Clinical improvement may not reflect metabolic homeostasis normalization in subjects with and without Roux-En-Y bariatric surgery after 12 years: comparison of surgical subjects to a lean cohort.

Background: A 12-year study comparing clinical outcomes following Roux-en-Y bariatric surgery showed long-term weight loss with remission/prevention of type-2-diabetes (T2D), hypertension and dyslipidemia. However, it is unknown whether the underlying homeostatic metabolic processes involving hepatokines, adipokines and myokines also normalize. Using this 12-year study, we determined whether metabolic indices improved in post-surgical (BMI:34.4kg/m2) versus non-surgical comparator-subjects-with-obesity (BMI:43.8kg/m2) at 12-year follow-up (both cohorts with baseline diabetes), and if post-surgical subjects normalized their metabolic processes to those of a normal-weight cohort without diabetes. Methods: Cross-sectional design. Plasma from a cohort of Roux-en-Y bariatric surgery (n=50) and non-surgery (n=76) comparator-subjects-with-obesity (both cohorts at 12-year follow-up) plus a normal-weight cohort (n=39) was assayed by Luminex immunoassay or ELISA for hepatokines [angiopoietin-like proteins-(ANGPTL3; ANGPTL4; ANGPTL6); fibroblast growth factors-(FGF19; FGF21; FGF23)]; adipokines [adipsin; adiponectin; FGF19] and myonectin. Results: After age and gender adjustment, surgery versus comparator-subjects-with-obesity had lower BMI (34.4 ± 1.0 vs 43.8 ± 0.9kg/m2; p<0.0001), HbA1c (6.2 ± 0.3 vs 7.7 ± 0.2%; p<0.0001), insulin resistance (HOMA-IR, 2.0 ± 1.5 vs 10.8 ± 1.4; p<0.0001) fat mass (45.6 ± 2.2 vs 60.0 ± 2.0; p<0.0001), HDL-C (55.4 ± 2.6 vs 42.6 ± 2.3mg/dL; p<0.0001), triglycerides (130 ± 14 vs 187 ± 12mg/dL; p<0.0001) and higher adiponectin (25.9 ± 2.3 vs 15.7 ± 2.0µg/ml; p<0.001); Adipsin, ANGPTL3, ANGPTL4, ANGPTL6, FGF19, FGF21, FGF23 and myonectin did not differ. Surgery versus normal-weight group: higher ANGPTL4 (156 ± 6 vs 119 ± 7ng/mL; p<0.0001), higher FGF23 (96.4 ± 10.1 vs 50.9 ± 11.5pg/mL; p=0.007) and lower myonectin (744 ± 55 vs 969 ± 66ng/mL; p=0.002); adiponectin, adipsin ANGPTL3, ANGPTL6, FGF19, FGF21 did not differ. Non-surgery comparator-subjects-with-obesity versus normal-weight group: higher adipsin (1859 ± 94 vs 1314 ± 133ng/mL; p=0.0001), higher FGF23 (84.6 ± 8.5 vs 50.9 ± 11.5pg/mL; p<0.0001) and higher ANGPTL4 (171 ± 5 vs 119 ± 7ng/mL; p<0.0001); adiponectin ANGPTL3, ANGPTL6, FGF19, FGF21 and myonectin did not differ. Conclusion: Bariatric surgery markedly improved anthropometric and metabolic features versus comparator-subjects-with-obesity at 12-year follow-up, indicating benefit of weight loss. However, despite weight loss, these patients still had class-1 obesity, as reflected in the adipokine, hepatokine and myokine markers of body homeostasis that did not completely normalize to indicative values of normal-weight subjects, suggesting either that this is the new normal for these patients or that weight loss to a BMI<25kg/m2 is needed for normalization of these parameters.

Long-term cancer outcomes after bariatric surgery.

