bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 01: Association of Copayment Level and Glucagon-Like Peptide-1 Receptor Agonist and Sodium-Glucose Cotransporter 2 Inhibitor Adherence in Diabetes and Heart Failure
Authors: Essien Utibe R , Singh Balvindar , Swabe Gretchen , Johnson Amber E , Eberly Lauren , Wadhera Rishi , Breathett Khadijah , Vaduganathan Muthiah , Magnani Jared W
Published: March 2023

Introduction:
Diabetes and heart failure (HF) rates are rising. Glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with improved outcomes in these conditions. Out-of-pocket cost may reduce medication adherence. We examined the association of medication copayment with 1-year adherence to these agents in individuals with diabetes and HF.

Hypothesis:
Individuals with high copayments have reduced adherence to GLP1RAs and SGLT2is.

Methods:
Using the Optum de-identified Clinformatics Data Mart Database, individuals with diabetes and HF and ≥12 months of enrollment with a GLP1RA or SLGT2i claim from 2014-2021 were included. We defined adherence as the proportion of days covered (PDC) ≥80%. We used multivariable logistic regression models to examine the adjusted odds of adherence by copayment level, defined as low (<$10 USD), medium ($10-<$50), and high (≥$50). Covariates included patient socioeconomic and clinical comorbidities.

Results:
We identified 94,610 individuals (age 61.8±11.4 years; 45.9% female) prescribed GLP1RAs or SGLT2is from 1/1/2014-9/30/2020, Overall, 39,149 individuals had a claim for a GLP1RA, of whom 25,557 (65.3%) had PDC ≥80%. In fully adjusted models, individuals with medium (adjusted odds ratio, aOR 0.61, 95% CI, 0.57-0.66) and high copayment (aOR 0.48, 95% CI, 0.44-0.51) were less likely to have PDC ≥80% with GLPRAs compared to those with low copayment (
Figure
). Overall, 51,072 individuals had a claim for an SGLT2i, of whom 37,339 (73.1%) individuals had PDC ≥80% at 1 year. Individuals with medium (aOR 0.67, 95% CI, 0.62-0.71) and high copayment (aOR 0.69, 95% CI, 0.64-0.74) were less likely to have PDC ≥80% with SGLT2is compared to those with low copayment.

Conclusion:
In a large cohort of individuals with diabetes and HF, 1-year adherence to GLP1RA or SGLT2i therapies was highest among individuals with low copayment. Improving adherence to guideline-based therapies requires interventions that reduce prescription costs.
Abstract 09: Trajectories of Insulin Resistance, Incident Heart Failure and All-Cause Death in Nondiabetics: The Atherosclerosis Risk in Communities Study
Authors: Xing Zailing , Schocken Douglas D , Zgibor Janice , Alman Amy C
Published: March 2023

Introduction:
Previous studies have suggested an association between insulin resistance (IR) trajectories and adverse changes in cardiac structure and function in nondiabetic populations. We studied the associations between IR trajectories and incident heart failure (HF) and all-cause death in nondiabetic participants of the Atherosclerosis Risk in Communities (ARIC) study. We hypothesized that long-term moderate and high IR levels would increase the risk of incident HF and all-cause death.

Methods:
We included 7,835 participants (3,505 men and 4,330 women) aged 45-64 from the ARIC study without diabetes mellitus at any visit, and no history of prevalent HF, myocardial infarction, stroke, arterial or coronary surgery, or cancer at baseline. We estimated IR using Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), triglyceride glucose (TyG) index and metabolic score for IR (METS-IR). Serum insulin was not available at visits 2 and 3, so HOMA-IR was calculated for visits 1, 4, and 5. Latent class analysis identified two HOMA-IR trajectories, low-increasing and high-increasing, and three trajectories for TG/HDL-C, TyG index, and METS-IR: low-increasing, moderate-stable, and high-decreasing. We employed Cox proportional-hazards models to examine the associations of IR trajectories with incident HF and all-cause death adjusting for potential confounders.

Results:
Compared to participants in the low-increasing group, those in the high-increasing group of HOMA-IR were more likely to have incident HF and all-cause death (Table 1). For TG/HDL-C, TyG index and METS-IR, we found an increased risk of incident HF in the moderate-stable and high-decreasing groups relative to the low-increasing group. For all-cause death, consistent associations were found only in women (Table 1).

Conclusions:
Reduction of insulin resistance in nondiabetic individuals may be a suitable target for prevention strategies to reduce cardiovascular disease.
Abstract 12: Associations Between Long-Term Body Mass Index Variability and Adverse Cardiovascular Outcomes: Million Veteran Program Study
Authors: Almuwaqqat Zakaria , Hui Qin , Zhou Jin , Voight Benjamin F , Ho Yuk-lam , Posner Daniel , Vassy Jason , Wilson Peter , Sun Yan
Published: March 2023

Objective:
Body mass index (BMI) is a commonly used estimate of obesity that is a complex multifactorial trait resulting from genetic and lifestyle factors. Weight gain and loss could correlate with adverse biological processes. Prior studies have reported that increased BMI variability predicts future adverse cardiovascular events. However, there have been no prior studies that have investigated this association in patients without cancer or preexisting cardiovascular disease among multiple ethnicities. Using the Million Veteran Program (MVP), a mega-biobank with longitudinal health record data from a large US healthcare system, we evaluated the association between BMI variability and incident cardiovascular events in an ethnically diverse longitudinal cohort (2011-2019).

