Atherosclerosis Flashcards
(46 cards)
What is atherosclerosis ?
- Lipoprotein-driven disease that leads to
plaque formation at specific sites of the
arterial tree through intimal
inflammation, necrosis, fibrosis, and
calcification - Leads to narrowing of the arteries; more
susceptible to formation of thrombi or
plaque rupture - Obstruction of blood flow to the heart,
brain or lower extremities
Steps of plaque formation
- Endothelial Damage
Hypertension, inflammation, smoking etc - Circulating LDL is taken up
LDL becomes oxidised and stimulates and
inflammatory response - Adhesion molecules are upregulated
on endothelial cells and monocytes
are recruited - Monocytes differentiate into
macrophages which phagocytose oxidisedLDL and turn into foam cells - T-cells release cytokines, which further activate macrophages
- Smooth muscles cells proliferate and migrate into the intimal layer and form a fibrous cap
- Smooth muscle cells synthesise extracellular
matrix proteins and become less contractile - Angiogenesis; new vessel formation within
the plaque. - Dead cells and lipids released from the dead cells
accumulate within the plaque creating a necrotic/ lipid core - Fibrous cap can become unstable and rupture causing thrombus formation
- Vascular calcification; smooth muscle cells differentiate into osteoblast-like cells. Angiogenesis; new vessel formation within the
plaque. The new vessels may lack stability
Endothelial cells
Master controllers of the artery
Control size of the artery - dilation and constriction
Control transport of molecules across artery
Control transport of immune cells across artery
Exist on a spectrum between activated or quiescent states
Turbulent flow patterns cause cells to become activated
Activated endothelial cells are more leaky
They let more fat particles (LDL) through the artery wall
Activated cells attract immune cells to the area
Endothelial dysfunction
Disturbed flow primes the endothelium for dysfunction/inflammation
Lifestyle factors can cause endothelial dysfunction – e.g. smoking,
diabetes, hypertension
Poor diet provides limited essential nutrients and antioxidants also
limiting endothelial health and protection from other risk factors
The combination of disturbed flow and other risk factors promotes
plaque formation
Angiogenesis and instability
- New or neo vessels originating from the vasa vasorum - new point for inflammatory infiltration
- Neo vessels lack stability due to lack of recruitment of mural cells; can be ‘leaky’
- May help expand the necrotic core
Smooth Muscle cell
Produce the collagen that gives strength to the artery
Control size of the artery - dilation and constriction
Proliferation and migration are suppressed by a functional endothelium –
endothelial dysfunction takes off the handbrake
They also respond to the developing damage caused by the plaque that triggers
further proliferation and also de-differentiation
Responsible for forming and maintaining the fibrous cap – cell death
(apoptosis) leads to weakening of the fibrous cap
How does vascular calcification occur
It is a regulated process involving differentiation of VSMCs.
Environment: Oxidative stress, glucose, inflammation, hypoxia, DNA damage -> affecting contractile smooth muscle cells -> causing osteogenic differentiation -> causing secretory smooth muscle cells which deposit calcium phosphate
Lesion types of atherosclerosis; proposed sequence of development
Xanthoma; Accumulation of
foam cells without a necrotic
core, fibrous cap or thrombosis
Fibrous caps; high content of
collagen I and proteoglycans
and elastin produced by
differentiated SMCs
Osteoblastic and contractile
phenotype reduced
Necrotic core; Acellular mix of
lipid and debris caused by
apoptosis and necrosis of
macs/foam cells, SMCs
Adaptable intimal thickning -> Xanthoma -> Pathological intimal thickening -> Necrotic core -> Fibrocalcific plaque
Atherosclerosis
Endothelial activation -> inflammatory cell infiltration -> atherosclerosis -> vascular calcification
RFs for endothelial activation
Risk factors,
inflammation, ox
stress, diabetes,
LDL, cholesterol,
turbulent flow
etc
Where do plaques normally occur?
