bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 28: Proteomic Signatures of Adiposity in Middle-Aged Adults: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Ozkan Bige , Aryee Ebenezer K , Chen Jingsha , Echouffo Tcheugui Justin B , Matsushita Kuni , North Kari E , Ballantyne Christie M , Yu Bing , Shah Amil M , Selvin Elizabeth , Coresh Josef , Ndumele Chiadi E
Published: March 2023

Background:
Excess adiposity is linked to adverse cardiovascular outcomes via direct and indirect effects on metabolic pathways. There is limited large-scale data assessing proteomic signatures of adiposity.

Methods:
We quantified 4,955 plasma proteins using SomaLogic v4.0 in stored plasma samples of 9,940 ARIC Visit 2 participants (1990-92, mean age: 57±6 years, 55% women, 22% Black adults, 28% with obesity). We used linear regression and Bonferroni-corrected p-values to identify proteins associated with body mass index (BMI) in 2/3 discovery and 1/3 validation samples. We performed additional analyses to assess key pathways associated with obesity.

Results:
In the discovery sample (28% with obesity), after adjusting for age, sex, race-center, eGFR, 1,312 proteins were significantly associated with BMI. After further adjustments for clinical and lifestyle risk factors (Figure), 975 proteins were significantly associated with BMI (p<10
-5
). There were 713 proteins confirmed in the validation sample (p<0.05/975). Among the confirmed proteins, there were >500 proteins that did not have previously described BMI associations in population studies (including serine protease HTRA1, seizure 6-like protein) as well as proteins with known BMI associations (including leptin, fatty acid binding proteins, insulin-like growth factor-binding proteins). Acute phase response, atherosclerosis signaling, hepatic fibrosis, pancreatic cancer and lipid metabolism were among the top biological pathways overrepresented by the proteins associated with BMI (Figure). The upstream regulators of these proteins included interleukins (IL-17A, IL-13, IL-4), as well as tumor necrosis factor (TNF), which was activated.

Conclusion:
We discovered several novel proteins associated with adiposity and confirmed previously identified proteins. Alteration in the plasma proteome related to adiposity is linked to differential regulation of inflammatory and metabolic pathways independent of cardiovascular risk mediators.
Abstract 30: Associations of Accelerometer-Measured Machine-Learning Classified Sitting With All-Cause and Cardiovascular Disease Mortality Among Older Women: The Opach Study
Authors: Nguyen Steve , Bellettiere John , Di Chongzhi , Anuskiewicz Blake , Natarajan Loki , Lamonte Michael J , LaCroix Andrea Z
Published: March 2023

Introduction:
Sedentary behavior (SB) is a recognized mortality and CVD risk factor. Most studies with accelerometry classified SB using cut-points, which do not capture postural transitions as accurately as thigh-worn devices. The recently published convolutional neural network hip accelerometer posture (CHAP) algorithm more accurately classifies sitting than cut-point methods.

Hypothesis:
Higher amounts of CHAP-classified sitting time (ST) and mean sitting bout duration (MSBD) are associated with higher all-cause (ACM) and CVD mortality risk.

Methods:
Older women (n=6,056; mean age=79±7; 34% Black, 17% Hispanic) in the Objective Physical Activity and Cardiovascular Health (OPACH) study without prior MI or stroke wore accelerometers for 7 days in May 2012-April 2014 and were followed through February 19, 2022 for mortality. The CHAP algorithm has been shown to have higher sensitivity (97.1% vs 88.2%) and specificity (88.6% vs 59.7%) for classifying sitting compared to the 100 counts/minute cut-point. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) for ACM and CVD mortality adjusting for age, race/ethnicity, education, alcohol, smoking, multimorbidity, self-rated health, physical functioning, HDL, triglycerides, SBP, and log hs-CRP.

Results:
There were 1,808 deaths and 651 CVD deaths over a median follow-up of 8.4 years. The HR (95% CI; P-trend) comparing women in the highest ST quartile (>11.6 hr/day) to those in the lowest (<9.2 hr/day) was 1.43 (1.23-1.66; <0.001) for ACM and 1.64 (1.27-2.14; <0.001) for CVD mortality. The HR (95% CI; P-trend) comparing women in the highest MSBD quartile (>15 minutes) to those in the lowest (<9.3 minutes) was 1.33 (1.15-1.55; <0.001) for ACM and 1.50 (1.16-1.94; <0.001) for CVD mortality. The HR (95% CI) for women with the highest ST and MSBD was 1.63 (1.38-1.93) for ACM and 1.95 (1.47-2.60) for CVD mortality.

Conclusions:
ST and MSBD were positively associated with ACM and CVD mortality risk, supporting interventions aimed at reducing both ST and MSBD.
Abstract 31: Associations Between Cardiorespiratory Fitness (CRF) in Early Adulthood, Retention Through Midlife, and Heart Failure (HF) Stages: Findings From Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Thangada Neela , Gidding Sam , Colangelo Laura A , Hornikel Bjoern , Khan Sadiya , Pandey Ambarish , Allen Norrina B , Sidney Stephen , Carnethon Mercedes R , Lewis Cora E , Lloyd-Jones Donald , Gabriel Kelley P
Published: March 2023

Introduction:
Prior studies demonstrate that poor CRF in early adulthood is associated with adverse cardiac structure and function in midlife. The purpose of this study is to examine if higher early adulthood CRF and retention of CRF through midlife are associated with lower subsequent risk of subclinical or clinical HF.

Methods:
CARDIA participants with available data on CRF at baseline (Year [Y] 0: 1985-86), follow-up (Y7 or Y20), and HF staging data by Y30 were included. CRF was estimated using treadmill duration from a maximal, symptom-limited graded exercise test via modified Balke protocol. An adjusted linear mixed model was used to estimate treadmill duration when CRF assessment was missing at Y7 or 20. HF stages were defined using AHA HF staging criteria, including Stage 0 (no HF risk factors). Clinical HF was adjudicated by committee. Adjusted multinomial models tested associations between Y0 CRF and percent CRF retained through Y20 with HF stages at Y30, with Stage 0 as the reference. Interactions by the four race-sex groups were examined.

