OAC s 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 ( HR s) and 95% confidence intervals ( CI s) 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.

Introduction: The American Heart Association's Life's Simple 7 includes seven metrics of ideal cardiovascular health to target for cardiovascular disease prevention. This study determined the relationship between Life's Simple 7 and incident peripheral artery disease in a biracial cohort of middle- and older-aged adults., Methods: This analysis included 12,865 participants from the Atherosclerosis Risk in Communities study recruited between 1987 and 1989 (mean age=54years, 55% women, 25% black) and free of peripheral artery disease or other cardiovascular disease at baseline. Overall, Life's Simple 7 score was calculated as the sum of the Life's Simple 7 component scores (two points if ideal, one point if intermediate, and zero if poor) and classified as inadequate (zero to four), average (five to nine), or optimal (ten to 14) cardiovascular health and linked to incident peripheral artery disease identified by hospital discharge diagnosis and leg revascularization. Analysis was conducted in 2017., Results: A total of 434 incident peripheral artery disease cases occurred over a median follow-up of 24.4years. Compared with the inadequate category (n=1,008), participants in the average (n=8,395) and optimal (n=3,462) categories each had a substantially lower risk of developing peripheral artery disease in a Cox proportional hazards model adjusted for potential confounders (hazard ratio=0.36, 95% CI=0.28, 0.46 for average, and hazard ratio=0.09, 95% CI=0.06, 0.15 for optimal). In a similar model, a one-point higher Life's Simple 7 score was associated with a 25% lower risk of incident peripheral artery disease (hazard ratio=0.75, 95% CI=0.72, 0.79)., Conclusions: Better cardiovascular health, as defined by higher Life's Simple 7 score, is associated with a substantially lower risk of peripheral artery disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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: Traditional cardiovascular (CV) risk factors have limited predictive value of CV mortality in patients with chronic kidney disease (CKD, creatinine clearance less than 60 mL/minute per 1.73 m 2 ). The aim of this study was to evaluate incremental and independent prognostic value of single-photon emission computerized tomography-myocardial perfusion imaging (SPECT-MPI) across continuum of renal function., Methods: We retrospectively studied 11,518 (mean age, 65 ± 12 years; 52% were men) patients referred for a clinical indication of SPECT-MPI between April 2004 and May 2009. Primary end point was composite of cardiac death and non-fatal myocardial infarction (CD/MI). We examined the relationship of total perfusion defect (TPD) and CD/MI in multiple Cox regression models for CV risk factors and GFR. The incremental predictive value of TPD was examined using Harrell's c-index, net reclassification index (NRI), and integrated discrimination index (IDI)., Results: Over a median follow-up of 5 years (25th to 75th percentiles, 3.0-6.5 years), 1,692 (14.5%) patients experienced CD/MI (740 MI and 1,182 CD). In a multivariable model adjusted for traditional CV risk factors and GFR, the presence of a perfusion defect was independently associated with increased risk of CD/MI (HR = 2.10; 95% CI 1.81, 2.43, p < .001). Using Cox regression, TPD improved the discriminatory ability beyond traditional CV risk factors and GFR [from AUC = 0.725, (95% CI 0.712-0.738) to 0.784, (95% CI 0.772-0.796), p < .0001]. Furthermore, TPD improves risk stratification of CKD patients over and above traditional CV risk factors and GFR [NRI = 14%, 95% CI (12%-16%, p < .001) and relative IDI = 60%, 95% CI (51%, 66%, p < .001)]., Conclusions: Across the spectrum of renal function, SPECT-MPI perfusion defects independently and incrementally reclassified patients for their risk of CD/MI, beyond traditional CV risk factors.

