41.4 Atherosclerosis

Question 1

What is atherosclerosis?

Answer 1

pathological build-up of fibrofatty lesions (in form of plaques) in tunica intima of major arteries.

Question 2

How does sex affect the development of atherosclerosis?

Answer 2

Women are less likely to develop plaques against age-matched men
UNTIL MENOPAUSE = women equally as likely to get atherosclerosis-related diseases

Question 3

What is the geographical distribution of atherosclerosis?

Answer 3

Leading cause of morbidity and mortality in the western world
Western diet is high in fat and salt

Question 4

How does age affect the incidence of atherosclerosis?

Answer 4

increasing risk with age (as fatty deposits continue to build up throughout life

Question 5

What are the 2 major epidemiological studies on atherosclerosis?

Answer 5

Framingham Heart Study (1948) + MRFIT (1973)

Question 6

What environmental factors can predispose an individual to atherosclerosis?

Answer 6

*Smoking (increases oxidative stress and cytokines)
*Obesity
*Hypertension
*Hyperlipidaemia (more LDLs compared to HDLs) from obesity, PCOS and FH
*Increased oxidised LDL

Question 7

How is cholesterol/ increased LDL associated with atherosclerosis?

Answer 7

LDL levels in plasma + duration of exposure to vessels → associated w/ graded ↑ in risk of dev atherosclerosis.

Question 8

How does hypertension predispose to atherosclerosis?

Answer 8

Shear stress + physical damage to endothelium from ↑ pressure flow → endothelial dysfunction

Question 9

How does smoking predispose to atherosclerosis?

Answer 9

↑ platelet activation, inflammatory environment, ↓ bioavailability of NO → loss of protective effect (vasodilation/ anti-platelet activity/ anti-inflammatory effects).

Question 10

How does diabetes predispose to atherosclerosis?

Answer 10

Glycation of proteins → glycated end products → associated w/ accelerated disease progression

Question 11

What genetic factors can predispose an individual to atherosclerosis?

Answer 11

Familial Hypercholesterolaemia
Sex (endocrine - oestrogen believed to be protective)
Diabetes

Question 12

What is familial hypercholesterolaemia?

Answer 12

*Loss of function mutations in the gene encoding the LDL receptor (LDLR) or gain of function of PCSK9.
*LDLR mediated pathways metabolise around 2/3 of LDL particles, with the majority being found on hepatocytes which endocytose, and enzymatically degrade LDLs.
*Non-functional, both LDL and IDL uptake is reduced and more IDL remains in the blood where it is converted to LDLs = more taken up by scavenger receptors on macorphages = more foam cells
(PCSK9 degrades LDLRs)

Question 13

Describe the appearance and structure of a mature atheroma?

Answer 13

core of foam cells, lymphocytes, OxLDLs and cholesterol crystals within the tunica intima, surrounded by a cap made of collagen and fibrin

Question 14

What is a fatty streak?

Answer 14

The initial accumulation of lipids in the tunica intima, which is taken up by macrophages that become foam cells. Most of the lipid is intracellular.
*Lesions begin as sub-endothelial fatty streak formation → LDL accumulation + oxidation.

Question 15

What is the fibro-fatty plaque?

Answer 15

The progressed form of a fatty streak, with increased infiltration of macrophages, smooth muscle cells and T-cells. Contains a core of extracellular lipids and some connective tissue.

Question 16

What is the complicated lesion?

Answer 16

When the atheroma ruptures, leading to surface events such as thrombosis.

Question 17

What happens during initiation of an atherosclerotic plaque?

Answer 17

1) Endothelial dysfunction. 2) inflammation. 3) Lipid accumulation.

Question 18

What does damaged/ dysfunctional endothelium lead to?

Answer 18

*↑ LDL permeability.
*Expresses VCAM/ secretes CKs +MCP → recruit monocytes + lymphocytes → inflammation.

Question 19

What happens to the recruited monocytes in atherosclerosis initiation?

Answer 19

• Recruited monocytes → enter subendothelial space via diapedesis → differentiate into macrophages (under influence of M-CSF → secreted by infiltrating T-lymphocytes)
  
  • Macrophages –take up ox-LDL via scavenger Rs→ foam cells.
    Exacerbate pathogenesis (secrete free radicals → further LDL oxidation)

Question 20

Although macrophages are initially protective, they become damaging. How?

Answer 20

*exacerbate progression
*produce free radicals
*act as chemoattractant (to recruit more immune cells) → ↑ inflammatory response.

Question 21

What causes the formation of OxLDLs in the subendothelial space?

Answer 21

Body is under oxidative stress (diabetes, ageing and cancer)
Production of reactive oxygen species (ROS) which oxidise trapped LDLs into OxLDLs

Question 22

What are the consequences of OxLDL accumulation in subendothelial space?

