bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 050: Phenome Wide Association Study of IL6R Variants Identifies a Drug Target for Cardiovascular Disease and Inflammation
Authors: Cai Tianxi , Zhang Yichi , Ho Yuk-Lam , Link Nicholas , Huang Jie , Ahuja Yuri , Cai Tianrun A , Honerlaw Jacqueline , Huang Jie , Costa Lauren , Sun Jiehuan , Hong Chuan , Damrauer Scott , Sun Yan V , Gagnon David , Gaziano Michael , Wilson Peter , Cho Kelly , Tsao Phillip , O'Donnell Christopher J , Liao Katherine P ,   on behalf of the VA Million Veteran Program
Published: July 2021

Background:
Individuals with an interleukin 6 receptor (IL6R) genetic variant not on IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. Thus, studying whether the
IL6R
variant is protective for a phenotype can inform which diseases may benefit from treatment with IL6R blockade. To test this hypothesis, we performed a Phenome-Wide Association Study (PheWAS) to screen for associations between an
IL6R
variant and a broad range of phenotypes in the electronic health records (EHR).

Methods:
We studied veteran participants in the Veteran’s Affairs Million Veteran’s Project using genomic data linked to EHR. We extracted all diagnoses codes and mapped them to phenotype groups using published PheWAS methods. Routine laboratory measurements, e.g. liver function tests, were also extracted. A PheWAS was performed by constructing logistic regression models testing associations between the
IL6R
variant (Asp358Ala, rs2228145) and 1,866 phenotype groups; linear regression models were constructed to screen for associations between
IL6R
and 26 routine laboratory measurements. All models were adjusted for age, gender, and race. Significance was reported using false discovery rate ≤0.05 and Bonferroni correction.

Results:
We studied 342,529 participants; the minor allele frequency of the
IL6R
variant was 35.3%.
IL6R
was most strongly associated with a reduced risk of aortic aneurysm (OR 0.91-0.92, 95% CI 0.89, 0.94) (Figure 1). We observed the expected association between
IL6R
and reduced C-reactive protein. We also observed known side effects of IL6R blockade, elevated transaminases, as well as elevated triglycerides, an initially unexpected result in the early clinical trials.

Conclusion:
In this proof of concept study, we demonstrate the utility of PheWAS to inform drug effects using the largest US-based biobank study. The strong association with aortic aneurysm corresponded with the newest indication for IL6R blockade to prevent aortic aneurysms due to large vessel vasculitis.
Abstract 053: Genome-wide
Tcea3
-SNP Interaction Study Identifies Novel QT Interval Loci
Authors: Avery Christy L , Arking Dan E , Baldassari Antoine , Buyske Steve , Concas Maria P , Kooperberg Charles , Lin Henry , Lin Ching-Ti , Müller-Nurasyid Martina , Noordam Raymond , North Kari E , Schramm Katharina , Soliman Elsayed , Sotoodehnia Nona , Trompet Stella , Newton-Cheh Christopher
Published: July 2021

Background:
QT interval (QT) genome-wide association studies (GWAS) have identified upwards of 35 common variant loci, including SNPs adjacent to putative transcription elongation factor
TCEA3.
Transcription elongation control has broad effects on gene expression, the misregulation of which is known to influence cardiac conduction system morphogenesis as well as activation or repression of key regulatory genes. Thus, we hypothesized that a genome-wide gene-gene interaction study of
TCEA3
lead SNP rs2298632 would identify novel loci that influence QT.

Methods:
Using 1000 Genomes imputed data (>20 million SNPs) in n=67,445 participants (69% Caucasian; 18% Hispanic/Latino; 11% African American) from 10 studies, we conducted genome-wide meta-analyses to test for the presence of: interaction effect loci by examining rs2298632xSNP interactions on QT; and joint effect loci by simultaneously examining SNP main effects and rs2298632xSNP interactions on QT. Inverse-variance weighted meta-analysis of genomically controlled ancestry- and study-specific summary effects estimated using multivariable adjusted linear models or generalized estimating equations that incorporated robust standard errors was performed using METAL. SNPs demonstrating evidence of heterogeneity (Cochran’s Q
P
< 0.05) and SNPs that were infrequent or rare (minor allele frequency [MAF] <5%) were excluded.

Results:
We identified one genome-wide significant interaction effect locus (
P
INT
<5x10
-8
) at
PVT1
(lead SNP: rs4733591; mean MAF = 32%), a long non-coding RNA gene for which previous GWAS identified suggestive associations with left ventricular systolic dysfunction. We also identified four genome-wide significant joint effect loci (
P
JOINT
<5x10
-8
) that mapped within or nearby
NUCKS1
(lead SNP: rs823094; MAF = 0.33)
, CASR
(lead SNP = rs17251221; MAF = 0.13)
, ACTBL2
(lead SNP = rs7737409; MAF = 0.22)
,
and
KDM1B
(lead SNP = rs34969716; MAF = 0.26)
,
loci with roles in calcium sensing, regulation of gene expression through histone modification, and tumor suppression.

Conclusion:
Extension of traditional main effects GWAS to interrogate gene-gene interactions for biologically motivated loci like
TCEA3
may help inform the structure and function of genetic pathways underlying complex traits like QT.
Abstract MP14: Proteinuria is Associated With a Greater Risk of Lower Limb Amputation in Patients With Peripheral Artery Disease
Authors: Shin Jung-Im , Grams Morgan , Coresh Josef , Chang Alex , Matsushita Kunihiro
Published: July 2021

Introduction:
Proteinuria is shown to be associated with increased risk of peripheral artery disease (PAD). However, its association with the risk of lower limb amputation in patients with PAD is unknown.