Background: Circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) predicts incidence of atrial fibrillation (AF), but the association of longitudinal changes in NT-proBNP concentrations with incident AF has not been explored., Methods: We studied 9705 individuals without prevalent AF in 1996-1998 and with available NT-proBNP measurements obtained in samples collected during two visits in 1990-1992 (visit 2) and 1996-1998 (visit 4) in the Atherosclerosis Risk in Communities (ARIC) Study. Participants were followed through the end of 2013. AF was ascertained from electrocardiograms, hospital discharge codes, and death certificates. Multivariable Cox regression was used to evaluate the association of absolute change in log-transformed NT-proBNP [ln(NT-proBNP)] with incident AF. We also assessed the impact of adding ln(NT-proBNP) change as a predictor of AF by difference in the C-statistic and net reclassification improvement (NRI)., Results: Over a median follow up of 16 years, there were 1503 incident cases of AF. The means (SD) ln(NT-proBNP) at visit 2 and visit 4 were 3.83 (1.01) and 4.35 (0.94), respectively. There was a 0.52 (0.79) increase in ln(NT-proBNP) over the 6-year period. Greater increases in ln(NT-proBNP) were associated with higher risk of AF [hazard ratio, 2.82 (95% confidence interval 2.34, 3.39), comparing top to bottom quintiles, and 1.74 (1.61, 1.87) per 1-unit increase in ln(NT-proBNP)]. Adding ln(NT-proBNP) change to a model with multiple predictors including baseline NT-proBNP had relatively limited impact in the C-statistic (increase from 0.748, 95%CI 0.736-0.761, to 0.762, 95%CI 0.750, 0.774). Adding ln(NT-proBNP) change to initial predictive models resulted in a categorical NRI of 0.062 (95% CI 0.033, 0.092) and a continuous NRI of 0.092 (95%CI, 0.017, 0.182)., Conclusion: Positive NT-proBNP change is associated with an increased incidence rate of AF. Adding NT-proBNP change into the prediction model modestly improved incident AF prediction. Future studies should assess the value of monitoring NT-proBNP concentration among individuals at high risk of developing AF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) and its associated economic burden are increasing globally. Although cardiac rehabilitation is a vital component of secondary prevention with proven benefits, it is underutilized due to numerous barriers, especially in resource-limited settings. New care models for delivery of comprehensive prevention programs such as community-based, home-based, and "hybrid" models implementing m-health, e-health, and telemedicine need to be adopted. Such new care models should be offered to all patients with established ASCVD (coronary, cerebral, and peripheral) and additionally to those at high risk of developing ASCVD with multiple risk factors for panvascular prevention., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: No scores presently exist to predict bleeding in atrial fibrillation (AF) populations using direct oral anticoagulants (DOACs). We used data from two independent healthcare claims databases to develop and validate a predictive model of major bleeding in a contemporary AF population., Methods: Patients with non-valvular AF initiating oral anticoagulation were identified in the MarketScan databases from 2007-2014. Using Cox regression models in 1000 bootstrapped samples, we developed a model that selected variables predicting major bleeding in the first year after anticoagulant initiation. The final model was validated in patients with non-valvular AF in the Optum Clinformatics database in the period 2009-2015. The discriminative ability of existing bleeding scores were individually evaluated and compared with the new bleeding model termed Anticoagulation-specific Bleeding Score (ABS) in both MarketScan and Optum., Results: Among 119,083 patients with AF initiating oral anticoagulation in the derivation cohort, 4,030 experienced a bleeding event. The variable selection model identified 15 variables (including individual type of oral anticoagulant) associated with major bleeding. Discrimination of the model was modest [c-statistic 0.68, 95% confidence interval (CI) 0.67-0.69]. The model was subsequently applied to 81,285 AF patients in the validation data set (3,238 bleeding events), showing similar discrimination (c-statistic 0.68, 95% CI 0.67-0.69). In both cohorts, the predictive performance of the ABS was better than the existing models for bleeding prediction in AF., Conclusions: We developed a model that uses administrative healthcare data for the identification of AF patients at higher risk of bleeding after initiation of oral anticoagulation, taking into account the lower bleeding risk in DOAC compared to warfarin users., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Lindsay Bengtson is an employee of Optum. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have declared that no competing interests exist.

