Atrial fibrillation and risk of incident heart failure with reduced versus preserved ejection fraction.

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.

Posttraumatic Stress Disorder, Myocardial Perfusion, and Myocardial Blood Flow: A Longitudinal Twin Study.

BACKGROUND: The link between posttraumatic stress disorder (PTSD) and ischemic heart disease remains elusive owing to a shortage of longitudinal studies with a clinical diagnosis of PTSD and objective measures of cardiac compromise. METHODS: We performed positron emission tomography in 275 twins who participated in two examinations approximately 12 years apart. At both visits, we obtained a clinical diagnosis of PTSD, which was classified as long-standing (both visit 1 and visit 2), late onset (only visit 2), and no PTSD (no PTSD at both visits). With positron emission tomography, we assessed myocardial flow reserve (MFR), which, in absence of significant coronary stenoses, indexes coronary microvascular function. We compared positron emission tomography data at visit 2 across the three categories of longitudinally assessed PTSD and examined changes between the two visits. RESULTS: Overall, 80% of the twins had no or minimal obstructive coronary disease. Yet, MFR was depressed in twins with PTSD and was progressively lower across groups with no PTSD (2.13), late-onset PTSD (1.97), and long-standing PTSD (1.93) (p = .01). A low MFR (a ratio <2.0) was present in 40% of the twins without PTSD, in 56% of those with late-onset PTSD, and in 72% of those with long-standing PTSD (p < .001). Associations persisted in multivariable analysis, when examining changes in MFR between visit 1 and visit 2, and within twin pairs. Results were similar by zygosity. CONCLUSIONS: Longitudinally, PTSD is associated with reduced coronary microcirculatory function and greater deterioration over time. The association is especially noted among twins with chronic, long-standing PTSD and is not confounded by shared environmental or genetic factors.

Effect of intensive blood pressure lowering on left atrial remodeling in the SPRINT.

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 V1 (PTFV1) > 4000 µV × ms. Secondary outcomes were regression of the left atrial abnormality and the change in PTFV1 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 PTFV1. 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 PTFV1 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.

Objectively Measured Physical Activity and the Risk of Atrial Fibrillation (from the REGARDS Study).

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.

Association of Atrial Fibrillation Without Cardiovascular Comorbidities and Stroke Risk: From the REGARDS Study.

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.

Circulating electrolytes and the prevalence of atrial fibrillation and supraventricular ectopy: The Atherosclerosis Risk in Communities (ARIC) study.

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.

Resting heart rate and incident venous thromboembolism: the Multi-Ethnic Study of Atherosclerosis.

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.

Abnormal P-wave axis and myocardial ischemia development during mental stress.

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.

Association of household income and adverse outcomes in patients with atrial fibrillation.

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.

Clinical significance of zero coronary artery calcium in individuals with LDL cholesterol ≥190 mg/dL: The Multi-Ethnic Study of Atherosclerosis.

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 ±â€¯9.4 years; 42% male; 31% white; 37% CAC = 0) with LDL-C ≥190 mg/dL were identified (mean LDL-C = 215 ±â€¯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.

Joint Associations of Obesity and NT-proBNP With the Incidence of Atrial Fibrillation in the ARIC Study.

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.

Sex and racial differences in cardiovascular disease risk in patients with atrial fibrillation.

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.

Heart rate variability and heart rate recovery in lung cancer survivors eligible for long-term cure.

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.

Comparison of autonomic stress reactivity in young healthy versus aging subjects with heart disease.

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.

Association of Antidepressant Medication Type With the Incidence of Cardiovascular Disease in the ARIC Study.

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.