Fundamentals of atherogenesis Flashcards
What is atherosclerosis?
Is the principal cause of heart attack, stroke and gangrene of the extremities
What is the main problem with atherosclerosis?
The main problem is plaque rupture leading to thrombus formation, partial/complete arterial blockage leading to a heart attack
What are risk factors for atherosclerosis?
- Age
- Tobacco Smoking
- Toxins damages endothelium
- High Serum Cholesterol
- Obesity
- Diabetes
- Hypertension
- Family History
Describe the distribution of atherosclerosis?
- 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
- Changes in flow/turbulence (eg
- Altered gene expression in the key cell types is key
Which of the following is not in artery walls?
- Tunica intima
- Tunica media
- Epithelial cells
- Neutrophils
Epithelial cells
What does an atherosclerotic plaque consist of?
- Lipid
- Necrotic core
- Connective tissue
- Fibrous “cap”
What eventually happens to an atherosclerotic plaque?
Eventually the plaque will either occlude the vessel lumen resulting in a restriction of blood flow (angina), or it may rupture (thrombus formation – death)
What is the response to injury hypothesis of atherosclerosis?
- Initiated by an injury to the endothelial cells which leads to endothelial dysfunction
- Signals sent to circulating leukocytes which then accumulate and migrate into the vessel wall
- Inflammation ensues
When is inflammation good?
- Pathogens
- Parasites
- Tumors
- Wound healing
When is inflammation bad?
- Myocardial reperfusion injury
- Atherosclerosis
- Ischaemic heart disease
- Rheumatoid arthritis
- Asthma
- Inflammatory bowel disease
- Shock
- Excessive wound healing
Describe how inflammation is ignited in arterial walls
- 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)
How is sticky endothelium a stimulus for leukocytes?
- 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
How are leukocytes recruited to vessel walls?
- 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
What are the steps in the progression of atherosclerosis?
- Fatty streaks
- Intermediate Lesions
- Fibrous Plaques or Advanced Lesions
- Plaque Rupture
- Plaque Erosion
Describe fatty streaks
- 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
Describe intermediate lesions
- 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
Describe fibrous plaques or advanced lesions
- 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
Describe plaque rupture
- 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
Describe plaque erosion
- 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
Compare ruptured plaques and eroded plaques
- 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
What is a treatment of coronary artery disease?
PCI
What is PCI?
Percutaneous Coronary Intervention
What was a limitation of PCI?
Restenosis was a major limitation, no longer though due to drug eluting stents
How do drug eluting stents help restenosis?
Drug eluting stents improve duration of stents: anti-proliferative and inhibits healing
What are useful drugs when it comes to CAD?
- 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