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rationale: Blacks compared with whites have a greater risk of adverse cardiovascular outcomes. Impaired regenerative capacity, measured as lower levels of circulating progenitor cells (CPCs), is a novel determinant of adverse outcomes; however, little is known about racial differences in CPCs., Objective: To investigate the number of CPCs, PC-mobilizing factors, PC mobilization during acute myocardial infarction and the predictive value of CPC counts in blacks compared with whites., Methods and Results: CPCs were enumerated by flow cytometry as CD45med + blood mononuclear cells expressing CD34+, CD133+, VEGF2R+, and CXCR4+ epitopes in 1747 subjects, mean age 58.4±13, 55% male, and 26% self-reported black. Patients presenting with acute myocardial infarction (n=91) were analyzed separately. Models were adjusted for relevant clinical variables. SDF-1α (stromal cell-derived factor-1α), VEGF (vascular endothelial growth factor), and MMP-9 (matrix metallopeptidase-9) levels were measured (n=561), and 623 patients were followed for median of 2.2 years for survival analysis. Blacks were younger, more often female, with a higher burden of cardiovascular risk, and lower CPC counts. Blacks had fewer CD34+ cells (-17.6%; [95% confidence interval (CI), -23.5% to -11.3%]; P<0.001), CD34+/CD133+ cells (-15.5%; [95% CI, -22.4% to -8.1%]; P<0.001), CD34+/CXCR4+ cells (-17.3%; [95% CI, -23.9% to -10.2%]; P<0.001), and CD34+/VEGF2R+ cells (-27.9%; [95% CI, -46.9% to -2.0%]; P=0.04) compared with whites. The association between lower CPC counts and black race was not affected by risk factors or cardiovascular disease. Results were validated in a separate cohort of 411 patients. Blacks with acute myocardial infarction had significantly fewer CPCs compared with whites ( P=0.02). Blacks had significantly lower plasma MMP-9 levels ( P<0.001) which attenuated the association between low CD34+ and black race by 19% (95% CI, 13%-33%). However, VEGF and SDF-1α levels were not significantly different between the races. Lower CD34+ counts were similarly predictive of mortality in blacks (hazard ratio, 2.83; [95% CI, 1.12-7.20]; P=0.03) and whites (hazard ratio, 1.79; [95% CI, 1.09-2.94]; P=0.02) without significant interaction., Conclusions: Black subjects have lower levels of CPCs compared with whites which is partially dependent on lower circulating MMP-9 levels. Impaired regenerative capacity is predictive of adverse outcomes in blacks and may partly account for their increased risk of cardiovascular events.

Smoking is an important risk factor in the development of heart failure with preserved ejection (HFpEF), and previous reports have identified smoking as a significant predictor of death in this population. However, the relation between smoking and heart failure-specific outcomes has not been examined in patients with HFpEF. This analysis included 1,717 patients (mean age = 71 ± 10 years; 50% men; 78% white) with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial from the Americas. Smoking was ascertained by self-reported history and categorized as never, former, or current. Multivariable Cox regression was used to examine the risk of hospitalization for heart failure, death, and cardiovascular death across smoking categories. There were 116 current smokers (7%), 871 former smokers (51%), and 729 never smokers (42%) in this analysis. Current smoking was associated with an increased risk of hospitalization for heart failure (never: hazard ratio [HR] 1.0; former: HR 1.25, 95% confidence interval [CI] 0.99 to 1.57; current: HR 1.68, 95% CI 1.08 to 2.61), death (never: HR 1.0; former: HR 1.02, 95% CI 0.81 to 1.29; current: HR 1.82, 95% CI 1.19 to 2.78), and cardiovascular death (never: HR 1.0; former: HR 1.00, 95% CI 0.74 to 1.35; current: HR 1.85, 95% CI 1.09 to 3.24) compared with former or never smokers in a multivariable model adjusted for cardiovascular risk factors. A similar increased risk of hospitalization for heart failure (former: HR 1.0; current: HR 1.54, 95% CI 1.01, 2.36), death (former: HR 1.0; current: HR 1.81, 95% CI 1.19, 2.75), and cardiovascular death (former: HR 1.0; current: HR 1.76, 95% CI 1.04, 2.98) was observed for current smokers when we limited the analysis to those with a history of smoking. In conclusion, current smoking is associated with an increased risk for adverse outcomes in HFpEF, including hospitalization for heart failure. Smoking cessation strategies possibly have a role to reduce the risk for adverse cardiovascular outcomes in patients with HFpEF., (Copyright © 2018. Published by Elsevier Inc.)

