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FINAL BISP EXAM NOTES FOR WEEKS 1-10
Paul A. Price. 3/10/09
The final exam will cover the material presented in lecture. The following list gives you a specific description of the major areas that will be covered in this exam, and a thorough understanding of this material should prepare you for the exam.
1. Lecture 1:
A. Statement of the problem. You should know that atherosclerosis is the leading cause of death in the
world, and that more people die of heart attacks and strokes than of all other causes of death combined. In order to gain an insight into the mechanism of this disease, we will examine a well-defined subset of people who die from atherosclerosis: women with postmenopausal osteoporosis. You should know two things about postmenopausal osteoporosis as it relates to artery disease: 1. Osteoporosis and artery calcification. Many studies over the past 50 years have shown that the women with the highest rate of bone loss have the most artery calcification. 2. Osteoporosis and cardiovascular disease. A number of studies over the last 8 years have shown that the women with the highest rate of bone loss are the most likely to die of heart attacks and strokes. Our goals in the course are to understand why artery calcification and atherosclerosis are both increased by bone loss.
B. Calcification.
1. Calcification. You should know that: calcification (mineralization) of a tissue always refers to the deposition of a calcium phosphate mineral phase within the tissue. This mineral is similar to hydroxyapatite, and is often called apatite-like. The biological mineral differs from hydroxyapatite in at least three ways: a. hydroxyapatite crystals are shaped like needles while biological apatites are shaped like plates; b. biological apatites contain a large amount of carbonate (and are therefore sometimes known as carbonate apatites), while hydroxyapatite contains no carbonate; c. hydroxyapatite grows into crystals that can be millimeters long, while biological apatite crystals are never larger than ~300 nm in their longest dimension. True hydroxyapatite is only found in tooth enamel. We are going to use hydroxyapatite to model the apatite-like crystals of bone and arteries. You should know that hydroxyapatite has a unit cell structure of [Ca2+]10[PO43-]6[OH-]2, and dissolves to yield 10 Ca2+ and 6 PO43- and 2 OH- The solubility constant that governs its solubility is Ksp = [Ca2+]5[PO43-]3[OH]. 2. Effect of pH. Phosphoric acid has three pKa values: 2.1, 7.2, and 12.7. As the pH value declines below pH 13, there is progressively less of the PO43- in the phosphoric acid pool, and more mineral must dissolve to achieve the solublility product. In consequence, pH has a massive effect on mineral solubility: biological apatite and hydroxyapatite both dissolve in acid and form in base. The removal of bone (by the osteoclast) requires the dissolving of bone mineral with acid. 3. Kinetic stability of serum: the barrier to apatite formation. You should know that there is a significant activation barrier to forming apatite crystals, and that a solution that has the same pH and the same concentrations of calcium and phosphate as serum will not form apatite crystals for years. This activation barrier is entropic: it is highly unlikely that the basic unit of apatite stability, the unit cell, will assemble by the random association of so many calcium and phosphate ions. You should know that any apatite crystals that do form in a person must be generated by a specific mechanism. No one has established how crystals normally form in bone, or how they form abnormally in the artery wall. This course will examine how bone loss in osteoporosis could cause the appearance of crystals in arteries. 4 Thermodynamic instability of serum: the danger of becoming a pillar of salt. You should know that our serum is at all times supersaturated with respect to the mineral phase of bone and arteries. If you dont inhibit the growth of mineral in some way, it will grow at the 1 mM calcium and phosphate concentrations of your blood and you will eventually become a pillar of salt. This is an absolutely critical concept: your bodys
homeostatic mechanisms maintain your blood in a supersaturated state at all times, so any crystal that forms in your artery will grow spontaneously (unless you remove it or inhibit its growth).
