American Heart Journal (C) Mosby-Year Book Inc. 1995. All Rights Reserved. Volume 130(3), September 1995, pp 580-600 Preventing and arresting coronary atherosclerosis [PROGRESS IN CARDIOLOGY] Roberts, William Clifford MD Dallas, Texas. >From the Baylor Cardiovascular Institute, Baylor University Medical Center. Received for publication Oct. 28, 1994; accepted Dec. 14, 1994. Reprint requests: William C. Roberts, MD, Baylor Cardiovascular Institute, Baylor University Medical Center, 3500 Gaston Ave., Dallas, TX 75246. AM HEART J 1995;130:580-600. ---------------------------------------------- Outline HOW MUCH ATHEROSCLEROSIS IS PRESENT IN THE CORONARY ARTERIES IN PATIENTS WITH SYMPTOMATIC MYOCARDIAL ISCHEMIA? WHAT DO CORONARY ATHEROSCLEROTIC PLAQUES CONSIST OF IN PATIENTS WITH SYMPTOMATIC MYOCARDIAL ISCHEMIA? WHAT ACUTE LESIONS OCCUR IN THE CORONARY ARTERIES IN PATIENTS WITH SYMPTOMATIC MYOCARDIAL ISCHEMIA, AND HOW FREQUENTLY DO THEY OCCUR IN THE THREE ACUTE CORONARY EVENTS? HOW MANY DIRECT ATHEROSCLEROTIC RISK FACTORS EXIST? Elevated serum (or plasma) total cholesterol, LDL cholesterol, and low HDL cholesterol. Systemic hypertension. Cigarette smoking. Family history. Severe obesity. Diabetes mellitus. Male sex. WHAT FACTORS INDICATE THAT CHOLESTEROL CAUSES ATHEROSCLEROSIS? 1. Feeding high-cholesterol diets to certain animals produces atherosclerotic plaques similar to those in human beings. 2. Cholesterol is found in both experimentally induced atherosclerotic plaques in nonhuman animals and in plaques in human beings. 3. Atherosclerotic plaques large enough to produce clinical problems occur only in persons with serum or plasma total cholesterol levels greater than 150 mg/dl for long periods of time. 4. The higher the blood total cholesterol level is, the greater is the chance of having symptomatic and fatal atherosclerotic disease. 5. The higher the serum total and LDL cholesterol levels are, the greater is the extent of the atherosclerotic plaques. 6. Lowering the blood total cholesterol and LDL cholesterol levels decreases the chances of fatal or nonfatal atherosclerotic disease. 7. Atherosclerotic plaques may regress or fail to progress when high total and LDL cholesterol levels are lowered. HOW CAN SYMPTOMATIC ATHEROSCLEROSIS BE PREVENTED OR, IF PRESENT, ARRESTED? HOW CAN NORMAL SERUM CHOLESTEROL LEVELS BE PREVENTED FROM RISING, AND HOW CAN ELEVATED LEVELS BE LOWERED TO NORMAL? Cholesterol intake. Fat intake. Fast-food restaurants. Mexican food. Foods and liquids consumed in 1 day in the United States. Excessive body weight. Calculating the percentage of calories from fat and the grams of fat consumed daily to maintain an ideal body weight. Flesh consumption. Characteristics of carnivores and herbivores. Diseases infrequent in vegetarians. Diets and diseases of our stone-age ancestors. Lack of genetic change. Enormous environmental change. The late Paleolithic lifestyle. Nutrition. Physical exercise. Alcohol. Tobacco. Effects of changes in lifestyle on disease prevalence. Obesity. Atherosclerosis. Systemic hypertension. Diabetes mellitus. Effectiveness or noneffectiveness of various diets in lowering the total and low-density lipoprotein cholesterol levels. Lipid-lowering drugs. Primary prevention. Secondary prevention. Types of lipid-lowering drugs. Getting cardiologists interested in lipid-lowering drugs. Retail costs of lipid-lowering drugs. SUMMARY REFERENCES Graphics Table I. Deciles of ... Figure 1 Figure 2 Table II. Calories n... Table III. Maximal g... Figure 3 Table IV. Retail cos... Atherosclerosis is the biggest killer in the Western world. Approximately 45% of the inhabitants in this portion of the planet will die from its consequences. In the United States alone an estimated 7 million people have symptomatic myocardial ischemia resulting from coronary atherosclerosis, and countless more have consequences of its attacks on the aorta and the peripheral arteries. The sad thing about atherosclerosis is that in most of us it is preventable. It is estimated that only one in 500 people has the genetic form, namely heterozygous familial hypercholesterolemia. Thus the rest of us, 499 of 500 people, determine ourselves whether we will have sufficient quantities of atherosclerotic plaques to narrow our arterial lumens sufficiently to cause organ ischemia or infarction. This chapter reviews atherosclerosis, with a focus on that involving the coronary arteries, by asking seven questions. (1) How much atherosclerosis is present in the coronary arteries in patients with myocardial ischemia? (2) What do coronary atherosclerotic plaques consist of in patients with symptomatic myocardial ischemia? (3) What acute lesions occur in the coronary arteries in patients with symptomatic myocardial ischemia, and how frequently do they occur in the three acute coronary events, unstable angina pectoris (UAP), acute myocardial infarction (AMI), and sudden coronary death (SCD)? (4) How many direct atherosclerotic risk factors exist? (5) What factors indicate that cholesterol causes atherosclerosis? (6) How can symptomatic atherosclerosis be prevented or, if present, arrested? (7) How can normal cholesterol levels be prevented from rising, and how can elevated levels be lowered to normal? HOW MUCH ATHEROSCLEROSIS IS PRESENT IN THE CORONARY ARTERIES IN PATIENTS WITH SYMPTOMATIC