Cardiovasculaire Geneeskunde.nl

Changing world of CV-prevention: Does HDL-increase still fit the picture?

Slides (presentatie) - Mar. 12, 2009

Changing world of CV prevention: Does HDL-increase still fit the picture?

Increased survival compared to ‘70s

Statin therapy in CV prevention % of events not avoided

Is HDL-c(-raising) a good candidate?

HDL as therapeutic target

Atheroma formation & Plaque rupture

I. Initiation: (mm)LDL accumulation & phagocytosis

HDL mediates ‘reverse cholesterol transport’

HDL increases cholesterol excretion whole-body as well as ‘vascular’

Plasma HDL ‘not related’ to efficacy of Reverse cholesterol transport ?

RCT in low HDL patients

Below ‚threshold‘ HDL rate-limiting for RCT ?

II. Progression/destabilization Cellular infiltration & matrix degradation

HDL attenuates inflammation

rHDL limits inflammatory respons Endotoxin challenge

II. Progression & destabilization endothelial dysfunction

Endothelial Function: Restored endothelial function upon HDL infusion in ABC-A1 heterozygous subjects

III. Atherothrombosis cascade activation by tissue factor exposure

HDL attenuates thrombosis

HDL and the risk of venous thrombosis

HDL as ‘carrier’ of protective molecules

HDL as therapeutic target

HDL and CHD in Framingham HS A potent risk factor

HDLs’ apoAI The Interheart study

Heart Protection study low HDL predicts events during statin therapy

HDL as therapeutic target

HDL metabolism The Key Players

Heterozygosity for apoA-IL178P Intima Media Thickness

Genetic Disorders of Human HDL Metabolism and Risk of Atherosclerosis: Intima Media Thickness

CETP SNPs and HDL changes Meta-analysis

Lower CETP-status with higher HDLc protects against atherosclerosis ….

ABC-AI SNPs and HDL changes Copenhagen City Heart study

Lower HDL due to ABC-AI mutation not associated with increased CV risk ?

Is life-time exposure to low HDL a risk factor for cardiovascular disease ?  HDL ‘genes’ in Genome wide association studies ?

LDL genes in GWAS Fusion, Sardinia, DGI

HDL genes in GWAS Fusion, Sardinia, DGI

Common variants contribute to polygenic dyslipidemia

Common SNPs associate with dyslipidemia Malmo Diet and Cancer Study

Genotype associates with CV-disease

Summary Genetics:

HDL as therapeutic target

Benefits of raising HDL human studies

Nicotinic Acid Non-specific effects

rHDL infusion in ACS ERASE study

HDL delipidation and atheroma regression Comparison apoAI milano infusion

The CETP story How to continue?

Torcetrapib and CV-events Illuminate study

Hazard ratio for CHD death/MI according to HDL level adjusted or baseline HDL level

Torcetrapib associates with blood pressure increase

Radiance 1 & 2 Blood pressure change vs. IMT progression

What causes CV-harm: CETP-inhibition or compound-specific toxicity?

Stroes, Br J Pharmacol 2009 (revision)

Constant BP following dalcetrapib Analysis in 12-week study

Constant BP following Anacetrapib

Summary

HDL as therapeutic target

How to proceed with HDL

New Challenge: you can’t target what you can’t measure

13C-cholesterol infusion: Efflux Measured from Rise-to-Plateau Kinetics

Impact on lipid metabolism of LXR agonists

LXR Agonist and RCT experiments in mice

LXR agonist reduces atherosclerosis

Trans-Intestinal Cholesterol Excretion a novel HDL-independent excretion target?

13C-cholesterol infusion in patients ABC-AI/apoAI/LCAT carriers +/- rHDL infusion

Other targets

Summary

The end of the ‘HDL’ era ?

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