<h2>ABSTRACT</h2><h3>Background</h3><p>Atrial fibrillation (AF) is widely perceived to originate from the left atrium (LA). It is unclear whether increases in right ventricular (RV) afterload in older adults plays an etiological role in AF genesis independent of LA and left ventricular (LV) remodeling.</p><h3>Research Question</h3><p>Is higher RV afterload associated with greater AF risk independent of LA and LV remodeling?</p><h3>Study Design and Methods</h3><p>In this observational prospective study, we included 2246 community-dwelling older adults (mean age, 75 years) without known cardiovascular disease, with LV ejection fraction >50%, LA volume index <34 ml/m², and E/e' ratio <14 and a measurable functional tricuspid regurgitation jet velocity. From 2D-echocardiograms, we estimated pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR). We ascertained incident AF (through 2018) from hospital discharge codes and death certificates. We estimated hazard ratios (HR) by Cox regression.</p><h3>Results</h3><p>During follow-up (median 6.3 years, interquartile interval 5.5-6.9 years), 215 participants developed AF. AF risk was significantly higher in the third (vs first) tertile of PASP [HR 1.65, 95% confidence interval (CI) 1.08 - 2.54] and PVR [HR 1.38, 95% CI 1.00 - 2.08] independent of LA and LV structure and function, heart rate, body mass index, prevalent sleep apnea, systemic blood pressure, antihypertensive medications, lung, kidney, and thyroid function. These associations persisted after further exclusion of participants with tricuspid regurgitation jet velocity >2.8 m/s and lateral and septal mitral annular velocity above age- and sex-specific reference limits.</p><h3>Interpretation</h3><p>In older adults, higher RV afterload is associated with greater AF risk independent of LA and LV remodeling. Future research should focus on confirming this novel association and elucidate underlying mechanisms.</p>

Elevated levels of testosterone and fibroblast growth factor 23 (FGF-23) are both independently associated with a higher risk of cardiovascular disease (CVD). However, the relationship between sex hormones and FGF-23 is not well established. We explored the association between sex hormones and FGF-23 among middle-aged to older men and women in MESA. We studied 3,052 men and 2,868 postmenopausal women free of CVD at the time of enrollment with baseline serum sex hormones [total testosterone (T), free T, estradiol (E2) and sex hormone binding globulin (SHBG)] and intact FGF-23. In sex-stratified analyses, we examined the cross-sectional associations between log-transformed sex hormones (per 1 SD) and log-transformed FGF-23 using multiple linear regression adjusted for socio-demographics, CVD risk factors, estimated glomerular filtration rate and mineral metabolites (25-hydroxyvitamin D, calcium, phosphorus and parathyroid hormone). The mean (SD) age of study participants was 64 (10) years. The median (IQR) of FGF-23 was similar in women and men [38 (30–46) vs 38 (31–47) pg/mL]. In adjusted analyses, among women, 1 SD increment in free T was associated with 3% higher FGF-23 while SHBG was associated with 2% lower FGF-23. In men, 1 SD increment in E2 was associated with 6% higher FGF-23 whereas total T/E2 ratio was associated with 7% lower FGF-23. In conclusion, this exploratory analysis found that a more androgenic sex hormone profile was directly associated with FGF-23 in women and inversely associated with FGF-23 in men. Longitudinal studies are required to determine whether FGF-23 mediates the relationship between sex hormones and CVD risk.

Aim: We investigate if periodontal disease is prospectively associated with cerebrovascular and neurodegenerative markers of dementia and Alzheimer's pathology. Materials and Methods: N = 1306 participants (Visit 5 mean age = 76.5 [standard deviation = 5.4] years) in the Atherosclerosis Risk in Communities study with completed dental exams at Visit 4 underwent brain magnetic resonance imaging scans at Visit 5 while N = 248 underwent positron emission tomography scans. Participants were classified as edentulous or, among the dentate, by the modified Periodontal Profile Class. Brain volumes were regressed on periodontal status in linear regressions. Cerebrovascular measures and β-amyloid positivity were regressed on periodontal status in logistic regressions. Results: Periodontal disease was not associated with brain volumes, microhaemorrhages, or elevated β-amyloid. Compared with periodontally healthy individuals, odds ratios [95% confidence interval] for all-type infarcts were 0.37 [0.20, 0.65] for severe tooth loss and 0.56 [0.31, 0.99] for edentulous participants. Conclusions: Within the limitations of this study, periodontal disease was not associated with altered brain volumes, microhaemorrhages, or β-amyloid positivity. Tooth loss was associated with lower odds of cerebral infarcts.

