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Optimal weight loss involves decreasing adipose tissue while preserving lean muscle mass. Identifying molecular mediators that preserve lean muscle mass is therefore a clinically important goal. We have shown that circulating, postprandial FGF19 levels are lower in patients with obesity and decrease further with comorbidities such as type 2 diabetes and MASLD. Preclinical studies have shown that FGF15 (mouse ortholog of human FGF19) is necessary to protect against lean muscle mass loss following metabolic surgery-induced weight loss in a mouse model of diet-induced obesity. We evaluated if non-surgical weight loss interventions also lead to increased systemic levels of FGF19 and whether FGF19 levels are predictive of lean muscle mass following rapid weight loss in human subjects with obesity. Weight loss was induced in 176 subjects with obesity via a very low-energy diet, VLED (800 kcal/d) in the form of total liquid meal replacement for 3-4 months. We measured plasma FGF19 levels at baseline and following VLED-induced weight loss. Multiple linear regression was performed to assess if FGF19 levels were predictive of lean mass at baseline (obesity) and following VLED. Postprandial levels of FGF19 increased significantly following VLED-weight loss. Multiple linear regression analysis showed that baseline (obesity) FGF19 levels, but not post VLED FGF19 levels, significantly predicted the percent of lean muscle mass after VLED-induced weight loss, while controlling for age, sex, and the baseline percent lean mass. These data identify gut-muscle communication and FGF19 as a potentially important mediator of the preservation of lean muscle mass during rapid weight loss. [ABSTRACT FROM AUTHOR]

Abstract Adipose tissue dysfunction underlies the pathogenesis of metabolic disease. The metrics used to quantify adiposity and its association with metabolic disease, including body mass index, have limitations with important clinical implications. An understanding of the molecular and cellular mechanisms by which adipose tissue regulates systemic metabolism and contributes to metabolic disease will lead to next-generation adipose tissue–based therapy. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether sex-based differences exist in clinical effectiveness of percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) in patients with stable coronary artery disease.Background: A prior pre-specified unadjusted analysis from COURAGE showed that women randomized to PCI had a lower rate of death or myocardial infarction during a median 4.6-year follow-up with a trend for interaction with respect to sex.Methods: We analyzed outcomes in 338 women (15%) and 1949 men (85%) randomized to PCI plus OMT versus OMT alone after adjustment for relevant baseline characteristics.Results: There was no difference in treatment effect by sex for the primary end point (death or myocardial infarction; HR, 0.89; 95% CI, 0.77-1.03 for women and HR, 1.02, 95% CI 0.96-1.10 for men; P for interaction = .07). Although the event rate was low, a trend for interaction by sex was nonetheless noted for hospitalization for heart failure, with only women, but not men, assigned to PCI experiencing significantly fewer events as compared to their counterparts receiving OMT alone (HR, 0.59; 95% CI, 0.40-0.84, P < .001 for women and HR, 0.86; 95% CI, 0.74-1.01, P = .47 for men; P for interaction = .02). Both sexes randomized to PCI experienced significantly reduced need for subsequent revascularization (HR, 0.72; 95% CI, 0.62-0.83, P < .001 for women; HR, 0.84; 95% CI, 0.79-0.89, P < .001 for men; P for interaction = .02) with evidence of a sex-based differential treatment effect.Conclusion: In this adjusted analysis of the COURAGE trial, there were no significant differences in treatment effect on major outcomes between men and women. However, women assigned to PCI demonstrated a greater benefit as compared to men, with a reduction in heart failure hospitalization and need for future revascularization. These exploratory observations require further prospective study. [ABSTRACT FROM AUTHOR]

