MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN IN THE ISCHEMIC HEART

s / Atherosclerosis 263 (2017) e1ee28 e24 Aim: Catabolic, cold activated brown adipose tissue burns triglycerides for heat production. Consequently, endogenous lipid stores need to be replenished by anabolic processes including fatty acid uptake by active adipocytes. The aim of this study was to investigate the catabolic and anabolic processes in lipid handling of activated BAT. ĂMethods: BAT activity was stimulated by cold exposure or CL316,243 (CL) treatment in wildtype and transgenic mice. The uptake processes were investigated by metabolic turnover studies intravital microscopy and magnetic resonance imaging after injection of nanoparticle labelled TRL. Results: Increased BAT activity is accompanied by enhanced insulin secretion. CL treatment stimulated anabolic processes in BAT via insulin dependent phosphorylation of Akt kinase. This process is dependent on CD36 and is associated with facilitated whole particle uptake. Inhibition of insulin secretion using the potassium channel agonist diazoxide or impairing insulin signalling with insulin receptor blocking during activation abolished TRL uptake into BAT. Conclusions: Our data show that cold promotes catabolic as well as anabolic processes in BAT whereas insulin orchestrates metabolic pathways that controls lipoprotein handling for the replenishment of endogenous energy stores. Impaired lipoprotein processing mediated by BAT in insulin resistant states could lead to dyslipidemia observed in patients suffering from type 2 diabetes mellitus. W2.4:2. MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN IN THE ISCHEMIC HEART Martina Klevstig, Margareta Scharin T€ang, Marcus Ståhlman, Ewa Ehrenborg, Malin C. Levin, Jan Bor en. 1 The Wallenberg Laboratory, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden Aim: Myocardial ischemia is associated with cardiac dysfunction and lipid accumulation. However, the underlying molecular(s) are still poorly understood. The microsomal triglyceride transfer protein (MTTP), which is critical for hepatic lipoprotein assembly and secretion, is also expressed in cardiomyocytes. The aim of this study was to assess the relationship between the MTTP and cardiac function after a myocardial infarction. Methods: Patients with suspected coronary artery disease (n1⁄4310) underwent echocardiography and myocardial perfusion scintigraphy examinations, and were genotyped for the MTTP polymorphism rs1800804. The cardiac MTTP expression was examined in 126 biopsies from the left ventricle of patients undergoing elective heart surgery. Heart function in MTTP-A heart-specific knockout mice were analyzed using echocardiography at baseline and after myocardial infarction. Results: Subjects with the minor rs1800804 C-allele had lower MTTP expression and significantly lower stress systolic tissue velocity as well as higher infarct and wall motion scores compared with non-carriers. The minor allele of the MTTP polymorphism rs3816873 (known as Ile128Thr), which is in complete allelic association with rs1800804, was significantly (P1⁄40.001) associated with lower expression of MTTP in cardiomyocytes. In mice, MTTP-A deficiency did not affect the baseline heart function but displayed significantly smaller ejection fraction and stroke volume 24h after myocardial infarction, compare to littermates controls. Conclusions: The MTTP rs1800804 polymorphism showed significant associations with structural and perfusion abnormalities reflecting myocardial infarction and stress-induced cardiac dysfunction along with lower MTTP expression in cardiomyocytes. In mice, MTTP-A deficient mice displayed impaired heart function after an experimental myocardial infarction. W2.4:3. MITOCHONDRIAL ACTIVITY IS A MAJOR CONTRIBUTOR TO THE PROINFLAMMATORY CAPACITY OF MICROVESICLES Florian Puhm, Taras Afonyushkin, Georg Obermayer, Christoph Binder. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria; Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria Aim: Microvesicles (MVs) are recognized as promoters of inflammation and increased numbers of MVs have been described in cardiovascular diseases. Because mitochondrial content has been shown to be present in MVs and promotes pro-inflammatory responses, we investigated whether MVs released by LPS-stimulated monocytes are enriched in mitochondrial content and whether this content contributes to their ability to activate endothelial cells. Methods:MVswere isolated fromconditionedmedia of THP-1monocytesby differential centrifugation, characterized by flow-cytometry and their ability to activate human umbilical vein endothelial cells (HUVECs) was tested. Results: MVs from LPS-stimulated monocytes that had been labelled with a mitochondrial and cytoplasmic dye were enriched in mitochondrial dye, mitochondrial RNA, and stained positively the mitochondrial outer membrane protein TOM22. These MVs induced IL-8 production and VCAM and ICAM mRNA level in HUVECs. Blocking of IL-1beta, which has been previously reported to be present in MVs, only had a moderate effect on MV-induced HUVEC activation. However, the pro-inflammatory potential of MVs was dramatically reduced when MVs were derived from cells, i) depleted for mitochondrial DNA, and ii) cultivated in the presence of pyruvate, which alters mitochondrial activity. Moreover, only mitochondria isolated from LPS-stimulated monocytic cells were able to activate ECs. Conclusions: Thus, MVs released by LPS-stimulated monocytes are enriched in mitochondrial content. Furthermore, mitochondrial stress and activity rather than simply mitochondrial content defines ability of MVs released by LPS-stimulated monocytes to induce an EC response. Advanced Clinical Seminar 4 Familial Hypercholesterolaemia Practice Essentials ACS4:1. COST EFFECTIVENESS OF CASCADE TESTING FOR FAMILIAL HYPERCHOLESTEROLAEMIA, BASED ON DATA FROM FH SERVICES IN THE UK Steve Humphries, Robert Pears, Zofia Miedzybrodzka, Kate Haralambos, Moyra Cather, Melanie Watson, Marion Kerr. 1 Institute of Cardiovascular Science, University College London, London, United Kingdom; Hampshire County Council, Winchester, United Kingdom; University of Aberdeen, Polwarth Building, Aberdeen, United Kingdom; Wales Heart Research Institute, Heath Park, Cardiff University, Cardiff, United Kingdom; Northern Ireland Regional Genetics Centre, Belfast, United Kingdom; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; 7 Insight Health Economics Ltd, Southampton, United Kingdom Aim: Familial Hypercholesterolaemia (FH) is a vastly under-diagnosed genetic disorder associated with early development of coronary heart disease (CHD) and premature mortality, which can be substantially reduced by effective treatment. Patents have recently expired on highintensity statins used to treat FH, reducing treatment costs. Herewe build a model using UK data to estimate the costs and benefits of DNA testing of relatives of those with monogenic FH. Methods: A decision tree and a Markov model were used to estimate lifetime costs and cost effectiveness of cascade testing, using UK data from audit and on-going cascade services. Results: The estimated Incremental Cost Effectiveness Ratio (ICER) was £5,981 and the overall net marginal lifetime cost per relative tested was