Introduction: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demio...

Aims/hypothesis: Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology. Methods: Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined. Results: Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein–GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 × 10−3), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 × 10−3). Conclusions/interpretation: Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets. Graphical abstract: [Figure not available: see fulltext.]

Background: Clinical management of orthostatic hypotension (OH) prioritizes the prevention of standing hypotension (HYP), sometimes at the expense of supine hypertension (HTN). It is unclear whethe...

The aim of this work was to assess the association between diabetes and risk for infection-related hospitalisation and mortality. We conducted a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Diabetes was defined as a fasting glucose ≥7 mmol/l or non-fasting glucose ≥11.1 mmol/l, self-report of a diagnosis of diabetes by a physician, or current diabetes medication use. Hospitalisation for infection was ascertained from hospital discharge records. Participants were followed from 1987–1989 to 2019. We included 12,379 participants (mean age 54.5 years; 24.7% Black race; 54.3% female sex). During a median follow-up of 23.8 years, there were 4229 new hospitalisations for infection. After adjusting for potential confounders, people with (vs without) diabetes at baseline had a higher risk for hospitalisation for infection (HR 1.67 [95% CI 1.52, 1.83]). Results were generally consistent across infection type but the association was especially pronounced for foot infection (HR 5.99 [95% CI 4.38, 8.19]). Diabetes was more strongly associated with hospitalisation for infection in younger participants and Black people. Overall infection mortality was low (362 deaths due to infection) but the adjusted risk was increased for people with diabetes (HR 1.72 [95% CI 1.28, 2.31]). Diabetes confers significant risk for infection-related hospitalisation. Enhancing prevention and early treatment of infection in those with diabetes is needed to reduce infection-related morbidity and mortality.

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract Background: Venous thromboembolism (VTE) affects nearly 1 million Americans

Objectives Electronic health records (EHR) are a convenient data source for clinical trial recruitment and allow for inexpensive participant screening. However, EHR may lack pertinent screening variables. One strategy is to identify surrogate EHR variables which can predict the screening variable of interest. In this article, we use BMI to develop a prediction rule for arm circumference using data from the Atherosclerosis Risk in Communities (ARIC) Study. This work applies to EHR patient screening for clinical trials of hypertension. Methods We included 11 585 participants aged 52–75 years with BMI and arm circumference measured at ARIC follow-up visit 4 (1996–1998). We selected the following arm circumference cutpoints based on the American Heart Association recommendations for blood pressure (BP) cuffs: small adult (≤26 cm), adult (≤34 cm) and large adult (≤44 cm). We calculated the sensitivity and specificity of BMI values for predicting arm circumference using receiver operating characteristic curves. We report the BMI threshold that maximized Youden’s Index for each arm circumference upper limit of a BP cuff. Results Participants’ mean BMI and arm circumference were 28.8 ± 5.6 kg/m2 and 33.4 ± 4.3 cm, respectively. The BMI-arm circumference Pearson’s correlation coefficient was 0.86. The BMI threshold for arm circumference≤26 cm was 23.0 kg/m2, arm circumference≤34 cm was 29.2 kg/m2 and arm circumference≤44 cm was 37.4 kg/m2. Only the BMI threshold for arm circumference≤34 cm varied significantly by sex. Conclusions BMI predicts arm circumference with high sensitivity and specificity and can be an accurate surrogate variable for arm circumference. These findings are useful for participant screening for hypertension trials. Providers can use this information to counsel patients on appropriate cuff size for BP self-monitoring.

