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Atherosclerosis and Coronary Artery Disease
- One of the functions of the coronary arteries in the heart is to supply oxygen-carrying blood tothe heart. In atherosclerosis, a fatty sludge infiltrates the inner coronary artery walls so that thenarrowed coronary artery will carry less blood, as shown below:
- The heart muscle receives too little oxygen to function at maximum capacity and pumps with lessfuel. The situation is analogous to an eight cylinder automobile running on four cylinders. The heartis able to cope when an individual is resting. However, when the individual exercises, the narrowedcoronary arteries cannot supply sufficient oxygen-carrying blood and the individual experiences painin the chest (angina pectoris). With increased blockage of the coronary artery, a portion of the heartmuscle may be deprived of oxygen-carrying blood leading to irreversible damage to a portion of theheart muscle, a condition referred to as myocardial infarction (commonly referred to as a heart attack). The heart attack may be fatal. Atherosclerosis is the leading cause of death for both men and womenin western countries and Canada has one of the highest rates of coronary artery disease in the world.
Non-lipid (Non-fat) Risk Factors (for coronary heart disease and heart attacks)
There are several additional controllable factors for coronary heart disease. These are: obesity(20% or more overweight), cigarette smoking, hypertension, and lack of exercise.
Types of Lipids
The three major types of lipids are cholesterol (C), cholesterol esters (CE), and triglycerides (TG).
Cholesterol is a waxy, fat-like, ring-structured chemical present in all cells in the body. It is acomponent of cell membranes and it is used for the synthesis of sex hormones, bile salts and vitaminD. North Americans consume approximately 400-500 mg/day in their diet. The body synthesizesapproximately 1,000 mg/day, mainly in the liver. Considerable amounts are also produced in theintestines. Cholesterol only endangers health if the concentration in the blood is elevated and if itinfiltrates arterial walls, narrowing the lumen, decreasing blood flow, and hence decreasing theamount of oxygen available. It must be stressed that fats (C, CE and TG) are essential to life, as anenergy source and as providers of essential fatty acids (CE and TG).
Types of Lipoprotein
- Fats (C, CE and TG) are insoluble in water and they are therefore packaged for transport aslipoproteins as shown in the diagram below:
- Chylomicrons: These are the largest of the lipoproteins. They are formed in the intestine and carry triglycerides ofdietary origin.Very low density lipoproteins
- (VLDL): These lipoproteins are secreted by the liver and carry triglycerides to body tissues.
- Low density lipoproteins (LDL): LDL is sometimes referred to as the “bad” lipoprotein because it is taken up by macrophages (largewhite blood cells) and play a role in increasing fatty deposits inside the arteries and thickening theinside of blood vessels.
- High density lipoproteins (HDL): HDL is referred to as the “good” lipoprotein because it transports cholesterol away from the arteries tothe liver where cholesterol is biotransformed into bile acids and excreted. In this way, HDL helps toprotect against heart disease.
Secondary and Primary Hyperlipoproteinemias
- (a) Secondary: These arise as complications of more generalized metabolic disturbances such as diabetes mellitus, hypothyroidism, or chronic ingestion of large amounts of alcohol.
- (b) Primary: i. This type of hyperlipoproteinemia arises from an inherited single-gene defect inherited in apredictable Mendelian fashion.
- ii. Hyperlipoproteinemias may be caused by a combination of subtle genetic factors acting togetherwith environmental insults
Cholesterol Levels in Blood
These levels may be expressed in millimoles per litre (mmol/L) or milligrams per decilitre(mg/dL). Desirable levels of total cholesterol in adults is considered to be less than 200 mg/dL (5.5mmol/L). Borderline to high levels in adults are considered to be 200-239 mg/dL. High levels inadults are considered to be greater than or equal to 240 mg/dL. An accurate heart-risk assessmentrequires a detailed blood lipid (fat) analysis and a calculation of the HDL/LDL ratio.
Cholesterol – Heart Disease Link
Population studies have shown than an elevation of blood total cholesterol or of LDL-cholesterolis a major risk factor for atherosclerotic events. Thus, in individuals with blood cholesterol greaterthan 220-250 mg/dL, there will be a three-fold greater risk of heart attack than in individuals withblood cholesterol levels less than 195 mg/dL.
Does lowering of plasma concentration of LDL-cholesterol diminish the risk of coronary heartdisease?