Objective: In addition to adipocytes, adipose tissue contains large numbers of immune cells. A wide range of evidence links the activity of these cells to regulation of adipocyte and systemic metabolic function. Bariatric surgery improves several aspects of metabolic derangements and at least some of these effects occur in a weight-loss independent manner. We sought to investigate the impact of vertical sleeve gastrectomy (VSG) on adipose immune cell frequencies. Methods: We analyzed the frequencies of immune cells within distinct adipose tissue depots in obese mice that had VSG or sham surgery with a portion of the latter group pair-fed such that their body mass was matched to the VSG animals. Results: We demonstrate that VSG induced a shift in the epididymal adipose tissue leukocyte profile including increased frequencies of CD11c− macrophages, increased frequencies of T cells (CD4+, CD8+, and CD4−/CD8− T cells all increased), but a significantly decreased frequency of adipose tissue dendritic cells (ATDC) that, despite the continued high fat feeding of the VSG group, dropped below control diet levels. Conclusions: These results indicate that VSG induces substantial changes in the immune populations residing in the adipose depots independent of weight loss. [ABSTRACT FROM AUTHOR]

Background Limited data guide the prediction of weight loss success or failure after bariatric surgery according to presurgery factors. There is significant variation in weight change after bariatric surgery and much interest in identifying preoperative factors that may contribute to these differences. This report evaluates the associations of a comprehensive set of baseline factors and 3-year weight change. Setting: Ten hospitals in 6 geographically diverse clinical centers in the United States. Methods Adults undergoing a first bariatric surgical procedure as part of clinical care by participating surgeons were recruited between 2006 and 2009. Participants completed research assessments utilizing standardized and detailed data collection on over 100 preoperative and operative parameters for individuals undergoing Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB). Weight was measured 3 years after surgery. Percent weight change for RYGB or LAGB from baseline to 3 years was analyzed as both a continuous and dichotomous outcome with cut points at 25% for RYGB and 10% for LAGB. Multivariable linear and logistic regression models were used to identify independent baseline predictors of the continuous and categorical outcomes, respectively. Results The median weight loss 3 years after surgery for RYGB (n = 1513) participants was 31.5% (IQR: 24.6%–38.4%; range, 59.2% loss to .9% gain) of baseline weight and 16.0% (IQR: 8.1%–23.1%; range, 56.1% loss to 12.5% gain) for LAGB (n = 509) participants. The median age was 46 years for RYGB and 48 years for LAGB; 80% of RYGB participants and 75% of LAGB participants were female; and the median baseline body mass index (BMI) was 46 kg/m 2 for RYGB and 44 kg/m 2 for LAGB. For RYGB, black participants lost 2.7% less weight compared with whites and participants with diabetes at baseline had 3.7% less weight loss at year 3 than those without diabetes at baseline. There were small but statistically significant differences in weight change for RYGB in those with abnormal kidney function and current or recent smoking. For LAGB participants, those with a large band circumference had 75% greater odds of experiencing less than 10% weight loss after adjusting for BMI and sex. Conclusions Few baseline variables were associated with 3-year weight change and the effects were small. These results indicate that baseline variables have limited predictive value for an individual’s chance of a successful weight loss outcome after bariatric surgery. Trial registration: NCT00465829, ClinicalTrials.gov. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Adipose tissue inflammation is a cause of obesity-related metabolic disease. Natural killer (NK) cells are an understudied cell type in the context of obesity. The goal of this study was to determine the phenotype of human adipose tissue NK cells. Methods: We used flow cytometry phenotyping to study adipose tissue and peripheral blood NK cells from obese and lean humans. Results: Human adipose tissue NK cells, relative to peripheral blood NK cells, express increased levels of activation markers. Adipose tissue NK cells also demonstrate an activated phenotype in obese relative to lean subjects, with increased expression of the activating receptor NKG2D. Conclusions: These data are the first detailed phenotypic characterization of human adipose tissue NK cells, and suggest a role for NK cells in adipose tissue inflammation in obesity. [Copyright &y& Elsevier]

Abstract: Background: Although it is recognized that a standardized approach to reporting weight change is essential to meaningful comparisons among cohorts and across studies, consensus is lacking. This study aimed to propose a method of reporting weight change that would allow meaningful comparisons among studies of patients who underwent bariatric surgery and to demonstrate its utility using an example from the Longitudinal Assessment of Bariatric Surgery (LABS). Methods: Relationships among several measures of weight change are described. Results from an observational, longitudinal cohort study of adults undergoing bariatric surgery and from simulation studies are used to illustrate the proposed method. Results: Baseline weight is a critical parameter when assessing weight change. Men undergoing a bariatric procedure other than gastric bypass or adjustable band tended to have greater weight loss 12 months after surgery than men undergoing gastric bypass when not accounting for baseline weight, but the opposite was found when results were adjusted for baseline weight. Simulation results show that with relatively modest sample sizes, the adjusted weight loss was significantly different between the 2 groups of men. Conclusion: A consistent metric for reporting weight loss after bariatric surgery is essential to interpret outcomes across studies and among subgroups. The baseline weight adjusted percent of weight loss (A%WL) uses a standard population (e.g., the LABS cohort) to account for differences between cohorts with respect to baseline weight, and its use can change the interpretation of results compared with an unadjusted measure. [Copyright &y& Elsevier]

