Lecture 15 Atherosclerosis I Flashcards
Atherosclerosis is a chronic inflammatory disease T or F
T
What is the significance of atherosclerosis in cardiovascular disease
Atherosclerosis is the principal cause of heart attack stroke and gangrene of the extremities. It is also one of the major causes of death in Europe USA and Japan
What was atherosclerosis initially thought to be
A lipid storage disease
What is the main problem caused by atherosclerosis
The main problem in atherosclerosis comes when the plaque ruptures leading to thrombus formation and ultimately death
What factors influence atherosclerosis
It is influenced by a multitude of lifestyle choices medical conditions and haemodynamics of blood flow itself
Atherosclerosis can begin before birth T or F
T – particularly if there is maternal hypercholesterolaemia
Atherosclerosis often remains symptomless for the majority of the patients’ lifetime T or F
T
What initial trigger is required to start the process of atherosclerosis
Insult or injury to the vessel wall that leads to endothelial cell dysfunction
The risk factors of atherosclerosis can be subclassified into medical and behavioural factors give examples of medical risk factors
Medical risk factors include raised lipoprotein A levels high LDL and/or low LDL dyslipidaemia (high levels of circulating lipids) hypertension overweight/obese type 2 diabetes positive family history (genetically inherited) and infections (such as chlamydia pneumonia)
The risk factors of atherosclerosis can be subclassified into medical and behavioural factors give examples of behavioural risk factors
Behavioural risk factors include a diet high in fat smoking physical inactivity and alcohol consumption
What is the relationship between the behavioural risk factors of atherosclerosis and the trigger of the disease
Endothelial cell dysfunction linked to smoking dyslipidaemia and type 2 diabetes
What is the significance of age in atherosclerosis
Age is also a risk factor as we get older the more likely that atherosclerosis can progress to late stage disease
Where are atherosclerotic plaques found
In the peripheral and coronary arteries
What factors can influence the localisation of atherosclerotic plaques
The distribution of plaques may be governed by haemodynamic factors. Changes in flow/turbulance (e.g. at bifurcations) cause the artery to adjust its wall thickness and develop a neointima.
Where are atherosclerotic plaques often found
At bifurcations
Outline the structure of atherosclerotic plaques
Atherosclerotic plaques are complex lesions consisting of lipids a fibrous cap made of connective tissue and smooth muscle cells a necrotic core buried within the lesion between the media of the vessel and the fibrous cap and then also connective tissue
Discuss the fate of atherosclerotic plaques
Eventually the plaques will either occlude the vessel lumen resulting in a restriction of blood flow (angina) or they may rupture resulting in thrombus formation which can lead to death
The atherosclerotic pathway is initiated by an injury to the endothelial cells which leads to endothelial dysfunction T or F
T
What is the effect of endothelial dysfunction
Endothelial dysfunction can cause altered NO biosynthesis which affects blood pressure control regional blood flow and predisposes a vessel to atherosclerosis. Similarly the damaged endothelium sends signals to inflammatory cells which then accumulate and migrate into the vessel walls. These signals such as cytokines including IL-1 selectins and integrins act as chemoattractants for the invading immune system cells
How does endothelial dysfunction lead to adhesion of immune cells to the vessel wall
The damaged endothelium releases chemoattractants that produce a concentration gradient that is recognised by leukocytes. The endothelial cells when also begin to upregulate cell adhesion molecules that promote the adhesion of the leukocytes
What happens following leukocyte attraction to the damaged endothelium
In response to the chemoattractant gradient the leukocyte will become captured by the vessel. This is followed by rolling along the endothelium of the vessel. This rolling then slows down to become slow rolling. After rolling stops the leukocyte undergoes firm adhesion. This adhesion is then followed by transmigration across the vessel wall
Outline the lipid stimulus in atherosclerotic plaque development
LDL can normally pass in and out of the arterial wall however in the presence of macrophages LDL is captured leading to an excess accumulation in the arterial wall. Endothelial cells and macrophages generate free radicals and these free radicals oxidise LDL to oxLDL. oxLDL is then engulfed by macrophages via scavenger receptors to form foam cells. Foam cells then release more pro-inflammatory cytokines and then incorporate into the vessel wall and atherosclerotic lesion
