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
