Galectin-3, Metabolic Risk, and Incident Heart Failure: The ARIC Study.

BACKGROUND: It is unclear how metabolic syndrome (MetS) and diabetes affect Gal-3 (galectin 3) levels and the resulting implications for heart failure (HF) risk. We assessed relationships of MetS and diabetes with Gal-3, and their joint associations with incident HF. METHODS AND RESULTS: We included 8445 participants without HF (mean age, 63 years; 59% men; 16% Black race) at ARIC (Atherosclerosis Risk in Communities) study visit 4 (1996-1999). We categorized participants as having MetS only, MetS with diabetes, or neither, and by quartiles of MetS severity Z score. We assessed cross-sectional associations of metabolic risk categories with high Gal-3 level (≥75th percentile) using logistic regression. We used Cox regression to evaluate combined associations of metabolic risk categories and Gal-3 quartiles with HF. In cross-sectional analyses, compared with no MetS and no diabetes, MetS only (odds ratio [OR], 1.24 [95% CI, 1.10-1.41]) and MetS with diabetes (OR, 1.59 [95% CI, 1.32-1.92]) were associated with elevated Gal-3. Over a median follow-up of 20.5 years, there were 1749 HF events. Compared with individuals with neither diabetes nor MetS and with Gal-3 in the lowest quartile, the combination of MetS with diabetes and Gal-3 ≥75th percentile was associated with a 4-fold higher HF risk (hazard ratio, 4.35 [95% CI, 3.30-5.73]). Gal-3 provided HF prognostic information above and beyond MetS, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, and CRP (C-reactive protein) (ΔC statistic for models with versus without Gal-3: 0.003; P=0.004). CONCLUSIONS: MetS and diabetes are associated with elevated Gal-3. The HF risk significantly increased with the combination of greater metabolic risk and higher Gal-3.

Recruitment and baseline data of the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study: A randomized trial of a hearing loss intervention for reducing cognitive decline.

INTRODUCTION: Hearing loss is highly prevalent among older adults and independently associated with cognitive decline. The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study is a multicenter randomized control trial (partially nested within the infrastructure of an observational cohort study, the Atherosclerosis Risk in Communities [ARIC] study) to determine the efficacy of best-practice hearing treatment to reduce cognitive decline over 3 years. The goal of this paper is to describe the recruitment process and baseline results. METHODS: Multiple strategies were used to recruit community-dwelling 70-84-year-old participants with adult-onset hearing loss who were free of substantial cognitive impairment from the parent ARIC study and de novo from the surrounding communities into the trial. Participants completed telephone screening, an in-person hearing, vision, and cognitive screening, and a comprehensive hearing assessment to determine eligibility. RESULTS: Over a 24-month period, 3004 telephone screenings resulted in 2344 in-person hearing, vision, and cognition screenings and 1294 comprehensive hearing screenings. Among 1102 eligible, 977 were randomized into the trial (median age = 76.4 years; 53.5% female; 87.8% White; 53.3% held a Bachelor's degree or higher). Participants recruited through the ARIC study were recruited much earlier and were less likely to report hearing loss interfered with their quality of life relative to participants recruited de novo from the community. Minor differences in baseline hearing or health characteristics were found by recruitment route (i.e., ARIC study or de novo) and by study site. DISCUSSION: The ACHIEVE study successfully completed enrollment over 2 years that met originally projected rates of recruitment. Substantial operational and scientific efficiencies during study startup were achieved through embedding this trial within the infrastructure of a longstanding and well-established observational study. Highlights: The ACHIEVE study tests the effect of hearing intervention on cognitive decline.The study is partially nested within an existing cohort study.Over 2 years, 977 participants recruited and enrolled.Eligibility assessed by telephone and in-person for hearing, vision, and cognitive screening.The ACHIEVE study findings will have significant public health implications.

Limonene Enantiomeric Ratios from Anthropogenic and Biogenic Emission Sources.