MYOCARDIAL ISCHEMIA? The amount of coronary arterial narrowing observed at necropsy in patients with UAP, AMI, and SCD is generally enormous, and certain evidence suggests that patients with symptomatic myocardial ischemia have as much plaque as do those with fatal myocardial ischemia. From study of 80 patients at autopsy with these three coronary events, an average of 2.9 of the four major (right, left main, left anterior descending, and left circumflex) coronary arteries were severely (> 75% decrease in cross-sectional area) narrowed at some point, and no significant differences were observed among the three coronary subsets. [1,2] Patients with UAP had a much higher frequency of severe narrowing of the left main coronary artery (10 [45%] of 22 patients compared with those with AMI (three [11%] of 27 patients and SCD (three [10%] of 31 patients). [1,2]. A more sophisticated approach to determining degrees of luminal narrowing is to examine the entire lengths of the four major epicardial coronary arteries. One technique involves incising each of the four major coronary arteries transversely at 5 mm intervals and then preparing a histologic section from each 5 mm segment. Normally the total length of the four major arteries is approximately 27 cm (right = 10 cm, left main = 1 cm, left anterior descending = 10 cm, and left circumflex = 6 cm), and thus approximately 55 five-millimeter-long segments are available for examination from each heart. Of the 4016 five-millimeter-long segments studied in the 80 previously mentioned patients, 38% were narrowed 76% to 100% in cross-sectional area by plaque alone (control 3%); 34% were narrowed 51% to 75% (control 22%); 20% were narrowed 26% to 50% (control 44%); and only 7% were narrowed 25% or less (control 31%). [1,2] Similar degrees of narrowing by plaque alone in all four categories of narrowing were observed in the groups with AMI and SCD; patients with UAP had significantly more severe coronary narrowing than the other two groups. [1,2]. Thus in general patients with fatal UAP have more extensive severe narrowing by plaque alone of the four major epicardial coronary arteries than patients with either AMI or SCD, and patients with UAP compared with the other two groups have a significantly higher frequency of severe narrowing of the left main coronary artery. The good news is that it takes a huge quantity of plaque before overt myocardial ischemia occurs; the bad news is that despite the requirement for huge quantities of plaque before problems occur, nearly half of us in the Western world eventually have these huge quantities of plaque. WHAT DO CORONARY ATHEROSCLEROTIC PLAQUES CONSIST OF IN PATIENTS WITH SYMPTOMATIC MYOCARDIAL ISCHEMIA? Until recently no detailed information was available concerning the composition of atherosclerotic plaques in the epicardial coronary arteries of patients with fatal coronary events. With the use of a computerized morphometric system, Kragel et al. [3,4] determined the various components of atherosclerotic plaques in histologic sections prepared from 1438 five-millimeter-long segments of the four major epicardial coronary arteries in 37 patients with fatal coronary artery disease. The dominant component of the coronary atherosclerotic plaques in all three subsets of patients was fibrous tissue, composing approximately 80% of the plaques in each subset; extracellular lipid (pultaceous debris) and calcium each made up approximately 5% of the plaques, and several miscellaneous components composed the remainder of the plaques. The cellular component of the fibrous tissue occupied a larger portion of plaque in the patients with UAP and SCD, and the acellular (dense) component of fibrous tissue occupied a larger portion of the plaque in the group with AMI. In all three subsets the amount of dense fibrous tissue increased as plaque size increased (or as lumen size decreased), and the amount of cellular fibrous tissue decreased as plaque size increased. Plaques in women had a higher percent of cellular fibrous tissue and a lower percent of acellular fibrous tissue than did those of men in a similar age group. [5] Plaques in saphenous veins used as aortocoronary conduits became similar to those in the native coronary arteries in the same patients at approximately 7 years after the bypass operation, and the dominant component of the plaques at this point also was fibrous tissue. [6]. WHAT ACUTE LESIONS OCCUR IN THE CORONARY ARTERIES IN PATIENTS WITH SYMPTOMATIC MYOCARDIAL ISCHEMIA, AND HOW FREQUENTLY DO THEY OCCUR IN THE THREE ACUTE CORONARY EVENTS? In recent years considerable effort has been directed toward understanding the acute coronary events that may be responsible for the development of UAP, AMI, and SCD. From angiographic, angioscopic, and autopsy studies it has been speculated that plaque rupture and hemorrhage with overlying intraluminal thrombus, which are the acute lesions usually responsible for AMI, are also responsible for UAP and possibly SCD. Kragel et al. [7] examined 3101 five-millimeter-long segments of 268 epicardial coronary arteries from 67 patients with fatal coronary events. The frequency of intraluminal thrombus was similar in the groups with UAP and SCD (29% in each) and significantly lower than that in the group with AMI (69%). The thrombus was nonocclusive in all