2. Lecture 2
A. Bone structure. You should know that bone has mechanical properties similar to concrete that has been
reinforced by steel bars: the apatite in bone is analogous to concrete and gives bone its resistance to compression, and the collagen in bone is analogous to steel rods and gives bone its resistance to breaking when stretched (tensile strength). You should also known that bone consists of type I collagen, the same type of collagen found in skin, cornea, the adventitia of arteries, tendons, and other tissue structures. The only difference between collagen in bone and other tissues is that bone collagen is mineralized. You should know that type I collagen molecules are long, three stranded ropes, with two 1 polypeptide chains and a single 2 chain. Each chain has about 1000 amino acid residues, and the collagen molecule is a long, thin, relatively rigid rod that is 1.1 nm in diameter and 300 nm in length. You should know that collagen fibrils are formed by the lateral association of collagen molecules, that the resulting collagen fibrils are far longer than an individual collagen molecule, and that the interior of the fibril is about 30% collagen and 70% water by volume. Bone is formed by the lateral association of collagen fibrils into collagen fibers, which are then packed densely together to form the matrix of bone. You should know that most of the mineral in bone is found within the collagen fibril. You should know that removing mineral from bone with acid leaves behind a collagen matrix with exactly the same dimensions as the original bone. The only difference is that the bone collagen is now flexible and has a volume of water within it that is comparable to the volume of mineral it had before mineral is removed. You should also know that removing protein from bone leaves behind a mineral structure with exactly the same dimensions as the original bone. The only difference is that the bone mineral is now rigid and brittle, with no resistance to bending or stretching. This is the key concept: the calcification of collagen replaces water within the fibril with mineral, and demineralization replaces mineral within the fibril with water. Bone is therefore a composite structure at the nano level, with the interspersal of the collagen molecules and crystals in the fibril at lateral separations of about a nanometer. B. Serum calcium homeostasis. You should know that the level of ionic calcium in serum must be rigorously maintained at about 1 mM. There are two reasons for this: 1. Calcium is a second messenger in a variety of intracellular signaling pathways. When a gated channel opens in the plasma membrane, it is important that the right amount of calcium diffuse into the cell from the extracellular fluid (which has the same calcium concentration as serum). For example, if serum calcium drops by as much as 50%, there is insufficient calcium to operate the mechanism of skeletal muscle contraction and you go into hypocalcemic tetany (which is acutely lethal). 2. Calcium can form mineral. If you increase calcium by as much as 50%, you drive the formation of a calcium phosphate mineral phase in serum and tissues within days. (This is the basis for the use of vitamin D as rat poison, and a rat ingesting such toxic doses of the vitamin D has massive calcification of many soft tissue structures, including the heart, and dies in 3 days). You should know that bone contains over 99% of total body calcium, and that serum calcium levels can only be maintained on a day-to-day basis by either removing calcium from bone (when serum calcium levels fall due to a meal low in calcium) or adding calcium to bone (when serum calcium levels rise due to a meal rich in calcium). Bone is the only storage site of calcium in the body. The only way to maintain serum calcium when you eat calcium-deficient meals is by removing calcium from bone. You should know that serum calcium homeostasis is maintained by the activity of osteoclasts and osteoblasts: osteoclasts (OCs) remove (resorb) bone, and osteoblasts (OBs) form bone. a. If serum calcium levels fall, we obtain calcium from bone by activating OCs and inhibiting OBs. b. If serum calcium levels rise (typically due to eating a source of calcium), we store calcium in bone by activating OBs and inhibiting OCs. You should know that serum calcium is hormonally regulated: a. When serum calcium levels fall, serum levels of parathyroid hormone (PTH) and calcitriol (the active form of vitamin D) both increase; these changes activate OCs and inhibit OBs.
b. When serum calcium levels rise, serum levels of calcitonin increases; this change activates OBs and inhibits OCs. C. Osteoporosis. You should know that bone is by far the most dynamic extracellular matrix in the body, since it must balance the competing goals of mechanical strength and calcium homeostasis: Mechanisms must exist to remove bone uniformly throughout the skeleton when dietary calcium is low, because removing all of the calcium from one bone will cause it to weaken and break. And bone must remember that it lost bone during the period of dietary calcium deficiency so that exactly the same amount of calcium is put back into the bone when dietary calcium is normal. This is a difficult and intricate balancing act, many of whose mechanisms are unknown. The failure of these mechanisms causes the net bone loss that is the hallmark of osteoporosis (and the artery calcification and atherosclerosis that is linked to osteoporosis).
Lecture 3.
