Long-term aspartame and saccharin intakes are related to greater volumes of visceral, intermuscular, and subcutaneous adipose tissue: the CARDIA study.

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/m2 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 ptrend ≤ 0.001), but no associations were observed for sucralose intake (all ptrend > 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 (ptrend = 0.13), ArtSw, including diet soda, was associated with greater risks of incident obesity over a median 17.5-year follow-up (all ptrend < 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.

Longer lactation duration is associated with decreased prevalence of non-alcoholic fatty liver disease in women.

BACKGROUND & AIMS: Lactation lowers blood glucose and triglycerides, and increases insulin sensitivity. We hypothesized that a longer duration of lactation would be associated with lower prevalence of non-alcoholic fatty liver disease (NAFLD), which is the leading cause of chronic liver disease in the United States. METHODS: Participants from the Coronary Artery Risk Development in Young Adults cohort study who delivered ≥ 1 child post-baseline (Y0: 1985-1986), and underwent CT quantification of hepatic steatosis 25 years following cohort entry (Y25: 2010-2011) were included (n = 844). The duration of lactation was summed for all post-baseline births, and NAFLD at Y25 was assessed by central review of CT images and defined by liver attenuation ≤ 40 Hounsfield Units after exclusion of other causes of hepatic steatosis. Unadjusted and multivariable logistic regression analyses were performed using an a priori set of confounding variables; age, race, education, and baseline body mass index. RESULTS: Of 844 women who delivered after baseline (48% black, 52% white, mean age 49 years at Y25 exam), 32% reported lactation duration of 0 to 1 month, 25% reported >1 to 6 months, 43% reported more than 6 months, while 54 (6%) had NAFLD. Longer lactation duration was inversely associated with NAFLD in unadjusted logistic regression. For women who reported >6 months lactation compared to those reporting 0-1 month, the odds ratio for NAFLD was 0.48 (95% CI 0.25-0.94; p = 0.03) and the association remained after adjustment for confounders (adjusted odds ratio 0.46; 95% CI 0.22-0.97; p = 0.04). CONCLUSIONS: A longer duration of lactation, particularly greater than 6 months, is associated with lower odds of NAFLD in mid-life and may represent a modifiable risk factor for NAFLD. LAY SUMMARY: A longer duration of breastfeeding has been associated with multiple potential health benefits for the mother including reduction in heart disease, diabetes and certain cancers. In this study we found that breastfeeding for longer than 6 months was associated with a lower risk of non-alcoholic fatty liver disease in mid-life.

Apolipoprotein L1 and Chronic Kidney Disease Risk in Young Potential Living Kidney Donors.

OBJECTIVE: The aim of this study was to develop a novel chronic kidney disease (CKD) risk prediction tool for young potential living kidney donors. SUMMARY OF BACKGROUND DATA: Living kidney donor selection practices have evolved from examining individual risk factors to a risk calculator incorporating multiple characteristics. Owing to limited long-term data and lack of genetic information, current risk tools lack precision among young potential living kidney donors, particularly African Americans (AAs). METHODS: We identified a cohort of young adults (18-30 years) with no absolute contraindication to kidney donation from the longitudinal cohort study Coronary Artery Risk Development in Young Adults. Risk associations for CKD (estimated glomerular filtration rate <60 mL/min/1.73 m) were identified and assigned weighted points to calculate risk scores. RESULTS: A total of 3438 healthy adults were identified [mean age 24.8 years; 48.3% AA; median follow-up 24.9 years (interquartile range: 24.5-25.2)]. For 18-year olds, 25-year projected CKD risk varied by ethnicity and sex even without baseline clinical and genetic abnormalities; risk was 0.30% for European American (EA) women, 0.52% for EA men, 0.52% for AA women, 0.90% for AA men. Among 18-year-old AAs with apolipoprotein L1 gene (APOL1) renal-risk variants without baseline abnormalities, 25-year risk significantly increased: 1.46% for women and 2.53% for men; among those with 2 APOL1 renal-risk variants and baseline abnormalities, 25-year risk was higher: 2.53% to 6.23% for women and 4.35% to 10.58% for men. CONCLUSIONS: Young AAs were at highest risk for CKD, and APOL1 renal-risk variants drove some of this risk. Understanding the genetic profile of young AA potential living kidney donors in the context of baseline health characteristics may help to inform candidate selection and counseling.

