Corrigendum: APOE4 allele-specific associations between diet, multimodal biomarkers, and cognition among Puerto Rican adults in Massachusetts.

[This corrects the article DOI: 10.3389/fnagi.2023.1285333.].

APOE4 allele-specific associations between diet, multimodal biomarkers, and cognition among Puerto Rican adults in Massachusetts.

Background: Apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD), and the ε4 allele (APOE4) may interact with lifestyle factors that relate to brain structural changes, underlying the increased risk of AD. However, the exact role of APOE4 in mediating interactions between the peripheral circulatory system and the central nervous system, and how it may link to brain and cognitive aging requires further elucidation. In this analysis, we investigated the association between APOE4 carrier status and multimodal biomarkers (diet, blood markers, clinical diagnosis, brain structure, and cognition) in the context of gene-environment interactions. Methods: Participants were older adults from a longitudinal observational study, the Boston Puerto Rican Health Study (BPRHS), who self-identified as of Puerto Rican descent. Demographics, APOE genotype, diet, blood, and clinical data were collected at baseline and at approximately 12th year, with the addition of multimodal brain magnetic resonance imaging (MRI) (T1-weighted and diffusion) and cognitive testing acquired at 12-year. Measures were compared between APOE4 carriers and non-carriers, and associations between multimodal variables were examined using correlation and multivariate network analyses within each group. Results: A total of 156 BPRHS participants (mean age at imaging = 68 years, 77% female, mean follow-up 12.7 years) with complete multimodal data were included in the current analysis. APOE4 carriers (n = 43) showed reduced medial temporal lobe (MTL) white matter (WM) microstructural integrity and lower mini-mental state examination (MMSE) score than non-carriers (n = 113). This pattern was consistent with an independent sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) of n = 283 non-Hispanic White adults without dementia (mean age = 75, 40% female). Within BPRHS, carriers showed distinct connectivity patterns between multimodal biomarkers, characterized by stronger direct network connections between baseline diet/blood markers with 12-year blood/clinical measures, and between blood markers (especially lipids and cytokines) and WM. Cardiovascular burden (i.e., hypertension and diabetes status) was associated with WM integrity for both carriers and non-carriers. Conclusion: APOE4 carrier status affects interactions between dietary factors, multimodal blood biomarkers, and MTL WM integrity across ~12 years of follow-up, which may reflect increased peripheral-central systems crosstalk following blood-brain barrier breakdown in carriers.

Red meat consumption, incident CVD and the influence of dietary quality in the Jackson Heart Study.

OBJECTIVES: We investigated the prospective associations between meat consumption and CVD and whether these relationships differ by dietary quality among African American (AA) adults. DESIGN: Baseline diet was assessed with a regionally specific FFQ. Unprocessed red meat included beef and pork (120 g/serving); processed meat included sausage, luncheon meats and cured meat products (50 g/serving). Incident total CVD, CHD, stroke and heart failure were assessed annually over 9·8 years of follow-up. We characterised dietary quality using a modified Healthy Eating Index-2010 score (m-HEI), excluding meat contributions. SETTING: Jackson, MS, USA. PARTICIPANTS: AA adults (n 3242, aged 55 y, 66 % female). RESULTS: Mean total, unprocessed red and processed meat intakes were 5·7 ± 3·5, 2·3 ± 1·8 and 3·3 ± 2·7 servings/week, respectively. Mostly, null associations were observed between meat categories and CVD or subtypes. However, greater intake of unprocessed red meat (three servings/week) was associated with significantly elevated risk of stroke (hazard ratio = 1·43 (CI: 1·07,1·90)). With the exception of a more positive association between unprocessed meat consumption and stroke among individuals in m-HEI Tertile 2, the strength of associations between meat consumption categories and CVD outcomes did not differ by m-HEI tertile. In formal tests, m-HEI did not significantly modify meat-CVD associations. CONCLUSIONS: In this cohort of AA adults, total and processed meat were not associated with CVD outcomes, with the exception that unprocessed red meat was related to greater stroke risk. Dietary quality did not modfiy these associations. Research is needed in similar cohorts with longer follow-up and greater meat consumption to replicate these findings.

The Association of Stress, Metabolic Syndrome, and Systemic Inflammation With Neurocognitive Function in the Hispanic Community Health Study/Study of Latinos and Its Sociocultural Ancillary Study.

