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Intraabdominal fat (IAF) area is often measured indirectly in epidemiologic studies. The authors recruited 147 participants from the second examination (1990-1992) of the Atherosclerosis Risk in Communities Study to examine IAF area and determine whether there were differences in IAF area and distribution by location. Magnetic resonance imaging was used to image four 10-mm slices between the second and fourth lumbar vertebrae by an inverse recovery method, and IAF was calculated from each image. The authors constructed gender-specific mixed models with IAF area as the outcome and the location of imaging along the torso as the independent variable, using random intercepts to account for between-person variation in IAF area. The torso location of IAF measurement was a significant predictor of IAF area in both men (p = 0.02) and women (p < 0.0001) after adjustment for body mass index. A significant positive interaction between age and location was seen in men, with increasing IAF area moving down the torso with older ages. Using magnetic resonance imaging, location along the torso yields different IAF areas and distributions independently of body mass index in both genders, with measurement at the second lumbar vertebra (slightly above the umbilicus) capturing the largest amount of IAF. Studies that attempt to link IAF with cardiovascular disease risk factors should consider measurement location to accurately capture the association. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) morbidity and mortality are high among black adults. We aimed to study the granular subclinical relations of aortic stiffness and left ventricular (LV) function and remodeling in blacks, in whom limited data are available. In the Jackson Heart Study, 1050 U.S. community-dwelling black adults without CVD underwent 1.5 T cardiovascular magnetic resonance. We assessed regional and global aortic stiffness and LV structure and function, including LV mass indexed to body surface area (LVMI), end-diastolic volume (LVEDV), ejection fraction (EF), and global and regional circumferential strain (Ecc). Phase contrast images of the cross-sectional aorta at the pulmonary artery bifurcation and abdominal aorta bifurcation were acquired to measure pulse wave velocity of the aortic arch (AA-PWV) and thoracic aorta (T-PWV). Results of multivariable-adjusted analyses are presented as SD unit change in LV variables per SD change in PWV variables. Participants were 62% women with mean age of 59 ± 10 years. Higher AA-PWV and T-PWV were associated with greater LVMI: for T-PWV, β = 0.10, 95% CI = 0.03-0.16, p = 0.002. Higher AA-PWV and T-PWV were associated with worse (more positive) Ecc at the LV base (for AA-PWV, β = 0.13, 95% CI = 0.05-0.20, p = 0.0007), but not mid-LV or apex. AA-PWV and T-PWV were not associated with LV mass/LVEDV or EF. In this cross-sectional study of blacks without CVD in the U.S., aortic stiffness is associated with subclinical adverse LV function in basal segments. Future studies may elucidate the temporal relationships of aortic stiffness on the pattern and progression of LV remodeling, dysfunction, and associated prognosis in blacks., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Higher levels of perceived stress are associated with adverse cardiovascular health. It is plausible that these associations are attenuated among individuals with positive psychological factors such as social support and health-enhancing behaviors. Therefore, this study examined longitudinal associations of chronic stress with cardiovascular disease (CVD) events, and whether social support and physical activity (PA) modify these associations., Methods: Data from 3,401 adults (mean age 40.2 years; 46.7% Black; 56.2% women) from the Coronary Artery Risk Development in Young Adults (CARDIA) study, with no prior CVD event in 2000-2001 were analyzed. Chronic stress lasting ≥6 months across 5 life domains (work, financial, relationships, health of self, and health of close other) was self-reported. Adjudicated CVD events (fatal/or nonfatal CVD event) were ascertained yearly through 2020. PA and social support were self-reported via questionnaires. Statistical analyses were conducted in 2023 using multivariable stepwise Accelerated Failure Time analysis to assess associations between key study variables., Results: The mean chronic stress score was 1.30±1.33 stressors and, by 2020, 220 participants had experienced a CVD event. Chronic stress was associated with lowered survival (time ratio: 0.92; 95% CI: 0.854-0.989), when adjusted for sociodemographic and lifestyle variables but no longer significant when adjusting for clinical factors. Neither PA nor social support were significant modifiers (all ps>0.05)., Conclusions: Chronic stress was associated with the risk of having a CVD event among middle-aged adults, due at least in part to clinical mediators. Studies should continue exploring positive psychosocial and behavioral factors that may modify this association., (Copyright © 2023 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease., Methods: Computationally predicted damaging or loss-of-function (REVEL>0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n=1,062,595)., Results: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n=787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n=585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (Odds Ratio [OR]: 0.66 95% Confidence Interval [CI]: 0.54-0.81, p=6.1×10 -5 ) and coronary artery disease (OR: 0.74 95%CI: 0.63-0.87, p=2.9×10 -4 ) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers., Conclusions: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach., Competing Interests: Conflicts of Interest: The other authors have nothing to declare.