Background: The COURAGE trial reported similar clinical outcomes for patients with stable ischemic heart disease (SIHD) receiving optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI). The current post hoc substudy analysis examined the relationship between baseline stress myocardial ischemia and clinical outcomes based on randomized treatment assignment. Methods: A total of 1,381 randomized patients (OMT n = 699, PCI + OMT n = 682) underwent baseline stress myocardial perfusion single-photon emission computed tomographic imaging. Site investigators interpreted the extent of ischemia by the number of ischemic segments using a 6-segment myocardial model. Patients were divided into those with no to mild (<3 ischemic segments) and moderate to severe ischemia (≥3 ischemic segments). Cox proportional hazards models were calculated to assess time to the primary end point of death or myocardial infarction. Results: At baseline, moderate to severe ischemia occurred in more than one-quarter of patients (n = 468), and the incidence was comparable in both treatment groups (P = .36). The primary end point, death or myocardial infarction, was similar in the OMT and PCI + OMT treatment groups for no to mild (18% and 19%, P = .92) and moderate to severe ischemia (19% and 22%, P = .53, interaction P value = .65). There was no gradient increase in events for the overall cohort with the extent of ischemia. Conclusions: From the COURAGE trial post hoc substudy, the extent of site-defined ischemia did not predict adverse events and did not alter treatment effectiveness. Currently, evidence supports equipoise as to whether the extent and severity of ischemia impact on therapeutic effectiveness. [Copyright &y& Elsevier]

Abstract: Adipose tissue macrophages are important mediators of inflammation and insulin resistance in obesity. IFN-γ is a central regulator of macrophage function. The role of IFN-γ in regulating systemic inflammation and insulin resistance in obesity is unknown. We studied obese IFN-γ knockout mice to identify the role of IFN-γ in regulating inflammation and insulin sensitivity in obesity. IFN-γ-knockout C57Bl/6 mice and wild-type control litter mates were maintained on normal chow or a high fat diet for 13 weeks and then underwent insulin sensitivity testing then sacrifice and tissue collection. Flow cytometry, intracellular cytokine staining, and QRTPCR were used to define tissue lymphocyte phenotype and cytokine expression profiles. Adipocyte size was determined from whole adipose tissue explants examined under immunofluorescence microscopy. Diet-induced obesity induced systemic inflammation and insulin resistance, along with a pan-leukocyte adipose tissue infiltrate that includes macrophages, T-cells, and NK cells. Obese IFN-γ-knockout animals, compared with obese wild-type control animals, demonstrate modest improvements in insulin sensitivity, decreased adipocyte size, and an M2-shift in ATM phenotype and cytokine expression. These data suggest a role for IFN-γ in the regulation of inflammation and glucose homeostasis in obesity though multiple potential mechanisms, including effects on adipogenesis, cytokine expression, and macrophage phenotype. [Copyright &y& Elsevier]

The article provides information on a study which examined angiographic progression of lesions underlying symptom progression during contemporary optimal medical therapy (OMT). It highlights the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial undergone by patients, who were treated with OMT. A single index lesion was identified for each patient and was considered to be the lesion most likely to be responsible for the change in symptom status.

The article discusses a research study on the cost-effectiveness of percutaneous coronary intervention (PCI) as a function of angina severity in patients with stable angina. The researchers assessed angina severity using the Seattle Angina Questionnaire (SAQ). They determined that incremental cost of PCI to provide meaningful clinical benefit was lower for patients with severe angina than those with mild or no angina.