- Establishing a link between cholesterol blood levels and heart disease was important. However,despite many years of research in this area, until 1984 therapy of hyperlipoproteinemia remainedcontroversial since prior to this date lowering of plasma lipids had not been shown in prospectivestudies to prolong life or to diminish complications of atherosclerosis. Thus, the results of the LipidResearch Clinic’s Primary Prevention Trial, reported in 1984, constituted a milestone in thistherapeutic area. This major trial was a multicentre, randomized, double-blind study and providedstrong evidence that a decrease in plasma concentration of LDL-cholesterol was associated with adecrease in risk of coronary heart disease.
- Analysis of this study showed that, in patients with hyperlipoproteinemia, the incidence ofcoronary heart disease was decreased by approximately 50% for individuals with a decrease of 25% inplasma total cholesterol or a decrease of 35% in plasma LDL-cholesterol.
These consist of elimination of aggravating factors and the institution of dietary measures. Ifdietary measures alone fail to provide desired changes in blood lipids, the dietary measures arecontinued and drug therapy instituted. The details of the therapy will depend upon accurate lipidanalysis of the blood to help to pinpoint the nature of the hyperlipoproteinemia. The choice of drugwill be influenced by the type of lipid that is causing the problem.
Elimination of aggravating factors
- The following needs to be done in conjunction with lowering of lipids:
- (a) Cessation of smoking.
- (b) Therapy of hypertension.
- (c) Institution of physical fitness program.
- (d) Control of blood glucose in diabetics.
- (e) Therapy of hypothyroidism.
- (f) Therapy of alcohol dependence.
- It is advisable to try to maintain a normal body weight. The diet should be low in cholesterol andsaturated fats. The consumption of saturated fats results in an elevation of blood cholesterol. Reducing saturated fat intake is considered the most effective way to lower blood cholesterol rather than exclusively cutting out cholesterol-rich foods (such as eggs, cream and liver). Saturated fats aremainly of animal origin (butter, bacon fat), but include palm and coconut oils. In North America, wetend to eat too much saturated fat from meats, dairy products, baked goods, salad dressings, soups andcheeses.
- Polyunsaturated fats are found in fish and in vegetable oils such as corn, sunflower, walnut, oliveand canola oil. The polyunsaturated fats assist in lowering blood cholesterol and improving the HDL(good)/LDL (bad) ratio.
Drugs for the Treatment of Hyperlipoproteinemia
There are four major drugs used in the treatment of the hyperlipoproteinemias – cholestyramine,gemfibrozil, niacin (nicotinic acid) and lovastatin (and several related compounds, e.g. simvastatin). Before choosing a particular drug or drug combination, the physician requires to take a careful patienthistory and to have a lipid analysis done on a blood sample to be able to identify the nature of the lipiddisorder. Different lipid disorders will require different drugs to be selected for therapy.A fifth class of drugs inhibit sterol (fat) absorption in the gastrointestinal tract (eg. Eztimibe).
- Cholestyramine is a large, insoluble, positively-charged resin that binds bile acids in the intestineand prevents their reabsorption. The resin is not absorbed from the intestine and thus is a relativelysafe drug.
- Cholesterol is metabolized in the liver to bile acids which are then excreted into the intestine. Most of the bile acids are normally reabsorbed from the intestine. The negatively-charged bile acidsare absorbed in the intestine by the positively-charged resin, thus inhibiting their reabsorption andgreatly enhancing their excretion. The enhanced excretion of bile acids by cholestyramine results inenhanced transformation of cholesterol to bile acids in the liver. This process results in the need foradditional cholesterol in the liver. The additional cholesterol is provided by enhanced uptake of LDLfrom the blood into the liver and a lowering of blood LDL-cholesterol by approximately 20%. Cholestyramine is therefore useful in hyperlipoproteinemias in which LDL levels are elevated. Cholestyramine was employed in the 1984 Lipid Research Clinic’s Coronary Primary PreventionTrial, the results of which were discussed above.
- The major therapeutic use of gemfibrozil is in the treatment of hypertriglyceridemia. This is aform of hyperlipoproteinemia in which triglycerides predominate. In this condition, VLDL iselevated. Gemfibrozil decreases levels of VLDL in plasma due to causing enhanced breakdown oftriglycerides and decreased secretion of VLDL by the liver.