Sites of low oscillatory/disturbed shear stress- at branch points
They primarily occur at regions of disturbed blood flow patterns
This is typically seen at bifurcations (branch points) in arteries
Curved sections of artery
Endothelial cells respond to shear stress
Disturbed flow
- Response to inflammatory stimuli
* Reactive oxygen species production
* Permeability
* Apoptosis and proliferation
* Bioavailability of nitric oxide (NO)
RFs for plaque formation
- HTN
- High blood lipids
- Age
- Atherosclerosis
- Diabetes, lupus etc
- Genetics e.g. HF
- Lifestyle - smoking, inactivity, XS alcohol, obesity
Risk Factors… Smoking
Cigarette smoke contains between 5-8000 different chemicals
Also contains very large amounts of free radicals
Damage the lungs and increases systemic levels of inflammatory
cytokines
Soluble chemicals circulate in blood and induce endothelial dysfunction
‘Toxic’ damage response to chemical components
Oxidative damage response to free radicals
Chronic stress response
Risk Factors… Diet
Excessive intake of saturated and hydrogenated fats increases circulating
cholesterol and triglyceride levels
High salt diet increases risk of hypertension
High sugar diet increases risk of diabetes
Low fruit and veg diet limits the intake of antioxidants
Low fruit and veg diet limits the intake of vitamins, increasing susceptibility to
disease and associated increase in inflammatory cytokine levels
Low fibre diet limits the body’s ability to excrete excess cholesterol
Risk Factors… Inactivity
Low activity levels promotes endothelial dysfunction
Activity increases blood flow over endothelial cells (shear stress) and the protective mechanisms triggered by laminar shear stress
Regular activity increases the amount of glucose stored as glycogen in muscles, reducing risk of diabetes
Reduces blood pressure and increases HDL production
Aerobic activity: Get at least 150 minutes of moderate aerobic activity or 75
minutes of vigorous aerobic activity a week, or a combination of moderate and vigorous activity. (don’t drive to work… 15 minutes brisk walk twice a day will reduce your risk of a heart attack)
Risk Factors… Diabetes
Increases circulating glucose levels, which in turn increases the production
of oxygen free radicals
Increases production of advanced glycation end products (AGEs) which damage cells and artery wall
Insulin reduction/ absence (type 1 or insensitivity (type 2)
Compounded with other risk factors
Diabetics are 2-4 times more likely to have a heart attack
Risk Factors… Hypertension
Increases/linked to endothelial dysfunction
Increases thickness and stiffness of artery wall
Increased/modification of artery wall potentially increases trapping of LDL in
artery wall and atherosclerosis
Increases production of reactive oxygen species (free radicals)
‘Heart attacks’ - v cardiac arrest
Heart attack: One of the coronary arteries becomes blocked leading to a decrease in blood supply to the heart muscle. If left untreated, the cells will begin to die because there isn’t enough oxygen.
Cardiac arrest: when the heart stops pumping blood around the body and patient stops breathing normally
Vulnerable vs stable plaque
Vulnerable plaque - thin fibrous cap, large lipid pool, many inflammatory cells, few smooth muscle cells -> CV event
Measures that may stabilises an atheroma = Decrease LDLs, increase HDLs, decrease angiotensin II, decrease insulin resistance, decrease oxidative stress, decrease blood pressure
-> causing it to become a stable plaque - thick fibrous cap, smaller lipid pool, few inflammatory cells, dense extracellular matrix
Atherosclerotic Plaque Rupture
Accounts for ~65% type 1 MI
Rupture of fibrous cap allowing blood to communicate with the lipid rich necrotic core, precipitating a thrombus.
Proinflammatory, macrophage driven
Plaques have thin fibrous caps and large lipid cores
Frequently expansively remodelled
Smooth muscle cell apoptosis and Matrix degradation
Biomechanical failure of fibrous cap
Rupture of a thin-cap fibroatheroma with nonfatal thrombus and subsequent healing with fibrous tissue formation and constrictive remodelling
Endothelial Erosion
Accounts for ~31% Type 1 MI
Endothelial erosion, loss of endothelial cells overlying a plaque that precipitates a thrombus
Predominantly an endothelial pathology
Little involvement of inflammatory cells (e.g. macrophage)
Endothelial loss overlying a thick fibrous cap
Smooth muscle rich sub endothelial matrix
Cigarette smoking an identified risk factor
Plaque composition
Ruptured plaque - occlusive thrombus, fractured thin fibrous cap, high macrophage infiltration, large lipid core, expansively remodelled artery
Eroded plaque - Partially occlusive thrombus, proteoglycan, hyaluronan and smooth muscle cell-rich sub endothelial matrix, thick fibrous cap, small deep-seated lipid core
Smoking and female gender are strong risk factors for erosion
Other contributors to erosion;
endothelial dysfunction, leukocyte activation, modification of sub-endothelial matrix by endothelial or SMCs, leading to loss of adhesion to the ECM or apoptosis
Blood flow and shear stress
- Endothelial activation can occur in regions of elevated shear stress
- Elevated flow may play a role in both plaque rupture and plaque erosion
- Endothelial cells change their behaviour depending on the flow pattern they experience
