BeyondBeyond thethe statinstatin therapytherapy TheThe importanceimportance ofof HDLHDL cholesterolcholesterol

KiKi HoonHoon HanHan MDMD AsanAsan MedicalMedical CenterCenter

LowLow--densitydensity lipoproteinlipoprotein (LDL)(LDL) ;; atherogenicatherogenic HighHigh--densitydensity lipoproteinlipoprotein (HDL)(HDL) ;; antianti--atherogenicatherogenic HDLHDL andand atherosclerosisatherosclerosis

„ 2-4 % reduction of cardiovascular disease (CVD) in every 1 mg/dl elevation ; more powerful than LDL reduction

„ Low serum HDL-C level (<40mg/dl) is recognized as an major risk factor of CVD (NCEP-III guideline, 2001) StructureStructure ofof HDLHDL Surface Monolayer of Phospholipids and Free apoAapoA--II Cholesterol

apoAapoA--IIII Hydrophobic Core of Triglyceride and Cholesteryl Esters

Rye KA et al. Atherosclerosis 1999;145:227-238. AntiAnti--atherogenicatherogenic RoleRole ofof HDLHDL

„ Anti-inflammatory

„ Anti-oxidative

„ Reverse Cholesterol Transport HDLHDL isis antianti--inflammatoryinflammatory The Process of Atherosclerosis

CCR2

‘Rolling’ ‘Sticking’ Cell Proliferation ‘Transmigration’ Matrix Degradation

Growth Factors E-Selectin VCAM-1 Metalloproteinases ICAM-1 MCP-1 ICAM-1 Modified LDL Cytokines Mo no Foam Cell

Macrophage LipoproteinLipoprotein ClassesClasses andand InflammationInflammation

ChylomicronsChylomicrons,, LDLLDL HDLHDL VLDL,VLDL, andand theirtheir cataboliccatabolic remnantsremnants >> 3030 nmnm 2020––2222 nmnm 99––1515 nmnm

Potentially proinflammatory Potentially anti- inflammatory

Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000; 149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. HDLHDL inhibitsinhibits thethe ExpressionExpression ofof AdhesionAdhesion MoleculesMolecules

Monocyte HDL Inhibits Adhesion Molecule Expression LDL Vessel Lumen

Adhesion Endothelium MCP-1 Endothelium Molecules LDL

Cytokines Modified LDL

Foam Cell Macrophage Intima

Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. Pro-inflammatory ------HDLHDL ------Anti-inflammatory

paraoxonase

SAA

ceruloplasmin

PAF-AH HDLHDL isis antianti--oxidativeoxidative HDLHDL InhibitsInhibits thethe OxidativeOxidative ModificationModification ofof LDLLDL

Monocyte Vessel Lumen LDL

Adhesion Endothelium MCP-1 Endothelium Molecules LDL HDL Inhibits Oxidation Cytokines Modified LDL of LDL

Foam Cell Macrophage Intima

Mackness MI et al. Biochem J 1993;294:829-834. HDLHDL promotespromotes cholesterolcholesterol effluxefflux HDLHDL PreventsPrevents FormationFormation ofof FoamFoam CellsCells

Monocyte Vessel Lumen LDL

Adhesion Endothelium MCP-1 Endothelium Molecules LDL

Cytokines Modified LDL

Foam Cell Macrophage HDL Promotes Cholesterol Efflux Intima

Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80. CholesterolCholesterol FluxFlux inin MacrophagesMacrophages TherapeuticTherapeutic modalitiesmodalities toto enhanceenhance cholesterolcholesterol effluxefflux fromfrom atheromaatheroma

„ Agents that increase functionally active HDL - Niasin, Statins, Fibrates

„ Apo A-1 recombinant protein or agents that upregulate Apo A-1

„ Agents that upregulate ABCA1 ; PPARs agonists

„ Mutants of Apo A-1 ; Apo A-1 milano or paris ApoApo AA--11 milanomilano

„ Arginine to cysteine substitution at a.a. position 173 of apo A-1

„ Subjects with apoA-1 milano does not develop atherosclerosis despite low HDL levels

„ Intermittent Apo A-1 milano/phospholipid complex infusion to patients with ACS resulted in significant 4.2 % reduction in plaque volume (JAMA 2003:292) “ HDL in reverse cholesterol transport “

Cholesterol LCAT in Plasma in Tissue i.e. Plaque

Cholesterol Ester (CE)

HDL3 HDL2 TRL CETP Chylomicron Remnants

Apo A-I,II,and, IV

HDLR (CLA-1/SRB-1)

Small intestine LIVER CholesterolCholesterol EsterEster TransportTransport ProteinProtein (CETP)(CETP)

CETP TRL VLDL TG or HDLHDL CE LDL RegulatoryRegulatory RoleRole ofof CETPCETP (( )) UnderUnder usualusual statestate

TG CE

(V)LDL(V)LDL HDLHDL RegulatoryRegulatory RoleRole ofof CETPCETP (( )) UnderUnder hyperhyper--TGTG statestate TG CE

(V)LDL HDL CETPCETP inin DyslipidemiaDyslipidemia

Fat Cells Liver

Ç FFA CE Ç Ç TG Ç (hepatic VLDL CETP HDL Ç Apo B lipase) IR XX Ç VLDL TG Apo A-1 CECE CETP TG Kidney Insulin SDSD LDLLDL LDL

Slide Source: (lipoprotein oror hepatichepatic lipase)lipase) Lipids Online www.lipidsonline.org PotentialPotential BenefitsBenefits ofof CETPCETP inhibitioninhibition

„ May elevate HDL

„ May reduce small dense LDL LearningLearning fromfrom geneticgenetic CETPCETP--deficiencydeficiency

„ Japan (probably Korea, too) is an endemic area of genetic CETP deficiency.

„ G-to A mutation of +1 position of int 14 and D442G mutation are prevalent in Japan.

„ They show elevated HDL-C, apoA-1, A-II, and E levels.

„ LDLR expression levels are also upregulated due to CETP-deficiency. HonoluluHonolulu HeartHeart StudyStudy

„ Prevalence of CHD in immigrant Japanese with D442G mutation ; not significantly different from wild-type phenotypes. – at least not atherogenic.

PMPM inin CETPCETP genesgenes ((TaqTaq IB)IB)

„ Presence of B2 allele (low CETP levels) showed higher HDL levels and lower incidence of CHD.

AnimalAnimal experimentsexperiments

„ Consistently show that CETP is atherogenic. DevelopmentDevelopment ofof CETPCETP inhibitorinhibitor ;; TorcetrapibTorcetrapib (NEJM(NEJM 20042004 350;1505)350;1505)

„ Increases HDL

„ Decreases small dense LDL

„ Further decreases LDL when combined with atorvastatin

WrapWrap--upup ;; HDLHDL andand CETPCETP inhibitioninhibition SummarySummary

„ Low serum HDL level is a major risk factor.

„ The anti-atherogenic function of HDL is attributed to - Anti-inflammatory - Anti-oxidative - Reverse cholesterol transport

„ Cholesterol efflux directly from atheroma can be induced by Apo A-1 milano.

„ Raising serum HDL cholesterol level can be achieved by a CETP inhibitor, i.e. Torcetrapib. CETPCETP inhibitorsinhibitors toto bebe provedproved inin thethe future..future..

„ Can raise HDL cholesterol levels (in subjects with dyslipidemia).

„ HDL particles that appear after (partial) CETP inhibition seem to be functionally intact. - Is that so in hypercholesterolemic patients ? - Is it functional enough to prevent atherogenesis ?