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-A1 SRB-1

reverse transport

reverse transport

apoA1phospholipid

+ freecholesterol

HDL3 HDL2

LCATCETP 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

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