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Anatomy of the Atherosclerotic PlaqueAnatomy of the Atherosclerotic Plaque
LumenLipidCore
Fibrous cap
Shoulder
Intima
Media Elasticlaminæ
InternalExternal
Thrombosis of a Disrupted Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Atheroma, the Cause of Most Acute Coronary Syndromes, Results from:Coronary Syndromes, Results from:
Weakening of Weakening of the fibrous capthe fibrous cap
Thrombogenicity of the lipid core
Illustration courtesy of Michael J. Davies, M.D.
Matrix Metabolism and Integrity of Matrix Metabolism and Integrity of the Plaque’s Fibrous Capthe Plaque’s Fibrous Cap
Libby P. Circulation 1995;91:2844-2850.
+ + + +
++
–
Synthesis Breakdown
Lipid core
IL-1TNF-MCP-1M-CSF
FibrouscapIFN-IFN-
CD-40L
Collagen-degradingCollagen-degradingProteinasesProteinases
Tissue FactorTissue FactorProcoagulantProcoagulant
Plaque Rupture with ThrombosisPlaque Rupture with ThrombosisThrombus Fibrous cap
1 mm Lipid coreIllustration courtesy of Frederick J. Schoen, M.D., Ph.D.
Potential Time Course of Statin EffectsPotential Time Course of Statin Effects
* Time course establishedDaysDays YearsYears
LDL-C LDL-C lowered*lowered*
InflammationInflammationreducedreduced
VulnerableVulnerableplaquesplaques
stabilizedstabilized
EndothelialEndothelialfunctionfunctionrestoredrestored
IschemicIschemicepisodesepisodesreducedreduced
CardiacCardiaceventsevents
reduced*reduced*
HDL Metabolism and HDL Metabolism and Reverse Cholesterol TransportReverse Cholesterol Transport
A-I
Liver
CECE
CEFCFCLCATFC
Bile
SR-BI
A-I
ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR-BI = scavenger receptor class BI
ABC1Macrophage
Mature HDL
Nascent HDL
Role of CETP in HDL MetabolismRole of CETP in HDL Metabolism
A-I
Liver
CECE
FCFCLCATFC
Bile
SR-BI
A-I
ABC1
Macrophage
CE B
CETP = cholesteryl ester transfer proteinLDL = low-density lipoprotein LDLR = low-density lipoprotein receptorVLDL = very-low-density lipoprotein
LDLR
VLDL/LDL
CETP
Mature HDL Nascent HDL
CE
SRA
Oxidation
CETP DeficiencyCETP Deficiency
• Autosomal co-dominant; due to mutations in both alleles of CETP gene
• Markedly elevated levels of HDL-C and apoA-I• Delayed catabolism of HDL cholesteryl ester and apoA-I• HDL particles enlarged and enriched in cholesteryl
ester• No evidence of protection against atherosclerosis;
possible increased risk of premature atherosclerotic vascular disease
SummarySummary• HDL metabolism is complex• HDL-C and apoA-I levels are determined by both
production and catabolic rates• Rates of reverse cholesterol transport cannot be
determined solely by steady-state levels of HDL-C and apoA-I
• Effect of genetic defects or of interventions that alter HDL metabolism on atherosclerosis depends on specific metabolic effects on HDL
• Genes and proteins involved in HDL metabolism are potential targets for development of novel therapeutic strategies for atherosclerosis
• Increase apo A-I production
• Promote reverse cholesterol transport
• Delay catabolism of HDL
HDL as a Therapeutic Target: HDL as a Therapeutic Target: Potential StrategiesPotential Strategies
A-I
HDL and Reverse Cholesterol HDL and Reverse Cholesterol TransportTransport
LiverLiver
CECECEFC
LCATLCATFCFC
BileBile
SR-BISR-BI ABCA1ABCA1
MacrophageMacrophageMature Mature HDLHDL
Nascent Nascent HDLHDL
A-IA-I
FCCECE FC
• Antioxidant effects• Inhibition of adhesion molecule expression• Inhibition of platelet activation• Prostacyclin stabilization• Promotion of NO production
Mechanisms Other Than Reverse Mechanisms Other Than Reverse Cholesterol Transport by Which HDL Cholesterol Transport by Which HDL
May be AntiatherogenicMay be Antiatherogenic
ApoA-I MutationsApoA-I Mutations
• Modest to marked reduction in HDL-C and apoA-I• Rapid catabolism of apoA-I• Systemic amyloidosis • Premature atherosclerotic disease (rare)
• Small molecule upregulation of apo A-I gene transcription
• Intravenous infusion of recombinant protein (wild-type apo A-I, apo A-IMilano)
• Administration of peptides based on apo A-I sequence
• Somatic gene transfer of apo A-I DNA (liver, intestine, muscle, hematopoetic cells)