patients with UAP and in 5 of 6 patients with SCD, but it was nonocclusive in only four of 22 patients with AMI. The composition of the nonocclusive and occlusive thrombi also was different, that is, the nonocclusive thrombus consisted mainly of platelets, and the occlusive thrombus consisted mainly of fibrin. Plaque rupture was found in 33 (49%) of 67 patients. Its frequency was insignificantly different in the groups with UAP (36%) and SCD (19%); in both groups the frequency was significantly lower than in the group with AMI (75%). Plaque hemorrhage was observed in 27 (40%) of 67 patients, and its frequency was significantly lower in the groups with UAP (21%) and SCD (19%) compared with that in the group with AMI (63%). Multiple small vascular channels were present in 60 (90%) of 67 patients and with an insignificantly different frequency in each of the three groups of patients. Thus comparison of findings from examination of a histologic section from each of 3101 five-millimeter-long segments of 268 major epicardial coronary arteries from 67 patients with fatal coronary artery disease disclosed that the frequency of three acute coronary lesions (intraluminal thrombus, plaque rupture, and plaque hemorrhage) was similar in patients with UAP and SCD and significantly higher in patients with a fatal first transmural AMI. HOW MANY DIRECT ATHEROSCLEROTIC RISK FACTORS EXIST? Several factors have been considered to predispose to atherosclerosis including elevated low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol, systemic hypertension, cigarette smoking, family history of atherosclerotic disease, obesity, diabetes mellitus, and male sex. [8] The key word in the question posed is direct, which can be defined in many ways. If this word is used to mean that this risk factor must be present for atherosclerosis to occur, all but one of these factors can be eliminated. Atherosclerosis of severe degree may occur in individuals with normal blood pressures, in nonsmokers, in nonobese persons, in those with normal glucose metabolism, and in women. Thus these factors are indirect and may worsen the atherosclerotic process, but in the absence of the direct factor they do not cause atherosclerosis. This section examines each of these atherosclerotic risk factors to ask whether it is a direct or independent factor. Elevated serum (or plasma) total cholesterol, LDL cholesterol, and low HDL cholesterol. In my view the only absolute, unequivocal, independent atherosclerotic risk factor is an elevated serum total or LDL cholesterol, a low HDL cholesterol level, or both. [9] What constitutes an elevated total cholesterol level is debated. If an elevated level is that minimal level above which atherosclerotic events occur, then that level would be approximately 150 mg/dl (3.9 mmol/L). If it is the level where the risk of atherosclerotic events is substantially increased compared with lower levels, then that level would be approximately 200 mg/dl. Irrespective of which level is chosen, the higher the level is, the greater is the risk of an atherosclerotic event. From study of more than 350,000 men, Stamler et al. [10] clearly demonstrated that the higher the serum total cholesterol level is, the greater is the risk of an atherosclerotic event. The Framingham study, [11] involving approximately 5000 residents of that Massachusetts community, also showed that the higher the total and LDL cholesterol levels are and the lower the HDL cholesterol level is, the greater the risk is of having an atherosclerotic event. International epidemiologic studies [12] have shown that populations with serum total cholesterol levels less than 150 mg/dl for decades have a near absence of atherosclerotic events. A certain critical serum total cholesterol level is necessary before an atherosclerotic event can occur, and this critical level appears to be approximately 150 mg/dl. As the level increases above this value, the risk of an atherosclerotic event increases roughly proportional to the level and to the amount of time that this level has been present. [13]. In adults in the United States the mean plasma HDL level in men is 45 mg/dl and in women, 55 mg/dl. [14] Data, especially from Framingham, Massachusetts, have shown that high levels of HDL are associated with decreased risk and that low levels are associated with increased risk of atherosclerotic events. [11,15] The evidence is convincing that high HDL is good and low HDL is bad. But what is the risk of a serum HDL level of 20 mg/dl, if the LDL-choresterol is less than 100 mg/dl and the serum total cholesterol is less than 150 mg/dl? The answer is no risk. Is an HDL of 100 mg/dl protective when the total cholesterol is 300 (ratio = 3) and LDL cholesterol is near 200 mg/dl? The answer is probably no. Whether the HDL-cholesterol is an independent risk factor, that is, independent of the LDL-cholesterol level, is not yet clear. It is reasonable to view a low HDL-cholesterol as an additive atherosclerotic risk factor if the LDL-cholesterol is elevated, but not as an additive atherosclerotic risk factor if the LDL-cholesterol is low. Mautner et al. [16] studied a 72-year-old man who had had a coronary bypass operation at age 60 and who during his last 17 years of life had 30 fasting lipoprotein analyses; the serum total cholesterol averaged 70, the LDL