A. Types of bone. You should know that there are two major types of bone in the body: 1. Cortical bone (compact bone) is grossly solid in appearance and accounts for 80% of bone mass in
humans. (The bone rings I showed in class were cut from the midshaft region of a cows femur, and are exclusively cortical bone). 2. Trabecular bone (cancellous bone, spongy bone) is an intricate lattice composed of individual interconnected bone segments called trabeculae. Trabecular bone accounts for about 20% of bone mass in humans. You should know that cortical bone is primarily found in the middle region of long bones, and that cancellous bone is primarily found at the ends of the long bones and in vertebra. You should know that all bone is highly vascular, and that about 10% of blood flow goes to bone. B. Bone turnover. You should know that bone is turned over by an anatomical structure called the Bone Multicellular Unit (BMU), and that there are significant differences in the structure of the cortical and trabecular bone types of BMU. Be able to diagram each type of BMU (see lecture handouts). Know that osteoblasts build bone and osteoclasts remove bone (=resorb bone); that the BMU is a vascular compartment with vessels that bring blood to and from it; and that some osteoblasts become entrapped within the new bone matrix to become osteocytes. 1. Cortical BMU. Know that the cortical BMU is found within the interior of cortical bone and moves parallel to the long axis of long bones, with osteoclasts (OCs) removing bone at one end and osteoblasts (OBs) forming bone at the other. Bone formation occurs in two stages: the deposition of a 6 micron thick layer of collagen called osteoid, then the mineralization of this collagen, then the deposition of a new layer of collagen, then its mineralization, etc. This process creates an osteon, with 6 micron thick rings around a central Halversian canal. A bone cross section has many osteons, each of which look like slices thru an onion, and each created by a BMU cycle. 2. Trabecular BMU. Know that the trabecular BMU is found on the surface of trabeculae (and not on the interior); that trabecular BMUs are far more numerous than the cortical BMUs; and that the overall rate of trabecular bone turnover in humans is 10 to 50 times greater than that for cortical bone. C. Functions of bone turnover. Know that we turn over bone for two reasons: 1. To remove microfractures, and thereby restore normal strength to bone. 2. To regulate serum calcium levels (see lecture 2). If serum Ca is low, we activate the OC and inactivate OB in order to release calcium from bone to serum. If serum Ca is high, we activate OB and inactivate OC in order to store serum calcium in bone. Know that these activities are under hormonal control: serum levels of parathyroid hormone and calcitriol (the hormonally active form of vitamin D) are elevated by low serum calcium, and act to release calcium from bone. Serum levels of calcitonin are elevated by high calcium, and promote calcium deposition into bone.
D. Osteoporosis.
1. Definition of osteoporosis. Know that osteoporosis is defined by the extent of bone loss, not the presence of a bone fracture: osteoporosis is defined as a bone mineral density (BMD) that is 2.5 standard deviations below the peak BMD achieved by the person in their 20s. Know that osteoporosis is most common
in women after menopause (1/3 of women over 50 have it) and that osteoporosis is asymptomatic (other than that it increases fracture risk). 2. Cause of bone loss in osteoporosis. Know that osteoporosis is caused by a greater rate of bone resorption than bone formation within the BMU, and that it therefore typically affects the regions of the skeleton that have the most BMUs (which is the trabecular bone at the ends of the long bones and in the vertebra). The most common osteoporotic fractures are: a. Vertebral fractures (crush fractures that reduce a persons height); hip fractures (fractures of the trabecular bone in the proximal femur); and wrist fractures (fractures of the trabecular bone in the distal radius). In the US, osteoporosis causes about 700,000 vertebral fractures per year, and it is estimated that 35 to 50% of all women over 50 have at least one vertebral fracture. (Crush fractures of the vertebra are the sole reason that some people become shorter as they get older.) b. Hip fractures (fractures of the trabecular bone in the proximal femur; about 250,000 /year in US). c. Wrist fractures (fractures of the trabecular bone in the distal radus; about 250,000/ year in the US)
E. Osteoporosis treatment.
1. Know that the least invasive treatment is dietary calcium and vitamin D supplementation. Dietary calcium is intended to reduce the need to activate the BMU to release calcium from bone to serum, and vitamin D is intended to improve calcium absorption from the gut into blood. 2. Know that the other major treatment strategy is to poison the osteoclast. The most common method involves using a class of drugs called bisphosphonates. These drugs are very potent inhibitors of the osteoclast, and the newer generation of these drugs need only be taken a few times a year. It is clear that these drugs do effectively prevent further bone loss in osteoporotic women, but their effect on the number of fractures is less clear. A possible explanation is that the inhibition of bone loss by poisoning the osteoclast also inhibits normal bone turnover by the BMU, so microfractures may accumulate and so reduce the strength of the remaining bone. 3. Know that estrogen replacement therapy can reduce bone loss in osteoporotic women, but that this treatment advantage is usually offset by the increased risk of stroke and bleeding in women receiving estrogen. 4. Know that there is no therapy that has been developed to restore the bone loss in osteoporosis, and no therapy that has been developed to restore the normal coupling of bone loss and bone formation within the BMU of osteoporotic women.
