Atherosclerosis & treatment of CVD Flashcards
(39 cards)
Risk factors for atherosclerosis
- smoking
- diabetes
- genetic (LDL receptors)
- endocrine (sex)
- hypertension
- hyperlipidaemia (raised LDL as opposed to HDL)
- oxidised LDL
What is LDL?
Sphere of phospholipids containing high concentrations of cholesterol and apo-B
What is the function LDL?
Transport of water-soluble cholesterol in the blood
What does PCSK9 do?
binding LDL receptors and promoting their intracellular degradation - could be targetted by anti-LDL antibodies
How may LDL cause atherosclerosis (mechanism is unknown)?
thought LDL particles infiltrate the intima where they undergo modification that make the immunogenic, as well as proinflammatory
How is HDL a risk factor? Discuss
- low levels are a risk factor
- HDL is involved in transport from peripheral tissues back to the liver where it is excreted
How may changes to the endothelial layer lead to atherosclerosis?
- plaques tend to form at points of flow disturbance and endothelial sheer stress is partially responsible for the induction of an atherogenic endothelial phenotype
Possible clinical manifestations of atherosclerosis
- angina
- MI
- claudication (pain caused by too little blood flow to the legs and arms)
- embolism
- aneurysm
- ischaemic stroke
Is atherosclerosis more common in makes or females?
Males
What stages can the pathogenesis of atherosclerosis be considered in?
- LDL oxidation (due to endothelial injury or dysfunction)
- monocyte/ macrophage recruitment
- foam cell recruitment
- lesion progression
- plaque stability
What do atherosclerotic lesions begin as and what is the major cellular event contributing to the formation of these structures?
- They begin as fatty streaks underlying the endothelium of large arteries
- uptake of LDL-derived cholesterol by macrophages
- can be argued that oxidation of LDL is the main cellular event
Which vessels do plaques form in?
Absent from veins and the microvasculature
Why ox-LDL taken up by macrophages in particular?
It can no longer be recognised by LDL receptors on cells but is instead recognised by scavenger receptors found on surface of macrophages and SMCs
Discuss how endothelial dysfunction leads to monocyte recruitment
- loss of protective effects of NO in particular
- starts expressing a range of adhesion molecules which capture circulating monocytes
- e.g. VCAM-1
- E and P selectin
- ICAM-1
- oxLDL can also directly attract monocytes via the expression of monocyte chemotactic molecules
Describe platelet recruitment to endothelium
Endothelial erosion exposes collagen-rich prothombotic sub-endothelium, to which platelets adhere and form microthrombi
Aside from monocyte and platelet recruitment, what may endothelial injury cause?
- generation of proatherogenic ET-1
- generation of superoxide (oxidising free radical)
Describe the inflammation that occurs after endothelial injury
- monocytes → macrophages → generate pro-oxidant species
- platelets degranulate → release of pro-inflammatory mediators
- SMCs begin to proliferate and for the ‘neointima’ in response to GFs and absence to anti-mitogenic NO
- SMCs of neointima → become non-contractile and secrete ECM to stabilise developing plaque
When do foam cells form?
- caused by uptake of cholesterol by macrophages
What is the transition from a fatty streak to a complex lesion characterised by?
- Immigration of SMCs from the medial layer past the internal elastic lamina and into the sub-endothelial space
- Intimal SMCs proliferation and take up modified lipoproteins, contributing to foam cell formation and synthesize ECM that leads to the development of the fibrous cap
What forms the necrotic core of the apoptotic lesions?
SMCs and macrophages which have formed foam cells begin to apoptose and necrose
What may happen in the plaque is unstable?
- it may rupture
- can cause an ischaemic event
What do statins do?
lower cholesterol by inhibiting HMG-CoA reductase and increase hepatic LDL-receptor expression
- leads to decreased plasma LDL-C and increased plasma triglycerides (and HDL)
Aside from lowering LDL, what else may statins do?
- restoration of healthy endothelium
- anti-platelet effects
- plaque stabilisation
How to prevent CVD through lifestyle choices?
- smoking
- obesity
- physical activity
- blood pressure
- diet
