Atherogenesis Flashcards
What is atherogenesis?
- formation of fatty deposits in arteries
- progressive inflammation follows
What are some risk factors that are not able to be modified for atherogenesis?
- gender (male 10 years earlier)
- genetic abnormalities
- increasing age (MAIN RISK)
- family history
What are some risk factors that are modifiable for atherogenesis?
- smoking
- high cholesterol
- high blood pressure
- diabetes
What are the 3 main layers of the arterial walls? (inner to out layers)
- innermost = intima
- middle = media
- outermost = adventitia
What is the inner most layer of arterial walls composed of?
- endothelium
- squamous epithelial cells
What is the middle layer of arterial walls, called media composed of?
- smooth muscle
What is the outer most layer of arterial walls, called adventitia composed of?
- tough fibrous tissue
What does atherosclerosis mean?
- athero = greek for gluey/fatty yellow
- sclerosis = german for hardening
What are the 2 main parts of an atheromatous plaque?
1 - fibrous cap
2 - necrotic core
What is a fibrous cap?
- layer of fibrous tissue connective tissue
What layer of the arterial walls does the fibrous cap form in?
- below endothelium
Generally what cells are found within a fibrous cap?
- smooth muscle cells
- macrophages
- lymphocytes
What are the fibres that contribute towards the fibrous cap?
- elastin
- collagen
- proteoglycans
As fibrous cap formation is inflammation, what do arterial walls need to create to supply the fibrous cap with blood?
- neovascularisation
What is the necrotic core formed in atherosclerosis?
- forms inside the intima below fibrotic cap
- necrotic components under fibrous cap
What are the main components of the necrotic core that also contribute to stiffening of the arteries?
- cholesterol crystals
- Ca2+ salts
- foam cells (from macrophages)
In the lipid hypothesis, roughly when was LDL cholesterol linked with atherosclerosis?
- 1980s
What is the lipid oxidation hypothesis in atherosclerosis?
- free radicals modify LDL cholesterol
If free radicals have modified LDL cholesterol, what can that cause in the innate immune system?
- macrophages absorb LDL, but do not normally
- macrophages become foam cells and undergo necrosis
What was the main problem with the lipid oxidation hypothesis?
- did not account for non lipid risk factors
- age, genetics, smoking
What was the conclusion about the lipid oxidation hypothesis?
- contributes
- NOT primary cause
When looking at research into atherosclerosis, what is one important thing to keep in mind?
- evidence is based on pre-clinical models
What is the response to injury hypothesis?
- atherosclerosis in a chronic inflammatory process to endothelial injury
In order for fatty streaks to form and then go onto atherosclerosis, what is the first thing that must happen in the endothelium in the injury hypothesis?
- endothelial are damaged and injuryed
- endothelial dysfunction follows
Following the initial injury/dysfunction in endothelium in the response to injury hypothesis, what then accumulates at the site of injury/dysfunction?
- lipoproteins
In a similar manner to acute inflammation, once there is an initial injury/dysfunction to endothelium what migrates to the area as part of the response to injury hypothesis?
- leukocyte, specifically monocytes
- margination, adhesion and migration into intima
What is primary leukocyte (WBCs) involved in the early phase of the response to injury hypothesis?
- monocytes differentiate into macrophages
- lipids accumulate and macrophages phagocytose them
- macrophages become foam cells
- macrophages undergo necrosis and release contents
Following macrophages becoming foam cells, what do smooth muscle cells of the media do?
- recruited, migrate and proliferate into intima
Once recruited, migrated and proliferating in the intima what do smooth muscles form?
- extracellular matrix
What are some basic day to day things that can cause endothelial injury/dysfucntion?
- ageing
- high BP
- toxins (smoking)
- hyperlipidaemia
What are cytokines?
- signalling proteins
- signal inflammation, immunity and hematopoiesis processes
What do nitric oxide and endothelium derived relaxing factor do to the endothelium?
- contribute to vasodilation
What are the 4 basic groups of small molecules involved in atherscleroisis?
1 - cytokines 2 - growth factors 3 - chemokines 4 - adhesion molecules
What do common lipoprotein abnormalities commonly cause in the blood markers?
- ⬆️ LDL - ⬇️ HDL - ⬆️ Lp (a) highly atherogenic sub-fraction of LDL
What does endothelial injury cause a reduction in the production and release of in endothelial cells?
- nitric oxide
What does endothelial injury cause an increase in the production and release of in endothelial cells?
