BSc Y2 CPP – Atherosclerosis Lecture

Dr Asif J. Iqbal

Asif Iqbal, Associate Professor, ICVS

Topics covered in this lecture

• What is atherosclerosis?

• Cell types and cell-cell interactions in atherosclerotic lesions

• Atherosclerosis - pathogenesis

• Plasma components and risk factors

• Genetic risk factors for CVD

What is Atherosclerosis ?
Atherosclerosis is a pathological process that damages the
major arteries and leads to cardiovascular disease (CVD)
• Acute coronary syndromes
- stable & unstable angina
- myocardial infarction (heart attacks)
• Cerebrovascular disease
- strokes
- transient ischaemic attacks (TIAs)
• Peripheral vascular disease
- intermittent claudication
- renal failure
How Prevalent is Cardiovascular Disease?

• Every two minutes someone in the UK has a heart attack

• In the USA there are over 6 million people with angina

• Strokes are the leading cause of adult disability in the UK

• 1 in 3 of all deaths of men between 34 and 65 are from CVD

• Economic burden estimated at €169 billion p.a. in the EU

(62% healthcare costs, 21% lost productivity, 17% carers)
Cause of Death - Men aged 34 - 65
How Prevalent is Cardiovascular Disease?

https://www.bhf.org.uk/what-we-do/our-research/heart-statistics/
Where does Atherosclerosis Occur?

• Large arteries not veins

• Especially at bifurcations (turbulent flow)

• All large arteries affected but especially important are

lesions in
Coronary arteries
Carotid arteries
Renal arteries
Femoral arteries
 Carotid Atherosclerosis

• Atherosclerotic plaque normally forms at the

common carotid bifurcation
 Intermittent Claudication

69 year old man. Arteriography with

critical stenosis in common iliac arteries

• Claudication affects ~5 percent of the over 65s.

• Patients with claudication nearly always have disease in other

parts of the circulation, especially the coronary arteries.
 Coronary Atherosclerosis

54 yr old man 4 hours crushing NB Athero from Greek word for

central chest pain ECG shows
ST wave elevation, angiogram
gruel or porrridge
shows two stenoses in RCA
Atherogenesis

After Peter Libby

Atherosclerosis – Part 2 - The role of
different cell types in atherosclerosis

Macrophage foam cell

Cell Types in Atherosclerotic Plaques

• Endothelial cells

• Smooth Muscle Cells

• Platelets

• Macrophages

• CD4+ helper T cells

N.B. Importance of cellular interactions in atherosclerosis
Response to Injury Hypothesis (Russell Ross)
Normal Artery
Endothelial Cells

• Provide a smooth, anti-thrombogenic surface for blood flow

• Bind LDL and translocate LDL to the sub-endothelium

• Express cell adhesion molecules

e.g. ICAM-1, VCAM, E-selectin, P-selectin

in response to
Turbulent flow, IL-1, TNF-, oxLDL, LPS

• Secrete important mediators

Vasodilators & vasoconstrictors
Pro-thrombotic and anti-thrombotic mediators
Factors Released by Endothelial Cells
• Vasodilatorsasodilators
Nitric oxide (EDRF)
Prostaglandin I2 (PGI2) aka prostacyclin

• Vasoconstrictors
Endothelin
Angiotensin II

• Anti-thrombotic factors
Tissue Plasminogen Activator (tPA)
Prostaglandin I2 (PGI2)

• Prothrombotic factors
Thromboxane A2
Plasminogen Activator Inhibitor-1(PAI-1)
Thromboxane A2
 Platelets

• Small cytoplasmic fragments of megakaryocytes (2-5M)

• Play a key role in endothelial cell repair

• Essential role in haemostasis (evident in thrombocytopenia)

Platelets

• Adhere to sub-endothelium via collagen receptors

• Secrete important SMC growth factors (esp. PDGF)

• Secrete vasoactive mediators (TxA2, 5HT)

• Life span 8-10 days in circulation

Vascular Smooth Muscle Cells
(VSMCs)
• Provide muscular arteries with their elasticity