OBJECTIVES: Identifying sociocultural correlates of neurocognitive dysfunction among Hispanics/Latinos, and their underlying biological pathways, is crucial for understanding disparities in Alzheimer's disease and related dementias. We examined cross-sectional associations between stress and neurocognition, and the role that metabolic syndrome (MetS) and systemic inflammation might play in these associations. METHOD: Participants included 3,045 adults aged 45-75 (56% female, education 0-20+ years, 86% Spanish-speaking, 23% U.S.-born), enrolled in the Hispanic Community Health Study/Study of Latinos and its Sociocultural Ancillary Study. Global neurocognition was the primary outcome and operationalized as the average of the z scores of measures of learning and memory, word fluency, and processing speed. Stress measures included self-report assessments of stress appraisal (perceived and acculturative stress) and exposure to chronic and traumatic stressors. MetS was defined via established criteria including waist circumference, high blood pressure, elevated triglycerides, fasting plasma glucose, and high levels of high-density lipoprotein cholesterol. Systemic inflammation was represented by high-sensitivity C-reactive protein (hs-CRP). RESULTS: Separate survey multivariable linear regression models adjusting for covariates showed that higher perceived (b = -0.004, SE = 0.002, p < .05) and acculturative stress (b = -0.004, SE = 0.001, p < .0001) were significantly associated with worse global neurocognition, while lifetime exposure to traumatic stressors was associated with better global neurocognition (b = 0.034, SE = 0.009, p < .001). Neither MetS nor hs-CRP were notable pathways in the association between stress and neurocognition; rather, they were both independently associated with worse neurocognition in models including stress measures (ps < .05). DISCUSSION: These cross-sectional analyses suggest that stress appraisal, MetS, and systemic inflammation may be targets to reduce neurocognitive dysfunction among Hispanics/Latinos.

Associations between dietary fatty acid patterns and cognitive function in the Hispanic Community Health Study/Study of Latinos.

Our objective was to quantify the cross-sectional associations between dietary fatty acid (DFA) patterns and cognitive function among Hispanic/Latino adults. This study included data from 8,942 participants of the Hispanic Community Health Study/Study of Latinos, a population-based cohort study (weighted age 56.2 y and proportion female 55.2%). The NCI (National Cancer Institute) method was used to estimate dietary intake from two 24-hr recalls. We derived DFA patterns using principal components analysis with 26 fatty acid and total plant and animal monounsaturated fatty acid (MUFA) input variables. Global cognitive function was calculated as the average z-score of 4 neurocognitive tests. Survey linear regression models included multiple potential confounders such as age, sex, education, depressive symptoms, physical activity, energy intake, and cardiovascular disease. DFA patterns were characterized by consumption of long-chain saturated fatty acids (SFA), animal-based MUFA, and trans fatty acids (Factor 1); short to medium-chain SFA (Factor 2); very-long-chain omega-3 polyunsaturated fatty acids (PUFA) (Factor 3); very-long-chain SFA and plant-based MUFA and PUFA (Factor 4). Factor 2 was associated with greater scores for global cognitive function (ß=0.037 ± 0.012) and the Digit Symbol Substitution (DSS) (ß=0.56±0.17), Brief Spanish English Verbal Learning-Sum (B-SEVLT) (ß=0.23 ± 0.11), and B-SEVLT-Recall (ß=0.11 ± 0.05) tests (P<0.05 for all). Factors 1 (ß=0.04 ± 0.01) and 4 (ß=0.70 ± 0.18) were associated with the DSS test (P<0.05 for all). Consumption of short to medium-chain SFA may be associated with higher cognitive function among U.S.-residing Hispanic/Latino adults. Prospective studies are necessary to confirm these findings.

Circulating Plasma Metabolites and Cognitive Function in a Puerto Rican Cohort.