Hypothesis:
We hypothesized that proteinuria is associated with the risk of amputation in patients with PAD in a graded fashion.

Methods:
We identified 3,388 PAD patients with data on urine dipstick proteinuria within two years prior to PAD diagnosis between 1997 and 2017 in the Geisinger Health System (mean age 69.7 years, 44.8% female, 97.4% non-Hispanic White, 57.8% diabetic). We quantified the association of proteinuria with the risk of amputation using Cox proportional hazards models, adjusting for demographics, calendar year, estimated glomerular filtration rate, HbA1c, comorbidities including diabetic retinopathy/neuropathy, and medication use (antiplatelet drug, statin, and renin-angiotensin system inhibitor).

Results:
There were 55.2% with negative dipstick proteinuria, 11.1% trace, 14.1% with 1+, and 19.5% with ≥2+. A total of 245 patients underwent amputations over a median follow-up of 3.4 years. Incidence rate of amputation was 1.15 per 100 person-years for dipstick negative, 1.47 for trace, 2.11 for 1+, and 3.78 for ≥2+. This dose-response relationship remained similar even after accounting for potential confounders (p-trend=0.015), with particularly evident association for ≥2+ of dipstick (an adjusted hazard ratio of 1.52 [95% confidence interval: 1.08-2.17, p=0.017) (Figure). When we added proteinuria to other covariates, the risk discrimination slightly improved (Δc-statistic 0.007 [0.001-0.014]).

Conclusions:
Higher proteinuria was associated with a greater risk of lower limb amputation among patients with newly diagnosed PAD. Our results suggest the importance of considering proteinuria in risk assessment of limb loss in PAD patients.
Abstract MP16: Trends in Statin Utilization Among Adults With Severe Peripheral Artery Disease Including Critical Limb Ischemia in an Integrated Healthcare Delivery System
Authors: Reynolds Kristi , Mues Katie , Qian Lei , Chen Songyue , Harrison Teresa N , Hsu Jin-Wen Y , Philip Kiran J , Monda Keri L , Reading Stephanie , Brar Somjot
Published: July 2021

Background:
Studies have demonstrated benefit of statin therapy in patients with peripheral artery disease (PAD). However, use of statins in patients with PAD has been found to be suboptimal. We examined trends in statin use and discontinuation among adults with severe PAD including critical limb ischemia (CLI) from 2002-2015.

Methods:
Using electronic health record data from a large, integrated healthcare delivery system, we identified patients aged ≥40 yrs with incident severe PAD/CLI and 12 months of prior continuous coverage of health and drug benefits. Statin intensity was defined at first prescription fill. Discontinuation of statin therapy was defined as the first 90-day gap in treatment within 1 yr after diagnosis.

Results:
We identified 11,059 patients with incident severe PAD/CLI from 2002-2015. Mean (SD) age was 69 (11.3) yrs, 40% were female, 54% were White, 23% Hispanic, 16% Black and 4% Asian/Pacific Islander. Statin use in the yr before diagnosis increased from 50% in 2002 to 66% in 2015. Overall, 60% (n=6578) were on a statin in the yr before diagnosis. Of these patients, 18%, 54% and 28% were receiving high, moderate and low intensity statins, respectively. The proportion of patients on high intensity statins increased from 7.3% in 2002 to 41.9% in 2015 while the proportion on low intensity statins decreased (Figure). Of the 40% (n=4481) who were not on a statin in the yr before diagnosis, 13.5% (n=607) newly initiated statin therapy within 1 month after diagnosis. The proportion of patients with no statin use increased with increasing LDL-C, while the percentage with any statin use decreased (Figure). Following diagnosis of PAD/CLI, 13% discontinued statin therapy within 1 yr.

Conclusions:
Use of statins and high intensity statins increased from 2002-2015 among a population of patients with severe PAD including CLI. However, a substantial proportion remained untreated with statins, representing a significant treatment gap in this population at high risk for cardiovascular events and adverse limb outcomes.
Abstract MP19: Can Clinical Measurements of Blood Pressure Replace Research-based Measurements?
Authors: Tang Olive , Juraschek Stephen , Appel Lawrence , Cooper Lisa , Charleston Jeanne , Carson Kathryn , Yeh Hsin-Chieh , Miller Edgar R
Published: July 2021

Introduction:
There is growing interest in embedding research protocols into clinical practice, including use of electronic health records (EHR) for measures of blood pressure (BP). However, the accuracy and reliability of EHR-derived BP compared to research-based BP are unknown.

Hypothesis:
We hypothesized EHR-derived measurements would overestimate systolic BP (SBP) and have higher variance compared to research measurements.

Methods:
We analyzed EHR-derived BP and research BP measurements in participants from a randomized trial, Five+ Nuts and Beans. EHR-derived measurements were made following the implementation of a standardized BP protocol, including the use of automated devices, clinical training, and systems support, to enhance the quality of clinic BP measurements. EHR-derived SBP measurements and change in SBP, calculated from closest clinic visits prior to the start and after the end of the trial period, were compared with measures obtained in the research setting.

Results:
Participants were 87% female (107 of 123); mean age was 58.6±9.7 yrs. Of the 123 participants, 118 had at least one primary care visit within 6 months of the research period. EHR-derived SBP were higher and more variable than research measurements, though these differences were attenuated for visits occurring within 7 days of research measurements (Table 1). EHR-based change in SBP was also more variable (SD=19.6) than research-based change (SD=14.0); using these SD’s, we estimate that a 2-arm trial conducted with clinic measurements would need to enroll 95% more participants (324 vs 166) to detect a 5 mmHg difference in SBP at a power of 0.9.