Results:
Of 2,565 individuals (25.1±3.5 y, 43% Black, 55% female), 30% (n=778), 37% (n=952), 32% (n=813), and 1% (n=32) were classified as Stages 0, A, B, or C/D by Y30 exam, respectively. Compared with Stage 0, every 1-minute increment higher CRF in early-adulthood was associated with a lower adjusted odds ratio of HF [Stage A: 0.72 (95% CI 0.68, 0.76), Stage B: 0.80 (95% CI 0.75, 0.84), Stage C/D 0.86 (95% CI 0.71, 1.04)]. Compared with Stage 0, every 1-standard deviation of % CRF retained at Y20 (midlife) was also associated with a lower odds of Stage A, B, and C/D HF at Y30 (Figure). A race-sex interaction was not observed (p-interaction 0.42).

Conclusion:
Higher early adulthood CRF, and greater retention of CRF through midlife, were associated with lower risk of developing subclinical or clinical HF. Strategies to maintain optimal CRF across the young adulthood to midlife transition may be important in prevention of HF.
Abstract 32: Physical Activity Fragmentation and Mortality in Hispanics/Latinos: The Hispanic Community Health Study / Study of Latinos (HCHS/SoL)
Authors: Mediano Mauro F , Mok Yejin , Ballew Shoshana , Gonzalez Franklyn , Sotres-Alvarez Daniela , Mossavar-Rahmani Yasmin , Kaplan Robert , Carlson Jordan A , Alver Sarah , Daviglus Martha L , Garcia-Bedoya Olga , Evenson Kelly R , Schrack Jennifer , Matsushita Kunihiro
Published: March 2023

Background:
Physical activity (PA) fragmentation, an emerging concept of PA patterns, indicates the frequency of transitioning from an active to a sedentary state. Whether PA fragmentation provides prognostic information beyond conventional PA measures is unclear, especially in Hispanics/Latinos.

Aim:
To examine the association between PA fragmentation and mortality in Hispanics/Latinos.

Methods:
We included 9,856 participants (mean age 41.7 [SE 0.27] years; 52.1% women) from HCHS/SOL with baseline PA evaluation from an Actical accelerometer (≥3 days with ≥10 hr/day of wear). We defined sedentary as <10 counts/min and active as ≥10 counts/min. PA fragmentation was calculated using the active-to-sedentary transition probability (ASTP), defined as the reciprocal of the average active bout duration on a minute-level basis across valid days. We used daily mean total log activity counts (TLAC) as a measure of total PA volume. We modeled the residuals of ASTP regressed on TLAC (total-PA-adjusted ASTP) to investigate ASTP independently of total PA. Deaths were identified from annual follow-up contacts until December 31, 2018. We explored multivariable Cox regression models accounting for the multi-stage sampling design.

Results:
There were 242 deaths (2.5%) over a mean of 7.1 years. ASTP was associated with mortality in all models (
Table
). Each 0.10-unit increase of ASTP at baseline was associated with a 38% higher mortality risk after accounting for demographic, clinical, and lifestyle factors. Similarly, the highest ASTP tertile indicated a 2-times greater risk of death compared to the lowest tertile. The results were largely similar when we modeled using total-PA-adjusted ASTP. Higher TLAC was also associated with reduced mortality. Similar results were observed after excluding early deaths (first 2 years).

Conclusion:
PA fragmentation was robustly associated with mortality, independent of total PA volume. Our findings support PA fragmentation as an emerging novel measure that is informative beyond total PA.
Abstract 34: A Quarter of a Mile More Steps Are Incrementally Associated With Lower Risk of Proximal CVD Events Among Older Adults: Atherosclerosis Risk in Communities (ARIC) Study
Authors: Dooley Erin E , Rippon Brady , Martinez-Amezcua Pablo , Paluch Amanda E , Pompeii Lisa , Palta Priya , Pettee Gabriel Kelley
Published: March 2023

Introduction:
Steps are an easily interpretable metric that could be used in patient-clinician communication regarding the health benefits of physical activity for cardiovascular disease (CVD). However, most studies are conducted in younger populations with daily steps goals (e.g., 10,000 steps) that may be unsuitable for older adults.

Hypothesis:
We tested the hypothesis that more daily steps are associated with lower risk of proximal CVD events (within 3.5 years) among older adults (≥70 years).

Methods:
We analyzed a subsample of participants from the ARIC study visit 6 (2016-17) who wore an accelerometer (ActiGraph GT3X) on the waist ≥3 days for ≥10 hr/day. Daily steps were analyzed continuously and by quartiles. Adjudicated outcomes, through December 2019, included fatal and non-fatal CVD events (coronary heart disease, stroke, and heart failure). Multivariable adjusted Cox proportional hazard models were used to estimate the hazard ratio of CVD events across step measures, adjusted for age, sex, race, education, body mass index (BMI), and accelerometer wear time.

Results:
Among the 452 adults with step data (mean age = 78.4; 59% women; 20% Black), 7.5% (34/452) had a CVD event over 1,269 person-years of follow-up. Mean (SD) step count was 3447 (1796) steps/day. CVD cumulative incidence was highest among those in the least active step quartile (Q1: <2077 steps/day) (11.5%) compared to the most active quartile (Q4: ≥4453 steps/day) (3.5%). Every 500 steps/day (about 1/4 mile) was associated with a 14% reduced risk of a CVD event (HR = 0.86, 95% CI: 0.76, 0.98). Further, compared to participants in Q1, participants in Q4 had a 77% reduced risk of a proximal CVD event (HR = 0.23, 95% CI: 0.07, 0.83). Cubic spline HR are presented (figure).

