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Cardiovascular disease is the leading cause of death in the rich industrialised nations, but it is much less common in the poorer countries of the world. This suggests that the condition might be associated with lifestyle and diet, however the connection is not straightforward and the exact mechanism remains a matter for dispute.
We don't expect you to read all of these, because most of them tell more or less the same story, in varying degrees of detail. However, these titles are much in demand and the books are often on loan, so we have given you plenty of alternatives.
Atherosclerosis involves a narrowing and obstruction of the arteries anywhere in the body. The heart is commonly affected because the coronary vessels have little spare capacity and this organ ordinarily removes most of the available oxygen from its arterial blood supply, but atherosclerosis may also involve the brain, leading to strokes, and leg muscles causing intermittent claudication. There are two components to this process.
Abnormal fat deposits, chiefly cholesterol and partly oxidised lipids are deposited within the arterial wall. The process starts with isolated fatty streaks, but may progress to the point where the vessel lumen is partially obstructed. Foam cells are macrophages that have taken up these abnormal lipid droplets into their cytoplasm, leading to a characteristic foamy appearance in microscope sections. The abnormal lipid deposit is known as an atherosclerotic plaque.
Blood clotting is a dynamic equilibrium, where new clots are continuously on the point of forming, but this process is usually aborted and existing clots are dissolved. Moving blood within an intact vascular system does not normally clot, but damage to the blood vessel walls, or even the lack of normal movement can result in clot formation.
Blood clots have two components: a protein matrix formed from fibrinogen by proteolysis, and a cellular component formed from blood platelets.
The endothelial cells covering intact blood vessel walls are very smooth and continuously secrete anti-clotting factors, but if the underlying layers are damaged by abnormal lipid deposits, this may break the continuity of the endothelial lining and expose collagen and other molecules that promote clotting. This is known as "plaque rupture". The "stickiness" of the blood platelets is critical in determining whether or not a clot will grow.
Clot formation greatly narrows the blood vessel. This is a dynamic process and clots may be partially re-canalised. Large clots may detach from their original location, and move downstream until they become stuck in a narrower part of the vessel, occluding it completely.Back to the learning objectives
Genetic and lifestyle variations mean that some individuals remain largely free from disease, but it is possible to identify a number of factors that increase the risk:
Inadequate coronary perfusion may produce the transient chest pain of angina pectoris, commonly during exercise. If the blockage is severe this will lead to the death of cardiac muscle cells and myocardial infarction.Back to the learning objectives
Many interventions have been suggested to reduce the risk of cardiovascular disease. Some of these undoubtedly provide benefit, but the improvement is often smaller than people hope. Deaths from other causes have sometimes increased instead. We will examine the reasons for this.
Cholesterol is an essential constituent of animal cells, where it produces the correct degree of fluidity and impermeability in cell membranes. It is rarely found in plant tissues, which have alternative ways of achieving the same effect.Back to the learning objectives
Cholesterol is widely distributed in all foods derived from animals, but the richest source in the normal diet is egg yolks. We don't eat all that many eggs, so for most people meat products make the biggest contribution.
|Cholesterol sources in the American diet|
|meat products||egg yolks||milk & cheese||oils & fats||others|
Unfortunately (or perhaps fortunately if you like eggs!) cutting down on cholesterol intake has only a small effect on cholesterol levels in the blood. This is because we can make our own cholesterol.Back to the learning objectives
Many cells can synthesise cholesterol from acetate, but it is mostly made in the liver. The key enzyme is HMG-CoA reductase. The pathway is strongly inhibited by free cholesterol, which blocks gene expression, and promoted by insulin. The existence of this regulatory system explains why reductions in dietary cholesterol have so little effect.Back to the learning objectives
Cholesterol is an essential component of the plasma lipoproteins: chylomicrons, VLDL, LDL and HDL. It is present both as free cholesterol in the phospholipids surrounding these particles, and as cholesterol esters in the cores.
These are the largest and lightest of the blood lipid droplets. They are produced from dietary fats by the cells lining the gut, and travel through the lymphatic drainage to enter the left subclavian vein. They can be broken down in the tissues and the lipids are taken up and used by many cells. They contain apolipoprotein B48 and many other proteins in small amounts.
VLDL is produced by liver cells, usually from dietary carbohydrate which has been converted into fat. These particles are smaller than chylomicrons, and have a different apolipoprotein B100.
Breakdown of VLDL by lipoprotein lipase in the tissue capillaries leads to progressive loss of fats and a reduction in particle size. LDL can be taken up into cells by receptor mediated endocytosis, which chiefly occurs in liver, but is an important source of cholesterol for extraheptatic cells. Chylomicrons are similarly degraded to chylomicron remnants.
HDL is the so-called "good" cholesterol which is being returned to the liver for recycling and excretion. High levels of HDL are associated with a reduced risk of disease.Back to the learning objectives
The principal way to dispose of cholesterol is by oxidation in the liver to give bile acids, which are excreted in the bile as bile salts. These are detergents which play a major role in fat digestion. Bile salts are taken up again in the large intestine, and returned to the liver in the portal blood. Only about 10% of the molecules secreted by the liver are actually lost and excreted in the faeces each day. The liver secretes and the gut recycles free cholesterol through the bile and the chylomicrons in a similar way. (Gallstones are mostly cholesterol that has precipitated in the gall bladder.) Dietary soluble fibre may help to increase the quantity of steroids lost from the body, thereby lowering cholesterol levels in the blood.Back to the learning objectives
Although interventions have only modest effects on the general population, they do have life-saving results for high-risk groups: those with an inherited genetic predisposition or who have already had a heart attack. This is an area where you can do more research for yourselves.
If you have comments, queries or suggestions, email me at J.A.Illingworth@leeds.ac.uk