Conclusions:
Despite implementation of a standardized BP protocol, clinic measurements of SBP were higher and more variable than research protocol-based measurements. These results suggest that, in clinical trials, use of BP measurements obtained in clinical care, even if standardized, will reduce power and require greater sample size compared to measurements obtained in research settings.
Abstract MP37: Diet Quality and Lifetime Risk of Total Cardiovascular Disease in US Adults
Authors: Zhong Victor W , Ning Hongyan , Van Horn Linda V , Wilkins John T , Lloyd-Jones Donald M , Allen Norrina B
Published: July 2021

Introduction:
Suboptimal diet is a leading risk factor for cardiovascular disease (CVD). Yet, the relationship between diet quality and lifetime CVD risk, and whether it differs by age, are unclear.

Methods:
Diet data from 10 US prospective cohorts were harmonized according to a standard protocol. Three diet quality indices were calculated within each cohort: Dietary Approaches to Stop Hypertension (DASH) diet, alternate Healthy Eating Index 2010 (aHEI-2010), and alternate Mediterranean (aMED) diet. CVD included coronary heart disease, stroke and heart failure. Study sample was divided into younger (<40 years old), middle-aged (40-60) and older (>60) groups based on age at the first dietary assessment. Cumulative CVD risk according to 5-year interval was estimated using modified Kaplan-Meier analysis, adjusting for competing risk of death. Multivariable proportional hazards regression was applied to determine the association between the three diet quality indices and CVD by sex and age.

Results:
A total of 129,892 participants with 1,603,199 person years of follow-up were analyzed. The adjusted cumulative CVD risk was lower in younger and middle-aged men and all women who had higher DASH score (Figure 1). Age modified the diet-CVD association in both men and women (P <0.0005). Compared to the lowest DASH score quintile (poorest diet), the adjusted hazard ratio (HR) for CVD decreased with increasing quintile of diet quality. The HR for the highest quintile was 0.41 (95% CI: 0.20-0.87) in younger men, 0.97 (0.82-1.16) in middle-aged men, 1.03 (0.89-1.19) in older men, 0.47 (0.21-1.05) in younger women, 0.73 (0.63-0.84) in middle-aged women, and 0.82 (0.76-0.88) in older women. Results were similar for aMED and aHEI-2010 score.

Conclusions:
Better diet quality is associated with lower lifetime CVD risk in all women and men except older men. Stronger inverse diet quality-CVD association in younger than middle-aged and older adults suggests that relative benefits of a healthy diet for CVD risk reduction may be greater at younger ages.
Abstract MP39: Trends in Diet Quality Among US Adults by Supplemental Nutrition Assistance Program Participation Status: 1999-2014
Authors: Zhang Fangfang , Liu Junxiu , Rehm Colin D , Wilde Parke , Mande Jerold R , Mozaffarian Dariush
Published: July 2021

Introduction:
Unhealthful diet is one of the top contributors to the chronic disease burden in the U.S. There are growing concerns that socioeconomic disparities exist in Americans’ diets and this disparity may have widened over time.

Aim:
To characterize trends in dietary intake of key food groups and nutrients among low-income Americans who participated in the Supplemental Nutrition Assistance Program (SNAP), and assess whether disparities in U.S. diets have persisted, improved, or worsened over time.

Methods:
Nationally representative sample of 6,162 adults aged 20 years or older who participated in SNAP, 6,692 income-eligible nonparticipants, and 25,842 higher-income nonparticipants from 8 National Health and Nutrition Examination Survey (NHANES) cycles (1999-2014). Exposures are calendar year and SNAP participation status. Survey-weighted, energy-adjusted mean scores and proportion meeting the American Heart Association (AHA) 2020 Strategic Impact Diet Goals (5 primary components: fruits/vegetables, whole grains, fish/shellfish, sugar-sweetened beverages (SSBs), sodium; 3 secondary components: nuts/seeds/legumes, processed meats, saturated fat). Intakes of individual food groups and nutrients were also assessed.

Results:
From 2003-2004 to 2013-2014 among SNAP participants with data on two-day dietary recall, primary diet score (maximum of 50) modestly increased (15.6 to 16.6; P-trend =0.03) while the secondary diet score (maximum of 80 points) did not change (31.5 to 32.1; P-trend =0.11). The proportion of SNAP participants having a poor diet decreased from 74.3% to 68.6%, the proportion having an intermediate-quality diet increased from 25.5% to 31.2%, and the proportion of having an ideal diet remained unchanged (0.2%.). Among primary components, changes were strongest for SSBs (-0.43 servings/d, P-trend=0.001) and whole grains (+0.25 servings/d, P-trend<0.001). Compared to higher-income nonparticipants and income-eligible

nonparticipants, SNAP participants had weaker improvements in both primary and secondary diet scores. From 1999-2000 to 2013-2014, disparities persisted for most dietary components, worsened for nuts/seeds and added sugars, and weakened for sodium.

Conclusion:
Despite some improvements in diet quality, SNAP participants still fall far short of meeting the AHA Goals for a healthful diet, and dietary disparities persisted or worsened for most dietary components.
Abstract MP40: Associations of Monounsaturated Fatty Acids From Plant and Animal Sources With Total and Cardiovascular Mortality Risk
Authors: Guasch Marta , Zong Geng , Willett Walter , Zock Peter , Wanders Anne , Hu Frank , Sun Qi
Published: July 2021

Background:
Studies regarding monounsaturated fatty acid(MUFA) intake and mortality have reported inconsistent findings.Dietary MUFAs can come from both plant and animal sources with divergent nutrient components that potentially obscure the associations for total MUFAs.