Aims: Numerous studies report positive associations between total carbohydrate (CHO) intake and incident metabolic syndrome (MetS), but few differentiate quality or type of CHO relative to MetS. We examined source of CHO intake, including added sugar (AS), AS-rich CHO foods, and sugar-sweetened beverages (SSBs) associated with incident MetS in adults enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study., Methods and Results: Among 3154 Black American and White American women and men aged 18-30 years at baseline, dietary intake was assessed by diet history three times over 20 years. Sources of AS-rich CHO foods and beverages include sugar-rich refined grain products, candy, sugar products, and SSBs. Incident MetS was created according to standard criteria. Time-dependent Cox proportional hazards regression analysis evaluated the associations of incident MetS across quintiles of cumulative intakes of AS-rich CHO foods and beverages, AS, and SSBs adjusted for potential confounding factors over 30 years of follow-up. The associations of AS-rich CHO foods and beverages, AS, and SSB intakes with incident MetS were consistent. Compared with the lowest intake, the greatest intakes of AS-rich CHOs, AS, and SSBs were associated with 59% (Ptrend < 0.001), 44% (Ptrend = 0.01), and 34% (Ptrend = 0.03) higher risk of developing MetS, respectively. As expected, diet quality was lower across increasing quintiles of AS-rich CHO foods and beverages, AS, and SSBs (all Ptrend < 0.001)., Conclusion: Our study findings are consistent with an elevated risk of developing MetS with greater consumption of AS, AS-rich CHO foods, and SSBs, which support consuming fewer AS-rich CHO foods and SSBs., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Context: Cardiometabolic diseases are common in persons with HIV (PWH) on antiretroviral therapy (ART), which has been attributed to preferential lipid storage in visceral adipose tissue (VAT) compared with subcutaneous adipose tissue (SAT). However, the relationship of SAT-specific cellular and molecular programs with VAT volume is poorly understood in PWH., Objective: We characterized SAT cell-type specific composition and transcriptional programs that are associated with greater VAT volume in PWH on contemporary ART., Methods: We enrolled PWH on long-term ART with a spectrum of metabolic health. Ninety-two participants underwent SAT biopsy for bulk RNA sequencing and 43 had single-cell RNA sequencing. Computed tomography quantified VAT volume and insulin resistance was calculated using HOMA2-IR., Results: VAT volume was associated with HOMA2-IR (p < 0.001). Higher proportions of SAT intermediate macrophages (IMs), myofibroblasts, and MYOC + fibroblasts were associated with greater VAT volume using partial Spearman's correlation adjusting for age, sex, and body mass index (ρ=0.34-0.49, p < 0.05 for all). Whole SAT transcriptomics showed PWH with greater VAT volume have increased expression of extracellular matrix (ECM)- and inflammation-associated genes, and reduced expression of lipolysis- and fatty acid metabolism-associated genes., Conclusions: In PWH, greater VAT volume is associated with higher proportion of SAT IMs and fibroblasts, and a SAT ECM and inflammatory transcriptome, which is similar to findings in HIV-negative persons with obesity. These data identify SAT cell-type specific changes associated with VAT volume in PWH that could underlie the high rates of cardiometabolic diseases in PWH, though additional longitudinal studies are needed to define directionality and mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Non-alcoholic fatty liver disease (NAFLD) is recognized as a prevalent determinant of cardiometabolic diseases. The association between NAFLD and obesity warrants further research on how NAFLD modifies associations between body mass index (BMI) and Waist circumference (WC) with cardiometabolic risk (CMR)., Objective: This study assessed whether NAFLD modifies associations between BMI and WC with 5-year changes in CMR in 2366 CARDIA study participants., Methods: Non-contrast CT was used to quantify liver attenuation, with ≤51 Hounsfield Units (HU) used to define NAFLD in the absence of secondary causes of excess liver fat. The dependent variable was the average Z score of fasting glucose, insulin, triglycerides [log], (-) high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure(SBP). Multivariable linear regression was used to estimate the associations between BMI and WC with CMR. Effect modification by NAFLD was assessed by an interaction term between NAFLD and BMI or WC., Results: The final sample had 539 (23%) NAFLD cases. NAFLD modified the association of BMI and WC with CMR (interaction p  < 0.0001 for both). BMI and WC were associated with CMR in participants without NAFLD ( p  < 0.001), but not among those with NAFLD. Participants with NAFLD and normal BMI and WC had CMR estimates that were higher than those without NAFLD in the obese categories. Among those without NAFLD the 5 years CMR change estimate was 0.09 (95% CI: 0.062, 0.125) for BMI ≥30 kg/m 2 compared to -0.06 (-0.092, -0.018) for BMI < 25 kg/m 2 , and among those with NAFLD, these estimates were 0.15 (0.108, 0.193) and 0.16 (-0.035, 0.363)., Conclusions: NAFLD modifies associations of BMI and WC with CMR. Compared with BMI and WC, NAFLD was more strongly associated with CMR. In the presence of NAFLD, BMI and WC were not associated with CMR. These findings have implications for clinical screening guidelines., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Objective: The gut microbiome has been associated with visceral fat (VAT) in European and Asian populations; however, associations with VAT and with ectopic fats among African-ancestry individuals are not known. Our objective was to investigate cross-sectional associations of fecal microbiota diversity and composition with VAT and ectopic fat, as well as body mass index (BMI), among middle-aged and older African Caribbean men., Methods: We included in our analysis n = 193 men (mean age = 62.2 ± 7.6 years; mean BMI = 28.3 ± 4.9 kg/m 2 ) from the Tobago Health Study. We assessed fecal microbiota using V4 16s rRNA gene sequencing. We evaluated multivariable-adjusted associations of microbiota features (alpha diversity, beta diversity, microbiota differential abundance) with BMI and with computed tomography-measured VAT and ectopic fats (pericardial and intermuscular fat; muscle and liver attenuation)., Results: Lower alpha diversity was associated with higher VAT and BMI, and somewhat with higher pericardial and liver fat. VAT, BMI, and pericardial fat each explained similar levels of variance in beta diversity. Gram-negative Prevotellaceae and Negativicutes microbiota showed positive associations, while gram-positive Ruminococcaceae microbiota showed inverse associations, with ectopic fats., Conclusions: Fecal microbiota features associated with measures of general adiposity also extend to metabolically pernicious VAT and ectopic fat accumulation in older African-ancestry men.

Background: We aim to determine the added value of carotid intima-media thickness (cIMT) in stroke risk assessment for hypertensive Black adults., Methods: We examined 1,647 participants with hypertension without a history of cardiovascular (CV) disease, from the Jackson Heart Study. Cox regression analysis estimated hazard ratios (HRs) for incident stroke per standard deviation increase in cIMT and quartiles while adjusting for baseline variables. We then evaluated the predictive capacity of cIMT when added to the pool cohort equations (PCEs)., Results: The mean age at baseline was 57 ± 10 years. Each standard deviation increase in cIMT (0.17 mm) was associated with approximately 30% higher risk of stroke (HR 1.27, 95% confidence interval: 1.08-1.49). Notably, cIMT proved valuable in identifying residual stroke risk among participants with well-controlled blood pressure, showing up to a 56% increase in the odds of stroke for each 0.17 mm increase in cIMT among those with systolic blood pressure <120 mm Hg. Additionally, the addition of cIMT to the PCE resulted in the reclassification of 58% of low to borderline risk participants with stroke to a higher-risk category and 28% without stroke to a lower-risk category, leading to a significant net reclassification improvement of 0.22 (0.10-0.30)., Conclusions: In this community-based cohort of middle-aged Black adults with hypertension and no history of CV disease at baseline, cIMT is significantly associated with incident stroke and enhances stroke risk stratification., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: South Asian individuals have high risk of atherosclerotic cardiovascular disease (ASCVD). Some investigators suggest smaller coronary artery size may be partially responsible., Methods: We compared the left anterior descending (LAD) artery cross-sectional area (CSA) (lumen and arterial wall) among South Asians in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study with White and Black participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, adjusting for BMI, height, and other ASCVD risk factors. We used thin-slice non-contrast cardiac computed tomography to measure LAD CSA. We used linear regression models to determine whether race/ethnicity was associated with LAD CSA after adjusting for demographic factors, BMI, height, coronary artery calcium (CAC), and traditional cardiovascular risk factors., Results: Our sample included 3,353 participants: 513 self-identified as South Asian (44.4% women), 1286 as Black (59.6% women), and 1554 as White (53.5% women). After adjusting for age, BMI, height, there was no difference in LAD CSA between South Asian men and women compared to White men and women, respectively. After full adjustment for CVD risk factors, LAD CSA values were: South Asian women (19.9 mm 2 , 95% CI [18.8 - 20.9]) and men (22.3 mm 2 , 95% CI [21.4 - 23.2]; White women (20.0 mm 2 , 95% CI [19.4-20.5]) and men (23.6 mm 2 , 95% CI [23.0-24.2]); and Black women (21.6 mm 2 , 95% CI [21.0 - 22.2]) and men (26.0 mm 2 , 95% CI [25.3 - 26.7]). Height, BMI, hypertension, CAC, and age were positively associated with LAD CSA; current and former cigarette use were inversely associated., Conclusions: South Asian men and women have similar LAD CSA to White men and women, and smaller LAD CSA compared to Black men and women, respectively, after accounting for differences in body size. Future studies should determine whether LAD CSA is associated with future ASCVD events., (© 2024. The Author(s).)