Lecture 4.
A. The possible link between osteoporosis and artery calcification: formation of calcium phosphate crystals in the BMU. Be able to reproduce the diagram of the relationship between bone
turnover in the BMU and the concentration of calcium and phosphate in the aqueous compartment of the BMU (see lecture notes). Know that whenever osteoclasts remove bone more rapidly than osteoblasts form it (that is, when there is net bone loss), there will be a predictable changes in the chemistry of the aqueous compartment of the BMU: the concentration of calcium and phosphate will be higher and the pH will be more alkaline. Know that in a buffer that has the same pH, calcium, and phosphate as serum, no apatite crystals form for years. However, if the concentrations of calcium, phosphate, and hydroxide are increased by 1.5-fold each, crystals form in seconds. It is hard to imagine that rapid bone loss within the BMU can increase calcium, phosphate, and hydroxide by less than 1.5-fold, so it seems likely that bone loss generates crystals within the aqueous compartment of the BMU. Because the BMU is a vascular compartment, these crystals appear in serum within minutes. The women with postmenopausal osteoporosis that have the highest rate of bone loss will have the greatest increase in calcium, phosphate, and hydroxide in the BMU, will therefore form the most crystals in the BMU, and will have the most crystals in their blood. Lecture 8 looks at how crystals in seum can promote atherosclerosis in these women. B. Artery structure and function. Be able to diagram the structure of an artery, as shown in lecture, and to identify the intima, the media, and the adventitia. In this same diagram, be able to show the location of elastic lamellae and vascular smooth muscle cells within the artery media.
1. Know that the major connective tissue in the adventitia is collagen, and that the function of the adventitia collagen is to limit the maximum extent to which the artery can expand with each pulse of blood (beat of the heart). 2. Know that the elastic lamellae are rubber-like that sheets surround the artery lumen. The lamellae expand and contract with each pulse of blood and thereby facilitate blood flow. Know that the vascular smooth muscle cells play an important role in maintaining blood pressure, and that they do so by contracting and thereby limiting the extent to which the artery wall can expand with each pulse of blood. 3. Know that the cells that line the artery wall are called vascular endothelial cells. These cells are part of the intima, and perform a critical function in determining the ability of different blood components to diffuse into the remainder of the intima and into the media. C. The major types of vascular calcification. Know that artery calcification occurs in two regions of the artery, the media and the intima: 1. Medial calcification is seen in renal failure, diabetes, and some women with osteoporosis. Know that this calcification is initially seen as small foci of mineral about 1 micron in diameter that lie within the elastic lamellae. With time, these foci grow to calcify the entire lamellae (they grow because serum is supersaturated with calcium and phosphate). The mineral eventually grows into the space occupied by vascular smooth muscle cells, which then die. In the end, the entire artery media becomes a solid tube that will fracture if it is bent. 2. Intimal calcification is seen in the atherosclerotic plaque. Know that it begins at the earliest stage of plaque development, the fatty streak, and is seen as innumerable small, spherical mineral foci around 1 micron in diameter. These are not typically associated with an elastin or collagen matrix. With time, the mineral grows to form a solid mass of mineral that is palpably hard, and additional cholesterol is deposited in the intima above the mineral. Both the steady accumulation of mineral and the progressive accumulation of cholesterol occur in parallel. This shows that calcification and cholesterol could be linked mechanistically, but does not prove that they are linked. D. Blood coagulation. Know that cardiovascular disease (atherosclerosis) causes heart attacks and about 70% of all strokes, and that the terminal event in both cases is the formation of a blood clot. Know that hemostasis is the name given to the process by which the vascular system seals a leak, and that it occurs in several discrete stages. Know that the first stage of hemostasis is the formation of a platelet plug: Platelets bind to the site of a leak due to exposure of molecules (collagen, elastin, etc.) that are not normally in direct contact with blood. Binding activates these platelets, which release substances that promote platelet aggregration and lead to the formation of a platelet plug. This is the first stage in hemostasis: the stemming of the leak by the formation of a platelet plug. Know that aspirin reduces the aggregration of platelets in response to vascular injury by irreversibly inhibiting the enzyme that is required to synthesize prostaglandins, cyclo oxygenase (COX). Because platelets have no nuclei, they cannot replace the inactive COX and their ability to form the platelet plug is permanently reduced. Know that cardiovascular disease (atherosclerosis) causes heart attacks and about 70% of all strokes, and that the terminal event in both cases is the formation of a blood clot. Know that hemostasis is the name given to the process by which the vascular system seals a leak, and that it occurs in several discrete stages:
Lecture 5. Blood coagulation.