Conclusions:
In this community-based cohort of older adults, every 500 steps (~1/4 of a mile) was associated with a 14% lower risk of a CVD event over 3.5 years of follow-up. Additional follow-up is needed to determine if higher steps prevent or delay CVD or if low steps serve as a biomarker of underlying disease.
Abstract 35: Adherence to Life’s Essential 8, Genetic Susceptibility, and Incident Cardiovascular Disease: A Prospective Study of 137,794 UK Biobank Participants
Authors: Li Xiang , Xue Qiaochu , Ma Hao , Feng Han , Wang Xuan , Heianza Yoriko , Qi Lu
Published: March 2023

Introduction:
The American Heart Association recently introduced an enhanced approach to assess cardiovascular health (CVH): Life’s essential 8 (LE8). Sleep was included as a new component. The current study sought to analyze the relationship between levels of CVH, indicated by the LE8 score, and risks of coronary heart disease (CHD), stroke, and cardiovascular disease (CVD).

Hypothesis:
We hypothesized that higher CVH, indicated by the LE8 score, was associated with lower risks of CHD, stroke, and CVD; LE8 might also interact with genetic susceptibility.

Methods:
The current study included 137,794 participants free of CVD from the UK Biobank. CVH was scored at baseline by LE8 (DASH diet score, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure). The LE8 score ranged from 0 to 100; and was categorized as low (0-49), moderate (50-79), and high (80-100). Weighted genetic risk scores (GRS) for CHD and stroke were calculated. Cox proportional hazard model was used to assess the relationship between LE8 and incident CVD outcomes, and potential interaction with age, gender, and GRS. We also compared the performance of LE8 with Life’s Simple 7 (LS7) using Harrell’s C-index.

Results:
During a median of 10 years, 8,595 CVD cases (6,968 CHD and 1,948 strokes) were documented. A higher LE8 score was associated with remarkably lower risks of CHD, stroke, and CVD (p<0.001 for all). Comparing the high CVH to the low CVH, the adjusted HRs (95% CI) were 0.34 (0.30, 0.38) for CHD, 0.45 (0.37, 0.54) for stroke, and 0.36 (0.33, 0.40) for CVD. Moreover, the model with LE8 achieved higher accuracy and outperformed the model with LS7 (C-index: 0.7417 vs. 0.7345, p<0.001 for CHD, 0.7208 vs. 0.7165, p<0.001 for stroke, and 0.7339 vs. 0.7276, p<0.001 for CVD). The protective associations of the LE8 score with CVD outcomes were more pronounced among women (p-interaction <0.001 for CHD and 0.0013 for CVD, respectively), and among younger adults (p-interaction <0.001, 0.007, and <0.001 for CHD, stroke, and CVD, respectively). In addition, we found a significant interaction between the GRS of CHD and the LE8 score (p-interaction <0.001). The inverse association was stronger among those with a lower genetic risk of CHD.

Conclusions:
High level of CVH, defined by LE8, was associated with significantly lower risks of CHD, stroke, and CVD. Such relationships are more pronounced among women, younger adults, and people with a lower genetic predisposition.
Abstract 38: A Novel Two-Question Antihypertensive Medication Adherence Scale Predicts Blood Pressure Control and Cardiovascular Disease Outcomes
Authors: Allouch Farah , Peacock Erin , Mills Katherine T , Whelton Paul K , Chen Jing , He Jiang
Published: March 2023

Introduction:
Poor medication adherence is a major contributor to uncontrolled hypertension, the leading preventable risk factor for CVD and mortality worldwide. Simple and accessible tools are needed to quantify medication adherence. We developed a novel two-question adherence scale in the Implementation of Multifaceted Patient-Centered Treatment Strategies for Intensive Blood Pressure Control (IMPACTS) trial and tested its prediction of BP control and CVD.

Methods:
We collected data on the IMPACTS Medication Adherence Scale (IMPACTS-MAS) and the eight-item Morisky Medication Adherence Scale (MMAS-8) in 1,206 IMPACTS participants. The IMPACTS-MAS consists of two questions, (1) “Over the last 7 days, on how many days did you not take any BP pills”, and (2) “Over the last 7 days, on how many days did you cut back on your BP pills?” and is categorized as low or high adherence. Linear and logistic mixed effects regressions examined the association between IMPACTS-MAS, MMAS-8, and uncontrolled BP. We also assessed IMPACTS-MAS in 33,995 China Rural Hypertension Control Project (CRHCP) participants studied at baseline and followed for CVD outcomes during a 36 month period. Cox regression examined the association between IMPACTS-MAS and CVD outcomes adjusting for treatment group, age, sex, education, and history of CVD.

Results:
The IMPACTS participants had an average age of 58 years and 56% (676/1,206) were female. Compared to high adherence, low adherence on IMPACTS-MAS and MMAS-8 was associated with

3.5

(95% CI: 1.9,5.1) and

2.6

(1.1,4.1) mmHg

higher SBP

,

2.5

(1.3,3.7) and

2.0

(0.87,3.1)

higher DBP

, and

73%

[OR=1.73 (1.27,2.36)] and

68%

[OR=1.68 (1.27,2.23)]

higher uncontrolled BP

(≥140/90 mmHg), respectively. The CRHCP participants had an average age of 63 years and 61% (20,825/33,995) were female. Compared to high adherence, low adherence on IMPACTS-MAS was associated with

3.6

mmHg (3.2,4.0)

higher SBP

,

0.89

mmHg (0.76,1.0)

higher DBP

, and with

42%

[OR=1.42 (1.37,1.47)]

higher uncontrolled BP

, during follow-up. Further, low adherence was associated with

53%

[HR=1.53 (1.30,1.81)]

higher levels of CVD

,

88%

[HR=1.88 (1.11,3.17)]

higher levels of myocardial infarction

, and

54%

[HR=1.54 (1.28,1.86)]

higher levels of stroke

during follow-up. Finally, low adherence was associated with

51%

[HR=1.51 (1.31,1.75)]

higher levels of CVD death

and

47%

[HR=1.47 (1.31,1.65)]

higher levels of all-cause mortality

, during follow-up.

