Anatomy of the Atherosclerotic Plaque

Fibrous cap

Lumen
Lipid Shoulder
Core
Intima
Elastic Internal
Media laminæ
External
 Thrombosis of a Disrupted
Atheroma, the Cause of Most Acute
Coronary Syndromes, Results from:
 Weakening of
the fibrous cap

 Thrombogenicity
of the lipid core

Illustration courtesy of Michael J. Davies, M.D.

 Matrix Metabolism and Integrity of
the Plaque’s Fibrous Cap

e s is Brea
Synth kdow
n

Collagen-degrading Fibrous
IFN-γ Proteinases
– cap
CD-40L + + + +
IL-1
+ TNF-α
+ MCP-1
M-CSF

Lipid core Tissue Factor

Procoagulant
Libby P. Circulation 1995;91:2844-2850.
 Plaque Rupture with Thrombosis
Thrombus Fibrous cap

1 mm
Lipid core
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.
Potential Time Course of Statin Effects
Vulnerable
LDL-C Inflammation plaques
lowered* reduced stabilized

Endothelial Ischemic Cardiac

function episodes events
restored reduced reduced*

Days Years
* Time course established
 HDL Metabolism and
Reverse Cholesterol Transport

Bile
A-I
A-I
FC CE
CE LCAT
CE FC FC
ABC1
SR-BI Nascent
HDL Macrophage
Liver Mature
HDL

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
 Role of CETP in HDL Metabolism

Bile Macrophage
Mature HDL
A-I Nascent HDL
A-I
FC CE
CE LCAT
CE FC FC
ABC1
SR-BI
SRA
Liver CETP
n
LDLR atio
id
Ox
CE B

VLDL/LDL
CETP = cholesteryl ester transfer protein
LDL = low-density lipoprotein
LDLR = low-density lipoprotein receptor
VLDL = very-low-density lipoprotein
 CETP 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
 Summary
• 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
 HDL as a Therapeutic Target:
Potential Strategies
• Increase apo A-I production

• Promote reverse cholesterol transport

• Delay catabolism of HDL

 HDL and Reverse Cholesterol
Transport
Bile
A-I
A-I
FC CE LCAT CE
FC
FC FC
CE
SR-BI Nascent ABCA1
HDL Macrophage
Liver Mature
HDL
 Mechanisms Other Than Reverse
Cholesterol Transport by Which HDL
May be Antiatherogenic
• Antioxidant effects

• Inhibition of adhesion molecule expression

• Inhibition of platelet activation

• Prostacyclin stabilization

• Promotion of NO production
 ApoA-I Mutations

• Modest to marked reduction in HDL-C and apoA-I

• Rapid catabolism of apoA-I
• Systemic amyloidosis
• Premature atherosclerotic disease (rare)
 Approaches to Increasing Apo A-I
Production
• 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)
 CETP 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 Metabolism
Potential Targets for Development of
Novel 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
Induces Regression of Atherosclerosis
in LDLR–/– Mice
5
Aortic lesion (%)
4

2
*
1

0
Baseline Adnull AdhapoA-I
* P ≤ 0.05
Tangirala R et al. Circulation 1999;100:1816–1822
 Overexpression of LCAT Prevents
Development of Atherosclerosis in
Transgenic
50
Rabbits

surface area (%)

Atherosclerotic
40

30

20

10 *
0
Control LCAT Tg
* P < 0.003
LCAT = lecithin-cholesterol acyltransferase; Tg = transgenic
Hoeg JM et al. Proc Natl Acad Sci U S A. 1996;93:11448–11453
Copyright ©1996 National Academy of Sciences, USA.
 Inflammation 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 deposition
Libby P. Circulation 1995;91:2844-2850.
Ross R. N Engl J Med 1999;340:115-126.
 Increased Apo A-I Production is
Antiatherogenic in Animals
• Reduced initiation and progression of atherosclerosis in
transgenic mice and rabbits