A. The first stage of hemostasis is the formation of a platelet plug:
Platelets bind to the site of a leak due to exposure of molecules (collagen, elastin, lipid, etc.) that are not normally in direct contact with blood. Binding activates these platelets, which release substances that promote platelet aggregration and lead to the formation of a platelet plug. This is the first stage in hemostasis: the stemming of the leak by the formation of a platelet plug. Know that aspirin reduces the aggregration of platelets in response to vascular injury by irreversibly inhibiting the enzyme that is required to synthesize prostaglandins, cyclo oxygenase (COX). Because platelets
have no nuclei, they cannot replace the inactivated COX and their ability to form the platelet plug is permanently reduced. Know that the surface composition of the platelet membrane changes with its activation. Initially, the platelet and all other cells have an asymmetric distribution of phosphatidyl serine, the only glycerophospholipid with a net negative charge: virtually all phosphatidyl serine is in the inner leaflet of the plasma membrane. After activation, the distribution of phosphatidyl serine is randomized, and the external surface of the platelet thereby acquires a net negative charge for the first time (and in fact becomes the only cell in the body to have a negatively charged plasma membrane).
B. The second stage of hemostasis is the formation of a fibrin clot:
The negatively charged, phosphatidyl serine-rich plasma membrane of the activated platelets in the plug provides the surface that triggers formation of the fibrin clot. Be able to diagram the complete extrinsic arm of the blood coagulation pathway, at the level of the lecture handout. Indicate which steps in the pathway require calcium, and which require an activated platelet membrane surface. Know that the function of this cascade is signal amplification: a small number of initiating events (eg, tissue factor supplied by macrophages in an atherosclerotic plaque) is all that is necessary to form a massive clot! Know that fibrinogen is a large, soluble protein that accounts for 3% of all blood protein, and that thrombin is a protease that cleaves fibrinogen at four sites to create fibrin and 4 fibrinopeptides. Know that the fibrin monomers so created associate to form fibrin fibers within milliseconds. This forms a mesh of fibrin fibers on the activated platelet surface, and therefore in contact with blood. Know that a transamidase (factor XIIIa) then forms a peptide bond cross link between glutamine and lysine residues that stabilizes the clot. Know which coagulation factors contain the vitamin K-dependent amino acid -carboxyglutamic acid (prothrombin, factors X, IX, and VII); Know the structure of -carboxyglutamic acid, and be able to diagram how it binds calcium and so links the prothrombin to the anionic platelet surface. Know that the thrombin that diffuses away from the clot is inactivated by forming a 1:1 complex with a serum protein called antithrombin III, and that the rate at which this complex is formed is increased over 1000fold by heparin. Know that this is the basis for the therapeutic action of heparin in patients, and for the use of heparin to make blood plasma. Know why calcium chelators such as citrate and EDTA inhibit clotting. Know how clotting is inhibited by warfarin (coumadin) (by inhibiting the -carboxylation of the vitamin K-dependent clotting factors and thereby reducing their ability to be activated by the cascade) and aspirin (by reducing the rate at which platelets aggregate by as much as 50%). Know that clots are eventually removed by the protease plasmin, and that the first step in clot removal is the activation of plasminogen to plasmin by cleavage with tissue plasminogen activator (TPA). Know that injection of TPA within 1 hour of a heart attack markedly reduces mortality.
Lecture 6. Cholesterol.