Methods:
We studied 92,363 adults free of cardiovascular disease and cancer at baseline. BMI was longitudinally assessed from the baseline visit. BMI variability was assessed using the standard deviation (SD) and coefficient of variation (CV) of each participant. Cardiovascular disease (CVD) risk factors including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking status, diabetes status and statin use were assessed as covariates. We followed patients for the composite CVD events of incident non-fatal myocardial infarction, acute ischemic stroke, and cardiovascular death. Cox proportional hazards modeling was used to examine the association between BMI variability and incident CVD events after adjustment for dichotomous and continuous measures. We also assessed if results were affected sensitive to adjustment for the BMI polygenic score.

Results:
The cohort (88% men) included 60,180 non-Hispanic White (NHW), 22,488 non-Hispanic Black (NHB), and 9,695 Hispanic (HIS) participants with mean age 56.8 years. Patients were followed from 2011 to 2019. We observed 4,855 composite CVD events. The CV of BMI was associated with incident composite CVD across all groups, but to a stronger degree for Hispanic participants. Among the NHW, each SD increase of CV (indicative of greater BMI variability) was associated with a 15% rise in the risk of CVD events (i.e HR 1.15, 95%CI, 1.11-1.19 after adjustment of covariates. Among the NHB and HIS, results were similar: HR, 1.16 (95%CI, 1.09 - 1.22) and HR, 1.24 (95%CI, 1.12-1.38), respectively. In sensitivity analyses, we found that BMI variability is similarly predictive of the composite outcome after adjustment for BMI polygenic score.

Conclusions and Relevance:
Increased BMI variability is an independent risk factor for future CVD events.
Abstract 13: Circadian Misalignment is Associated With Impaired Heart Rate Variability in Adolescents
Authors: Morales-Ghinaglia Natasha , He Fan , Liao Jason , Calhoun Susan , Vgontzas Alexandros , Bixler Edward O , Liao Duanping , Fernandez-Mendoza Julio
Published: March 2023

Introduction:
Adequate sleep has been recognized by AHA as part of Life’s Essential 8 in the prevention of cardiovascular disease (CVD). The circadian system, which governs the sleep-cycle, is also involved in cardiac, metabolic and autonomic regulation. Heart rate variability (HRV), a marker of cardiac autonomic modulation (CAM), is known to predict CVD. As a result, circadian misalignment of the sleep-wake cycle, which is highly prevalent in adolescents, may impact CAM and be a potential risk factor for adverse CVD outcomes in early life.

Hypothesis:
We hypothesize that deviations in the circadian timing of sleep are associated with blunted HRV in adolescents.

Methods:
We analyzed data from 337 population-based randomly-selected adolescents from the Penn State Child Cohort (median 16 years; 47% female; 21% racial/ethnic minority) who had at least 3-night at-home actigraphy (ACT), in-lab 9-h polysomnography (PSG) and 24-h Holter-monitoring heart rate variability (HRV) data. ACT-sleep duration and sleep midpoint (SM) were calculated as the intra-individual mean total sleep time and midpoint of the sleep period, respectively. ACT-sleep variability and sleep regularity (SR) were calculated as the intra-individual standard deviation of sleep duration and sleep midpoint across nights, respectively. Frequency and time-domain HRV indices, including HR oscillations at high frequencies (HF), standard deviation between normal heart beats or R-R intervals (SDNN), and root mean square of successive differences between normal heartbeats (RMSSD), were primary outcomes. Linear regression models tested SM and SR as predictors of HRV indices, while accounting for sex, race/ethnicity, age, body mass index, ACT-sleep duration, ACT-sleep variability, and PSG-apnea/hypopnea index.

Results:
While there were no meaningful associations between SM or SR with daytime HRV, there were significant associations between SM with nighttime HRV. A later SM was associated with lower nighttime Log-HF, SDNN and RMSSD, yet higher nighttime LF/HF (all p<0.03). For each standard deviation increase in SM (i.e., 1.5 hours later), there was a decrease of -5.50ms (1.92) in nighttime RMSSD (p=0.004). More specifically, the nighttime RMSSD of adolescents with a SM at 5:30 (i.e., sleep onset at 2:00, sleep offset at 9:00), was 18.2ms (6.7) lower (p=0.007) than that of adolescents with a SM at 2:30 (i.e., sleep onset at 23:00, sleep offset at 6:00).

Conclusions:
A delayed sleep phase is associated with impaired CAM in adolescents. These data support that circadian misalignment of the sleep-wake cycle may independently contribute to CVD risk.
Abstract 23: Genome Wide Association Study and Multi-Ancestry Meta-Analysis Identify Common Variants Associated With Carotid Artery Intima Media Thickness
Authors: Dehghan Abbas , Huang Jian , Hesbani Natalie , Romuald Palwende , Zare Marjan ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,   The CHARGE Consortium, Franceschini Nora , de Vries Paul , Tzoulaki Ioanna , Meena Devendra
Published: March 2023