Background: GrimAge acceleration (GAA), an epigenetic marker that represents physiologic aging, is associated with age-related diseases including cancer and cardiovascular diseases. However, the associations between GAA and muscle mass and function are unknown., Methods: We estimated measures of GAA in 1 118 Black and White participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Study at exam years (Y) 15 (2000-2001) and 20 (2005-2006). Abdominal muscle composition was measured using CT scans at the Y25 (2010-2011) visit. We used multivariate regression models to examine associations of GAA estimates with muscle imaging measurements., Results: In the CARDIA study, each 1-year higher GAA was associated with an average 1.1% (95% confidence interval [CI]: 0.6%, 1.5%) higher intermuscular adipose tissue (IMAT) volume for abdominal muscles. Each 1-year higher GAA was associated with an average -0.089 Hounsfield unit (HU; 95% CI: -0.146, -0.032) lower lean muscle attenuation and an average -0.049 HU (95% CI: -0.092, -0.007) lower IMAT attenuation for abdominal muscles. Stratified analyses showed that GAA was more strongly associated with higher abdominal muscle IMAT volume in females and significantly associated with lower lean muscle attenuation for White participants only., Conclusions: Higher GAA is associated with higher abdominal muscle IMAT volume and lower lean muscle attenuation in a midlife population., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Frailty associates with worse outcomes after transcatheter aortic valve replacement (TAVR). Sarcopenia underlies frailty, but the association between a comprehensive assessment of sarcopenia-muscle mass, strength, and performance-and outcomes after TAVR has not been examined., Methods: From a multicenter prospective registry of patients with symptomatic severe aortic stenosis undergoing TAVR, 445 who had a preprocedure computed tomography and clinical assessment of frailty were included. Cross-sectional muscle (psoas and paraspinal) areas were measured on computed tomography and indexed to height. Gait speed and handgrip strength were obtained, and patients were dichotomized into fast versus slow; strong versus weak; and normal versus low muscle mass. As measures of body composition, cross-sectional fat (subcutaneous and visceral) was measured and indexed to height., Results: The frequency of patients who were slow, weak, and had low muscle mass was 56%, 59%, and 42%, respectively. Among the 3 components of sarcopenia, only slower gait speed (muscle performance) was independently associated with increased post-TAVR mortality (adjusted hazard ratio, 1.12 per 0.1 m/s decrease [95% CI, 1.04-1.21]; P =0.004; adjusted hazard ratio, 1.38 per 1 SD decrease [95% CI, 1.11-1.72]; P =0.004). Meeting multiple sarcopenia criteria was not associated with higher mortality risk than fewer. Lower indexed visceral fat area (adjusted hazard ratio, 1.48 per 1 SD decrease [95% CI, 1.15-1.89]; P =0.002) was associated with mortality but indexed subcutaneous fat was not. Death occurred in 169 (38%) patients., Conclusions: Among patients with symptomatic severe aortic stenosis and comprehensive sarcopenia and body composition phenotyping, gait speed was the only sarcopenia measure associated with post-TAVR mortality. Lower visceral fat was also associated with increased risk pointing to an obesity paradox also observed in other patient populations. These findings reinforce the clinical utility of gait speed as a measure of risk and a potential target for adjunctive interventions alongside TAVR to optimize clinical outcomes., Competing Interests: Disclosures Dr Fearon receives institutional research support from Edwards, Abbott, Boston Scientific, and Medtronic; Dr Elmariah has received research grants from Edwards Lifesciences, Medtronic, and Abbott and consulting fees from Edwards Lifesciences; Dr Gillam is an advisor to Philips and Edwards Lifesciences and directs an imaging core laboratory with contracts with Edwards Lifesciences, Medtronic, and Abbott (no direct compensation); Dr Zajarias is a consult at Edwards Lifescience; Dr Welt formerly sat on the Medtronic Advisory Board; Dr Coylewright received research funding from Edwards LifeSciences; Dr Piana serves on the data safety monitoring boards for Abbott Medical and Baim Cardiovascular Research Institute; Dr Gupta receives research support from Imara Inc; and Dr Lindman has served on the scientific advisory board for Roche Diagnostics and has received research grants from Edwards Lifesciences and Roche Diagnostics. The other authors report no conflicts

Background: Aging is associated with changes in body composition, and preventing loss of muscle mass and accumulation of excess adipose tissue in middle-aged adults may reduce age-related conditions at older ages. Dietary intake is one lifestyle factor shown to improve or maintain body composition. However, few studies have examined the Healthy Eating Index2015 (HEI2015), a measure of diet quality, and the association with body composition in adult men and women., Methods: Participant data (n = 3017) from the Coronary Artery Risk Development in Young Adults (CARDIA) study were used to examine the associations of the HEI2015 with body composition measures at Year 25 (Y25), including (1) 25 year-change in weight, body mass index (BMI), and waist circumference and (2) a computed tomography (CT) scan at Y25 measured muscle mass, muscle quality (better quality = less lipid within the muscle), and adipose tissue depots visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and adipose within skeletal muscle (intermuscular adipose tissue; IMAT). Dietary intake was assessed by a diet history three times over 20 years, at years 0, 7, and 20. HEI2015, averaged over three exams, was created and categorized into quintiles. Multiple regression analysis evaluated the associations of body composition stratified across quintiles of HEI2015 adjusted for demographic characteristics, energy intake, lifestyle factors, and baseline anthropometric measures as appropriate. Race-sex interaction was tested (P interaction  > 0.30)., Results: Over 25 years of follow-up, averaged HEI2015 was significantly and inversely associated with weight gain (Quintile 1 (Q1) 37.3 lb vs. 32.9 in Q5; P trend  = 0.01), change in BMI (Q1 5.8 kg/m 2 vs. 5.0 in Q5; P trend  = 0.005), and change in waist circumference (Q1 17.5 cm vs. 15.2 cm in Q5; P trend  < 0.001). By Y25, HEI2015 was inversely associated with VAT Q1 136.8 cm 3 vs. 116.6 in Q5; P trend  < 0.001) and IMAT volumes (Q1 9.52 vs. 8.12 cm 3 in Q5; P trend  < 0.001). Although total muscle volume declined (P trend  = 0.03), lean muscle mass volume was similar across quintiles (P trend  = 0.55). The IMAT/total muscle mass ratio declined across HEI2015 quintiles (P trend  < 0.001). Finally, higher HEI2015 was associated with better muscle quality at Y25 (higher value = less lipid within the muscle; Q1 41.1 vs. 42.2 HU in Q5; P trend  = 0.002). HEI2015 was nonlinearly, but inversely, associated with SAT (nonlinear P = 0.011)., Conclusions: Improving diet quality in young to middle-aged adults is a recommended strategy to promote better measures of body composition. Our study findings suggest that healthier food choices may influence body composition., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC ( ARSE and MMP16 ), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease., Competing Interests: Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Leslie S. Emery is now an employee of Celgene/Bristol Myers Squibb. Celgene/Bristol Myers Squibb had no role in the funding, design, conduct, or interpretation of this study. Nathan O. Stitziel has received research funding from Regeneron Pharmaceuticals, unrelated to this work. Karine A. Viaud-Martinez is an employee at Illumina Inc. Ryan W. Kim is an employee at Psomagen Inc. Roxona Mehran reports institutional research grants from Abbott Laboratories, Abiomed, Applied Therapeutics, AstraZeneca, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich; consultant fees from Abbott Laboratories, Boston Scientific, CardiaWave, Chiesi, Janssen Scientific Affairs, Medscape/WebMD, Medtelligence (Janssen Scientific Affairs), Roivant Sciences, Sanofi, Siemens Medical Solutions; consultant fees paid to the institution from Abbott Laboratories, Bristol-Myers Squibb; advisory board, funding paid to the institution from Spectranetics/Philips/Volcano Corp; consultant (spouse) from Abiomed, The Medicines Company, Merck; Equity <1% from Claret Medical, Elixir Medical; DSMB Membership fees paid to the institution from Watermark Research Partners; consulting (no fee) from Idorsia Pharmaceuticals Ltd., Regeneron Pharmaceuticals; Associate Editor for ACC, AMA. Rajeev Malhotra is a consultant for MyoKardia (now owned by BMS), Epizon Pharma, Renovacor, and Third Pole, a co-founder of Patch and Angea Biotherapeutics, and has received research funding from Angea Biotherapeutics, Bayer Pharmaceuticals, and Amgen. Adrienne M. Stilp receives funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. Pradeep Natarajan reports grants from Amgen, Apple, Boston Scientific, AstraZeneca, Allelica, Novartis, and Genentech, consulting income from GV, Blackstone Life Sciences, Foresite Labs, Apple, AstraZeneca, Allelica, Novartis, HeartFlow, and Genentech, is a scientific advisor to Esperion Therapeutics, Preciseli, and TenSixteen Bio, is a scientific co-founder of TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. Clint L. Miller received a research grant from AstraZeneca for an unrelated project. The remaining authors declare no competing interests.

