Bariatric Surgery and Incident Heart Failure: a Propensity Score Matched Nationwide Cohort Study.

BACKGROUND: Bariatric surgery results in significant weight loss and a reduction in the incidence of cardiovascular disease in patients with obesity; however, relatively little research considers its effect on the incidence of heart failure (HF). We aimed to determine whether bariatric surgery reduces the incidence of HF in patients with obesity, compared to non-surgical management. METHODS: A propensity-score matched, retrospective cohort study using patients records from the nationwide Clinical Practice Research Database (CPRD) was conducted. 3052 patients who received bariatric surgery were matched with 3052 patients who did not, according to propensity to receive bariatric surgery, determined through a logistic regression model. Patients were eligible if >18 years old, BMI > 35 kg/m2, and no prior diagnosis of HF. The pre-defined primary endpoint was the development of new HF, and secondary endpoints were all-cause mortality and hospitalisations due to HF. RESULTS: Patients who received bariatric surgery had a significantly lower incidence of new HF (hazard ratio 0.45, 95% confidence interval 0.28-0.73, p = 0.0011) and all-cause mortality (hazard ratio 0.56, 95% confidence interval 0.38-0.83, p = 0.0036). CONCLUSIONS: This study provides evidence of lower rates of HF and all-cause mortality in patients who undergo bariatric surgery, compared to propensity-score matched controls. Future studies to understand the mechanism(s) involved in this reduction and explore the lifetime benefits in high-risk cohorts are paramount.

The addition of genetic testing and cardiovascular magnetic resonance to routine clinical data for stratification of etiology in dilated cardiomyopathy.

Background: Guidelines recommend genetic testing and cardiovascular magnetic resonance (CMR) for the investigation of dilated cardiomyopathy (DCM). However, the incremental value is unclear. We assessed the impact of these investigations in determining etiology. Methods: Sixty consecutive patients referred with DCM and recruited to our hospital biobank were selected. Six independent experts determined the etiology of each phenotype in a step-wise manner based on (1) routine clinical data, (2) clinical and genetic data and (3) clinical, genetic and CMR data. They indicated their confidence (1-3) in the classification and any changes to management at each step. Results: Six physicians adjudicated 60 cases. The addition of genetics and CMR resulted in 57 (15.8%) and 26 (7.2%) changes in the classification of etiology, including an increased number of genetic diagnoses and a reduction in idiopathic diagnoses. Diagnostic confidence improved at each step (p < 0.0005). The number of diagnoses made with low confidence reduced from 105 (29.2%) with routine clinical data to 71 (19.7%) following the addition of genetics and 37 (10.3%) with the addition of CMR. The addition of genetics and CMR led to 101 (28.1%) and 112 (31.1%) proposed changes to management, respectively. Interobserver variability showed moderate agreement with clinical data (κ = 0.44) which improved following the addition of genetics (κ = 0.65) and CMR (κ = 0.68). Conclusion: We demonstrate that genetics and CMR, frequently changed the classification of etiology in DCM, improved confidence and interobserver variability in determining the diagnosis and had an impact on proposed management.

Long-term cardiovascular outcomes after orlistat therapy in patients with obesity: a nationwide, propensity-score matched cohort study.

AIMS: The rising prevalence of obesity and its associated comorbidities represent a growing public health issue; in particular, obesity is known to be a major risk factor for cardiovascular disease. Despite the evidence behind the efficacy of orlistat in achieving weight loss in patients with obesity, no study thus far has quantified its long-term effect on cardiovascular outcomes. The purpose of this study is to explore long-term cardiovascular outcomes after orlistat therapy. METHODS AND RESULTS: A propensity-score matched cohort study was conducted on the nation-wide electronic primary and integrated secondary healthcare records of the Clinical Practice Research Datalink (CPRD). The 36 876 patients with obesity in the CPRD database who had completed a course of orlistat during follow-up were matched on a 1:1 basis with equal numbers of controls who had not taken orlistat. Patients were followed up for a median of 6 years for the occurrence of the primary composite endpoint of major adverse cardiovascular events (fatal or non-fatal myocardial infarction or ischaemic stroke), and a number of secondary endpoints including primary endpoint components individually, the occurrence of new-onset heart failure, coronary revascularization, new chronic kidney disease stage III+ (CKD3+), and all-cause mortality. During the median study follow-up of 6 years, the occurrence of major adverse cardiovascular events was lower in the orlistat cohort [hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.66-0.83, P < 0.001]. Patients who took orlistat experienced lower rates of myocardial infarction (HR 0.77; 95% CI 0.66-0.88, P < 0.001) and ischaemic stroke (HR 0.68; 95% CI 0.56 to -0.84, P < 0.001) as well as new-onset heart failure (HR 0.79; 95% CI 0.67-0.94, P = 0.007). There was no differences in revascularization rates (HR 1.12; 95% CI 0.91-1.38, P = 0.27), but a lower rate of both CKD3+ development (HR 0.78; 95% CI 0.73-0.83, P < 0.001) and mortality (HR 0.39, 95% CI 0.36 to -0.41, P < 0.001) was observed. CONCLUSION: In this nation-wide, propensity-score matched study, orlistat was associated with lower rates of overall major adverse cardiovascular events, new-onset heart failure, renal failure, and mortality. This study adds to current evidence on the known improvements in cardiovascular risk factor profiles of orlistat treatment by suggesting a potential role in primary prevention.

Mechanisms underlying the therapeutic potential of mesenchymal stem cells in atherosclerosis.