Know that the fluidity of membranes is maintained by the presence of polyunsaturated fatty acids in the membrane lipids of plants and bacteria, and by the presence of cholesterol in the membranes of animals (which have saturated fatty acids in their membrane lipids). Know that most mammalian membranes are about 20 to 25% cholesterol, and that without this cholesterol the membranes would not be fluid, and would not be able to carry out certain functions. For these reasons, a vegan diet is very low in cholesterol, and a diet rich in steak and eggs is high in cholesterol. Know that cholesterol is synthesized starting with acetyl CoA, that most cells in a person can synthesize cholesterol, that the committed step in cholesterol biosynthesis is catalyzed by an enzyme called HMG-CoA reductase, and that the product of this step is mevalonic acid. Know that the level of HMG-CoA reductase in liver cells can vary by more than 200 fold, depending on dietary levels of cholesterol. For this reason, it is usually not possible to reduce serum cholesterol by simply eliminating most foods that contain cholesterol from the diet.
Lipoproteins.
1. Know that mammals have no ability to degrade cholesterol for energy, and that any excess cholesterol in the body must therefore be excreted. Know that this is the function of liver, and that all excess cholesterol is excreted in bile fluid as cholesterol or as bile acids (which are made from cholesterol). 2. Know that there is more cholesterol in blood than glucose, and that this cholesterol concentration is 1,000fold higher than the solubility of cholesterol in water. Know that this high cholesterol concentration in blood is due to the presence of lipoproteins. 3. Know that all lipoproteins are composed of a lipid core, and a coat that consists of phospholipids and cholesterol arranged in a structure that looks like the outer leaflet of a plasma membrane, plus one or more specific proteins. 4. Know that the coat of the lipoprotein is more dense than the core, and that the relative fraction of the lipoprotein in the coat decreases as the size of the lipoprotein increases. Lipoprotein density therefore always predicts lipoprotein size: the least dense lipoproteins are the largest, and the most dense are the smallest. 5. Know that liver makes very low density lipoproteins (VLDLs) that have a lipid core that contains cholesterol esters and triacyl glycerols (TAG), and that with time the triacyl glycerols are hydrolyzed and transferred to one or another cell type. The eventual product contains little TAG, and all of the initial cholesterol; this is called the low density lipoprotein (LDL), and of course it is smaller than the VLDL from which it was generated. 6. Know that LDL cholesterol plays a role in the development of atherosclerosis, and that drugs have been developed to reduce serum LDL cholesterol. Know that these drugs are called statins, that they reduce cholesterol synthesis in the liver by inhibiting HMG-CoA reductase, and that they are the best selling class of drugs in the world. Know that HMG-CoA reductase is found in most cells of the body, and that the same drug that is effective in lowering serum cholesterol will inhibit the entire mevalonic acid pathway in these cells. There could therefore be side effects associated with taking statins.
Lecture 7. Atherosclerosis.
1. Be able to diagram three stages in atherosclerotic plaque development, at the level of detail shown in lecture: the fatty streak stage, the fibrous cap stage, and the ruptured plaque stage. Show in your diagram the location of the intima and media, the endothelial cells, and the location of lipid, macrophages, mineral, and the collagen of the fibrous coat. 2. Know that the intima has the highest concentration of LDLs of any extracellular matrix in the body, a concentration about the same as in serum. Know that the likely reason for this is the absence of lymph ducts in the intima, since the lymphatic system is needed to remove LDLs from tissues. Know that the rate of diffusion of LDLs into and out of the intima is very, very slow, and that a given LDL can reside in the intima for weeks to months. 3. Know that LDLs become damaged during their long residence in the intima, and that macrophages take up these damaged LDLs by specific mechanisms. 4. Know that numerous macrophages are found at all stages of plaque development, and that many of these contain massive amounts of cholesterol. These cholesterol-laden macrophages are called foam cells, and liberate massive amounts of cholesterol when they die. 5. Know that cholesterol liberated from dead macrophages and damaged LDLs is extremely insoluble, and so eventually coalesces to form a lipid rich core. 6. Know that cholesterol itself, and oxidation products of cholesterol, are extremely toxic to cells, so the gradual accumulation of cholesterol in the plaque is accompanied by increased cell death. 7. Know that the death of macrophages and smooth muscle cells in the plaque liberates proteases that degrade the fibrous cap, leading to plaque rupture. 8. Know that the lipid exposed in the ruptured plaque triggers local platelet aggregation. Know that macrophages in the clot have tissue factor, and that this activates the extrinsic arm of the clotting cascade to form a fibrin clot within seconds to minutes. 9. Know that: If the clot forms on the surface of a ruptured plaque in a coronary artery, it can block blood flow causing a heart attack. If the clot forms on the surface of a ruptured plaque in a carotid artery, release of the clot from the site creates an embolus that will travel to the brain and eventually plug an artery and kill part of the brain, causing a stroke.