Background: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D., Methods: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test., Results: Using a Bonferroni-corrected significance threshold of P <1.6×10 -4 , we identified 3 genes ( ATP1B1 , ARVCF , and LIPG ) associated with CAC and 2 genes ( ABCG8 and EIF2B2 ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both ATP1B1 and ARVCF also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis., Conclusions: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC., Competing Interests: Disclosures Dr Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Raffield is a consultant for the Trans-Omics for Precision Medicine (TOPMed) Administrative Coordinating Center (through WeStat). Dr Malhotra receives research funding from Aeglea BioTherapeutics and Amgen and serves as a consultant for Myokardia/Bristol Myers Squibb, Renovacor, Epizon Pharma, and Third Pole. The other authors report no conflicts.

Importance: Physical activity (PA) is recommended for preventing and treating nonalcoholic fatty liver disease (NAFLD). Yet, how long-term patterns of intensity-based physical activity, including moderate-intensity PA (MPA) and vigorous-intensity PA (VPA), might affect the prevalence of NAFLD in middle age remains unclear., Objective: To identify distinct intensity-based PA trajectories from young to middle adulthood and examine the associations between PA trajectories and NAFLD prevalence in midlife., Design, Setting, and Participants: This population-based cohort of 2833 participants used the Coronary Artery Risk Development in Young Adults study data. The setting included field clinics in Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California. Data analysis was completed in March 2023., Exposures: PA was self-reported at 8 examinations over 25 years (1985-1986 to 2010-2011) and separately scored for MPA and VPA., Main Outcomes and Measures: NAFLD was defined as liver attenuation values less than 51 Hounsfield units after exclusion of other causes of liver fat, measured using computed tomography in year 25 (2010-2011)., Results: Among a total of 2833 participants included in the sample, 1379 (48.7%) self-identified as Black, 1454 (51.3%) as White, 1206 (42.6%) as male, and 1627 (57.4%) as female from baseline (1985-1986) (mean [SD] age, 25.0 [3.6] years) to year 25 (2010-2011) (mean [SD] age, 50.1 [3.6] years). Three MPA trajectories were identified: very low stable (1514 participants [53.4%]), low increasing (1096 [38.7%]), and moderate increasing (223 [7.9%]); and 3 VPA trajectories: low stable (1649 [58.2%]), moderate decreasing (1015 [35.8%]), and high decreasing (169 [6.0%]). After adjustment for covariates (sex, age, race, study center, education, smoking status, and alcohol consumption), participants in the moderate decreasing (risk ratio [RR], 0.74; 95% CI, 0.54-0.85) and the high decreasing (RR, 0.59; 95% CI, 0.44-0.80) VPA trajectories had a lower risk of NAFLD in middle age, relative to participants in the low stable VPA trajectory. Adjustments for baseline body mass index and waist circumference attenuated these estimates, but the results remained statistically significant. The adjusted RRs across the MPA trajectories were close to null and not statistically significant., Conclusions and Relevance: This cohort study of Black and White participants found a reduced risk of NAFLD in middle age for individuals with higher levels of VPA throughout young to middle adulthood compared with those with lower VPA levels. These results suggest the need for promoting sustainable and equitable prevention programs focused on VPA over the life course to aid in lowering NAFLD risk.

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Artificial sweetener (ArtSw) intakes have been previously associated with higher BMI in observational studies and may promote visceral and skeletal muscle adipose tissue (AT) accumulation. This study aimed to determine whether habitual, long-term ArtSw or diet beverage intakes are related to greater AT depot volumes and anthropometry-related outcomes., Methods: A validated diet history questionnaire was administered at baseline, year 7, and year 20 examinations in 3088 men and women enrolled in the Coronary Artery Risk Development in Young Adults cohort (CARDIA), mean age of 25.2 years and mean BMI of 24.5 kg/m 2 at baseline. Volumes of visceral (VAT), intermuscular (IMAT), and subcutaneous adipose tissue (SAT) were assessed by computed tomography at year 25. Linear regression evaluated associations of aspartame, saccharin, sucralose, total ArtSw, and diet beverage intakes with AT volumes, anthropometric measures, and 25-year change in anthropometry. Cox regression estimated associations of ArtSw with obesity incidence. Adjustments were made for demographic and lifestyle factors, total energy intake, and the 2015 healthy eating index., Results: Total ArtSw, aspartame, saccharin, and diet beverage intakes were positively associated with VAT, SAT, and IMAT volumes (all p trend  ≤ 0.001), but no associations were observed for sucralose intake (all p trend  > 0.05). In addition, total ArtSw, saccharin, aspartame, and diet beverage intakes were associated with greater body mass index, body weight, waist circumference, and their increases over a 25-year period. Except for saccharin (p trend  = 0.13), ArtSw, including diet soda, was associated with greater risks of incident obesity over a median 17.5-year follow-up (all p trend  < 0.05)., Conclusions: Results suggest that long-term intakes of aspartame, saccharin, or diet soda may increase AT deposition and risk of incident obesity independent of diet quality or caloric intake. Coupled with previous evidence, alternatives to national recommendations to replace added sugar with ArtSw should be considered since both may have health consequences., (© 2023. The Author(s).)

Purpose: Hepatic steatosis (fatty liver disease) affects 25% of the world's population, particularly people with HIV (PWH). Pharmacoepidemiologic studies to identify medications associated with steatosis have not been conducted because methods to evaluate liver fat within digitized images have not been developed. We determined the accuracy of a deep learning algorithm (automatic liver attenuation region-of-interest-based measurement [ALARM]) to identify steatosis within clinically obtained noncontrast abdominal CT images compared to manual radiologist review and evaluated its performance by HIV status., Methods: We performed a cross-sectional study to evaluate the performance of ALARM within noncontrast abdominal CT images from a sample of patients with and without HIV in the US Veterans Health Administration. We evaluated the ability of ALARM to identify moderate-to-severe hepatic steatosis, defined by mean absolute liver attenuation <40 Hounsfield units (HU), compared to manual radiologist assessment., Results: Among 120 patients (51 PWH) who underwent noncontrast abdominal CT, moderate-to-severe hepatic steatosis was identified in 15 (12.5%) persons via ALARM and 12 (10%) by radiologist assessment. Percent agreement between ALARM and radiologist assessment of absolute liver attenuation <40 HU was 95.8%. Sensitivity, specificity, positive predictive value, and negative predictive value of ALARM were 91.7% (95%CI, 51.5%-99.8%), 96.3% (95%CI, 90.8%-99.0%), 73.3% (95%CI, 44.9%-92.2%), and 99.0% (95%CI, 94.8%-100%), respectively. No differences in performance were observed by HIV status., Conclusions: ALARM demonstrated excellent accuracy for moderate-to-severe hepatic steatosis regardless of HIV status. Application of ALARM to radiographic repositories could facilitate real-world studies to evaluate medications associated with steatosis and assess differences by HIV status., (© 2023 John Wiley & Sons Ltd.)