BACKGROUND: Although a few studies reported an association between varicose veins and physical function, this potentially bi-directional association has not been systematically evaluated in the general population. METHODS: In 5,580 participants (aged 71-90 years) from the Atherosclerosis Risk in Communities study, varicose veins were identified in outpatient and inpatient administrative data prior to (prevalent cases) and after (incident cases) visit 5 (2011-2013). Physical function was evaluated by the Short Physical Performance Battery (SPPB, score ranging from 0-12). We evaluated 1) cross-sectional association between prevalent varicose veins and physical function, 2) association of prevalent varicose veins with subsequent changes in physical function from visit 5 to visits 6 (2016-2017) and 7 (2018-2019), 3) association of physical function at visit 5 with incident varicose veins during a median follow-up of 3.6 years (105 incident varicose veins among 5,350 participants without prevalent cases at baseline). RESULTS: At baseline, varicose veins were recognized in 230 (4.1%) participants and cross-sectionally associated with reduced physical function. Longitudinally, prevalent varicose veins were not significantly associated with a decline in SPPB over time. In contrast, a low SPPB ≤6 was associated with a greater incidence of varicose veins compared to SPPB ≥10 (adjusted hazard ratio 2.13 [95% CI 1.19, 3.81]) . CONCLUSION: In community-dwelling older adults, varicose veins and low physical function were associated cross-sectionally. Longitudinally, low physical function was a risk factor for incident varicose veins, but not vice versa. Our findings suggest an etiological contribution of low physical function to incident varicose veins.

Data are needed on the use of oral anticoagulation in patients with atrial fibrillation (AF) in rural versus urban areas, including the initiation of direct oral anticoagulants (DOACs). We used Medicare data to examine rural/urban differences in anticoagulation use in patients with AF. We identified incident AF in a 20% sample of fee-for-service Medicare beneficiaries (aged ≥&nbsp;65&nbsp;years) from 2011 to 2016 and collected ZIP code and covariates at the time of AF. We identified the first anticoagulant prescription filled, if any, following AF diagnosis. We categorized beneficiaries into four rural/urban areas using rural–urban commuting area codes and used Poisson regression models to compare anticoagulant use. We included 447,252 patients with AF (mean age 79&nbsp;±&nbsp;8&nbsp;years), of which 82% were urban, 9% large rural, 5% small rural, and 4% isolated. The percentage who initiated an anticoagulant rose from 34% in 2011 to 53% in 2016, paralleling the uptake of DOACs. In a multivariable-adjusted analysis, those in rural areas (vs. urban) were more likely to initiate an anticoagulant. However, rural beneficiaries (vs. urban) were less likely to initiate a DOAC; those in isolated areas were 17% less likely (95% confidence interval [CI] 13–20), those in small rural areas were 12% less likely (95% CI 9–15), and those in large rural areas were 10% less likely (95% CI 8–12). Among Medicare beneficiaries with AF, anticoagulation use was low but increased over time with the introduction of DOACs. Rural beneficiaries were less likely to receive a DOAC.

Background: Randomized trials suggest that direct oral anticoagulants (DOACs) are at least as effective as warfarin for primary treatment of VTE and that bleeding risk may be lower for some DOACs relative to warfarin. However, there is very little information regarding potential bleeding risks for DOACs versus warfarin in secondary prevention of VTE. Objective: The aim of this study was to compare rates of bleeding events resulting in inpatient admissions between individuals taking apixaban, rivaroxaban, and warfarin for secondary prevention of VTE during the period 2013-2017. Methods: We used the IBM MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database (IBM Watson Health, Ann Arbor, MI) to establish a retrospective cohort. Initial venous thrombolism events were defined from medical claims, and follow-up for this cohort began 6 months after the initial event. Bleeding events resulting in inpatient admission were identified from claims data over the subsequent year of secondary prevention. Results: A total of 69 264 individuals were identified for the cohort, with 567 bleeding events. The crude rate of bleeding was highest among warfarin users (1.47/100 person-years; 95% confidence interval [CI], 1.24-1.74) and lower among those on either apixaban (1.00/100 person-years; 95% CI, 0.65-1.54) or rivaroxaban (0.84/100 person-years; 95% CI, 0.66-1.08). In multivariable adjusted Cox models, those on apixaban (hazard ratio [HR], 0.80; 95% CI, 0.50-1.29) and rivaroxaban (HR, 0.81; 95% CI, 0.59-1.09) had somewhat lower rates of bleeding events relative to those on warfarin. Conclusions: We found modest evidence of decreased risk of bleeding for apixaban and rivaroxaban. These estimates were relatively imprecise.