Conclusion:
The novel two-question IMPACTS-MAS score is associated with BP control and predicts CVD outcomes and mortality in diverse populations. It is a simple, accessible tool that can be used in research and clinical practice to identify medication nonadherence.
Abstract 48: Associations of Diet and Physical Activity With Biological Aging Among US Adults: National Health and Nutrition Examination Survey 1999-2018
Authors: Thomas Aline , Belsky Daniel W , Gu Yian
Published: March 2023

Background:
Behavioral lifestyle factors are promising for prevention of numerous diseases and mortality risk by contributing to overall healthy ageing. Healthy diet and regular physical activity have been associated with longer telomere length, indicating younger biological aging. More recently, algorithm-based measurements of biological aging, which integrate information across panels of molecular or clinical indicators, have proven both more technically reliable and more precise in their predictions of morbidity and mortality than telomere length. The aim of this study was to examine the association of diet, physical activity, and their interaction with biological ageing measured by PhenoAge blood chemistry algorithm.

Methods:
This study included adult participants (≥20 years-old) from the National Health and Nutrition Examination Survey (NHANES), 1999-2018. We evaluated adherence to a Mediterranean diet (MeDi) and level of leisure time physical activity (LTPA) using standard instruments. We measured biological aging using the PhenoAge algorithm, developed using data from NAHNES III (1988-1994) and validated as a predictor of morbidity/mortality in the NHANES data we analyzed. We defined PhenoAge advancement as the difference between biological age derived from eight blood biomarkers and chronological age, with higher score indicating being biologically older. We evaluated the associations of MeDi and LTPA with PhenoAge in adjusted linear regressions. We explored synergies between these two health behaviors and heterogeneity in their associations across strata of sex age, gender, and body mass index (BMI).

Results:
In total, 38,617 participants (mean age 47.1 years, 51% women) were included. Both higher adherence to MeDi and higher level of LTPA were associated with lower PhenoAge advancement, in mutually adjusted model controlled for demographic, socioeconomic and lifestyle variables (β = 0.15 SD [95% CI, -0.18; -0.11] for high vs low tertile of adherence to MeDi, and β = 0.12 SD [-0.15; -0.09] for

high LTPA level vs sedentarity). The associations of diet and physical activity phenotypes with biological aging were independent and additive (p-interaction >0.05). Stratified analyses indicated consistent significant associations across strata of age, gender, and BMI, although stronger associations were observed among women and participants with normal weight than among their respective counterparts for MeDi (p-interaction = 0.001 and 0.04, respectively) and among older participants for LTPA (p-interaction <0.001). Sensitivity analysis using the Healthy Eating Index 2015 did not change the results.

Conclusion:
Healthy diet and regular physical activity are independently associated with lower clinically defined biological aging, regardless of age, sex, and BMI category.
Abstract 55: Racial/Ethnic Disparities in Sleep Outcomes Among Adults With Hypertension in the 2011-2018 National Health and Nutrition Examination Survey
Authors: Metlock Faith E , Hinneh Thomas , Ogungbe Oluwabunmi , Liu Xiaoyue , Elias Sabrina d , Koirala Binu , Dennison Himmelfarb Cheryl R , Commodore-Mensah Yvonne
Published: March 2023

Introduction:
Ethnic/racial minority groups in the US bear a disproportionate burden of hypertension (HTN). Given the association between poor sleep outcomes and HTN, we examined racial disparities differences in sleep outcomes among persons adults living with HTN in the US.

Methods:
We analyzed cross-sectional data from the National Health and Nutrition Examination Survey
(2011-2018)
. Sleep outcome variables were examined via self-report questionnaires as daytime sleepiness (no/mild/and excessive), sleep duration (recommended 7-9 hours/short ≤6 hours/and long >9 hours), sleep quality (good/ or poor). Multinomial logistic regression models were used to assess the association between race/ethnicity categories (Non-Hispanic White Americans [NHW], Non-Hispanic Black Americans [NHB], Non-Hispanic Asian Americans [NHA], and Mexicans/Hispanic Americans) and sleep outcomes, adjusting for covariates.

Results:
In a sample of 10,934 adults diagnosed with HTN (with mean age 58 (±16) years; and 48% female); prevalence of short sleep duration (≤ 6 hours) among NHW, NHB, NHA, and Mexicans/Hispanic Americans were 55%, 21%, 5%, and 14%, respectively. While the odds of abnormal daytime sleepiness (mild and excessive) were lower across all race/ethnic categories compared to NHW; the odds of short sleep duration were higher among NHB (adjusted odds ratio [aOR]:= 2.02; 95% confidence interval [CI]: 1.53-2.65). Similarly, the odds of poor sleep quality were higher among NHA (aOR: 1.90; 95% CI: 1.24-2.91) and Mexicans/Hispanic Americans (aOR: 1.66; 95% CI: 1.21-2.28).

Conclusion:
Significant racial disparities exist in sleep outcomes among adults with HTN in the US. Efforts to improve equity in HTN and CVD prevention and management must also address sleep outcomes.
Abstract 61: Frequency of Pediatric Lipid Screening Using a Large National Electronic Health Record System
Authors: Thompson-Paul Angela M , Kraus Emily , Porter Renee M , Pierce Samantha L , Kompaniyets Lyudmyla , Sekkarie Ahlia , Goodman Alyson B , Jackson Sandra L
Published: March 2023

Background:
Universal lipid screening is recommended for U.S. youth aged 9-11 and 17-21 years. Our objective was to describe the prevalence of pediatric lipid screening and elevated lipid measurements among those screened, by patient characteristics.