BACKGROUND: Minorities, including mainland Puerto Ricans, are impacted disproportionally by Alzheimer's disease (AD), dementia, and cognitive decline. Studying blood metabolomics in this population has the potential to probe the biological underpinnings of this health disparity. OBJECTIVE: We performed a comprehensive analysis of circulating plasma metabolites in relation to cognitive function in 736 participants from the Boston Puerto Rican Health Study (BPRHS) who underwent untargeted mass-spectrometry based metabolomics analysis and had undergone a battery of in-person cognitive testing at baseline. METHODS: After relevant exclusions, 621 metabolites were examined. We used multivariable regression, adjusted for age, sex, education, apolipoprotein E genotype, smoking, and Mediterranean dietary pattern, to identify metabolites related to global cognitive function in our cohort. LASSO machine learning was used in a complementary analysis to identify metabolites that could discriminate good from poor extremes of cognition. We also conducted sensitivity analyses: restricted to participants without diabetes, and to participants with good adherence to Mediterranean diet. RESULTS: Of 621 metabolites, FDR corrected (p < 0.05) multivariable linear regression identified 3 metabolites positively, and 10 negatively, associated with cognitive function in the BPRHS. In a combination of FDR-corrected linear regression, logistic regression regularized via LASSO, and sensitivity analyses restricted to participants without diabetes, and with good adherence to the Mediterranean diet, ß-cryptoxanthin plasma concentration was consistently associated with better cognitive function and N-acetylisoleucine and tyramine O-sulfate concentrations were consistently associated with worse cognitive function. CONCLUSION: This untargeted metabolomics study identified potential biomarkers for cognitive function in a cohort of Puerto Rican older adults.

Dietary Intake and Its Determinants Among Adults Living in the Metropolitan Area of Puerto Rico.

There is scarce information regarding the dietary intake of adults living in Puerto Rico (PR). We aimed to assess intake of nutrients and foods, adherence to recommended intake of nutrients and diet quality, and sociodemographic and lifestyle factors correlated with diet quality among adults in the San Juan metropolitan area of PR. Data were obtained from participants of the cross-sectional convenience-sample Puerto Rico Assessment of Diet, Lifestyle, and Diseases (n = 248; ages 30-75 years). Diet quality was defined using the Alternate Healthy Eating Index 2010 (AHEI; range 0-110 indicating lower-higher quality). Linear regression models were used to relate AHEI to sociodemographic and lifestyle factors. Most participants met the Estimated Average Requirement (EAR) for iron, folate, and vitamins B12 and B6; 61% met the EAR for magnesium and 56% for calcium. Only 4% met the EAR for vitamin D, and 7% met the adequate intake for potassium. The main contributors to total energy intake were sugary beverages (11.8%), sweets/desserts (10.2%), dairy (8.5%), mixed dishes (7.6%), starches (6.3%), fast foods (5.5%), and rice (4.9%). The mean (SD) AHEI score was 59.8 (11.0). The lowest AHEI components for which recommended servings were met were red/processed meats, fruit, sodium, sugary beverages, and polyunsaturated fats, and the highest were nuts/legumes, omega-3 fats, and whole grains. Significantly higher AHEI scores were noted for older adults, other ethnicities (vs. Puerto Rican), being single, having some college or higher education, and never/formerly smoking. Adults living in PR report healthy and unhealthy dietary intakes, providing an opportunity to improve diet at the population level.

The Mediterranean Diet and 2-Year Change in Cognitive Function by Status of Type 2 Diabetes and Glycemic Control.

OBJECTIVE: To determine associations of a Mediterranean diet score (MeDS) with 2-year change in cognitive function by type 2 diabetes and glycemic control status and contrast it against other diet quality scores. RESEARCH DESIGN AND METHODS: We used data from the longitudinal Boston Puerto Rican Health Study (n = 913; 42.6% with type 2 diabetes at 2 years). Glycemic control at baseline was categorized as uncontrolled (hemoglobin A1c ≥7% [53 mmol/mol]) versus controlled. Two-year change in glycemic control was defined as stable/improved versus poor/declined. We defined MeDS, Healthy Eating Index, Alternate Healthy Eating Index, and Dietary Approaches to Stop Hypertension scores. Adjusted mixed linear models assessed 2-year change in global cognitive function z score, executive and memory function, and nine individual cognitive tests. RESULTS: Higher MeDS, but no other diet quality score, was associated with higher 2-year change in global cognitive function in adults with type 2 diabetes (ß ± SE = 0.027 ± 0.011; P = 0.016) but not in those without (P = 0.80). Similar results were noted for Mini-Mental State Examination, word recognition, digit span, and clock drawing tests. Results remained consistent for individuals under glycemic control at baseline (0.062 ± 0.020; P = 0.004) and stable/improved over 2 years (0.053 ± 0.019; P = 0.007), but not for individuals with uncontrolled or poor/declined glycemic control. All diet quality scores were associated with higher 2-year memory function in adults without type 2 diabetes. CONCLUSIONS: Both adhering to a Mediterranean diet and effectively managing type 2 diabetes may support optimal cognitive function. Healthy diets, in general, can help improve memory function among adults without type 2 diabetes.