Hypothesis:
We hypothesized that MUFA from plant sources(MUFA-P) is more likely to be inversely associated with mortality than MUFA from animal sources (MUFA-A).Replacing saturated fatty acids(SFA),
trans
fat,or refined carbohydrates by MUFA-P would be associated with a lower risk.

Methods:
We included 63,412 women from the Nurses’ Health Study(1990-2012) and 29,966 men from Health Professionals Follow-up Study(1990-2010). MUFA-Ps and MUFA-As were calculated based on validated food frequency questionnaires collected every 4-y and food composition databases that capture changes in composition over time.

Results:
During 1,896,864 person-years of follow-up, 20,672 total and 4,588 cardiovascular deaths occurred.MUFA-P was inversely associated with total mortality after adjusting for potential confounders [HR:0.84(95%CI:0.79,0.89)
P
<0.01], whereas MUFA-A was associated with higher risk [1.21(1.07,1.37),
P
<0.01].Isocalorically replacing SFAs (5% of total energy), refined carbohydrates (5% energy),or trans fat (2% energy) with MUFA-Ps was associated with 15%, 14%, and 10% lower risk of total mortality, respectively. Mortality risk was 24% lower when MUFA-Ps were modelled to replace MUFA-As(5% energy),and 20% lower when the sum of SFAs and MUFA-As(5% energy) was replaced.Similar results were observed for cardiovascular mortality for the same substitutions:HR(95%CI) were 0.74 (0.64, 0.85;
P
<0.01) for replacing MUFA-A and 0.83 (0.76, 0.92;
P
<0.01) for replacing SFA+MUFA-A.

Conclusions:
Higher MUFA-P intake was associated with lower total mortality and MUFA-A was associated with higher mortality.Significantly lower mortality was observed when SFAs,
trans
fats,or refined carbohydrates were replaced by MUFA-P, but not MUFA-A.
Abstract MP54: Circulating Prolactin Concentrations and Risk of Type 2 Diabetes in US Women
Authors: Li Jun , Rice Megan S , Huang Tianyi , Hankinson Sue , Clevenger Charles , Hu Frank , Tworoger Shelley
Published: July 2021

Background:
Prolactin, a multifunctional hormone, is involved in regulating insulin sensitivity and glucose homeostasis in experimental and cross-sectional human studies. However, whether circulating levels of prolactin are associated with risk of type 2 diabetes (T2D) remains unclear.

Methods:
We analyzed the prospective relationship between circulating prolactin levels and T2D risk in in the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) with up to 22 years of follow-up. Total plasma prolactin was measured using immunoassay in 8,637 women free of T2D and cardiovascular disease at baseline blood collection (NHSI: 1989-1990; NHSII: 1996-1999) and a subset of 1,017 NHS women who provided a second blood sample in 2000-2002. In addition, baseline bioactive prolactin levels were measured in a subset of 2,658 women using the Nb2 lymphoma cell bioassay. We calculated hazard ratios (HRs) using Cox regressions.

Results:
A total of 701 incident T2D cases were documented during 159,517 person-years of follow-up. Circulating prolactin levels were inversely associated with T2D risk; the multivariable HR comparing the highest with the lowest quartile of prolactin levels was 0.71 (95% confidence interval, 0.54-0.93;
P
trend
=0.02). The associations were similar by menopausal status and risk factors (
P
>0.70 for interaction). Additional adjustment for sex hormones, growth factors, adipokine, and inflammatory markers did not alter the results. The association of bioactive prolactin with T2D risk was suggestively stronger than that of total prolactin (comparable HR=0.56 vs. 0.82 among the 2,658 women). The inverse association of total plasma prolactin with incident T2D waned linearly with time, with a significant association observed during the first 9 years after blood draw.

Conclusion:
High circulating prolactin level was independently associated with lower risk of T2D in women. Our findings are consistent with experimental evidence, supporting a possible protective role for prolactin in the pathogenesis of T2D.
Abstract MP70: Pre-pregnancy Beta Cell Compensation for Insulin Resistance Associated With Subsequent Gestational Diabetes Mellitus: The CARDIA Study
Authors: Gunderson Erica P , Krefman Amy , Lewis Cora E , Catov Janet , Allen Norrina B
Published: July 2021

Hypothesis:
Gestational diabetes mellitus (GDM) is a disorder of glucose metabolism during pregnancy characterized by pancreatic beta cell dysfunction and greater insulin resistance, but it is unclear whether dysfunction exists before pregnancy. The disposition index (DI) is a physiologic measure of beta cell compensation for insulin resistance strongly predictive of future diabetes. This prospective study evaluates whether a clinical approximation of DI before pregnancy is associated with risk of GDM.

Methods:
This analysis included 696 women (45% black, 55% white) enrolled in the CARDIA Study, a U.S. multi-center prospective cohort of young adults aged 18-30 at baseline (1985-86) who gave birth at least once during 30 years of follow up, reported GDM status and had fasting glucose and insulin measured before one or more post-baseline births. DI was defined as HOMA-B divided by HOMA-IR using standard formulas. Multinomial logistic regression models estimated odds ratios (OR) and 95%CI for GDM among pre-pregnancy DI tertiles (low, moderate, high) and fully adjusted for time to birth, race, age, parity, BMI, lifestyle behaviors and family history of diabetes, and also stratified by pre-pregnancy BMI.

