Fundamentals of atherogenesis

Question 1

What is atherosclerosis?

Answer 1

Is the principal cause of heart attack, stroke and gangrene of the extremities

Question 2

What is the main problem with atherosclerosis?

Answer 2

The main problem is plaque rupture leading to thrombus formation, partial/complete arterial blockage leading to a heart attack

Question 3

What are risk factors for atherosclerosis?

Answer 3

• Age
• Tobacco Smoking
  
  • Toxins damages endothelium
• High Serum Cholesterol
• Obesity
• Diabetes
• Hypertension
• Family History

Question 4

Describe the distribution of atherosclerosis?

Answer 4

• Governed by flow
• Found within peripheral and coronary arteries
• Focal distribution along the artery length
• Distribution may be governed by haemodynamic factors:
  
  • Changes in flow/turbulence (eg
    at bifurcations) cause the artery
    to alter endothelial cell function
  • Wall thickness is also changed
    leading to neointima
• Altered gene expression in the key cell types is key

Question 5

Which of the following is not in artery walls?
- Tunica intima
- Tunica media
- Epithelial cells
- Neutrophils

Answer 5

Epithelial cells

Question 6

What does an atherosclerotic plaque consist of?

Answer 6

• Lipid
• Necrotic core
• Connective tissue
• Fibrous “cap”

Question 7

What eventually happens to an atherosclerotic plaque?

Answer 7

Eventually the plaque will either occlude the vessel lumen resulting in a restriction of blood flow (angina), or it may rupture (thrombus formation – death)

Question 8

What is the response to injury hypothesis of atherosclerosis?

Answer 8

1. Initiated by an injury to the endothelial cells which leads to endothelial dysfunction
2. Signals sent to circulating leukocytes which then accumulate and migrate into the vessel wall
3. Inflammation ensues

Question 9

When is inflammation good?

Answer 9

• Pathogens
• Parasites
• Tumors
• Wound healing

Question 10

When is inflammation bad?

Answer 10

• Myocardial reperfusion injury
• Atherosclerosis
• Ischaemic heart disease
• Rheumatoid arthritis
• Asthma
• Inflammatory bowel disease
• Shock
• Excessive wound healing

Question 11

Describe how inflammation is ignited in arterial walls

Answer 11

• LDL - can pass in and out of the arterial wall in excess it accumulates in arterial wall, and undergoes oxidation and glycation
• Endothelial dysfunction (Response to Injury hypothesis)

Question 12

How is sticky endothelium a stimulus for leukocytes?

Answer 12

• Once inflammation is initiated,chemoattractants (chemicals that attract leukocytes) are released from endothelium and send signals to leukocytes
• Chemoattractants are released from site of injury and a concentration-gradient is produced to guide more leukocytes into the arterial wall

Question 13

How are leukocytes recruited to vessel walls?

Answer 13

• Selectins on the vessel wall capture the leukocyte and roll it along the vessel wall
• Integrins and chemoattractants are responsible for firm adhesion of the leukocytes, and the
  transmigration into the vessel

Question 14

What are the steps in the progression of atherosclerosis?

Answer 14

1. Fatty streaks
2. Intermediate Lesions
3. Fibrous Plaques or Advanced Lesions
4. Plaque Rupture
5. Plaque Erosion

Question 15

Describe fatty streaks

Answer 15

• Earliest lesion of atherosclerosis
• Appear at a very early age (<10 years)
• Consist of aggregations of lipid–laden macrophages and T lymphocytes within the intimal layer of the vessel wall

Question 16

Describe intermediate lesions

Answer 16

• Composed of layers of :
  
  • Lipid laden macrophages (foam cells)
  • Vascular smooth muscle cells
  • T lymphocytes
  • Adhesion and aggregation of platelets to vessel wall
  • Isolated pools of extracellular lipid

Question 17

Describe fibrous plaques or advanced lesions

Answer 17

• Impedes blood flow
• Prone to rupture
• Covered by dense fibrous cap made of ECM proteins including collagen (strength) and elastin (flexibility) laid down by SMC (smooth muscle cells) that overlies lipid core and necrotic debris
• May be calcified
• Contains: smooth muscle cells, macrophages and foam cells and T lymphocytes

Question 17

Describe plaque rupture

Answer 17

• Plaques constantly grow and recede
  
  • Lesions can change
• Fibrous cap has to be resorbed and redeposited in order to be maintained
• If balance shifted eg. in favour of inflammatory conditions (increased enzyme activity), the cap becomes weak and the plaque ruptures
• Basement membrane, collagen, and necrotic tissue exposure as well as haemorrhage of vessels within the plaque
• Thrombus formation and vessel occlusion

Question 17

Describe plaque erosion

Answer 17

• Second most prevalent cause of coronary thrombosis
• Lesions tend to be small ‘early lesions’
• A thickened fibrous cap may lead to collagen triggering thrombosis rather than tissue factor (as in plaque rupture)
• A platelet-rich clot may overlie the luminal surface
• There is usually a small lipid core

Question 18

Compare ruptured plaques and eroded plaques

Answer 18

• Ruptured plaque has a large lipid core with abundant inflammatory cells
• Eroded plaques have a small lipid core, disrupted endothelium, more fibrous tissue and a larger lumen

Question 19

What is a treatment of coronary artery disease?

Answer 19

PCI

Question 20

What is PCI?

Answer 20

Percutaneous Coronary Intervention

Question 21

What was a limitation of PCI?

Answer 21

Restenosis was a major limitation, no longer though due to drug eluting stents

Question 22

How do drug eluting stents help restenosis?

Answer 22

Drug eluting stents improve duration of stents: anti-proliferative and inhibits healing

Question 23

What are useful drugs when it comes to CAD?

Answer 23

• Aspirin – irreversible inhibitor of platelet cyclo-oxygenase
• Clopidogrel/Ticagrelor – inhibitors of the P2Y12 ADP receptor on platelets and other drugs with antiplatelet actions
• Statins – inhibit HMG CoA reductase, reducing cholesterol synthesis