Faculty Bibliography

BACKGROUND:Bariatric surgery (BS) is associated with improved cardiovascular (CV) outcomes in individuals with obesity. One proposed mechanism is reduced inflammation. S100A9, a pro-inflammatory cytokine, is elevated in obesity. S100A9, particularly expression in platelets, has been associated with CV risk. The impact of BS on circulating and platelet S100A9 in obesity is unknown. METHODS:We studied serum, plasma, and platelet supernatants from subjects with obesity pre- and post-BS (n = 23) and lean volunteers (n = 8). S100A9 levels were quantified using an S100A9 immunoassay. Wilcoxon, Mann-Whitney, and t-tests were performed to assess changes in S100A9 levels pre- and post-operatively and compare levels across sample and subject types. Spearman tests were used to assess correlations between S100A9 levels in different sample types and neutrophil/platelet counts. RESULTS:Serum and plasma S100A9 concentrations were elevated in individuals with obesity relative to lean individuals. Levels decreased to lean subject levels at 1-year post-BS, despite subjects with obesity remaining overweight. Circulating neutrophil counts also decreased post-BS, and post-BS differences in serum S100A9 were eliminated when calculated per-neutrophil. Platelet supernatant S100A9 levels were lower than in serum and plasma and did not change post-BS. Platelet supernatant S100A9 correlated with plasma, but not serum, levels. CONCLUSION/CONCLUSIONS:We found that S100A9 concentrations differ substantially between blood components, are elevated in obesity, and normalize post-BS. Reductions in circulating S100A9 may contribute to reduced inflammation and be largely driven by resolution of obesity-associated neutrophilia. Our data suggest minimal platelet contribution to circulating (or systemic) S100A9, but a local level inflammatory impact cannot be excluded.

BACKGROUND:Individuals who report meeting weekly moderate to vigorous physical activity (MVPA) guidelines have lower risk of atrial fibrillation (AF). However existing studies have relied on subjective questionnaires or short-duration (<1 week) objective assessments using accelerometry. The objective of this research was to investigate an association between MVPA levels and the incidence of AF, utilizing long-term, free-living accelerometry data. METHODS:1-year Fitbit data, in addition to survey and electronic health record (EHR) data, were extracted from the NIH All of Us (AoU) research database. Cox proportional hazards regression was used to model the association of average MVPA and incident AF over a five-year follow-up period. RESULTS:, 41±12 complete weeks of Fitbit wear). 97 individuals (0.6%) experienced incident AF in the five-year follow-up period. Every additional hour of MVPA was associated with 8% lower AF risk (HR = 0.92 [0.86,0.99], p=0.02). In a subset of 10533 participants with genomic data, this association persisted after adjustment for AF genetic risk score. CONCLUSIONS:Higher amounts of objectively measured MVPA, measured using free-living, long-term accelerometry data, were inversely associated with risk of incident AF, independent of clinical and genetic risk factors.

BACKGROUND AND AIMS/OBJECTIVE:Low functional capacity is an independent risk factor for cardiovascular (CV) events. Regular physical activity may reduce CV risk through suppression of inflammation and reduced platelet activity. We aimed to investigate the association of functional capacity quantified by the validated Duke Activity Status Index (DASI) with platelet activity and incident major adverse CV and limb events (MACLE) in individuals with peripheral artery disease (PAD) undergoing lower extremity revascularization (LER). METHODS:Light transmission aggregometry and platelet RNAseq were performed on specimens isolated from men and women prior to LER. Functional capacity was assessed using DASI. Prospective follow-up occurred at 1, 6, 12, and every 6 months following the LER. Subjects were separated into tertiles of DASI scores and incidence rates for MACLE were calculated using log-rank tests. Mediation analysis using linear regression fit with least squares was performed to test whether DASI exerted its effect on MACLE via platelet aggregation. RESULTS:281 patients completed the DASI questionnaire with scores ranging from 0.0 to 50.2 (bottom tertile: 0.0-9.95). Mean age was 74.4 ± 10.9 years and 32.4 % were female. During a median follow-up of 19 months, 163 (58.0 %) participants experienced a MACLE. After correction for demographics and CV risk factors, individuals in the lowest DASI tertile experienced significantly more MACLE than participants in other tertiles. The association between DASI and MACLE was consistent across multiple subgroups stratified by age, sex, body mass index, antiplatelet therapy, and clinical comorbidities. Mediation analyses suggested higher platelet aggregation to epinephrine in the bottom DASI tertile mediated 24.7 % [5.0 %, 103 %] of increased MACLE risk. Platelet mRNA demonstrated upregulation of inflammation pathways in the most sedentary individuals (lowest DASI tertile). CONCLUSIONS:Patients with PAD and low functional capacity have increased platelet activity and high incidence of MACLE. Our data suggest that elevated platelet aggregation mediates one-quarter of the MACLE risk in persons with low functional capacity undergoing LER. Our findings support a potential platelet-mediated mechanism for improved CV outcomes associated with regular physical activity.