Approaches to Increasing Apo A-I Approaches to Increasing Apo A-I ProductionProduction
CETP DeficiencyCETP Deficiency
• Autosomal co-dominant; due to mutations in both alleles of CETP gene
• Markedly elevated levels of HDL-C and apoA-I• Delayed catabolism of HDL cholesteryl ester and apoA-I• HDL particles enlarged and enriched in cholesteryl
ester• No evidence of protection against atherosclerosis;
possible increased risk of premature atherosclerotic vascular disease
Genes Involved in HDL MetabolismGenes Involved in HDL MetabolismPotential Targets for Development of Potential Targets for Development of Novel Therapies for AtherosclerosisNovel Therapies for Atherosclerosis
• HDL-associated apolipoproteins— ApoA-I — ApoE— ApoA-IV
• HDL-modifying plasma enzymes and transfer proteins
— LCAT — Lipoprotein lipase— CETP — Hepatic lipase— PLTP — Endothelial lipase
• Cellular and cell-surface proteins that influence HDL metabolism
— ABC1 — SR-BI
Gene Transfer of ApoA-I to Liver Gene Transfer of ApoA-I to Liver Induces Regression of Atherosclerosis Induces Regression of Atherosclerosis
in LDLRin LDLR–/––/– Mice Mice
0
1
2
3
4
5
Baseline Adnull
Aorti
c le
sion
(%)
AdhapoA-I
*
* P 0.05Tangirala R et al. Circulation 1999;100:1816–1822
Overexpression of LCAT Prevents Overexpression of LCAT Prevents Development of Atherosclerosis in Development of Atherosclerosis in
Transgenic RabbitsTransgenic Rabbits
* P < 0.003LCAT = lecithin-cholesterol acyltransferase; Tg = transgenicHoeg JM et al. Proc Natl Acad Sci U S A. 1996;93:11448–11453Copyright ©1996 National Academy of Sciences, USA.
0
10203040
50
Control LCAT Tg
Athe
rosc
lero
tic
surfa
ce a
rea
(%)
*
Inflammation and AtherosclerosisInflammation and Atherosclerosis Inflammation may determine plaque stability - Unstable plaques have increased leukocytic infiltrates - T cells, macrophages predominate rupture sites - Cytokines and metalloproteinases influence both stability
and degradation of the fibrous cap Lipid lowering may reduce plaque inflammation - Decreased macrophage number - Decreased expression of collagenolytic enzymes (MMP-1) - Increased interstitial collagen - Decreased expression of E-selectin - Reduced calcium depositionLibby P. Circulation 1995;91:2844-2850. Ross R. N Engl J Med 1999;340:115-126.
• Reduced initiation and progression of atherosclerosis in transgenic mice and rabbits
• Regression of pre-existing atherosclerosis in animals
Increased Apo A-I Production is Increased Apo A-I Production is Antiatherogenic in AnimalsAntiatherogenic in Animals
Lipid Levels Lipid Levels as the Targetas the Target
Atherosclerosis Atherosclerosis as the Targetas the Target
Treatment ApproachTreatment Approach
Measure and treat levels Only patients with levels
above normal benefit Start on low dose and
titrate Goal is “normal” levels Benefit same regardless
of Rx Based on epidemiologic
and observational data
Find patients with disease or at risk
All patients benefit, regardless of lipid levels
Start on clinical trial–proven doses
Goal is getting on and staying on Rx
Statins have independent benefits
Based on randomized clinical trial evidence
Role of Lipoproteins in Role of Lipoproteins in InflammationInflammation
Atherosclerosis is an Inflammatory Atherosclerosis is an Inflammatory DiseaseDisease
Ross R. N Engl J Med 1999;340:115-126.
EndotheliumEndothelium
Vessel LumenVessel Lumen
IntimaIntimaFoam CellFoam Cell
MonocyteMonocyte
CytokinesCytokines
Growth FactorsGrowth FactorsMetalloproteinasesMetalloproteinases
Cell ProliferationCell ProliferationMatrix DegradationMatrix Degradation MacrophageMacrophage
Lipoprotein Classes and InflammationLipoprotein Classes and Inflammation
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.
HDLHDLLDLLDLChylomicrons,Chylomicrons,VLDL, and VLDL, and
their catabolic their catabolic remnantsremnants> 30 nm> 30 nm 20–22 nm20–22 nm
Potentially proinflammatoryPotentially proinflammatory
9–15 nm9–15 nmPotentially anti- Potentially anti-
inflammatoryinflammatory
Structure of LDLStructure of LDL
Murphy HC et al. Biochemistry 2000;39:9763-970.