Results:
9% of women reported GDM (64/696) for 794 births. 55% of GDM and 30% of non-GDM were categorized as low DI. Low pre-pregnancy DI compared to moderate DI was associated with higher fully adjusted odds of GDM (OR=2.71, 95%CI:1.37-5.35) in the entire sample. In models stratified by pre-pregnancy BMI, low DI was associated with 4-fold higher odds of GDM among Overweight/Obese (OR=4.22, 95%CI: 1.35-13.91) and somewhat attenuated higher odds of GDM among Normal BMI (OR=1.94, 95%CI: 0.78–4.86); Table 1. Only family history of diabetes was strongly associated with GDM independent of DI.

Conclusions:
Inadequate beta cell compensation is present before pregnancy and discriminates greatest risk of GDM among high BMI, and may identify higher risk among women of normal BMI.
Abstract P004: Higher Socioeconomic Position Strengthens Intergenerational Transmission of Ideal Health Behaviors
Authors: Komulainen Kaisla , Mittleman Murray , Jokela Markus , Elovainio Marko , Laitinen Tomi , Pahkala Katja , Juonala Markus , Kähönen Mika , Raitakari Olli , Keltikangas-Järvinen Liisa , Pulkki-Råback Laura
Published: July 2021

Introduction:
Promoting ideal health behaviors is an objective of the AHA 2020 goals. We assessed the hypothesis that ideal health behaviors transmit from one generation to the next and that higher socioeconomic position (SEP) in parents and their adult offspring promotes intergenerational transmission of ideal health behaviors.

Methods:
Data were from the intergenerational Cardiovascular Risk in Young Finns Study. We included 1857 participants who had repeated measures of educational attainment (as a proxy for SEP) and smoking status, BMI, physical activity and diet recorded in 2001, 2007 and 2011. Parental educational attainment and health behaviors were collected in 1980. We categorized data on health behaviors as ideal vs non-ideal (1/0) using AHA definitions of ideal cardiovascular health. The number of ideal health behaviors (0 to 4) was treated as a continuous outcome. The number of parental heath behaviors (0 to 8; each parent contributing equally) was the primary exposure. Intergenerational associations and interactions with SEP were examined in linear multilevel regression with random intercepts applicable to longitudinal data, adjusting for sex, study year, age, single-parent family and parental education.

Results:
Participants were 55% women; in 2001, mean age was 31.1 (SD, 5.0) and mean number of ideal health behaviors 2.0 (SD, 1.1). Overall, the adjusted mean number of ideal health behaviors increased with the number of parental ideal health behaviors, from 1.7 (95% CI, 1.6-1.7) to 2.1 (95% CI, 2.0-2.2) among participants with parents in the lowest vs highest 20% of ideal health behaviors. The increments were greater for those with higher levels of education (interaction p=.004) or those whose parents had higher levels of education (p=.007) (
Figure
).

Conclusions:
In this prospective study, higher number of ideal health behaviors in parents was associated with higher number of ideal health behaviors in offspring. Higher SEP in either generation strengthened the protective intergenerational associations.
Abstract P008: Have Trends in Preventable Hospitalizations Related to Hypertension Decreased Among Elderly Americans? Results From National Inpatient Sample, 2005-2014
Authors: Saxena Anshul , Rubens Muni , Das Sankalp , Arias Lara , Veledar Emir , Nasir Khurram
Published: July 2021

Introduction:
As number of elderly Americans is projected to double by 2050, population aged ≥65 years will have the highest impact on Medicare spending. The prevalence of elderly population with hypertension (HTN) is around 65% and if patients receive good primary care or an early intervention, these HTN related hospitalizations could be prevented saving millions in Medicare spending. Our objective was to examine the trends in hospitalizations related to HTN and total cost over 10 years among aged ≥65 years.

Methods:
Using data from Nationwide Inpatient Sample database from 2005-2014, we explored the existence of trends in HTN admission rates and corresponding hospitalization costs among adults ≥65 years vs other age groups. Weighted estimates for rates and mean total cost were reported using SUDAAN after adjusting for complex survey design.

Results:
Overall, hospitalizations due to HTN increased by 26% in 2014 from 2005. Hospitalizations were highest among patients ≥65 years (57.8%) followed by 40-64 (32.6%) and 18-39 years (9.6%). During 2005-2014, hospitalization rates among ≥65 years increased significantly (10.7%,
p
<0.001), where as a decreasing trend was observed in other age groups. The total cost of hospitalization significantly increased from $302M in 2005 to $472M in 2014 among ≥65 years (
p
<0.001). In general, highest change in total cost was observed among Medicare patients where it increased by 53% to $145 million in 2014 compared to 2005.

Conclusion:
Hospitalizations and costs associated with HTN, especially Medicare, have increased over the past 10 years among elderly. Although these trends are alarming, these events could be prevented through symptom management at primary care, medication adherence, care coordination, or modifying care-seeking behavior resulting in potential savings of 851M over a year. This would reduce burden of Medicare spending, which is projected to surpass the rate of growth in federal revenues.
Abstract P014: Associations of Depression, and Perceived Stress With Telomere Length in African Americans: The Minority Health Genomics and Translational Research Bio-Repository Database Study
Authors: Khan Rumana J
Published: July 2021

Background:
African Americans (AA) experience higher levels of psychological distress. Adverse psychological conditions and mental stress could be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (TL), which could underlie this association.

Hypothesis:
In this study, we hypothesized that depressive symptoms and higher stress level would be associated with shorter telomere length in AA. We also hypothesized that the associations would be attenuated after adjusting for individual-level sociodemographic variable, various disease conditions, and lifestyle factors.