Carotid artery intima-media thickness (cIMT) is a measurement of subclinical atherosclerosis that predicts future cardiovascular events, including stroke and myocardial infarction. Genome-wide association studies (GWAS) in the past have identified only a fraction of the genetic variants associated with cIMT. We performed the largest GWAS to date for cIMT in a multi-ancestry meta-analysis in up to 131,000 individuals of African, Asian (Chinese), Brazilian, European, and Hispanic ancestries. Our study identified 57 independent loci (51 loci from the multi-ancestry single variant analysis of which 17 are novel, P<5x10
-8
; 6 novel in gene-based analysis from single variant analysis, P = 2.6x10
-6
) associated with cIMT. Gene-based, tissue-expression and gene-set enrichment analyses revealed novel genes of potential interest and highlighted significant relationships between vascular tissues (aorta, coronary and tibial arteries) and genetic associations. We found strong genome-wide correlation between cIMT and various cardiometabolic, smoking and lipid traits. Using Mendelian randomisation, our analyses provide robust evidence for causal associations between cIMT and several clinically relevant traits, including lipids, blood pressure, and waist circumference. Our results provide the first evidence of substantial pleiotropy in colocalisation signals between APOE SNPs and metabolite biomarkers for coronary artery disease and cIMT but not for Alzheimer's disease.In summary, we identify 57 loci robustly associated with cIMT that are expressed in a range of vascular tissue types including aorta, coronary and tibial arteries. Our findings suggest a bidirectional relationship between cIMT and hypertension but do not support a link between atherosclerosis and Alzheimer’s disease based on the APOE locus.
Abstract 47: Mid-Life Vascular Risk and Rate of Physical Function Decline Among Older Adults: The Atherosclerosis Risk in Communities Study
Authors: Skow Laura , Schrack Jennifer , Coresh Josef , Deal Jennifer A , Gottesman Rebecca F , Sharrett A R , Palta Priya , Griswold Michael , Sullivan Kevin , Windham B Gwen
Published: March 2023

Introduction:
Physical function decline is associated with poor outcomes, including disability and death. Late-life vascular risk burden is associated with faster physical decline, but earlier life course influence is still unknown. We hypothesized that higher mid-life vascular risk is associated with faster late-life physical function decline.

Methods:
We studied 5,481 adults at visit 5 (mean [SD] age=75.8 [5.0], range=67-91 years, 58% women, 21% Black) without stroke or Parkinson disease. Mid-life hypertension (≥140/90 mm Hg or treatment), diabetes (≥126 mg/dL or treatment), high cholesterol (≥240 mg/dL or treatment), and current smoking were assessed at visit 1 (age=45-64 years) and across visits 1-4. Late-life physical function in the Short Physical Performance Battery (SPPB) was assessed at visits 5-7 (median follow-up: 4.8 years). Random-slope, random-intercept linear mixed models tested interactions between rate of SPPB decline and mid-life risk factors, adjusted for visit 5 age, sex, race-site, education, BMI, coronary heart disease, and heart failure.

Results:
Mid-life hypertension (+57% decline: 0.47 per 5 years, 95% CI: 0.30-0.64, p<0.001) and diabetes (+73% decline: 0.67 per 5 years, 95% CI: 0.24-1.09, p=0.002) were associated with faster SPPB decline compared to midlife low risk (Figure 1), as were higher systolic blood pressure (+17% per SD: 0.16 per 5 years, 95% CI: 0.10-0.23, p<0.001) and fasting blood glucose (+16% per SD: 0.015 per 5 years, 95% CI: 0.06-0.24, p=0.002). Greater cumulative years of exposure to hypertension and diabetes were associated with faster rates of SPPB decline (+32% decline: 0.93 per 5 years, 95% CI: 0.61-1.25, p<0.001) and diabetes (+35% decline: 1.03 per 5 years, 95% CI: 0.38-1.68, p=0.002).

Conclusions:
Older adults with mid-life hypertension and diabetes had faster rates of late-life physical function decline. Midlife control of blood pressure and diabetes may ameliorate late-life functional decline.
Abstract 54: Newly Initiation of Antihypertensive Medication on Reduction of Incident Dementia: Emulation of Target Trials Based on the Health and Retirement Study
Authors: Wei Jingkai , Xu Hanzhang , Zhang Donglan , Tang Huilin , Wang Tiansheng , Steck Susan E , Zhang Jiajia , Divers Jasmin , Merchant Anwar T
Published: March 2023

Background:
Although antihypertensive medication use is associated with a lower risk of dementia in observational studies, such an effect is rarely found in randomized controlled trials (RCTs). As midlife high blood pressure is more predictive of incident dementia than hypertension in late life, so midlife hypertension may be the target for intervention. However, no such an RCT has been conducted to prevent incident dementia through reducing high blood pressure from midlife. Therefore, we aimed to emulate a target trial with an observational study design to estimate the effect of initiating antihypertensive medication from midlife on reducing incident dementia.

Hypothesis:
We assessed the hypothesis that newly initiating antihypertensive medication among midlife adults with hypertension reduces incident dementia.

Methods:
New-user design was used to emulate a target trial using data from the Health and Retirement Study from 1996 to 2018 with non-institutional dementia-free participants aged 45 to 65 years without taking antihypertensive medication in past two years. Participants with information of self-reported hypertension diagnosis and new use of antihypertensive medication, as well as no dementia based on algorithm were included in the analysis and represented group with/without initiating antihypertensive medication. An intention-to-treat approach was applied for analysis, and sequential emulation was used to increase the efficiency of intention-to-treat analysis. Proportional hazards models were applied to estimate the effect of initiating antihypertensive medication on incident dementia. Inverse probability of treatment and censoring weights were created to adjust for confounding and selection bias due to loss to follow-up, and death was considered as a competing event. Another emulated target trial with the same specifications was conducted among late-life adults aged 66 years or older for comparison.

Results:
A total of 3,151 non-unique participants (baseline mean age: 59.0 ± 4.0 years, 54.6% (n=1,719) women, 78.3% (n=2468) Whites, 71.4% (n=2,249) initiating antihypertensive medication) were included in the analysis. Initiating antihypertensive medication showed benefit in reducing incident dementia over a total of 22-year follow-up, with a reduction of risk by 19% (hazards ratio=0.81, 95% confidence interval: 0.66, 0.99). No significant reduction was observed for initiators of antihypertensive medication from late life.