OBJECTIVE: Obesity is associated with increased cancer risk. Because of the substantial and sustained weight loss following bariatric surgery, postsurgical patients are ideal to study the association of weight loss and cancer. METHODS: Retrospectively (1982-2019), 21,837 bariatric surgery patients (surgery, 1982-2018) were matched 1:1 by age, sex, and BMI with a nonsurgical comparison group. Procedures included gastric bypass, gastric banding, sleeve gastrectomy, and duodenal switch. Primary outcomes included cancer incidence and mortality, stratified by obesity- and non-obesity-related cancers, sex, cancer stage, and procedure. RESULTS: Bariatric surgery patients had a 25% lower risk of developing any cancers compared with a nonsurgical comparison group (hazard ratio [HR] 0.75; 95% CI 0.69-0.81; p < 0.001). Cancer incidence was lower among female (HR 0.67; 95% CI 0.62-0.74; p < 0.001) but not male surgery patients, with the HR lower for females than for males (p < 0.001). Female surgery patients had a 41% lower risk for obesity-related cancers (i.e., breast, ovarian, uterine, and colon) compared with nonsurgical females (HR 0.59; 95% CI 0.52-0.66; p < 0.001). Cancer mortality was significantly lower after surgery in females (HR 0.53; 95% CI 0.44-0.64; p < 0.001). CONCLUSIONS: Bariatric surgery was associated with lower all-cancer and obesity-related cancer incidence among female patients. Cancer mortality was significantly lower among females in the surgical group versus the nonsurgical group.

Long-term all-cause and cause-specific mortality for four bariatric surgery procedures.

OBJECTIVE: This retrospective study incorporated long-term mortality results after different bariatric surgery procedures and for multiple age at surgery groups. METHODS: Participants with bariatric surgery (surgery) and without (non-surgery) were matched (1:1) for age, sex, BMI, and surgery date with a driver license application/renewal date. Mortality rates were compared by Cox regression, stratified by sex, surgery type, and age at surgery. RESULTS: Participants included 21,837 matched surgery and non-surgery pairs. Follow-up was up to 40 years (mean [SD], 13.2 [9.5] years). All-cause mortality was 16% lower in surgery compared with non-surgery groups (hazard ratio, 0.84; 95% CI: 0.79-0.90; p < 0.001). Significantly lower mortality after bariatric surgery was observed for both females and males. Mortality after surgery versus non-surgery decreased significantly by 29%, 43%, and 72% for cardiovascular disease, cancer, and diabetes, respectively. The hazard ratio for suicide was 2.4 times higher in surgery compared with non-surgery participants (95% CI: 1.57-3.68; p < 0.001), primarily in participants with ages at surgery between 18 and 34 years. CONCLUSIONS: Reduced all-cause mortality was durable for multiple decades, for multiple bariatric surgical procedures, for females and males, and for greater than age 34 years at surgery. Rate of death from suicide was significantly higher in surgery versus non-surgery participants only in the youngest age at surgery participants.

Following Roux-en-Y gastric bypass surgery, serum ceramides demarcate patients that will fail to achieve normoglycemia and diabetes remission.

BACKGROUND: Obesity is a prevalent health threat and risk factor for type 2 diabetes. In this study, we evaluate the relationship between ceramides, which inhibit insulin secretion and sensitivity, and markers of glucose homeostasis and diabetes remission or recursion in patients who have undergone a Roux-en-Y gastric bypass (RYGB). METHODS: The Utah Obesity Study is a prospective cohort study, with targeted ceramide and dihydroceramide measurements performed on banked serum samples. The Utah Obesity Study consists of 1,156 participants in three groups: a RYGB surgery group, a non-surgery group denied insurance coverage, and severely obese population controls. Clinical examinations and ceramide assessments were performed at baseline and 2 and 12 years after RYGB surgery. FINDINGS: Surgery patients (84% female, 42.2 ± 10.6 years of age at baseline) displayed lower levels of several serum dihydroceramides and ceramides at 2 and 12 years after RYGB. By contrast, neither the control group (77% female, 48.7± 6.4 years of age at baseline) nor the non-surgery group (95% female, 43.0± 11.4 years of age at baseline) experienced significant decreases in any species. Using a linear mixed effect model, we found that multiple dihydroceramides and ceramides positively associated with the glycemic control measures HOMA-IR and HbA1c. In surgery group participants with prevalent diabetes, ceramides inversely predict diabetes remission, independent of changes in weight. CONCLUSIONS: Ceramide decreases may explain the insulin sensitization and diabetes resolution observed in most RYGB surgery patients. FUNDING: Funded by the National Institutes of health (NIH), The Juvenile Diabetes Research Foundation, and the American Heart Association.

Proteome-wide associations with short- and long-term weight loss and regain after Roux-en-Y gastric bypass surgery.