Body mass index trajectories in young adulthood predict non-alcoholic fatty liver disease in middle age: The CARDIA cohort study.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease is an epidemic. Identifying modifiable risk factors for non-alcoholic fatty liver disease development is essential to design effective prevention programmes. We tested whether 25-year patterns of body mass index change are associated with midlife non-alcoholic fatty liver disease. METHODS: In all, 4423 participants from Coronary Artery Risk Development in Young Adults, a prospective population-based biracial cohort (age 18-30), underwent body mass index measurement at baseline (1985-1986) and 3 or more times over 25 years. At Year 25, 3115 had liver fat assessed by non-contrast computed tomography. Non-alcoholic fatty liver disease was defined as liver attenuation ≤40 Hounsfield Units after exclusions. Latent mixture modelling identified 25-year trajectories in body mass index per cent change (%Δ) from baseline. RESULTS: We identified four distinct trajectories of BMI%Δ: stable (26.2% of cohort, 25-year BMI %Δ = 3.1%), moderate increase (46.0%, BMI%Δ = 21.7%), high increase (20.9%, BMI%Δ = 41.9%) and extreme increase (6.9%, BMI%Δ = 65.9%). Y25 non-alcoholic fatty liver disease prevalence was higher in groups with greater BMI %Δ: 4.1%, 9.3%, 13.0%, and 17.6%, respectively (P-trend <.0001). In multivariable analyses, participants with increasing BMI%Δ had increasingly greater odds of non-alcoholic fatty liver disease compared to the stable group: OR: 3.35 (95% CI: 2.07-5.42), 7.80 (4.60-13.23) and 12.68 (6.68-24.09) for moderate, high and extreme body mass index increase, respectively. Associations were only moderately attenuated when adjusted for baseline or Y25 body mass index. CONCLUSIONS: Trajectories of weight gain during young adulthood are associated with greater non-alcoholic fatty liver disease prevalence in midlife independent of metabolic covariates and baseline or concurrent body mass index highlighting the importance of weight maintenance throughout adulthood as a target for primary non-alcoholic fatty liver disease prevention.

Rapid decline in lung function is temporally associated with greater metabolically active adiposity in a longitudinal study of healthy adults.

RATIONALE: Adiposity is associated with low lung function, but the longitudinal relationship between lung function and adiposity is inadequately studied. OBJECTIVE: To examine the bidirectional longitudinal associations between rapid decline in lung function and adiposity phenotypes in healthy adults. METHODS: This secondary analysis used a 25-year longitudinal dataset from the Coronary Artery Risk Development in Young Adults (CARDIA) study that enrolled 5115 participants. MEASUREMENTS: In the first analysis, metabolic syndrome at or before CARDIA year (Y) 10 (Y10) was the predictor, and subsequent rapid decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1) between Y10 and Y20 was the outcome. In the second analysis, rapid decline was the predictor, and incident metabolic syndrome at Y20 and/or Y25 was the outcome. In the third analysis, rapid decline was the predictor, and subsequent CT-assessed regional fat depots at Y25 were the outcome. RESULTS: Metabolic syndrome at or before Y10 is temporally associated with rapid decline in FVC between Y10 and Y20 (adjusted p=0.04), but this association was explained by body mass index (BMI) at Y10. Rapid decline in FVC or FEV1 is temporally associated with greater incident metabolic syndrome at Y20 and/or Y25 (adjusted OR 2.10 (1.69, 2.61); p<0.001, and 1.56 (1.26, 1.94); p<0.001, respectively) and greater CT-assessed intrathoracic visceral adiposity at Y25 (adjusted standardised ß 0.09; p<0.001 for both analyses). These associations were not explained by BMI levels prior to the outcome measurement. CONCLUSIONS: Healthy adults with rapid decline in lung function are at risk for developing metabolic syndrome and for disproportionate accumulation of intrathoracic visceral fat. Metabolic abnormalities may be an early extrapulmonary manifestation of lung impairment that may be preventable by improving lung health.

Gestational Diabetes Mellitus Is Strongly Associated With Non-Alcoholic Fatty Liver Disease.

OBJECTIVES: Insulin resistance is central to the development of non-alcoholic fatty liver disease (NAFLD), and gestational diabetes mellitus (GDM) is an early marker of insulin resistance. We hypothesized that a history of GDM would identify women at higher risk of NAFLD in middle age. METHODS: Women from the multicenter Coronary Artery Risk Development in Young Adults (CARDIA) cohort study who delivered ≥1 birth, were free of diabetes prior to pregnancy(ies), and underwent CT quantification of hepatic steatosis 25 years following cohort entry (Y25: 2010-2011) were included (n=1,115). History of GDM by self-report, validated in a subsample by review of antenatal glucose testing, and metabolic risk factors were assessed prospectively. NAFLD was defined by liver attenuation (LA)≤40 Hounsfield Units on CT scan after exclusion of other causes of hepatic steatosis. RESULTS: Of 1,115 women meeting selection criteria (57% black, 43% white, median age 25 years at baseline), 124 (11%) reported a history of GDM and 75 (7%) met the CT definition for NAFLD at year 25. The crude risk of NAFLD at the 25-year visit was significantly higher in women with GDM compared to those without (14 vs. 5.8%, OR: 2.56, 95% CI: 1.44-4.55, P<0.01). History of GDM remained associated with NAFLD (OR: 2.29, 95% CI: 1.23-4.27, P=0.01) after adjustment for covariates in multivariable logistic regression. Addition of incident diabetes mellitus (DM) into the final model attenuated the association between GDM and NAFLD (OR: 1.48, 95% CI: 0.73-3.02, P=0.28). CONCLUSION: GDM is a risk marker for NAFLD and represents an opportunity to identify women at risk for NAFLD at a young age and may be mediated by the development of incident DM.