Prospective Associations of Erythrocyte Composition and Dietary Intake of n-3 and n-6 PUFA with Measures of Cognitive Function.

Polyunsaturated fatty acid (PUFA) consumption is recommended as part of a healthy diet, but evidence of the impact of individual species and biological concentrations on cognitive function is limited. We examined prospective associations of PUFA erythrocyte composition and dietary intake with measures of cognitive function among participants of the Boston Puerto Rican Health Study (aged 57 years). Erythrocyte and dietary PUFA composition were ascertained at baseline and associated with 2-year scores on the Mini-Mental State Exam (MMSE) (n = 1032) and cognitive domain patterns derived from a battery of tests (n = 865), as well as with incidence of cognitive impairment. Erythrocyte and dietary n-3 PUFA were not significantly associated with MMSE score. However, total erythrocyte and dietary n-3 very-long-chain fatty acids (VLCFA), and intake of individual species, were associated with better executive function (P-trend < 0.05, for all). There was evidence that greater erythrocyte n-6 eicosadienoic acid concentration was associated with lower MMSE and executive function scores (P-trend = 0.02). Only erythrocyte arachidonic acid (ARA) concentration predicted cognitive impairment (Odds Ratio = 1.26; P = 0.01). Among Puerto Rican adults, we found that n-3 VLCFA consumption may beneficially impact executive function. Further, these findings provide some evidence that n-6 metabolism favoring greater ARA tissue incorporation, but not necessarily dietary intake, could increase the risk of cognitive impairment.

The Mediterranean Diet Score Is More Strongly Associated with Favorable Cardiometabolic Risk Factors over 2 Years Than Other Diet Quality Indexes in Puerto Rican Adults.

Background: Multiple diet quality scores have been used to evaluate adherence to specific dietary recommendations or to consumption of healthful foods and nutrients. It remains unknown which score can more strongly predict longitudinal changes in cardiometabolic risk factors.Objective: We aimed to determine associations of 5 diet quality scores [AHA diet score (AHA-DS), Dietary Approaches to Stop Hypertension (DASH), Healthy Eating Index (HEI)-2005, Mediterranean diet score (MeDS), and Alternative Healthy Eating Index (AHEI)] with 2-y changes in cardiometabolic risk factors in adults 45-75 y old.Methods: Data from the Boston Puerto Rican Health Study were analyzed (n = 1194). Diet quality scores were calculated from a baseline-validated food-frequency questionnaire. Multivariable-adjusted, repeated-subjects, mixed-effects models, adjusted for baseline measures, estimated associations between each z score and 14 individual cardiometabolic factors measured at 2 y.Results: MeDS was significantly associated with lower 2-y waist circumference (ß coefficient ± SE: -0.52 ± 0.26, P = 0.048); body mass index (BMI; -0.23 ± 0.08, P = 0.005); log-insulin (-0.06 ± 0.02, P = 0.005); log-homeostasis model assessment of insulin resistance (HOMA-IR; -0.05 ± 0.02, P = 0.030), and log-C-reactive protein (-0.13 ± 0.03, P = 0.0002). Similar but weaker associations were observed for the AHEI with BMI, insulin, and HOMA-IR. The AHA-DS was inversely associated with BMI (-0.17 ± 0.08, P = 0.033). Neither the HEI-2005 nor DASH was significantly associated with any variable. Traditional Puerto Rican foods consumed by individuals with high MeDSs included vegetables and meats in homemade soups, orange juice, oatmeal, beans and legumes, fish, whole milk, corn oil, and beer.Conclusions: The MeDS comprises food components and scores associated with a favorable cardiometabolic profile over 2 y in Puerto Rican adults. An overall healthy diet may be particularly beneficial for maintaining a lower BMI. These results can help identify suitable measures of diet quality in epidemiologic studies and craft meaningful nutritional messages and dietary recommendations for the intended population. This study was registered at clinicaltrials.gov as NCT01231958.

Nutritional status and feeding practices in gastrointestinal surgery patients at Bach Mai Hospital, Hanoi, Vietnam.

