Effect of liraglutide on thigh muscle fat and muscle composition in adults with overweight or obesity: Results from a randomized clinical trial.

BACKGROUND: Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown. METHODS: This is a pre-specified secondary analysis of a randomized, double-blind, placebo-controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30 kg/m2 or ≥27 kg/m2 and metabolic syndrome. Participants were randomly assigned to a once-daily subcutaneous injection of liraglutide (target dose 3.0 mg) or matching placebo for 40 weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40-week follow-up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least-square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored. RESULTS: Among the 128 participants with follow-up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow-up of 36 weeks was -2.87% among participants randomized to liraglutide (n = 73) and 0.05% in the placebo group (absolute change: -0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was -0.24% (95% CI, -0.41 to -0.06, P-value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow-up with liraglutide, but there was no change with placebo. CONCLUSIONS: In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once-daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study.

Trends and Outcomes Associated With Bariatric Surgery and Pharmacotherapies With Weight Loss Effects Among Patients With Heart Failure and Obesity.

BACKGROUND: Utilization patterns of bariatric surgery among older patients with heart failure (HF), and the associations with cardiovascular outcomes, are not well known. METHODS: Medicare beneficiaries with HF and at least class II obesity from 2013 to 2020 were identified with Medicare Provider Analysis and Review 100% inpatient files and Medicare 5% outpatient files. Patients who underwent bariatric surgery were matched to controls in a 1:2 ratio (matched on exact age, sex, race, body mass index, HF encounter year, and HF hospitalization rate pre-surgery/matched period). In an exploratory analysis, patients prescribed pharmacotherapies with weight loss effects (semaglutide, liraglutide, naltrexone-bupropion, or orlistat) were identified and matched to controls with a similar strategy in addition to HF medical therapy data. Cox models evaluated associations between weight loss therapies (as a time-varying covariate) and mortality risk and HF hospitalization rate (calculated as the rate of HF hospitalizations following index HF encounter per 100 person-months) during follow-up. RESULTS: Of 298 101 patients with HF and body mass index ≥35 kg/m2, 2594 (0.9%) underwent bariatric surgery (45% men; mean age, 56.2 years; mean body mass index, 51.5 kg/m2). In propensity-matched analyses over a median follow-up of 4.7 years, bariatric surgery was associated with lower risk of all-cause mortality (HR, 0.55 [95% CI, 0.49-0.63]; P<0.001), greater reduction in HF hospitalization rate (rate ratio, 0.72 [95% CI, 0.67-0.77]; P<0.001), and lower atrial fibrillation risk (HR, 0.78 [95% CI, 0.65-0.93]; P=0.006). Use of pharmacotherapies with weight loss effects was low (4.8%), with 96.3% prescribed GLP-1 (glucagon-like peptide-1) agonists (semaglutide, 23.6%; liraglutide, 72.7%). In propensity-matched analysis over a median follow-up of 2.8 years, patients receiving pharmacotherapies with weight loss effects (versus matched controls) had a lower risk of all-cause mortality (HR, 0.82 [95% CI, 0.71-0.95]; P=0.007) and HF hospitalization rate (rate ratio, 0.87 [95% CI, 0.77-0.99]; P=0.04). CONCLUSIONS: Bariatric surgery and pharmacotherapies with weight loss effects are associated with a lower risk of adverse outcomes among older patients with HF and obesity; however, overall utilization remains low.

A Phenomapping Tool and Clinical Score to Identify Low Diuretic Efficiency in Acute Decompensated Heart Failure.

