OBJECTIVE: Elevated carotid intima-media thickness (cIMT) and carotid plaque are markers of arterial injury and may be linked to structural brain injury. We hypothesized cIMT or presence of carotid plaque at midlife are associated with presence of infarcts and cerebral microbleeds, greater white matter hyperintensity (WMH) volume, and smaller regional brain volumes in late-life. METHODS: We included 1,795 Atherosclerosis Risk in Communities (ARIC) Study participants (aged 57±6 years, 57% female, 23% Black) with carotid ultrasounds in 1990-1992 and brain MRI scans in 2011-2013. Weighted linear regression was used for brain volume outcomes, while logistic regression was used for infarcts and cerebral microbleeds. RESULTS: After multivariable adjustments, the highest cIMT quintile was associated with smaller deep gray matter (β [95% CI]: -0.11 [-0.22, -0.01]) and cortical volume in a temporal-parietal meta region of interest (ROI) (β [95% CI]: -0.10 [-0.20, -0.01]) in late-life. Similarly, those with carotid plaque had smaller regional brain volumes than those without (βs [95% CIs]: -0.05 [-0.12, 0.03] and -0.06 [-0.13, 0.01] for deep gray matter and temporal-parietal meta ROI). No significant relations were observed with WMH volume, infarcts, or cerebral microbleeds. CONCLUSION: Over a median follow-up of 21 years, greater midlife cIMT and presence of carotid plaque were associated with smaller deep gray matter volume and cortical volume in a meta ROI involving temporal and parietal lobe regions typically involved in neurodegeneration, including Alzheimer's disease, in later life. Contrary to our hypothesis, associations between measures of arterial injury and markers of vascular brain injury were null.

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

BACKGROUND: The risk of pregnancy-related mortality in the United States has nearly doubled since 1990, with venous thromboembolism (VTE) accounting for approximately 10% of these deaths. OBJECTIVES: The objective of this study was to assess whether preexisting autoimmune disease is a risk factor for postpartum VTE. METHODS: Using the MarketScan Commercial and Medicare Supplemental administrative databases, a retrospective cohort study analyzed whether postpartum persons with autoimmune disease had a higher risk of postpartum VTE incidence than postpartum persons without autoimmune disease. Using International Classification of Diseases codes, we identified 757,303 individuals of childbearing age who had a valid delivery date with at least 12 weeks of follow-up. RESULTS: Individuals were, on average, 30.7 years old (SD, 5.4), and 3.7% (N = 27,997 of 757,303) of them had evidence of preexisting autoimmune disease. In covariate-adjusted models, postpartum persons with preexisting autoimmune disease had higher rates of postpartum VTE than postpartum persons without autoimmune disease (hazard ratio [HR], 1.33; 95% CI, 1.07-1.64). When analyzed by individual autoimmune disease, those with systemic lupus erythematosus (HR, 2.49; 95% CI, 1.47-4.21) and Crohn's disease (HR, 2.49; 95% CI, 1.34-4.64) were at an elevated risk of postpartum VTE compared with those without autoimmune disease. CONCLUSION: Autoimmune disease was associated with a higher rate of postpartum VTE, with evidence that the association was most pronounced among individuals with systemic lupus erythematosus and Crohn's disease. These findings suggest that postpartum persons of childbearing age with autoimmune disease may require more monitoring and prophylactic care after delivery to prevent potentially fatal VTE events.

BACKGROUND: Black Americans have more atrial fibrillation risk factors but lower atrial fibrillation risk than White Americans. Left atrial (LA) enlargement and/or dysfunction, frequent atrial tachycardia (AT), and premature atrial contractions (PAC) are associated with increased atrial fibrillation risk. Racial differences in these factors may exist that could explain the difference in atrial fibrillation risk. METHODS AND RESULTS: We included 2133 ARIC (Atherosclerosis Risk in Communities) study participants (aged 74±4.5 years[mean±SD], 59% women, 27% Black participants) who had echocardiograms in 2011 to 2013 and wore the Zio XT Patch (a 2-week continuous heart monitor) in 2016 to 2017. Linear regression was used to analyze (1) differences in AT/day or PAC/hour between Black and White participants, (2) differences in LA measures between Black and White participants, and (3) racial differences in the association of LA measures with AT or PAC frequency. Compared with White participants, Black participants had a higher prevalence of cardiovascular risk factors and disease, lower AT frequency, greater LA size, and lower LA function. After multivariable adjustments, Black participants had 37% (95% CI, 24%– 47%) fewer AT runs/day than White participants. No difference in PAC between races was noted. Greater LA size and reduced LA function are associated with more AT and PAC runs; however, no race interaction was present. CONCLUSIONS: Differences in LA measures are unlikely to explain the difference in atrial fibrillation risk between Black and White individuals. Despite more cardiovascular risk factors and greater atrial remodeling, Black participants have lower AT frequency than White participants. Future research is needed to elucidate the protective mechanisms that confer resilience to atrial ar-rhythmias in Black individuals.