Introduction: Plasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease., Methods: We measured circulating 2-AAA using two methods in 1) a sample of 261 healthy individuals (2-AAA Study), and 2) in a sample of 134 persons comprising 110 individuals with treated HIV, with or without T2D, a population at high risk of metabolic disease and cardiovascular events despite suppression of circulating virus, and 24 individuals with T2D without HIV (HATIM Study). We examined associations between plasma 2-AAA and markers of cardiometabolic health within each cohort., Results and Discussion: We observed differences in 2-AAA by sex and race in both cohorts, with higher levels observed in men compared with women, and in Asian compared with Black or white individuals (P<0.05). There was no significant difference in 2-AAA by HIV status within individuals with T2D in the HATIM Study. We confirmed associations between 2-AAA and dyslipidemia in both cohorts, where high 2-AAA associated with low HDL cholesterol (P<0.001) and high triglycerides (P<0.05). As expected, within the cohort of people with HIV, 2-AAA was higher in the setting of T2D compared to pre-diabetes or normoglycemia (P<0.001). 2-AAA was positively associated with body mass index (BMI) in the 2-AAA Study, and with waist circumference and measures of visceral fat volume in HATIM (all P<0.05). Further, 2-AAA associated with increased liver fat in persons with HIV (P<0.001). Our study confirms 2-AAA as a marker of cardiometabolic risk in both healthy individuals and those at high cardiometabolic risk, reveals relationships with adiposity and hepatic steatosis, and highlights important differences by sex and race. Further studies are warranted to establish molecular mechanisms linking 2-AAA to disease in other high-risk populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Desine, Gabriel, Smith, Antonetti, Wang, Calcutt, Doran, Silver, Nair, Terry, Carr, Linton, Brown, Koethe and Ferguson.)

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) in U.S. adults is over 30%, yet the role of lifestyle factors in the etiology of NAFLD remains understudied. We examined the associations of physical activity, by intensity and type, and television viewing with prevalent NAFLD., Methods: Cross-sectional analysis of a population-based sample of 2726 Black (49%) and White (51%) adults (Mean (SD) age, 50 (3.6) years; 57.3% female) from the CARDIA study. Exposures were aerobic activity by intensity (moderate, vigorous; hours/week); activity type (aerobic, muscle-strengthening; hours/week); and television viewing (hours/week), examined concurrently in all models and assessed by validated questionnaires. Our outcome was NAFLD (liver attenuation < 51 Hounsfield Units), measured by non-contrast computed tomography, after exclusions for other causes of liver fat. Covariates were sex, age, race, study center, education, diet quality, smoking status, alcohol consumption, and body mass index or waist circumference., Results: 648 participants had NAFLD. In the fully adjusted modified Poisson regression model, the risk ratios per interquartile range of each exposure were moderate-intensity aerobic activity, 1.10 (95% CI, 0.97-1.26); vigorous-intensity aerobic activity, 0.72 (0.63-0.82); muscle-strengthening activity, 0.89 (0.80-1.01); and television viewing, 1.20 (1.10-1.32). Relative to less active participants with higher levels of television viewing, those who participated in ≥2 h/week of both vigorous-intensity aerobic and muscle-strengthening activity and <7 h/week of television viewing had 65% lower risk of NAFLD (risk ratio = 0.35, 95% CI = 0.23-0.51)., Conclusion: Adults who follow public health recommendations for vigorous-aerobic and muscle-strengthening activity, as well as minimize television viewing, are considerably less likely to have NAFLD than those who do not follow the recommendations and who have relatively high levels of television viewing.

Background An artificial intelligence (AI) algorithm has been developed for fully automated body composition assessment of lung cancer screening noncontrast low-dose CT of the chest (LDCT) scans, but the utility of these measurements in disease risk prediction models has not been assessed. Purpose To evaluate the added value of CT-based AI-derived body composition measurements in risk prediction of lung cancer incidence, lung cancer death, cardiovascular disease (CVD) death, and all-cause mortality in the National Lung Screening Trial (NLST). Materials and Methods In this secondary analysis of the NLST, body composition measurements, including area and attenuation attributes of skeletal muscle and subcutaneous adipose tissue, were derived from baseline LDCT examinations by using a previously developed AI algorithm. The added value of these measurements was assessed with sex- and cause-specific Cox proportional hazards models with and without the AI-derived body composition measurements for predicting lung cancer incidence, lung cancer death, CVD death, and all-cause mortality. Models were adjusted for confounding variables including age; body mass index; quantitative emphysema; coronary artery calcification; history of diabetes, heart disease, hypertension, and stroke; and other PLCO M2012 lung cancer risk factors. Goodness-of-fit improvements were assessed with the likelihood ratio test. Results Among 20 768 included participants (median age, 61 years [IQR, 57-65 years]; 12 317 men), 865 were diagnosed with lung cancer and 4180 died during follow-up. Including the AI-derived body composition measurements improved risk prediction for lung cancer death (male participants: χ 2 = 23.09, P < .001; female participants: χ 2 = 15.04, P = .002), CVD death (males: χ 2 = 69.94, P < .001; females: χ 2 = 16.60, P < .001), and all-cause mortality (males: χ 2 = 248.13, P < .001; females: χ 2 = 94.54, P < .001), but not for lung cancer incidence (male participants: χ 2 = 2.53, P = .11; female participants: χ 2 = 1.73, P = .19). Conclusion The body composition measurements automatically derived from baseline low-dose CT examinations added predictive value for lung cancer death, CVD death, and all-cause death, but not for lung cancer incidence in the NLST. Clinical trial registration no. NCT00047385 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Fintelmann in this issue.