BACKGROUND: Individuals with acute decompensated heart failure (ADHF) have a varying response to diuretic therapy. Strategies for the early identification of low diuretic efficiency to inform decongestion therapies are lacking. OBJECTIVES: The authors sought to develop and externally validate a machine learning-based phenomapping approach and integer-based diuresis score to identify patients with low diuretic efficiency. METHODS: Participants with ADHF from ROSE-AHF, CARRESS-HF, and ATHENA-HF were pooled in the derivation cohort (n = 794). Multivariable finite-mixture model-based phenomapping was performed to identify phenogroups based on diuretic efficiency (urine output over the first 72 hours per total intravenous furosemide equivalent loop diuretic dose). Phenogroups were externally validated in other pooled ADHF trials (DOSE/ESCAPE). An integer-based diuresis score (BAN-ADHF score: blood urea nitrogen, creatinine, natriuretic peptide levels, atrial fibrillation, diastolic blood pressure, hypertension and home diuretic, and heart failure hospitalization) was developed and validated based on predictors of the diuretic efficiency phenogroups to estimate the probability of low diuretic efficiency using the pooled ADHF trials described earlier. The associations of the BAN-ADHF score with markers and symptoms of congestion, length of stay, in-hospital mortality, and global well-being were assessed using adjusted regression models. RESULTS: Clustering identified 3 phenogroups based on diuretic efficiency: phenogroup 1 (n = 370; 47%) had lower diuretic efficiency (median: 13.1 mL/mg; Q1-Q3: 7.7-19.4 mL/mg) than phenogroups 2 (n = 290; 37%) and 3 (n = 134; 17%) (median: 17.8 mL/mg; Q1-Q3: 10.8-26.1 mL/mg and median: 35.3 mL/mg; Q1-Q3: 17.5-49.0 mL/mg, respectively) (P < 0.001). The median urine output difference in response to 80 mg intravenous twice-daily furosemide between the lowest and highest diuretic efficiency group (phenogroup 1 vs 3) was 3,520 mL/d. The BAN-ADHF score demonstrated good model performance for predicting the lowest diuretic efficiency phenogroup membership (C-index: 0.92 in DOSE/ESCAPE validation cohort) that was superior to measures of kidney function (creatinine or blood urea nitrogen), natriuretic peptide levels, or home diuretic dose (DeLong P < 0.001 for all). Net urine output in response to 80 mg intravenous twice-daily furosemide among patients with a low vs high (5 vs 20) BAN-ADHF score was 2,650 vs 660 mL per 24 hours, respectively. Participants with higher BAN-ADHF scores had significantly lower global well-being, higher natriuretic peptide levels on discharge, a longer in-hospital stay, and a higher risk of in-hospital mortality in both derivation and validation cohorts. CONCLUSIONS: The authors developed and validated a phenomapping strategy and diuresis score for individuals with ADHF and differential response to diuretic therapy, which was associated with length of stay and mortality.

Favorable Neighborhood Walkability is Associated With Lower Burden of Cardiovascular Risk Factors Among Patients Within an Integrated Health System: The Houston Methodist Learning Health System Outpatient Registry.

This is the first study to investigate the relationship between neighborhood walkability and cardiovascular (CV) risk factors in the United States using a large population-based database. Cross-sectional study using data from 1.1 million patients over the age of 18 in the Houston Methodist Learning Health System Outpatient Registry (2016-2022). Using the 2019 WalkScore, patients were assigned to one of the 4 neighborhood walkability categories. The burden of CV risk factors (hypertension, diabetes, obesity, dyslipidemia, and smoking) was defined as poor, average, or optimal (>3, 1-2, 0 risk factors, respectively). We included 887,654 patients, of which 86% resided in the two least walkable neighborhoods. The prevalence of CV risk factors was significantly lower among participants in the most walkable neighborhoods irrespective of ASCVD status. After adjusting for age, sex, race/ethnicity, and socioeconomic factors, we found that adults living in the most walkable neighborhoods were more likely to have optimal CV risk profile than those in the least walkable ones (RRR 2.77, 95% CI 2.64-2.91). We observed an inverse association between neighborhood walkability and the burden of CV risk factors. These findings support multilevel health system stakeholder engagements and investments in walkable neighborhoods as a viable tool for mitigating the growing burden of modifiable CV risk factors.

Team-based strategies to prevent heart failure.