Hydrophobic CoreHydrophobic Core of Triglyceride and of Triglyceride and Cholesteryl EstersCholesteryl Esters
apoBapoB
Surface Monolayer Surface Monolayer of Phospholipids of Phospholipids and Free and Free CholesterolCholesterol
Role of LDL in InflammationRole of LDL in Inflammation
Steinberg D et al. N Engl J Med 1989;320:915-924.
EndotheliumEndothelium
Vessel LumenVessel LumenLDLLDL
LDL Readily Enter the Artery Wall Where They May be ModifiedLDL Readily Enter the Artery Wall Where They May be Modified
LDLLDL
IntimaIntimaModified LDLModified LDL
Modified LDL are ProinflammatoryModified LDL are Proinflammatory
Hydrolysis of PhosphatidylcholineHydrolysis of Phosphatidylcholineto Lysophosphatidylcholineto LysophosphatidylcholineOther Chemical ModificationsOther Chemical Modifications
Oxidation of LipidsOxidation of Lipidsand ApoBand ApoB
AggregationAggregation
LDLLDL
LDLLDL
Modified LDL Stimulate Expression Modified LDL Stimulate Expression of MCP-1 in Endothelial Cellsof MCP-1 in Endothelial Cells
Navab M et al. J Clin Invest 1991;88:2039-2046.
EndotheliumEndothelium
Vessel LumenVessel Lumen
IntimaIntima
MonocyteMonocyte
Modified LDLModified LDL
MCP-1MCP-1
LDLLDL
LDLLDL
Differentiation of Monocytes into Differentiation of Monocytes into MacrophagesMacrophages
Steinberg D et al. N Engl J Med 1989;320:915-924.
EndotheliumEndothelium
Vessel LumenVessel Lumen
IntimaIntima
MonocyteMonocyte
Modified LDLModified LDLModified LDL PromoteModified LDL Promote
Differentiation ofDifferentiation ofMonocytes intoMonocytes intoMacrophagesMacrophages
MCP-1MCP-1
MacrophageMacrophage
LDLLDL
LDLLDL
Modified LDL Induces Macrophages to Release Modified LDL Induces Macrophages to Release Cytokines That Stimulate Adhesion Molecule Cytokines That Stimulate Adhesion Molecule
Expression in Endothelial CellsExpression in Endothelial Cells
Nathan CF. J Clin Invest 1987;79:319-326.
EndotheliumEndothelium
Vessel LumenVessel LumenMonocyteMonocyte
Modified LDLModified LDL
MacrophageMacrophage
MCP-1MCP-1
AdhesionAdhesionMoleculesMolecules
CytokinesCytokines
IntimaIntima
LDLLDL
LDLLDLEndotheliumEndothelium
Vessel LumenVessel LumenMonocyteMonocyte
MacrophageMacrophage
MCP-1MCP-1
AdhesionAdhesionMoleculesMolecules
Steinberg D et al. N Engl J Med 1989;320:915-924.
Macrophages Express Receptors Macrophages Express Receptors That Take up Modified LDLThat Take up Modified LDL
Foam CellFoam Cell
Modified LDL Modified LDL Taken up by Taken up by MacrophageMacrophage
IntimaIntima
LDLLDL
LDLLDLEndotheliumEndothelium
Vessel LumenVessel LumenMonocyteMonocyte
MacrophageMacrophage
AdhesionAdhesionMoleculesMolecules
Macrophages and Foam Cells Macrophages and Foam Cells Express Growth Factors and Express Growth Factors and
ProteinasesProteinases
Foam CellFoam Cell
IntimaIntimaModified Modified
LDLLDLCytokinesCytokines
Cell ProliferationCell ProliferationMatrix DegradationMatrix Degradation
Growth FactorsGrowth FactorsMetalloproteinasesMetalloproteinases
Ross R. N Engl J Med 1999;340:115-126.
MCP-1MCP-1
EndotheliumEndothelium
Vessel LumenVessel LumenMonocyteMonocyte
MacrophageMacrophage
MCP-1MCP-1AdhesionAdhesionMoleculesMolecules
The Remnants of VLDL and Chylomicrons The Remnants of VLDL and Chylomicrons are Also Proinflammatoryare Also Proinflammatory
Foam CellFoam Cell
IntimaIntimaModifiedModifiedRemnantsRemnantsCytokinesCytokines
Cell ProliferationCell ProliferationMatrix DegradationMatrix Degradation
Doi H et al. Circulation 2000;102:670-676.
Growth FactorsGrowth FactorsMetalloproteinasesMetalloproteinases
Remnant LipoproteinsRemnant Lipoproteins
RemnantsRemnants
Structure of HDL ParticleStructure of HDL Particle
A-IA-I
A-II
A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides
CETG
Structure of HDLStructure of HDL
Rye KA et al. Atherosclerosis 1999;145:227-238.