Background Acute outpatient management of venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is perceived to be as safe as inpatient management in some settings. How widely this strategy is used is not well documented. Methods and Results Using MarketScan administrative claims databases for years 2011 through 2018, we identified patients with International Classification of Diseases (ICD) codes indicating incident VTE and trends in the use of acute outpatient management. We also evaluated healthcare utilization and hospitalized bleeding events in the 6 months following the incident VTE event. A total of 200 346 patients with VTE were included, of whom 50% had evidence of PE. Acute outpatient management was used for 18% of those with PE and 57% of those with DVT only, and for both DVT and PE its use increased from 2011 to 2018. Outpatient management was less prevalent among patients with cancer, higher Charlson comorbidity index scores, and whose primary treatment was warfarin as compared with a direct oral anticoagulant. Healthcare utilization in the 6 months following the incident VTE event was generally lower among patients managed acutely as outpatients, regardless of initial presentation. Acute outpatient management was associated with lower hazard ratios of incident bleeding risk for both patients who initially presented with PE (0.71 [95% CI, 0.61, 0.82]) and DVT only (0.59 [95% CI, 0.54, 0.64]). Conclusions Outpatient management of VTE is increasing. In the present analysis, it was associated with lower subsequent healthcare utilization and fewer bleeding events. However, this may be because healthier patients were managed on an outpatient basis.

Background: Circulating high sensitivity cardiac troponin T (hs-cTnT) is associated with incidence of atrial fibrillation (AF), but the association of changes in hs-cTnT over time on incident AF has not been explored. Hypothesis: Six-year increase in circulating hs-cTnT will be associated with increased risk of AF and will contribute to improved prediction of incident AF. Methods: We conducted a prospective cohort analysis of 8431 participants from the Atherosclerosis Risk in Communities (ARIC) study. hs-cTnT change was categorized at visit 2 and 4 as undetectable (<5 ng/L), detectable (≥5 ng/L, <14 ng/L), or elevated (≥14 ng/L). We used Cox regression to examine the association between the combination of hs-cTnT categories at two visits and incident AF. We also assessed the impact of adding absolute hs-cTnT change on risk discrimination for AF by C-statistics and net reclassification improvement (NRI). Results: Over a mean follow-up of 16.5 years, 1629 incident AF cases were diagnosed. Among participants with undetectable hs-cTnT at visit 2, the multivariable HR of AF was 1.28 (95% CI 1.12–1.48) among those with detectable or elevated hs-cTnT at visit 4 compared to those in which hs-cTnT remained undetectable. Among those with detectable hs-cTnT at visit 2, compared to those who remained in the detectable hs-cTnT group, reduction to undetectable at visit 4 was associated with lower risk of AF (HR 0.74, 95% CI 0.59–0.94), while increment to elevated was associated with higher AF risk (HR 1.30, 95% CI 1.01–1.68). Adding hs-cTnT change to our main model with baseline hs-cTnT did not result in significant improvement in the C-statistic or substantial NRI. Conclusion: Six-year increase in circulating hs-cTnT was associated with elevated risk of incident AF.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Background: Serum magnesium (Mg) has been reported to be inversely associated with the risk of atrial fibrillation (AF), coronary artery disease (CAD), and major adverse cardiovascular events (MACE). The association between serum Mg and the risk of MACE, heart failure (HF), stroke, and all-cause mortality among patients with AF has not been evaluated. Objective: We aim to examine whether higher serum Mg is associated with a lower risk of MACE, heart failure (HF), stroke, and all-cause mortality among patients with AF. Methods: We evaluated prospectively 413 participants of the Atherosclerosis Risk in Communities (ARIC) Study with a diagnosis of AF at the time of Mg measurement participating in visit 5 (2011–2013). Serum Mg was modeled in tertiles and as a continuous variable in standard deviation units. Endpoints (HF, MI, stroke, cardiovascular (CV) death, all-cause mortality, and MACE) were identified and modeled separately using Cox proportional hazard regression adjusting for potential confounders. Results: During a mean follow-up of 5.8 years, there were 79 HFs, 34 MIs, 24 strokes, 80 CV deaths, 110 MACEs, and 198 total deaths. After adjustment for demographic and clinical variables, participants in the second and third tertiles of serum Mg had lower rates of most endpoints, with the strongest inverse association for the incidence of MI (HR 0.20, 95% CI 0.07, 0.61) comparing top to bottom tertile. Serum Mg modeled linearly as a continuous variable did not show clear associations with endpoints except MI (HR 0.50, 95% CI 0.31, 0.80). Due to the limited number of events, the precision of most estimates of association was relatively low. Conclusions: Among patients with AF, higher serum Mg was associated with a lower risk of developing incident MI and, to a lesser extent, other CV endpoints. Further studies in larger patients with AF cohorts are needed to evaluate the role of serum Mg in preventing adverse CV outcomes in these patients.

