Search

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer’s disease. While some common aetiological mechanisms are known, the role of amyloid beta 42 (Aβ42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aβ42, which is increased from adipose tissue of obese mice and is associated with higher plasma Aβ42. Increasing circulating Aβ42 levels in non-obese mice had no effect on systemic glucose homeostasis but had obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. These effects on cardiac function were not observed when circulating levels of the closely related Aβ40 isoform were increased. Administration of an Aβ neutralising antibody prevented obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aβ neutralising antibody administration in established obesity prevented further deterioration of cardiac function. Multi-contrast transcriptomic analyses revealed that Aβ42 impacted pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aβ42 inhibited mitochondrial function. These data reveal a role for systemic Aβ42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer’s disease could be effective in combating obesity-induced heart failure.

Aims/Hypothesis Current drugs used to treat metabolic diseases such as obesity and type 2 diabetes have limited efficacy in directly normalising muscle insulin action, while exercise is effective in enhancing this aspect of metabolic disease. We recently identified Scriptaid as a compound that can replicate aspects of the exercise adaptive response, through disruption of the class IIa HDAC corepressor complex. The Aim of this study was to determine the effect of Scriptaid on muscle insulin action in obesity. Materials and Methods Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily i.p. injection for four weeks. Whole body and skeletal muscle metabolic phenotyping of mice was performed in addition to echocardiography to assess cardiac morphology and function. Results Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function. Conclusion These data show that pharmacological targeting of the class IIa HDACs corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.

Reduced nitric oxide (NO) bioavailability plays a central role in the pathogenesis of myocardial ischemia-reperfusion injury (I-R), and reduced l-arginine transport via cationic amino acid transporter-1 is a key contributor to the reduced NO levels. Insulin can increase NO levels by increasing the transport of its substrate l-arginine but insulin alone exerts minimal cardiac protection in I-R. We hypothesized that combined insulin and l-arginine may provide cardioprotective effects in the setting of myocardial I-R. The effect of supplemental insulin, l-arginine and the combination was examined in cardiomyocytes exposed to hypoxia/reoxygenation and in isolated perfused mouse hearts undergoing ischemia/reperfusion. When compared to controls, cardiomyocytes treated upon reoxygenation with 1nM insulin+1mM l-arginine exhibited significant (all P

We aimed to compare hypofibrinogenaemia prevalence in major bleeding patients across all clinical contexts, fibrinogen supplementation practice, and explore the relationship between fibrinogen concentrations and mortality. This cohort study included all adult patients from 20 hospitals across Australia and New Zealand who received massive transfusion between April 2011 and October 2015. Of 3566 patients, 2829 (79%) had fibrinogen concentration recorded, with a median first and lowest concentration of 2·0 g/l (interquartile range [IQR] 1·5-2·7) and 1·8 g/l (IQR 1·3-2·4), respectively. Liver transplant (1·7 g/l, IQR 1·2-2·1), trauma (1·8, IQR 1·3-2·5) and vascular surgery (1·9 g/l, IQR 1·4-2·5) had lower concentrations. Total median fibrinogen dose administered from all products was 7·3 g (IQR 3·3-13·0). Overall, 1732 (61%) received cryoprecipitate and 9 (1%) fibrinogen concentrate. Time to cryoprecipitate issue in those with initial fibrinogen concentration1 g/l was 2·5 h (IQR 1·2-4·3 h). After adjustment, initial fibrinogen concentration had a U-shaped association with in-hospital mortality [adjusted odds ratios: fibrinogen1 g/l, 2·31 (95% confidence interval (CI) 1·48-3·60); 1-1·9 g/l, 1·29 (95% CI 0·99-1·67) and4 g/l, 2·03 (95% CI 1·35-3·04), 2-4 g/l reference category]. The findings indicate areas for practice improvement including timely administration of cryoprecipitate, which is the most common source of concentrated fibrinogen in Australia and New Zealand.

To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity.Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function.Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function.These data show that pharmacological targeting of the class IIa HDAC corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.