• Mediate vasodilation and vasoconstriction

• Play a key role in regulating blood pressure

• SMC differentiation, synthetic and contractile SMCs

• Secrete elastin and collagens in stable plaques

• M-induced SMC apoptosis seen in vulnerable plaques

Monocyte Recruitment in Atherosclerosis

Hypercholesterolaemic primate - thoracic aorta. Image from Russell Ross

 Macrophages (M)
• M differentiate from recruited monocytes
• M accumulate modified LDL via Scavenger Receptors (SRs)

• M foam cells are the main cell type in fatty streak lesions

• M secrete inflammatory mediators

e.g. IL-1, TNF-, LTB4, Chemokines
• M secrete growth factors (M-CSF, PDGF, FGFs)

• M are important in plaque rupture (via MMPs & TIMPs)

MMP = Matrix metalloproteinase TIMP = Tissue inhibitor of metalloproteinase

TNF= Tumour Necrosis Factor LTB4 = Leukotriene B4 an eicosanoid
PDGF = Platelet Derived Growth Factor FGF = Fibroblast Growth Factor
Macrophages (M)
VSMC - M Interactions in Atherosclerosis
VSMC - M Interactions in Atherosclerosis

MMPs

TNF- 
Fibrous
IL-1
Cap
PDGF etc INF-g

MMP = Matrix metalloproteinase

PDGF = Platelet derived Growth factor
Atherosclerotic Plaque Stability

CD68 Ms Ms

SMC
Collagen

van der Wal AC, Becker AE.

Atherosclerotic plaque rupture--pathologic basis of plaque stability and instability.
Cardiovasc Res. 1999; 41: 334-44. Review.
Atherosclerotic Plaque Stability

Smooth muscle cells Macrophages & T cells

Repair Inflammation

plaque stability plaque rupture

Atherogenesis – Part 3

Initiation

Progression

Complication

Clinical Sequelae
Atherogenesis - Initiation
• LDL transported to sub endothelial space

• Protein and lipids of LDL damaged (MM-LDL, oxLDL)

• Endothelial damage -> express ICAM-1, VCAM and MCP-1

• Monocyte adhesion, diapedesis and chemotaxis

• Monocytes differentiate into macrophages

• Macrophage uptake of modified LDL via scavenger receptors

• Macrophage derived foam cells in fatty streak lesions

Early Events in Atherogenesis Glass & Witztum, Cell 2001
Atherogenesis - Progression
• Continued mononuclear cell recruitment
• Lipid-rich necrotic core in atheromatous lesions
• Continued SMC migration and proliferation -> fibrous cap
• M - SMC interactions important for plaque growth
• Development of intra plaque microvessels from adventitia
• Raised fibro-fatty plaques may cause arterial stenosis
• Raised fibro-fatty plaques are sites of arterial thrombosis
Atherosclerotic Plaque Growth Glass & Witztum, Cell 2001
Atherogenesis - Complication
Potential fates of fibro-fatty plaques
• Ulceration
• Thrombosis
• Vasospasm
• Embolism
• Plaque haemorrhage
• Aneurysm (local dilatation)
• Artery rupture (especially in cerebral arteries)
Atherosclerotic Plaque Rupture Glass & Witztum, Cell 2001
Atherosclerosis – Part 4 - The role of
plasma components in atherosclerosis and
risk factors for Cardiovascular Disease (CVD)
Plasma Components in Atherogenesis

• Lipoproteins (LDL, mod.LDL, HDL)

• Coagulation cascade components

• C- Reactive Protein (CRP)

• Complement components

• Oxidants / anti-oxidants
General structure of lipoprotein particle
Classification of Lipoproteins
Based on density:
• Chylomicrons
• Very low density lipoprotein (VLDL)
• Intermediate density lipoprotein (IDL)
• Low density lipoprotein (LDL)
• High density lipoprotein (HDL)

VLDL, IDL and LDL are pro-atherogenic

HDL is anti-atherogenic (reverse cholesterol transport
and anti oxidant properties)
LDL Cholesterol