PURPOSE OF REVIEW: The burden of heart failure (HF) in the United States and worldwide is projected to rise. Prevention of HF can curb the burden of this chronic syndrome, but current approaches are limited. This review discusses team-based strategies aimed to prevent HF. RECENT FINDINGS: Individuals at high risk for developing HF can be identified using HF risk scores, biomarkers, and cardiac imaging. Electronic medical records (EMR) can integrate clinical data to estimate HF risk and identify individuals who may benefit most from preventive therapies. Team-based interventions can lead to enhanced adherence to medications, optimization of medical management, and control of risk factors. Multifaceted interventions involve EMR-based strategies, pharmacist- and nurse-led initiatives, involvement of community personnel, polypills, and digital solutions. SUMMARY: Team-based strategies aimed to prevent HF incorporate a broad group of personnel and tools. Despite implementation challenges, existing resources can be efficiently utilized to facilitate team-based approaches to potentially reduce the burden of HF.

Cost-Related Medication Nonadherence in Adults With Diabetes in the United States: The National Health Interview Survey 2013-2018.

OBJECTIVE: Health-related expenditures resulting from diabetes are rising in the U.S. Medication nonadherence is associated with worse health outcomes among adults with diabetes. We sought to examine the extent of reported cost-related medication nonadherence (CRN) in individuals with diabetes in the U.S. RESEARCH DESIGN AND METHODS: We studied adults age ≥18 years with self-reported diabetes from the National Health Interview Survey (NHIS) (2013-2018), a U.S. nationally representative survey. Adults reporting skipping doses, taking less medication, or delaying filling a prescription to save money in the past year were considered to have experienced CRN. The weighted prevalence of CRN was estimated overall and by age subgroups (<65 and ≥65 years). Logistic regression was used to identify sociodemographic characteristics independently associated with CRN. RESULTS: Of the 20,326 NHIS participants with diabetes, 17.6% (weighted 2.3 million) of those age <65 years reported CRN, compared with 6.9% (weighted 0.7 million) among those age ≥65 years. Financial hardship from medical bills, lack of insurance, low income, high comorbidity burden, and female sex were independently associated with CRN across age groups. Lack of insurance, duration of diabetes, current smoking, hypertension, and hypercholesterolemia were associated with higher odds of reporting CRN among the nonelderly but not among the elderly. Among the elderly, insulin use significantly increased the odds of reporting CRN (odds ratio 1.51; 95% CI 1.18, 1.92). CONCLUSIONS: In the U.S., one in six nonelderly and one in 14 elderly adults with diabetes reported CRN. Removing financial barriers to accessing medications may improve medication adherence among these patients, with the potential to improve their outcomes.

Effect of Anacetrapib on Cholesterol Efflux Capacity: A Substudy of the DEFINE Trial.

Background Anacetrapib is the only cholesteryl ester transfer protein inhibitor proven to reduce coronary heart disease (CHD). However, its effects on reverse cholesterol transport have not been fully elucidated. Macrophage cholesterol efflux (CEC), the initial step of reverse cholesterol transport, is inversely associated with CHD and may be affected by sex as well as haptoglobin copy number variants among patients with diabetes mellitus. We investigated the effect of anacetrapib on CEC and whether this effect is modified by sex, diabetes mellitus, and haptoglobin polymorphism. Methods and Results A total of 574 participants with CHD were included from the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib) trial. CEC was measured at baseline and 24-week follow-up using J774 macrophages, boron dipyrromethene difluoride-labeled cholesterol, and apolipoprotein B-depleted plasma. Haptoglobin copy number variant was determined using an ELISA assay. Anacetrapib increased CEC, adjusted for baseline CEC, risk factors, and changes in lipids/apolipoproteins (standard ß, 0.23; 95% CI, 0.05-0.41). This CEC-raising effect was seen only in men (P interaction=0.002); no effect modification was seen by diabetes mellitus status. Among patients with diabetes mellitus, anacetrapib increased CEC in those with the normal 1-1 haptoglobin genotype (standard ß, 0.42; 95% CI, 0.16-0.69) but not the dysfunctional 2-1/2-2 genotypes (P interaction=0.02). Conclusions Among patients with CHD, anacetrapib at a dose linked to improved CHD outcomes significantly increased CEC independent of changes in high-density lipoprotein cholesterol or other lipids, with effect modification by sex and a novel pharmacogenomic interaction by haptoglobin genotype, suggesting a putative mechanism for reduced risk requiring validation.