Methods:
The analysis included 225 women and 142 men aged 30-55 years from the Minority Health Genomics and Translational Research Bio-Repository Database Study. Relative TL (T/S ratio) was measured using quantitative polymerase chain reaction. The 20-item Center for Epidemiologic Studies Depression Scale and 14-item Perceived Stress Scale were used to assess the presence of depressive symptoms and perceived stress respectively. Summation of the scores and the Principal Component Analysis were performed for both the scales. Multivariable linear regression models were used to estimate mean differences in log T/S associated with depressive symptoms and perceived stress after adjusting for sociodemographic variable, various disease conditions, and lifestyle factors.

Results:
No evidence of association between stress and TL was observed. We found effect modification by hypertension affecting the association between depressive symptoms and log T/S. Depressive symptom, especially higher psychosomatic symptoms, was associated with increased TL in normotensive participants (β= 0.11 for mid-level psychosomatic symptoms and β= 0.12 for high-level psychosomatic symptoms; p value <0.05 for both). No association was observed in hypertensive participants.

Conclusions:
We found a positive association between psychosomatic depressive symptoms and TL, which do not support the hypothesis that depression is associated with shorter TL and aging in AA. Longitudinal studies with larger samples are needed to better understand and confirm this relationship.
Abstract P023: Lifetime Risk of Atrial Fibrillation by Race and Socioeconomic Status: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Mou Liping , Norby Faye , Chen Lin , O'Neal Wesley , Lewis Tene , Loehr Laura , Soliman Elsayed , Alonso Alvaro
Published: July 2021

Background:
The lifetime risk of atrial fibrillation (AF) has been previously reported in whites, but not in African Americans. Moreover, we lack current estimates of lifetime risk of AF that take into account recent trends in the incidence of this arrhythmia. Lifetime risk of AF by socioeconomic status has not been investigated before.

Methods:
We studied 15,343 whites and African Americans in the Atherosclerosis Risk in Communities study who were followed for an average of 21 years (maximum 27 years). Total family income was categorized as <$25,000, $25,000-$49,999, and ≥$50,000, and education as < high school graduate, high school graduate, and at least some college. Incident AF was ascertained from study electrocardiograms, hospital discharge records, and death certificates. Lifetime risk of AF was estimated by a modified Kaplan-Meier method that accounted for the competing risk of death.

Results:
We identified 2760 AF cases during follow-up. Lifetime risk of AF was 36% (95% CI: 32-38%) in white men, 30% (26-32%) in white women, 21% (13-24%) in African American men, and 22% (16-25%) in African American women (Figure). Regardless of race and sex, incidence rates of AF decreased from the lowest to highest categories of income and education. In contrast, lifetime risk of AF increased in individuals with higher income and education in most sex-race groups. Cumulative incidence of AF was lower in those with higher income and education compared to their low socioeconomic status counterparts through earlier life, but was reversed after age 80.

Conclusion:
Lifetime risk of AF in a contemporary cohort in the United States was approximately 1 in 3 among whites and 1 in 5 among African Americans. Socioeconomic status was inversely associated with cumulative incidence of AF before the last decades of life.
Abstract P029: Racial Differences in Sudden Cardiac Death: Findings From the Atherosclerosis Risk in Communities Study (ARIC)
Authors: Zhao Di , Guallar Eliseo , Blasco-Colmenares Elena , Sotoodehnia Nona , Post Wendy
Published: July 2021

Background:
In hospital-based studies and in studies of participants with pre-existing conditions, African Americans have a higher risk of in- and out-of-hospital sudden cardiac death (SCD) compared with Whites. However, the risk of SCD of African Americans and Whites has never been compared in large-scale community-based cohort studies.

Objective:
To compare the risk of SCD among African Americans and Whites, and to evaluate the risk factors that may explain racial differences in incidence.

Methods:
Cohort study of 3,838 African Americans and 11,245 Whites participating in ARIC. Race was self-reported. SCD cases were defined as a sudden pulseless condition from a cardiac cause in a previously stable individual and adjudicated by an expert committee. Mediation effect of covariates was calculated using boot-strapping method. Cox proportional hazards models were adjusted for demographics, social economic status, cardiovascular (CVD), and electrocardiographic risk factors.

Results:
The mean (SD) age was 53.6 (5.8) for African Americans and 54.4 (5.7) years for Whites. During 25.3 years of follow-up, 215 African Americans and 332 Whites experienced SCD. In

multivariable-adjusted models, the HRs (95% CI) for SCD comparing African Americans and Whites were 1.70 (1.37, 2.10) overall, 2.00 (1.40, 2.84) in women, and 1.46 (1.10, 1.92) in men (p-value for race by sex interaction 0.02;
Table
). CVD and electrocardiographic risk factors explained 36.6% (21.4, 51.8%) of the excess risk of SCD in African Americans, with a large proportion of racial differences unexplained.

Conclusions:
The risk of SCD in community-dwelling African Americans was significantly higher than in Whites, particularly among women. CVD risk factors, including higher prevalence of obesity, diabetes, hypertension and LV hypertrophy in African Americans, explained only a small fraction of this difference. Further research is needed to identify factors responsible for race differences in SCD and to implement prevention strategies in high-risk minorities.
Abstract P038: The Association Between Thyroid Function and Cardiac Structure and Function in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Gyarmati Georgina , Chen Yuan , McEvoy John W , Martin Seth , Kottgen Anna , Shah Amil M , Solomon Scott , Coresh Josef , Selvin Elizabeth , Matsushita Kunihiro
Published: July 2021

Background:
Most prior studies evaluating thyroid function and cardiac structure and function have been small and have not included the full spectrum of thyroid function hormones.