Mitral annular calcification as a predictor of stroke in the multiethnic study of atherosclerosis.

BACKGROUND: Mitral annular calcification (MAC) is associated with an increased risk for cardiovascular morbidity and mortality. This study provides recent data on the association between cardiac computed tomography (CT) derived MAC and 15 years of stroke risk in a racially diverse cohort. METHODS: All multiethnic studies of atherosclerosis participants ( n  = 6814) who completed a cardiac CT at baseline were included in this analysis. MAC score was calculated from cardiac CT using the Agatston and volume score methods. Multivariable Cox proportional hazard regression models were used to compute hazard ratios for the association between MAC and stroke after adjusting for traditional cardiovascular risk factors, inflammatory markers, coronary artery calcium score, atrial fibrillation, and left atrial size. RESULTS: Overall, 9% of participants (644/6814) had MAC at baseline. Over a surveillance period of 15 years, 304 strokes occurred, and 79% were ischemic strokes. After adjusting for age, sex, race/ethnicity, SBP, diabetes, smoking, fibrinogen, IL-6, high-sensitivity C-reactive protein, and coronary artery calcium score, baseline MAC was associated with increased risk for all strokes [hazard ratio 1.68; 95% confidence interval (CI) 1.22-2.30: P  = 0.0013]. When atrial fibrillation/flutter and left atrial size were included in the final multivariable model, MAC remained a predictor of all strokes (hazard ratio 1.93; 95% CI 1.22-3.05: P  < 0.0051) and ischemic stroke (hazard ratio 2.03; 95% CI 1.24-3.31: P  < 0.0046). CONCLUSION: MAC is an independent predictor of long-term stroke risk in a racially diverse population beyond conventional cardiovascular risk factors and atrial fibrillation.

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

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.

Ten-Year Changes in Television Viewing and Physical Activity Are Associated With Concurrent 10-Year Change in Pericardial Adiposity: The Coronary Artery Risk Development in Young Adults Study.

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 (ß = 2.96 mL, P < .01). Participants in both middle (ß = -3.93 mL, P < .01) and highest (ß = -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.

Relationship of Subcutaneous Adipose Tissue Inflammation-Related Gene Expression With Ectopic Lipid Deposition in Persons With HIV.

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.

Association of Abdominal Aorta Calcium and Coronary Artery Calcium with Incident Cardiovascular and Coronary Heart Disease Events in Black and White Middle-Aged People: The Coronary Artery Risk Development in Young Adults Study.

Background Assessing coronary artery calcium (CAC) is among AHA/ACC prevention guidelines for people at least 40 years old at intermediate risk for coronary heart disease (CHD). To study enhanced risk stratification, we investigated the predictive value of abdominal aorta calcium (AAC) relative to CAC for cardiovascular disease (CVD) and CHD events in Black and White early middle-aged participants, initially free of overt CVD. Methods and Results In the CARDIA (Coronary Artery Risk Development in Young Adults) study, a multi-center, community-based, longitudinal cohort study of CVD risk, the CAC and AAC scores were assessed in 3011 participants in 2010-2011 with follow-up until 2019 for incident CVD and CHD events. Distributions and predictions, overall and by race, were computed. During the 8-year follow-up, 106 incident CVD events (55 were CHD) occurred. AAC scores tended to be much higher than CAC scores. AAC scores were higher in Black women than in White women. CAC predicted CVD with HR 1.77 (1.52-2.06) and similarly for AAC, while only CAC predicted CHD. After adjustment for risk factors and calcium in the other arterial bed, the association of CAC with CVD was independent of risk factors and AAC, while the association of AAC with CVD was greatly attenuated. However, AAC predicted incident CVD when CAC was 0. Prediction did not vary by race. Conclusions AAC predicted CVD nearly as strongly as CAC and could be especially useful as a diagnostic tool when it is an incidental finding or when no CAC is found.

Prediction of Type II Diabetes Onset with Computed Tomography and Electronic Medical Records.