Emissions from volatile chemical products (VCPs) have been identified as contributors to air quality degradation in urban areas. Limonene can be a tracer compound for VCPs containing fragrances in densely populated regions, but limonene is also emitted from conifers that are planted in urban areas. This creates challenges for using limonene to estimate VCP emissions. In this study, the -/+ enantiomeric ratios of limonene from VCP and conifer emission sources were quantified to evaluate if this measurement could be used to aid in source apportionment and emission inventory development. Samples were analyzed using a gas chromatograph equipped with a chiral column and mass spectrometry. The results demonstrate that limonene exhibits distinct enantiomeric ratios when sourced from VCPs versus conifers. (+)-Limonene was dominant in VCP sources (>97%), which was not universally true for conifer sources. The results were compared to those of air samples collected outside at two locations and indoors. The levels of (-)-limonene in outdoor air in Irvine and Portland and in indoor air were 50%, 22%, and 4%, respectively. This suggests outdoor limonene had both VCP and plant emission sources while indoor air was dominated by VCP sources. This study demonstrates the potential utility of enantiomeric analysis for improving VCP emission estimates in urban areas.

Description of the Baseline Audiologic Characteristics of the Participants Enrolled in the Aging and Cognitive Health Evaluation in Elders Study.

PURPOSE: The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study is a randomized clinical trial designed to determine the effects of a best-practice hearing intervention versus a successful aging health education control intervention on cognitive decline among community-dwelling older adults with untreated mild-to-moderate hearing loss. We describe the baseline audiologic characteristics of the ACHIEVE participants. METHOD: Participants aged 70-84 years (N = 977; Mage = 76.8) were enrolled at four U.S. sites through two recruitment routes: (a) an ongoing longitudinal study and (b) de novo through the community. Participants underwent diagnostic evaluation including otoscopy, tympanometry, pure-tone and speech audiometry, speech-in-noise testing, and provided self-reported hearing abilities. Baseline characteristics are reported as frequencies (percentages) for categorical variables or medians (interquartiles, Q1-Q3) for continuous variables. Between-groups comparisons were conducted using chi-square tests for categorical variables or Kruskal-Wallis test for continuous variables. Spearman correlations assessed relationships between measured hearing function and self-reported hearing handicap. RESULTS: The median four-frequency pure-tone average of the better ear was 39 dB HL, and the median speech-in-noise performance was a 6-dB SNR loss, indicating mild speech-in-noise difficulty. No clinically meaningful differences were found across sites. Significant differences in subjective measures were found for recruitment route. Expected correlations between hearing measurements and self-reported handicap were found. CONCLUSIONS: The extensive baseline audiologic characteristics reported here will inform future analyses examining associations between hearing loss and cognitive decline. The final ACHIEVE data set will be publicly available for use among the scientific community. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24756948.

Omega-3 Polyunsaturated Fatty Acids are not associated with Peripheral Artery Disease in a Meta-Analysis from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study Cohorts.

BACKGROUND: Research suggests omega-3 polyunsaturated fatty acids (PUFAs) exert favorable effects on several biological processes involved in the development and progression of atherosclerotic cardiovascular disease (ASCVD). However, studies examining the relationship between omega-3 PUFAs and peripheral artery disease (PAD) are scarce. OBJECTIVES: We evaluated the associations between omega-3 PUFAs and incident PAD in a meta-analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and Atherosclerosis Risk in Communities (ARIC) study cohorts. METHODS: Omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured at baseline for all MESA (n = 6495) and Minnesota ARIC participants (n = 3612). Incident clinical PAD events (MESA n = 106; ARIC n = 149) identified primarily through ICD discharge codes were assessed through follow-up of each cohort. Associations between omega-3 PUFAs (EPA, DHA, and EPA+DHA) and incident PAD were modeled in MESA and ARIC as quartiles and continuously using Cox proportional hazards regression, respectively. A fixed-effects meta-analysis was conducted to evaluate associations in the 2 cohorts combined. RESULTS: In the fully adjusted model, in 10,107 participants, no significant associations were observed between EPA, DHA, or EPA+DHA, and incident PAD modeled as quartiles or continuously for either MESA or ARIC cohorts separately or in the meta-analysis after a follow-up of approximately 15 y. CONCLUSION: This study is consistent with previous literature indicating that the beneficial effects of omega-3 PUFAs on the markers of ASCVD may not translate to a clinically meaningful decrease in PAD risk.

