UCP1 expression in human brown adipose tissue is inversely associated with cardiometabolic risk factors.

OBJECTIVE: Brown adipose tissue (BAT) is a therapeutic target for obesity. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is commonly used to quantify human BAT mass and activity. Detectable 18F-FDG uptake by BAT is associated with reduced prevalence of cardiometabolic disease. However, 18F-FDG uptake may not always be a reliable marker of BAT thermogenesis, for example, insulin resistance may reduce glucose uptake. Uncoupling protein 1 (UCP1) is the key thermogenic protein in BAT. Therefore, we hypothesised that UCP1 expression may be altered in individuals with cardiometabolic risk factors. METHODS: We quantified UCP1 expression as an alternative marker of thermogenic capacity in BAT and white adipose tissue (WAT) samples (n = 53) and in differentiated brown and white pre-adipocytes (n = 85). RESULTS: UCP1 expression in BAT, but not in WAT or brown/white differentiated pre-adipocytes, was reduced with increasing age, obesity, and adverse cardiometabolic risk factors such as fasting glucose, insulin, and blood pressure. However, UCP1 expression in BAT was preserved in obese subjects of <40 years of age. To determine if BAT activity was also preserved in vivo, we undertook a case-control study, performing 18F-FDG scanning during mild cold exposure in young (mean age ∼22 years) normal weight and obese volunteers. 18F-FDG uptake by BAT and BAT volume were similar between groups, despite increased insulin resistance. CONCLUSION: 18F-FDG uptake by BAT and UCP1 expression are preserved in young obese adults. Older subjects retain precursor cells with the capacity to form new thermogenic adipocytes. These data highlight the therapeutic potential of BAT mass expansion and activation in obesity.

The serotonin transporter sustains human brown adipose tissue thermogenesis.

Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.

Human brown adipose tissue function: insights from current in vivo techniques.

The identification of brown adipose tissue (BAT) as a thermogenic organ in human adults approximately 20 years ago raised the exciting possibility of activating this tissue as a new treatment for obesity and cardiometabolic disease. [18F]Fluoro-2-deoxyglucose (18F-FDG) combined positron emission tomography and computed tomography (PET/CT) scanning is the most commonly used imaging modality to detect and quantify human BAT activity in vivo. This technique exploits the substantial glucose uptake by BAT during thermogenesis as a marker for BAT metabolism. 18F-FDG PET has provided substantial insights into human BAT physiology, including its regulatory pathways and the effect of obesity and cardiometabolic disease on BAT function. The use of alternative PET tracers and the development of novel techniques such as magnetic resonance imaging, supraclavicular skin temperature measurements, contrast-enhanced ultrasound, near-infrared spectroscopy and microdialysis have all added complementary information to improve our understanding of human BAT. However, many questions surrounding BAT physiology remain unanswered, highlighting the need for further research and novel approaches to investigate this tissue. This review critically discusses current techniques to assess human BAT function in vivo, the insights gained from these modalities and their limitations. We also discuss other promising techniques in development that will help dissect the pathways regulating human thermogenesis and determine the therapeutic potential of BAT activation.

Staphylococcus caprae native mitral valve infective endocarditis.

INTRODUCTION: Staphylococcus caprae is a rare cause of infective endocarditis. Here, we report a case involving the native mitral valve in the absence of an implantable cardiac electronic device. CASE PRESENTATION: A 76-year-old man presented with a 2 week history of confusion and pyrexia. His past medical history included an open reduction and internal fixation of a humeral fracture 17 years previously, which remained non-united despite further revision 4 years later. There was no history of immunocompromise or farm-animal contact. Two sets of blood culture bottles, more than 12 h apart, were positive for S. caprae. Trans-thoracic echocardiography revealed a 1×1.2 cm vegetation on the mitral valve, with moderate mitral regurgitation. Due to ongoing confusion, he had a magnetic resonance imaging brain scan, which showed a subacute small vessel infarct consistent with a thromboembolic source. A humeral SPECT-CT (single-photon emission computerized tomography-computerized tomography) scan showed no clear evidence of acute osteomyelitis. Surgical vegetectomy and mitral-valve repair were considered to reduce the risk of further systemic embolism and progressive valve infection. However, the potential risks of surgery to this patient led to a decision to pursue a cure with antibiotic therapy alone. He remained well 3 months after discharge, with repeat echocardiography demonstrating a reduction in the size of the vegetation (0.9 cm). CONCLUSION: Management of this infection was challenging due to its rarity and its unclear progression, complicated by the dilemma surrounding surgical intervention in a patient with a complex medical background.

