1031 talk2

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

CEFCFCLCATFC

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

FCFCLCATFC

Macrophage

CETP = cholesteryl ester transfer proteinLDL = low-density lipoprotein LDLR = low-density lipoprotein receptorVLDL = very-low-density lipoprotein

VLDL/LDL

Mature HDL Nascent HDL

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

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

Baseline Adnull

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

10203040

Control LCAT Tg

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.

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

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.

IntimaIntima

MonocyteMonocyte

Modified LDLModified LDL

MCP-1MCP-1

LDLLDL

Differentiation of Monocytes into Differentiation of Monocytes into MacrophagesMacrophages

IntimaIntima

MonocyteMonocyte

Modified LDLModified LDLModified LDL PromoteModified LDL Promote

Differentiation ofDifferentiation ofMonocytes intoMonocytes intoMacrophagesMacrophages

MCP-1MCP-1

MacrophageMacrophage

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.

Vessel LumenVessel LumenMonocyteMonocyte

MCP-1MCP-1

AdhesionAdhesionMoleculesMolecules

CytokinesCytokines

IntimaIntima

LDLLDL

LDLLDLEndotheliumEndothelium

MCP-1MCP-1

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

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

Ross R. N Engl J Med 1999;340:115-126.

MCP-1MCP-1

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.

Remnant LipoproteinsRemnant Lipoproteins

RemnantsRemnants

Structure of HDL ParticleStructure of HDL Particle

A-IA-I

A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides

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

Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.

CytokinesCytokines

HDL Prevent Formation of Foam CellsHDL Prevent Formation of Foam Cells

IntimaIntimaHDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux

Foam Foam CellCell

LDLLDL

Mackness MI et al. Biochem J 1993;294:829-834.

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

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

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

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

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

• 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

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

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

oxysterolsLXR/RXRLXR/RXR

PPARsPPARsA-I

Pharmacologic Manipulation of Pharmacologic Manipulation of Cholesterol EffluxCholesterol Efflux

LXR/RXR

PPARsPPARs

Fibrates, TZDs, new agents Fibrates, TZDs, new agents

New agents

• 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

ABCA1ABCA1MacrophageMacrophage

A-IA-I

TGTGCECE

HDL Metabolism: Intravascular HDL Metabolism: Intravascular Remodeling of HDLRemodeling of HDL

KidneyKidney

FCFCPLPL

LiverLiverHLHL

A-IA-I

TGTGCECE

HDL Metabolism: Role of Hepatic HDL Metabolism: Role of Hepatic LipaseLipase

KidneyKidney

HDLHDL22 A-IA-I

CECEPLPL

HDLHDL33

LiverLiver

CECECEFCFCFC

LCATLCATFCFC

BileBile

SR-BISR-BI

A-IA-I

FCCECE

HDL Metabolism: Role of CETPHDL Metabolism: Role of CETP

KidneyKidney

LDLRLDLR

CETPCETP

VLDL/LDLVLDL/LDL

HDL Metabolism in CETP DeficiencyHDL Metabolism in CETP Deficiency

CEFCFCFC

LCATLCATA-I

ABCA1ABCA1

A-IA-I

CECE FCFC

CETPCETP

VLDL/LDLVLDL/LDL

DelayedDelayedcatabolismcatabolism

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

Control SimvastatinJTT-705

HDL Metabolism: Influence of CETP HDL Metabolism: Influence of CETP InhibitionInhibition

LiverLiver

CECECEFCFCFC

LCATLCATFCFC

BileBile

SR-BISR-BI

A-IA-I

FCCECE FCFC

LDLRLDLR

CETPCETP

VLDL/LDLVLDL/LDL

• 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?

• Therapeutic lifestyle changes• Pharmacologic therapy

– Statins

– Statins– Fibrates

– Statins– Fibrates– Niacin

• Lifestyle changes and secondary causes• Pharmacologic therapy

– If LDL-C elevated: statin– If TG elevated: fibrate– If isolated low HDL-C: niacin

• Combination therapy

• 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

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

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.

– T lymphocyte

– Macrophagefoam cell (tissue factor+)

– “Activated” intimal SMC (HLA-DR+)– Normal medial SMC

Fibrouscap

Intima

Lipidcore

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

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

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

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

Time on Diet: 12 – 14 weeks+/+ -/-

+/+ -/-20 – 25 weeks

*P = 0.001 compared to +/+**p = 0.005 compared to +/+

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.

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