OBJECTIVE: Gastric bypass surgery results in long-term weight loss. Small studies have examined protein changes during rapid weight loss (up to 1 or 2 years post surgery). This study tested whether short-term changes were maintained after 12 years. METHODS: A 12-year follow-up, protein-wide association study of 1,297 SomaLogic aptamer-based plasma proteins compared short- (2-year) and long-term (12-year) protein changes in 234 individuals who had gastric bypass surgery with 144 nonintervened individuals with severe obesity. RESULTS: There were 51 replicated 12-year protein changes that differed between the surgery and nonsurgery groups. Adjusting for change in BMI, only 12 proteins remained significant, suggesting that BMI change was the primary reason for most protein changes and not non-BMI-related surgical effects. Protein changes were related to BMI changes during both weight-loss and weight-regain periods. The significant proteins were associated primarily with lipid, uric acid, or resting energy expenditure clinical variables and metabolic pathways. Eight protein changes were associated with 12-year diabetes remission, including apolipoprotein M, sex hormone binding globulin, and adiponectin (p < 3.5 × 10-5 ). CONCLUSIONS: This study showed that most short-term postsurgical changes in proteins were maintained at 12 years. Systemic protection pathways, including inflammation, complement, lipid, and adipocyte pathways, were related to the long-term benefits of gastric bypass surgery.

Sugar-Sweetened Beverage Consumption and Calcified Atherosclerotic Plaques in the Coronary Arteries: The NHLBI Family Heart Study.

BACKGROUND: Sugar-sweetened beverage (SSB) intake is associated with higher risk of weight gain, diabetes, hypertension, cardiovascular disease, and cardiovascular mortality. However, the association of SSB with subclinical atherosclerosis in the general population is unknown. OBJECTIVE: Our primary objective was to investigate the association between SSB intake and prevalence of atherosclerotic plaque in the coronary arteries in The National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. METHODS: We studied 1991 participants of the NHLBI Family Heart Study without known coronary heart disease. Intake of SSB was assessed through a semi-quantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac Computed Tomography (CT) and prevalent CAC was defined as an Agatston score ≥100. We used generalized estimating equations to calculate adjusted prevalence ratios of CAC. A sensitivity analysis was also performed at different ranges of cut points for CAC. RESULTS: Mean age and body mass index (BMI) were 55.0 years and 29.5 kg/m2, respectively, and 60% were female. In analysis adjusted for age, sex, BMI, smoking, alcohol use, physical activity, energy intake, and field center, higher SSB consumption was not associated with higher prevalence of CAC [prevalence ratio (95% confidence interval) of: 1.0 (reference), 1.36 (0.70-2.63), 1.69 (0.93-3.09), 1.21 (0.69-2.12), 1.05 (0.60-1.84), and 1.58 (0.85-2.94) for SSB consumption of almost never, 1-3/month, 1/week, 2-6/week, 1/day, and ≥2/day, respectively (p for linear trend 0.32)]. In a sensitivity analysis, there was no evidence of association between SSB and prevalent CAC when different CAC cut points of 0, 50, 150, 200, and 300 were used. CONCLUSIONS: These data do not provide evidence for an association between SSB consumption and prevalent CAC in adult men and women.

Characterizing a Common CERS2 Polymorphism in a Mouse Model of Metabolic Disease and in Subjects from the Utah CAD Study.

CONTEXT: Genome-wide association studies have identified associations between a common single nucleotide polymorphism (SNP; rs267738) in CERS2, a gene that encodes a (dihydro)ceramide synthase that is involved in the biosynthesis of very-long-chain sphingolipids (eg, C20-C26) and indices of metabolic dysfunction (eg, impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved. OBJECTIVE: The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes. DESIGN: We performed in-depth lipidomic and metabolic characterization of a novel CRISPR knock-in mouse modeling the rs267738 variant. In parallel, we conducted mass spectrometry-based, targeted lipidomics on 567 serum samples collected through the Utah Coronary Artery Disease study, which included 185 patients harboring 1 (n = 163) or both (n = 22) rs267738 alleles. RESULTS: In-silico analysis of the amino acid substitution within CERS2 caused by the rs267738 mutation suggested that rs267738 is deleterious for enzyme function. Homozygous knock-in mice had reduced liver CERS2 activity and enhanced diet-induced glucose intolerance and hepatic steatosis. However, human serum sphingolipids and a ceramide-based cardiac event risk test 1 score of cardiovascular disease were not significantly affected by rs267738 allele count. CONCLUSIONS: The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study.

