update from the ias 2012 jonathan silberberg march 2012
Post on 14-Dec-2015
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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
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
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
eventsMallat, 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
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