Conclusions:
Initiating antihypertensive medication from midlife, but not from late life may reduce incident dementia. Future studies are warranted to estimate the effect of blood pressure lowering in midlife through other means of intervention in reducing incident dementia.
Abstract 56: DNA Methylation of Birthweight-Blood Pressure Genes and Changes of Blood Pressures in Response to Weight-Loss Diets
Authors: Kou Minghao , Li Xiang , Wang Xuan , Ma Hao , Heianza Yoriko , Bray George , Sacks Frank M , Qi Lu
Published: March 2023

Introduction:
DNA methylation (DNAm) may play a critical role in bridging prenatal adverse events and cardiometabolic disorders including hypertension in later life.

Hypothesis:
DNAm levels of genes related to both birthweight and blood pressure were associated with changes in blood pressures in response to dietary weight-loss interventions.

Methods:
We included 672 adult participants with overweight or obesity, who participated in a 2-year randomized weight-loss dietary intervention study. Baseline blood DNAm levels were profiled by high-resolution methylC-capture sequencing. We defined the regional DNAm levels as the average methylation level within 500 bp of
LINC00319
(cg01820192),
ATP2B1
(cg00508575), and
LMNA
(cg12593793). Generalized linear regression models were used to assess the association between the regional DNAm and 2-year blood pressure changes. Trajectory analysis was used to identify subgroups that shared a similar underlying trajectory of 2-year blood pressure changes.

Results:
We found that the regional DNAm at
LINC00319,
but not the other genes, showed different associations with 2-year changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) among participants assigned low- or high-fat diets (P for interaction < 0.05 for all,
Figure
). In response to low-fat diet, per standard deviation higher regional DNAm at
LINC00319
was associated with greater reductions in both 2-year changes in SBP (β: -1.481; standard error [SE]: 0.632; P = 0.020) and DBP (β: -1.096; SE: 0.413; P = 0.009). Three trajectories of changes in SBP and DBP were identified, and participants with higher baseline regional DNAm at
LINC00319
were less likely to have stable or increased blood pressure levels.

Conclusions:
Our findings indicate that higher regional DNAm level at
LINC00319
was significantly associated with greater long-term reduction in blood pressure in response to a low-fat diet, suggesting people with higher regional DNAm levels benefited more from eating a low-fat weight-loss diet.
Abstract 59: Social Determinants of Health and Incident Apparent Treatment Resistant Hypertension in a National Cohort of Black and White US Adults
Authors: Akinyelure Oluwasegun P , Jaeger Byron C , Oparil Suzanne , Carson April P , Safford Monika M , Hannon Lonnie , Sims Andrew M , Howard George , Muntner Paul , Hardy Shakia T
Published: March 2023

Background:
Identifying social determinants of health (SDOH) associated with incident apparent treatment resistant hypertension (aTRH) may guide interventions to reduce the incidence of aTRH and its associated cardiovascular disease risk.

Methods:
We analyzed data from 2,769 White and 2,254 Black US adults from the REasons for Geographic and Racial Differences in Stroke study taking antihypertensive medication with controlled blood pressure (BP) at baseline to estimate the association of SDOH with incident aTRH. SDOH were guided by the Healthy People 2030 domains of education, economic stability, social context, neighborhood environment and healthcare access. Incident aTRH was defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg, systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg for those with diabetes or chronic kidney disease, while taking ≥3 classes of antihypertensive medication or taking ≥4 classes of antihypertensive medication regardless of BP level, at a follow-up visit.

Results:
Over a median 9.5 years of follow-up, 16.1% of White versus 23.7% of Black adults developed aTRH. After age and sex adjustment, the SDOH associated with incident aTRH (hazard ratio; 95% CI) included having less than a high school education (1.51; 1.22 - 1.87), being a high school graduate (1.30; 1.10 - 1.53), and attending some college (1.29; 1.10 - 1.52) versus college graduate; annual household income <$20,000 (1.83; 1.46 - 2.30), $20,000 to <$35,000 (1.53; 1.23 - 1.90) and $35,000 to <$75,000 (1.24; 1.00 - 1.53) versus ≥$75,000; having no one to care for you if ill (1.29; 1.08 - 1.55); living in a disadvantaged neighborhood in quartiles 1 (1.72; 1.42 - 2.08) and 2 (1.48; 1.22 - 1.80) versus 4, or a high poverty zip code (1.26; 1.09 - 1.47); not having health insurance (1.36; 1.06 - 1.74) and residing in a state with low public health infrastructure (1.17; 1.02 - 1.33). Results stratified by race are presented in the Table.

Conclusion:
SDOH were associated with transitioning from controlled BP to incident aTRH among White and Black adults.
Abstract 62: Life’s Essential 8 and Mortality Risk: Associations of an Enhanced Cardiovascular Health Construct With All-Cause, Cardiovascular, and Cancer Mortality in US Adults From the 2011-2018 National Health and Nutrition Examination Survey
Authors: Makarem Nour , Dinh Vanessa , Hosalli Rahul , Aggarwal Brooke A , German Charles A , Mullachery Pricila
Published: March 2023

Introduction:
Cardiovascular health (CVH), measured using the AHA’s Life’s Simple 7, is linked to mortality. Associations of AHA’s Life’s Essential 8 (LE8), an enhanced approach to defining CVH, with mortality risk have not yet been evaluated in a nationally representative sample of US adults.