Associations of Visceral, Subcutaneous, Epicardial, and Liver Fat with Metabolic Disorders up to 14 Years After Weight Loss Surgery.

Background: Bariatric surgery leads to long-term remission and reduced incidence of diabetes, hypertension, and dyslipidemia. Short-term studies suggest reduction in specific fat depots may be more predictive of health improvement than reduced body mass index (BMI). Visceral, subcutaneous, epicardial, and liver fat, measured 11 years after bariatric surgery, were associated with long-term remission and incidence of diabetes, dyslipidemia, and hypertension. Methods: Fat depots an average of 11 (maximum 14) years after surgery were quantified by noncontrast computed tomography in subjects who did (N = 261; 86% gastric bypass) or did not (N = 243) have bariatric surgery. Multiple regression related fat depots to disease endpoints with and without adjustment for change in BMI and surgical status. Results: Visceral fat was 42% lower, subcutaneous fat 20% lower, epicardial fat 30% lower, and liver-to-spleen density ratio 9% higher at follow-up in the bariatric surgery group compared with the nonsurgery group (all P < 0.01). Higher visceral fat at follow-up exam was significantly associated with reduced remission and increased incidence of diabetes, hypertension, and dyslipidemia. Subcutaneous fat was not associated with disease. The liver-to-spleen ratio was associated with the remission and incidence of hypertriglyceridemia and not with other fat depots. Epicardial fat was related to incidence of elevated low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol. Conclusions: Whether or not a patient shows greater long-term diabetes, dyslipidemia, or hypertension remission or incidence after bariatric surgery appears dependent on the amount of fat within specific fat depots measured at follow-up. Furthermore, associations of the three disease endpoints with different fat depots suggest varied fat depot pathology.

Mediators of suicidality 12 years after bariatric surgery relative to a nonsurgery comparison group.

BACKGROUND: Individuals undergoing bariatric surgery report higher levels of suicidality than the general population, but it is unknown what mediates this phenomenon or how this compares with individuals with severe obesity not receiving surgery. OBJECTIVES: We evaluated suicidality in 131 individuals 12 years post surgery compared with 205 individuals with severe obesity who did not undergo surgery. Changes in health-related quality of life (HRQOL) and metabolic health were assessed as mediators of suicidality. SETTING: University. METHODS: Suicidality was assessed with the Suicide Behaviors Questionnaire-Revised at 12 years. Metabolic health and HRQOL (Short Form-36 [SF-36] Mental Component Summary score, Physical Component Summary score, and Impact of Weight on Quality of Life-Lite) were assessed at baseline and 2 and 6 years. The effects of bariatric surgery on suicidality at 12 years were assessed through univariate and multivariate sequential moderated mediation models, with changes in metabolic health and HRQOL from 0-2 years and 2-6 years as mediators. RESULTS: Suicidality was higher in the surgery group versus the nonsurgery group (estimate [est.] = .708, SE = .292, P < .05). Only the indirect pathways at 2 years after surgery for SF-36 Mental Component Summary in the univariate models (est. = -.172, SE = .080, P < .05) and for SF-36 Physical Component Summary in the multivariate model (est. = .593, SE = .281, P < .05) were significant. CONCLUSION: Individuals undergoing bariatric surgery reported higher levels of suicidality at 12 years, which was mediated by less improvement in the mental and physical components of HRQOL in the first 2 years after surgery, suggesting the need for additional clinical monitoring.

Genetics and geography of leukocyte telomere length in sub-Saharan Africans.

Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL measured in 1295 sub-Saharan Africans (SSAs) with 559 African-Americans (AAms) and 2464 European-Americans (EAms). LTL differed significantly across SSAs (P = 0.003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms [P = 6.5(e-16)] whose LTL was significantly longer than EAms [P = 2.5(e-7)]. Genetic variation in SSAs explained 52% of LTL variance versus 27% in AAms and 34% in EAms. Adjustment for genetic variation removed the LTL differences among SSAs. LTL genetic variation among SSAs, with the longest LTL in the San, supports the hypothesis that longer LTL was ancestral in humans. Identifying factors driving LTL variation in Africa may have important ramifications for LTL-associated diseases.

Longitudinal Changes in Cardiac Structure and Function in Severe Obesity: 11-Year Follow-Up in the Utah Obesity Study.