cholesterol 45, the triglycerides 45, and the HDL cholesterol 1 mg/dl. Thus severe atherosclerosis occurred despite low LDL and total cholesterol levels and virtually absent HDL cholesterol. The total cholesterol-HDL cholesterol ratio in that patient was 70! Systemic hypertension. In experimental animals given atherogenic diets (high fat, high cholesterol), those previously made hypertensive have more atherosclerotic plaques than do the normotensive animals. Hypertensive persons with total and LDL-cholesterol levels similar to those in normotensive persons have a higher frequency of atherosclerotic events compared with normotensive subjects. These two facts have supported the contention that systemic hypertension is an atherosclerotic risk factor. Most studies describing benefits of antihypertensive therapy have not demonstrated a reduction in coronary or peripheral atherosclerotic events by such therapy. No evidence exists that systemic hypertension accelerates atherosclerosis if the serum total cholesterol level is less than 150 mg/dl. It appears that systemic hypertension is a cholesterol-dependent risk factor, because the serum total cholesterol must be greater than 150 mg/dl before hypertension has the ability to accelerate atherosclerosis, and therefore hypertension is not an independent atherosclerotic risk factor. Although evidence implicating systemic hypertension as a direct atherosclerotic risk factor is lacking, systemic hypertension clearly is the major risk factor for development of stroke and aortic dissection. [17] These two lesions are not atherosclerotic-dependent. The prime effect of hypertension is on the media of arteries, causing this arterial layer to tear, dissect, or rupture. Atherosclerosis is an intimal process, and only indirectly is the media affected. Cigarette smoking. Although it is incompatible with good health, cigarette smoking does not in and of itself produce atherosclerotic plaques. In populations where serum total cholesterol levels are less than 150/mg/dl, atherosclerotic events are rare, even when cigarette smoking is widespread. In Japan cigarette smoking is common, but atherosclerotic events are relatively uncommon. The average serum total cholesterol in adults in Japan is approximately 170 mg/dl, which is not a level associated with a high frequency of atherosclerotic events. Many Japanese adults have serum total cholesterol levels less than 150 mg/dl. In populations where the average serum total cholesterol level in adults is greater than 200 mg/dl, such as the United States, smoking cigarettes appears to accelerate atherosclerosis, but this acceleration appears to be a cholesterol-dependent phenomenon. Family history. When atherosclerotic events occur in persons younger than 55 years of age, it generally means (1) that the affected individuals have serum total cholesterol levels considerably higher than persons of similar age and sex without atherosclerotic events, and (2) that the affected individuals have total cholesterol levels much higher than those found in older individuals with atherosclerotic events. In persons with untreated familial hypercholesterolemia of the heterozygous type, the serum total cholesterol level is usually 300 to 400 mg/dl, and these individuals usually have atherosclerotic events when they are 31 to 50 years of age. [18,19] In untreated individuals with familial hypercholesterolemia of the homozygous variety, the serum total cholesterol is usually greater than 800 mg/dl, and these individuals usually have atherosclerotic events before they are 20 years of age. [18,19] Thus individuals who have atherosclerotic events before the age of 50 years generally have higher total LDL cholesterol levels than do individuals who have atherosclerotic events later in life, and the genetic forms of hyperlipidemia are primarily in these younger groups. An atherosclerotic event occurring in a young person simply denotes very high serum total cholesterol levels, and it is the cholesterol level, not the patient's age or the presence of atherosclerotic events in other family members, that is the villain. Severe obesity. In general, obese persons have higher total and LDL-cholesterol levels than do nonobese persons of similar age and sex. [20] This fact is of course not surprising, because obese persons eat more fat than do nonobese persons. Although few exist to study, I am not aware that obese adults with serum total cholesterol levels less than 150 mg/dl have any risk of development of atherosclerotic events. Thus obesity is a cholesterol-dependent risk factor, not an independent risk factor. Diabetes mellitus. Juvenile diabetic patients clearly have more atherosclerotic plaques and a higher frequency of atherosclerotic events than do nondiabetic patients of similar age and sex. [21,22] But the juvenile diabetics usually have higher serum total and LDL-cholesterol and lower HDL-cholesterol levels than do their nondiabetic counterparts. Likewise adult-onset diabetics have more atherosclerosis and a higher frequency of atherosclerotic events than do nondiabetics of similar age and sex. [23] Moreover, the adult-onset diabetics have higher serum total and LDL-cholesterol, triglyceride, and lower HDL-cholesterol levels than do their nondiabetic counterparts. [24] No evidence exists that diabetics who have serum