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Atherosclerosis summary to pass your exam
- Vak
- Atherosclerosis
- Instelling
- Universiteit Leiden (UL)
This is an accurate summary of the atherosclerosis lectures. It contains all the given lectures and is very detailed.
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Atherosclerosis courseLecture 1: Introduction
Cardiovascular diseases are the main cause of death worldwide. More than 18.5 million people die of
CVD each year, which is 32% of all deaths worldwide.
There are different types of cardiovascular
disease. For example, you have Aorta diseases,
such as an aortic aneurysm. You could also have
an inflammation of the sack like structure around
the heart which is called pericarditis. You can
have a dysfunctional heart muscle, such as
cardiomyopathy. The heart valves cannot work
efficiently anymore and you can also have
arrythmia’s.
We are going to look at the plaque that can build
up in the arteries, which causes coronary heart
disease and eventually leads to heart failure.
Atherosclerosis is a chronic inflammatory disease
resulting from endothelial damage, cholesterol and immune cell accumulation in the arterial wall. The
development of an atherosclerotic plaque leads to narrowing of the blood vessel. Many different immune
cells are involved in this process.
Atherosclerosis develops mostly at the bifurcations of our artery system. So, for example the carotid
artery in the neck has a bifurcation, where the atherosclerotic plaque usually forms. The aortic arch has
several branches, where atherosclerotic plaques can develop as well. The oxygen rich blood is pumped
out of the heart and will go through those branches to get to different parts of the body. Coronaries, the
arteries on the heart, can also develop atherosclerosis, which directly causes an myocardial infarction.
The healthy artery consists of three layers. The first layer is the intima, which is covered by a layer of
endothelial cells. This is in direct contact with blood. Underneath the endothelial cell layer, you have a
few residential smoot muscle cells. Underneath the intima you have the media, which has a lot of smoot
muscle cells that are imbedded in extracellular matrix. Under the media is the adventitia, which consists
,of micro-vessels, nerve endings, mast cells and fibroblasts. For instance, high blood pressure, can make
the endothelial cell layer upregulate adhesion molecules. Adhesion molecules on the intima can cause
the infiltration of immune cells, such as monocytes, dendritic cells and T-cells. The monocytes can turn
into macrophages and when they take up lipids in the intima, they form foam cells. They take up a lot
of lipids and form a so-called fatty streak. As atherosclerosis progresses, a lot of things happen in for
example the intimal layer. Smooth muscle cells from the media layers migrate to the surface of the
intima layer and form a fibrous cap. Under the fibrous cap, there are a lot of foam cells. These cells take
up a lot of lipids, which can become toxic, leading to their death. This makes them release all their
content in the intimal area, which leads to the formation of the necrotic core.
The fibrous cap
actually is
something that
the body does to prevent rupturing of the plaque. However, further advancement of atherosclerosis can
lead to the rupturing. This leads to thrombus formation, which can result in disease. Complete occlusion
of a blood vessel can lead to an acute cardiovascular event such as a myocardial infarction or a stroke.
Myocardial infarction => dying of parts of the heart due to occlusion of oxygen providing arteries
Stroke => thrombus formation travels to arteries in the brain causing the arteries there to occlude.
Treatment of atherosclerosis: statins (lower the lipids), betablockers, surgery (bypass for coronary heart
disease) and lifestyle changes. These treatments result in a decrease of cardiovascular disease deaths.
The fibrous cap prevents the plaque from rupturing.
Lecture 2: Experimental models of Atherosclerosis
,Atherosclerosis is a chronic inflammatory disease resulting from
endothelial damage, cholesterol and immune cell accumulation in
the arterial wall. The development of an atherosclerotic plaque
leads to narrowing of the blood vessel. Atherosclerosis is the
underlying pathology of acute cardiovascular evens such as MI
(myocardial infarction ) or a stroke. The narrowing of the vessel
happens unnoticed until it reaches the end-stage.
The rupturing of the plaque can lead to a thrombosis. The formation
of atherosclerosis starts with the expression of adhesion molecules
on the vessel wall.