Plasma Neuronal Growth Regulator 1 May Link Physical Activity to Reduced Risk of Type 2 Diabetes: A Proteome-Wide Study of ARIC Participants.

Habitual physical activity (PA) impacts the plasma proteome and reduces the risk of developing type 2 diabetes (T2D). Using a large-scale proteome-wide approach in Atherosclerosis Risk in Communities study participants, we aimed to identify plasma proteins associated with PA and determine which of these may be causally related to lower T2D risk. PA was associated with 92 plasma proteins in discovery (P < 1.01 × 10-5), and 40 remained significant in replication (P < 5.43 × 10-4). Eighteen of these proteins were independently associated with incident T2D (P < 1.25 × 10-3), including neuronal growth regulator 1 (NeGR1; hazard ratio per SD 0.85; P = 7.5 × 10-11). Two-sample Mendelian randomization (MR) inverse variance weighted analysis indicated that higher NeGR1 reduces T2D risk (odds ratio [OR] per SD 0.92; P = 0.03) and was consistent with MR-Egger, weighted median, and weighted mode sensitivity analyses. A stronger association was observed for the single cis-acting NeGR1 genetic variant (OR per SD 0.80; P = 6.3 × 10-5). Coupled with previous evidence that low circulating NeGR1 levels promote adiposity, its association with PA and potential causal role in T2D shown here suggest that NeGR1 may link PA exposure with metabolic outcomes. Further research is warranted to confirm our findings and examine the interplay of PA, NeGR1, adiposity, and metabolic health.

Loneliness and Social Network Characteristics Among Older Adults With Hearing Loss in the ACHIEVE Study.

BACKGROUND: Hearing loss is linked to loneliness and social isolation, but evidence is typically based on self-reported hearing. This study quantifies the associations of objective and subjective hearing loss with loneliness and social network characteristics among older adults with untreated hearing loss. METHODS: This study uses baseline data (N = 933) from the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study. Hearing loss was quantified by the better ear, speech-frequency pure tone average (PTA), Quick Speech-in-Noise test, and hearing-related quality of life. Outcomes were validated measures of loneliness and social network characteristics. Associations were assessed by Poisson, negative binomial, and linear regression adjusted for demographic, health, and study design characteristics. RESULTS: Participants were mean of 76.8 (4.0) years, 54.0% female, and 87.6% White. Prevalence of loneliness was 38%. Worse PTA was associated with a 19% greater prevalence of moderate or greater loneliness (prevalence ration [PR]: 1.19.95% CI: 1.06, 1.33). Better speech-in-noise recognition was associated with greater social network characteristics (eg, larger social network size [IRR: 1.04, 95% CI: 1.00, 1.07]). Worse hearing-related quality of life was associated with a 29% greater prevalence of moderate or greater loneliness (PR: 1.29, 95% CI: 1.19, 1.39) and worse social network characteristics (eg, more constricted social network size [IRR: 0.96, 95% CI: 0.91, 1.00]). CONCLUSIONS: Results suggest the importance of multiple dimensions of hearing to loneliness and social connectedness. Hearing-related quality of life may be a potentially useful, easily administered clinical tool for identifying older adults with hearing loss associated with greater loneliness and social isolation.

Menthol and Other Flavor Chemicals in Cigarettes from Vietnam and the Philippines.