Methods:
IQVIA’s Ambulatory Electronic Medical Records (version 5, release: October 2021) database, containing medical records from 100,000 physicians in the U.S., was used for this analysis. The study population included 3,131,956 patients aged 9-21 years with ≥1 valid measure of height and weight during our observation period (01/01/2018-11/30/2021). Lipid screening was defined as ≥1 valid measurement any time during the observation period. Body mass index (BMI) was calculated and categorized using pediatric percentiles (ages 9-20 years) and adult interpretations (age ≥21 years) (
Table
). After excluding biologically implausible values, lipid measurements were considered elevated if ≥1 of the following was identified: low density lipoprotein ≥130 mg/dL, very low-density lipoprotein ≥31 mg/dL, non-high-density lipoprotein ≥145 mg/dL, triglycerides ≥130 mg/dL, or total cholesterol ≥200 mg/dL.

Results:
A total of 354,764 (11.3%) youth had documented lipid screening. The frequency of lipid screening increased by age group (9-11 years: 9.1%; 12-16 years: 11.0%,17-21 years: 12.9%) and BMI category (underweight and healthy weight: 9.5%; overweight: 11.0%; obesity: 16.7%; severe obesity: 19.6%). Frequency of screening varied across race/ethnicity (White: 10.8%; Black 14.5%; Asian: 18.0%). Among those screened, 30.2% had ≥1 elevated measure with highest prevalence among those with obesity (44.8%) or severe obesity (48.1%).

Conclusions:
Our findings indicate that among youth aged 9-11y and 17-21y, lipid screening is suboptimal, and prevalence of elevated lipid levels is high among those screened. Increased pediatric lipid screening could lead to improvements in treatment, management, and prevention of adverse, long-term cardiovascular outcomes.
Abstract 66: Clonal Hematopoiesis of Indeterminate Potential and Incident Type 2 Diabetes Risk
Authors: Tobias Deirdre K , Manning Alisa , Wessel Jennifer , Raghavan Sridharan , Westerman Kenneth , Bick Alexander G , Dicorpo Daniel , Whitsel Eric A , Collins Jason M , Dupuis Josee , Goodarzi Mark O , Howard Barbara V , Lange Leslie , Liu Simin , Raffield Laura M , Reiner Alexander P , Rich Stephen S , Tinker Lesley , Wilson James , Carson April P , Vasan Ramachandran , Kooperberg Charles , Rotter Jerome I , Meigs James , Manson Joann E
Published: March 2023

Introduction:
Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in elevated risks for coronary heart disease (CHD) and death, but its association with incident type 2 diabetes (T2D) is unknown.

Hypothesis:
We hypothesized that CHIP is associated with elevated risk of incident T2D.

Methods:
CHIP was derived from whole genome sequencing of blood DNA in NHLBI Trans-omics for Precision Medicine (TOPMed) cohorts. We analyzed 17,637 participants without prior T2D, cardiovascular disease, or cancer at blood draw, with prospective follow-up for incident T2D. We evaluated baseline prevalence of CHIP vs. no CHIP with incident T2D risk using Cox regression. We also investigated CHIP variants previously related to CHD:
DNMT3A
,
TET2
,
ASXL1
,
JAK2
, and
TP53
. We estimated multivariable-adjusted hazard ratios and 95% confidence intervals (HR [CI]) adjusted for age, sex, body mass index, smoking, alcohol, and education. We combined cohort estimates via fixed effects meta-analysis.

Results:
On average, participants were age 63.4 years (SD=11.5) and 76% female. Prevalence of CHIP was 6.0% (1,055) at baseline. There were 2,467 incident T2D cases over mean=9.8 years follow-up. Compared to those without a mutation, having CHIP was associated with a 23% higher T2D risk, both overall (combined HR=1.23; 95% CI=1.04, 1.45), and among those with CHD-related CHIP mutations (87% of total CHIP): HR=1.23 (1.03, 1.46). Although those with CHIP mutations of
TET2
(HR=1.48; 1.05, 2.08) and
ASXL1
(HR=1.76; 1.03, 2.99) had larger elevations in T2D risk, and
DNMT3A
was suggestive of increased T2D risk (HR=1.15; 0.93, 1.43), statistical power was limited for
JAK2
and
TP53
mutation analyses.

Conclusions:
CHIP was associated with higher incidence of T2D. CHIP mutations located on loci previously implicated in aging and CHD were also related to T2D, suggesting shared pathology of atherosclerosis and T2D.
Abstract 68: Interleukin-6, Diabetes and Metabolic Syndrome in a Biracial Cohort: The Reasons for Geographic and Racial Differences in Stroke (REGARDS)
Authors: Palermo Brittney , Wilkinson Katherine , Plante Tim B , Nicoli Charles D , Judd Suzanne E , Kamin Mukaz Debora , Long Leann , Olson Nels C , Cushman Mary
Published: March 2023

Background:
Type 2 diabetes mellitus (DM) is more common in Black than White adults in the US. The inflammatory cytokine interleukin-6 (IL-6) is implicated in DM pathogenesis and circulates at higher levels in Black people. Metabolic syndrome (MetS), a group of conditions related to insulin resistance, often precedes or coexists with DM. Little evidence is available on associations of IL-6 with these disorders in Black people.

Methods:
REGARDS enrolled 30,239 Black and White adults in 2003-07 and conducted a follow up visit 9.5 years later. Baseline IL-6 was measured in a sample of 4,400 participants (equal by race/sex groups) attending both visits. Modified Poisson regression estimated relative risk (RR) by level of baseline IL-6 for incident DM among those without prevalent DM; similar analyses were conducted for MetS. Inverse odds weighting estimated the percent mediation of the racial disparity in incident DM by IL-6.