• Regression of pre-existing atherosclerosis in animals

Treatment Approach
Lipid Levels Atherosclerosis
as the Target as the Target
 Measure and treat levels  Find patients with disease
or at risk
 Only patients with levels
above normal benefit  All patients benefit,
regardless of lipid levels
 Start on low dose and
titrate  Start on clinical trial–
proven doses
 Goal is “normal” levels
 Goal is getting on and
 Benefit same regardless
staying on Rx
of Rx
 Statins have independent
 Based on epidemiologic
benefits
and observational data
 Based on randomized
clinical trial evidence
Role of Lipoproteins in
Inflammation
 Atherosclerosis is an Inflammatory
Disease
Vessel Lumen
Monocyte

Endothelium

Cytokines

Growth Factors
Metalloproteinases

Cell Proliferation
Matrix Degradation Foam Cell Macrophage Intima

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

Lipoprotein Classes and Inflammation

Chylomicrons, LDL HDL

VLDL, and
their catabolic
remnants
> 30 nm 20–22 nm 9–15 nm
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.
 Structure of LDL
Surface Monolayer
of Phospholipids
and Free
Cholesterol

apoB

Hydrophobic Core
of Triglyceride and
Cholesteryl Esters

Murphy HC et al. Biochemistry 2000;39:9763-970.

 Role of LDL in Inflammation
LDL Readily Enter the Artery Wall Where They May be Modified

Vessel Lumen
LDL

Endothelium
Oxidation of Lipids LDL Hydrolysis of Phosphatidylcholine
and ApoB to Lysophosphatidylcholine

Aggregation Other Chemical Modifications

Modified LDL
Modified LDL are Proinflammatory Intima

Steinberg D et al. N Engl J Med 1989;320:915-924.

Modified LDL Stimulate Expression of
MCP-1 in Endothelial Cells
Monocyte
Vessel Lumen
LDL

Endothelium
MCP-1 LDL

Modified LDL

Intima

Navab M et al. J Clin Invest 1991;88:2039-2046.

 Differentiation of Monocytes into
Macrophages
Monocyte
Vessel Lumen
LDL

Endothelium
MCP-1
LDL
Intima
Modified LDL
Modified LDL Promote
Differentiation of
Monocytes into
Macrophage Macrophages

Steinberg D et al. N Engl J Med 1989;320:915-924.

 Modified LDL Induces Macrophages to Release
Cytokines That Stimulate Adhesion Molecule
Expression in Endothelial Cells
Monocyte Vessel Lumen
Adhesion LDL
Molecules

Endothelium
MCP-1
LDL

Cytokines
Modified LDL

Macrophage
Intima

Nathan CF. J Clin Invest 1987;79:319-326.

 Macrophages Express Receptors
That Take up Modified LDL
Monocyte Vessel Lumen

Adhesion LDL
Molecules

Endothelium
MCP-1
LDL

Modified LDL
Taken up by
Macrophage

Intima
Foam Cell Macrophage

Steinberg D et al. N Engl J Med 1989;320:915-924.

 Macrophages and Foam Cells
Express Growth Factors and
Monocyte
Proteinases Vessel Lumen
LDL

Adhesion Endothelium
MCP-1
MCP-1
Molecules LDL
Intima
Modified
Cytokines LDL Growth Factors
Metalloproteinases

Cell Proliferation
Macrophage
Foam Cell Matrix Degradation

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

The Remnants of VLDL and Chylomicrons
are Also Proinflammatory
Monocyte Vessel Lumen
Remnant Lipoproteins

Adhesion Endothelium
MCP-1
MCP-1
Molecules
Remnants
Modified Intima
Cytokines Remnants Growth Factors
Metalloproteinases

Cell Proliferation
Macrophage
Foam Cell Matrix Degradation

Doi H et al. Circulation 2000;102:670-676.

