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Lectue 2.odt

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Michael Baker

Chapter 2 Risk factors contributing to CAD 1. Age Group 2. Total Cholesterol level 3. HDL 4. BP after treatment; if no treatment- BP before treatment 5. Smoker/Non smoker 17 risk points for men and 25 for women means that there is a 30% chance of coronary artery disease in 10 years Risk Category 3 Treatment target High 10 years risk of CAD> 20% (considering LDL < 2.5AND the above mentioned factors) OR Total cholesterol/ HDL ratio < 4 History of CVD OR History of diabetes Moderate 10 years risk of CAD 11-19% LDL <3.5AND Total cholesterol/ HDL ratio < 5 Low 10 years risk of CAD < 11% LDL < 4.5AND Total cholesterol/ HDL ratio < 6 You can do a lipid scan of the body because lipids contribute to the formation of plaques in the arteries- how****? What is a lipoprotein? • LPs are small particles that have a shell of phospholipids, cholesterol and proteins, and a core interior made up of cholesterol esters and triglycerides • Cholesterol travels in the blood in particles called lipoproteins • High content of lipoproteins hence mean high level of cholesterol and thus increase in risk factor • Triglycerides (TG) are fatty acid esters of glycerol (2 fatty acids attached to a glycerol backbone) – they are a major component in fat cells- also found in lipoproteins ▪ They are the main form of fat storage ▪ burn very brightly- oil heats up at the burst of flame ▪ provide more energy than carbohydrates Lipoprotein structure – used in the transport of cholesterol and TAG • Apolipoprotein B- 100 – found in LDL – is on the surface of the lipoprotein ▪ They help to characterize ▪ You need these particles of LDL to carry lipids otherwise they would cluster together • Ashell of phospholipids • Cholesteryl ester (modified cholesterol) and Triacylglyceral in the core • Unesterfied cholesterol – found randomly within the phospholipids Lipoproteins can be made in two ways 1. When you eat and digest fat in your intestine, cells lining the intestine (the digestive system) take up and break down the fatty acid and cholesterol • They then use it to make triglycerides , cholesterol esters, and proteins- combined lipoprotein called Chylomicrons (CM) • They are much bigger than LDL(produced by liver) • Also have a phospholipid cholesterol shell – amphipathic- allowing it to flow • They are released into blood for usage by tissues- supplies tissues with fatty acids from their triglycerides 2. Also possible for other tissues such as liver to make different types of lipoproteins using triglycerides, cholesterol, cholesterol esters and proteins • Livers can easily convert excess dietary carbohydrates to triglycerides (recall intestine converts fat into TG) – excess sugar into fat • These liver lipoproteins are called VLDL – very low-density lipoproteins • VLDL are smaller and heavier than Chylomicrons but still effective carrier • VLDL are released by the liver and enter the blood The loss of TG • VLDL and CM are attacked in the blood by an enzyme called lipoprotein lipase LPL • LPL is made by heart or fat tissues and they come out near the circulation and set a post in the capillaries • It hydrolyzes tryglycerides – breaks up ester linkages- making fatty acids and glycerol • This is done by LPL posted on a stalk on a capillary, as it identifies the protein tag on triacylglycerides • Fatty acids, an important byproduct, can then diffuse out to heart tissues as necessary • Thus both CM and VLDL decrease in size • Both small CM and LDL (smaller denser lipoproteins than VLDL) are supposed to be absorbed by the liver and degraded, but prolonged elevated levels in the blood can create problems Lipoproteins • Chylomicrons – largest in size with mostly triacylglycerides • **Triacylglyceides = triglycerides? nd • VLDL - 2 largest – mostly triacylglycerides but also some cholesterol and cholesterol ester • LDL- made after degrading TAG- what puts you at risk- mostly cholesterol + chol. Ester • HDL – a mixture of both low levels of cholesterol (10-30%) and low level of TAG (5-10%) ▪ HDL is good because it picks up cholesterol and brings it back to the liver ▪ HDL like VLDL is also made by liver ▪ It goes out and picks up cholesterol and brings it back to the liver where it is engulfed and removed Liver • Clearing house for cholesterol- also synthesizing house of cholesterol? • Rich in cholesterol • Bile carrying cholesterol goes into the intestine and eventually outside the body – thus removing cholesterol (no need for degradation) • Muscles don't have bile so can't get rid of cholesterol LDL • enriched in cholesterol and cholesterol esters • high LDL = high cholesterol = high risk • function: to transport cholesterol from the liver to other tissue • Liver surface proteins called the LDL receptor recognizes LDL ( just like the remnant receptors that recognize chylomicrons) • These receptors bind to LDL and allow its uptake by liver cells where they are digested by the lysosomal system ( after cholesteryl oleate and proteins are separated) • Receptors are then recycled back to the plasma membrane • LDL thus enter the cell via receptors through a process called receptor mediated endocytosis • Receptor mediated endocytosis- LDL binding, internalization- lysosomal hydrolysis If the LDL receptor is impaired, it will actually promote a rise in the cholesterol, especially following high VLDL • LDL levels remain elevated in the blood • this problem is called hypercholesterolemia – too much cholesterol in the blood- indicator of high risk cardiovascular disease • This problem is often inherited- FH = familal hypercholestero,ia ◦ It could be that the receptors aren't working (smoking, eating habits) or simply that you have fewer receptors if you have one bad copy of the gene (Aa) LDL particles if prolonged in the circulatory system (as they are not being sucked up by receptor mediated endocytosis, it increases the chance of going into the artery wall. LDL arterial pathology- artherosclerotic plaque ***Only in muscle cells? • LDL can be modified by oxidation reactions- promotes LDL entry into the arteries ◦ If you have high LDL levels + you smoke -(increase oxidated LDL), it means that LDL will be taken up by arteries more often instead of the liver. This will increase your risk of getting CAD or a stroke • Arteries cannot handle the fat in LDL well • Also cholesterol which is difficult to degrade -can't get out of the artery wall- it's stuck inside, making the situation worse ◦ This is because artery is not well supplied with blood capillaries coming to the outside ◦ With LDL coming in, pressure builds up and the exit blood capillaries flatten out ◦ With low diffusion of LDL out, cholesterol accumulates as LDL particles are trapped in muscle cells • These stuck oxidated LDL in arteries trigger inflammatory response • They bind to connective tissues and release signal traces to attract cell white blood cells to enter • White blood cells act as macrophages and eat up LDL particles but it can degrade everything other than cholesterol • The macrophage gets bigger and bigger to form foam cell • The foam cell tries leaving but it's too big (so while white blood cells could come in they can't go out) • Eventually the foam cell dies and dumps all its cholesterol against the artery wall • Cholesterol and proliferation muscles building up (proliferation is turned on by cholesterol being dumped on the artery wall) • Smooth muscle also produce connective tissue spread over the artery wall forming a cap • Now instead of a smooth wall you have a bump causing the formation of a thrombus from platelets to become activated • Blood will start spiraling when it hits the bump, reactivating particles in the cell called platelets • This causes stenosis, turbulence in the blood flow, aggregation in platelets in thrombus • Thrombus breaks off into embolous – takes off speech • After years of buildup, the cholesterol rich lipid pool and connective tissue cap form a large Atherosclerotic plaque The blood consists of: – Red blood cells – white cells – Platelets – important in blood coagulation as the cells stick together when they are activated (e.g.following a cut or vessel injury)- good thing in this case helps with glycoligation but harmful when there is no vessel damage or bleeding – Platelets can also be activated by 2 ways: – the irregular surface of the artery that has a bulging plaque (vortex around the bump-spiraling) – – lack of epithelial cells – formation of connective tissues ? **** The overall process 1. Oxidated LDL gets in artery 2. Plaque builds up due to high cholesterol build up near the artery wall 3. This bulge in the wall reduces the size of the artery lumen leading to artery narrowing – stenosis- causes a high pitch sound 4. Stenosis in turn leads to irregular blood flow patters- the cause of unusual flow noises heard over Nat's carotid artery 5. Blood flowing through activates platelet cells which stick together and their purpose is that if there is a damage to the artery wall- it sticks to it and seals it – They stick to the plaque surface and form an aggregate with cholesterol called thrombus 6. As sticky walls come together thrombi is formed at the surface of the plaque 7. Emboli breaks off the thrombi and flows to t
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