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., (Copyright © 2018. Published by Elsevier Inc.)

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., (© 2018 American Heart Association, Inc.)

It is unknown whether the association of high-sensitivity troponin I (hs-TnI) with adverse cardiovascular outcomes varies by the presence of chronic kidney disease (CKD). We examined the association of hs-TnI with adverse cardiovascular outcomes in those with and without CKD in 4,107 (mean age, 64 years; 63% men; 20% black) patients from the Emory Cardiovascular Biobank who underwent coronary angiography. CKD (n = 1,073) was defined as estimated glomerular filtration rate <60 ml/min/1.73 m 2 or urine albumin/creatinine ratio >30 mg/g at baseline. Cox regression was used to compute hazard ratios (HR) for the association between hs-TnI levels (per doubling of hs-TnI: log 2 [hs-TnI] + 1) and death, cardiovascular death, and major adverse cardiac events (MACE), separately. Hs-TnI was a stronger predictor of death (CKD: HR 1.23, 95% confidence interval [CI] 1.15 to 1.31; no CKD: HR 1.11, 95% CI 1.05 to 1.17, p-interaction = 0.023), cardiovascular death (CKD: HR 1.24, 95% CI 1.14 to 1.34; no CKD: HR 1.15, 95% CI 1.07 to 1.22, p-interaction = 0.12), and MACE (CKD: HR 1.18, 95% CI 1.11 to 1.25; no CKD: HR 1.11, 95% CI 1.06 to 1.16, p-interaction = 0.095) in CKD compared with non-CKD. The association between hs-TnI and death in patients with CKD was stronger for patients without obstructive coronary artery disease (no obstructive coronary artery disease: HR 1.60, 95% CI 1.27 to 2.01; obstructive coronary artery disease: HR 1.19, 95% CI 1.11 to 1.27, p-interaction = 0.041). In conclusion, hs-TnI is a stronger predictor of adverse cardiovascular events in patients who have CKD than those without, even in the absence of obstructive coronary artery disease. Hs-TnI may identify CKD patients who are high risk for adverse cardiovascular outcomes in whom aggressive risk factor modification strategies are warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Aims: Left-sided valvular calcification is associated with cardiovascular disease (CVD) morbidity and mortality. Resting heart rate (RHR) may influence valvular calcium progression through shear stress. Whether RHR, an established CVD risk factor, is associated with valvular calcium progression is unknown. We assessed whether RHR predicts incidence and progression of mitral annular calcium (MAC) and aortic valve calcium (AVC) in a community-based cohort free of CVD at baseline., Methods: RHR was obtained from baseline electrocardiograms of 5498 MESA participants. MAC and AVC were quantified using Agatston scoring from cardiac computed tomography scans obtained at baseline and at a second examination during follow-up. We examined associations of RHR with incident MAC/AVC and annual change in MAC/AVC scores, after adjusting for demographics, CVD risk factors, physical activity, and atrioventricular nodal blocker use., Results: At baseline, participants had mean age of 62 ± 10 years and mean RHR of 63 ± 10 bpm; 12.3% and 8.9% had prevalent AVC and MAC, respectively. Over a median of 2.3 years, 4.1% and 4.5% developed incident AVC and MAC, respectively. Each 10 bpm higher RHR was significantly associated with incident MAC [Risk Ratio 1.17 (95% CI 1.03-1.34)], but not incident AVC. However, RHR was associated with AVC progression [β = 1.62 (0.45-2.80) Agatston units/year for every 10 bpm increment], but not MAC progression., Conclusions: Higher RHR was associated with MAC incidence and AVC progression, independent of traditional CVD risk factors. Future studies are needed to determine whether modification of RHR through lifestyle or pharmacologic interventions can reduce valvular calcium incidence or progression., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rationale: Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS)., Objective: We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS., Methods and Results: In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31-2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18-5.13) increase in all-cause mortality, P =0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS., Conclusions: CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality., (© 2018 American Heart Association, Inc.)