total cholesterol levels less than 150 mg/dl have an increased frequency of atherosclerotic events compared with nondiabetic counterparts with similar cholesterol levels. Indeed, no evidence exists that diabetics with low serum total cholesterol levels have atherosclerosis of any significance. Thus diabetes mellitus also appears to be a cholesterol-dependent risk factor. Male sex. As many women as men die from atherosclerotic events. The average age of death from atherosclerotic coronary artery disease in men (without angioplasty or bypass) is 60 years; in women it is 68 years. [25,26] Men have higher total and LDL serum cholesterol levels earlier in life than do women, but later in life women have higher levels than do men. [27] Neither men nor women, however, have atherosclerotic events unless the total cholesterol level is greater than 150 mg/dl, and the higher the level is, the greater is the chance of an event, and the earlier the event occurs irrespective of sex. Thus it is the person's blood cholesterol level, not the sex, that determines whether an atherosclerotic event occurs. Therefore male sex cannot be viewed as an independent atherosclerotic risk factor. WHAT FACTORS INDICATE THAT CHOLESTEROL CAUSES ATHEROSCLEROSIS? Although the relation between cholesterol and atherosclerosis has been discussed for nearly 90 years, only in recent years has sufficient evidence accumulated to indicate without reasonable doubt that cholesterol plays a major role in the development of atherosclerotic plaques. This section reviews the various factors linking cholesterol to atherosclerosis: 1. Feeding high-cholesterol diets to certain animals produces atherosclerotic plaques similar to those in human beings. The initial connection between cholesterol and atherosclerotic plaques began in 1912, when Anitschkow [28,29] reported finding atherosclerotic plaques similar to those occurring in humans in rabbits fed diets high in cholesterol. (This was the same year that James Herrick [30] first reported that acute myocardial infarction could be diagnosed clinically and that it was not always immediately fatal.) Subsequently atherosclerotic plaques were produced also in other animals (guinea pig, chicken, monkey) by feeding them high-cholesterol diets. [29] Anitschkow, from his experiment, laid down the dictum that increased cholesterol in the blood was the inciting cause of atherosclerosis. It is not possible to produce atherosclerosis in a carnivore (dog, cat, lion, tiger) no matter how much fat or cholesterol is provided, unless the thyroid gland is excised before the atherogenic diet is initiated. Feeding humans a diet high in fat and cholesterol obviously readily produces atherosclerotic plaques. This fact suggests that humans basically are herbivores. 2. Cholesterol is found in both experimentally induced atherosclerotic plaques in nonhuman animals and in plaques in human beings. Three main types of lipid accumulate in atherosclerotic lesions: free sterols (almost exclusively cholesterol), cholesterol esters (mainly cholesteryl linoleate, oleate, and palmitate), and phospholipids (mainly phosphatidylcholine and spingomyelines). [31] All three lipids are insoluble in water. These lipids make up approximately 95% of the total lipids in both normal intima and in atheromatous plaques. The lipids present in small amounts include triacylglycerols, fatty acids, and lysophospholipids. Cholesterol esters are nearly absent in newborn intima, but they are a major part of atherosclerotic plaques. [31] Triglycerides are lowest in newborn intima, and they never become a major component of plaques, although they rise to 6% in the gruel-like material of plaques. [31]. 3. Atherosclerotic plaques large enough to produce clinical problems occur only in persons with serum or plasma total cholesterol levels greater than 150 mg/dl for long periods of time. Most native African, Latin American, and oriental populations have a low frequency of coronary atherosclerosis. [12,32] Their diets are low in saturated fat, cholesterol, and animal protein. Most adults in these populations have serum total cholesterol levels less than 150 mg/dl. Fatal atherosclerotic vascular disease in the United States is rare in anyone with a serum total cholesterol level less than 150 mg/dl for many years. In the United States, however, only 5% of the population older than 40 years of age has a serum or plasma total cholesterol level less than 150 mg/dl. [33]. 4. The higher the blood total cholesterol level is, the greater is the chance of having symptomatic and fatal atherosclerotic disease. Although the Framingham, [34] the "Seven Countries," [12,32] and the Israeli [35] studies have demonstrated that persons with higher serum total cholesterol levels have higher incidences of atherosclerotic disease than do persons of similar age and sex with lower levels, in my view the best study demonstrating the relation between serum total cholesterol level and symptomatic or fatal atherosclerotic disease is the Multiple Risk Factor Intervention Trial (MRFIT) [10] (Table I). The reason is that MRFIT involved more than 350,000 persons, whereas the seven-country study involved just more than 12,000 men from each of seven nations and the Framingham study, 5127 persons. The 356,222 persons without clinical evidence of coronary artery