Hydrophobic CoreHydrophobic Core of Triglyceride and of Triglyceride and Cholesteryl EstersCholesteryl Esters
apoA-IIapoA-II
Surface Monolayer Surface Monolayer of Phospholipids of Phospholipids and Free and Free CholesterolCholesterolapoA-IapoA-I
LDLLDL
LDLLDL
Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.
EndotheliumEndothelium
Vessel LumenVessel LumenMonocyteMonocyte
Modified LDLModified LDL
MacrophageMacrophage
MCP-1MCP-1AdhesionAdhesionMoleculesMolecules
CytokinesCytokines
HDL Prevent Formation of Foam CellsHDL Prevent Formation of Foam Cells
IntimaIntimaHDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux
Foam Foam CellCell
LDLLDL
LDLLDL
Mackness MI et al. Biochem J 1993;294:829-834.
EndotheliumEndothelium
Vessel LumenVessel LumenMonocyteMonocyte
Modified LDLModified LDL
MacrophageMacrophage
MCP-1MCP-1AdhesionAdhesionMoleculesMolecules
CytokinesCytokines
HDL Inhibit the Oxidative Modification of LDLHDL Inhibit the Oxidative Modification of LDL
Foam Foam CellCell
HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux IntimaIntima
HDL InhibitHDL InhibitOxidationOxidation
of LDLof LDL
Inhibition of LDL Oxidation by Inhibition of LDL Oxidation by HDL:HDL:
Role of ParaoxonaseRole of Paraoxonase• Paraoxonase is transported in plasma as a
component of HDL• Paraoxonase is known to inhibit the oxidative
modification of LDL• Thus, the presence of paraoxonase in HDL may
account for a proportion of the antioxidant properties of these lipoproteins
Mackness MI et al. FEBS Lett 1991;286:152-154.
Role of HDL Apolipoproteins in Role of HDL Apolipoproteins in Removing Oxidized Lipids from Removing Oxidized Lipids from
LDLLDL
• CETP transfers oxidized lipids from LDL to HDL• The oxidized lipids in HDL are reduced by HDL
apolipoproteins• The liver takes up reduced lipids from HDL more
rapidly than from LDL
Christison JK et al. J Lipid Res 1995;36:2017-2026; Gardner B et al. J Biol Chem 1998;273:6088-6095.
LDLLDL
LDLLDL
Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.
EndotheliumEndothelium
Vessel LumenVessel LumenMonocyteMonocyte
Modified LDLModified LDL
MacrophageMacrophage
MCP-1MCP-1AdhesionAdhesionMoleculesMolecules
CytokinesCytokines
Inhibition of Adhesion MoleculesInhibition of Adhesion Molecules
IntimaIntima
HDL InhibitHDL InhibitOxidationOxidation
of LDLof LDL
HDL Inhibit Adhesion Molecule ExpressionHDL Inhibit Adhesion Molecule Expression
Foam Foam CellCell
HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux
EndotheliumEndothelium
Vessel LumenVessel Lumen
MCP-1MCP-1E-SelectinE-Selectin
Charo IF. Curr Opin Lipidol 1992;3:335-343.
Recruitment of Blood Monocytes by Recruitment of Blood Monocytes by Endothelial Cell Adhesion MoleculesEndothelial Cell Adhesion Molecules
IntimaIntima
VCAM-1VCAM-1ICAM-1ICAM-1
StickingStickingMonocyteMonocyte RollingRolling
TransmigrationTransmigration
HDL Inhibit Endothelial Cell HDL Inhibit Endothelial Cell Sphingosine KinaseSphingosine Kinase
Xia P et al. J Biol Chem 1999;274:33143-33147.
SphingomyelinSphingomyelin
CeramideCeramide
SphingosineSphingosine
Sph-1-PSph-1-P
HDLHDL
NF-NF-KKBB Adhesion Protein Adhesion Protein SynthesisSynthesis
SM-aseSM-ase
Sph KinaseSph Kinase
++TNFTNF
XX
Heterogeneity of HDLHeterogeneity of HDL
Rye KA et al. Atherosclerosis 1999;145:227-238.