INTRODUCTION: Tobacco product flavors can increase product appeal, adolescent initiation and experimentation, and difficulty quitting. Flavored tobacco products are not restricted in Vietnam or the Philippines despite the high smoking prevalence among those 15 years of age and older (24% and 23%, respectively). There are no published reports to our knowledge on the levels of flavor chemicals in the cigarettes sold in these two countries. METHODS: Cigarettes were purchased in Vietnam (32 brand variants) and the Philippines (19 brand variants) during 2020. Chemical analyses gave the mg/filter, mg/rod, and mg/stick (= mg/(filter + rod)) values for 180 individual flavor chemicals. Values were calculated for menthol, clove-related compounds, and "other flavor chemicals" (OFCs). RESULTS: Five flavor groupings were found among the brand variants purchased in Vietnam: menthol + OFCs (n = 15), OFCs only (n = 8), nonflavored (n = 7), menthol + OFCs with a clove flavorant (n = 1) and menthol only (n = 1). Three flavor groupings were found among the brand variants purchased in the Philippines: menthol + OFCs (n = 10), nonflavored (n = 5), and menthol only (n = 4). CONCLUSIONS: A range of flavored cigarette products are being offered by tobacco companies in Vietnam and the Philippines, presumably to maximize cigarette sales. Regulation of flavor chemicals should be considered in these two countries. IMPLICATIONS: Article 9 of the WHO Framework Convention on Tobacco Control (FCTC), ratified by both Vietnam and the Philippines, states that "there is no justification for permitting the use of ingredients, such as flavoring agents, which help make tobacco products attractive." Flavors increase product appeal, adolescent initiation and experimentation, and difficulty quitting. These analyses found that cigarettes purchased in Vietnam and the Philippines contained menthol and other flavor chemicals. Tobacco companies are offering multiple flavor chemical profiles and nominally nonflavored versions in these countries; regulation of flavor chemicals should be considered in these two countries.

Hearing loss and cognition: A protocol for ensuring speech understanding before neurocognitive assessment.

INTRODUCTION: Many neurocognitive evaluations involve auditory stimuli, yet there are no standard testing guidelines for individuals with hearing loss. The ensuring speech understanding (ESU) test was developed to confirm speech understanding and determine whether hearing accommodations are necessary for neurocognitive testing. METHODS: Hearing was assessed using audiometry. The probability of ESU test failure by hearing status was estimated in 2679 participants (mean age: 81.4 ± 4.6 years) using multivariate logistic regression. RESULTS: Only 2.2% (N = 58) of participants failed the ESU test. The probability of failure increased with hearing loss severity; similar results were observed for those with and without mild cognitive impairment or dementia. DISCUSSION: The ESU test is appropriate for individuals who have variable degrees of hearing loss and cognitive function. This test can be used prior to neurocognitive testing to help reduce the risk of hearing loss and compromised auditory access to speech stimuli causing poorer performance on neurocognitive evaluation.

Depression and Health-Related Quality of Life Among Older Adults With Hearing Loss in the ACHIEVE Study.

Hearing loss is associated with cognitive/physical health; less is known about mental health. We investigated associations between hearing loss severity, depression, and health-related quality of life among older adults with unaided hearing loss. Data (N = 948) were from the Aging and Cognitive Health Evaluation in Elders Study. Hearing was measured by pure-tone average (PTA), Quick Speech-in-Noise (QuickSIN) test, and the Hearing Handicap Inventory for the Elderly (HHIE-S). Outcomes were validated measures of depression and health-related quality of life. Associations were assessed by negative binomial regression. More severe hearing loss was associated with worse physical health-related quality of life (ratio: .98, 95% CI: .96, 1.00). Better QuickSIN was associated with higher mental health-related quality of life (1.01 [1.00, 1.02]). Worse HHIE-S was associated with depression (1.24 [1.16, 1.33]) and worse mental (.97 [.96, .98]) and physical (.95 [ .93, .96]) health-related quality of life. Further work will test effects of hearing intervention on mental health.

Impact of individual and environmental factors on dietary or lifestyle interventions to prevent type 2 diabetes development: a systematic review.

BACKGROUND: The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D. METHODS: We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier. RESULTS: The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. CONCLUSIONS: We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

Clinical trials to prevent development of type 2 diabetes (T2D) that test dietary and lifestyle interventions have resulted in different results for different study participants. We hypothesized that the differing responses could be because of different personal, social and inherited factors. We searched different databases containing details of published research studies investigating this to look at the effect of these factors on prevention of the development of T2D. We found a small amount of evidence suggesting that those with poorer health, particularly those with a higher amount of sugar in their blood, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our results suggest that further clinical trials that are designed to examine the effect of personal and social factors on interventions for T2D prevention are needed to better determine the impact of these factors on the success of diet and lifestyle interventions for T2D.