disease sampled in the MRFIT study were divided into deciles on the basis of their serum total cholesterol levels. The 6-year coronary-artery-disease mortality rate per 100 persons increased as the serum total cholesterol level increased. This study shows dramatically that the serum total cholesterol level is a quantity and that the greater the quantity is, the greater is the risk of symptomatic and fatal coronary artery disease. ---------------------------------------------- Table I. Deciles of serum total cholesterol and 6-year coronary artery disease mortality rate in 356,222 primary screenees (all men 35 to 37 years of age in 1973 to 1975) of the Multiple Risk Factor Intervention Trial* ---------------------------------------------- Persons with enormously elevated (6 to 10 times normal) LDL cholesterol levels usually die of consequences of atherosclerosis in the first 2 decades of life. [11,12,36,37] These individuals have familial hypercholesterolemia of the homozygote variety. They inherit two mutant genes at the LDL receptor locus, one from each parent, and approximately one in 1 million persons have this abnormality. The heterozygous variety of familial hypercholesterolemia has a twofold increase in blood LDL levels, and these individuals often have fatal heart attacks in their 30s and 40s. Approximately one in every 500 persons among most ethnic groups throughout the world have familial hypercholesterolemia of the heterozygous variety. Both the homozygous and heterozygous varieties of familial hypercholesterolemia provide strong evidence that persons with severe elevations of serum LDL and total cholesterol levels have both symptomatic and fatal coronary artery disease at much earlier ages than do persons with lower levels. 5. The higher the serum total and LDL cholesterol levels are, the greater is the extent of the atherosclerotic plaques. The International Atherosclerosis Project quantified the extent of coronary and aortic atherosclerotic plaques at necropsy in 23,207 persons in 14 countries. [38] The extent of the atherosclerotic plaques differed markedly among populations, and the mean serum total cholesterol level correlated positively with the severity of the atherosclerotic plaques. The severity of the atherosclerotic plaques in aorta also correlated positively with the percent of dietary calories from fat. [39]. 6. Lowering the blood total cholesterol and LDL cholesterol levels decreases the chances of fatal or nonfatal atherosclerotic disease. Two studies, the Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) (cholestyramine) [40-43] and the Helsinki Primary Prevention Trial (gemfibrozil), [44-45] provided evidence that lowering the blood total and LDL cholesterol levels reduces the frequency of fatal and nonfatal coronary artery disease. Both studies were randomized, double-blind, placebo-controlled, multicenter, primary prevention trials analyzed by the intention-to-treat method. The LRC trial included 3806 men 35 to 59 years of age (mean 48 years) at entry with plasma total cholesterol levels greater or equal to 265 mg/dl (after dieting); half the subjects received cholestyramine (24 gm a day) and the other half, placebo (24 gm a day). All subjects underwent follow-up for a minimum of 7 years and up to 10 years (mean 7.4 years). The cholestyramine group (1899 men) had average total and LDL cholesterol reductions at the end of the first year of 18% (292 --> 239 mg/dl) and 28% (216 --> 159 mg/dl), respectively, and by the end of the seventh year of 12% (292 --> 257 mg/dl) and 19% (216 --> 175 mg/dl), respectively. In contrast, the placebo group (1907 men), also on a cholesterol-lowering diet, had average total and LDL cholesterol reductions at the end of the first year of 6% (292 --> 275 mg/dl) and 8% (216 --> 199 mg/dl), respectively, and by the end of the seventh year of 5% (292 --> 277 mg/dl) and 9% (216 --> 198 mg/dl), respectively. The primary end points, fatal coronary artery disease or nonfatal acute myocardial infarction, were reduced 19%, which is the difference in the cumulative 7-year incidence of the primary end point, which was 7% in the cholestyramine group (133 of 1899 men) and 8.6% (164 of 1907 men) in the placebo group, or the difference in the cumulative rate of cardiac end points at 7 years of 70 of 1000 in the cholestyramine group and 86 of 1000 in the placebo group. In addition, other cardiovascular events also decreased in the cholestyramine group compared with the placebo group: positive exercise test results fell 25% (260[14.9%] vs 345 [19.8%]); angina pectoris fell 18% (235[12.4%] vs 287 [15.1%]); and need for coronary artery bypass grafting fell 17% (93[4.9%] vs 122 [5.9%]). The Helsinki trial included 4081 men 40 to 55 years of age (mean 47 years) at entry with serum non-HDL cholesterol greater than 200 mg/dl. The mean serum total cholesterol for the 4081 men was 290 mg/dl, and the mean HDL cholesterol was 48 mg/dl. Half of the subjects received gemfibrozil (1.2 gm/day) and the other half, placebo (1.2 gm/day). All subjects underwent follow-up for a minimum of 5 years. The gemfibrozil group had average total and LDL cholesterol reductions during both the first 2 years and during the last 3 years of study of 9% (270 --> 245 mg/dl) and 9% (189 --> 173 mg/dl), respectively. The HDL cholesterol rose during both the