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...

Introduction: We evaluated whether better cardiovascular health at midlife and

We previously showed that mutations in LIS1 and DCX account for ∼85% of patients with the classic form of lissencephaly (LIS). Some rare forms of LIS are associated with a disproportionately small cerebellum, referred to as lissencephaly with cerebellar hypoplasia (LCH). Tubulin alpha1A (TUBA1A), encoding a critical structural subunit of microtubules, has recently been implicated in LIS. Here, we screen the largest cohort of unexplained LIS patients examined to date to determine: (i) the frequency of TUBA1A mutations in patients with lissencephaly, (ii) the spectrum of phenotypes associated with TUBA1A mutations and (iii) the functional consequences of different TUBA1A mutations on microtubule function. We identified novel and recurrent TUBA1A mutations in ∼1% of children with classic LIS and in ∼30% of children with LCH, making this the first major gene associated with the rare LCH phenotype. We also unexpectedly found a TUBA1A mutation in one child with agenesis of the corpus callosum and cerebellar hypoplasia without LIS. Thus, our data demonstrate a wider spectrum of phenotypes than previously reported and allow us to propose new recommendations for clinical testing. We also provide cellular and structural data suggesting that LIS-associated mutations of TUBA1A operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins (MAPs).

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 ≥ 65 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 ± 8 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.

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.

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...

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.

Stiff arteries increase left ventricular (LV) end-systolic workload, leading over time to left atrial and ventricular remodeling, and providing the substrate for atrial fibrillation (AF) development. We investigated if carotid femoral pulse wave velocity (cfPWV), a measure of central arterial stiffness, is associated with incident AF. In 2011–2013, cfPWV was measured in 3882 participants of the Atherosclerosis Risk in Communities Cohort Study (ARIC) without prevalent AF. Participants were followed through 2017 for the incidence of AF. Individuals were categorized in cfPWV quartiles based on visit measurements. Multivariable Cox regression models were used to evaluate the association of cfPWV with incident AF. Mean age was 75 years (SD 5), 60% were female and 20% were African American. Over a median follow-up of 5.5 years we identified 331 incident cases of AF. cfPWV demonstrated U-shaped associations with AF risk. In models adjusted for age, race, center, sex, education levels, and hemodynamic and clinical factors, hazard ratios (HR) of AF for participants in the first, third and fourth quartiles were 1.49 (95% CI 1.06, 2.10), 1.59 (1.14, 2.10), and 1.56(1.10, 2.19), respectively, compared to those in the second quartile. Among community-dwelling older adults, low and high central arterial stiffness is associated with AF risk.

Inconsistent evidence suggests that use of certain antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), in patients using oral anticoagulants (OACs) might be associated with an elevated risk of bleeding. This study aims to investigate the risk of bleeding associated with initiation of different types of antidepressants among atrial fibrillation (AF) patients on OAC therapy. A total of 30,336 AF patients (mean age 72.2 years; 54% female) on OAC therapy that started antidepressant treatment were identified from the Truven Health Analytics MarketScan Commercial and Medicare Databases for the period 2007–2015. Exposure was defined as filling a prescription for antidepressant, and categorized as SSRI, serotonin/norepinephrine reuptake inhibitors (SNRIs), serotonin reuptake inhibitors (SRIs), tricyclic antidepressants (TCAs), or other antidepressants. The primary outcome was incident hospitalized bleeding. Associations of antidepressant type with bleeding were assessed calculating hazard ratios (HRs) and 95% confidence intervals (CIs) with adjusted Cox models in pairwise propensity score-matched cohorts. During a mean follow-up of 21 months, we identified 1612 bleeding episodes. In pairwise comparisons, SSRI use was associated with an increased risk of bleeding when compared to most other antidepressants (HR 1.22, 95% CI 0.96–1.54 vs SNRI; HR 1.10, 95% CI 0.90–1.35 vs SRI; HR 1.03, 95% CI 0.82–1.30 vs TCA). SNRI use was associated with the lowest bleeding risk. Results did not differ by OAC type, age, and sex. Among AF patients on OAC initiating antidepressants, risk of bleeding varied across antidepressant type. This information can inform treatment choices among patients receiving OAC.

Background: Periodontal disease (PD) is associated positively with neurocognitive outcomes. Few studies have investigated the relationship between PD and indicators of brain aging and vascular chan...