 Structure of HDL Particle

A-I
A-I
CE
TG

A-II

A-I, A-II = apolipoprotein A-I, A-II;

CE = cholesteryl ester; TG = triglycerides
 Structure of HDL
Surface Monolayer
of Phospholipids
and Free
apoA-I Cholesterol

apoA-II Hydrophobic Core

of Triglyceride and
Cholesteryl Esters

Rye KA et al. Atherosclerosis 1999;145:227-238.

HDL Prevent Formation of Foam Cells

Monocyte Vessel Lumen

LDL

Adhesion Endothelium
Molecules MCP-1
LDL

Cytokines Modified LDL

Foam
Cell
Macrophage

HDL Promote Cholesterol Efflux Intima

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

HDL Inhibit the Oxidative Modification of LDL

Monocyte Vessel Lumen

LDL

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

Foam
Cell
Macrophage
Intima
HDL Promote Cholesterol Efflux

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

 Inhibition of LDL Oxidation by
HDL:
Role 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
Removing Oxidized Lipids from
LDL

• 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.
Inhibition of Adhesion Molecules

Monocyte HDL Inhibit Adhesion Molecule Expression

LDL Vessel Lumen

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

Foam
Cell
Macrophage
Intima
HDL Promote Cholesterol Efflux

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

 Recruitment of Blood Monocytes by
Endothelial Cell Adhesion Molecules
Monocyte Rolling Vessel Lumen
Sticking

Transmigration

E-Selectin VCAM-1 Endothelium

ICAM-1
MCP-1

Intima

Charo IF. Curr Opin Lipidol 1992;3:335-343.

 HDL Inhibit Endothelial Cell
Sphingosine Kinase
Sphingomyelin +
SM-ase TNF
Ceramide α
Sphingosine
HDL X Sph Kinase

Sph-1-P

Adhesion Protein
NF-KB
Synthesis
Xia P et al. J Biol Chem 1999;274:33143-33147.
 Heterogeneity of HDL
Particle Shape Apolipoprotein Composition
Discoidal

Spherical
A-I HDL A-I/A-II HDL A-II HDL

Particle Size Lipid Composition

TG, CE, and PL

HDL2b HDL2a HDL3a HDL3b HDL3c

Rye KA et al. Atherosclerosis 1999;145:227-238.

 Inhibition of Endothelial Cell
VCAM-1 Expression by HDL:
Effect 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 IS affected by varying HDL phospholipids

Baker PW et al. J Lipid Res 1999;40:345-353.

 Additional Anti-inflammatory
Properties 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 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 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. Circulation 1998;98:839-844; Hackman A et al. Circulation

1996;93:1334-1338.
 Summary
• 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
 Conclusions
• 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 Target
 Is HDL-C Simply a Marker of
Increased Cardiovascular Risk?
Low HDL-C levels are commonly found in
patients who:
• Smoke
• Are sedentary
• Are obese
• Are insulin resistant or diabetic
• Have hypertriglyceridemia
• Have chronic inflammatory disorders
Production of Apo A-I by Liver and
Intestine
Intestine
Liver

A-I A-I

A-II

HDL HDL
 Increased Apo A-I Production is
Antiatherogenic in Animals
• Reduced initiation and progression of atherosclerosis in
transgenic mice and rabbits

• Regression of pre-existing atherosclerosis in animals

 HDL Metabolism as a Therapeutic
Target: Potential Strategies
• Increase apo A-I production

• Promote reverse cholesterol transport

• Delay catabolism of HDL

 Approaches to Increasing Apo A-I
Production
• 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)
 HDL as a Therapeutic Target:
Potential Strategies
• Increase apo A-I production

• Promote reverse cholesterol transport

• Delay catabolism of HDL

 HDL and Reverse Cholesterol
Transport
Bile
A-I
A-I
FC CE LCAT CE
FC
FC FC
CE
SR-BI Nascent ABCA1
HDL Macrophage
Liver Mature
HDL
Regulation of Cholesterol Efflux in
the Macrophage