Background Progressive cardiac remodeling and worsening myocardial function over time have been proposed as potential mediators of heart failure in obesity. Methods and Results We serially assessed cardiac structure and function in 254 subjects participating in a longitudinal study of obesity. Demographic, clinical, laboratory, and echocardiographic features were determined at baseline and 2-, 6-, and 11-year follow-up. We measured body mass index (BMI) exposure as the area under the curve of the BMI at each of the 4 visits. At enrollment, mean age of the subjects was 47 years, 79% were women, mean BMI was 44 kg/m2, 26% had diabetes mellitus, 48% had hypertension, and 53% had hyperlipidemia. Between baseline and 11 years, BMI increased by 1.1 and 0.3 kg/m2 in men and women, respectively. There were modest increases in left ventricular (LV) end-diastolic volume, LV mass, and left atrial volume, and significant decreases in early/late mitral diastolic flow velocity ratio and E wave deceleration time. However, there were no significant changes in LV ejection fraction or ratio of early mitral diastolic flow velocity/early mitral annular velocity, whereas right ventricular fractional area change increased. Significant predictors of the change in LV mass were male sex, baseline BMI, BMI area under the curve, and change in LV stroke volume, but not smoking, hypertension, or diabetes mellitus. Conclusions In long-standing, persistent severe obesity, there was evidence of cardiac remodeling over a period of 11 years, but no clear worsening of systolic or diastolic function. Measures of remodeling were most strongly related to BMI. The observed changes might predispose to heart failure with preserved ejection fraction, but are not classic for an evolving dilated cardiomyopathy.

Gut microbiota differs a decade after bariatric surgery relative to a nonsurgical comparison group.

BACKGROUND: Few studies have assessed differences in the gut microbiota composition after bariatric surgery in the long term or whether differences are correlated with remission of type 2 diabetes. OBJECTIVES: This observational study assessed differences in the gut microbiota between individuals at up to 13 years after surgery and a comparison group of individuals with severe obesity. The relationship between type 2 diabetes remission and the gut microbiota was also assessed. SETTING: University. METHODS: Stool samples were collected from individuals completing bariatric surgery (surgery group; n = 16) and individuals with severe obesity that did not receive surgery (nonsurgery group; n = 19) as part of the 12-year follow-up in the Utah Obesity Study. Metabolic health data were collected at baseline and the follow-up examination. The gut microbiota was quantified by sequencing the V4 region of the 16 S rRNA gene. Significant differences in microbiota composition with surgery and other covariates were determined by Unifrac distance analysis and permutational multivariate analysis of variance. Significant differences in the relative abundance of individual bacterial taxa were assessed using analysis of composition of microbiomes software. RESULTS: The surgery group had higher relative abundances of Verrucomicrobiaceae (5.7 ± 1.3% versus 1.1 ± .3%) and Streptococcaceae (6.3 ± 1.0% versus 3.2 ± .8%), but lower relative abundances of Bacteroidaceae (8.8 ± 1.8% versus 18.6 ± 2.3%) 10.6 years after surgery. In a small subset of 8 individuals, a higher relative abundance of Akkermansia muciniphila was correlated with type 2 diabetes remission. CONCLUSIONS: Differences in the gut microbiota are evident a decade after bariatric surgery compared with individuals with severe obesity that did not undergo surgery. The observed long-term differences are consistent with previous findings.

Machine learning reveals serum sphingolipids as cholesterol-independent biomarkers of coronary artery disease.

BACKGROUNDCeramides are sphingolipids that play causative roles in diabetes and heart disease, with their serum levels measured clinically as biomarkers of cardiovascular disease (CVD).METHODSWe performed targeted lipidomics on serum samples from individuals with familial coronary artery disease (CAD) (n = 462) and population-based controls (n = 212) to explore the relationship between serum sphingolipids and CAD, using unbiased machine learning to identify sphingolipid species positively associated with CAD.RESULTSNearly every sphingolipid measured (n = 30 of 32) was significantly elevated in subjects with CAD compared with measurements in population controls. We generated a novel sphingolipid-inclusive CAD risk score, termed SIC, that demarcates patients with CAD independently and more effectively than conventional clinical CVD biomarkers including serum LDL cholesterol and triglycerides. This new metric comprises several minor lipids that likely serve as measures of flux through the ceramide biosynthesis pathway rather than the abundant deleterious ceramide species that are included in other ceramide-based scores.CONCLUSIONThis study validates serum ceramides as candidate biomarkers of CVD and suggests that comprehensive sphingolipid panels should be considered as measures of CVD.FUNDINGThe NIH (DK112826, DK108833, DK115824, DK116888, and DK116450); the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B); the American Diabetes Association; the American Heart Association; the Margolis Foundation; the National Cancer Institute, NIH (5R00CA218694-03); and the Huntsman Cancer Institute Cancer Center Support Grant (P30CA040214).

