Athersclerosis Flashcards
Where does the necrotic core of a plaque develop?
intima/subendothelial space
What is the plaque made of?
- Fibrous cap
- Cellular layer
- Necrotic core
What is the fibrous cap made of and what does it do?
- smooth muscle and collagen in dynamic equilibrium
- keeps lesion in place
What is the cellular layer made of?
- smooth muscle: migrate and proliferate up from the media into the intima
- macrophages infiltrate in
- lymphocytes
- foam cells (they take up cholesterol) develop
it has less connective tissue
What is the necrotic core made of?
- lipids
- cholesterol clefts
- fibrin
- foam cells
- cell debris
What can start thrombosis?
There can be fissures in the core which can damage the endothelium and start thrombosis
When does the development of atheromatous plaques start?
Early:
- <20 y ~ 20% already have significant coronary atherosclerosis/some type of early lesion/lipid accumulation
- 20-29 y ~ 50%
- 30-39 y it’s up to 65%
How are plaques classified?
Plaques are classified depending on development – sequence progression
What classification is used for plaques?
AHA classification:
- Six types of atherosclerotic lesion
- Shows how smooth muscle thickens, lipid and foam cells accumulate
What does a type IV lesion/classification look like?
- Extracellular lipid forms a confluent core in the musculoelastic layer of eccentric adaptive thickening that is always present in this location.
- The region between the core and the endothelial surface contains macrophages and macrophage foam cells (fc)
- an increase in smooth muscle cells or collagenous fibres is not yet present.
What does a type VI lesion look like?
- The region between the lipid core and thrombus consists of closely layered smooth muscle cells.
- The lipid core also contains cholesterol crystals (calcification) and dark staining aggregates of microcrystalline calcium (arrows).
- Smooth muscles have proliferated and migrated from media.
What are the most common sites of plaque build up?
- Internal carotid – emboli can lodge in the cerebral vessel, may lead to ischaemic stroke
- Coronary vessels
- Descending and abdominal aorta – atherosclerosis can lead to weakening of the vessel wall, aneurysm and thrombosis
- Atherosclerosis in the lower limb vasculature – can lead to tissue ischaemia
What are the clinical presentations of atherosclerosis?
:• Myocardial infarction – if there’s occlusion in the coronary arteries
- Stroke – if there’s atheroma in the carotid artery
- Aneurysm
- Peripheral vascular disease ie non healing ulcers and non-healing wounds due to tissue hypoxia and ischaemia
- Kidney injury
Risk factors for atherosclerosis?
- Age
- Male sex (premenopausal women protected)
- Genetics
- Hyperlipidaemia
- Smoking
- Hypertension
- Diabetes mellitus
- Obesity
- Metabolic syndrome
- Alcohol
- Drugs
What are the 9 age-dependent changes to cardiovascular tissues?
- Increased size/hypertrophy of the cardiac muscle cells/cardiac myocytes – due to age related changes of genes
- Cell death/apoptosis – leads to reduced contractility
- Fibrosis – age related changes in the heaty vessels and walls
- Ischaemic tissue
- Decreased heart rate/ increased arrhythmia – due to gene changes
- Changes to cholesterol homeostasis genes – increased risk of cholesterol build up
- Increases proliferation and infiltration of smooth muscle cells
- Changes to nitric oxide and contractility of vessels – vessels stiffen
- Thickening of media and intima
What genes/proteins play a role in cholesterol homeostasis?
o apolipoprotein B – involved with cholesterol uptake
o LDL receptor – also involved wit cholesterol uptake
o PCSK9 (proprotein convertase subtilisin/kexin type 9) – risk factor for atherosclerosis, involved in the regulation of cholesterol
What genes/proteins are associated with CVD?
- Variants in angiotensinogen protein associated with hypertension
- Predisposition to type 2 diabetes
- Ion channel proteins affecting arrhythmias
What atherosclerosis risk factors are also associated with metabolic syndrome and type 2 diabetes?
- Obesity
- Hypertension
- Inflammation
- Thrombosis
- Hyperglycemia
- Atherogenic dyslipidemia
- Microalbuminuria
What is the classic mechanism of atherosclerosis?
- Injury to the endothelium (dysfunctional endothelium)
- Chronic inflammatory response – inflammation drives atherosclerosis
- Migration of SMC from media to intima
- Proliferation of SMC in the intima
- Excess production of extracellular matrix
- Enhanced lipid accumulation
What are the normal functions of epithelial cells?
Epithelial cells normally act as a barrier, it’s the inner most cell of the vessels.
- Main function is to maintain vascular homeostasis
- Normally they have an anticoagulant function
- Involved in mediating vessel tone as they release vasodilators and vasoconstrictors
- Oxygen and co2 diffuse into blood stream through it
What can cause thrombosis in endothelial cells?
EC’s experience a lot of stimuli ie shearing forces and inflammatory mediators – physiological stimuli that can lead to EC activation
However, injured endothelial cells/exposure of subendothelial collagen to blood – it can lead to thrombosis
What does atherosclerosis start with?
Starts with endothelial cell activation – this happens because of uptake of LDL through LDL receptor, it becomes oxidised in the intima and that can result in proinflammatory lipids
Describe how atherosclerosis happens
- The proinflammatory lipids cans stimulate EC to express adhesion molecules (VCAM) on the surface – they attract circulating monocytes
- Monocytes bind to activated EC layer, migrate into intima and respond to chemokines like MCP-1.
- Monocytes then differentiate into macrophages and migrate into the intimal layer
- M-CSF (macrophage colony stimulating factor) increase differentiation and expression of receptors on the surface of macrophages – they mediate the uptake of oxidised LDL
- cholesterol accumulates in the macrophages and they become foam cells
- Macrophage’s release and respond to proinflammatory mediators like interleukins and TNF – increase the activation of macrophages and the release of more proinflammatory mediators
- All of this increases foam cell formation and cholesterol accumulation
- Proinflammatory mediators can also cause an increase in smooth muscle cell proliferation, migration and contractile function
- they switch to synthetic smooth muscle cells: they lose their contractile apparatus and express collagen
- Some become apoptotic – necrotic core builds
What can cause further fissures/damage to endothelium cells?
Proteins secreted from the macrophages: proteases and collagenases break up the collagen/cause proteolysis
An increase in lipids, macrophages, inflammation and endothelial cell damage can cause a break in the plaque/endothelial layer – can cause thrombosis
What can increase the stability of the plaque?
An increase in fibres and smooth muscle cells increases the stability of the plaque
How can a thrombotic obstruction of an artery be overcome?
Thrombotic obstruction of an artery can be overcome by opening of new channels by recanalization (may lead to emboli)
Thrombus causes the initiation of fibrinolysis – a break down of the thrombotic clot and infiltration of other cells, this is recanalization
What can occur as a result of a thrombus formation?
Ischaemia
What can ischaemia do?
it can open up collateral vessels for collateral circulation
How can collateral circulation develop in the heart?
Luminal narrowing occurs gradually enough for heart to adapt by opening alternative circulatory paths