Ethnic Enclaves and Incidence of Cancer Among US Ethnic Minorities in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Since immigrants and their descendants represent a growing proportion of the US population, there is a strong demographic imperative for scientists to better understand the cancer risk factors at multiple levels that exist for these populations. Understanding the upstream causes of cancer, including neighborhood context, may help prevention efforts. Residence in ethnic enclaves may be one such contextual cause; however, the evidence is mixed, and past research has not utilized prospective designs examining cancer incidence or mortality. METHODS: We examined the association between residency in ethnic enclaves and cancer events among Hispanic (n = 753) and Chinese (n = 451) participants without a history of cancer in the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study that enrolled participants ages 45-84 in six US cities. Cancer events included deaths and hospitalization for any cancer diagnosis from 2000-2012. Residency in an ethnic enclave was operationalized as their geocoded baseline census tract having a concentration of residents of the same ethnicity greater than the 75th percentile (compared to non-ethnic enclave otherwise). Potential confounders were blocked into three categories: sociodemographic, acculturation, and biomedical/health behavior variables. To examine the association between ethnic enclaves and cancer, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards models. RESULTS: Among Hispanic participants, residing in ethnic enclaves (vs. not) was associated with a 39% reduction in cancer risk (HR 0.61, 95%CI: 0.31, 1.21) after adjusting for sociodemographic variables. Among Chinese participants, residing in ethnic enclaves was associated with a 2.8-fold increase in cancer risk (HR 2.86, 95%CI; 1.38, 5.94) after adjusting for sociodemographic variables. CONCLUSIONS: Our results suggest that the association between ethnic enclaves and cancer events differs by ethnic group, suggesting that different social and contextual factors may operate in different communities.

Development and Characterization of Proteomic Aging Clocks in the Atherosclerosis Risk in Communities (ARIC) Study.

Biological age may be estimated by proteomic aging clocks (PACs). Previous published PACs were constructed either in smaller studies or mainly in White individuals, and they used proteomic measures from only one-time point. In the Atherosclerosis Risk in Communities (ARIC) study of about 12,000 persons followed for 30 years (around 75% White, 25% Black), we created de novo PACs and compared their performance to published PACs at two different time points. We measured 4,712 plasma proteins by SomaScan in 11,761 midlife participants, aged 46-70 years (1990-92), and 5,183 late-life pariticpants, aged 66-90 years (2011-13). All proteins were log2-transformed to correct for skewness. We created de novo PACs by training them against chronological age using elastic net regression in two-thirds of healthy participants in midlife and late life and compared their performance to three published PACs. We estimated age acceleration (by regressing each PAC on chronological age) and its change from midlife to late life. We examined their associations with mortality from all-cause, cardiovascular disease (CVD), cancer, and lower respiratory disease (LRD) using Cox proportional hazards regression in all remaining participants irrespective of health. The model was adjusted for chronological age, smoking, body mass index (BMI), and other confounders. The ARIC PACs had a slightly stronger correlation with chronological age than published PACs in healthy participants at each time point. Associations with mortality were similar for the ARIC and published PACs. For late-life and midlife age acceleration for the ARIC PACs, respectively, hazard ratios (HRs) per one standard deviation were 1.65 and 1.38 (both p<0.001) for all-cause mortality, 1.37 and 1.20 (both p<0.001) for CVD mortality, 1.21 (p=0.03) and 1.04 (p=0.19) for cancer mortality, and 1.46 and 1.68 (both p<0.001) for LRD mortality. For the change in age acceleration, HRs for all-cause, CVD, and LRD mortality were comparable to those observed for late-life age acceleration. The association between the change in age acceleration and cancer mortality was insignificant. In this prospective study, the ARIC and published PACs were similarly associated with an increased risk of mortality and advanced testing in relation to various age-related conditions in future studies is suggested.

Epigenome-wide association study of incident type 2 diabetes in Black and White participants from the Atherosclerosis Risk in Communities Study.

