Lecture 7 Flashcards
Why is atherosclerosis important?
It indirectly contributes to >50% of deaths in the Western World.
What is the definition of atherosclerosis?
It affects the innermost layer of large and medium sized arteries. It appears as focal thickenings called plaques, which are deposits of fibrous tissues and lipids.
What does the TI contain?
Contains endothelial cells which sit on the basement membrane. Then there is an Internal Elastic Lamina. The endothelial cells are very important (when new blood vessels grow or regress, these cells coordinate the whole process and control blood pressure and the coagulation system and aspects of inflammation). The basement membrane, it traps growth factors which are presented to the endothelial cells.
What does the TM contain?
It has smooth muscles cell layers and elastic lamina layers as well. The elastic laminae (can provide good landmarks - the anatomy of the vessel wall is very altered so it helps to see what layer is is). The smooth muscle cell layers are contractile and they can regulate blood flow via contraction, they also stabilise the endothelial cells by secreting soluble factors that diffuse through and bind to the endothelial cells (such as TGF-beta).
What does the TA contain?
Contain supporting cells: fibroblasts (to synthesise and remodel the fibroskeleton of the cell), leucocytes, nerves, lymphatics, and blood vessels (if the blood vessels are relatively thick walls - vasa vasorum).
What is the aetiology of atherosclerosis?
Multiple aetiologies - environment. Largely a disease of westernised and affluent nations. Starting to appear in developed nations as well now. There are many risk factors that underly this geographical distribution. Risk factors are divided into positive (increases the risk) and negative (decreases the risk) risk factors. A variety of different risk factors synergise with each other.
Describe the affect alcohol has on atherosclerosis?
Alcohol is a negative risk factor (light to moderate consumption) where as heavy alcohol is a positive risk factor. It is called a J-shaped curve - where no alcohol you will have low level risk, low alcohol consumption no risk, high alcohol consumption high risk. Alcohol has some sort of antioxidants in it.
Describe positive risk factors?
There are five factors:
1. Hyperlipidaemia
2. Cigarette smoking
3. Hypertension
4. Diabetes mellitus
5. Advancing age - disease that manifests more as age progresses. The plaque will build up during our lifetime, once you reach a certain age you’ve had a longer period of the build up to occur.
Atherosclerosis has a polygenic inheritance - multiple genes. Male gender. High saturated fat diet (affect on coagulation). Stressful and sedentary lifestyles. Obesity. Low birth weight (a period where you have to catch up in weight, may program inflammation cells to make it slightly more likely for you to get atherosclerosis in life). Low SES. infections and a general propensity for inflammation.
Describe negative risk factors?
These are factors that reduce the risk of getting atherosclerosis. High levels of circulating HDL (high density lipoproteins). Moderate alcohol consumption. Cardiovascular fitness.
Describe metabolic syndrome?
Combination of abdominal obesity, hypertension, elevated blood glucose, elevated triglycerides and decreased HDL. There is fat in organs which are not designed to hold fat. This will lead to insulin resistance and mitochondrial dysfunction and inflammation. If you are obese without metabolic syndrome it may not increase cardiovascular risk as much.
Describe lipoproteins?
Consist of a core of lipid which is carried by apolipoproteins (allows the lipid core to be carried in blood). Increased plasma conc of LDL is associated with atherosclerosis. Powerful risk modifiers.
Describe the pathogenesis of atherosclerosis?
The TI is being thickened by a plaque - enough to almost block the vessel wall. The initiation may involve endothelial cell injury - could be an example of chronic inflammation.
Describe Endothelial Cell Injury in terms of atherosclerosis?
Combination of stresses to the endothelial cells:
1. Haemodynamic forces - hypertension, more shear stresses and tearing of the endothelial cells. Strongly seen at junctions of smaller vessels off big vessels.
2. Chemical insults - smoking and lipids.
3. Cytokines.
Ongoing chronic inflammation. When the cells and injured and activated. May lead to:
1. Altered permeability - so the endothelial cells allow proteins and fluids to come through their tight junctions. High concentration of lipid in the blood, the endothelial cells appear more able to allow lipids to fuse in (synergy).
2. Adhesion of leucocytes (selections and interns) - pump out cytokines which will turn on an inflammatory process. The plaque starts to build up underneath the endothelial cells.
3. Activation of thrombosis - blood clot on top of the plaque.
4. Endothelial progenitors are recruited.
Describe leucocyte migration into the developing plaque?
This is a type of chronic inflammation. Monocytes are pulled through and differentiate into active macrophages - the macrophages take up lipoproteins and cholesterol. The macrophages oxidise lipoproteins first, and when the lipoproteins are taken up in efficient volume the macrophages are bursting full of the lipoproteins. They turn into foam cells - often they die by necrosis or apoptosis and spill their ingested lipids which escape into the extracellular space. This will further increase inflammation, and often the lipids are crystallised and are so hard that they leave cholesterol clefts.
Describe smooth muscle cell activation and migration?
The smooth muscle cells proliferate and migrate into the Ti form the TM. This may be accelerated by failure of the IEL. Once in the TI they become secretory cells (pump out proteins).