Introduction: Leisure-time physical activity (LTPA) is associated with lower heart failure (HF) risk. However, reported associations with incident HF with preserved (HFpEF) and reduced ejection fra...

Study Objectives: To quantify the gender-specific associations between insomnia symptoms and subclinical atherosclerosis, measured by coronary artery calcium (CAC) scores, which has strong predictive value for incident cardiovascular disease. Methods: We analyzed data from 1,429 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants completed standardized questionnaires and underwent polysomnography (PSG) and 7-day actigraphy. Insomnia symptoms were defined as: self-reported trouble falling, staying or returning to sleep, early-morning awakenings, or hypnotic use, for ≥5 nights/week. MESA assessed CAC using computed tomography. We employed multivariable linear regression to model the probability of CAC >0 overall and to model the linear continuous effect among those with nonzero CAC. Results: Our sample was a mean age of 68.1 ± 9.1 years, 53.9% female, and 36.2% white, 28.0% black, 24.2% Hispanic, and 11.5% Chinese-American. Insomnia symptoms were present in 49.7% of men and 47.2% of women. In multivariable-adjusted analyses, insomnia symptoms was associated with an 18% higher prevalence of CAC (PR 1.18, 95% CI 1.04, 1.33) among females, but no association was observed among males (PR 1.00, 95% CI 0.91, 1.08). There was no evidence that the association between insomnia symptoms and prevalence of CAC >0 differed by objective sleep duration status (by single-night PSG or multi-night actigraphy) in females or males. Conclusions: We found that among women, insomnia symptoms were associated with an 18% higher prevalence of CAC compared to no insomnia. Insomnia symptoms were not associated with CAC prevalence in men. Additionally, there was no evidence that the association between insomnia symptoms and CAC score >0 differed by objective short sleep duration status. Statement of Significance Cardiovascular disease is a leading cause of death for both women and men worldwide. There are known gender differences in the presentation , risk factors, and mechanisms of cardiovascular disease, including female-specific risk factors. Previous work suggests that insomnia , which has a higher prevalence among women, confers a higher risk of future cardiovascular events. However, few studies have examined gender-specific differences, and none previously accounted for sleep-disordered breathing, a risk factor for cardiovascular disease that is more common among males. This study seeks to examine the gender-specific association between insomnia symptoms and subclinical atherosclerotic disease and explore the interaction by sleep duration status.

Background: Fibroblast growth factor-23 (FGF-23), a protein regulating phosphorus levels, is associated with the risk of heart failure, particularly in patients with chronic kidney disease (CKD), a...

Background: Kidney function is a crucial determinant of bone-mineral metabolism (BMM); however, the contribution of kidney dysfunction, especially at mild to moderate stages, to vascular calcificat...