Apolipoprotein CompositionApolipoprotein Composition
A-I HDLA-I HDL A-I/A-II HDLA-I/A-II HDL A-II HDLA-II HDL
Particle ShapeParticle ShapeDiscoidalDiscoidal
SphericalSpherical
Lipid CompositionLipid CompositionTG, CE, and PLTG, CE, and PL
Particle SizeParticle Size
HDLHDL2b2b HDLHDL2a2a HDLHDL3a3a HDLHDL3b3b HDLHDL3c3c
Inhibition of Endothelial Cell Inhibition of Endothelial Cell VCAM-1 Expression by HDL: VCAM-1 Expression by HDL: Effect of HDL CompositionEffect of HDL Composition
• Inhibition unaffected by replacing apoA-I with apoA-II• Inhibition unaffected by replacing apoA-I with SAA• Inhibition unaffected by varying the cholesteryl ester or
triglyceride content of HDL• Inhibition ISIS affected by varying HDL phospholipids
Baker PW et al. J Lipid Res 1999;40:345-353.
Additional Anti-inflammatory Additional Anti-inflammatory Properties of HDLProperties of HDL
• HDL bind and neutralize proinflammatory lipopolysaccharides
• The acute phase reactant SAA binds to plasma HDL, which possibly neutralizes the effects of SAA
Baumberger C et al. Pathobiology 1991;59:378-383; Benditt EP et al. Proc Natl Acad Sci U S A 1977;74:4025-4028.
Animal StudiesAnimal Studies• Increasing the concentration of LDL or remnant
particles in animal models results in expression of endothelial cell adhesion molecules at the sites where atherosclerotic lesions develop
• Infusion or overexpression of apoA-I in animal models reduces oxidation of LDL and reduces endothelial cell adhesion molecule expression
Sakai A et al. Arterioscler Thromb Vasc Biol 1997;17:310-316; Dimayuga P et al. Biochem Biophys Res Commun 1999;264:465-468; Cockerill GW et al. Circulation 2001;103:108-112; Theilmeier G et al. FASEB J 2000;14:2032-2039.
Studies in HumansStudies in Humans• Treatments that reduce the level of LDL reduce
the plasma levels of C-reactive protein and soluble adhesion molecules
BUT
• These effects may represent pleiotropic effects of lipid-modifying agents and be unrelated to the changes in lipoprotein levels
Ridker PM et al. Ridker PM et al. CirculationCirculation 1998;98:839-844; Hackman A et al. 1998;98:839-844; Hackman A et al. CirculationCirculation 1996;93:1334-1338. 1996;93:1334-1338.
SummarySummary• The evidence that atherosclerosis is an
inflammatory disorder is overwhelming• LDL are subject to proinflammatory modifications
that may account for their atherogenicity• HDL have anti-inflammatory properties that may
contribute to their ability to protect against atherosclerosis
ConclusionsConclusions• Strategies that reduce proinflammatory
modifications to LDL may reduce atherosclerosis• Strategies that increase the anti-inflammatory
properties of HDL may also reduce atherosclerosis• More research is needed to determine whether
pharmacological increases in HDL are anti-inflammatory and reduce atherosclerosis
HDL as a Therapeutic TargetHDL as a Therapeutic Target
Is HDL-C Simply a Marker of Is HDL-C Simply a Marker of Increased Cardiovascular Risk? Increased Cardiovascular Risk?
• Smoke• Are sedentary• Are obese• Are insulin resistant or diabetic• Have hypertriglyceridemia• Have chronic inflammatory disorders
Low HDL-C levels are commonly found in patients who:
Production of Apo A-I by Liver and Production of Apo A-I by Liver and IntestineIntestine
A-IA-I
A-IIA-II
LiverLiverIntestineIntestine
HDLHDL
A-IA-I
HDLHDL
• Reduced initiation and progression of atherosclerosis in transgenic mice and rabbits
• Regression of pre-existing atherosclerosis in animals
Increased Apo A-I Production is Increased Apo A-I Production is Antiatherogenic in AnimalsAntiatherogenic in Animals
• Increase apo A-I production