The evidence on the association between resting heart rate (HR) and incident atrial fibrillation (AF) is conflicting. Whether change in resting HR is associated with incident AF is unknown. We evaluated 11,545 participants (mean [±standard deviation] age: 57 ± 5.7 years) free of AF at baseline (1990 to 1992). Resting HR was obtained from 10-second electrocardiograms at baseline and 3 years later. AF diagnosis was ascertained from visit electrocardiograms, hospital discharge records, and death certificates through 2013. High and low resting HR were defined as ≥80 and <55 beats/min, respectively. Increase and decrease in HR were defined as a 3-year HR difference >15 and <-15 beats/min, respectively. Over a median follow-up of 22.5 years, 1,746 (15%) participants developed AF. Both baseline high resting HR and increase in HR were independently associated with incident AF (hazard ratio = 1.2, 95% confidence interval = 1.0 to 1.5 and hazard ratio = 1.4, 95% confidence interval = 1.1 to 1.9). Increase in HR was no longer associated with incident AF after additional adjustment for incident heart failure. In stratified analyses, increase in HR was associated only with AF in participants <60 years, with bachelor's degree or above, without diabetes, and without hypertension (p values for interaction ≤0.05). In conclusion, in a middle-aged population, high resting HR is associated with higher AF risk. Increase in resting HR is also associated with higher AF risk, especially in individuals without traditional AF risk factors. Whether interventions to decrease HR can prevent AF remain to be examined., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The American Heart Association has defined metrics of ideal cardiovascular health known as Life's Simple 7 (LS7) to prevent cardiovascular disease. We examined the association between LS7 and incident atrial fibrillation (AF) in a biracial cohort of middle- and older-aged adults without known cardiovascular disease., Methods and Results: This analysis included 13 182 ARIC (Atherosclerosis Risk in Communities) study participants (mean baseline age=54±5.7 years; 56% women; 25% black) free of AF and cardiovascular disease. An overall LS7 score was calculated as the sum of the LS7 component scores and classified as inadequate (0-4), average (5-9), or optimal (10-14) cardiovascular health. The primary outcome was incident AF, identified primarily by ECG and hospital discharge coding of AF through December 31, 2014. A total of 2266 (17%) incident AF cases were detected over a median follow-up of 25.1 years. Compared with the inadequate category (n=1057), participants in the average (n=8629) and optimal (n=3496) categories each had a lower risk of developing AF in a multivariable Cox proportional hazards model (hazard ratio 0.59, 95% confidence interval 0.51, 0.67 for average; and hazard ratio 0.38, 95% confidence interval 0.32, 0.44 for optimal). In a similar model, a 1-point-higher LS7 score was associated with a 12% lower risk of incident AF (hazard ratio 0.88, 95% confidence interval 0.86, 0.89)., Conclusions: A higher LS7 score is strongly associated with a lower risk of AF in individuals without baseline cardiovascular disease. Determining whether interventions that improve the population's cardiovascular health also reduce AF incidence is needed., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Coronary arteries perfuse cardiac myocytes during diastole. We hypothesized that marked lowering of diastolic blood pressure (DBP) is associated with increased risk of subclinical myocardial injury (SC-MI)., Methods: This analysis included 6107 participants without history of cardiovascular disease (CVD) from the third National Health and Nutrition Examination Survey. SC-MI was determined by a validated electrocardiogram-based scoring system. Logistic regression was used to examine the cross-sectional association between DBP (< 70, 70-80 mmHg (reference group), and > 80 mmHg; and per each 10 mmHg decrease, separately) with SC-MI across levels of systolic blood pressure (SBP) (< 120, 120-139, or > 140 mmHg)., Results: In a multivariable model, DBP < 70 mmHg was associated with a higher risk of SC-MI [OR (95% CI) 1.40 (1.02, 1.94)] in participants with SBP > 140 mmHg. This association was consistent in subgroups stratified by age, race, diabetes, hypertension, obesity and smoking, but was stronger in women than in men [OR (95% CI) 1.58 (1.06, 2.37) vs. 1.10 (0.62, 1.94), respectively; interaction p value = 0.006]. Also, among participants with SBP > 140 mmHg, every 10 mmHg decrease in DBP was associated with a 12% increased odds of SC-MI [OR (95% CI) 1.12 (1.01, 1.23)]. No significant associations between DBP and SC-MI were observed in those with SBP < 120 mmHg or 120-139 mmHg, or between DBP > 80 mmHg and SC-MI in any of SBP levels., Conclusions: Low DBP < 70 mmHg in those with SBP > 140 mmHg carries higher risk of SC-MI, especially in women. Further research is needed to understand the therapeutic implications of these findings.

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.)

Aims: To determine if progression of mitral annular calcium (MAC) detected by cardiac computed tomography (CT) predicts incident atrial fibrillation (AF)., Methods and Results: This analysis included 5683 participants (mean age 64 ± 10 years; 52% women; 40% whites; 27% blacks; 21% Hispanics; 12% Chinese-Americans) from the Multi-Ethnic Study of Atherosclerosis. MAC was measured by cardiac CT at baseline and at a follow-up CT scan over a mean time of 2.4 ± 0.84 years. AF was ascertained by review of hospital discharge records and from Medicare claims data through 31 December 2012. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MAC progression and AF. Over a median follow-up of 8.6 years, a total of 533 (9.4%) incident AF cases were detected. In a model adjusted for age, sex, race/ethnicity, education, income, baseline MAC, systolic blood pressure, body mass index, diabetes, smoking, total cholesterol, high-density lipoprotein cholesterol, antihypertensive medications, lipid-lowering therapies, and aspirin, any MAC progression (>0/year) was associated with an increased risk for AF (HR = 1.50, 95% CI = 1.20-1.87). Multiplicative interactions were not significant between MAC progression and AF by age (<65 year vs. older), sex, or race/ethnicity (whites vs. non-whites)., Conclusion: Important prognostic information regarding AF risk is obtained with follow-up MAC measurement, as the risk for participants with any MAC progression was substantively greater than participants without progression. MAC progression may detect underlying left atrial abnormalities that predispose to AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Background: Although abnormalities of the QT interval are associated with atrial fibrillation (AF), it is unclear whether ventricular depolarization (QRS duration) or repolarization (JT interval) is a more important marker of AF risk., Methods: This analysis included 4,181 (95% white; 59% women) participants from the Cardiovascular Health Study (CHS) who were free of baseline AF and major intraventricular delay. A linear scale was used to compute heart rate adjusted QT (QTa), QRS (QRS a ), and JT (JT a ) intervals. Prolonged QT a , QRS a , and JT a were defined by values greater than the sex-specific 95th percentile for each measurement. AF events were ascertained during the annual study electrocardiograms and from hospitalization discharge data. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the associations of prolonged QT a , QRS a , and JT a with AF, separately., Results: Over a mean follow-up of 12.1 years, a total of 1,236 (30%) AF events were detected. An increased risk of AF (HR = 1.50. 95% CI = 1.20, 1.88) was observed with prolonged QT a . When we examined the association between individual components of the QT a interval and AF, the risk of AF was limited to prolonged JT a (HR = 1.31, 95% CI = 1.04, 1.65) and not prolonged QRS a (HR = 1.00, 95% CI = 0.77, 1.30). Similar results were obtained per 1-SD increase in QT a (HR = 1.07, 95% CI = 1.01, 1.13), QRS a (HR = 0.99, 95% CI = 0.94, 1.06), and JT a (HR = 1.07, 95% CI = 1.01, 1.13)., Conclusions: The JT interval is a more important marker of AF risk in the QT interval among persons who do not have ventricular conduction delays., (© 2017 Wiley Periodicals, Inc.)