Hypothesis:
Lower CVH will be associated with higher risk for all-cause, CVD, and cancer mortality.

Methods:
We included 21,164 adults (mean age: 48y, 51% female, 11% Black, 15% Hispanic, 65% White) from the 2011-2018 NHANES whose mortality through 2019 was determined via linkage to the National Death Index. The CVH score (range: 0-100, high: 80-100, moderate: 50-79, low: 0-49) and component scores were computed consistent with the LE8 framework. The Kaplan-Maier method and multivariable Cox proportional hazards models were used to evaluate the CVH score and its component scores in relation to all-cause mortality (primary outcome) as well as CVD and cancer mortality (secondary outcomes), accounting for the complex stratified survey design of NHANES.

Results:
During a median follow-up of 5y, there were 1,397 deaths, including 414 and 329 deaths from CVD and cancer, respectively. Low vs. high CVH was related to 3-fold higher risk for all-cause mortality and >3-fold higher risk of CVD and cancer mortality, and a linear trend across CVH categories was detected (Figure). Lower scores for the diet, physical activity, nicotine exposure, sleep health, BMI, blood glucose, and blood pressure components predicted 25% to 2-fold higher mortality risk, and a gradient in risk was observed. Associations did not vary by sex, but there were differences by race and ethnicity (p-interaction<0.05); the magnitude of associations was strongest among Whites, while no relation was observed among Hispanics.

Conclusions:
CVH measured using the enhanced LE8 is a strong predictor of all-cause, CVD, and cancer mortality in US adults, with evidence of a dose-response relationship. Improving CVH could result in substantial population-level reductions in mortality.
Abstract 69: Dietary Fiber, Gut Microbiota, Circulating Metabolomics, and Risk of Diabetes in US Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Wang Zheng , Xing Jiaqian , Peters Brandilyn A , Yu Bing , Grove Megan , Hu Gang , Wang Tao , Thyagarajan Bharat , Daviglus Martha L , Boerwinkle Eric , Sotres-Alvarez Daniela , Knight Rob , Burk Robert D , Kaplan Robert , Qi Qibin
Published: March 2023

Introduction:
Emerging evidence suggesting diabetes -protective effects of dietary fiber intake. However, the underlying mechanisms are not fully understood.

Hypothesis:
We hypothesize that higher dietary fiber intake can alter gut microbial composition /functional capacity and host circulating metabolomic profile, which may contribute to lower risk of diabetes.

Methods:
We evaluated the associations of dietary fiber intake with gut microbiome (measured by shotgun metagenomic sequencing, n=2959) and serum metabolome (639 metabolites measured by untargeted metabolomic approach, n=6198) in the HCHS/SOL cohort. We further examined prospective associations of baseline fiber/microbial-associated metabolites with incident diabetes over 6-years follow-up.

Results:
We identified 39 bacterial genera associated with fiber intake, after adjustment for sociodemographic, behavioral, and clinical factors. 12 of these fiber-associated genera were related with diabetes (e.g. the fiber-associated
Roseburia
was inversely associated with diabetes,
Fig.1A
). We identified 83 fiber-associated metabolites which were clustered into 13 modules in network, 7 of which were significantly associated with risk of diabetes (
Fig.1B
). Some of these diabetes-associated metabolite modules were also associated with fiber/diabetes-associated bacterial taxa (
Fig.1C
). In particular, indolepropionate module, and another module comprised of the pro-vitamins such as beta-cryptoxanthin, were positively associated with fiber (all P<0.001) and inversely associated with diabetes risk (RR [95% CI] = 0.78[0.69, 0.89] and 0.83[0.72, 0.94] respectively), and both associated with the fiber-degradation genera
Butyrivibrio
(P<0.001).

Conclusion:
Among US Hispanics/Latinos, higher fiber intake was associated with favorable profiles of gut microbiota and circulating metabolites for diabetes, suggesting a potential role of gut microbiota and related metabolites in the link between dietary fiber intake and risk of diabetes.
Abstract MP01: Midlife Diabetes and Lifetime Risk of Dementia: During 30 Years Follow-Up From the ARIC Study
Authors: Hu Jiaqi , Fang Michael , Pike James R , Lutsey Pamela L , Sharrett A. R , Wagenknecht Lynne E , Hughes Timothy M , Seegmiller Jesse , Gottesman Rebecca F , Mosley Thomas , Selvin Elizabeth , Coresh Josef
Published: March 2023

Introduction:
Diabetes is associated with both dementia and death. Ignoring the competing risk of mortality may result in overestimation of the lifetime of dementia.

Hypothesis:
The lifetime cumulative incidence of dementia associated with diabetes will be much lower when taking into account the competing risk of mortality, particularly at the oldest ages.

Methods:
We conducted a prospective cohort analysis of data from the Atherosclerosis Risk in Communities (ARIC) Study (midlife baseline at visit 2, 1990-1992). Diabetes was defined as a self-reported physician diagnosis, diabetes medication use, or HbA1C of 6.5% or greater. Incident dementia was ascertained via active surveillance involving interviews and adjudication. We conducted survival analysis using age as the time scale with age 50 as the origin and December 31st, 2019 as the administrative censoring date. Dementia risk was analyzed with death treated as a censoring event or as a competing risk.

Results:
Among 13,381 participants, 1798 (13.4%) had diabetes at baseline (mean age: 56.8 years). Using a standard Cox model, diabetes was associated with an increased hazard of dementia (HR 1.36; 95% CI 1.21, 1.52) and death (HR 1.87; 95% CI 1.76, 1.99). Censoring mortality (ignoring competing risk), diabetes was associated with a higher cumulative incidence of dementia at all ages (
Figure A
). Competing risk models showed a lower risk of dementia than models censoring death. Furthermore, diabetes was associated with a higher risk of dementia only before age 85 but a lower cumulative risk after age 85 due to the large excess risk of mortality (
Figures B and C
).