Methods:
Among 5122 ARIC participants (aged 66- 90 at the visit 5, 2011-2013) we evaluated the cross-sectional associations of clinical categories of thyroid function and thyroid hormone levels (triidothyronine [T3], thyroxine [T4], and thyroid-stimulating hormone [TSH]) with left ventricular structure, systolic function, and diastolic function based on echocardiogram after accounting for potential confounders including prevalent coronary heart disease and heart failure.

Results:
There were 417 participants (9.4%) with hypothyroidism and 155 participants (3.5%) with hyperthyroidism. Hypothyroidism tended to be associated with more echocardiographic parameters compared to hyperthyroidism. Among individual thyroid hormones, T3 was most robustly associated with left ventricular structure and function. Specifically, lower T3 level was associated with higher left ventricular mass and diameter and reduced systolic and diastolic dysfunction (Figure).

Conclusions:
In community-dwelling older adults, hypothyroidism was more evidently associated with altered left ventricular structure and function than hyperthyroidism. Among T3, T4, and TSH, lower T3 demonstrated most robust associations. Our findings highlight the importance of recognizing hypothyroidism for cardiac health and assessing T3 in addition to T4 and TSH for thyroid function assessment among older adults.
Abstract P040: GlycA, a Novel Inflammatory Marker, and Subclinical Coronary Atherosclerosis in the Multicenter AIDS Cohort Study (MACS)
Authors: Fashanu Oluwaseun E , Tibuakuu Martin , Zhao Di , Otvos James D , Brown Todd T , Haberlen Sabina A , Guallar Eliseo , Budoff Matthew J , Palella Frank J , Martinson Jeremy J , Akinkuolie Akintunde O , Mora Samia , Post Wendy S , Michos Erin D
Published: July 2021

Background:
Inflammation may link HIV infection to cardiovascular disease (CVD). GlycA, a novel nuclear magnetic resonance (NMR) biomarker of systemic inflammation, has been associated with incident CVD events in the general population. The relation between GlycA and the presence, extent and composition of subclinical coronary plaque in men with HIV infection (HIV+) or at risk for HIV (HIV-) is unknown.

Methods:
This is a cross-sectional analysis of 935 men enrolled in MACS with plasma measurement of GlycA and non-contrast cardiac CT and/or coronary CT angiography. We used multivariable adjusted Poisson and linear regression to assess associations of GlycA with prevalent coronary atherosclerosis and plaque extent, respectively.

Results:
Mean ± SD age was 54 ± 7 yrs; 31% were black, and 63% HIV+ with 81% having undetectable viral load (VL). GlycA levels were higher in HIV+ compared to HIV- men (397 ± 68 vs 380 ± 60 μmol/L, p=0.0001), and higher for those with detectable VL vs. undetectable (413 ± 79 vs 393 ± 65 μmol/L, p=0.004). After adjusting for demographic and CVD risk factors, every 1 SD increment in GlycA was associated with an increased prevalence of coronary artery calcium (CAC>0) (prevalence ratio: 1.09, 95% CI: 1.03-1.15), coronary stenosis ≥ 50% (1.20, 1.02-1.41), and calcified plaque (1.12, 1.02-1.23); p for all < 0.03. These associations remained significant after adjusting for other inflammatory markers and did not differ by HIV status. Among men with plaque, GlycA was positively associated with the extent of CAC, total plaque and mixed plaque (
Table
). Associations were weaker in HIV+ men for total and mixed plaque (P
interaction
= 0.003 and 0.03, respectively). GlycA was not associated with non-calcified plaque.

Conclusion:
HIV+ men have higher levels of GlycA than HIV- men. Higher GlycA is positively and independently associated with subclinical coronary atherosclerosis. Whether modification of GlycA through lifestyle or pharmacotherapy can reduce coronary plaque burden and future CVD events requires further study.
Abstract P046: Sex Hormone Levels and 10-Year Change in N-Terminal Pro-Brain Natriuretic Peptide Among Men and Post-Menopausal Women: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Ying Wendy , Zhao Di , Ouyang Pamela , Vaidya Dhananjay , Ndumele Chiadi E , Sharma Kavita , Subramanya Vinita , Guallar Eliseo , Heckbert Susan R , Lima Joao A , deFilippi Christopher R , Budoff Matthew J , Post Wendy S , Michos Erin D
Published: July 2021

Background:
The risk of cardiovascular disease (CVD) differs between men and women, and sex hormones are thought to play a key role. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a sensitive biomarker of ventricular wall stress and a strong predictor of incident cardiovascular disease (CVD) and heart failure (HF). It can thus be seen as an early marker of CVD. We evaluated whether sex hormones levels were associated with change in NT-proBNP concentrations over 10 years in MESA.

Methods:
We studied 2348 men and 2041 post-menopausal women. Serum testosterone (T), estradiol, dehydroepiandrosterone (DHEA), and sex hormone binding globulin (SHBG) were measured at Exam 1 (2000-02); free T and bioavailable T were calculated. NT-proBNP was measured by Roche assay at Exam 1, plus Exam 3 (2004-05) and/or Exam 5 (2010-12). Multivariable-adjusted linear mixed effects models were used to study associations between sex hormone levels and change in NT-proBNP over an approximately 10-year period.

Results:
Mean (SD) age (years) at baseline was 65 (9) for women and 62 (10) for men. Women had higher NT-proBNP than men (median 76.6 vs 37.1 pg/ml). Among women, after adjusting for demographic, socioeconomic, and CVD risk factors, higher total T, bioavailable T, and free T were independently associated with a greater increase in NT-proBNP over 10 years, whereas estradiol and SHBG were inversely associated with change in NT-proBNP (
Table
). When sex hormones were analyzed together in the same model, total T was positively associated and SHBG was inversely associated with change in NT-proBNP. In men, higher estradiol was associated with greater 10-year increase in NT-proBNP. These associations were preserved after excluding individuals with ejection fraction <50%.