Background: Although diastolic blood pressure (DBP) is independently associated with an increased risk of adverse cardiovascular outcomes in the general population, it is unclear if a similar relationship exists in patients with heart failure with preserved ejection fraction., Methods and Results: This analysis included 1703 (mean age, 72±10 years; 50% men; 78% white) patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) Trial from the Americas who were treated for hypertension. Multivariable Cox regression was used to examine the risk of hospitalization for heart failure, death, and cardiovascular death associated with DBP. The relationship between hospitalization for heart failure and DBP was linear, with an increased risk observed with decreasing DBP values (≥90 mm Hg: referent; 80-89 mm Hg: hazard ratio [HR], 1.44; 95% confidence interval [CI], 0.85-2.44; 70-79 mm Hg: HR, 1.18; 95% CI, 0.69-2.01; 60-69 mm Hg: HR, 1.54; 95% CI, 0.90-2.63; <60 mm Hg: HR, 2.12; 95% CI, 1.20-3.74; P =0.0055 for trend). The associations of DBP with death (≥90 mm Hg: HR, 1.86; 95% CI, 1.12-3.06; 80-89 mm Hg: HR, 1.23; 95% CI, 0.89-1.70; 70-79 mm Hg: referent; 60-69 mm Hg: HR, 1.20; 95% CI, 0.90-1.59; <60 mm Hg: HR, 1.68; 95% CI, 1.21-2.33) and cardiovascular death (≥90 mm Hg: HR, 2.02; 95% CI, 1.10-3.71; 80-89 mm Hg: HR, 1.17; 95% CI, 0.77-1.79; 70-79 mm Hg: referent; 60-69 mm Hg: HR, 1.16; 95% CI, 0.80-1.70; <60 mm Hg: HR, 1.85; 95% CI, 1.21-2.82) were nonlinear, with a greater risk of each outcome observed with DBP values ≥90 and <60 mm Hg., Conclusions: DBP values ≥90 and <60 mm Hg are associated with a significant risk of adverse outcomes in patients with heart failure with preserved ejection fraction who are treated for hypertension. Further research is needed to determine optimal DBP targets to reduce the risk of adverse events in patients with heart failure with preserved ejection fraction., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The associations between high-sensitivity troponin I (hsTnI) levels and coronary artery disease (CAD) severity and progression remain unclear. We investigated whether there is an association between hsTnI and angiographic severity and progression of CAD and whether the predictive value of hsTnI level for incident cardiovascular outcomes is independent of CAD severity., Methods and Results: In 3087 patients (aged 63±12 years, 64% men) undergoing cardiac catheterization without evidence of acute myocardial infarction, the severity of CAD was calculated by the number of major coronary arteries with ≥50% stenosis and the Gensini score. CAD progression was assessed in a subset of 717 patients who had undergone ≥2 coronary angiograms >3 months before enrollment. Patients were followed up for incident all-cause mortality and incident cardiovascular events. Of the total population, 11% had normal angiograms, 23% had nonobstructive CAD, 20% had 1-vessel CAD, 20% had 2-vessel CAD, and 26% had 3-vessel CAD. After adjusting for age, sex, race, body mass index, smoking, hypertension, diabetes mellitus history, and renal function, hsTnI levels were independently associated with the severity of CAD measured by the Gensini score (log 2 ß=0.31; 95% confidence interval, 0.18-0.44; P <0.001) and with CAD progression (log 2 ß=0.36; 95% confidence interval, 0.14-0.58; P =0.001). hsTnI level was also a significant predictor of incident death, cardiovascular death, myocardial infarction, revascularization, and cardiac hospitalizations, independent of the aforementioned covariates and CAD severity., Conclusions: Higher hsTnI levels are associated with the underlying burden of coronary atherosclerosis, more rapid progression of CAD, and higher risk of all-cause mortality and incident cardiovascular events. Whether more aggressive treatment aimed at reducing hsTnI levels can modulate disease progression requires further investigation., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

