Atheroma - Revision Flashcards
What are the 3 layers of an arterial vessel?
- Intima
- Media
- Outer adventitia
Which layer of the arterial vessel is located closest to the arterial lumen?
Intima
What is the intima composed of?
A single layer of endothelial cells (endothelium)
Effect of NO and prostacyclin?
Relax blood vessels (vasodilation) and inhibit platelet activation (limit thrombosis)
What are NO and prostacyclin released by?
Endothelial cells
In normal endothelium, describe and explain the;
a) smooth muscle cells?
b) net coagulant or anticoagulation?
c) adhesion molecules?
a) relaxed - due to release of NO and prostacyclin
b) net anticoagulant properties
c) no expression of leucocyte adhesion molecule
How does the endothelium modulate contraction of smooth muscle cells in the media?
By releasing substances such as vasodilators and vasoconstrictors
Examples of vasodilators?
NO and prostacyclin
Example of vasoconstrictor?
Endothelin
What does ‘endothelial cell activation’ refer to? What could this be caused by?
Endothelium undergoes changes to allow it to contribute in the inflammatory response.
Caused by e.g: common stresses (e.g. shear stress and mild changes in temperature), transient infections and minor trauma.
What are the five core changes of endothelial cell activation?
- Loss of vascular integrity
- Expression of leucocyte adhesion molecules
- Change from antithrombotic to prothrombotic
- Cytokine production
- Vasoconstriction
What characterises the normal arterial endothelium?
- Net anticoagulant properties
- Net relaxation of smooth muscle cells
- Anti-inflammatory characteristics
What is the elasticity of a vessel regulated by?
The lamina elastica
Purpose of lamina elastica?
Provide elasticity and prevent the vascular wall from collapsing
Why is lamina elastica important in atherosclerosis
it prevents the weakening of the vessel wall that can prevail as a complication of atherosclerosis
Where is lamina elastica found?
Between intima and media
Normally, what do smooth muscle cells synthesise that contributes to connective tissue matrix of the vessel wall?
Collagen, elastin and proteoglycans
What inflammatory and vasoactive mediators do smooth muscle cells synthesis
E.g. IL-6 and TNF-a
Effect of IL-6 and TNF-a?
Stimulate leukocyte migration and induce the endothelial cells to express leukocyte adhesion molecules
What is an atheroma?
An abnormal accumulation of material in the intima
What are the 5 key stages of atheroma formation?
- Endothelial dysfunction
- Formation of lipid layer or fatty streak within theintima
- Migration of leukocytes and smooth muscle cells into the vessel wall
- Foam cell formation
- Degradation of extracellular matrix
What 3 main stages can the formation of the plaque be divided into?
- Fatty streak
- Plaque progression
- Plaque disruption
Does a fatty streak protrude substantially into the artery wall or impede blood flow?
No (people over 20 tend to have)
What allows circulating LDLs into the intima?
Disruption of endothelial barrier due to endothelial dysfunction
What does entry of lipids into the intima stimulate?
Creates a proinflammatory environment and initiates the migration of leukocytes and formation of foam cells
What are factors associated with endothelial dysfunction?
Increased age Male sex Family history of CHD Smoking Elevated cholesterol Low HDL-cholesterol Diabetes mellitus Hypertension Obesity High fat consumption
How does NO function as an anti-atherosclerotic substance?
- Vasodilation
- Inhibition of platelet aggregation
- Anti-inflammatory effects
Why are atheromas more likely to occur at sites of bifuraction?
Disturbed flow can impair protective functions
How can smoking lead to atheromas?
Exposure to chemical irritants promotes endothelial dysfunction by increasing endothelial production of reactive oxygen species.
This leaves the endothelium become inclined to exhibit pro-inflammatory processes, such as secreting inflammatory cytokines.
How do macrophages become foam cells?
Macrophages adhere to dysfunctional endothelial cells and transmigrate into the intima.
These macrophages are called ‘foam cells’ after they have taken up LDLs.
What hypothesis can explain the recruitment of inflammatory cells after injury?
Response to injury hypothesis
How do foam cells encourage the plaque progression?