PPARs
A-I oxysterols
FC LXR/RXR FC
ABCA1
Pharmacologic Manipulation of
Cholesterol Efflux

Fibrates, TZDs, new agents

PPARs
A-I

FC LXR/RXR
ABCA1
New agents
 HDL as a Therapeutic Target:
Potential Strategies
• Increase apo A-I production

• Promote reverse cholesterol transport

• Delay catabolism of HDL

 Mechanisms Other Than Reverse
Cholesterol Transport by Which HDL
May be Antiatherogenic
• Antioxidant effects

• Inhibition of adhesion molecule expression

• Inhibition of platelet activation

• Prostacyclin stabilization

• Promotion of NO production
 HDL Metabolism: Intravascular
Remodeling of HDL

Bile
A-I
A-I
FC CE LCAT CE
FC
CE FC FC
PL
SR-BI PL TG ABCA1
Macrophage
Liver

Kidney
HDL Metabolism: Role of Hepatic
Lipase
A-I
PL
CE
TG
HL
Liver A-I
HDL2
PL
CE

HDL3 Kidney
 HDL Metabolism: Role of CETP

Bile
A-I
A-I
FC CE LCAT CE
FC
FC
FC FC
CE ABCA1
SR-BI
Macrophage
Liver
LDLR CETP

B
CE
TG Kidney

VLDL/LDL
HDL Metabolism in CETP Deficiency

Delayed A-I
catabolism A-I
LCAT CE
FC
FC FC
CE
ABCA1
Macrophage
X
CETP

CE B
TG
VLDL/LDL
 Inhibition of CETP by JTT-705 in
Cholesterol-Fed Rabbits Significantly
Reduced Aortic Atherosclerosis
35
30
25
20
15
10
5
0
s eL ci t r o A %

Control JTT-705 Simvastatin

Okamoto H et al. Nature 2000;406:203-207.

 HDL Metabolism: Influence of CETP
Inhibition
Bile
A-I
A-I
FC CE LCAT CE
FC
FC
FC FC
CE ABCA1
SR-BI
Macrophage
Liver
LDLR X
CETP

B
CE
TG
VLDL/LDL
 Management of Low HDL-C
• 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

Expert Panel on Detection, Evaluation, and Treatment of High Blood

Cholesterol in Adults. JAMA 2001;285:2486-2497.
 Management of Low HDL-C
• Therapeutic lifestyle changes

– Smoking cessation

– Regular aerobic exercise

– Weight loss

– Alcohol use?
 Management of Low HDL-C

• Therapeutic lifestyle changes

• Pharmacologic therapy

– Statins
 Management of Low HDL-C

• Therapeutic lifestyle changes

• Pharmacologic therapy

– Statins

– Fibrates
 Management of Low HDL-C
• Therapeutic lifestyle changes

• Pharmacologic therapy

– Statins

– Fibrates

– Niacin
 Management 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
 Summary
• 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
 Approach to the Patient with Low
HDL-C
• 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

Check list of common cardiac drugs
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 liver

vit. K antagonist
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
Atherogenesis
Ischemic Heart
Disease

Cerebrovascular
Disease

Peripheral Vascular
Disease

Transition from chronic to acute atheroma

 Atherosclerosis: A Progressive
Process
Occlusive
Plaque
Rupture/
Fatty Fibrous Atherosclerotic Fissure & Unstable
Normal Streak Plaque Plaque Thrombosis Angina

MI

Coronary
Death

Stroke

Clinically Silent Effort Angina Critical Leg

Claudication Ischemia

Increasing Age

Courtesy of P Ganz.
 The Anatomy of Atherosclerotic
Plaque

Intima

Fibrous Lipid
cap core

Lumen
Media

– T lymphocyte

– Macrophage
foam cell (tissue factor+)
– “Activated” intimal SMC (HLA-DR+)
– Normal medial SMC

Libby P. Lancet. 1996;348:S4-S7.