Introduction:Multiple myeloma diagnosis is associated with a 10-15% absolute risk of venous thromboembolism (VTE) due to disease-related (i.e., vascular inflammation, hyperviscosity) and treatment-related risk factors (i.e., immunomodulatory drugs [IMiDs], high-dose dexamethasone). This has led to ongoing clinical trials to determine the best thromboprophylaxis strategy. In contrast, the risk of major bleeding following incident VTE events in patients with MM is not well described. We conducted a real-world analysis of bleeding complications in MM following anticoagulation treatment for VTE.Methods:The IBM MarketScan Commercial Claims Database was used to identify adults with MM diagnosis and an incident VTE event between 2011 and 2019. MM and VTE were defined as 1 inpatient or 2 outpatient claims based on International Classification of Diseases (ICD) 9th and 10 th Revision codes, and at least 1 prescription for anticoagulation within 31 days of first VTE claim. IMiD-related VTE was defined in subjects with an IMiD prescription prior to the VTE event. Major bleeding was defined as bleeding requiring hospitalization using inpatient ICD codes as previously validated (Cunningham algorithm). Patients were followed from index VTE and initiation of anticoagulation to first major bleeding event, disenrollment (due to death or other reasons) or December 31, 2019. Descriptive statistics were used to calculate the rate of major bleeding. Cox regression was used to determine risk factors associated with major bleeding.Results:Our population included 1,605 patients with a diagnosis of multiple myeloma and an incident VTE event requiring treatment. Anticoagulant agent of choice was warfarin in 45.7% (734), low-molecular weight heparin (LMWH) in 29% (466), and direct oral anticoagulants (DOAC) in 25.3% (405). There were no significant differences in age/sex distribution, comorbidity burden, history of significant bleeding, or use of IMiD across the different types of anticoagulation (Table 1). Hospitalized bleeding occurred in 63 (3.9%) patients during an average follow-up of 1.6 years, yielding an overall incidence rate of major bleeding in multiple myeloma patients starting anticoagulation for a new VTE event of 24.1 per 1,000 person-years. Adjusting for age and sex, risk factors significantly associated with risk of major bleeding included Charlson comorbidy index [CCI] (per standard deviation [SD] increment, HR 1.29, 95%CI 1.03 - 1.62), diabetes (HR 1.71, 95%CI 1.06 - 2.92), and liver disease (HR 1.96, 95%CI 1.04 - 3.68). The use of IMiDs was not associated with increased risk of major bleeding (Table 2). The cumulative incidence of major bleeding by VTE anticoagulation strategy in multiple myeloma was 4.8% in warfarin group and 3.2% in the LMWH and DOAC groups, though the difference was not statistically significant after adjusting for age and sex. The estimated incidence rate of bleeding was 25.7, 20.1, and 25.2 per 1,000 person-years for patients treated with warfarin, LMWH, and DOACs, respectively. In an adjusted model for age, sex, CCI, diabetes and liver disease, patients treated with LMWH and DOACs had HR for major bleeding of 0.91 and 0.82, respectively, compared to anticoagulation with warfarin, though this was not statistically significant.Discussion:In a real-world analysis of commercial claims data, the rate of major bleeding in patients with multiple myeloma receiving anticoagulation for VTE appears to be comparable to those reported in other subsets of cancer associated VTE. Surprisingly, almost half of identified patients were treated with warfarin, a non-preferred option in this setting. The point estimate of major bleeding was lower in patients treated with LMWH or DOACs compared to warfarin, though the association was not statistically significant and larger studies are needed. Higher CCI, diabetes and liver disease were clinical factors associated with higher risk of major bleeding and may be included in risk assessment models to help clinicians assess individual bleeding risk in patients with multiple myeloma treated for VTE.Figure 1 Figure 1.

OBJECTIVE The 2021 American Diabetes Association (ADA) guidelines recommend different A1C targets in older adults that are based on comorbid health status. We assessed risk of mortality and hospitalizations in older adults with diabetes across glycemic control (A1C <7%, 7 to <8%, ≥8%) and ADA-defined health status (healthy, complex/intermediate, very complex/poor) categories. RESEARCH DESIGN AND METHODS Prospective cohort analysis of older adults aged 66–90 years with diagnosed diabetes in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS In the 1,841 participants (56% women, 29% Black), 32% were classified as healthy, 42% as complex/intermediate, and 27% as very complex/poor health. Over a median 6-year follow-up, there were 409 (22%) deaths and 4,130 hospitalizations (median [25th–75th percentile] 1 per person [0–3]). In the very complex/poor category, individuals with A1C ≥8% (vs. <7%) had higher mortality risk (hazard ratio 1.76 [95% CI 1.15–2.71]), even after adjustment for glucose-lowering medication use. Within the very complex/poor health category, individuals with A1C ≥8% (vs. <7%) had more hospitalizations (incidence rate ratio [IRR] 1.41 [95% CI 1.03–1.94]). In the complex/intermediate group, individuals with A1C ≥8% (vs. <7%) had more hospitalizations, even with adjustment for glucose-lowering medication use (IRR 1.64 [1.21–2.24]). Results were similar, but imprecise, when the analysis was restricted to insulin or sulfonylurea users ( n = 663). CONCLUSIONS There were substantial differences in mortality and hospitalizations across ADA health status categories, but older adults with A1C <7% were not at elevated risk, regardless of health status. Our results support the 2021 ADA guidelines and indicate that <7% is a reasonable treatment goal in some older adults with diabetes.