Background and Aims: NAFLD strongly associates with cardiovascular disease (CVD) risk factors; however, the association between NAFLD and incident CVD, CVD-related mortality, incident cancer, and all-cause mortality is unclear., Approach and Results: We included 10,040 participants from the Framingham Heart Study, the Coronary Artery Risk Development in Young Adults Study, and the Multi-ethnic Study of Atherosclerosis to assess the longitudinal association between liver fat (defined on CT) and incident CVD, CVD-related mortality, incident cancer, and all-cause mortality. We performed multivariable-adjusted Cox regression models including age, sex, diabetes, systolic blood pressure, alcohol use, smoking, HDL, triglycerides, and body mass index at baseline or time-varying covariates. The average age was 51.3±3.3 years and 50.6% were women. Hepatic steatosis was associated with all-cause mortality after 12.7 years of mean follow-up when adjusting for baseline CVD risk factors, including body mass index (HR: 1.21, 1.04-1.40); however, the results were attenuated when utilizing time-varying covariates. The association between hepatic steatosis and incident CVD was not statistically significant after we accounted for body mass index in models considering baseline covariates or time-varying covariates. We observed no association between hepatic steatosis and CVD-related mortality or incident cancer., Conclusions: In this large, multicohort study of participants with CT-defined hepatic steatosis, accounting for change in CVD risk factors over time attenuated associations between liver fat and overall mortality or incident CVD. Our work highlights the need to consider concurrent cardiometabolic disease when determining associations between NAFLD and CVD and mortality outcomes., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Enlarged perivascular spaces (ePVS) are difficult to quantify, and their etiologies and consequences are poorly understood. Vanderbilt Memory and Aging Project participants (n = 327, 73 ± 7 years) completed 3T brain MRI to quantify ePVS volume and count, longitudinal neuropsychological assessment, and cardiac MRI to quantify aortic stiffness. Linear regressions related (1) PWV to ePVS burden and (2) ePVS burden to cross-sectional and longitudinal neuropsychological performance adjusting for key demographic and medical factors. Higher aortic stiffness related to greater basal ganglia ePVS volume (β = 7.0×10 -5 , p = 0.04). Higher baseline ePVS volume was associated with worse baseline information processing (β = -974, p = 0.003), executive function (β = -81.9, p < 0.001), and visuospatial performances (β = -192, p = 0.02) and worse longitudinal language (β = -54.9, p = 0.05), information processing (β = -147, p = 0.03), executive function (β = -10.9, p = 0.03), and episodic memory performances (β = -10.6, p = 0.02). Results were similar for ePVS count. Greater arterial stiffness relates to worse basal ganglia ePVS burden, suggesting cardiovascular aging as an etiology. ePVS burden is associated with adverse cognitive trajectory, emphasizing the clinical relevance of ePVS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: African Caribbeans have higher levels of myosteatosis than other populations; however, little is known about the impact of myosteatosis on physical function in African Caribbeans. Herein, we examined the association between regional myosteatosis of the calf, thigh, and abdomen versus physical function in 850 African-Ancestry men aged 64.2 ± 8.9 (range 50-95) living on the Caribbean Island of Tobago., Methods: Myosteatosis was measured using computed tomography and included intermuscular adipose tissue (IMAT) and muscle density levels of the thigh, calf, psoas, and paraspinous muscles. Outcomes included grip strength, time to complete 5 chair-rises, and 4-meter gait speed. Associations were quantified using separate linear models for each myosteatosis depot and were adjusted for age, height, demographics, physical activity, and chronic diseases. Beta coefficients were presented per standard deviation of each myosteatosis depot., Results: Higher thigh IMAT was the only IMAT depot significantly associated with weaker grip strength (β = -1.3 ± 0.43 kg, p = .003). However, lower muscle density of all 4 muscle groups was associated with weaker grip strength (all p < .05). Calf and thigh myosteatosis (IMAT and muscle density) were significantly associated with both worse chair rise time and gait speed (all p < .05), whereas psoas IMAT and paraspinous muscle density were associated with gait speed., Conclusion: Myosteatosis of the calf and thigh-but not the abdomen-were strongly associated with grip strength and performance measures of physical function in African Caribbean men. However, posterior abdominal myosteatosis may have some utility when abdominal images are all that are available., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Our long-range goal is to improve whole-heart CT calcium scores by extracting quantitative features from individual calcifications. Here, we perform deconvolution to improve bias/reproducibility of small calcification assessments, which can be degraded at the normal CT calcium score image resolution., Approach: We analyzed features of individual calcifications on repeated standard (2.5 mm) and thin (1.25 mm) slice scans from QRM-Cardio phantom, cadaver hearts, and CARDIA study participants. Preprocessing to improve the resolution involved of Lucy-Richardson deconvolution with a measured point spread function (PSF) or three-dimensional blind deconvolution in which the PSF was iteratively optimized on high detail structures such as calcifications in images., Results: Using QRM with inserts having known mg-calcium, we determined that both blind and conventional deconvolution improved mass measurements nearly equally well on standard images. Further, deconvolved thin images gave an excellent recovery of actual mass scores, suggesting that such processing could be our gold standard. For CARDIA images, blind deconvolution greatly improved results on standard slices. Bias across 33 calcifications (without, with deconvolution) was (23%, 9%), (18%, 1%), and ( - 19 % , - 1 % ) for Agatston, volume, and mass scores, respectively. Reproducibility was (0.13, 0.10), (0.12, 0.08), and (0.11, 0.06), respectively. Mass scores were more reproducible than Agatston scores or volume scores. For many other calcification features, blind deconvolution improved reproducibility in 21 out of 24 features. Cadaver images showed similar improvements in bias/reproducibility and slightly better results with a measured PSF., Conclusions: Deconvolution improves bias and reproducibility of multiple features extracted from individual calcifications in CT calcium score exams. Blind deconvolution is useful for improving feature assessments of coronary calcification in archived datasets., (© 2023 Society of Photo-Optical Instrumentation Engineers (SPIE).)

Objectives: We examined whether pericardial adipose tissue (PAT) is predictive of prediabetes and type 2 diabetes over time., Methods: In total, 2,570 adults without prediabetes/diabetes from the Coronary Artery Risk Development in Young Adults Study were followed up over 15 years. PAT volume was measured by computed tomography scans, and the new onset of prediabetes/diabetes was examined 5 years, 10 years, and 15 years after the PAT measurements. Multivariable Cox regression models were used to examine the association between the tertile of PAT and incident prediabetes/diabetes up to 15 years later. The predictive ability of PAT (vs. waist circumference [WC], body mass index [BMI], waist-to-height ratio [WHtR]) for prediabetes/diabetes was examined by comparing the area under the receiver operating characteristic curve (AUC)., Results: The highest tertile of PAT was associated with a 1.56 times (95% confidence interval [CI], 1.03 to 2.34) higher rate of diabetes than the lowest tertile; however, no association was found between the highest tertile of PAT and prediabetes in the fully adjusted models, including additional adjustment for BMI or WC. In the fully adjusted models, the AUCs of WC, BMI, WHtR, and PAT for predicting diabetes were not significantly different, whereas the AUC of WC for predicting prediabetes was higher than that of PAT., Conclusions: PAT may be a significant predictor of hyperglycemia, but this association might depend on the effect of BMI or WC. Additional work is warranted to examine whether novel adiposity indicators can suggest advanced and optimal information to supplement the established diagnosis for prediabetes/diabetes.

Background Persons with HIV have a higher prevalence of coronary artery disease compared with their HIV-negative counterparts. Earlier identification of subclinical atherosclerosis may provide a greater opportunity for cardiovascular disease risk reduction. We investigated coronary cross-sectional area (CorCSA) by noncontrasted computed tomography imaging as a noninvasive measure of arterial remodeling among virally suppressed persons with HIV. Methods and Results We assessed 105 persons with HIV with a spectrum of cardiometabolic health. All participants underwent computed tomography imaging to assess the mean corCSA of the proximal left anterior descending artery and 28 participants underwent additional coronary computed tomography angiography. Partial Spearman rank correlations adjusted for cardiovascular disease risk factors were used to assess relationships of corCSA with anthropometric measurements, HIV-related factors, and plasma cytokines. Mean corCSA measured by noncontrast computed tomography and coronary computed tomography angiography were strongly correlated (ρ=0.91, P <0.0001). Higher mean corCSA was present in those with coronary artery calcium ( P =0.005) and it correlated with participants' atherosclerotic cardiovascular disease risk score (ρ=0.35, P =0.01). After adjusting for established cardiovascular disease risk factors, we observed an inverse relationship between corCSA and CD4 + T-cell count (ρ=-0.2, P =0.047). Removal of age from the model strengthened the relationships between corCSA and antiretroviral therapy duration (from ρ=0.19, P =0.08 to ρ=0.3, P =0.01). CorCSA was also inversely correlated with plasma IL-10 (ρ=-0.25, P =0.03) but had no relationship with IL-6 (ρ=0.11, P =0.4) or IL-1β (ρ=0.08, P =0.5). Conclusions Positive coronary arterial remodeling, an imaging marker of subclinical atherosclerosis, is associated with a lower CD4 T-cell count, lower circulating IL-10, and possibly a longer antiretroviral therapy duration in persons with HIV. Registration Clinicaltrials.gov; Unique identifier: NCT04451980.