Conclusion
Standard methods dramatically overestimate the lifetime risk of dementia in persons with and without diabetes. Competing risk models are critical for accurate absolute risk estimates, particularly in the oldest ages. Interventions which increase life expectancy in patients with diabetes may increase the cumulative risk of dementia in old age.
Abstract MP30: Metabolomics Analyses Identified Factors Modifying the Association of Aspirin Use With Kidney Function
Authors: Zhang Ruiyuan , Sun Xiao , Huang Zhijie , Rao Varun , Pan Yang , Cao Xi , Liu Yizhuo , Li Shengxu , Bazzano Lydia A , Chen Wei , He Jiang , Kelly Tanika N , Li Changwei
Published: March 2023

Introduction:
Uncontrolled high dose aspirin use impairs kidney function. Short-term low dose aspirin treatment has also been associated with kidney function in older patients. We aimed to evaluate the association of regular aspirin use with kidney function in middle-aged adults and to identify factors modifying the association.

Methods:
We performed cross-sectional analyses among 1,261 participants of the 2016 Bogalusa Heart Study (BHS) visit. Regular aspirin use was self-reported and confirmed by serum biomarker,
salicyluric glucuronide
. Aspirin users were categorized at the median of
salicyluric glucuronide
levels into low and high dose users. A total of 887 known metabolites were profiled from the serum. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-Epi equation. We tested associations of aspirin use with eGFR and examined interactions of aspirin with serum metabolites on eGFR. Age, sex, race, education, smoking, drinking, physical activity, BMI, blood pressure, and fasting glucose were adjusted in all analyses.

Results:
The mean age of BHS participants was 48.2, and 133 (10.5%) were self-reported aspirin users. Serum
salicyluric glucuronide
level was significantly correlated with self-reported aspirin usage (P=2.00х10
-21
). After adjusting for all covariables, mean eGFR for never, low dose, and high dose aspirin users were 92.9, 90.2, and 89.9 mL/min/1.73m
2
, respectively (P for trend=0.004). After Bonferroni correction, 28 metabolites modified the associations of aspirin use with eGFR (P<5.52х10
-5
), of which, 26 increased the aspirin's nephrotoxicity effect, while
behenoylsphingomyelin
and
tricosanoylsphingomyelin
significantly attenuated the eGFR lowering effect of aspirin (Table).

Conclusion:
Aspirin use is associated with decreased eGFR among middle-aged adults, and this association was modified by dietary, gut microbiome, and biomarkers of kidney disease, cardiovascular disease, and cancer. The findings may help develop better use strategies for regular users.
Abstract MP37: DNA Methylation of Leptin Mediates the Relationship Between Stress-Associated Inflammation and Insulin Resistance: Data From the Washington DC Cardiovascular Health and Needs Assessment
Authors: Ortiz-Whittingham Lola R , Baumer Yvonne , Collins Billy S , Mitchell Valerie M , Corley Michael J , Powell-Wiley Tiffany M
Published: March 2023

Introduction:
Chronic psychosocial stressors are associated with inflammation and cardiovascular (CV) risk, including insulin resistance (IR); however, potential DNA methylation (DNAm) mediators between stress-related inflammation and IR are not known.

Hypothesis:
DNAm biomarkers mediate the relationship between stress-related inflammation and IR.

Methods:
Participants from the DC Cardiovascular Health and Needs Assessment (DC-CHNA) underwent phenotyping at the NIH Clinical Center. Homeostatic Model Assessment for Insulin Resistance was calculated using insulin and glucose values. Social isolation, loneliness, and depression were determined using validated surveys. IL-8 was measured using an ELISA-based method. Principal component DNAm-based surrogate markers of leptin, cystatin C, and plasminogen activator inhibitor-1 were calculated from DNAm data obtained from participants' buffy coat samples. We examined relationships of interest with regression models adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score and body mass index (BMI). Mediation analysis was used to evaluate DNAm measures as possible mediators.

Results:
The DC-CHNA consisted of 60 African American participants (mean age 61±11 years, 93% female) with ASCVD risk. Social isolation (β=0.34, p=0.009) and depression (β=0.30, p=0.04) associated with IL-8. IL-8 then inversely associated with DNAm-based surrogate leptin levels and directly associated with IR; leptin DNAm mediated the IL-8-IR relationship (
Figure
).

Conclusions:
We show a relationship between stress-associated IL-8 and IR mediated by DNAm-based surrogate leptin levels. While relationships between inflammation, serum leptin, and IR are documented, the impact of chronic stress on leptin DNAm in the context of CV risk requires further investigation in larger, diverse cohorts. DNAm-based surrogate markers of plasma proteins, such as leptin, could serve as a marker for increased CV risk in populations disproportionately exposed to chronic stress.
Abstract MP55: Glucose Abnormalities Detected by Continuous Glucose Monitoring in Older Adults With Prediabetes
Authors: Daya Malek Natalie , Fang Michael , Wang Dan , Jeon Yein , Echouffo Tcheugui Justin B , Coresh Josef , Selvin Elizabeth
Published: March 2023

Introduction:
The 2019 Endocrine Society guidelines recommend screening all older adults with prediabetes with a two-hour oral glucose tolerance test. Continuous glucose monitoring (CGM) is a minimally invasive technology that provides insights into glucose patterns and abnormalities not reflected in hemoglobin A1c (HbA1c).