The article compares three distinct healthcare systems (HCS) in North America, namely Department of Veterans Affairs HCS (VA HCS), US non-VA HCS and Canadian system, and determines treatment difference in cardiovascular outcomes by HCS. It mentions that the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial has similar baseline demographics within each HCS. The article concludes that the addition of percutaneous coronary intervention to optimal medical therapy did not improve five-year survival among the 3 HCS.

Abstract: The classification of patients with angina pectoris into various subgroups, which clearly differ in risk based on the patient''s characteristics, is difficult. Changes in pain threshold occur frequently. The variation in intensity of the “chest discomfort” makes the history and physical of limited value in making the diagnosis. It may be necessary to use noninvasive testing to demonstrate myocardial ischemia and/or coronary angiography to define stenotic coronary artery stenosis. Within the past 30 years, there have been major advances in the successful medical and invasive treatment of angina pectoris. There are now several forms of effective therapy, which are discussed in detail in this monograph. [Copyright &y& Elsevier]

Abstract: Background: The goals were to compare the morbidity and mortality between primary and revisional bariatric surgery and to identify the clinical predictors of adverse outcomes among patients undergoing revisional surgery in the Longitudinal Assessment of Bariatric Surgery consortium. The study was multi-institutional at university hospitals in the United States. Methods: Data from the LABS-1 (safety) cohort were analyzed, excluding primary gastric banding patients. A total of 3802 LABS-1 patients were included: 3577 who underwent primary surgery and 225 who underwent revisional surgery. The demographic, clinical, operative, and 30-day outcome data were compared between the 2 groups. A nonlinear mixed effects logit model was used to identify independent risk factors for adverse outcomes (death, deep vein thrombosis, pulmonary embolism, reintubation, reoperation, or discharge after 30 days). Results: Compared with those undergoing revisional surgery, the primary surgery patients were younger (median age 44 versus 49 years, P <.0001) and more likely to be male (20.5% versus 12.7%, P = .006) and heavier (median body mass index 47.3 versus 41.2 kg/m2, P <.0001) and to have more co-morbidities (P <.0001), including hypertension (56.0% versus 46.0%, P = .0044), diabetes (35.7% versus 20.0%, P <.0001), and sleep apnea (50.3% versus 27.2%, P <.0001). The operative time for the revisional procedures was longer (median 181 versus 135 min, P <.0001) and associated with greater blood loss (median 100 versus <50 mL, P <.0001). Adverse outcomes were more likely after revisional surgery (15.1% versus 5.3%, P <.0001, odds ratio 2.4, 95% confidence interval 1.6–3.6). After adjusting for patient characteristics previously shown to be associated with adverse outcomes, this difference remained statistically significant (odds ratio 2.3, 95% confidence interval 1.5–3.8). The 30-day mortality rate was similar in the 2 groups (.4%). Conclusion: Revisional surgery was performed without substantial mortality but with a greater incidence of adverse outcomes than was primary bariatric surgery. [Copyright &y& Elsevier]

Background: COURAGE compared outcomes in stable coronary patients randomized to optimal medical therapy plus percutaneous coronary intervention (PCI) versus optimal medical therapy alone. Methods and Results: Angiographic data were analyzed by treatment arm, health care system (Veterans Administration, US non-Veterans Administration, Canada), and gender. Veterans Administration patients had higher prevalence of coronary artery bypass graft surgery and left ventricular ejection fraction < or =50%. Men had worse diameter stenosis of the most severe lesion, higher prevalence of prior coronary artery bypass graft surgery, lower left ventricular ejection fraction, and more 3-vessel disease that included a proximal left anterior descending lesion (P<0.0001 for all comparisons versus women). Failure to cross rate (3%) and visual angiographic success of stent procedures (97%) were similar to contemporary practice in the National Cardiovascular Data Registry. Quantitative angiographic PCI success was 93% (residual lesion <50% in-segment) and 82% (<20% in-stent), with only minor nonsignificant differences among health care systems and genders. Event rates were higher in patients with higher jeopardy scores and more severe vessel disease, but rates were similar irrespective of treatment strategy. Within the PCI plus optimal medical therapy arm, complete revascularization was associated with a trend toward lower rate of death or nonfatal myocardial infarction. Complete revascularization was similar between genders and among health care systems. Conclusions: PCI success and completeness of revascularization did not differ significantly by health care system or gender and were similar to contemporary practice. Angiographic burden of disease affected overall event rates but not response to an initial strategy of PCI plus optimal medical therapy or optimal medical therapy alone. [ABSTRACT FROM AUTHOR]