Results:
Incident DM occurred in 460/3,399 (14%) at risk, and there were 384/1,957 (20%) cases of incident MetS. As shown in the
Figure
, DM and MetS incidence increased across baseline IL-6 quartiles overall, with a steeper rise and higher incidence among Black than White adults. Adjusting for confounders, the RR of DM for IL-6 in the 4
th
vs 1
st
quartile was 1.91 (95% CI 1.38-2.65). Higher IL-6 was also associated with MetS (RR 1.65 (95% CI 1.22-2.22)). In adjusted models there were no material differences in these associations by race. The RR of DM in Black compared with White people was 1.90 (95% CI 1.59-2.27); there was no association of race with MetS. IL-6 significantly mediated 13.4% of the racial disparity in DM adjusting for demographic factors.

Conclusions:
Higher IL-6 is a risk factor for incident DM and MetS in Black and White adults. The race disparity in DM was partly mediated by IL-6. Interventions to reduce IL-6 may lower risk of DM and MetS and lessen the racial disparity in DM.

Figure:
Diabetes and Metabolic Syndrome Incidence (bars) and Relative Risk (95% CI) by Baseline IL-6 Quartile
Abstract MP06: Women but Not Men With a Systolic Blood Pressure Greater the 110mmhg Was Associated With Higher Risk of All-Cause Dementia
Authors: Dong Caiyun , Zhu Dongshan
Published: March 2023

Introduction:
Whether the association of blood pressure levels and risk of dementia differed by sex remains unclear.

Hypothesis:
We hypothesized that there might be a sex difference in the association between blood pressure levels and dementia.

Methods:
We used cohort data from UK Biobank, a large population-based prospective cohort study that recruited 502 649 individuals ages 40-69, between 2006 and 2010. Cox proportional hazards models were used to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI) for the association between blood pressure levels and incident dementia (including all-cause dementia, Alzheimer's Disease (AD), vascular dementia). We conducted subgroup analyses to divide people into two categories of baseline age < 60 years and ≥60 years. Restricted cubic spline models were used to estimate the association between blood pressure levels and all-cause dementia.

Results:
Overall, 425504 (53.9% women) people with no prevalent dementia were included. After 11.4 (median) years follow-up, 5114 participants (46.2% women) developed dementia. The crude incidence rates were 10.3 for women and 14.0 for men, per 10,000 person-years. The relationship between diastolic blood pressure (DBP) and dementia was U-shaped in both men and women. Women with higher SBP levels were associated with higher risk of all-cause dementia, with an SBP threshold of 110mmhg. Also, women with SBP levels greater than a threshold of 120mmhg and 150mmhg was linked to higher risk of AD and VD, respectively. No relationship between SBP and dementia was observed in men. After the analyses were stratified by age when the SBP was measured (<60 years or ≥60 years), we found that in women younger than 60 years, a nonlinear relationship was observed, i.e., high SBP level greater than 120mmhg was linked to higher risk of all-cause dementia.

Conclusions:
Women with a threshold of SBP level greater the 110mmhg was associated with higher risk of all-cause dementia, while no such relationship was observed in men.
Abstract MP08: Association of a Mediterranean Lifestyle With All-Cause and Cause-Specific Mortality: A Prospective Cohort Study From UK Biobank
Authors: Sotos-Prieto Mercedes , Maroto Rodriguez Javier , Delgado-Velandia Mario , Perez-Cornago Aurora , Ortola Rosario , Rodriguez-Artalejo Fernando
Published: March 2023

Background:
There is strong evidence that the Mediterranean diet protects from cardiovascular disease (CVD); however, beyond diet, the Mediterranean lifestyle may have synergistic effects through the combination of other health behaviors, such as adequate rest or sociability. While most evidence on this lifestyle pattern comes from Mediterranean countries, little is known about the health effects of a Mediterranean lifestyle in non-Mediterranean populations. Our aim was to examine the association between a Mediterranean lifestyle index (MEDLIFE) and all-cause, (CVD), and cancer mortality in a British population.

Methods:
We used data from 110,799 individuals free of CVD or cancer, aged 40-69 years, from the UK Biobank cohort, who were followed from 2006-2010 to 2020. The Mediterranean lifestyle was assessed through the validated 26-item MEDLIFE index derived from the lifestyle questionnaire and from 2 or more Oxford WebQ Online 24-hour diet recalls. MEDLIFE comprised three blocks: a) Block 1 (13 items): Mediterranean food consumption, b) Block 2 (7 items): Mediterranean dietary habits, c) Block 3 (6 items): Physical activity, rest, social habits, and conviviality. Mortality was obtained from the death register records. Multivariable-adjusted Cox proportional-hazards regression models were used to analyse associations between MEDLIFE and all-cause, CVD, and cancer mortality.

Results:
After a mean 9.4-year follow-up, 4,247 deaths were identified. Higher adherence to the MEDLIFE index was associated with lower all-cause and cancer mortality in a dose-response manner. Compared to the first quartile of adherence to the MEDLIFE, the increasingly higher quartiles had a HR (95% CI) of 0.89 (0.81 -0.97), 0.81 (0.74-0.89) and 0.71 (0.65-0.78), p-trend <0.001, for all-cause mortality; and 0.90 (0.80-1.01), 0.83 (0.74-0.93) and 0.72 (0.64-0.82),
p
-trend <0.001, for cancer mortality. All MEDLIFE blocks were independently associated with lower risk of all-cause and cancer death, and block 3 with lower CVD mortality.