The development of diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes (T2D). Current therapeutic interventions for T2D have limited impact on the development of diabetic cardiomyopathy. Clearly, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD), which is activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We therefore hypothesised that PKD inhibition would enhance cardiac function in T2D mice. We first validated the obese and T2D db/db mouse as a model of early stage diabetic cardiomyopathy, which was characterised by both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. These functional characteristics were also associated with increased PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. Acute administration of the PKD inhibitor CID755673 to normal mice reduced both PKD1 and 2 phosphorylation in a time and dose-dependent manner. Chronic CID755673 administration to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition could be an effective strategy to enhance heart function in obese and diabetic patients and provide an impetus for further mechanistic investigations into the role of PKD in diabetic cardiomyopathy.

Introduction: Major obstetric hemorrhage (MOH) can develop rapidly and, due to the unique characteristics of maternity patients, early recognition and management can be challenging. Use of blood components in MOH can be life-saving however there is uncertainty about optimal use of these products and the role of adjunctive therapies. The ANZ-MTR generates observational data on current transfusion management and outcomes in critically bleeding patients receiving massive transfusion (MT) across all clinical settings. This study aimed to describe the transfusion strategies used in the MOH population and report their outcomes. Methods: Patients who had a MOH and received a MT (≥5 units of red blood cells [RBC] in 4h) between April 2011 and December 2013 at 15 Australian & NZ hospitals were identified. Data on the type and volume of blood products transfused as well as selected laboratory results and clinical outcomes were reviewed. Results: A total of 154 cases were identified and reviewed, representing 6% of the total ANZ-MTR cohort. Median age was 34 [IQR29-37] years and 99% of women had a Charlson Comorbidity Index score ≤ 1. Table 1 presents the blood products transfused. The median [IQR] fresh frozen plasma (FFP) to RBC ratio and platelets to RBC ratio was 0.6 [0.3-0.8] and 0.1 [0-0.2], respectively. FFP, platelets and cryoprecipitate were transfused in 87%, 66% and 49% of patients. Prothrombinex-HT was administered to 1 patient and 3 patients received rFVIIa. Table 2 presents the laboratory results taken prior to MT onset as well as the lowest and highest result reported within 24hours after the MT onset. Fibrinogen levels following MT onset was available for 121 (79%) patients. Of these, 46% women had a fibrinogen level Table 1. Number of patients and median number of units transfused 24h post-MT onset (n = 154). Blood product n (%) Median units (IQR) Red blood cells 154 (100) 7 [6-10] Fresh frozen plasma 134 (87) 4 [2-6] Platelets 102 (66.2) 1 [0-1] Cryoprecipitate 76 (49.4) 0 [0-5] Table 2. Laboratory values* reported Value prior to MT onset Lowest value 0-24h post-MT onset Highest value 0-24h post-MT onset Hemoglobin (g/L) 102 [81-120], 84 77 [67-90]; 92 108 [95-119]; 92 INR 1.1 [0.9-1.2]; 33 1.1 [.9-1.2]; 72 1.3 [1.1-1.4]; 72 aPPT(s) 31 [28-35]; 39 31 [29-34]; 88 37 [33-46]; 88 Fibrinogen level (g/L) 3.2 [1.6-3.9]; 25 1.9 [1.4-2.6]; 79 2.9 [2.5-3.5]; 79 Platelet Count (109/L) 210 [158-249];84 102 [74-135]; 92 146 [110-190]; 92 pH 7.3 [7.3-7.4]; 22 7.3 [7.2-7.3]; 70 7.4 [7.4-7.5]; 70 *Data are Median [IQR]; % patients with laboratory test available Conclusion: Women with MOH requiring massive transfusion were generally healthier and younger than patients of other clinical contexts in the ANZ-MTR. Although there were few in-hospital deaths reported (1.9%), a large proportion of the cohort required a hysterectomy during their hospital admission. Further information on transfusion practice, including understanding optimal blood component ratios, is required to inform clinical practice and minimize risk in the obstetric setting. Disclosures McLintock: Novo Nordisk Australasia: Honoraria.