BACKGROUND AND OBJECTIVES: The nutritional status and hospital feeding practices of surgical patients in Vietnam are not well documented. Based on a cross-sectional study at Bach Mai Hospital (BMH), the prevalence of malnutrition was found to be 33% in the surgical ward using a body mass index (BMI<18.5 kg/m(2). We conducted an observational study over a three month period to evaluate the feeding practices in the gastrointestinal (GI) surgery ward at Bach Mai Hospital (BMH) in Hanoi, Vietnam. METHODS AND STUDY DESIGN: Investigators from the U.S. and the Vietnamese National Institute of Nutrition (NIN) enrolled 72 subjects admitted for elective GI surgery in an observational study at BMH. Baseline anthropometrics and changes over time, body mass index (BMI), Subjective Global Assessment (SGA) and daily kcal and protein intake from oral diet, tube feeding, and parenteral nutrition (PN) from admission until discharge were documented. RESULTS: A total of 50% of subjects scored a B or C on the SGA; 48% of subjects had a BMI<18.5, while mean mid upper arm circumference was in the lownormal range (24±4 cm). Nearly all patients (98%) were given PN postoperatively, with oral feeding starting on an average of postoperative day 4. Only one patient was tube fed. Mean daily total calorie intake was 15 kcal/kg/day and protein intake was 0.61 g/kg/day during hospitalization. Micronutrient supplementation was minimal in subjects receiving PN. CONCLUSIONS: Hospital malnutrition in surgical patients in Vietnam is a significant problem, peri-operative feeding appears suboptimal and use of early postoperative PN was routine.

The Omega-3 Index Is Inversely Associated with Depressive Symptoms among Individuals with Elevated Oxidative Stress Biomarkers.

BACKGROUND: Omega-3 (n-3) fatty acid (FA) consumption is thought to improve depressive symptoms. However, current evidence is limited, and whether this association exists among Puerto Ricans, a population burdened by depression, remains uncertain. OBJECTIVES: We examined the association between ω-3 FA biomarkers and depressive symptoms as well as the potential influence of oxidative stress. METHODS: Baseline and longitudinal analyses were conducted in the Boston Puerto Rican Health Study (n= 787; participants aged 57 ± 0.52 y, 73% women). Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentration, a measure of oxidative stress, and erythrocyte FA composition were collected at baseline. We calculated the omega-3 index as the sum of eicosapentaenoic and docosahexaenoic acids, expressed as a percentage of total FAs. Baseline and 2-y depressive symptoms were characterized by using the Center for Epidemiological Studies-Depression Scale (CES-D). Statistical analyses included linear and logistic regression. RESULTS: Urinary 8-OHdG concentration tended to modify the relation between the erythrocyte omega-3 index and baseline CES-D score (P-interaction = 0.10). In stratified analyses, the omega-3 index was inversely associated with CES-D score (ß = -1.74, SE = 0.88;P= 0.02) among those in the top quartile of 8-OHdG concentration but not among those in the lower quartiles. The relation between the omega-3 index and CES-D at 2 y was more clearly modified by 8-OHdG concentration (P-interaction = 0.04), where the omega-3 index was inversely associated with CES-D at 2 y, adjusted for baseline (ß = -1.66, SE = 0.66;P= 0.02), only among those with elevated 8-OHdG concentrations. Among individuals not taking antidepressant medications and in the top tertile of urinary 8-OHdG concentration, the omega-3 index was associated with significantly lower odds of a CES-D score ≥16 at baseline (OR: 0.72; 95% CI: 0.53, 0.96) but not at 2 y (OR: 0.83; 95% CI: 0.60, 1.15). CONCLUSIONS: An inverse association between the omega-3 index and depressive symptoms was observed among participants with elevated oxidative stress biomarkers. These data suggest that oxidative stress status may identify those who might benefit from ω-3 FA consumption to improve depressive symptoms.

Associations of erythrocyte fatty acid patterns with insulin resistance.