DNA methylation studies of incident type 2 diabetes in US populations are limited, and to our knowledge none included individuals of African descent living in the US. We performed an epigenome-wide association analysis of blood-based methylation levels at CpG sites with incident type 2 diabetes using Cox regression in 2,091 Black and 1,029 White individuals from the Atherosclerosis Risk in Communities study. At an epigenome-wide significance threshold of 10-7, we detected 7 novel diabetes-associated CpG sites in C1orf151 (cg05380846: HR= 0.89, p = 8.4 × 10-12), ZNF2 (cg01585592: HR= 0.88, p = 1.6 × 10-9), JPH3 (cg16696007: HR= 0.87, p = 7.8 × 10-9), GPX6 (cg02793507: HR= 0.85, p = 2.7 × 10-8 and cg00647063: HR= 1.20, p = 2.5 × 10-8), chr17q25 (cg16865890: HR= 0.8, p = 6.9 × 10-8), and chr11p15 (cg13738793: HR= 1.11, p = 7.7 × 10-8). The CpG sites at C1orf151, ZNF2, JPH3 and GPX6, were identified in Black adults, chr17q25 was identified in White adults, and chr11p15 was identified upon meta-analyzing the two groups. The CpG sites at JPH3 and GPX6 were likely associated with incident type 2 diabetes independent of BMI. All the CpG sites, except at JPH3, were likely consequences of elevated glucose at baseline. We additionally replicated known type 2 diabetes-associated CpG sites including cg19693031 at TXNIP, cg00574958 at CPT1A, cg16567056 at PLBC2, cg11024682 at SREBF1, cg08857797 at VPS25, and cg06500161 at ABCG1, 3 of which were replicated in Black adults at the epigenome-wide threshold. We observed modest increase in type 2 diabetes variance explained upon addition of the significantly associated CpG sites to a Cox model that included traditional type 2 diabetes risk factors and fasting glucose (increase from 26.2% to 30.5% in Black adults; increase from 36.9% to 39.4% in White adults). We examined if groups of proximal CpG sites were associated with incident type 2 diabetes using a gene-region specific and a gene-region agnostic differentially methylated region (DMR) analysis. Our DMR analyses revealed several clusters of significant CpG sites, including a DMR consisting of a previously discovered CpG site at ADCY7 and promoter regions of TP63 which were differentially methylated across all race groups. This study illustrates improved discovery of CpG sites/regions by leveraging both individual CpG site and DMR analyses in an unexplored population. Our findings include genes linked to diabetes in experimental studies (e.g., GPX6, JPH3, and TP63), and future gene-specific methylation studies could elucidate the link between genes, environment, and methylation in the pathogenesis of type 2 diabetes.

SGLT2 Inhibitors Are Associated With Reduced Cardiovascular Disease in Patients With Type 2 Diabetes: An Analysis of Real-World Data.

OBJECTIVE: To assess the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and other second-line diabetes therapies with risk of cardiovascular disease (CVD), as well as conduct head-to-head comparisons between SGLT2 inhibitors. PATIENTS AND METHODS: Using data from the MarketScan databases (January 1, 2013, through December 31, 2019), SGLT2 inhibitor users were matched with up to five other second-line therapy users by age, sex, date of enrollment, and date of second-line therapy initiation. The primary composite outcome included stroke, atrial fibrillation, myocardial infarction, and heart failure. Hazard ratios were estimated, adjusting for demographics and a propensity score reflecting comorbidities and medications. RESULTS: In this study population of 313,396 patients (mean age 53±10 years; 47% female), 9787 incident CVD events occurred over a median follow-up of 1.36 years. After multivariable adjustments, SGLT2 inhibitor users had a lower risk of CVD than other second-line therapy users (HR, 0.66; 95% CI, 0.62 to 0.71). Significant associations were also observed when each CVD outcome was assessed separately. No differences were noted when comparing individual SGLT2 inhibitors. CONCLUSION: SGLT2 inhibitors were associated with a clinically meaningfully lower CVD risk in the real-world setting. In head-to-head comparisons, the different SGLT2 inhibitors were consistent in their protective associations with CVD. This suggests that as a class, SGLT2 inhibitors may have widespread benefit in preventing CVD among patients with type 2 diabetes.

Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation.

BACKGROUND: The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial. OBJECTIVES: This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF. METHODS: We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively. CONCLUSIONS: In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.

Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial.

