Proteomics, Human Environmental Exposure, and Cardiometabolic Risk.

BACKGROUND: The biological mechanisms linking environmental exposures with cardiovascular disease pathobiology are incompletely understood. We sought to identify circulating proteomic signatures of environmental exposures and examine their associations with cardiometabolic and respiratory disease in observational cohort studies. METHODS: We tested the relations of >6500 circulating proteins with 29 environmental exposures across the built environment, green space, air pollution, temperature, and social vulnerability indicators in ≈3000 participants of the CARDIA study (Coronary Artery Risk Development in Young Adults) across 4 centers using penalized and ordinary linear regression. In >3500 participants from FHS (Framingham Heart Study) and JHS (Jackson Heart Study), we evaluated the prospective relations of proteomic signatures of the envirome with cardiovascular disease and mortality using Cox models. RESULTS: Proteomic signatures of the envirome identified novel/established cardiovascular disease-relevant pathways including DNA damage, fibrosis, inflammation, and mitochondrial function. The proteomic signatures of the envirome were broadly related to cardiometabolic disease and respiratory phenotypes (eg, body mass index, lipids, and left ventricular mass) in CARDIA, with replication in FHS/JHS. A proteomic signature of social vulnerability was associated with a composite of cardiovascular disease/mortality (1428 events; FHS: hazard ratio, 1.16 [95% CI, 1.08-1.24]; P=1.77×10-5; JHS: hazard ratio, 1.25 [95% CI, 1.13-1.38]; P=6.38×10-6; hazard ratioexpressed as per 1 SD increase in proteomic signature), robust to adjustment for known clinical risk factors. CONCLUSIONS: Environmental exposures are related to an inflammatory-metabolic proteome, which identifies individuals with cardiometabolic disease and respiratory phenotypes and outcomes. Future work examining the dynamic impact of the environment on human cardiometabolic health is warranted.

Associations of Fecal Microbiota with Ectopic Fat in African Caribbean Men.

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/m2) 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.

Epigenetic Aging Is Associated With Measures of Midlife Muscle Volume and Attenuation in CARDIA Study.

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.

Diet quality is associated with adipose tissue and muscle mass: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

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 (Pinteraction  > 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; Ptrend  = 0.01), change in BMI (Q1 5.8 kg/m2 vs. 5.0 in Q5; Ptrend  = 0.005), and change in waist circumference (Q1 17.5 cm vs. 15.2 cm in Q5; Ptrend  < 0.001). By Y25, HEI2015 was inversely associated with VAT Q1 136.8 cm3 vs. 116.6 in Q5; Ptrend  < 0.001) and IMAT volumes (Q1 9.52 vs. 8.12 cm3 in Q5; Ptrend  < 0.001). Although total muscle volume declined (Ptrend  = 0.03), lean muscle mass volume was similar across quintiles (Ptrend  = 0.55). The IMAT/total muscle mass ratio declined across HEI2015 quintiles (Ptrend  < 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; Ptrend  = 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.

Young Adult Physical Activity Trajectories and Midlife Nonalcoholic Fatty Liver Disease.

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.

Aerobic and Muscle-Strengthening Physical Activity, Television Viewing, and Nonalcoholic Fatty Liver Disease: The CARDIA Study.

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.

Association of alpha-aminoadipic acid with cardiometabolic risk factors in healthy and high-risk individuals.

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.

Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.

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.

Association of potato consumption with calcified atherosclerotic plaques in the coronary arteries: The NHLBI Family Heart Study.

BACKGROUND AND AIMS: While the association of potato consumption with risk factors for coronary artery disease has been inconsistent, no data are available in the literature on the influence of potato consumption on subclinical disease. Thus, we sought to examine whether baked/mashed potato consumption is associated with calcified atherosclerotic plaques in the coronary arteries. METHODS AND RESULTS: In a cross-sectional design, we studied 2208 participants of the NHLBI Family Heart Study. These subjects were selected based on their elevated cardiovascular disease risk compared to the general population. Potato consumption was assessed by a semi-quantitative food frequency questionnaire. We defined prevalent CAC using an Agatston score of at least 100 and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Mean age at initial clinic visit was 58.2 years and 55% were female. Median consumption of potatoes was 2-4/week. There was no statistically significant association between frequency of potato consumption and prevalent CAC: odds ratios (95% CI) for CAC were 1.0 (reference), 0.85 (0.56-1.30), 0.85 (0.58-1.26), and 0.95 (0.60-1.53) among subjects reporting potato consumption of <1/week, 1/week, 2-4/week, and 5+/week, respectively (p for linear trend 0.83), adjusting for age, sex, BMI, smoking, exercise, diabetes, hypertension, total calories, prevalent coronary heart disease, income, education, and daily red meat intake. CONCLUSIONS: We found no significant association between baked/mashed potato consumption and CAC in older adults. STUDY REGISTRATION NUMBER: NCT00005136. Study registration date: 5/25/2000.

