Update from the IAS 2012 Jonathan Silberberg March 2012

overview 796 abstracts New pathways to chd Hdl therapy Mast cells, T & B cells, chemokines microRNAs AAA, diabetes, alzheimers

niacin General agreement that AIM-high (NEJM Nov 2011) was underpowered Awaiting HPS2-THRIVE n=25000 Effects on HDL and LDL Induces heme-oxygenase 1, cellular protective, inhibits vascular inflammation in non-lipid models Kastelein, Wu, others

HDL and diabetes Low HDL predicts future diabetes Mechanism is non-insulin mediated glucose uptake, via AMP kinase Cellular fuel gauge in active tissues eg skeletal muscle, preserves ATP HDL rx lowers blood glucose and also increases insulin, rescues beta cell B Kingwell, Baker IDI

Reverse transport ABC-A1SRB-1

reverse transport

apoA1 phospholipid + free cholesterol HDL 3 HDL 2 LCAT CETP vldl

HDL infusion Rvx-8 Orally active, increases apoA1 SUSTAIN trial, ASSURE ivus Cerenis cer001 More potent than apoA1 Milano Ivus trial ChiSquare AHA 2012

HDL infusion (2) CSL112 Nascent HDL discs Increase ABC-a1 dependent efflux ACC 2013 Delipidated HDL Brewer et al JACC 2010;55:2727

HDL: questions Does it matter whether HDL acquires cholesterol via ABC-A1 (preBeta and delipidated HDL) or ABC-G1 (mature HDL) transporters? Infusions show reduction in plaque volume, vessel wall inflammation Equivalent to 2 y statin treatment

HDL controversies Is CETP inhibition the opposite of pre-beta HDL treatment? Which HDL functions need cholesterol efflux, and which are due to other proteins associating with HDL?

microRNAs “just another way to control gene expression” Or are they special? One microRNA can repess numerous mRNAs Stable in plasma, hide in lipid carriers eg LDL, HDL, exosomes

ATVB 2011; 31:2383

ATVB 2011; 31:2378

microRNAs from plaque 250 from monocytes, 80 exported 140 from dendritic cells, 80 exported Each cell type transmits unique signature to HDL via microRNA Delivers inflammatory signal to liver How organs communicate with each other

miR223 most abundant in plaque Upregulated in FH (LDL receptor defect); one of 22 miRs abnormal Downregulates several genes and enzymes involved in lipid metabolism Opposite in NASH

Mast cells Contribute to plaque rupture Subendothelial, accumulate in neovascularised areas Immediate degranulation, chymase Activates MMPs (collagenases), degrade fibronectin which anchor SMC to matrix. Apoptosis from loss of survival signal

T cell response to oxLDL Dendritic cells patrol artery, present antigen to T-cells in regional LN Effector T cells are specific; reenter arterial wall & initiate secondary cascade with macrophages etc Il-10 redirect dendritic cell to Treg, tolerant phenotype prospects for specific immunorx Hanson Nature Immunol 2011

B cells B1 cells innate immunity Antigen independent, atheroprotective, remove oxLDL and apoptotic debris B2 adaptive immunity Bone marrow derived, activated by BAFF, targetted by rituximab Expressed in unstable plaque, predicts events Mallat, Cambridge

chemokines Mouse models of early atherosclerosis Noel & Weber Nature Medicine 2011 Cell recruitment, survival Specific regulation, not general antiinflammatory effect Best target platelet-derived peptide ?regional delivery of miRNA

Alzheimers >65yo CNS lipoproteins resemble HDL but major apo is E, not A1 aBeta protein fragment is degraded by macrophages after lpE uptake, needs lipid-rich particle E4/E4 onset 17 y early E4/other onset 10y early ?LXR agonists for short-term Wellington Vancouver