IMPORTANCE Perceived stress can have long-term physiological and psychological consequences and has shown to be a modifiable risk factor for Alzheimer disease and related dementias. OBJECTIVE To investigate the association between perceived stress and cognitive impairment in a large cohort study of Black and White participants aged 45 years or older. DESIGN, SETTING, AND PARTICIPANTS The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study is a national population-based cohort of 30 239 Black and White participants aged 45 years or older, sampled from the US population. Participants were recruited from 2003 to 2007, with ongoing annual follow-up. Data were collected by telephone, selfadministered questionnaires, and an in-home examination. Statistical analysis was performed from May 2021 to March 2022. EXPOSURES Perceived stresswas measured using the 4-item version of the Cohen Perceived Stress Scale. It was assessed at the baseline visit and during 1 follow-up visit. MAIN OUTCOMES AND MEASURES Cognitive function was assessed with the Six-Item Screener (SIS); participants with a score below 5 were considered to have cognitive impairment. Incident cognitive impairment was defined as a shift from intact cognition (SIS score >4) at the first assessment to impaired cognition (SIS score_4) at the latest available assessment. RESULTS The final analytical sample included 24 448 participants (14 646 women [59.9%]; median age, 64 years [range, 45-98 years]; 10 177 Black participants [41.6%] and 14 271 White participants [58.4%]). A total of 5589 participants (22.9%) reported elevated levels of stress. Elevated levels of perceived stress (dichotomized as low stress vs elevated stress) were associated with 1.37 times higher odds of poor cognition after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (adjusted odds ratio [AOR], 1.37; 95%CI, 1.22-1.53). The association of the change in the Perceived Stress Scale score with incident cognitive impairment was significant in both the unadjusted model (OR, 1.62; 95%CI, 1.46-1.80) and after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (AOR, 1.39; 95%CI, 1.22-1.58). There was no interaction with age, race, and sex. CONCLUSIONS AND RELEVANCE This study suggests that there is an independent association between perceived stress and both prevalent and incident cognitive impairment. The findings suggest the need for regular screening and targeted interventions for stress among older adults.

Background: Paroxysmal atrial fibrillation (AF) is challenging to diagnose due to its intermittent nature. Circadian rhythmicity has been reported for cardiovascular events such as myocardial infarction; whether diurnal variation exists for paroxysmal AF is less known. We characterized the temporal pattern of AF initiation in the Atherosclerosis Risk in Communities (ARIC) study, a prospective community-based cohort study. Methods: We included 74 ARIC study participants with paroxysmal AF detected by the Zio XT Patch at ARIC Visit 6 in 2016–17. We divided each participant's 2-week continuous monitoring data into 3-h intervals and summed the number of AF episodes in each interval. We performed Poisson regression using generalized estimating equations to estimate the effect of time of day on the number of AF episodes. Results: Compared to the reference interval of time 00:00–02:59, the time intervals 12:00–14:59, 15:00–17:59, and 18:00–20:59 had significantly higher frequency of AF initiation. Rate ratios (95% CI) for mean number of episodes in these three intervals were 1.91 (1.11, 2.92), 2.54 (1.42, 4.53), and 1.99 (1.19, 3.25) respectively. Furthermore, we found no significant association between duration of episode and time of day. Conclusion: There is diurnal variation in the initiation of AF episodes, with a peak in frequency in the late afternoon. Our finding is consistent with sympathetically driven AF. Pulse palpation or obtaining an electrocardiogram in the late afternoon may produce the highest diagnostic yield for AF.