Objective:
Characterize the prevalence of hyperglycemia and other abnormal glucose patterns in older adults with prediabetes.

Methods:
Participants in the Atherosclerosis Risk in Communities (ARIC) Study wore a CGM system at visit 9 (2021-2022). We evaluated CGM parameters according to diabetes status.

Results:
There were 944 participants (272 with diabetes, 342 with prediabetes, and 330 without diabetes) (mean age 83, 58% female, 25% Black). Compared to normoglycemic persons (HbA1c<5.7%), persons with prediabetes (HbA1c 5.7-<6.5%) had slightly higher mean glucose (103 vs 98 mg/dL, p<0.001), a higher percentage of people with mean glucose>140 mg/dL (1.5% vs 0%, p=0.03), spent more time with any hyperglycemia (median % time glucose >180 mg/dL: 0.23% vs 0.04%, p<0.001), spent similar time in range (86.6% vs 86.9%, p=0.68), and had similar glucose variability (CV 21.0% vs 20.8%, p=0.59) (
Table
). The mean amplitude of glycemic excursions, continuous overall net glycemic action and mean of daily differences were also higher in persons with prediabetes compared to normoglycemic persons but the differences are not clinically significant. Mean glucose and other CGM measures of hyperglycemia were substantially higher in persons with diabetes.

Conclusion:
CGM did not reveal a high prevalence of glucose abnormalities among older adults with prediabetes defined by HbA1c. Our findings do not support the current Endocrine Society guideline recommendations for additional post-load glucose testing in older adults with prediabetes.
Abstract MP57: Coagulation Factor IX and Incident Diabetes Risk: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Zhou Megan , Wilkinson Katherine , Plante Timothy B , Kamin Mukaz Debora , Long D. Leann , Zakai Neil A , Cushman Mary , Olson Nels C
Published: March 2023

Introduction:
A prothrombotic state is implicated in the vascular complications of type 2 diabetes (DM), and such complications disproportionately affect Black compared to White adults. However, it is not known if this is due to DM or whether coagulation factor levels are related to DM incidence. Higher coagulation factor IX (FIX) was related to increased risk of CHD and stroke among Black but not White participants in the REGARDS cohort. We hypothesized higher FIX antigen would be associated with incident DM risk, with stronger relationships in Black versus White adults.

Methods:
REGARDS enrolled 30,239 Black and White adults from across the contiguous US from 2003-2006 with a second in-home visit from 2013-2016. The Biomarkers as MEDiators of Racial Disparities in Risk Factors (BioMedioR) nested cohort study included 4,400 participants who completed both visits, balanced on race and sex. Modified Poisson regression models estimated the RR of incident DM per 1-SD increment log FIX. We tested for a FIX-by-race interaction a priori due to differential associations of FIX with CHD and stroke by race in REGARDS.

Results:
Among 3,381 participants without baseline DM (mean age 63 years, 44% Black race, 51% women), 456 (13.5%) developed incident DM over 9.5-years. Adjusting for age, sex, and race, there was a significant difference in the association of FIX with DM by race (p-interaction<0.01). As shown in the Figure, adjusted for age and sex (Model 1), the RR (95% CI) for incident DM was 1.19 (1.05, 1.34) for Black adults and 1.49 (1.23, 1.81) for White adults. Adjusting for clinical risk factors (Model 2) fully attenuated this association for Black adults, and further adjusting for behavioral factors (Model 3) fully attenuated this association for Black and White adults.

Conclusions:
Higher FIX levels were associated with incident DM risk. Relationships between FIX and incident DM were stronger for White than Black adults. The FIX-DM association may be due to adverse clinical and behavioral risk factors.
Abstract MP60: Prediabetes and Undiagnosed Diabetes Predisposing Women to Excess Risk of Cardiovascular Disease
Authors: Yoshida Yilin , Chen Zhipeng , Mauvais-Jarvis Franck
Published: March 2023

Objective:
Women with type 2 diabetes (T2DM) have a 25-50% higher risk of cardiovascular disease (CVD) than their men counterparts. The reasons for this sex disparity are incompletely understood. We sought to examine if pre-diabetes (preDM) and undiagnosed T2DM are associated with a greater magnitude of CVD risk in women than in men.

Methods:
We pooled CVD-free individuals (N=18,745) from the Atherosclerosis Risk in Communities, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. CVD outcomes included incident coronary heart disease (CHD) (myocardial infarction, CHD death, or cardiac procedures including percutaneous coronary interventions, bypass surgery, or coronary revascularization), stroke (ischemic or hemorrhagic stroke), and a composite atherosclerotic CVD (ASCVD) (any CHD condition or stroke). Multivariable Cox models examined the outcomes associated with preDM (fasting glucose [FG] 100-125 mg/dL or HbA1c 5.7-6.4%) or undiagnosed T2DM (FG ≥126 mg/dL or HbA1c ≥6.5% and without a DM diagnosis or anti-diabetes medication use) adjusted for age, race/ethnicity, education, BMI, blood pressure, total cholesterols, smoking, anti-hypertensive and lipid-lowering medications, and cohort indicator. An interaction term sex x preDM or undiagnosed DM was added to models to test the sex modifying effect. We consider p-interaction<0.2 as significant.