Conclusion:
A more androgenic sex hormone profile in post-menopausal women and a more estrogenic profile in men were independently associated with 10-year change in NT-proBNP levels. Sex hormone patterns may thus explain in part sex differences in the development of CVD and HF.
Abstract P052: Circulating Natural Killer Cells and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Jenny Nancy S , Olson Nels C , Ellis Alicia M , Doyle Margaret F , Huber Sally A , Kronmal Richard A , Psaty Bruce M , Tracy Russell P
Published: July 2021

Introduction:
Clinically, natural killer (NK) cells are important in inflammatory and autoimmune diseases. As part of innate immunity, NK cells produce chemokines and inflammatory cytokines, potentially linking them to cardiovascular disease (CVD) development and progression as well. However, their role in human CVD is not clear.

Hypothesis:
NK cells are proatherogenic in humans and are associated with CVD risk factors and subclinical CVD measures.

Methods:
We examined cross-sectional associations of circulating NK cell levels with CVD risk factors, subclinical CVD measures and coronary artery calcium (CAC) in 891 White, Black, Chinese and Hispanic men and women (mean age 66 y) in the Multi-Ethnic Study of Atherosclerosis (MESA) at Exam 4 (2005-07). NK cell percent, percent of circulating lymphocytes that were CD3
-
CD56
+
CD16
+
, was measured in whole blood by flow cytometry. CAC presence was defined as Agatston score > 0.

Results:
Mean (standard deviation) NK percent differed by race/ethnicity; 8.2% (4.7) in Whites, 11.3% (7.5) in Chinese (p<0.001 compared to Whites), 7.1 (4.2) in Blacks (p=0.007) and 8.4 (5.2) in Hispanics (p=0.6). NK cell percent was positively associated with age (p<0.001) and systolic blood pressure (P=0.003) in the full group. However, NK cell percent was lower in current smokers than in never smokers (p=0.002). Adjusting for age, sex, race/ethnicity, smoking, body mass index, systolic blood pressure, diabetes and dyslipidemia, NK cell percent was negatively associated with common carotid intima media thickness (IMT; β coefficient -0.01; 95% confidence interval -0.03, -0.003) but was not associated with internal carotid IMT (-0.002; -0.037, 0.033). Likewise, NK cell percent was not associated with the presence of CAC (compared those with no detectable CAC; relative risk 1.02; 95% confidence interval 0.96, 1.08) or continuous Agatston score in those with a positive score (β coefficient 0.16, 95% confidence interval -0.003, 0.32) in the full group (models adjusted as above). Results were similar across race/ethnic groups.

Conclusions:
Of clinical interest, CD3
-
CD56
+
CD16
+
NK cell percent varied significantly by race/ethnicity in these men and women from MESA. However, NK cell percent was inconsistently associated with CVD risk factors; positively with age and systolic blood pressure, and negatively with smoking. NK cell percent was also negatively associated with common carotid IMT. Larger sample sizes and longitudinal analyses will be required to clarify the potential relationship between NK cells and atherosclerosis in humans.
Abstract P065: Lifetime Risk of Developing Type 2 Diabetes by Levels of Adiposity in the US Population
Authors: Echouffo Tcheugui Justin B , Banks Michael P , Hongyan Ning Hongyan , Canerthon Mercedes R , Vasan Ramachandran S , Lloyd-Jones Donald J , Wilkins John T
Published: July 2021

Introduction:
Prior estimates of lifetime risk (LTR) for developing type 2 diabetes (diabetes) among US adults have been derived using Markov modeling, thus were not based on longitudinal data. We use pooled data from several US community-based cohorts to estimate the LTR of diabetes according to age, sex and body mass index (BMI).

Hypothesis:
Higher BMI is associated with higher LTR of diabetes irrespective of the index age; and men have a higher LTR of diabetes compared to women.

Methods:
We pooled individual-level data from 7 US-based cohorts: Framingham Heart Study; Framingham Offspring Heart Study; Coronary Artery Risk Development in Young Adults (CARDIA); Atherosclerosis Risk in Communities (ARIC); Cardiovascular Health Study (CHS); Multi-Ethnic Study of Atherosclerosis (MESA); and Jackson Heart Study (JHS). Participants were free of diabetes (fasting blood glucose ≥126 mg/dl or use of medications) at index age, and were categorized by BMI (normal weight [<25 kg/m
2
], overweight [25-29 kg/m
2
] and obese (BMI≥30 kg/m
2
)]. The LTR of diabetes, at index age 55, was derived modified Kaplan-Meier estimator adjusting for competing risk of death free from diabetes.

Results:
Our sample consisted of 14139 Black and White participants (56% female). At index age 55 years, the 25-year adjusted risk for diabetes was 5.3% (95% confidence interval: 4.1-6.6%) in men and 2.8% (2.2-3.5%) in women with normal weight (Figure). The corresponding risks for diabetes among overweight participants were 11.0% (9.7-12.3%) in men and 8.5% (7.3-9.7%) in women. In obese individuals, the 25-year risk for diabetes was 24.3% (21.9- 26.6%) in men, and 20.4% (18.6-22.2%) in women.

Conclusions:
In this sample of middle-aged US adults
,
long-term risk for diabetes was substantially higher in overweight and obese participants. These data strongly suggest that lowering the population burden of obesity is critical for lowering the population burden of diabetes.