Objective: The aim of this study was to determine whether displacement of sedentary time with activity was cross-sectionally associated with less adiposity among Black Caribbean men in the Tobago Health Study., Methods: Objectively assessed activity was categorized as sedentary (< 1.5 metabolic equivalents; METs), light (≥ 1.5 to < 3.0 METs), or moderate-to-vigorous (≥ 3.0 METs) using the SenseWear Pro armband. Computed tomography scans of the chest, abdomen, liver, and thigh were used to assess subcutaneous and ectopic adipose tissue. The isotemporal substitution framework paired with linear regression was used to examine associations between activity and adiposity adjusting for age, height, total awake time, and multiple comparisons., Results: On average, participants (n = 271) were 63 years old with 11.2 h/d of sedentary behavior, 4.5 h/d of light activity, and 54 min/d of moderate-to-vigorous activity. Replacing sedentary time with light activity was cross-sectionally associated with lower volume and higher density of abdominal and thigh subcutaneous adiposity, visceral adiposity, abdominal and thigh intermuscular adiposity, and pericardial adiposity and higher liver attenuation (p values ≤ 0.0001)., Conclusions: Displacement of sedentary time with light activity was associated with less adiposity among this Black Caribbean cohort. Interventions focused on increasing light activity may be easier to maintain than higher intensity interventions and thus may be more successful at reducing adiposity., (© 2022 The Obesity Society.)

The field of artificial intelligence (AI) in medical imaging is undergoing explosive growth, and Radiology is a prime target for innovation. The American College of Radiology Data Science Institute has identified more than 240 specific use cases where AI could be used to improve clinical practice. In this context, thousands of potential methods are developed by research labs and industry innovators. Deploying AI tools within a clinical enterprise, even on limited retrospective evaluation, is complicated by security and privacy concerns. Thus, innovation must be weighed against the substantive resources required for local clinical evaluation. To reduce barriers to AI validation while maintaining rigorous security and privacy standards, we developed the AI Imaging Incubator. The AI Imaging Incubator serves as a DICOM storage destination within a clinical enterprise where images can be directed for novel research evaluation under Institutional Review Board approval. AI Imaging Incubator is controlled by a secure HIPAA-compliant front end and provides access to a menu of AI procedures captured within network-isolated containers. Results are served via a secure website that supports research and clinical data formats. Deployment of new AI approaches within this system is streamlined through a standardized application programming interface. This manuscript presents case studies of the AI Imaging Incubator applied to randomizing lung biopsies on chest CT, liver fat assessment on abdomen CT, and brain volumetry on head MRI., (© 2022. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Background: Longitudinal association of television (TV) viewing and moderate- to vigorous-intensity physical activity (MVPA) with pericardial adipose tissue (PAT) is unclear., Methods: We studied Coronary Artery Risk Development in Young Adults Study participants transitioning from early to middle age at Coronary Artery Risk Development in Young Adults (CARDIA) exam years 15 (2000-2001; N = 1975, mean age = 40.4, 55.4% women, 45.3% Black) and 25 (2010-2011). TV viewing (in hours per day) and MVPA (in exercise units) were measured using a self-report questionnaire. PAT volume (in milliliters) was measured using computed tomography. Multivariable linear regression was used to examine the associations of tertiles of 10-year change (years 25-15) in TV viewing and MVPA with a concurrent change in PAT with adjustments for covariates., Results: Participants in the highest tertile of 10-year increase in TV viewing had a greater increase in PAT (β = 2.96 mL, P < .01). Participants in both middle (β = -3.93 mL, P < .01) and highest (β = -6.22 mL, P < .01) tertiles of 10-year changes in MVPA had smaller mean increases in PAT over 10 years when compared with the lowest tertile in fully adjusted models., Conclusions: Reducing or maintaining early-midlife levels of TV viewing and increasing MVPA may be associated with less PAT accumulation with age.