Conclusions:
A Mediterranean lifestyle was associated to reduced all-cause and cancer-mortality in British middle-aged and older adults; this suggests that adopting a Mediterranean lifestyle adapted to the local characteristics of non-Mediterranean populations is possible and can be part of a healthy lifestyle.
Abstract MP10: Healthy Diet Perception vs Actual Diet Quality for Cardiovascular Health: Prevalence and Predictors of Perceiving a Poor Diet as Healthy Among Adults
Authors: Lee Eileen , Visaria Aayush , Downs Shauna , Fitzgerald Nurgul , Kuhrt Nathaniel , Setoguchi Soko
Published: March 2023

Objective:
A healthy diet is key to preventing and managing CVD. Despite clear AHA guidelines, eating healthy can be difficult due to misinformation. We investigated perceived vs. actual diet quality and what contributes to perceiving a poor diet ‘healthy’.

Methods:
We identified adults aged > 19 in 2005-2018 National Health and Nutrition Examination Survey. Healthy perceived diet was defined as answering “excellent” or “very good” to “how healthy is the diet?”. We assessed actual diet quality by calculating AHA Healthy Diet Score based on a 24-hour dietary recall and scaled the raw score to 0-100%; ‘poor diet’ was defined as AHA score < 40%. We first estimated prevalence of poor actual diet and perceived healthy diet. Among those with poor diet (AHA score < 40%), we fit modified-Poisson regression models to identify factors associated with perceiving a poor diet as ‘healthy’ and reported risk ratios with 95% confidence limits.

Results:
Among 31,621 adults (50% female, mean age 50, 43% non-Hispanic White, mean BMI 29), prevalence of ‘healthy’ perceived diet and actual ‘poor diet’ was 29% and 47%, respectively. Among adults with a ‘poor diet’ (n=14,951), 23% perceived their diet as ‘healthy’ and many sociodemographic and lifestyle factors and comorbidities were significantly associated with perceiving a poor diet as healthy in univariate analyses (Table). In multivariable analysis, increased age, male sex, White race (compared to Black and Hispanic race), MI history, smaller waist circumference, higher physical activity, and alcohol use were independently associated with perceiving their poor diet as ‘healthy’ (RR ranged from 0.77-1.48, Table).

Conclusion:
Nearly half of US adults had a poor diet based on dietary targets from AHA 2020 Strategic Impact Goals for CV health, yet nearly a quarter of them perceived their diet as ‘healthy’. Targeting high risk adults with focused educational interventions to calibrate their perception of a healthy diet can be effective in modifying their eating behavior and promoting CV health.
Abstract MP14: Association Between Housing Insecurity With Reduced Access to Healthcare and Cardiovascular Disease Prevention: The Behavior Risk Factor Surveillance System (BRFSS) Study
Authors: Khwaja Bisma , Ng Jamie , Sinks Lauren J , Aguilar-Cruz Diana , Wang Frances M
Published: March 2023

Introduction:
Risk factors including hypertension and hyperlipidemia increase the risk of cardiovascular disease (CVD). Yet, the significantly increased prevalence of CVD in housing insecure populations cannot be explained by the diagnosed prevalence of these risk factors alone. These populations may face unique barriers to care related to lack of access to screening, prevention, and treatment that complicate heart health.

Hypothesis:
Access to quality healthcare and CVD prevention is reduced for the housing insecure population, independent of income and sociodemographic factors, compared to housing secure populations.

Methods:
Using data from the 2017 Behavior Risk Factor Surveillance System (BRFSS), housing insecurity was self-reported as not being able to pay mortgage, rent, or utility bills over the past 12 months. Weighted multivariable logistic regressions were used to calculate adjusted odds ratios for the healthcare access variables.

Results:
In our study population, 8.79% (51.8% female, 71.7% white) experienced housing insecurity. Compared to housing secure individuals, housing insecure individuals were more likely to not have a primary care doctor (OR 1.25 [1.16-1.35]), be unable to afford doctor visits (3.89 [3.63-4.16]), report pending medical bills (2.62 [2.33-2.93]), have Medicare (1.26 [1.01-1.57]) or Medicaid (1.83 [1.46-2.28]), experience gaps in healthcare coverage (2.94 [2.45-3.53]), delayed medical care (2.38 [2.10-2.70]), and were 4 times more likely to not take medications as prescribed due to cost (4.39 [3.86-4.99]). Among those with known hypertension and hypercholesterolemia, respectively, people experiencing housing insecurity were more likely to not be taking antihypertensive (1.35 [1.20-1.51]) and cholesterol-lowering medications (1.33 [1.18-1.48]).

Conclusion:
Housing insecure populations experience significant healthcare access disparities, potentially exacerbating health outcomes through the underdiagnosis, prevention, and treatment of CVD.
Abstract MP18: Associations of Individual and Area-Based Socioeconomic Status With Cardiovascular Outcomes and Mortality: A Prospective Cohort Study
Authors: Han Han , Zong Geng
Published: March 2023

Introduction:
Evidence is limited regarding the interactions between individual socioeconomic status (SES) and neighborhood deprivation on long-term health outcomes. We aimed to evaluate the joint impacts of individual- and area-based SES on risks of disease-specific incidence and mortality.

Hypothesis:
We hypothesized that neighborhood deprivation would be related to disproportionate harm on health outcomes in those of lower individual SES.

Methods:
Data were sourced from UK Biobank. We assessed individual SES by self-reported education attainment (college or university degree/others) and measured area-based SES by the Townsend deprivation index (in quintiles: Q1 was the least deprived and Q5 was the most deprived). Poisson regression was used to examine the associations of individual- and area-based SES with incident CVD and heart failure (HF), and mortality from all, CVD, and cancer causes.

Results:
During a mean follow-up of 11.9-12.3 years, we documented 24,936 incident CVD cases, 10,887 HF cases, and 36,584 deaths. Individual- and area-based SES were each significantly associated with higher risks of incident cardiovascular events and mortality. Compared with those with college/university degrees, the multivariable-adjusted relative risks (95% CIs) for less-educated participants were 1.18 (1.14, 1.21) for CVD, 1.24 (1.19, 1.30) for HF, 1.14 (1.12, 1.17) for all-cause mortality, 1.11 (1.05, 1.17) for CVD mortality, and 1.09 (1.06, 1.13) for cancer mortality. Being in the Q5 group (vs. Q1) was associated with 19-48% higher risks of health outcomes. A significant interaction between education attainment and neighborhood deprivation was found for incident CVD and HF, all-cause and cancer mortality, but not for CVD mortality (Fig1). The associations between higher deprivation and increased risks of CVD events and mortality were more prominent in less-educated subgroups.