Serving as a source of proinflammatory cytokines.
What are the 2 features of an atherosclerotic plaque?
- Lipid-rich necrotic core
2. Fibrous cap
What does the fibrous cap contain?
Dead foam cells, macrophages, smooth muscle cells, lymphocytes and extracellular matrix
How can the vessel compensate during the early stages of the atherosclerotic plaque?
a compensatory outward remodeling of the plaque wall (preserves the diameter of the vessel lumen)
Progressive vessel narrowing may result in ischaemia. What are some ischemic symptoms?
angina pectoris or intermittent claudication
During the phase of transition from fatty streak to plaque formation, where do the smooth muscle cells migrate from/to?
From the media to the intima
Once in the intima, what do smooth muscle cells do?
proliferate within the intima and secrete extracellular matrix molecules
What do foam cells release that directly contribute to the migration and proliferation process of SMCs?
platelet derived growth factor (PDGF), cytokines and growth factors
What predisposes a plaque to rupture? What influences this process?
Metabolic processes in extracellular matrix weaken the fibrous cap.
This process is influenced by the balance of matrix deposition synthesis by smooth muscle cells and degradation by matrix metalloproteinases (MMP)
What is MMP secreted by?
Foam cells that are stimulated by inflammatory cytokines
How does MMP weaken the fibrous cap?
degrades collagen and elastin of the fibrous cap
What causes the lipid core to grow?
Cell death leads to release of cellular contents, whereby more lipids and cellular debris is absorbed to the dynamic lipid core
What is released when the fibrous cap is ruptured? What does this lead to?
The highly thrombogenic components of the necrotic core are in direct contact with the circulating monocytes in the blood
Will lead to the formation of thrombus at the rupture site.
What does inflammatory stimuli in the plaque environment iniciate?
smooth muscle cells, endothelial cells, and foam cells to release tissue factor that initiates the extrinsic coagulation pathway
also stimulate expression of antifibrinolytics
How can activated endothelial cells contribute to thrombosis?
depositing fibrin at the vascular wall
What are the most common locations of atherosclerosis?
- Dorsal section of the abdominal aorta
- Proximal coronary arteries
- Popliteal arteries
- Descending thoracic aorta
- Internal carotid arteries
6, Renal arteries
What is angina pectoris?
chest pain or discomfort due to coronary heart disease –> when the heart muscle doesn’t get as much blood as it needs
What are the 2 ways in which atherosclerosis can cause occlusion?
- Growing plaque/thrombus occluding vessel
2. Embolisation
What are the 4 major clinical consequences of atherosclerosis?
- Acute narrowing of vessel lumen
- Chronic occlusion
- Embolism
- Aneurysm
If the thrombus formed after plaque rupture causes a complete occlusion, what can it result in? What can this manifest as?
results in ischemic necrosis (infarction) of the tissue
manifested as stroke, MI, gangrene of several possible organs such as intestine, spleen or lower extremities
What characterises chronic occlusion?
When the occlusion is gradual and incomplete, it may chronically disturb the blood supply to tissues
What can chronic occlusion lead to? What are the clinical manifestations?
This can result in chronic ischemia of those tissues
Manifestations:
- angina pectoris
- intermittent claudication
- organ atrophy (atrophy due to impairment of blood flow )
What is embolisation?
The transfer of the fragments of disrupted atheroma to distal vascular sites, which results into occlusion of those sites.
Fragments of thrombi in abdominal aorta may transfer to the popliteal artery.
What may this result in?
Gangrene of the leg
How can a plaque lead to an aneurysm?
Atherosclerotic lesion may extend into the medial layer, resulting into atrophy and loss of elastic tissue. This can subsequently cause dilatation and weakness of the artery, forming aneurysm.
What are dangers of aneurysms?
may suddenly rupture
Purpose of expression of leucocyte adhesion molecules in endothelial activation?
Facilitates the recruitment and attachment of circulating leukocytes to the vessel wall.
What is endothelial cell activation typically induced by?
Endothelial cell activation is typically induced by proinflammatory cytokines, such as TNF-α and IL-6