Objective: To examine whether premenopausal reproductive age, as indicated by serum antimüllerian hormone (AMH), is associated with leukocyte aging biomarkers., Design: Prospective cohort analysis., Setting: The Coronary Artery Risk Development in Young Adults study, a population-based study of Black and White adults from four US communities (Birmingham, AL; Chicago, IL; Minneapolis, MN; Oakland, CA)., Patient(s): Premenopausal women with serum AMH measures at examination year 15 as well as leukocyte aging markers., Intervention(s): None., Main Outcome Measure(s): Telomere length, mitochondrial deoxyribonucleic acid (mtDNA) copy number, and intrinsic and extrinsic epigenetic age acceleration (EAA) at examination years 15, 20, and 25 as well as change between examination years., Result(s): Women were 40.2 (standard deviation, 3.7) years of age at examination year 15 when the AMH and initial measures of telomere length and mtDNA copy number (n = 386) were obtained and EAA occurred. After adjustment for chronological age, race, and smoking history, AMH quartile at examination year 15 was not associated with telomere length at examination years 15 and 25 or telomere length change between these years, mtDNA copy number at examination years 15 and 25 or change between these years, or intrinsic EAA at examination years 15 and 20 or change between these years. Women in the second AMH quartile had faster extrinsic EAA than women in the lowest AMH quartile (β-coefficient, 1.84; 95% confidence interval, 0.20-3.49)., Conclusion(s): In a population-based cohort, AMH did not have associations with leukocyte telomere length, mtDNA copy number, or intrinsic EAA., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Pericardial adipose tissue (PAT), an ectopic adipose depot surrounding the coronary arteries, is a pathogenic risk marker for cardiometabolic disease; however, the association between cardiorespiratory fitness (CRF) and PAT is unclear. Young adults (n = 2,614, mean age 25.1 years, 55.8% women, and 43.8% Black at baseline [1985 to 1986]) from the Coronary Artery Risk Development in Young Adults study were included. Maximal CRF was estimated at baseline, examination year 7 (1992 to 1993) and year 20 (2005 to 2006), using a symptom-limited maximal treadmill exercise test (duration in minutes) among those achieving ≥85% of age-predicted maximal heart rate. PAT volume (ml) was quantified at examination year 15 (2000 to 2001) and year 25 (2010 to 2011) using computed tomography. Multivariable linear and linear mixed regressions with covariates (sociodemographics, cardiovascular disease risk factors, inflammation, waist circumference) from baseline, year 7, and/or year 20 were used. Separate multivariable regression models revealed inverse associations of CRF at baseline, year 7, or year 20 with PAT at year 25 in fully adjusted models (all p <0.001). The linear mixed model showed that a 1-minute increase in treadmill exercise test duration over 20 years was associated with 1.49 ml lower subsequent PAT volume (p <0.001). In conclusion, findings suggest that higher CRF is inversely associated with subsequent PAT volume. Strategies to optimize CRF may be preventive against excessive PAT accumulation with age., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Extracellular small RNAs (sRNAs) are abundant in many biofluids, but little is known about their mechanisms of transport and stability in RNase-rich environments. We previously reported that high-density lipoproteins (HDLs) in mice were enriched with multiple classes of sRNAs derived from the endogenous transcriptome, but also from exogenous organisms. Here, we show that human HDL transports tRNA-derived sRNAs (tDRs) from host and nonhost species, the profiles of which were found to be altered in human atherosclerosis. We hypothesized that HDL binds to tDRs through apolipoprotein A-I (apoA-I) and that these interactions are conferred by RNA-specific features. We tested this using microscale thermophoresis and electrophoretic mobility shift assays and found that HDL binds to tDRs and other single-stranded sRNAs with strong affinity but did not bind to double-stranded RNA or DNA. Furthermore, we show that natural and synthetic RNA modifications influenced tDR binding to HDL. We demonstrate that reconstituted HDL bound to tDRs only in the presence of apoA-I, and purified apoA-I alone were able to bind sRNA. Conversely, phosphatidylcholine vesicles did not bind tDRs. In summary, we conclude that HDL binds to single-stranded sRNAs likely through nonionic interactions with apoA-I. These results highlight binding properties that likely enable extracellular RNA communication and provide a foundation for future studies to manipulate HDL-sRNA interactions for therapeutic approaches to prevent or treat disease., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Fat redistribution from subcutaneous adipose tissue (SAT) to the abdominal viscera, pericardium, liver, and skeletal muscle contributes to the rising burden of cardiometabolic disease among persons with HIV (PWH). Previous studies found SAT inflammation in PWH impairs lipid storage and persists despite plasma viral suppression on antiretroviral therapy (ART). In this study, we identified SAT immune-related genes associated with ectopic fat deposition in PWH on long-term ART., Design and Methods: A total of 92 PWH with well-controlled viremia underwent computed tomography imaging and abdominal SAT biopsy for gene expression analysis. SAT gene expression was measured using a NanoString panel of 255 immune-related genes. Associations between gene expression and computed tomography measurements of the volume and attenuation (radiodensity) of metabolically relevant ectopic fat depots were assessed using multivariable linear regression and network analysis., Results: Greater SAT volume was associated with higher visceral and pericardial adipose tissue volume, but lower skeletal muscle attenuation. Lower SAT attenuation, a measure of lipid content, was associated with lower visceral adipose tissue attenuation. Hierarchical clustering identified a subset of macrophage-related genes in SAT, including CCL2, CCL22, CCL13, CCR1, CD86, CD163, IL-6, IL-10, MRC1, and TREM2, which were associated with an increased lipid deposition in multiple ectopic depots., Conclusion: Altered expression of macrophage-related genes in SAT is associated with differences in ectopic fat depot morphometrics among PWH on long-term ART, including in the pericardial and visceral compartments. These findings provide basis for future studies to assess host, virus, and treatment factors shaping the SAT immune environment and its effects on morphometric changes and metabolic comorbidities in PWH., Competing Interests: J.R.K. has served as a consultant to Gilead Sciences, Merck, ViiV Healthcare, Janssen, and Theratechnologies and has received research support from Gilead Sciences and Merck. C.N.W. has served as a consultant to ViiV Healthcare. J.A.K. has served as a consultant for Boehringer Ingelheim, Janssen, and APIE Therapeutics, received grant support from Boehringer Ingelheim and Bristol-Meyers-Squibb, and other study support from Genentech. S.N., J.G.T., and J.J.C. receive grant support from Theratechnologies and IBM Watson. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-β, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure., Methods: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE -ε4 positive, LV mass index 51.4±8.1 g/m 2 , NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE -ε 4 . In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations., Results: Among all participants, LV mass index was unrelated to CSF biomarkers ( P >0.33). LV mass index interacted with MCI ( P =0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE -ε4 carriers ( P =0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage., Conclusions: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE -ε4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage.

The prevalence of nonalcoholic fatty liver disease is rapidly rising. We aimed to investigate associations of diet quality and dietary patterns with nonalcoholic fatty liver disease (NAFLD) in Black and White adults. We included 1726 participants who attended the Year 20 Exam of the Coronary Artery Risk Development in Young Adults (CARDIA) study and had their liver attenuation (LA) measured using computed tomography at Year 25 (2010-2011). NAFLD was defined as an LA of ≤51 Hounsfield units after the exclusion of other causes of liver fat. The a priori diet-quality score (APDQS) was used to assess diet quality, and dietary patterns were derived from principal components analysis. Univariate and multivariable logistic regression models were used to evaluate the association between the APDQS, dietary patterns, and NAFLD, and were adjusted for Year 20 covariates. NAFLD prevalence at Year 25 was 23.6%. In a model adjusted for age, race, sex, education, alcohol use, physical activity, smoking, and center at Year 25, the APDQS was inversely associated ( p = 0.004) and meat dietary pattern was positively associated ( p < 0.0001) with NAFLD, while the fruit-vegetable dietary pattern was not significantly associated ( p = 0.40). These associations remained significant when additionally adjusting for comorbidities (type 2 diabetes mellitus, dyslipidemia, hypertension), however, significant associations were diminished after additionally adjusting for body mass index (BMI). Overall, this study finds that the APDQS and meat dietary patterns are associated with prevalent NAFLD in mid-life. The associations appear to be partially mediated through higher BMI.

Background: Neighborhood-level racial residential segregation has been linked to several cardiovascular disease risk factors and outcomes in Black adults, but its impact on subclinical atherosclerosis remains unknown. In addition, although the impact of segregation on health may vary over the life course, most studies have examined segregation exposure at a single point in time. This article takes a life course approach by examining associations of exposure to neighborhood-level racial residential segregation in young adulthood and patterns of exposure from young adulthood to midlife with coronary artery calcification (CAC) incidence., Methods: We used data on 1125 Black CARDIA study (Coronary Artery Risk Development in Young Adults) participants free of CAC. Residential segregation was assessed using the G i * statistic and measured when participants were young adults (18-30 years old, in 1985-1986) and as the pattern from young adulthood to midlife (15 years later). Poisson regression with generalized estimating equations models was used to measure CAC incidence., Results: We found participants living in low segregation neighborhoods in young adulthood had 0.52 (rate ratio [95% CI: 0.28-0.98]) times lower risk of developing CAC compared with high segregation after adjusting for young adulthood sociodemographic characteristics and neighborhood poverty. Associations were attenuated and no longer statistically significant with adjustment for midlife CAC risk factors hypothesized to be on the causal pathway (rate ratio: 0.56 [95% CI: 0.29-1.09]). Findings for patterns of segregation over time suggest participants living in low segregation neighborhoods in young adulthood were less likely to develop CAC than those who started out in medium/high segregation neighborhoods, regardless of where they lived in midlife (rate ratio for increase from low to medium/high: 0.42 [95% CI: 0.19-0.95]; rate ratio for continuously low versus continuously medium/high segregation neighborhoods: 0.75 [95% CI: 0.31-1.83])., Conclusions: We found that participants living in more segregated neighborhoods in young adulthood were more likely to develop CAC due at least in part to differences in CAC risk factor burden accumulated over follow-up.