Case 5 Flashcards
(115 cards)
what is atherosclerosis
refers to plaque formation which is the build up of fats and cholesterol inner artery walls that can restrict or block the blood flow
what happens when the blood flow is restricted or blocked,
tissues or organs can suffer from ischaemia which means lack of oxygen.
what is atherosclerosis described as
chronic inflammatory process triggered by the accumulation of cholesterol containing low-density lipoprotein LDL particles in the arterial wall
how common is it for death in males
most common cause of death in males
what does cigarette smoke cause in the arteries
endothelial dysfunction
when is pharmacotherapy recommend
if BP is over 140/90mmHg
Dyslipidemia mechanism
Hydrophobic fat molecules, such as triglycerides, phospholipids and cholesterol are transported to all the cells and tissues of the body in lipoprotein particles
Lipoprotein particles consist of a triglyceride and cholesterol centre, surrounded by a phospholipid outer shell
There is a special kind of protein, called apolipoprotein, embedded in the outer shell, to stabilise the complex and to give it a functional identity
Two main types of lipoproteins: the bad low density one (LDL) and the good high density one (HDL)
Lipoproteins are very low and intermediate densities are also considered bad.
In terms of apolipoproteins, apoliprotein B (ApoB) , is embedded in LDL and ApoA1 is in HDL
LDL in the circulation can be brought into the artery wall across the endothelial cells, for example by scavenger receptors
LDL will then be taken by macrophages to become foam cells, leading to plaque formation
On the other hand, HDLs transport the cholesterol back to the liver through reverse cholesterol transport (RCT)
In the liver, cholesterol will be excreted through the biliary route
For the ease of transporting via RCT, cholesterol is usually converted to cholesteryl ester
While reduction of LDL in the blood has proven to lower CAD risk, scientists had been wondering if increasing HDL, for example by taking Niacin, a form of vitamin B3, will help prevent CAD
When proper studies are conducted, increasing HDL levels don’t really show an effect on CAD
when genotyping what do most CAD patients tend to have
at the single nucleotide polymorphism they tend to have a C instead of. A T
what are the genes associated with CAD
PCSK9
how does PCSK9 affect CAD
- increases plasma LDL-C levels by downregulating LDL receptor (LDLR) expression after transcription.- when the 9p21 region is deleted, only the expression of CDKN2a and CDKN2b genes are reduced. without the 9p21 region, the proliferation and senescence of aortic smooth muscle cells are increased, both characteristics of smooth muscle cells in CAD
what are the layers of the arterial wall
- blood
- endothelial cells
- intima
- internal elastic lamina
- media
- adventitia
(1) infiltration and uptake modification of LDL
- at the hotspots of bifurcation, turbulent flow can happen and cause local recirculation and increase of the local conc of plasma LDL.
- LDL transport into the arterial wall radially and can be retained by proteoglycans
- the disturbed blood flow also causes shear stress on the endothelial cells leading to the activation of the pro inflammatory transcriptional programs I the cells
- given the injury and pro inflammatory activation, endothelial cells losing the function as the barrier, causing more influx of cholesterol and lipoproteins go into the arterial intimata
(2) uptake modification
- the LDL particles are retained in the intima and can be modified
- it is considered as sterile inflammation without external pathogens and so called danger associated molecular pattern against external pathogens
(3) endothelial adhesion molecule expression
- the oxidesed LDL particles can induce endothelial cell surface expression of the leukocyte adhesion molecules.
- these adhesion molecules bind to the ligands expressed on leukocytes
- the combinational expression of endothelial adhesion molecules and their ligands such as integrins and selectins lead to inflammatory process
(4) leukocyte recruitment
- leukocytes that are recruited to the atherosclerotic lesion produce a number of inflammatory mediators
- they amplify the inflammatory reaction through continuous activation of both leukocytes and endothelial cells and by recruiting further immune cells
(5) monocyte to macrophage differentiation
monocytes are the most numerous white blood cells recruited into atherosclerotic sites
They differentiate into macrophages under the influence of monocyte-colony stimulation factor (M-CSF) present in lesions
Two types of macrophages activated:
Classically activated or M1 macrophages. They further enrich the proinflammatory milieu through inflammatory proteins and lipid mediators such as cytokines and leukotrienes, to sustain inflammatory responses causing tissue damage
Alternatively activated or M2 macrophages that secrete anti-inflammatory mediators promoting the resolution of inflammation by means of clearance of apoptotic cells and dampening of immune responses. Therefore this type of macrophage promote tissue repair and healing
what is the stimulation factor that turns monocytes into macrophages
M-CSF
(6) Event of oxLDL uptake and foam cell production
- now the atherosclerotic lesion is emerging with retained LDL and activated leukocytes
- the oxidised LDL particles can bind to scavenger receptors on macrophages
- the macrophage then uptake the lipoprotein particles and become foam cells
- these lipid laden macrophages is a characteristic of the atherosclerotic lesion
(7) antigen presentation
the immune system is cracking up a level from innate to adaptive immunity
The uptake of oxLDL by macrophages and dendritic cells will lead not only to foam cell formation, but also antigen presentation
Leukocyte adhesion molecules and chemotactic factors, produced as a consequence of innate immune activation, can recruit effector CD4+ T cells
The antigen presentation by macrophages and dendritic cells can then activate or differentiate CD4+ T cells into helper T cells and regulatory T cells
Th1 cells promote macrophage activation and inflammation whilst Treg cells act by inhibiting immune responses and inflammation, therefore are considered atheroprotective
Th17 cell subtype promises fibrosis through action of its cytokine IL-17. Th17 activity can therefore enhance the formation of the fibrous cap and plaque stability
(8) macrophages apoptosis and necrotic core formation
in the atherosclerotic lesion, several factors, such as oxidative stress, induce macrophage death through apoptosis
Apoptotic cells are normally cleared by specific phagocytosis process, efferocytosis derived from the Greek word ‘to bury’.
Efferocytosis is important for the normal steady state of tissue and the resolution of inflammation
However, clearance of lipid-laden apoptotic macrophages in the atherosclerotic lesion can be defective and create a lipid necrotic core
(9) tertiary lymphoid organs
In addition to the inflammation happening in the intima, complex adaptive immune responses also develop in the adventitia
Inflammatory cells observed in the adventitia, include dendritic cells, macrophages, mast cells and lymphocytes. T and B cell activation is present in the adventitia and in advanced stages of atherosclerosis, large lymphoid structures, referred to as adventitial tertiary lymphoid organs, may develop
These adventitial tertiary lymphoid organs are sites of antibody production, including antibodies to plasma lipoproteins
what do malfunctioning endothelial cells release
vasoactive hormones such as nitric oxide and prostacyclin
what is secreted from the endothelial cells in the media
platelet derived growth factor
what is in the fibrous cap
bundles of muscle cells, macrophages, foam cells, lymphocytes, collagen and elastin