FGF19 Analog as a Surgical Factor Mimetic That Contributes to Metabolic Effects Beyond Glucose Homeostasis.

Bariatric surgery has proven to be the most effective treatment for controlling hyperglycemia in severely obese patients with diabetes. We show that fibroblast growth factor 19 (FGF19), a gut hormone, is rapidly induced by bariatric surgery in rodents and humans. Administration of FGF19 achieves diabetes remission independent of weight loss in animal models of diabetes, supporting a role for FGF19 in the hormonal remodeling that restores metabolic function after the surgery. Through an unbiased, systematic screen in diabetic mice, we identified selective, safe, and effective FGF19 analogs. Unexpectedly, a lead FGF19 analog, NGM282, did not correct hyperglycemia in patients with type 2 diabetes. In contrast, administration of NGM282 resulted in a rapid, robust, and sustained reduction in liver fat content and an improvement in liver histology in patients with nonalcoholic steatohepatitis, faithfully replicating another key benefit of bariatric surgery. Our work identifies a strategy for replacing the surgery with an equally effective, but less invasive, treatment for nonalcoholic steatohepatitis.

12-year trajectory of health-related quality of life in gastric bypass patients versus comparison groups.

BACKGROUND: Few prospective studies compare long-term health-related quality of life (HRQOL) outcomes between bariatric surgery patients and individuals with severe obesity who do not undergo bariatric surgery. OBJECTIVES: This 12-year, prospective study evaluated the trajectory and durability of HRQOL changes in gastric bypass patients (surgery group; n = 418) and compared these changes to 2 nonsurgical groups. The nonsurgery group 1 (n = 417) sought but did not have surgery; nonsurgery group 2 (n = 321) had severe obesity but did not seek surgery. SETTING: Bariatric surgery center. METHODS: Weight-related (impact of weight on quality of life-lite [IWQOL-Lite]) and general (short-form health survey-36 [SF-36]) HRQOL questionnaires were administered at baseline and 2, 6, and 12 years postsurgery. RESULTS: At 12 years, the surgery group showed greatly improved weight-related HRQOL (IWQOL-Lite) and physical HRQOL (physical component summary of short-form health survey-36) from baseline, and differences between the surgery group and both nonsurgery groups were significant for IWQOL-Lite and physical component summary. IWQOL-Lite and physical component summary scores peaked at 2 years, followed by declines from 2 to 6 and 6 to 12 years. Small improvements in mental/psychosocial aspects of HRQOL (mental component summary of short-form health survey-36) seen in the surgery group at 2 years were not maintained at either 6 or 12 years. CONCLUSIONS: Gastric bypass patients demonstrated significantly higher weight-related and physical HRQOL at 12 years compared with their very low baseline scores, with the trajectory peaking at 2 years. Despite declining HRQOL between 2 and 12 years, the magnitude of improvement supports the clinical relevance of bariatric surgery for enhancing patients' quality of life.

Changes in Blood microRNA Expression and Early Metabolic Responsiveness 21 Days Following Bariatric Surgery.