BACKGROUND: Hearing loss is associated with increased cognitive decline and incident dementia in older adults. We aimed to investigate whether a hearing intervention could reduce cognitive decline in cognitively healthy older adults with hearing loss. METHODS: The ACHIEVE study is a multicentre, parallel-group, unmasked, randomised controlled trial of adults aged 70-84 years with untreated hearing loss and without substantial cognitive impairment that took place at four community study sites across the USA. Participants were recruited from two study populations at each site: (1) older adults participating in a long-standing observational study of cardiovascular health (Atherosclerosis Risk in Communities [ARIC] study), and (2) healthy de novo community volunteers. Participants were randomly assigned (1:1) to a hearing intervention (audiological counselling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed up every 6 months. The primary endpoint was 3-year change in a global cognition standardised factor score from a comprehensive neurocognitive battery. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, NCT03243422. FINDINGS: From Nov 9, 2017, to Oct 25, 2019, we screened 3004 participants for eligibility and randomly assigned 977 (32·5%; 238 [24%] from ARIC and 739 [76%] de novo). We randomly assigned 490 (50%) to the hearing intervention and 487 (50%) to the health education control. The cohort had a mean age of 76·8 years (SD 4·0), 523 (54%) were female, 454 (46%) were male, and most were White (n=858 [88%]). Participants from ARIC were older, had more risk factors for cognitive decline, and had lower baseline cognitive scores than those in the de novo cohort. In the primary analysis combining the ARIC and de novo cohorts, 3-year cognitive change (in SD units) was not significantly different between the hearing intervention and health education control groups (-0·200 [95% CI -0·256 to -0·144] in the hearing intervention group and -0·202 [-0·258 to -0·145] in the control group; difference 0·002 [-0·077 to 0·081]; p=0·96). However, a prespecified sensitivity analysis showed a significant difference in the effect of the hearing intervention on 3-year cognitive change between the ARIC and de novo cohorts (pinteraction=0·010). Other prespecified sensitivity analyses that varied analytical parameters used in the total cohort did not change the observed results. No significant adverse events attributed to the study were reported with either the hearing intervention or health education control. INTERPRETATION: The hearing intervention did not reduce 3-year cognitive decline in the primary analysis of the total cohort. However, a prespecified sensitivity analysis showed that the effect differed between the two study populations that comprised the cohort. These findings suggest that a hearing intervention might reduce cognitive change over 3 years in populations of older adults at increased risk for cognitive decline but not in populations at decreased risk for cognitive decline. FUNDING: US National Institutes of Health.

Coronary Artery Calcium Scores in Older Adults With Diabetes and Their Association With Diabetes-Specific Risk Enhancers (from the Atherosclerosis Risk in Communities Study).

Coronary artery calcium (CAC) is a validated marker of atherosclerotic cardiovascular disease (ASCVD) risk; however, it is not routinely incorporated in ASCVD risk prediction in older adults with diabetes. We sought to assess the CAC distribution among this demographic and its association with "diabetes-specific risk enhancers," which are known to be associated with increased ASCVD risk. We used the ARIC (Atherosclerosis Risk in Communities) study data, including adults aged >75 years with diabetes, who had their CAC measured at ARIC visit 7 (2018 to 2019). The demographic characteristics of participants and their CAC distribution were analyzed using descriptive statistics. Multivariable-adjusted logistic regression models were used to estimate the association between diabetes-specific risk enhancers (duration of diabetes, albuminuria, chronic kidney disease, retinopathy, neuropathy, and ankle-brachial index) and elevated CAC, adjusting for age, gender, race, education level, dyslipidemia, hypertension, physical activity, smoking status, and family history of coronary heart disease. The mean age in our sample was 79.9 (SD 3.97) years, with 56.6% women and 62.1% White. The CAC scores were heterogenous, and the median CAC score was higher in participants with a greater number of diabetes risk enhancers, regardless of gender. In the multivariable-adjusted logistic regression models, participants with ≥2 diabetes-specific risk enhancers had greater odds of elevated CAC than those with <2 (odds ratio 2.31, 95% confidence interval 1.34 to 3.98). In conclusion, the distribution of CAC was heterogeneous among older adults with diabetes, with the CAC burden associated with the number of diabetes risk-enhancing factors present. These data may have implications for prognostication in older patients with diabetes and supports the possible incorporation of CAC in the assessment of cardiovascular disease risk in this population.

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.

BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.