 Angiographically Inapparent
Atheroma

Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995.

 The Matrix Skeleton of Unstable
Coronary Artery Plaque
Fissures in
the fibrous
cap

Davies MJ. Circulation. 1996;94:2013-2020.

 Characteristics of Plaques Prone to
Rupture
Fibrous cap
Media
Lipid
Lumen core

area of
detail

“Vulnerable” plaque

Lumen – T lymphocyte
Lipid – Macrophage
core foam cell (tissue factor+)
– “Activated” intimal SMC (HLA-DR+)
– Normal medial SMC
“Stable” plaque

Libby P. Circulation. 1995;91:2844-2850.

 Proposed Mechanisms of Event
Reduction 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

Libby P. Circulation. 1995;91:2844-2850.

 Atheroma are not merely filled with
lipid, but contain cells whose functions
critically influence atherogenesis:
Intrinsic Vascular Wall Cells:
 Endothelium
 Smooth Muscle Cells
Inflammatory Cells:
 Macrophages
 T Lymphocytes
 Mast Cells
 Cell Types in the Human Atheroma

Monocyte/
Macrophage

Intima Endothelium

Tunica T-lymphocytes
Media
Smooth muscle
cells
 Schematic Time Course of Human
Atherogenesis
Ischemic Heart
Disease

Cerebrovascular
Disease

Peripheral Vascular
Lesion initiation Disease

No
symptoms + Symptoms Symptoms

Time (y)
 Macrophage Functions in
Atherogenesis

Attachment
Leukocyte–Endothelial Adhesion
Mono
Molecules
T PMN
B
 Vascular Cell Adhesion Molecule 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
VCAM-1, a cytokine-regulatable
mononuclear leukocyte adhesion
molecule, in rabbit aortic
endothelium

Li H et al. Arterioscler Thromb 1993;13:197-204.

 VCAM-1 Expression in Rabbit Aorta
3 weeks on
atherogenic diet

Li H et al. Arterioscler Thromb 1993;13:197-204.

Macrophage Functions in
Atherogenesis

Penetration
 Monocyte Chemoattractant Protein 1
(MCP-1)
 A potent mononuclear cell chemoattractant

 Produced by endothelial and smooth muscle

cells

 Localizes in human and experimental

atheroma
 Absence of monocyte
chemoattractant protein-1 reduces
atherosclerosis in low-density
lipoprotein receptor–deficient mice

Gu L et al. Mol Cell 1998;2:275-281.

 Reduced Lipid Deposition in MCP-1–
Deficient Atherosclerotic Mice

LDL-R –/–
MCP-1 +/+

LDL-R –/–
MCP-1 –/–

Gu L et al. Mol Cell 1998;2:275-281.

 Reduced Lipid Deposition in MCP-1–
Deficient Atherosclerotic Mice
% Aortic Surface Stained 30

25
Oil Red Staining

20

15

10

5 **
*
0

+/+ -/- +/+ -/-

Time on Diet: 12 – 14 weeks 20 – 25 weeks
*P = 0.001 compared to +/+
Gu L et al. Mol Cell 1998;2:275-281. **p = 0.005 compared to +/+
Macrophage Functions in
Atherogenesis

Division
Molecular Mediators of Atherogenesis

VCAM-1

MCP-1 M-CSF
 Matrix Metabolism and Integrity of
the Plaque’s Fibrous Cap

e s is Brea
Synth kdow
n

Collagen-degrading Fibrous
IFN-γ Proteinases
– cap
CD-40L + + + +
IL-1
+ TNF-α
+ MCP-1
M-CSF

Lipid core Tissue Factor

Procoagulant
Libby P. Circulation 1995;91:2844-2850.
 Increased Expression of Interstitial
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