BACKGROUND: Synergistic or additive effects or both on cardiometabolic risk may be missed by examining individual fatty acids (FAs). A pattern analysis may be a more useful approach. In addition, it remains unclear whether erythrocyte FA composition relates to insulin resistance among Hispanics/Latinos. OBJECTIVE: We derived erythrocyte FA patterns for a Puerto Rican cohort and examined their association with diet and insulin resistance in cross-sectional and prospective analyses. DESIGN: At baseline, principal components analysis was used to derive factor patterns with the use of 24 erythrocyte FAs from 1157 participants of the Boston Puerto Rican Health Study (aged 45-75 y). Dietary intake was assessed with a validated semiquantitative food-frequency questionnaire. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated at baseline and at the 2-y follow-up. Relations between FA patterns and HOMA-IR were analyzed in a sample of 922 participants with available data. RESULTS: Five FA patterns were derived, differentiated by 1) relatively high de novo lipogenesis (DNL) FAs and low n-6 (ω-6) FAs, 2) high very-long-chain saturated FAs, 3) high n-3 (ω-3) FAs, 4) high linoleic acid and low arachidonic acid, and 5) high trans FAs. The DNL pattern was positively correlated with sugar and inversely with n-6 and monounsaturated FA intakes. Only the DNL pattern was positively related to baseline HOMA-IR [adjusted geometric means (95% CIs) for quartiles 1 and 4: 1.72 (1.58, 1.87) and 2.20 (2.02, 2.39); P-trend < 0.0001]. Similar associations were observed at 2 y, after adjustment for baseline status [quartiles 1 and 4 means (95% CIs): 1.61 (1.48, 1.76) and 1.84 (1.69, 2.00); P-trend = 0.02]. These results remained consistent after the exclusion of participants with diabetes (n = 485). CONCLUSION: Our findings suggest that upregulated DNL associated with a diet high in sugar and relatively low in unsaturated FAs may adversely affect insulin sensitivity in a Hispanic/Latino cohort.

Sugar-sweetened beverage consumption and central and total adiposity in older children: a prospective study accounting for dietary reporting errors.

OBJECTIVE: To determine the prospective relationship between changes in sugar-sweetened beverage (SSB) intake and central adiposity in older children. DESIGN: Dietary intakes of children were obtained by 3 d food records at ages 10 and 13 years. Waist circumference (WC) and weight and height to determine BMI were measured at 10 and 13 years and total body fat mass (TBFM) at 13 years by dual-energy X-ray absorptiometry. Analyses were conducted using multivariable linear regression. Reporting errors were measured and participants were categorized as under-, plausible and over-reporters of dietary intakes. SETTING: Community-based British cohort of children participating in the Avon Longitudinal Study of Parents and Children. RESULTS: Among 2455 older children, increased SSB consumption from ages 10 to 13 years was associated with higher WC (standardized ß=0.020, P=0.19), BMI (ß=0.028, P=0.03) and TBFM (ß=0.017, P=0.20) at 13 years. Effects were strengthened among plausible dietary reporters (n 1059): WC (ß=0.097, P<0.001), BMI (ß=0.074, P<0.001) and TBFM (ß=0.065, P=0.003). The association between change in SSB and WC was weakened, but remained statistically significant after accounting for BMI (ß=0.042, P=0.02) and TBFM (ß=0.048, P=0.01). CONCLUSIONS: Higher consumption of SSB from ages 10 to 13 years was associated with a larger WC at age 13 years independent of differences in total adiposity. Accounting for dietary reporting errors strengthened associations. Our findings further support recommendations to limit intakes of SSB to reduce excess weight gain in children and suggest that SSB have an additional deleterious effect on central adiposity.

Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity.

BACKGROUND: Experimental studies suggest that visceral adiposity and adipose tissue dysfunction play a central role in obesity-related cardiometabolic complications. Impaired angiogenesis in fat has been implicated in the development of adipose tissue hypoxia, capillary rarefaction, inflammation, and metabolic dysregulation, but pathophysiological mechanisms remain unknown. In this study, we examined the role of a novel antiangiogenic isoform of vascular endothelial growth factor-A (VEGF-A), VEGF-A165b, in human obesity. METHODS AND RESULTS: We biopsied paired subcutaneous and visceral adipose tissue in 40 obese subjects (body mass index, 45±8 kg/m(2); age, 45±11 years) during bariatric surgery and characterized depot-specific adipose tissue angiogenic capacity using an established ex vivo assay. Visceral adipose tissue exhibited significantly blunted angiogenic growth compared with subcutaneous fat (P<0.001) that was associated with marked tissue upregulation of VEGF-A165b (P=0.004). The extent of VEGF-A165b expression correlated negatively with angiogenic growth (r=-0.6, P=0.006). Although recombinant VEGF-A165b significantly impaired angiogenesis, targeted inhibition of VEGF-A165b with neutralizing antibody stimulated fat pad neovascularization and restored VEGF receptor activation. Blood levels of VEGF-A165b were significantly higher in obese subjects compared with lean control subjects (P=0.02), and surgical weight loss induced a marked decline in serumVEGF-A165b (P=0.003). CONCLUSIONS: We demonstrate that impaired adipose tissue angiogenesis is associated with overexpression of a novel antiangiogenic factor, VEGF-A165b, that may play a pathogenic role in human adiposopathy. Moreover, systemic upregulation of VEGF-A165b in circulating blood may have wider-ranging implications beyond the adipose milieu. VEGF-A165b may represent a novel area of investigation to gain further understanding of mechanisms that modulate the cardiometabolic consequences of obesity.