IMPORTANCE/UNASSIGNED:Bariatric surgery, once the criterion standard in obesity treatment, has a small but concerning association with increased suicidality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed to treat diabetes, now provide substantial efficacy in the treatment of obesity. However, concerns of risk of suicidality with these medicines have been raised. OBJECTIVE/UNASSIGNED:To evaluate the risk of suicidality and self-harm in randomized, placebo-controlled trials of GLP-1 RAs in adults with diabetes or obesity. DATA SOURCES/UNASSIGNED:MEDLINE, Embase, ClinicalTrials.gov, and Cochrane databases were systematically searched from inception to August 29, 2023. STUDY SELECTION/UNASSIGNED:Reports of randomized clinical trials (RCTs) lasting 6 or more months comparing GLP-1 RAs with placebo for the treatment of diabetes or obesity published in peer-reviewed journals were identified. Two independent reviewers screened all search-identified studies for inclusion. Records of outcomes were queried from primary papers, ClinicalTrials.gov entries, and corresponding authors. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:Two independent researchers abstracted data and assessed data quality and validity using PRISMA guidelines. Data were pooled using random-effects models. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Pooled incidence of completed or attempted suicide, occurrences of suicidal ideation, or self-harm. RESULTS/UNASSIGNED:A total of 27 of 144 RCTs meeting inclusion criteria systematically recorded suicide and/or self-harm-related events and included 32 357 individuals receiving GLP-1 RAs and 27 046 treated with placebo, over 74 740 and 68 095 person-years of follow-up, respectively. Event incidence was very low in the GLP-1 RA (0.044 per 100 person-years) and placebo (0.040 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .24). Subgroup analyses did not suggest differences in outcomes based on diabetes status or GLP-1 RA used. Five studies were considered at risk of bias due to the loss of more than 5% of participants to follow-up. Otherwise, studies were not found to be heterogeneous nor at high risk of bias. CONCLUSIONS AND RELEVANCE/UNASSIGNED:There is unlikely to be an increase in the very low incidence of suicide-related adverse events among individuals receiving GLP-1 RAs within the context of RCTs. While these findings may further ease concerns about these adverse effects, continued monitoring is warranted to identify particular patients who may be at risk as extended use of GLP-1 RAs expands.

Although healthcare workers may be aware of the risks of physical inactivity, their levels of physical activity (PA) are similar to those of all US adults, with less than half engaging in sufficient PA. The purpose of this health promotion was to encourage daily PA among employees in a large academic healthcare system. We also tested whether individualized progress updates further influenced PA. This 10-week program was available to all employees of NYU Langone Health. Employees could sync their phone or accelerometer via app or web browser to count.it - the vendor chosen to monitor and manage step counts. Participants were asked to voluntarily provide basic information (age, sex, job role, work location) and complete the Physical Activity Vital Sign (minutes/week and intensity of PA) at enrollment and 10 weeks. For 10 weeks, participants were sent a message through their employee 'MyChart' portal with a link to information on the benefits of PA, and a reminder of that week's step-count challenge. Those meeting criteria for weekly challenges were included in gift card raffles. Participants were randomized 1:1 to receive the standard message ± additional emails detailing their progress. 3528 employees registered to participate (8% of all employees) although active users diminished over time (1225 at week 10). Average daily steps remained stable throughout (7319 + 4540 in week 1, 7229 + 5010 in week 10). Although there was no difference in any individual week, receipt of personalized feedback was associated with significantly higher average step counts throughout the 10-wk intervention as a whole (P = 0.01). Age and an urban work location were positively associated with steps, while female sex and a clerical job role were negatively associated with steps counts (all P < 0.005). Our findings provide important insight for workplace interventions to promote PA. They further suggest specific groups that may benefit from targeted efforts.

OBJECTIVES/OBJECTIVE:To describe the implementation of a workplace health promotion to address low levels of physical activity (PA). METHODS:Using the Exploration, Preparation, Implementation, Sustainment (EPIS) framework we implemented and evaluated a 10-week workplace step-count challenge to promote PA. All health system employees invited to participate. Data were collected on the exploration, preparation and implementation phases. RESULTS:During exploration, we recognized inadequate PA among employees. Meetings with key personnel were held to determine details of the health promotion and obtain support. We pursued a step-count PA intervention, capitalizing on employee ownership of smartphones with accelerometers. Vendors to host the intervention were evaluated. All employees were invited to participate. Participants received weekly messages about improving PA and notifications of weekly challenges. Exit interviews provided feedback and suggestions. CONCLUSION/CONCLUSIONS:A workplace health promotion focused on employee PA is feasible using EPIS.