Results:
During a median follow-up of 17 years, the adjusted model showed that preDM was significantly associated with a higher risk of CHD (Hazard ratio 1.09, 95%CI 1.04-1.14), stroke (1.08, 1.04-1.13), and ASCVD (1.09, 1.04-1.14) in women, but not in men (1.04, 0.99-1.1 for CHD, 1.03, 0.98-1.08 for stroke, and 1.03, 0.98-1.09 for ASCVD, respectively). Undiagnosed T2DM was significantly associated with the risk of CHD (1.27, 1.16-1.4 in women and 1.17, 1.05-1.3 in men), stroke (1.32, 1.21-1.45 in women and 1.2, 1.09-1.32 in men), and ASCVD (1.27, 1.16-1.4 in women and 1.15, 1.03-1.29 in men) in both sexes but with more pronounced effect in women (P-interactions ≤0.11). In racial-stratified analysis, a higher magnitude of CVD risk associated with preDM or undiagnosed DM was also found in non-Hispanic (NH) white women and NH-black women than in their men counterparts.

Conclusions:
PreDM and undiagnosed DM predispose women to excess CVD risk, possibly due to women’s higher susceptibility to metabolic dysfunction at a lower glucose level and the prolonged unmanaged time for risk factors relative to men. T2DM screening and risk factor control should be enhanced in both sexes to reduce future CVD risk, particularly in women.
Abstract MP64: Impact of a Vegan Diet Compared to Omnivorous Diet on Blood Lipids and Weight Among Identical Twins: The Twins Nutrition Study (TwiNS) Randomized Controlled Trial
Authors: Landry Matthew J , Ward Catherine P , Gardner Christopher D
Published: March 2023

Introduction:
Vegan diets, where animal- and all their by-products are excluded from the diet, have gained popularity. Growing evidence suggests potential cardiovascular benefits of vegan diets due to improvements in diet quality (i.e., higher consumption of vegetables, fruits whole grains, nuts, legumes, and seeds).

Methods:
The TwiNS randomized controlled trial examined the cardiometabolic impact of a healthy vegan diet compared to a healthy omnivorous diet (NCT05297825). These diets were examined in 22 pairs of identical twins, where one twin followed the vegan diet, and the other twin followed the omnivorous diet for 8 weeks. Diet specific meals were provided via a meal delivery service from baseline through week 4, and during weeks 5-8 participants prepared their own diet appropriate meals and snacks. The primary outcome was difference in LDL cholesterol from baseline to week 8. Secondary outcome measures included change in triglycerides, HDL-cholesterol and body weight. Adherence to study diets, ease/difficulty in following the diets, participant energy levels, and sense of wellbeing were also measured. A linear mixed model was used to investigate a difference in the change in primary and secondary outcomes from baseline and included a random effect for twin pair, to account for the correlation between identical twins.

Results:
Participants were generally healthy adults, average age 39.6 years, primarily non-Hispanic White, and had an average BMI of 26.2. On average, twins randomized to the healthy vegan diet had decreased their LDL-cholesterol more after 8 weeks compared to twins on the healthy omnivorous diet (-15.2 vs. -2.3mg/dL, 95% CI: 4.3-24.8). Participants on the healthy vegan diet also had decreased their body weight more after 8 weeks (-1.9 vs. -0.29 kg, 95% CI: 0.9-3.0). No significant differences were observed between the vegan and omnivorous diets for secondary outcomes of triglycerides or HDL-C.

Conclusion:
This study contributes to growing evidence that vegan diets may offer a protective cardiometabolic advantage compared to a healthy, omnivorous diet. Further analyses of the TwINS trial will examine changes to the gut microbiome (i.e., microbial diversity), inflammatory markers, and other health factors.
Abstract MP73: Cardiovascular Complications During Delivery Admissions Associated With Rheumatoid Arthritis: A National Inpatient Sample Analysis (2004-2019)
Authors: Zahid Salman , Mohamed Mohamed Salah , Khan Muhammad Z , Rajendran Aardra , Minhas Anum A , Nazir Noreen , Ocon Anthony , Weber Brittany N , Isiadinso Ijeoma , Michos Erin D
Published: March 2023

Background:
Individuals with rheumatoid arthritis (RA) have an increased risk of obstetric-associated complications as well as long term cardiovascular (CV) risk. However data on acute CV complications during pregnancy delivery remains limited.

Methods:
We used data from the National Inpatient Sample (2004-2019) utilizing ICD-9 or ICD-10 codes to identify delivery hospitalizations and a diagnosis of RA.

Results:
A total of 63,005,648 weighted delivery hospitalizations were identified, of which 0.1% were among persons with RA (n=62,402). Individuals with RA, vs those without, were older (median 31 vs. 28 years, p<0.01) and had a higher prevalence of polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), obesity, and dyslipidemia (p<0.01). After adjustment for age, race/ethnicity, comorbidities, insurance, and income, RA remained an independent predictor of peripartum CV complications including preeclampsia (adjusted odds ratio (aOR) 1.41 [95% CI, 1.36-1.45]), peripartum cardiomyopathy (aOR 1.80 [1.38-2.35]), and cardiac arrhythmias (aOR 2.13 [1.98-2.29]) compared with no RA. Likewise, the risk of acute kidney injury (AKI), stroke, and venous thromboembolism (VTE) were higher with RA. An overall increasing trend of obesity and GDM was also observed among individuals with RA. For resource utilization, length of stay and cost of hospitalization was higher for deliveries among persons with RA.

Conclusions:
Pregnant individuals with RA had higher risk of preeclampsia, peripartum cardiomyopathy, arrhythmias, AKI, stroke and VTE during delivery hospitalizations. Furthermore, cardiometabolic risk factors among pregnant individuals with RA rose over this 15 year period.