Left ventricular hypertrophy with strain and aortic stenosis.

BACKGROUND: ECG left ventricular hypertrophy with strain is associated with an adverse prognosis in aortic stenosis. We investigated the mechanisms and outcomes associated with ECG strain. METHODS AND RESULTS: One hundred and two patients (age, 70 years [range, 63-75 years]; male, 66%; aortic valve area, 0.9 cm(2) [range, 0.7-1.2 cm(2)]) underwent ECG, echocardiography, and cardiovascular magnetic resonance. They made up the mechanism cohort. Myocardial fibrosis was determined with late gadolinium enhancement (replacement fibrosis) and T1 mapping (diffuse fibrosis). The relationship between ECG strain and cardiovascular magnetic resonance was then assessed in an external validation cohort (n=64). The outcome cohort was made up of 140 patients from the Scottish Aortic Stenosis and Lipid Lowering Trial Impact on Regression (SALTIRE) study and was followed up for 10.6 years (1254 patient-years). Compared with those without left ventricular hypertrophy (n=51) and left ventricular hypertrophy without ECG strain (n=30), patients with ECG strain (n=21) had more severe aortic stenosis, increased left ventricular mass index, more myocardial injury (high-sensitivity plasma cardiac troponin I concentration, 4.3 ng/L [interquartile range, 2.5-7.3 ng/L] versus 7.3 ng/L [interquartile range, 3.2-20.8 ng/L] versus 18.6 ng/L [interquartile range, 9.0-45.2 ng/L], respectively; P<0.001) and increased diffuse fibrosis (extracellular volume fraction, 27.4±2.2% versus 27.2±2.9% versus 30.9±1.9%, respectively; P<0.001). All patients with ECG strain had midwall late gadolinium enhancement (positive and negative predictive values of 100% and 86%, respectively). Indeed, late gadolinium enhancement was independently associated with ECG strain (odds ratio, 1.73; 95% confidence interval, 1.08-2.77; P=0.02), a finding confirmed in the validation cohort. In the outcome cohort, ECG strain was an independent predictor of aortic valve replacement or cardiovascular death (hazard ratio, 2.67; 95% confidence interval, 1.35-5.27; P<0.01). CONCLUSION: ECG strain is a specific marker of midwall myocardial fibrosis and predicts adverse clinical outcomes in aortic stenosis.

Impact of the introduction of emergency ultrasound to one large UK emergency department: the REBUS study.

AIM: Firstly, to detail the experiences of one UK training region in establishing an emergency ultrasound (EU) training programme and secondly, to report the initial 30 months of EU scanning experience. METHODS: Prospective study of all documented emergency department (ED) ultrasound scans. Results were extracted from written paper reports and/or electronically saved images. Details of scan date, time, type of scan, grade of operator, supervision status (whether supervised by a level 1 competent scanner) and whether the scan was clinical (performed or supervised by a level 1 operator) or training, were recorded. EU scans were reviewed for quality (internal quality assurance) and for diagnostic accuracy (external quality assurance). RESULTS: Between 14 January 2009 and 4 July 2011, 626 scans were performed by 41 operators. 263 (42%) scans were completed outside of normal working hours (09:00 to 17:00). There were 251 abdominal aorta and inferior vena cava scans (40% of all scans) and 198 focused assessment with sonography in trauma scans (32%). The number of scans performed by each operator varied widely. 87 scans (14%) were supervised but the majority (459; 73%) were not. 484 (77%) scans were for training purposes, 124 (20%) were clinical scans and the majority (401; 63%) were performed by either speciality registrars (ST4-6) or specialist registrars (SpR). When the three commonest types of scans performed were analysed, eight false positives and 11 false negatives were identified. Only seven of these were deemed of poor quality and none led to poor patient outcome. CONCLUSIONS: Since the acquisition of our ED ultrasound machine and the development of a quality assured training programme, on average 20 scans per month have been performed in the ED, with no known adverse patient outcomes.