Identifying a low-flow phenotype in heart failure with preserved ejection fraction: a secondary analysis of the RELAX trial.

AIMS: The relationship between resting stroke volume (SV) and prognostic markers in heart failure with preserved ejection fraction (HFpEF) is not well established. We evaluated the association of SV index (SVI) at rest with exercise capacity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in stable patients with HFpEF. METHODS AND RESULTS: Participants enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial with available data on SVI by the Doppler method were included in this analysis (n = 185). A low-flow state defined by resting SVI < 35 mL/m2 was present in 37% of study participants. Multivariable adjusted linear regression analysis suggested that higher resting heart rate, higher body weight, prevalent atrial fibrillation, and smaller left ventricular (LV) end-diastolic dimension were each independently associated with lower SVI. Patients with low-flow HFpEF had lower systolic blood pressure and smaller LV end-diastolic dimension. In multivariable adjusted linear regression models, lower SVI was significantly associated with lower peak oxygen consumption (peak VO2 ) and higher NT-proBNP levels at baseline, and greater decline in peak VO2 at 6 month follow-up independent of other confounders. Resting LV ejection fraction was not associated with peak VO2 and NT-proBNP levels. CONCLUSIONS: There is heterogeneity in the resting SVI distribution among patients with stable HFpEF, with more than one-third of patients identified with the low-flow HFpEF phenotype (SVI < 35 mL/m2 ). Lower SVI was independently associated with lower peak VO2 , higher NT-proBNP levels, and greater decline in peak VO2 . These findings highlight the potential prognostic utility of SVI assessment in the management of patients with HFpEF.

Association of Hospital Performance Based on 30-Day Risk-Standardized Mortality Rate With Long-term Survival After Heart Failure Hospitalization: An Analysis of the Get With The Guidelines-Heart Failure Registry.

Importance: Among patients hospitalized with heart failure (HF), the long-term clinical implications of hospitalization at hospitals based on 30-day risk-standardized mortality rates (RSMRs) is not known. Objective: To evaluate the association of hospital-specific 30-day RSMR with long-term survival among patients hospitalized with HF in the American Heart Association Get With The Guidelines-HF registry. Design, Setting, and Participants: The longitudinal observational study included 106 304 patients with HF who were admitted to 317 centers participating in the Get With The Guidelines-HF registry from January 1, 2005, to December 31, 2013, and had Medicare-linked follow-up data. Hospital-specific 30-day RSMR was calculated using a hierarchical logistic regression model. In the model, 30-day mortality rate was a binary outcome, patient baseline characteristics were included as covariates, and the hospitals were treated as random effects. The association of 30-day RSMR-based hospital groups (low to high 30-day RSMR: quartile 1 [Q1] to Q4) with long-term (1-year, 3-year, and 5-year) mortality was assessed using adjusted Cox models. Data analysis took place from June 29, 2017, to February 19, 2018. Exposures: Thirty-day RSMR for participating hospitals. Main Outcomes and Measures: One-year, 3-year, and 5-year mortality rates. Results: Of the 106 304 patients included in the analysis, 57 552 (54.1%) were women and 84 595 (79.6%) were white, and the median (interquartile range) age was 81 (74-87) years. The 30-day RSMR ranged from 8.6% (Q1) to 10.7% (Q4). Hospitals in the low 30-day RSMR group had greater availability of advanced HF therapies, cardiac surgery, and percutaneous coronary interventions. In the primary landmarked analyses among 30-day survivors, there was a graded inverse association between 30-day RSMR and long-term mortality (Q1 vs Q4: 5-year mortality, 73.7% vs 76.8%). In adjusted analysis, patients admitted to hospitals in the high 30-day RSMR group had 14% (95% CI, 10-18) higher relative hazards of 5-year mortality compared with those admitted to hospitals in the low 30-day RSMR group. Similar findings were observed in analyses of survival from admission, with 22% (95% CI, 18-26) higher relative hazards of 5-year mortality for patients admitted to Q4 vs Q1 hospitals. Conclusions and Relevance: Lower hospital-level 30-day RSMR is associated with greater 1-year, 3-year, and 5-year survival for patients with HF. These differences in 30-day survival continued to accrue beyond 30 days and persisted long term, suggesting that 30-day RSMR may be a useful HF performance metric to incentivize quality care and improve long-term outcomes.