first 2 years and the last 3 years of study by 9% (47 --> 52 mg/dl). In contrast, the placebo group, also on a cholesterol-lowering diet, had no change in either serum total (270 --> 273 mg/dl) or LDL cholesterol (48 --> 47 mg/dl) during the entire 5 years of the trial. The primary end points, fatal coronary artery disease or nonfatal acute myocardial infarction, were reduced 34%, which is the difference between the 2.7% incidence of primary end points in the gemfibrozil group (56 in 2051 men) and the 4.1% incidence in the placebo group (84 in 2030 men), or the difference in the cumulative rate of cardiac end points at 5 years of 27 of 1000 in the gemfibrozil group and 41 of 1000 in the placebo group. Thus both the LRC and Helsinki primary prevention trials demonstrate that lowering the blood total and LDL cholesterol levels reduces the incidence of fatal and nonfatal coronary artery disease. The trials, when analyzed by the intention-to-treat method, showed that every 1% reduction in serum total cholesterol resulted in a 2% reduction in heart attack frequency during a 5- to 7-year period. If the trials had been analyzed by comparison of those who actually took the drugs in the prescribed amounts with those who did not take the drugs, the studies would have shown at least a 3% reduction in heart attack frequency for every 1% reduction in serum total cholesterol (Figure 1). ---------------------------------------------- Figure 1. Effect of increasing or decreasing serum total cholesterol level on frequency of fatal coronary artery disease or nonfatal acute myocardial infarction. These data are derived primarily from Helsinki heart study. For every 10% decrease in serum total cholesterol, there is 30% decrease in heart attack frequency. The reverse also is true. For every 10% increase in serum total cholesterol, there is 30% increase in frequency of heart attack. ---------------------------------------------- 7. Atherosclerotic plaques may regress or fail to progress when high total and LDL cholesterol levels are lowered. Several experimental studies in animals have shown that atherosclerotic plaques regress when blood lipid levels fall after atherogenic diets are eliminated. [46] Several studies, most published this decade, in humans have demonstrated that lipid-lowering retards the rate of progression of angiographically demonstrated coronary arterial narrowing, causes reduction in size of atherosclerotic plaques, or both, (Figure 2) as indicated by increased luminal diameters, and it usually decreases the frequencies of recurrences of atherosclerotic events. [47-62] For plaque progression to cease, it appears that the serum total cholesterol needs to be lowered to the 150 mg/dl area. In other words the serum total cholesterol must be lowered to that of the average pure vegetarian. Because relatively few persons are willing to abide by the vegetarian lifestyle, lipid-lowering drugs are required in most to reach the 150 mg/dl level. ---------------------------------------------- Figure 2. Mechanism of plaque regression. Left, Drawing of coronary artery that is narrowed > 75% in cross-sectional area by atherosclerotic plaque. Most of the plaque consists of fibrous tissue, and it is unlikely that fibrous tissue is reversible. Lipid portion, however, may shrink if serum total and LDL cholesterol levels are substantially reduced, probably down to the 150 mg/dl area. If lipid portion shrinks, lumen may widen as is shown in right portion of diagram. Unless lumen is narrowed > 75%, flow is not reduced. Thus opening lumen so that it is ---------------------------------------------- In summary, seven factors provide evidence that elevation of the blood total (specifically the LDL) cholesterol level is the cause of atherosclerosis. There no longer is any controversy about cholesterol's role in atherosclerosis. In my view physicians should provide a clear and united voice to the public regarding the dangers of elevation of the blood LDL cholesterol level. Every person needs to know his or her serum or plasma total cholesterol level, and if it is elevated, every attempt should be made to lower it. The most effective means of improving the health of the largest percent of Americans is for each to lower his or her LDL cholesterol level. HOW CAN SYMPTOMATIC ATHEROSCLEROSIS BE PREVENTED OR, IF PRESENT, ARRESTED? To prevent symptomatic or fatal atherosclerosis in those persons whose serum total cholesterol is approximately 150 mg/dl, this level must be prevented from rising, and to prevent symptomatic or fatal atherosclerosis in those persons with elevated serum total cholesterol levels, the level must be reduced to the 150 mg/dl area. The best news about atherosclerosis is that it can be prevented in 499 of 500 persons by keeping the total cholesterol in the 150 mg/dl area and that it can be arrested by lowering an elevated level to the 150 mg/dl level. The mean serum total cholesterol of umbilical blood of newborns is approximately 75 mg/dl (1.9 mmol/L). Within 2 weeks of life that value rises to a mean of 150 mg/dl (3.9 mmol/L) and remains at that level until approximately age 20 years, when it gradually starts to rise. The average serum total cholesterol level in the United States in persons 20 to 74 years of age is 215 mg/dl, and the average in persons in coronary care units