Atherosclerosis is a chronic inflammatory condition resulting in the formation of fibrofatty plaques within the intimal layer of arterial walls. The identification of resident stem cells in the vascular wall has led to significant investigation into their contributions to health and disease, as well as their therapeutic potential. Of these, mesenchymal stem cells (MSCs) are the most widely studied in human clinical trials, which have demonstrated a modulatory role in vascular physiology and disease. This review highlights the most recent knowledge surrounding the cell biology of MSCs, including their origin, identification markers and differentiation potential. The limitations concerning the implementation of MSC therapy are considered and novel solutions to overcome these are proposed.

Atherosclerotic disease burden after bariatric surgery in patients with obesity and type 2 diabetes.

BACKGROUND: The rising rates of obesity, along with its associated morbidities, represent an important global health threat. Atherosclerotic cardiovascular disease (ASCVD) is among the most common and hazardous obesity-related morbidity, and it is especially prevalent among those who suffer from type 2 diabetes (T2DM). Bariatric surgery (BS) is known to help with effective weight management and reduce the burden of cardiovascular risk factors, especially T2DM. METHODS: A nested propensity-matched cohort study was carried out using the Clinical Practice Research Datalink. The cohort included 1186 patients with no past history of ASCVD, 593 of whom underwent BS and 593 propensity-score matched controls, followed up for a mean of 42.7 months. The primary end point was the incidence of new ASCVD; defined as new coronary artery disease (CAD), cerebrovascular disease (CeVD), peripheral arterial disease (PAD), or miscellaneous atherosclerotic disease; secondary end points included primary end point components alone and all-cause mortality. RESULTS: Patients who underwent BS had significantly lower rates of new ASCVD (hazard ratio [HR] 0.53, confidence interval [CI] 0.30-0.95, P = 0.032. There were no significant differences in rates of CAD, CeVD, and PAD individually across cohorts, but a lower rate of all-cause mortality was observed in the BS cohort (HR 0.36, CI 0.19-0.71, P = 0.003). CONCLUSIONS: BS was associated with improved ASCVD outcomes and lower mortality in patients with obesity and T2DM. This study provides evidence for increased awareness of potential benefits of BS in the management of obesity by highlighting a potential role in primary prevention for ASCVD.

Microglia priming by interleukin-6 signaling is enhanced in aged mice.

During peripheral infection, excessive production of pro-inflammatory cytokines in the aged brain from primed microglia induces exaggerated behavioral pathologies. While the pro-inflammatory cytokine IL-6 increases in the brain with age, its role in microglia priming is not known. This study examined the functional role of IL-6 signaling on microglia priming. Our hypothesis is that IL-6 signaling mediates primed states of microglia in the aged. An initial study assessed age-related alteration in IL-6 signaling molecules; sIL-6R and sgp130 were measured in cerebrospinal fluid of young and aged wild-type animals. Subsequent studies of isolated microglia from C57BL6/J (IL-6+/+) and IL-6 knock-out (IL-6-/-) mice showed significantly less MHC-II expression in aged IL-6-/- compared to IL-6+/+ counterparts. Additionally, adult and aged IL-6+/+ and IL-6-/- animals were administered lipopolysaccharide (LPS) to simulate a peripheral infection; sickness behaviors and hippocampal cytokine gene expression were measured over a 24 h period. Aged IL-6-/- animals were resilient to LPS-induced sickness behaviors and recovered more quickly than IL-6+/+ animals. The age-associated baseline increase of IL-1ß gene expression was ablated in aged IL-6-/- mice, suggesting IL-6 is a key driver of cytokine activity from primed microglia in the aged brain. We employed in vitro studies to understand molecular mechanisms in priming factors. MHC-II and pro-inflammatory gene expression (IL-1ß, IL-10, IL-6) were measured after treating BV.2 microglia with sIL-6R and IL-6 or IL-6 alone. sIL-6R enhanced expression of both pro-inflammatory genes and MHC-II. Taken together, these data suggest IL-6 expression throughout life is involved in microglia priming and increased amounts of IL-6 following peripheral LPS challenge are involved in exaggerated sickness behaviors in the aged.

Dietary Luteolin Reduces Proinflammatory Microglia in the Brain of Senescent Mice.

Brain microglia become dysregulated during aging and express proinflammatory cytokines that play a role in cognitive aging. Recent studies suggest the flavonoid luteolin reduces neuroinflammation and improves learning and memory in aged mice. However, if dietary luteolin reduces microglia activity in the brain of senescent mice is not known. We hypothesized that feeding aged mice a diet with luteolin would reduce microglia activity. Adult (3-6 months) and aged (22-24 months) mice were fed American Institute of Nutrition (AIN)-93M or AIN-93M with luteolin (6 g/kg) for 4 weeks and injected intraperitoneally with saline or lipopolysaccharide (LPS) before microglia were isolated and stained for major histocompatibility complex (MHC) class II, interleukin (IL)-1ß, and IL-6 for flow cytometry. In saline-treated mice fed control diet, aging increased the proportion of microglia that stained for MHC class II (<3% for adults vs. 23% for aged), IL-1ß (<2% for adults vs. 25% for aged), and IL-6 (<2% for adults vs. 25% for aged), indicating an age-related increase in proinflammatory microglia. In saline-treated aged mice fed luteolin, the proportion of microglia that stained for MHC class II, IL-1ß, and IL-6 was reduced by nearly half (to 12%, 13%, and 12%, respectively). Interestingly, luteolin significantly reduced the proportion of microglia that stained for IL-1ß and IL-6 in LPS-treated adult mice but not aged. Collectively, the results show that a diet supplemented with luteolin inhibited brain microglia activity during aging and activation by LPS in adults. Therefore, luteolin may inhibit neuroinflammation and improve cognition in the otherwise healthy aged by constraining brain microglia.