Background: Early metabolic responses following bariatric surgery appear greater than expected given the initial weight loss and coincide with improvement in diabetes. We hypothesized that small non-coding microRNA changes might contribute to regulating mechanisms for metabolic changes and weight loss in patients with severe obesity and diabetes. Methods: Twenty-nine type 2 patients with severe obesity (mean BMI 46.2 kg/m2) and diabetes underwent Roux-en-Y gastric bypass (RYGB) surgery. Clinical measurements and fasting blood samples were taken preoperatively and at day 21 postoperatively. Normalization of fasting glucose and HbA1c following bariatric surgery (short-term diabetes remission) was defined as withdrawal of anti-diabetic medication and fasting glucose < 100 mg/dL (5.6 mmol/L) or HbA1c < 6.0%. MicroRNA expression was determined by quantitative polymerase chain reaction and tested for significant changes after surgery. Results: BMI decreased by 3.8 kg/m2 21 days postoperatively. Eighteen of 29 RYGB (62%) had short-term diabetes remission. Changes from pre- to post-surgery in 32 of 175 microRNAs were nominally significant (p < 0.05). Following multiple comparison adjustment, changes in seven microRNAs remained significant: miR-7-5p, let-7f-5p, miR-15b-5p, let-7i-5p, miR-320c, miR-205-5p, and miR-335-5p. Four pathways were over-represented by these seven microRNAs, including diabetes and insulin resistance pathways. Conclusion: Seven microRNAs showed significant changes 21 days after bariatric surgery. Functional pathways of the altered microRNAs were associated with diabetes-, pituitary-, and liver-related disease, with expression in natural killer cells, and pivotal intestinal pathology suggesting possible mechanistic roles in early diabetes responses following bariatric surgery.

Weight and Metabolic Outcomes 12 Years after Gastric Bypass.

BACKGROUND: Few long-term or controlled studies of bariatric surgery have been conducted to date. We report the 12-year follow-up results of an observational, prospective study of Roux-en-Y gastric bypass that was conducted in the United States. METHODS: A total of 1156 patients with severe obesity comprised three groups: 418 patients who sought and underwent Roux-en-Y gastric bypass (surgery group), 417 patients who sought but did not undergo surgery (primarily for insurance reasons) (nonsurgery group 1), and 321 patients who did not seek surgery (nonsurgery group 2). We performed clinical examinations at baseline and at 2 years, 6 years, and 12 years to ascertain the presence of type 2 diabetes, hypertension, and dyslipidemia. RESULTS: The follow-up rate exceeded 90% at 12 years. The adjusted mean change from baseline in body weight in the surgery group was -45.0 kg (95% confidence interval [CI], -47.2 to -42.9; mean percent change, -35.0) at 2 years, -36.3 kg (95% CI, -39.0 to -33.5; mean percent change, -28.0) at 6 years, and -35.0 kg (95% CI, -38.4 to -31.7; mean percent change, -26.9) at 12 years; the mean change at 12 years in nonsurgery group 1 was -2.9 kg (95% CI, -6.9 to 1.0; mean percent change, -2.0), and the mean change at 12 years in nonsurgery group 2 was 0 kg (95% CI, -3.5 to 3.5; mean percent change, -0.9). Among the patients in the surgery group who had type 2 diabetes at baseline, type 2 diabetes remitted in 66 of 88 patients (75%) at 2 years, in 54 of 87 patients (62%) at 6 years, and in 43 of 84 patients (51%) at 12 years. The odds ratio for the incidence of type 2 diabetes at 12 years was 0.08 (95% CI, 0.03 to 0.24) for the surgery group versus nonsurgery group 1 and 0.09 (95% CI, 0.03 to 0.29) for the surgery group versus nonsurgery group 2 (P<0.001 for both comparisons). The surgery group had higher remission rates and lower incidence rates of hypertension and dyslipidemia than did nonsurgery group 1 (P<0.05 for all comparisons). CONCLUSIONS: This study showed long-term durability of weight loss and effective remission and prevention of type 2 diabetes, hypertension, and dyslipidemia after Roux-en-Y gastric bypass. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Coffee consumption and calcified atherosclerotic plaques in the coronary arteries: The NHLBI Family Heart Study.

BACKGROUND & AIMS: While a recent meta-analysis of prospective studies reported that coffee consumption is associated with a lower risk of cardiovascular disease mortality, limited and inconsistent data are available on the relation of coffee intake with subclinical disease. Thus, the aim of the present study was to see the association of coffee consumption with the prevalence of atherosclerotic plaque in the coronary arteries in NHLBI Family Heart Study. METHODS: In a cross-sectional design, we studied 1929 participants of the NHLBI Family Heart Study without known coronary heart disease. Coffee consumption was assessed by a semi-quantitative food frequency questionnaire and coronary-artery calcium (CAC) was measured by cardiac computed tomography. We defined prevalent CAC as an Agatston score of ≥100 and used generalized estimating equations to calculate prevalence ratios of CAC as well as a sensitivity analysis at a range of cutpoints for CAC. RESULTS: Mean age was 56.7 years and 59% of the study subjects were female. In adjusted analysis for age, sex, BMI, smoking, alcohol, physical activity, field center, and energy intake, prevalence ratio (95% CI) for CAC was 1.0 (reference), 0.92 (0.57-1.49), 1.34 (0.86-2.08), 1.30 (0.84-2.02), and 0.99 (0.60-1.64) for coffee consumption of almost never, <1/day, 1/day, 2-3/day, and ≥4 cups/day, respectively. In a sensitivity analysis, there was no evidence of association between coffee consumption and prevalent CAC when CAC cut points of 0, 50, 150, 200, and 300 were used. CONCLUSIONS: These data do not provide evidence for an association between coffee consumption and prevalent CAC in adult men and women.