• Promote reverse cholesterol transport
• Delay catabolism of HDL
HDL Metabolism as a Therapeutic HDL Metabolism as a Therapeutic Target: Potential StrategiesTarget: Potential Strategies
• Small molecule upregulation of apo A-I gene transcription
• Intravenous infusion of recombinant protein (wild-type apo A-I, apo A-IMilano)
• Administration of peptides based on apo A-I sequence
• Somatic gene transfer of apo A-I DNA (liver, intestine, muscle, hematopoetic cells)
Approaches to Increasing Apo A-I Approaches to Increasing Apo A-I ProductionProduction
• Increase apo A-I production
• Promote reverse cholesterol transport
• Delay catabolism of HDL
HDL as a Therapeutic Target: HDL as a Therapeutic Target: Potential StrategiesPotential Strategies
A-I
HDL and Reverse Cholesterol HDL and Reverse Cholesterol TransportTransport
LiverLiver
CECECEFC
LCATLCATFCFC
BileBile
SR-BISR-BI ABCA1ABCA1
MacrophageMacrophageMature Mature HDLHDL
Nascent Nascent HDLHDL
A-IA-I
FCCECE FC
Regulation of Cholesterol Efflux in Regulation of Cholesterol Efflux in the Macrophagethe Macrophage
FC FC
oxysterolsLXR/RXRLXR/RXR
ABCA1
PPARsPPARsA-I
Pharmacologic Manipulation of Pharmacologic Manipulation of Cholesterol EffluxCholesterol Efflux
LXR/RXR
PPARsPPARs
Fibrates, TZDs, new agents Fibrates, TZDs, new agents
New agents
A-I
FC
ABCA1
• Increase apo A-I production
• Promote reverse cholesterol transport
• Delay catabolism of HDL
HDL as a Therapeutic Target: HDL as a Therapeutic Target: Potential StrategiesPotential Strategies
• Antioxidant effects• Inhibition of adhesion molecule expression• Inhibition of platelet activation• Prostacyclin stabilization• Promotion of NO production
Mechanisms Other Than Reverse Mechanisms Other Than Reverse Cholesterol Transport by Which HDL Cholesterol Transport by Which HDL
May be AntiatherogenicMay be Antiatherogenic
LiverLiver
CECECEFCFCFC
LCATLCATFCFC
BileBile
SR-BISR-BI
A-I
ABCA1ABCA1MacrophageMacrophage
A-IA-I
TGTGCECE
HDL Metabolism: Intravascular HDL Metabolism: Intravascular Remodeling of HDLRemodeling of HDL
KidneyKidney
PLPL
FCFCPLPL
LiverLiverHLHL
A-IA-I
TGTGCECE
HDL Metabolism: Role of Hepatic HDL Metabolism: Role of Hepatic LipaseLipase
KidneyKidney
PLPL
HDLHDL22 A-IA-I
CECEPLPL
HDLHDL33
LiverLiver
CECECEFCFCFC
LCATLCATFCFC
BileBile
SR-BISR-BI
A-I
ABCA1ABCA1MacrophageMacrophage
A-IA-I
FCCECE
HDL Metabolism: Role of CETPHDL Metabolism: Role of CETP
FCFC
KidneyKidney
LDLRLDLR
CETG
CETPCETP
BB
VLDL/LDLVLDL/LDL
HDL Metabolism in CETP DeficiencyHDL Metabolism in CETP Deficiency
CEFCFCFC
LCATLCATA-I
ABCA1ABCA1
MacrophageMacrophage
A-IA-I
CECE FCFC
CETG
CETPCETP
BB
VLDL/LDLVLDL/LDL
DelayedDelayedcatabolismcatabolism
X
05
101520253035
Okamoto H et al. Nature 2000;406:203-207.
Inhibition of CETP by JTT-705 in Inhibition of CETP by JTT-705 in Cholesterol-Fed Rabbits Significantly Cholesterol-Fed Rabbits Significantly
Reduced Aortic AtherosclerosisReduced Aortic Atherosclerosis
% A
ortic
Les
ion
Control SimvastatinJTT-705
HDL Metabolism: Influence of CETP HDL Metabolism: Influence of CETP InhibitionInhibition
LiverLiver
CECECEFCFCFC
LCATLCATFCFC
BileBile
SR-BISR-BI
A-I
ABCA1ABCA1MacrophageMacrophage
A-IA-I
FCCECE FCFC
LDLRLDLR
CETG
CETPCETP
BB
VLDL/LDLVLDL/LDL
X
• Weight reduction and increased physical activity• LDL-C is primary target of therapy• Non-HDL-C is secondary target of therapy
(if triglycerides 200 mg/dL)• Consider nicotinic acid or fibrates
Management of Low HDL-CManagement of Low HDL-C
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
• Therapeutic lifestyle changes– Smoking cessation– Regular aerobic exercise– Weight loss– Alcohol use?
