Pathophysiology of atherosclerosis

Question 1

UPSTREAM INFLAMMATORY RESPONSE

Answer 1

WBC(monocytes & lymphocytes) • 2nd line of defence in response to injury/damage/illness

Question 2

DOWNSTREAM INFLAMMATORY RESPONSE TNF-a

Answer 2

• Multiple roles and effects (pro & anti)
• Activates NF-kB (major transcription factor)
• Stimulates acute-phase response in the liver

Question 3

DOWNSTREAM INFLAMMATORY RESPONSE IL-6

Answer 3

• Multiple roles and effects like TNF-a
• Regulates immune function (pro & anti)
• In relation to atherosclerosis, released from smooth muscle cells (SMC) in response to macrophage-derived TNFa
• Messenger cytokine

Question 4

CRP

Answer 4

• Acute phase protein synthesised by hepatocytes (liver)
• Released in response to IL-6 (related to macrophage TNFa)
• High sensitivity CRP (more reflective of early-stage, low-grade inflammation)
• Stable biomarker

Question 5

CAD

Answer 5

1. Endothelial dysfunction
2. Oxidation of LDL
3. Infiltration of oxLDL
4. Attraction of WBC
5. Infiltration of WBC
6. Foam Cell Production
7. SMC Migration
8. Plaque formation
9. Plaque instability
10. Plaque rupture & thrombus

Question 6

Atherosclerosis

Answer 6

1. LDL enters intima through intact endothelium
2. intima LDL is oxidised into proinflammatory lipids
3. oxidised LDL causes adhesion and entry of monocytes and T lymphocytes across endothelium
4. monocytes differentiate into macrophages and then consume large amounts of LDL transforming into foam cells
5. foam cells release growth factors (cytokines) that encourage atherosclerosis

Question 7

Stage 1

Answer 7

Endothelial dysfunction
Decrease in NO leads to
decrease dilation of blood vessels
increased platelet stickiness
increased monocytes stickiness
increase multiplication of s.m.c. of artery wall
Increases release of superoxide radicals
Increases oxidation of LDL cholesterol

Question 8

Stage 2

Answer 8

Oxidation of LDL
Low density lipoproteins (LDL) within the circulation = normal
LDL can infiltrate into the intimal layer = normal Interaction of LDL with free radicals (risk factors) = oxidised

Question 9

Stage 3

Answer 9

Infiltration of oxLDL
Ox-LDL infiltrates through endothelial layer.
Initiates release of adhesion molecule VCAM-1*.
Adhesion molecule moves to endothelial layer.

Question 10

Stage 4

Answer 10

Attraction of WBC’s
Adhesion molecules are expressed on endothelium Activate the endothelial cells
Attract WBC’s (mainly monocytes)
T-lymphocytes attracted by expression of VCAM-1

Question 11

Stage 5

Answer 11

Infiltration of WBC’s

WBC migrate into intima leads to macrophages due to MCP-1 (Monocyte Chemoattractant Protein 1)

Question 12

Stage 6

Answer 12

Foam Cell Production
1. Macrophages engulf oxLDLvia M-CSF (Macrophage Colony-Stimulating Factor)
2. Become a foam cells
3. Ongoing secretion of M-CSF and other inflammatory mediators (TNF-a)
Augment expression of macrophage scavenger receptors leading to uptake of modified lipoprotein particles
4. Foam cells multiply to develop a fatty streak

Question 13

Stage 7

Answer 13

SMC Migration

Ongoing secretion inflammatory cytokines, growth factors … Migration of SMC from tunica media leads to intimal layer

Question 14

Stage 8

Answer 14

Plaque Formation

1. In response to ongoing inflammation leads to SMC proliferation
2. Collagen matrix and development of a fibrous cap
3. Plaque holding foam cells in
4. Possible stenosis but not immediately due to remodelling of the vessel

Question 15

Stage 9

Answer 15

Plaque Instability
Continued inflammation increases in enzymes expressed by SMC
Interfere with stability and strength of elastin & collagen matrix
-destructs existing collagen (enzymes)
-prevent new collagen Plaque weakens

Question 16

Stage 10

Answer 16

Plaque Rupture & Thrombus
• Ongoing inflammation and release of tissue factors
• Rupture of atheroma and thrombus released into blood
• Most probable cause of MI