The influence of pericardial fat upon left ventricular function in obese females: evidence of a site-specific effect.

BACKGROUND: Although increased volume of pericardial fat has been associated with decreased cardiac function, it is unclear whether this association is mediated by systemic overall obesity or direct regional fat interactions. We hypothesized that if local effects dominate, left ventricular (LV) function would be most strongly associated with pericardial fat that surrounds the left rather than the right ventricle (RV). METHODS: Female obese subjects (n = 60) had cardiovascular magnetic resonance (CMR) scans to obtain measures of LV function and pericardial fat volumes. LV function was obtained using the cine steady state free precession imaging in short axis orientation. The amount of pericardial fat was determined volumetrically by the cardiac gated T1 black blood imaging and normalized to body surface area. RESULTS: In this study cohort, LV fat correlated with several LV hemodynamic measurements including cardiac output (r = -0.41, p = 0.001) and stroke volume (r = -0.26, p = 0.05), as well as diastolic functional parameters including peak-early-filling rate (r = -0.38, p = 0.01), early late filling ratio (r = -0.34, p = 0.03), and time to peak-early-filling (r = 0.34, p = 0.03). These correlations remained significant even after adjusting for the body mass index and the blood pressure. However, similar correlations became weakened or even disappeared between RV fat and LV function. LV function was not correlated with systemic plasma factors, such as C-reactive protein (CRP), B-type natriuretic peptide (BNP), Interleukin-6 (IL-6), resistin and adiponectin (all p > 0.05). CONCLUSIONS: LV hemodynamic and diastolic function was associated more with LV fat as compared to RV or total pericardial fat, but not with systemic inflammatory markers or adipokines. The correlations between LV function and pericardial fat remained significant even after adjusting for systemic factors. These findings suggest a site-specific influence of pericardial fat on LV function, which could imply local secretion of molecules into the underlying tissue or an anatomic effect, both mechanisms meriting future evaluation.

Dairy intakes at age 10 years do not adversely affect risk of excess adiposity at 13 years.

Evidence of an association between milk intake and childhood adiposity remains inconsistent, with few data available regarding the effects of the amount of dairy fat consumed. This study examined the relation between dairy consumption (total, full, and reduced fat) at age 10 y on risk of excess adiposity at age 13 y in participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2455). Intakes were assessed by 3-d dietary records. Total body fat mass (TBFM) using dual-energy X-ray absorptiometry was examined at 13 y. Outcomes included excess TBFM (top quintile of TBFM), overweight, and change in body mass index (BMI). The highest vs. lowest quartile of total dairy consumers (g/d) at age 10 y did not have an increased risk of excess TBFM (OR: 0.73; 95% CI: 0.46, 1.16; P-trend = 0.28) or overweight (OR: 0.69; 95% CI: 0.41, 1.15; P = 0.24) at age 13 y. Children in the highest quartile of full-fat dairy intakes vs. those in the lowest quartile had a reduced risk of excess TBFM (OR: 0.64; 95% CI: 0.41, 1.00; P = 0.04) and a suggestion of a reduction in overweight (OR: 0.65; 95% CI: 0.40, 1.06; P = 0.19) at age 13 y. Furthermore, the highest vs. lowest consumers of full-fat products had smaller gains in BMI during follow-up [2.5 kg/m² (95% CI: 2.2, 2.7) vs. 2.8 kg/m² (95% CI: 2.5, 3.0); P < 0.01]. Associations with reduced-fat dairy consumption did not attain statistical significance. In this study, dairy consumption was not related to excess fat accumulation during late childhood. Estimates had wide confidence limits but generally showed inverse relations between dairy intakes and risk of excess adiposity. Additional prospective research is warranted to confirm the effects of dairy intake on obesity in children.