Management of Low HDL-CManagement of Low HDL-C
• Therapeutic lifestyle changes• Pharmacologic therapy
– Statins
Management of Low HDL-CManagement of Low HDL-C
• Therapeutic lifestyle changes• Pharmacologic therapy
– Statins– Fibrates
Management of Low HDL-CManagement of Low HDL-C
• Therapeutic lifestyle changes• Pharmacologic therapy
– Statins– Fibrates– Niacin
Management of Low HDL-CManagement of Low HDL-C
• Lifestyle changes and secondary causes• Pharmacologic therapy
– If LDL-C elevated: statin– If TG elevated: fibrate– If isolated low HDL-C: niacin
• Combination therapy
Management of Low HDL-CManagement of Low HDL-C
• LDL-C remains the primary target of lipid-altering therapies
• HDL-C is an important CHD risk factor
• Even small increases in HDL-C may confer substantial benefit
• Intervention to raise HDL-C levels should be considered in high-risk patients
SummarySummary
• 48-year-old man with metabolic syndrome and CHD• After therapeutic lifestyle changes and a starting dose of
statin:
Cholesterol 179 mg/dL
Triglycerides 252 mg/dL
LDL-C 97 mg/dL
HDL-C 32 mg/dL
Glucose 104 mg/dL
Approach to the Patient with Low Approach to the Patient with Low HDL-CHDL-C
Drugs Main effects Sites of action
abciximab anticoagulant stops platelet activation platelets
amiloride (combination with frusemide is frumil) potassium sparing diuretic kidney (distal tubules)
amiodarone class III anti-arrhythmic myocardium
aspirin anticoagulant stops platelet activation platelets
atropine (sometimes used to stop vagus bradycardia) parasympatholytic, increases heart rate pacemaker cells (sino-atrial node)
captopril reduces arterial blood pressure relaxes vascular smooth muscle
clopidogrel anticoagulant stops platelet activation platelets
digitalis and ouabain increase cardiac contractility, delay AV node triggering all tissues, but the Na/Ca exchanger is mainly in heart
dipyridamole (often used for X-ray imaging) coronary vasodilation coronary vasculature
furosemide (= frusemide) diuretic kidney (loop of Henle)
isoprenaline (and other adrenaline analogues) increase cardiac contractility many tissues
losartan reduces arterial blood pressure relaxes vascular smooth muscle
lovastatin reduces blood cholesterol levels liver
morphine pain relief (mainly) brain
nitroglycerine (and many other organic nitrates) reduce cardiac work load relaxes vascular smooth muscle
propranolol reduces cardiac contractility, class II anti-arrhythmic many tissues
quinidine, novocaine and other local anaesthetics class I anti-arrhythmics myocardium
spironolactone (usually added to other diuretics) reduces diuretic potassium losses kidney (distal tubules)
urokinase (streptokinase is cheaper but antigenic) dissolves blood clots (fibrinolytic) blood clots
verapamil, nifedipine and other dihydropyridines reduce cardiac work load, class IV anti-arrhythmic myocardium; relax vascular smooth muscle
warfarin anticoagulant vit. K antagonist
liver
Check list of common cardiac drugs
Plaque with multiple breaks in the cap and both an intraplaque and an intraluminal mural component of thrombosis
An episode of plaque disruption in which the torn cap projects into the lumen of the artery and thrombus is contained within the plaque core
Diagrammatic representation of stages of development of thrombosis after disruption
Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis
Transition from chronic to acute atheromaTransition from chronic to acute atheroma
Ischemic HeartIschemic HeartDiseaseDisease
CerebrovascularCerebrovascularDiseaseDisease
Peripheral VascularPeripheral VascularDiseaseDisease
NormalNormalFattyFatty
StreakStreakFibrousFibrousPlaquePlaque
Occlusive Occlusive AtheroscleroticAtherosclerotic
PlaquePlaque
PlaquePlaqueRupture/Rupture/Fissure &Fissure &
ThrombosisThrombosis
MIMI
StrokeStroke
Critical Leg Critical Leg IschemiaIschemia
Clinically SilentClinically Silent
Coronary Coronary DeathDeath
Increasing AgeIncreasing Age
Effort AnginaEffort AnginaClaudicationClaudication
UnstableUnstableAnginaAngina
Atherosclerosis: A Progressive Atherosclerosis: A Progressive ProcessProcess
Courtesy of P Ganz.
Libby P. Lancet. 1996;348:S4-S7.
Media
– T lymphocyte
– Macrophagefoam cell (tissue factor+)
– “Activated” intimal SMC (HLA-DR+)– Normal medial SMC
Fibrouscap
Intima
Lipidcore
Lumen
The Anatomy of Atherosclerotic The Anatomy of Atherosclerotic PlaquePlaque
Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995.
Angiographically Inapparent Angiographically Inapparent AtheromaAtheroma
The Matrix Skeleton of UnstableThe Matrix Skeleton of UnstableCoronary Artery PlaqueCoronary Artery Plaque
Davies MJ. Circulation. 1996;94:2013-2020.
Fissures inthe fibrous cap
Libby P. Circulation. 1995;91:2844-2850.
Characteristics of Plaques Prone to Characteristics of Plaques Prone to RuptureRupture
– T lymphocyte– Macrophage
foam cell (tissue factor+)– “Activated” intimal SMC (HLA-DR+)– Normal medial SMC“Stable” plaque
“Vulnerable” plaque
Lumenarea ofdetail
MediaFibrous cap
Lumen
Lipidcore
Lipidcore
Libby P. Circulation. 1995;91:2844-2850.