- Gemfibrozil was used in the Helsinki Heart Study, the results of which were reported in THENEW ENGLAND JOURNAL OF MEDICINE (Vol. 317, p. 1237, November 12, 1987). This was arandomized, double-blind, placebo-controlled, primary prevention trial in which 4,081 middle-agedmen were the subjects in a five-year study; the average blood cholesterol levels at baseline wereapproximately 275 mg/dl. The incidence of fatal or non-fatal myocardial infarction (heart attack) was27.3/1,000 in the gemfibrozil group and 41.4/1,000 in the placebo group, a reduction of 34% (highsignificant, p < 0.02 by a two-tailed t-test). However, surprisingly, the total mortality was notchanged by treatment. Later follow-up studies revealed that mortality was greater in the gemfibroziltreated than in the placebo group (THE MEDICAL LETTER, Vol. 35, No. 891, p. 19, March 5, 1993). Ithas therefore been recommended that gemfibrozil should not be used in patients with combinedhyperlipidemia (elevation of more than one lipoprotein in the blood) and who show symptoms ofatherosclerosis.
Niacin (Nicotinic Acid, Vitamin B3)
Niacin inhibits secretion of VLDL from the liver, and since LDL is a product of VLDL, it alsodecreases production of LDL. Niacin will therefore decrease levels of VLDL and LDL in the blood ofpatients in different types of hyperlipoproteinemias. It is employed either alone or in combinationwith other lipid-lowering drugs in most of the different hyperlipoproteinemias. It is the most effectiveagent in increasing levels of HDL.
- Lovastatin and related compounds – simvastatin, fluvastatin, atorvastatin and pravastatin (thisclass has been referred to as statins).
- Lovastatin and related compounds inhibit the enzyme which catalyzes the rate-limiting step incholesterol biosynthesis. This enzyme is known as HMG-CoA reductase. More LDL will be removedfrom the blood by the liver, thus decreasing blood levels of LDL. This group of drugs is employedeither alone or in combination where LDL levels are elevated in the blood. This group of drugs is themost effective in lowering LDL and total cholesterol.
- A Scandinavian simvastatin survival study was published in 1994 (LANCET, Vol. 345, p. 1383,1994; SCIENCE, Vol. 266, p. 1323, November 25, 1994). In this study, 4,400 patients were monitoredfor 5.4 years. Simvastatin reduced the incidence of non-fatal heart attacks by 30% and decreased theneed for coronary bypass surgery by 37%. There was a 30% reduction in mortality in individualsreceiving simvastatin compared to individuals receiving placebo. This was the first study todemonstrate that lowering plasma cholesterol resulted in a reduction in mortality from cardiac causes.
Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with AverageCholesterol Levels
- The background of this study is the following: It is known that lowering cholesterol levels inpatients with high cholesterol levels decreases the risk of coronary heart disease. The above studyexplores the effect of lowering cholesterol levels in patients with coronary disease who have averagelevels of cholesterol. Both women and men were included in the study. The following conclusionswere reached by the authors of the study:
- “. . . the benefit of cholesterol-lowering therapy extends to the majority of patients withcoronary disease who have average cholesterol levels”.
- M.S. Brown and S.M. Goldstein, two U.S. physician/scientists who are winners of the NobelPrize for Research in hyperlipoproteinemias, published a paper (SCIENCE, Vol. 272, p. 629, 1996)entitled: “Heart attacks: gone with the century?”. In this paper, they review three drug trials usingstatins (the name they give to this class of drugs). In these three trials, 15,198 people were followedfor five years. Cholesterol production was slowed and there was an enhancement of removal of LDLfrom the blood into the liver.
- The Scandinavian and North American studies enlisted individuals with coronary artery disease,while a Scottish study enlisted individuals with high cholesterol levels but without symptoms ofcoronary artery disease.
- All of the studies yielded similar results:
- Plasma levels of LDL were reduced by 26 to 35%.
- Heart attacks were reduced by 25 to 31%.
- In the Scandinavian study, deaths from heart attack were reduced by 42% and deaths from allcauses were reduced by 30%.
In my view
In my view, the views of Brown and Goldstein were over-optimistic. Nevertheless, these newdrugs – the statins – have certainly resulted in major improvements in the treatment of thehyperlipoproteinemias. Recent studies have confirmed the value of lowering cholesterol but there areother factors that contribute to cardiovascular diseases.
Eztimibe is a selective inhibitor of the intestinal absorption of cholesterol and plant sterols. It isusually used in combination with other drugs.