Give examples of cytokines released by atherosclerotic plaques
IL-1 IL-6 IL-8 IFN-γ TGF-β MCP-1 and PDGF
Give an overview of the process of atherosclerosis from initial plaque formation to thrombus formation
In the first instance excess LDL accumulates in the artery wall and is oxidised by free radicals produced by the damaged endothelium and macrophages. Oxidised LDL causes the endothelial cells to become inflamed and as a result they begin to express CAMs for leukocytes. Leukocytes move across the vessel wall into the intima where they begin to uptake some of the oxLDL. Upon taking up oxLDL the leukocytes transform into foam cells which incorporate into the lesion. Cytokines released by foam cells triggers the smooth muscle cells in the intima to proliferate and secrete extracellular matrix proteins such as collagen. Other smooth muscle cells from the media migrate into the intima to form the fibrous cap. Persistence of the risk factors causes growth of the plaque which triggers an inflammatory response. T lymphocytes that migrate into the plaque then activate macrophages and cause them to secrete matrix metalloproteases. These matrix metalloprotease enzymes breakdown the collagen of the fibrous cap and render the plaque prone to rupture. Rupture of the plaque subsequently causes thrombus formation by allowing the blood to contact the endothelium. This can then result in ischaemic events such as MI or stroke
What is the first stage of lesion in atherosclerosis
Fatty streak formation where the accumulation of lipid–laden macrophages foam cells and T lymphocytes within the intimal layer of the vessel wall (below endothelium) has begun to form a lesion. This occurs at a very early age (around 10years) although won’t cause any symptoms
Following fatty streak formation these lesions can progress to an intermediate stage. What is characteristic of atherosclerotic plaques at this stage
Intermediate lesions consist of layers of foam cells vascular smooth muscle cells isolated pools of extracellular lipid/cholesterol T lymphocytes and adhesions and aggregates of platelets to vessel wall
Symptoms of atherosclerotic disease will being to occur at the intermediate lesion stage due to occlusion of the vessel lumen T or F
F – no symptoms will occur at this stage in the disease as no lumen occlusion will have occurred
Why do most atherosclerotic plaques remain in the intermediate lesion stage
Due to the mechanism of reverse cholesterol transport
Briefly describe the reverse cholesterol transport pathway
Circulating HDL contains Apo-A1 particles that interact with foam cells to collect cholesterol. This mature HDL then travels to liver to release its cholesterol which is then processed for excretion. HDL then recirculates back to heart to repeat process
What factors are thought to provide the extra impetus for an intermediate atherosclerotic lesion to progress to advanced stage
The addition of another risk factor or area of disturbed flow
What is seen in advanced atherosclerotic lesions
There is the formation of a dense fibrous cap overlying a lipid-rich core. This cap consists of extracellular matrix proteins including collagen (strength) and elastin (flexibility). The lipid core consists of necrotic and apoptotic debris smooth muscle cells foam cells cholesterol crystals macrophages and T-lymphocytes
What is the name given to the cap and core of a late stage atherosclerotic lesion
Atheromatous plaque
What additional step may advanced atheromatous lesions undergo
Calcification
Advanced atheromatous plaques impede blood flow and are prone to rupture T or F
T
Atherosclerotic plaques are constantly growing and receding this is why the majority of lesions remain in the intermediate stage T or F
T – there is a balance between LDL moving into the lesion and depositing cholesterol and HDL clearing some of the cholesterol
As well as the lipid core growing and receding what is happening to the cap
The fibrous cap has to be resorbed and redeposited as well in order to be maintained. Macrophages stimulated by T cells are secreting matrix metalloproteases that breakdown the cap. Meanwhile a large number of VSMC and matrix proteins stabilise the cap.
What can cause plaque rupture
Large numbers of macrophages predisposes plaque to rupture due to increased matrix metalloproteinases and gelatinase secretion that causes the cap to become weak. Similarly cholesterol crystals released by the necrotic and apoptotic foam cells also play a role in plaque rupture. These crystals can either tear directly out of the plaque or erode the plaque itself
What is the result of plaque rupture
Plaque rupture provides a substrate for thrombus formation and vessel occlusion