Experimental models are needed to study atherosclerosis. There are
three types of experimental models:
1. In vitro: cell culture
2. In vivo: animal models
3. Ex vivo/in vivo: human tissue and clinical trials.
The choice of your model depends on the research question and
target protein. In vitro models are the least complex. When you
want to study only one type of cell, such as the endothelial cells or smooth muscle cells, a cell culture
system is used. Thus, cell culture systems are ideal if you aim to study the effects of a drug candidate
on a single cell type. There are also immune cell culture systems, for macrophages and T-cells. You
cannot study the different interactions between the different cell types with these models, thus they give
a very limited amount of information.
In vivo models are animal models. The mouse is resistant against atherosclerosis. LDL is the bad
cholesterol and the mouse does not have that. Thus, majority of cholesterol transported by
atheroprotective HDL and largely lack the typical pro-atherogenic lipoprotein LDL. LDL is the first
trigger for atherosclerosis.
Lipoproteins classes transport triglyceride and cholesterol through the blood. The biggest particle is
chylomicrons and they contain a lot of triglycerides and some cholesterol. VLDL also contains a lot of
triglycerides. LDL contains a lot of cholesterol. HDL brings cholesterol from the blood to the liver to
get it out the body. It removes the cholesterol from the circulation.
The lipoproteins are
measured based on size.
The method used for this is
Fast performance Liquid
chromatography (FPLC).
This method uses a column
with a kind of raisin that
has pores. The sample can
be injected, such as a
plasma sample. Then
based on the size of the
particle, it is eluted in
different fractions. The
large particles will pass
first through the resin then
the smaller particles. This
, is due to the resin that is used. The smaller particles can go into the pores and stay there a little bit longer
than the larger particles.
The normal wild-type mice on a regular chow diet has very small fractions of VLDL and LDL and a big
fraction of HDL.
In humans, the
cholesterol is mainly
present in the LDL
particles. In normal wild-
type mice, this is in the
HDL particles.
Paigen diet => 1.25%
cholesterol, 0.5% sodium
cholate and 15% cocoa
butter.
There are different places where atherosclerosis can develop in the mouse. Due to the stress at the 3-
valve area in the aorta in the heart, atherosclerosis develops there. It is also possible to look at
atherosclerosis in the whole aorta of the mouse. The aortic arch is a place where atherosclerosis can
develop as it has a very turbulent blood flow. Another place is around the kidneys, as it also has branches.
C75BL/6 mouse are the only mice that develop atherosclerosis when given the Paigen diet, thus you
need these types of mice. The Paigen model was nice, but the lesions were quite small.
New mouse models were introduced, ApoE knockout mice. ApoE is present on the VLDL particles.
Because this is lacking, these particles cannot be taken up by the liver. There are two receptors on the
surface of the liver that can take up VLDL to remove it out of the body, namely the LDL receptor and
the LDL receptor related protein. Thus, this leads to an accumulation of the VLDL particles in the
circulation. This leads to an advanced increase of atherosclerosis with age. This is a very good model to
study atherosclerosis. The lesions are much bigger now. The immune cells are also present there now,
because the plaque is much more advanced than in the normal C75BL/6 mice.
Another model came around, which is the LDL receptor knockout mice, which is less invasive then the
ApoE mice. In this case, the LDL particles accumulate in the circulation due to the lack of the LDL
receptor. The uptake of LDL and VLDL in the liver is non-existent through the LDL receptor. However,
the ApoE uptake can still take place through the LDL receptor related protein. Giving the LDL knockout
mice a western type diet (0.25% cholesterol, 15% cocoa butter), will also lead to an accumulation of
VLDL. Thus, this type of diet is mainly used with the LDL knockout mice as it represent the situation
in humans the most.
Based on the research question, you pick one of the models.
These are models of spontaneous atherosclerosis development. There are also models for accelerated
atherosclerosis. This is done by a surgical procedure that places a semi-constrictive silicone collar
around the carotid artery, which results in irregular blood flow, which leads to endothelial damage,
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