10. Know that coronary artery calcification can be measured quantitatively by electron beam computed tomography (EBCT), and that the resulting calcification score is a very strong predictor of heart attacks and heart-related death, a better predictor than serum LDL, HDL, smoking, diabetes, and obesity combined.
Lecture 8. Atherosclerosis and osteoporosis: is the link artery calcification?
A. The link between post menopausal bone loss and artery calcification.
1. The women with the highest rate of bone loss invariably have the most extensive artery calcification. 2. All bone loss occurs because of an imbalance between removal of bone by osteoclasts and formation of bone by osteoblasts within the Bone Multicellular Unit (BMU). 3. The BMU is a vascular compartment, with blood constantly entering and leaving the structure. Any chemical change that occurs in the BMU because of bone loss will therefore appear in the circulatory system within minutes. 4. One possible explanation for the link between bone loss and artery calcification is that an agent that promotes calcification is released from the BMU under conditions of excessive bone loss, then travels in blood, and then crosses the endothelial barrier into the intima, and then generates mineral. 5. The nature of this putative agent is not known. It could be crystals small enough to penetrate the endothelial barrier of the artery, or it could be an agent that promotes the formation of small crystals, or it could be something else entirely. The most plausible of these are small crystals, but the direct evidence is so far lacking. 6. The other possible explanation for the link between bone loss and artery calcification is that there is a systemic condition that drives both processes. There is no obvious candidate for such a systemic condition however.
B. The link between postmenopausal bone loss and atherosclerosis.
1. The women with the highest rate of bone loss invariably also have the highest risk for heart attacks and strokes. 2. One possible explanation for this observation is that bone loss drives artery calcification (see A above) and that artery calcification drives development of the atherosclerotic plaque. 3. This explanation is supported by the fact that coronary artery calcification is a very good predictor of myocardial infarction.
C. The possible link between atherosclerotic plaque development and artery calcification.
1. Calcium phosphate mineral and cholesterol are both found at all stages of plaque development, from the initial fatty streak to the terminal ruptured plaque that initiates the (possibly fatal) formation of a fibrin clot. 2. Small apatite crystals attract large numbers of macrophages to a subcutaneous site within hours, and that these macrophages engulf and remove these small apatite crystal aggregates. Macrophages therefore probably play a role in removing the small mineral foci found in the intima at all stages of plaque development, just as they play a role in removing damaged LDLs. 3. Macrophages recruited to the intima to remove mineral found at the site can also take up damaged LDLs, become foam cells, and die. 4. As cholesterol accumulates, the rate of cell death increases and the plaque becomes necrotic. The fibrous cap eventually ruptures, and a clot forms. 5. By this line of thought, the continuing generation of small mineral foci within the plaque is a required element of plaque development, and without the mineral there would be no macrophages, and if there were no macrophages there would be no lipid accumulation, no clot, and no death. 6. If this view is correct, the question is what forms the mineral foci.
D. A hypothetical scenario:
The women with the highest rate of bone loss form the most crystals in the BMU, have the highest number of crystals in serum, have the highest number of crystals in the intima, and therefore recruit the most
macrophages into the plaque. This is particularly lethal at the later stages of plaque development, where macrophages recruited to remove mineral from the intima also take up damaged LDLs, become foam cells. These macrophages are eventually killed by cholesterol, liberate proteases, break down the fibrous cap, and thereby trigger the clot that kills.
1. Required reading for the last lecture, discussion, and final exam: AtherosclerosisA story of cells, cholesterol, and clots, by John R. Guyton. This article can be found at the following URL:
http://www.docstoc.com/docs/2316263/1-ATHEROSCLEROSIS-%EF%BF%BD-A-STORYOF-CELLS-CHOLESTEROL-AND-CLOTS-John
2. The notes to the final for weeks 1 to 10 are on the course website:
http://www.biology.ucsd.edu/classes/bisp194-5.WI09
3. There will be a review session for the final exam that will be held at 1pm on Sunday March 15 in room 2130 Bonner Hall (the lecture room).