Proposed Mechanisms of Event Proposed Mechanisms of Event Reduction by Lipid-Lowering TherapyReduction by Lipid-Lowering Therapy
• Improved endothelium-dependent vasodilation• Stabilization of atherosclerotic lesions
– especially nonobstructive, vulnerable plaques• Reduction in inflammatory stimuli
– lipoproteins and modified lipoproteins• Prevention, slowed progression, or regression of
atherosclerotic lesions
Atheroma are not merely filled with Atheroma are not merely filled with lipid, but contain cells whose lipid, but contain cells whose functions critically influence functions critically influence
atherogenesis:atherogenesis:Intrinsic Vascular Wall Cells: Endothelium Smooth Muscle CellsInflammatory Cells: Macrophages T Lymphocytes Mast Cells
Cell Types in the Human AtheromaCell Types in the Human Atheroma
Monocyte/Monocyte/MacrophageMacrophage
T-lymphocytesT-lymphocytesTunicaMedia
Intima
Smooth musclecells
EndotheliumEndothelium
No No symptomssymptoms ++ Symptoms Symptoms
Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis
Time (y)Time (y)
SymptomsSymptoms
Lesion initiationLesion initiation
Ischemic HeartIschemic HeartDiseaseDisease
CerebrovascularCerebrovascularDiseaseDisease
Peripheral VascularPeripheral VascularDiseaseDisease
Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis
AttachmentAttachment
Leukocyte–Endothelial Adhesion Leukocyte–Endothelial Adhesion MoleculesMoleculesMonoMono
TT BB PMNPMN
Vascular Cell Adhesion Molecule 1Vascular Cell Adhesion Molecule 1(VCAM-1)(VCAM-1)
Binds monocytes and lymphocytes- Cells found in atheroma
Expressed by endothelium over nascent fatty streaks
Expressed by microvessels of the mature atheroma
An atherogenic diet rapidly induces An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable VCAM-1, a cytokine-regulatable
mononuclear leukocyte adhesion mononuclear leukocyte adhesion molecule, in rabbit aortic molecule, in rabbit aortic
endotheliumendothelium
Li H et al. Arterioscler Thromb 1993;13:197-204.
VCAM-1 Expression in Rabbit AortaVCAM-1 Expression in Rabbit Aorta
Li H et al. Arterioscler Thromb 1993;13:197-204.
3 weeks on atherogenic diet
PenetrationPenetration
Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis
Monocyte Chemoattractant Protein 1Monocyte Chemoattractant Protein 1(MCP-1)(MCP-1)
A potent mononuclear cell chemoattractant
Produced by endothelial and smooth muscle cells
Localizes in human and experimental atheroma
Absence of monocyte Absence of monocyte chemoattractant protein-1 reduces chemoattractant protein-1 reduces
atherosclerosis in low-density atherosclerosis in low-density lipoprotein receptor–deficient micelipoprotein receptor–deficient mice
Gu L et al. Mol Cell 1998;2:275-281.
Reduced Lipid Deposition in MCP-1–Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice
Gu L et al. Mol Cell 1998;2:275-281.
LDL-R –/–LDL-R –/–MCP-1 +/+MCP-1 +/+
LDL-R –/–LDL-R –/–MCP-1 –/–MCP-1 –/–
Gu L et al. Mol Cell 1998;2:275-281.
Reduced Lipid Deposition in MCP-1–Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice
0
5
10
15
20
25
30
Oil R
ed S
tain
ing
% A
ortic
Sur
face
Sta
ined
Time on Diet: 12 – 14 weeks+/+ -/-
***
+/+ -/-20 – 25 weeks
*P = 0.001 compared to +/+**p = 0.005 compared to +/+
Macrophage Functions in Macrophage Functions in AtherogenesisAtherogenesis
Division
Molecular Mediators of AtherogenesisMolecular Mediators of Atherogenesis
M-CSFMCP-1
VCAM-1
Matrix Metabolism and Integrity of Matrix Metabolism and Integrity of the Plaque’s Fibrous Capthe Plaque’s Fibrous Cap
Libby P. Circulation 1995;91:2844-2850.
+ + + +
++
–
Synthesis Breakdown
Lipid core
IL-1TNF-MCP-1M-CSF
FibrouscapIFN-IFN-
CD-40L
Collagen-degradingCollagen-degradingProteinasesProteinases
Tissue FactorTissue FactorProcoagulantProcoagulant
Increased Expression of Interstitial Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Collagenase (CL) by Smooth Muscle
Cells (SMC) and Macrophages (MCells (SMC) and Macrophages (M) in ) in Human AtheromaHuman Atheroma
Galis ZS et al. J Clin Invest 1994;94:2493-2503.