Abstract: Mitral regurgitation (MR) is increasingly prevalent and poses an important public health problem. There are several mechanisms through which MR can occur. Primary (organic) MR is due to intrinsic valvular disease, whereas secondary (functional) MR is due to disruption of an otherwise normal mitral apparatus because of abnormal ventricular geometry. Identification of the causative mechanism is important as this will dictate management strategy and may influence subsequent outcome. Careful assessment of MR severity is important with the use of quantitative measures. There is currently no effective medical treatment for chronic MR. Careful follow-up is paramount in the management of MR to accomplish timely surgical intervention. Mitral valve repair is preferable to valve replacement. In chronic primary MR, conventional timing of surgery is based upon appearance of symptoms and hemodynamic consequences of chronic volume overload. Optimal timing of surgery for asymptomatic patients with chronic severe MR remains controversial although there is an increasing trend toward earlier surgery. In recent years there have been significant advances in percutaneous valve interventions for MR. Although initial results are promising, longer term evaluation will answer questions concerning efficacy, durability, and safety of these interventions. [Copyright &y& Elsevier]

Abstract: Background: Revisional bariatric surgery is increasing in frequency, but the morbidity and efficacy have not been well defined. The primary aim of this study was to determine the clinical efficacy with respect to weight loss, and associated morbidity, of revisional bariatric surgery in an academic university hospital bariatric surgery program. Methods: A retrospective review of all patients who underwent revisional bariatric surgery for failed primary restrictive procedures, including gastroplasty and gastric bypass, but not including gastric banding or malabsorptive procedures, during a 10-year period at a single university hospital was performed. The perioperative morbidity and long-term weight loss and clinical results were determined from the medical charts. Results: A total of 41 patients met the inclusion criteria. The primary bariatric procedures included vertical banded gastroplasty in 20 and Roux-en-Y gastric bypass in 21. The indications for revisional surgery included poor weight loss, weight regain, and various technical problems, including anastomotic stenosis and ulcer. The major morbidity rate was 17%. No patients died. The weight loss results varied depending on the indication for the revisional surgery and reoperative solution applied. The resolution of technical problems was achieved in all patients. Conclusion: Revisional bariatric surgery can be performed with minimal mortality, albeit significant morbidity. The efficacy with respect to weight loss appeared acceptable, although the results were not as good as those after primary bariatric surgery. The analysis of patient subsets stratified by surgical history and revisional strategy provided important insights into the mechanisms of failure and efficacy of different revisional strategies. [Copyright &y& Elsevier]

Multiple clinical trials have demonstrated β-blockers improving survival after myocardial infarction (MI). Patients with “bradycardia-related” contraindications to β-blockers, such as those with asymptomatic bradycardia or AV conduction abnormalities, have been excluded from clinical trials of β-blockers and continue to be excluded from post-MI β-blocker therapy in routine clinical practice. These patients tend to be elderly and have a high 1-year mortality. If β-blockers provide benefit to the post-MI patient independent of their heart rate–lowering effect, then these patients could benefit substantially from initiation of β-blocker therapy. However, in this particular group of patients, β-blockers can be safely initiated only if more severe or significant bradycardia can be prevented by pacemaker implantation. It is unclear whether adverse effects related to pacemaker implantation could also negate some or all of the hypothesized benefit of β-blocker therapy. Although β-blockers are particularly effective in the elderly, the benefit of β-blocker therapy in patients with bradycardia-related contraindications to β-blockers has not been established. The PACE-MI trial is a randomized controlled trial that will address whether β-blocker therapy enabled by pacemaker implantation is superior to no β-blocker and no pacemaker therapy after MI in patients with rhythm contraindications to β-blockers or in those who have developed symptomatic bradycardia due to β-blockers. The trial will randomize 1124 patients to standard therapy (not to include β-blockers as patients must have a contraindication to be enrolled) or standard therapy plus pacemaker implantation and β-blocker. The primary end point is the composite end point of total mortality plus nonfatal reinfarction. [Copyright &y& Elsevier]