Insulin resistance: a key therapeutic target for cardiovascular risk reduction in obese patients?

The global obesity epidemic has emerged as one of the most important health care problems worldwide. Insulin resistance represents a prevalent pathophysiological abnormality that underlies mechanisms of cardiometabolic disease associated with obesity. Increasing basic, animal, and clinical data support a mechanistic link between insulin resistance and vascular dysfunction, and suggest that improving insulin sensitivity may represent a therapeutic target for combating atherosclerosis and cardiovascular disease. As clinical studies suggest that insulin resistance may play a key role in the cardiovascular benefit achieved with weight loss intervention, we will discuss our clinical perspective and provide evidence that obese individuals with hyperinsulinemia may derive the greatest improvement in vascular function with weight reduction. Lastly, we will address several important unanswered questions in the field that are likely to drive future clinical investigation.

Insulin status and vascular responses to weight loss in obesity.

OBJECTIVES: The aim of this study was to determine whether the effects of weight loss on arterial function are differentially modified by insulin status. BACKGROUND: Clinical studies suggest that plasma insulin levels may predict the extent of cardiovascular benefit achieved with weight loss in obese individuals, but mechanisms are currently unknown. METHODS: We prospectively followed 208 overweight or obese patients (body mass index [BMI] ≥25 kg/m(2)) receiving medical/dietary (48%) or bariatric surgical (52%) weight-loss treatment during a median period of 11.7 months (interquartile range: 4.6 to 13 months). We measured plasma metabolic parameters and vascular endothelial function using ultrasound at baseline and following weight-loss intervention and stratified analyses by median plasma insulin levels. RESULTS: Patients age 45 ± 1 years, with BMI 45 ± 9 kg/m(2), experienced 14 ± 14% weight loss during the study period. In individuals with higher baseline plasma insulin levels (above median >12 µIU/ml; n = 99), ≥10% weight loss (compared with <10%) significantly improved brachial artery macrovascular flow-mediated vasodilation and microvascular reactive hyperemia (p < 0.05 for all). By contrast, vascular function did not change significantly in the lower insulin group (≤12 µIU/ml; n = 109) despite a similar degree of weight loss. In analyses using a 5% weight loss cut point, only microvascular responses improved in the higher insulin group (p = 0.02). CONCLUSIONS: Insulin status is an important determinant of the positive effect of weight reduction on vascular function with hyperinsulinemic patients deriving the greatest benefit. Integrated improvement in both microvascular and macrovascular function was associated with ≥10% weight loss. Reversal of insulin resistance and endothelial dysfunction may represent key therapeutic targets for cardiovascular risk reduction in obesity.

Relationships between direct and indirect measures of central and total adiposity in children: what are we measuring?

OBJECTIVE: The relationship between central and total fat measured by anthropometry, dual energy X-ray absorptiometry, and magnetic resonance imaging (MRI) with each other and systolic blood pressure (SBP) was examined. DESIGN AND METHODS: Participants of the Avon Longitudinal Study of Parents and Children were examined at ages 9, 11, 13, and 15 years (n = 3,796-6,567). MRI was available on a subset of children at 11 (n = 156) and 13 (n = 95). RESULTS: Body mass index (BMI) and waist circumference (WC) were highly correlated (r = 0.84-0.91, across ages), and total body fat mass (TBFM) and trunk fat mass (TFM) were very strongly correlated (r ≥ 0.98). Among boys, BMI vs. WC explained a similar degree of variation in TBFM and TFM (41-71% vs. 43-76%, across age and overweight groups); in girls, BMI accounted for 62-73% variance and WC 47-69%. Adiposity measures were generally similarly correlated with SBP within age groups. Further, the relationship between intra-abdominal adipose tissue (IAAT) volume and adiposity measures did not vary greatly at 11 (0.65-0.67) and 13 (0.64-0.67). CONCLUSIONS: BMI and WC contain a large amount of overlapping information as evidenced by their high correlation and similarly sized associations with fat mass, SBP, and IAAT. This suggests that WC may be an inadequate marker of central adiposity during childhood.