• Strongly associated with Atherosclerosis and CVD

• 10% increase -> 20% increase in CVD risk

• Effects modified by other risk factors

• Can be decreased by:

Medical intervention (e.g. statins, bile acid sequestrants)
Lifestyle changes (diet, exercise, plant stanols)
HDL Cholesterol

• Low plasma HDL associated with risk of CVD

• Mediates reverse cholesterol transport

• Important source of anti-oxidants

• Can be increased by:

Medical intervention (niacin, fibrates)
Lifestyle changes (diet, exercise)
Modifiable Risk Factors for CHD

• High plasma LDL Cholesterol (>5.2mmol/L)

• Hypertension (>140/90mm Hg)

• Physical inactivity / Obesity (BMI > 30)

• Smoking

• Diabetes
Non-modifiable Risk Factors for CHD

• A personal history of CHD

• A family history of CHD

• Advanced age

• Gender
Atherosclerosis – Part 5 – Genetic
pre-disposition to cardiovascular disease
Mendelian Disorders Relevant to Atherosclerosis

Trait Disease (gene)

 LDL/ VLDL levels Familial Hypercholesterolaemia (LDLR) 1/500

Familial defective apoB-100 (apoB) 1/ 3,250

Low HDL levels Tangier Disease (ABC1 Transporter) Rare

ApoA1 deficiency (apoA1) Rare

Low LDL-C levels PSCK9 loss of function Rare

 Mendelian Disorders Relevant to Atherosclerosis

Michael Brown

Joseph Goldstein

http://www.nobelprize.org/nobel_prizes/medicine/laureates/1985/press.html
 Mendelian Disorders Relevant to Atherosclerosis

Figure 3. LDL-receptors, one healthy and two abnormal. The part of the receptor localized outside the cell
membrane is identical in all three cases. The difference is found in the portion of the receptor inside the
cell membrane. The healthy receptor is to the left in the figure. When the LDL via its apoprotein moors to
the receptor it is internalized by the normal healthy receptor. The two abnormal receptors are unable to
complete the internalization.

http://www.nobelprize.org/nobel_prizes/medicine/laureates/1985/press.html
 Loss-of-Function PCSK9 Mutations in AA Are Associated
with Low LDL-C and Low Prevalence of CHD Events
No Mutation
(N = 50th Percentile
30
3278)
Mean 113 mg/dL 88% fewer CHD events
12
20 during 15-year follow-up

10

Coronary Heart Disease (%)

8
0
Frequency

0 50 100 150 200 250 300

PCSK9142x or PCSK9679X
(%)

(N=85)
4
30 Mean 100 mg/dL
(-28%)
20

10 0
No Yes
0
0 50 100 150 200 250 300 PCSK9142x or PCSK9679X
Plasma LDL Cholesterol in Black Subjects (mg/dL)

Cohen JC. NEJM. 2006;354:1264-1267.

Genetic Variation Contributing to CHD Risk Factors

Trait Gene

LDL/ VLDL ApoE

HDL levels Hepatic lipase, ApoAI, CETP, LPL

Coagulation Fibrinogen B, PAI-1, Factor VIII

Blood pressure Angiotensin-converting enzyme

Further Reading
Macrophage differentiation and function in atherosclerosis:
opportunities for therapeutic intervention?
Williams HJ, Fisher EA, Greaves DR.
J Innate Immun. 2012;4(5-6):498-508.

Preclinical mouse models and methods for the discovery of the causes and
treatments of atherosclerosis.
Hewing B, Fisher EA.
Expert Opin Drug Discov. 2012 Mar;7(3):207-16.

Therapeutic strategies targeting endothelial function in humans: clinical implications.

Lee R, Channon KM, Antoniades C.
Curr Vasc Pharmacol. 2012 Jan;10(1):77-93.

Macrophages in the pathogenesis of atherosclerosis.

Moore KJ, Tabas I.
Cell. 2011; 145: 341-55. doi: 10.1016/j.cell.2011.04.005. Review