Lecture 9 - atherosclerosis Flashcards
what is atheroma?
atheroma is the accumulation of intracellular and extracellular lipid in the intimate of large and medium sized arteries
what is atherosclerosis ?
the thickening and hardening if arterial walls as a consequence of atheroma in large and medium sized arteries
what does atherosclerosis result from?
develops over several decades
it starts as early as infancy and childhood and progresses very slowly during life
it results from accumulation of lipid, connective tissue, inflammatory cells, and smooth muscle cells in the intima
where does atherosclerosis occur?
primarily in arteries
common sites
- aorta - especially abdominal
- coronary arteries
- carotid arteries
- cerebral arteries
- leg arteries
what is the detection of atherosclerosis ?
atherosclerosis is typically asymptomatic
it is most often found after it manifests itself as a heart attack or stroke
measure of low density lipoprotein (LDL) in blood as a predictor
20% of events occur in individuals with no major risk factors
what are the macroscopic features of atheroma?
fatty streak - comprises if a slightly elevated zone on the arterial wall caused by accumulation of a small number of lipid lien cells
simple (fibrous) plaque - lipid accumulates, both free and in cells. smooth muscles also migrates from the media. fibrosis develops around the lipid and forms a cap over the lesion
complicated plaque (ulcers and fissures of the fibrous cap expose plaque concepts resulting in thrombosis)
what is the current hypothesis of atherosclerosis?
the atherosclerotic process is not fully understood.
current hypothesis is the repose to injury
intimated by endothelial dysfunction
what are the main components of the plaque?
lipid containing macrophages
extracellular matrix
cells, proliferating smooth muscle cells
what is cholesterol attached to?
cholesterol is carried in the blood attached to proteins called lipoproteins
what are the two main forms of lipoproteins?
low density lipoprotein and high density lipoprotein
how much LDL is removed by LDL receptors and where are most located?
approximately 70% of LDL is removed by the LDL receptor dependant pathway
LDL are widely distributed but approx 75% are located on hepatocytes; bus liver plays important role in LDL metabolism
what are scavenger cells and what do they have that binds to it?
scavenger cells such as monocytes and macrophages have receptors that bind LDL that has been oxidised or chemically modified
what is amount of LDL removed by related to?
amount of LDL removed by scavenger pathway is directly related the plasma cholesterol level.
what happens when ldl levels exceed receptor availability?
amount of LDL that is removed by scavenger cells is greatly increased
how does oxidation of LDL occur?
the oxidation of LDL occurs when the LDL particles react with free radicals
what can increase the levels of oxidised LDL?
consuming a diet high in trans fats, smoking and poorly controlled diabetes
what does hyperlipidaemia particularly LDL with its high cholesterol content do?
it is believed to play an active role in the pathogenesis of the atherosclerotic lesion
what are possible injurious agents in what causes injury to the endothelial cell?
products associated with smoking
immune mechanisms
mechanical stress, such as that associated with hypertension
describe the major cellular events in the progression of atheroscelerosis
- when LDL becomes oxidised, it goes directly into the endothelium and may alter endothelial permeability - increased stiffness
- monocyte adhesion and transmigration - LDL encourages the accumulation of inflammatory cells, such as monocytes. monocytes transform into macrophages, more macrophages and cholesterol accumulate at the site forming a plaque
- macrophage transformation into foam cell - as more macrophages and cholesterol accumulate, the oxidised cholesterol loaded macrophage forms ‘foam cell’ and the plaque begins to grow thicker
- smc migration - macrophage releases growth factors that recruit smooth muscle cells to the plaque. The smooth muscle cells may proliferate and deposit extracellular matrix in the lesion (elastin, collagen, proteoglycans) and the plaque grows further. smooth muscle may form a cap around the plaque
lipids related from neurotic foam cells accumulate to form the lipid core of unstable plaques. connective tissue synthesis determines stiffness, calcium fixation and further ulceration of atheromatous plaque
how are smooth cells recruited to the plaque?
smooth muscle phenotypic modulation
smooth cells transform, migrate and phagocytise material.
they appear to take in macrophage-like properties
what are the primary prevention actions taken for atheroma treatment?
no smoking
diet - reduce fat intake. a diet high in fruits and veg decreases the risk of cardiovascular disease and death
not too much alcohol
regular exercise and weight control
what drugs are used in secondary prevention of atheroma?
antiplatelets and statins
beta blockers
ace inhibitors
what drugs are used for the symptoms control in atheroma?
beta blockers
calcium antagonists
nitrates (short and long acting)
potassium channel openers (nicrorandil)
if channel inhibition (ivabridine)
ranolazine
what is surgery treatment for atheroma ?
bypass
PCI (Percutaneous coronary intervention (PCI) refers to a family of minimally invasive procedures used to open clogged coronary arteries )
what are the platelet functions in normal vs damaged endothelium ?
normal endothelium - antiplatelet, anticoagulant and fibrinolytic
damaged endothelium - procoagulant functions
describe the antithrombotic functions
antiplatelet
- adenosine diphsopahtase
- prostacyclin (produced by the enzyme cyclooxyrgenase)
- nitric oxide
anticoagulant
- heparin-like molecules (activate antithrombin III)
- thrombomodulin (activates protein C)
- protein S
fibrinolytic (prevents clots from growing
- tPA
descrive procoagulant functions
Production of vWF
Production of tissue factor
Binding of factors IXa and Xa
describe platelet function - adhesion
Platelets adhere to the exposed subendothelial connective tissues. Following adhesion, platelets become more spherical and extrude long pseudopods which enhance interaction between adjacent platelets.
Platelet membrane glycoproteins contribute to platelet adhesion to collagen. The binding of von Willebrand factor(vWF) results in conformational changes within platelet glycoproteins allowing platelets to bind fibrinogen. Fibrinogen molecules then interconnect the platelets serving as the basis for platelet aggregation.
what do adherent platelets release?
ADP and thromboxane A2
what are ADP and thromboxane A2 ?
platelet agonists, activate more platelets and recruit them to the site of vascular injury
what are antiplatelet drugs?
aspirin
clopidogrel
what is the mechanism of action of aspirin ?
thromboxane A2 is a platelet agonist produced and released by platelets.
aspirin blocks production of thromboxane A2 by inhibiting the platelet enzyme responsible for its synthesis - cyclooxygenase-1 (COX-1)
the action of aspirin on platter COX-1 is permanent, lasting for the life of the platelet (7-10 days)
describe the mechanism of action of clopidogrel?
ADP is a platelet agonist produced and released by platelets
clopidogrel is an irreversible inhibitor of ADP receptor on platelets and so prevents ADP from activating platelets
what are statins used for ?
reduce plasma LDL
statins are HMG-CoA reductase inhibitors so inhibit the synthesis of cholesterol.
cholesterol greatest production at night - statins with shirt half life given at bedtime