- O2 free radicals
What are the 2 forms of lipid that begin to accumulate in the intima?
- oxidised LDL - cholesterol crystals
Damage to the endothelial can cause an increase in the release of proteins that are involved in regulating inflammation, immunity and hematopoiesis, what are these proteins?
- cytokines
What is the first visible manifestation of atherosclerosis?
- fatty streaks
What are fatty streaks?
- combination of foam cells and smooth muscle cells
Do fatty streaks cause symptoms and are they common in everyone?
- can be present with no symptoms - can be in anyone
When looking at fatty streak formation, are macrophages or smooth muscle cells referred to as good?
- smooth muscle cells = good - macrophages = bad
What do smooth muscles secrete to form extra cellular matrix?
- mainly collagen - elastin and proteoglycans
Why are smooth muscle cells referred to as good in athersclerosis?
- aim to stabilise plaque - aim to prevent rupture of plaque
What is the main purpose of the extra cellular matrix in atherosclerosis?
- stabilisation of the atherosclerotic plaque
What are some examples of growth factors involved in stabilising the extra cellular matrix?
- platelet derived growth factor (PDGF) - fibroblast growth factor (FGF) - tissue growth factor alpha (TGF-a)
As the plaque develops more and more foam cells are formed that undergo necrosis and release their contents. What is the name of the cap that aims to maintain stability of this cap?
- fibrous cap - lipid rich underneath
Plaque formation generally expands inwards, but as it continues to grow and develop it can raise up from the vessel wall. What is the problem with this?
- can block arteries
As the plaque develops, what causes the hardening of the arteries?
- Ca2+ salt deposition - phosphate and hydroxyapatite
Roughly what amount of occlusion of the arteries begins to present with clinical problems?
- 70%
Is it easy to distinguish between a stable and unstable plaque?
- no
What is the main cause of a plaque becoming unstable and increasing the risk of rupture?
- thinning of the fibrous cap
If the plaque continues to expand in size, what can happen to the tunica media?
- becomes thinner and weaker - ⬆️ risk of aneurysm
What is an aneurysm?
- weakening of an artery wall - artery wall bulges/distends - can rupture causing internal bleeding
What is the main cause of the fibrous cap to begin to thin?
- continued accumulation of cholesterol in necrotic core - expands fibrous cap and thins it
If the plaque continues to increase in size it can eventually rupture. What will then be exposed into the circulating blood?
- collagen, free cholesterol and Ca2+ salts
Once a plaque ruptures, why is it bad if collagen, free cholesterol and Ca2+ salts from the necrotic core are released into the blood?
- all are highly thrombogenic
What does something mean if it is thrombogenic?
- cause coagulation of the blood - leads to thrombosis, commonly known as blood clot
If a thrombus that has been formed, how can this cause a myocardial infarction?
- occlusion of an artery - limited or no blood flow - common in coronary arteries
If a thrombus that has been formed, how can this cause unstable angina, which is essentially pain in chest even at rest?
- partial occlusion of an artery - reduced blood flow to heart - intermittent pain in chest
If a thrombus that has been formed due to rupture, but then becomes incorporated into fibrous cap, what is the most common clinical presentation of this?
- partial occlusion of an artery - reduced blood flow to heart - chest pain upon exertion
In a patient who is having or has previously had a myocardial infarction what may we expect to see on an ECG?
- ST elevation
If a thrombus that has been formed due to a rupture of a plaque, in addition to a central myocardial infarction, what could occur in the brain?
- stroke due to blockage of blood supply
If a thrombus that has been formed due to a rupture of a plaque, in addition to a central myocardial infarction, what could occur in the legs?
- thrombus lands in legs - results in acute ischemia
If a plaque continues to develop but does not rupture, it can continue through the media and into the adventitia. What can this cause?
- aneurysm formation - artery walls become weakened and can rupture - can cause a haemorrhage and be life threatening
In addition to acute presentations of atherosclerosis, there are a number of chronic conditions as well. How can atherosclerosis of the aorta impact renal system?
- branches of aorta become narrowed - caused renal artery stenosis
What does stenosis mean?
- narrowing of a space
In addition to acute presentations of atherosclerosis, there are a number of chronic conditions as well. How can atherosclerosis cause vascular dementia?
- blood flow to brain is impaired - similar to dementia
What are the most common symptoms patients with atherosclerosis can present with in the legs?
- claudication (pain) - foot ulcers - gangrene