Improved detection of myocardial damage in sarcoidosis using longitudinal strain in patients with preserved left ventricular ejection fraction.

BACKGROUND: Cardiac infiltration is an important cause of death in sarcoidosis. Transthoracic echocardiography (TTE) has limited sensitivity for the detection of cardiac sarcoidosis (CS). Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is used to diagnose CS but has limitations of cost and availability. We sought to determine whether TTE-derived global longitudinal strain (GLS) may be used to identify individuals with CS, despite preserved left ventricular ejection fraction (LVEF), and whether abnormal GLS is associated with major cardiovascular events (MCE). METHODS: We studied 31 patients with biopsy-proven extra-cardiac sarcoidosis, LVEF>50% and LGE on CMR (CS+ group), and 31 patients without LGE (CS- group), matched by age, sex, and severity of lung disease. GLS was measured using vendor-independent speckle tracking software. Parameters of left and right ventricular systolic and diastolic function were also studied. Receiver-operating characteristic curves were used to identify GLS cutoff for CS detection, and Kaplan-Meier plots to determine the ability of GLS to predict MCE. RESULTS: LGE was associated with reduced GLS (-19.6±1.9% in CS- vs -14.7±2.4% in CS+, P<.01) and with reduced E/A ratio (1.1±0.3 vs 0.9±0.3, respectively, P =.01). No differences were noted in other TTE parameters. GLS magnitude inversely correlated with LGE burden (r=-.59). GLS cutoff of -17% showed sensitivity and specificity 94% for detecting CS. Patients who experienced MCE had worse GLS than those who did not (-13.4±0.9% vs -17.7±0.4%, P=.0003). CONCLUSIONS: CS is associated with significantly reduced GLS in the presence of preserved LVEF. GLS measurements may become part of the TTE study performed to screen for CS.

Inducible tumor necrosis factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-κB pathway in TNF stimulation.

The NF-κB transcription factor mediates the inflammatory response through distinct (canonical and non-canonical) signaling pathways. The mechanisms controlling utilization of either of these pathways are largely unknown. Here we observe that TNF stimulation induces delayed NF-κB2/p100 processing and investigate the coupling mechanism. TNF stimulation induces TNF-associated factor-1 (TRAF-1) that directly binds NF-κB-inducing kinase (NIK) and stabilizes it from degradation by disrupting its interaction with TRAF2·cIAP2 ubiquitin ligase complex. We show that TRAF1 depletion prevents TNF-induced NIK stabilization and reduces p52 production. To further examine the interactions of TRAF1 and NIK with NF-κB2/p100 processing, we mathematically modeled TRAF1·NIK as a coupling signaling complex and validated computational inference by siRNA knockdown to show non-canonical pathway activation is dependent not only on TRAF1 induction but also NIK stabilization by forming TRAF1·NIK complex. Thus, these integrated computational-experimental studies of TNF-induced TRAF1 expression identified TRAF1·NIK as a central complex linking canonical and non-canonical pathways by disrupting the TRAF2-cIAP2 ubiquitin ligase complex. This feed-forward kinase pathway is essential for the activation of non-canonical pathway.