Background: Coronary heart disease (CHD) and diabetes may have synergistic effects on symptoms, self-management, and general and cardiac-specific health status. Purpose: We compared symptom distress, self-management difficulties, and general and cardiac-specific health status in patients with CHD by the presence and severity of diabetes. Methods: We performed a cross-sectional study of 1013 patients enrolled in the COURAGE trial, with the use of clinical data, the Symptom Distress Scale, the Self-Management Difficulties Scale, the Short-Form 36, and the Seattle Angina Questionnaire. Results: Patients with diabetes and greater severity of diabetes had worse findings in symptom distress, self-management difficulties, and general and cardiac-specific health status than patients without diabetes. Conclusions: A robust effect of diabetes on symptom distress and self-management difficulties was found in patients with CHD. The results from the Seattle Angina Questionnaire illustrate difficulty in attributing physical limitations to specific symptoms or conditions, and show the experience of comorbid conditions to be synergistic. Clinicians’ understanding of this synergy and integration of condition-specific care with general treatment and self-management practices are needed. [Copyright &y& Elsevier]

Percutaneous coronary intervention (PCI) remains a major therapeutic option for the treatment of chronic coronary artery disease. In the COURAGE trial, 2287 patients with chronic coronary disease were randomized between PCI with medical management and medical management alone. Embedded within the COURAGE trial is a detailed economic analysis being conducted in three health care systems: the US Veterans Administration (VA), Canada, and the US non-VA. Resource use and costs are being collected for each system and overall. Survival is assessed internally in the trial with mean follow-up of 4.5 years. Long-term mean survival will be estimated by projecting survival beyond the trial period by extrapolating the in-trial hazard rates. Utility is being assessed at baseline and at 1, 3, and 6 months and annually thereafter, using a computer-administered standard gamble. Quality-adjusted life years are calculated by multiplying survival by utility. The incremental cost-effectiveness ratio of PCI will be defined as the additional cost of PCI divided by the gain in life years and quality-adjusted life years. The 95% confidence regions of efficacy and costs will be determined by bootstrap over a range of acceptability thresholds, which will then be displayed in the cost-effectiveness plane and as a cost-effectiveness acceptability curve. A multilevel regression model will assess cost-effectiveness from a net benefit perspective. These approaches should provide the most detailed assessment available of the cost-effectiveness of PCI for coronary artery disease. [Copyright &y& Elsevier]

Background: Major improvements in medical therapy and percutaneous coronary intervention (PCI) for coronary heart disease have occurred during the past decade, but no randomized trial has compared these 2 strategies for the “hard” clinical end points of death or myocardial infarction nor have earlier studies incorporated the use of coronary stents and aggressive multifaceted medical therapy during long-term follow-up. Methods: The COURAGE trial is a multicenter study of patients with documented myocardial ischemia and angiographically confirmed single or multivessel coronary artery disease who are randomized to a strategy of PCI plus intensive medical therapy or intensive medical therapy alone. Medical therapy in both groups is guideline-driven and includes: aspirin, clopidogrel, simvastatin (low-density lipoprotein cholesterol target 60-85 mg/dL), long-acting metoprolol and/or amlodipine, lisinopril or losartan, and long-acting nitrates, as well as lifestyle interventions. The primary end point is a composite of all-cause mortality or acute myocardial infarction, and there will be 85% power to detect an absolute 4.6% (relative 22%) difference between strategies. The principal hypothesis is that PCI plus aggressive medical therapy (projected event rate 16.4%) will be superior to aggressive medical therapy alone (projected event rate 21%) during a 2.5- to 7-year (median of 5 years) follow-up. Conclusions: COURAGE is the largest prospective randomized trial of PCI versus intensive medical therapy to date and will define the incremental benefits of PCI in the setting of contemporary optimal medical therapy for chronic coronary heart disease. A total of 2287 patients have been enrolled, and follow-up will conclude in June 2006. [Copyright &y& Elsevier]