Association of Central Adiposity With Adverse Cardiac Mechanics: Findings From the Hypertension Genetic Epidemiology Network Study.

BACKGROUND: Central obesity, defined by increased waist circumference or waist:hip ratio (WHR), is associated with increased cardiovascular events, including heart failure. However, the pathophysiological link between central obesity and adverse cardiovascular outcomes remains poorly understood. We hypothesized that central obesity and larger WHR are independently associated with worse cardiac mechanics (reduced left ventricular strain and systolic [s'] and early diastolic [e'] tissue velocities). METHODS AND RESULTS: We performed speckle-tracking analysis of echocardiograms from participants in the Hypertension Genetic Epidemiology Network (HyperGEN) study, a population- and family-based epidemiological study (n=2181). Multiple indices of systolic and diastolic cardiac mechanics were measured. We evaluated the association between central obesity and cardiac mechanics using multivariable-adjusted linear mixed-effects models to account for relatedness among participants. The mean age of the cohort was 51±14 years, 58% were women, and 47% were black. Mean body mass index was 30.8±7.1 kg/m(2), waist circumference was 102±17 cm, WHR was 0.91±0.08, and 80% had central obesity based on waist circumference and WHR criteria. After adjusting for multiple potential confounders (including age, sex, race, physical activity, body mass index, heart rate, smoking status, systolic blood pressure, fasting glucose, total cholesterol, antihypertensive medication use, glomerular filtration rate, left ventricular mass index, wall motion abnormalities, and ejection fraction), central obesity and WHR remained associated with worse global longitudinal strain, early diastolic strain rate, s' velocity, and e' velocity (P<0.05 for all comparisons). There were no significant statistical interactions between WHR and obesity status. CONCLUSIONS: In this cross-sectional study of participants with multiple comorbidities, central obesity was found to be associated with adverse cardiac mechanics.

Walking and Calcified Atherosclerotic Plaque in the Coronary Arteries: The National Heart, Lung, and Blood Institute Family Heart Study.

OBJECTIVE: Studies have reported mixed findings on the association between physical activity and subclinical atherosclerosis. We sought to examine whether walking is associated with prevalent coronary artery calcification (CAC) and aortic calcification. APPROACH AND RESULTS: In a cross-sectional design, we studied 2971 participants of the National Heart, Lung, and Blood Institute Family Heart Study without a history of myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal angioplasty. A standardized questionnaire was used to ascertain the number of blocks walked daily to compute walking metabolic equivalent hours. CAC was measured by cardiac computed tomography. We defined prevalent CAC and aortic calcification using an Agatston score of at least 100 and used generalized estimating equations to calculate adjusted prevalence ratios. Mean age was 55 years, and 60% of participants were women. Compared with the ≤3.75-Met-h/wk group, prevalence ratios for CAC after adjusting for age, sex, race, smoking, alcohol use, total physical activity (excluding walking), and familial clustering were 0.53 (95% confidence interval, 0.35-0.79) for >3.75 to 7.5 Met-h/wk, 0.72 (95% confidence interval, 0.52-0.99) for >7.5 to 15 Met-h/wk, and 0.54 (95% confidence interval, 0.36-0.81) for >15 to 22.5 Met-h/wk, (P trend=0.01). The walking-CAC relationship remained significant for those with body mass index ≥25 (P trend=0.02) and persisted with CAC cutoffs of 300, 200, 150, and 50 but not 0. When examined as a continuous variable, a J-shaped association between walking and CAC was found. The walking-aortic calcification association was not significant. CONCLUSIONS: Our findings suggest that walking is associated with lower prevalent CAC (but not aortic calcification) in adults without known heart disease.