BACKGROUND/UNASSIGNED:Cholesterol efflux capacity (CEC) of HDL (high-density lipoprotein) is inversely associated with incident cardiovascular events, independent of HDL cholesterol. Obesity is characterized by low HDL cholesterol and impaired HDL function, such as CEC. Bariatric surgery, including Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), broadly leads to improved cardiovascular outcomes, but impacts on risk factors differ by procedure, with greater improvements in weight loss, blood pressure, and glycemic control after RYGB, but greater improvements in HDL cholesterol and CEC levels after SG. This study sought to determine effects of RYGB and SG on HDL protein and lipid cargo and investigate associations with CEC changes. METHODS/UNASSIGNED:We prospectively studied nondiabetic, premenopausal Hispanic women with severe obesity not using lipid medications undergoing RYGB (n=31) or SG (n=36). Anthropometric measurements and blood sampling were obtained before and at 6 and 12 months after surgery. HDL was isolated from plasma, and quantitative proteomic and lipidomic assessments were performed with LC-MS/MS (liquid chromatography with tandem mass spectrometry). CEC was assessed ex vivo using apoB-depleted serum. RESULTS/UNASSIGNED:Participants experienced similar, significant weight loss over 12 months following bariatric surgery (38.0±10.4 kg) regardless of the procedure. Relative quantities of 47 proteins (34 increased, 13 decreased) and 150 lipids (71 increased, 79 decreased) carried on HDL were significantly altered following either surgical procedure. Proteins with similar aggregate response patterns were clustered into 15 groups (5 increased, 5 decreased, 5 minimal change) and lipids with similar aggregate responses into 25 groups (7 increased, 11 decreased, 7 minimal change). Network mediation analyses suggested that changes in 4 protein and 2 lipid clusters mediated changes in ABCA1 (ATP-binding cassette transporter A1) CEC and that 1 lipid cluster mediated changes in non-ABCA1 CEC. The protein and lipid clusters that mediated changes in CEC were distinct between SG and RYGB. CONCLUSIONS/UNASSIGNED:Bariatric surgery produces substantial changes in HDL lipid and protein cargo, and specific changes may mediate changes in HDL function in CEC. Further study of these mechanisms may lead to improved interventions to reduce cardiovascular risk in patients with obesity.

BACKGROUND:Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) remains the gold standard for treating obesity. Most people regain weight from postsurgery nadir. OBJECTIVES/OBJECTIVE:Liraglutide 3.0 mg is approved for weight management. This study will examine the effects on liraglutide 3.0 mg on weight regain post-RYGB. SETTING/METHODS:University Hospital, United States. METHODS:A 56-week, double-blind, placebo-controlled study was conducted in 132 subjects, who achieved ≥25% total body weight loss (TBWL) status-post-RYGB and regained ≥10% TBWL after reaching nadir weight (NW). Subjects 18-120 months post-RYGB were randomized to receive liraglutide 3.0 mg/d (n = 89) or placebo (n = 43) with lifestyle counseling regularly for 56 weeks. The co-primary endpoints were the proportion of subjects losing at least 5%, 10%, and 15% TBWL and achieving weight lower than their NW. RESULTS:53.4% of the placebo group and 65% of the liraglutide group completed the trial due to Severe acute respiratory syndrome coronavirus 2 pandemic. The change in %TBWL from baseline to 56-weeks was -8.8 (8.5, -29.2 to 9.7) and 1.1 (3.5, -7.9 to 5.99) in the liraglutide and placebo groups, respectively. 76% and 17% of subjects achieved ≥5% TBWL at 56 weeks in the liraglutide and placebo groups, respectively; 51% and 26.0% of the liraglutide group achieved ≥10% and ≥15% TBWL, respectively. None of the placebo group lost ≥10% TBWL. Twenty-one percent of subjects receiving liraglutide surpassed postoperative NW. No subjects on placebo met this goal. Nonserious adverse events occurred in 41.6% of subjects on liraglutide. Serious adverse events (SAE) occurred less often on liraglutide. CONCLUSIONS:Liraglutide was significantly more effective than placebo in treating weight regain that occurs post-RYGB without increased SAE.

Fibroblast Growth Factor-23 (FGF23) is a bone secreted protein widely recognized as a critical regulator of skeletal and mineral metabolism. However, little is known about non-skeletal production of FGF23 and its role in tissues other than bone. Growing evidence indicates that circulating FGF23 levels rise with high fat diet (HFD) and they are positively correlated with body mass index (BMI) in humans. In the present study, we show for the first time that increased circulating FGF23 levels in obese humans correlate with increased expression of adipose Fgf23 and both positively correlate with BMI. To understand the role of adipose-derived Fgf23, we generated adipocyte-specific Fgf23 knockout mice (AdipoqFgf23Δfl/Δfl) using the Adiponectin (Adipoq)-Cre driver, which targets mature white, beige, and brown adipocytes. Our data show that targeted ablation of Fgf23 in adipocytes prevents HFD-fed female mice from gaining body weight and fat mass while preserving lean mass, but has no effect on male mice, indicating the presence of sexual dimorphism. These effects are observed in the absence of changes in food and energy intake. Adipose Fgf23 inactivation also prevents dyslipidemia, hyperglycemia, and hepatic steatosis in female mice. Moreover, these changes are associated with decreased respiratory exchange ratio (RER) and increased brown fat Ucp1 expression in KO mice compared to HFD-fed control mice (Fgf23fl/fl). In conclusion, this is the first study highlighting that targeted inactivation of Fgf23 is a promising therapeutic strategy for weight loss and lean mass preservation in humans.