Carriers of rare damaging CCR2 genetic variants are at lower risk of atherosclerotic disease.

Background: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease. Methods: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the CCR2 gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated. Results: A total of 45 predicted LoF or damaging missense variants were identified in the CCR2 gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent CCR2 damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (ORUKB: 0.62 95%CI: 0.39-0.96; ORexternal: 0.64 95%CI: 0.34-1.19; ORpooled: 0.64 95%CI: 0.450.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging CCR2 variants. Conclusions: Heterozygous carriers of damaging CCR2 variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

AI Body Composition in Lung Cancer Screening: Added Value Beyond Lung Cancer Detection.

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 PLCOM2012 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: χ2 = 23.09, P < .001; female participants: χ2 = 15.04, P = .002), CVD death (males: χ2 = 69.94, P < .001; females: χ2 = 16.60, P < .001), and all-cause mortality (males: χ2 = 248.13, P < .001; females: χ2 = 94.54, P < .001), but not for lung cancer incidence (male participants: χ2 = 2.53, P = .11; female participants: χ2 = 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.

Modeling the Environmental and Financial Impact of Multi-dose vs. Single-dose Iodinated Contrast Media Packaging and Delivery Systems.

RATIONALE AND OBJECTIVES: Iodinated contrast media (ICM) is used in computed tomography (CT) imaging to better visualize pathophysiology. ICM is commonly sold in "single-dose" bottles that require any unused volume to be discarded. Multi-dose bottles have been developed as an alternative packaging method. The objective of this study was to compare ICM waste, plastic waste, and the associated financial costs for both the single-dose and multi-dose ICM delivery systems. METHODS: Institutional data was used to estimate the average ICM administered per CT scan, average ICM wasted per CT scan, and the total ICM volume wasted annually. Waste estimates for the multi-dose bottles were generated by applying the average ICM administered per CT scan to the larger, multi-dose bottle volumes. Single-dose bottles, multi-dose bottles and injection syringes were weighed and used to calculate plastic waste generated by both packaging methods. Financial analysis was performed to compare the cost of supplies for single-dose and multi-dose ICM delivery systems. RESULTS: We found that 100 mL single-dose ICM bottles waste an average of 19.7 mL per CT scan, representing over 964 L of ICM wasted per year. The multi-dose ICM delivery system was projected to decrease pharmaceutical waste by at least 73% and reduce plastic waste by approximately 93%. We also estimate $494,000 in annual savings using the multi-dose ICM delivery method at our institution. CONCLUSION: Multi-dose ICM packaging can help conserve ICM, an important pharmaceutical that was only recently severely affected supply chain disruptions. The multi-dose delivery system can also reduce plastic waste and generate substantial financial savings to offset capital investment.

Improved bias and reproducibility of coronary artery calcification features using deconvolution.

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.

Enlarged perivascular space burden associations with arterial stiffness and cognition.

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 (ß = 7.0×10-5, p = 0.04). Higher baseline ePVS volume was associated with worse baseline information processing (ß = -974, p = 0.003), executive function (ß = -81.9, p < 0.001), and visuospatial performances (ß = -192, p = 0.02) and worse longitudinal language (ß = -54.9, p = 0.05), information processing (ß = -147, p = 0.03), executive function (ß = -10.9, p = 0.03), and episodic memory performances (ß = -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.

Mean Coronary Cross-Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV.

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-1ß (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.

Replacing sedentary time with light activity was associated with less adiposity across several depots in African ancestry men.

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.

Elucidation of physico-chemical principles of high-density lipoprotein-small RNA binding interactions.

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.

Workflow Integration of Research AI Tools into a Hospital Radiology Rapid Prototyping Environment.

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.

Cardiorespiratory Fitness in Adults Aged 18 to 34 Years and Long-Term Pericardial Adipose Tissue (from the Coronary Artery Risk Development in Young Adults Study).

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.