Answer 22

-Increased expression of adhesion molecules on endothelial surface (I-CAM and selectins)
-Production of inflammatory cytokines (prostaglandins and chenoattractants)
-Monocyte entry into intima and differentiation into macrophages

Question 23

Outline the general stages of atheroma development?

Answer 23

Endothelial damage
Lesion
Fatty streak formation
Intermediate lesion
Atheroma
Fibrous cap formation (plaque) = stable if thick
Advanced/vulnerable plaque

Question 24

How is the fibrous cap formed over the fatty streak?

Answer 24

Macrophages secrete inflammatory mediators (IL-1 and TNF-alpha) which further induce the expression of adhesion molecules and produciton of PDGF and FGF.
PDGF and FGF cause poliferation and migration of smooth muscle from media to intima, where they secrete proteoglycans, fibrin and collagen which forms a fibrous cap around the fatty plaque.

Question 25

What happens when macrophages infiltrate the subendothelial space? What forms as a result?

Answer 25

Exponetially engulf OxLDLs using scavenger receptors and OxLDL accumulates inside of them and they become foam cells which reduces their cellular function.
Macorphages die, leaving behind a nectrotic lipid core in the subendothelial (intimal) region of the artery.

Question 26

What is the ‘initial’ step in the development of atherosclerosis?

Answer 26

Endothelial injury and LDL accumulation
LDLs are endocytosed by LDLRs on endothelial cells (clathrin mediated endocytosis) and accumulate in to the subendothelial space

Question 27

Which arteries does atherosclerosis occur in?

Answer 27

LARGE ARTERIES:
-Carotid
-Femoral
-Coronary

Question 28

What is the difference between a stable and unstable plaque?

Answer 28

Stable → inflammation resolves
*Outward expansion of plaque into arterial lumen → flow-limiting lesions
Unstable → remain inflamed
*Large lipid core + thin fibrous cap → prone to rupture → arterial thrombosis

Question 29

What can stenosis in the coronary arteries caused by a stable plaque lead to?

Answer 29

stable angina pectoris (restricted flow through coronary arteries)
*↑ myocardial demand (e.g. exercise) → ischaemia

Question 30

What can stenosis in the femoral arteries caused by a stable plaque lead to?

Answer 30

intermittent claudication (pain in calf when ↑ O2 demand)

Question 31

What are the clinical manifestations of atherosclerosis?

Answer 31

Angina pectoris, MI, Claudication, embolism, aneurysm, ischaemic stroke.

Question 32

When do complications of atherosclerosis arise?

Answer 32

generally arise after decades (>50 years)

Question 33

How is the fibrous cap formed over the fatty streak?

Answer 33

Macrophages secrete inflammatory mediators (IL-1 and TNF-alpha) which further induce the expression of adhesion molecules and produciton of PDGF and FGF.
PDGF and FGF cause poliferation and migration of smooth muscle from media to intima, where they secrete proteoglycans, fibrin and collagen which forms a fibrous cap around the fatty plaque.

Question 34

How does unresolved inflammation in an unstable plaque lead to fibrous cap thinning?

Answer 34

*T-cells secrete mediators (e.g. IFN-gamma) → impair SMC’s ability to synthesise collagen + maintain fibrous cap overlying necrotic core.
*Activated macrophages –secrete→ matrix metalloproteinases → degrade interstitial collagen.

Question 35

How do T cell and macrophage entry into plaques result in their rupture?

Answer 35

T cells: secrete IFN-gamma which inhibits collagen synthesis
Macrophages: secrete MMPs which degrade collagen in the fibrous cap

Question 36

How can atherosclerosis lead to myocardial infarction?

Answer 36

Thrombosis on a ruptured lesion occludes coronary blood cessels resulting in ischaemia of the heart muscle and an MI

Question 37

How may atherosclerosis reult in ischaemic stroke?

Answer 37

Rupture causes thrombus to develop and block arteries supplying the brain, resulting in a stroke

Question 38

What are aneurysms?

Answer 38

Dilations of blood vessels or the heart
Occur as a result of reduced elasticity if the endothelium after the development of a fibrous cap around an atherosclerotic plaque

Question 39

What will cause a plaque to rupture?

Answer 39

Erosion
Ulceration
Increased inflammation = increased T cell and macrophage

Question 40

What is angina pectoris?

Answer 40

chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium)

Question 41

What happens to the plaque after rupture>

Answer 41

exposure of plaque contents to blood → thrombus formation
*Complete occlusion of BV
*Dislodge → embolus occluding smaller vessels further down arterial tree
Cause ↑ly fatal acute ischaemic events (e.g. MI/ stroke).