Conclusions:
The detrimental impacts of neighborhood deprivation on health outcomes might be exacerbated by low education attainment.
Abstract MP21: Associations Between Plasma Proteome, Leukocyte Telomere Length, and Polygenic Risk Score for Leukocyte Telomere Length: The Atherosclerosis Risk in Communities Study (ARIC)
Authors: Li Aixin , Jacobson Ingrid , Steffen Brian T , Xie Jiaqi , Pankratz Nathan , Lane John , Arking Dan E , Mosley Thomas , Guan Weihua , Sedaghat Sanaz , Pankow Jim S , Lutsey Pamela L , Tang Weihong
Published: March 2023

Introduction:
Leukocyte telomere length (LTL) is an important aging biomarker implicated in the pathogenesis of age-related conditions. We conducted a large-scale proteomics study to characterize the proteomic signatures of LTL and its genetic determinants measured by polygenic risk score (PRS).

Hypothesis:
We hypothesize that LTL and LTL PRS are associated with blood proteomic signatures linked to aging-related conditions.

Methods:
We used TelSeq to estimate LTL based on whole genome sequencing (WGS) data measured in samples collected in ARIC visits 1, 2, and 3 (i.e., the baseline for this study). TelSeq counted reads containing at least 12 TTAGGG repeats. This count was then normalized to the number of reads with GC content between 48% and 52%. Only samples with read lengths of 150 or 151 were included in subsequent analyses, and LTL estimates were inverse normalized within read length group and WGS group before being merged. We derived a PRS for LTL based on previously published genome-wide association study (GWAS) summary statistics for 150 significant autosomal SNPs and ARIC GWAS data. We then analyzed LTL or LTL PRS as a predictor and plasma levels of proteins as outcomes, measured at ARIC visit 2 (for the LTL PRS analysis) and visit 3 (for the LTL analysis) using SOMAscan v4 (~5,000 proteins). Race-specific linear regressions were performed to evaluate the association between LTL or LTL PRS and levels of each protein adjusting for potential confounders at baseline. We used a Bonferroni correction to account for multiple testing. The analysis in Whites served as a discovery (p≤1x10
-5
) and that in Blacks as a replication.

Results:
The final sample sizes were as follows: LTL PRS analysis (n=7,587 Whites and 2,094 Blacks) and LTL analysis (n=5,014 Whites and 884 Blacks). In Whites, LTL PRS was significantly associated with five proteins (p≤1x10
-5
) that also showed the same direction of association in Blacks: THPO, GP1Bα, PEAR1, KDR, and GP5, with the association for KDR reaching nominal significance in Blacks (p=0.02). For LTL as the predictor, GP1Bα, GDF15 and TXNDC5 were significant in Whites, with consistent direction of associations in Blacks (p>0.05). These proteins are linked to hemostasis (all), endothelial proliferation (KDR), heart disease and cancer (GDF15), and cancer and rheumatoid arthritis (TXNDC5) in the literature.

Conclusion:
This large-scale proteomic analysis reveals blood proteomic signatures for LTL PRS and LTL, which will likely improve the understanding of biological pathways and clinical conditions implicated by LTL.
Abstract MP29: High-Sensitivity Troponin-T is Associated With Incident Diabetic Foot Infections in the Atherosclerosis Risk in Communities Study
Authors: Hicks Caitlin W , Wang Dan , McDermott Katherine , Fang Michael , Matsushita Kunihiro , Windham B Gwen , Selvin Elizabeth
Published: March 2023

Background:
Diabetic foot infections (DFI) are associated with substantial morbidity and mortality. Glycemic control and prevalent cardiovascular disease have been associated with DFI risk, but the association of subclinical cardiovascular disease with incident DFI has not been explored.

Hypothesis:
We hypothesized that high-sensitivity troponin-T (hs-cTnT, a marker of microvascular disease) and N-terminal-pro hormone BNP (NT-proBNP, a marker of cardiac wall stress) would be associated with incident DFI in adults without prevalent cardiovascular disease.

Methods:
We conducted a prospective cohort analysis of 1733 Black and White participants in the Atherosclerosis Risk in Communities (ARIC) study who had diabetes without prevalent cardiovascular disease at visit 2 (1990-1992, mean age 57.7 yrs). We estimated the cumulative incidence of incident DFI through 2019 using hospitalization discharge codes. We used Cox models to assess the associations of categories of cardiac biomarkers (using clinical cut-points) with DFI after adjusting for traditional risk factors.

Results:
During a median follow-up of 25 years, there were 417 incident DFI events. The 25-year cumulative incidence of DFI was higher among participants with elevated hs-cTnT (≥14 ng/L) vs not elevated (35% vs. 21%; P<0.001), but not among participants with elevated NT-proBNP (≥125 pg/mL) (23% vs. 23%; P=0.73). In adjusted models, elevated hs-cTnT was associated with incident DFI (HR 1.98, 95%CI 1.46, 2.68). Elevated NT-proBNP was not significantly associated with incident DFI (HR 1.04, 95%CI 0.78, 1.41). Our results were similar when the biomarkers were modeled more flexibly using splines: we observed a robust association of hs-cTnT, but not NT-proBNP, with incident DFI (
Figure
).

Conclusions:
Elevated hs-cTnT was associated with incident DFI among middle-aged adults without prevalent cardiovascular disease. This suggests subclinical cardiovascular disease, possibly in the form of microvascular ischemia, may play a role in the etiology of DFI.