BackgroundThe response of progenitor cells (PCs) to transient myocardial ischemia in patients with coronary artery disease remains unknown. We aimed to investigate the PC response to exercise-induced myocardial ischemia (ExMI) and compare it to flow mismatch during pharmacological stress testing. Methods and ResultsA total of 356 patients with stable coronary artery disease underwent 99mTc-sestamibi myocardial perfusion imaging during exercise (69%) or pharmacological stress (31%). CD34 + and CD34 + /chemokine (C-X-C motif) receptor 4 PCs were enumerated by flow cytometry. Change in PC count was compared between patients with and without myocardial ischemia using linear regression models. Vascular endothelial growth factor and stromal-derived factor-1α were quantified. Mean age was 63±9 years; 76% were men. The incidence of ExMI was 31% and 41% during exercise and pharmacological stress testing, respectively. Patients with ExMI had a significant decrease in CD34 + /chemokine (C-X-C motif) receptor 4 (-18%, P =0.01) after stress that was inversely correlated with the magnitude of ischemia ( r =-0.19, P =0.003). In contrast, patients without ExMI had an increase in CD34 + /chemokine (C-X-C motif) receptor 4 (14.7%, P =0.02), and those undergoing pharmacological stress had no change. Plasma vascular endothelial growth factor levels increased (15%, P <0.001) in all patients undergoing exercise stress testing regardless of ischemia. However, the change in stromal-derived factor-1α level correlated inversely with the change in PC counts in those with ExMI ( P =0.03), suggesting a greater decrease in PCs in those with a greater change in stromal-derived factor-1α level with exercise. ConclusionsExMI is associated with a significant decrease in circulating levels of CD34 + /chemokine (C-X-C motif) receptor 4 PCs, likely attributable, at least in part, to stromal-derived factor-1α-mediated homing of PCs to the ischemic myocardium. The physiologic consequences of this uptake of PCs and their therapeutic implications need further investigation.

Background: Whether smoking increases the risk of atrial fibrillation (AF) remains debatable due to inconsistent reports., Methods: We examined the association between smoking and incident AF in 11,047 participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, one of the largest biracial, population-based cohort studies in the USA. Baseline (2003-2007) cigarette smoking status and amount (pack-years) were self-reported. Incident AF was determined by electrocardiography and history of a prior physician diagnosis at a follow-up examination conducted after a median of 10.6 years., Results: During follow-up, 954 incident AF cases were identified; 9.5% in smokers vs. 7.8% in non-smokers; p<0.001. In a model adjusted for socio-demographics, smoking (ever vs. never) was associated with a 15% increased risk of AF [OR (95%CI): 1.15(1.00, 1.31)], but this association was no longer significant after further adjustment for cardiovascular risk factors [OR (95% CI): 1.12 (0.97, 1.29)]. However, heterogeneities in the association were observed among subgroups; the association was stronger in young vs. old participants [OR (95%CI): 1.31 (1.03, 1.67) vs. 0.99 (0.83-1.18) respectively; interaction p-value=0.005] and in those with vs. without prior cardiovascular disease [OR (95%CI): 1.18 (0.90, 1.56) vs. 1.06 (0.90, 1.25) respectively; interaction p-value 0.0307]. Also, the association was significant in blacks but not in whites [OR (95%CI): 1.51 (1.12, 2.05) vs. 0.99 (0.84, 1.16), respectively], but the interaction p-value did not reach statistical significance (interaction p-value=0.65)., Conclusions: The association between smoking and AF is possibly mediated by a higher prevalence of cardiovascular risk factors in smokers, but there is marked heterogeneity in the strength of this association among subgroups which may explain the conflicting results in prior studies., (Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)