Type II diabetes mellitus (T2DM) is a significant public health concern with multiple known risk factors (e.g., body mass index (BMI), body fat distribution, glucose levels). Improved prediction or prognosis would enable earlier intervention before possibly irreversible damage has occurred. Meanwhile, abdominal computed tomography (CT) is a relatively common imaging technique. Herein, we explore secondary use of the CT imaging data to refine the risk profile of future diagnosis of T2DM. In this work, we delineate quantitative information and imaging slices of patient history to predict onset T2DM retrieved from ICD-9 codes at least one year in the future. Furthermore, we investigate the role of five different types of electronic medical records (EMR), specifically 1) demographics; 2) pancreas volume; 3) visceral/subcutaneous fat volumes in L2 region of interest; 4) abdominal body fat distribution and 5) glucose lab tests in prediction. Next, we build a deep neural network to predict onset T2DM with pancreas imaging slices. Finally, motivated by multi-modal machine learning, we construct a merged framework to combine CT imaging slices with EMR information to refine the prediction. We empirically demonstrate our proposed joint analysis involving images and EMR leads to 4.25% and 6.93% AUC increase in predicting T2DM compared with only using images or EMR. In this study, we used case-control dataset of 997 subjects with CT scans and contextual EMR scores. To the best of our knowledge, this is the first work to show the ability to prognose T2DM using the patients' contextual and imaging history. We believe this study has promising potential for heterogeneous data analysis and multi-modal medical applications.

Pulmonary Artery Acceleration Time in Young Adulthood and Cardiovascular Outcomes Later in Life: The Coronary Artery Risk Development in Young Adults Study.

BACKGROUND: Lower pulmonary artery acceleration time (PAcT) is correlated with higher pulmonary artery pressure. The aim of this study was to test the hypothesis that PAcT measured in young adulthood would be associated with future cardiovascular outcomes. METHODS: In the Coronary Artery Risk Development in Young Adults year 5 examination (1990-1991), PAcT was measured as the time interval from onset to peak flow velocity at the pulmonary valve annulus on Doppler echocardiography. The primary outcome was a composite of fatal or nonfatal cardiovascular disease events: myocardial infarction, non-myocardial infarction acute coronary syndrome, coronary revascularization, congestive heart failure, stroke, transient ischemic attack, carotid artery disease, and peripheral arterial disease. RESULTS: PAcT was obtained in 4,171 participants (mean age, 30 ± 4 years, 55% women, 51% white). PAcT groups obtained using linear spline methodology were as follows: group I, PAcT ≥ 196 msec (n = 122); group II, PAcT < 196 and ≥115 msec (n = 3,195); and group III, PAcT < 115 msec (n = 854). During follow-up (median, 24.9 years), the primary outcome occurred in 216 participants (5.2%); 66 of 854 (7.7%) of those with PAcT < 115 msec, 149 of 3,195 (4.7%) of those with intermediate PAcT level, and one of 122 (0.8%) of those with PAcT ≥ 196 msec. In a fully adjusted model, the lowest and intermediate PAcT groups had hazard ratios of 8.3 (95% CI, 1.1-62.1; P = .04) and 6.8 (95% CI, 0.9-50.5; P = .06), respectively, in comparison with the highest PAcT group. CONCLUSIONS: PAcT is useful for better identifying young adults at higher risk for cardiovascular events, who may benefit from a strict control of modifiable cardiovascular risk factors.

Coronary Artery Calcium From Early Adulthood to Middle Age and Left Ventricular Structure and Function.

Background The relationship of coronary artery calcium (CAC) with adverse cardiac remodeling is not well established. We aimed to study the association of CAC in middle age and change in CAC from early adulthood to middle age with left ventricular (LV) function. Methods CAC score was measured by computed tomography at CARDIA study (Coronary Artery Risk Development in Young Adults) year-15 examination and at year-25 examination (Y25) in 3043 and 3189 participants, respectively. CAC score was assessed as a continuous variable and log-transformed to account for nonlinearity. Change in CAC from year-15 examination to Y25 was evaluated as the absolute difference of log-transformed CAC from year-15 examination to Y25. LV structure and function were evaluated by echocardiography at Y25. Results At Y25, mean age was 50.1±3.6 years, 56.6% women, 52.4% black. In the multivariable analysis at Y25, higher CAC was related to higher LV mass (ß=1.218; adjusted P=0.007), higher LV end-diastolic volume (ß=0.811; adjusted P=0.007), higher LV end-systolic volume (ß=0.350; adjusted P=0.048), higher left atrial volume (ß=0.214; adjusted P=0.009), and higher E/e' ratio (ß=0.059; adjusted P=0.014). CAC was measured at both year-15 examination and Y25 in 2449 individuals. Higher change in CAC score during follow-up was independently related to higher LV mass index in blacks (ß=4.789; adjusted P<0.001), but not in whites (ß=1.051; adjusted P=0.283). Conclusions Higher CAC in middle age is associated with higher LV mass and volumes and worse LV diastolic function. Being free of CAC from young adulthood to middle age correlates to better LV function at middle age. Higher change in CAC score during follow-up is independently related to higher LV mass index in blacks.