with acute myocardial infarction is 225 mg/dl. [63] Men have higher levels earlier in life, and women, in later life. Nearly 50% of women in the United States older than 60 years of age have serum total cholesterol levels greater than 240 mg/dl (> 6.2 mmol/L), and 25% of the U.S. population 20 to 74 years of age have serum total cholesterol levels greater than 240 mg/dl; 5% have levels greater than 265 mg/dl (> 6.9 mmol/L). [27]. HOW CAN NORMAL SERUM CHOLESTEROL LEVELS BE PREVENTED FROM RISING, AND HOW CAN ELEVATED LEVELS BE LOWERED TO NORMAL? To keep a normal cholesterol level normal and to return an elevated level to normal, dietary intake of cholesterol, fat, and total calories must be restricted or one or more lipid-lowering drugs must be administered, or both. Cholesterol intake. The average adult in the United States consumes approximately 500 mg of cholesterol daily. To picture 500 mg, hardly a calorie, a toothpick may be useful. The average toothpick weighs approximately 100 mg, so we consume the equivalent of five toothpicks of cholesterol daily. Dietary cholesterol, of course, is derived exclusively from animals and their products, so limiting their intake automatically reduces the intake of cholesterol. Nearly 50% of the direct cholesterol consumed by adults in the United States comes from the visible and nonvisible eggs eaten, so giving up eggs eliminates nearly half of our direct cholesterol intake. Bovine muscle ("beef") accounts for nearly 30% of our direct cholesterol intake, so giving up these two items along with other bovine products (butter, cheese, milk) essentially eliminates the direct cholesterol intake problem. Men and women in the United States consume similar amounts of cholesterol, but through slightly different sources: men consume more meat, and women more cheese. Cholesterol contents of most flesh eaten by human beings is similar in amounts of cholesterol. A 100 gm portion of muscle from cows, pigs, deer, chicken, turkey, and fish each contains approximately 85 mg of cholesterol, and thus switching from one flesh to another has little impact on cholesterol intake. Fish is advantageous in that it contains relatively little fat, whereas the muscle of cows and pigs, at least those raised in the United States, is laden with fat. Fat intake. Most adults in the United States consume more than 100 gm of fat daily; many consume more than 150 gm daily. None of us should consume more than 75 gm of fat daily--the equivalent of a deck of cards--and ideally men should consume no more than 60 gm and women no more than 50 gm of fat daily. There are two problems, of course, with fat: (1) all fats possess a saturated component, and (2) all fats are high in calories. All fatty acids contain a polyunsaturated component, a monounsaturated component, and a saturated component. A polyunsaturated fat is one in which polyunsaturated component is dominant, and the remainder is divided between the monounsaturated and saturated components; a monounsaturated fat is one in which the monounsaturated component is dominant. The saturated fatty acids (coconut oil, palm kernel oil, beef fat) raise the serum total cholesterol level, and the polyunsaturated (safflower, cottonseed, corn, sesame, soybean, fish oils) and monounsaturated (olive, peanut, avocado) fatty acids either lower the level or have a neutral effect on the total cholesterol level. The reason the saturated fat component is so dangerous is that it is essentially converted into cholesterol as it is broken down in the body. Thus for an individual who consumes 120 gm of fat daily, usually approximately 40 gm of that is saturated, and when that 40 gm enters the body, it is essentially converted into cholesterol. The saturated fat can be identified by its being solid at room temperature; the polyunsaturated and monounsaturated fats are soft or liquid at room temperature. All three fatty acids are very high in calories (9 calories/gm). Although there are many sources of fat in contrast to the relatively few sources of direct cholesterol, a major source (approximately 30%) is flesh, primarily because of the way cattle are raised in the United States. Cows for slaughter in the United States are placed in feed lots their last 4 to 6 months of life, and there they are fed 20 to 25 pounds of various grains and soybeans each day. The purpose of this heavy feeding is to make the animals fat so that they taste better when cooked. Then once they are fat enough, we kill the cows, and then they kill us! This cycle is the merry-go-round of unhealthiness. Fast-food restaurants. One of the easiest means of rapidly acquiring a heavy dose of fat and cholesterol is the fast-food restaurant. [64,65] In the United States $5 of every $10 spent on restaurant food is spent at a fast-food restaurant. More than 160,000 fast-food restaurants are available in the United States, and more than $70,000,000,000 (10 zeros) are spent at them each year. The fast-food restaurants outnumber the traditional restaurants in the United States. One of five persons in the United States visits a fast-food restaurant every day, and four of five every month. Fast-food restaurants are located in hospitals, zoos, military bases, college campuses (including dormitories), museums, airports, naval ships and boats, bus stations, amusement parks, private-office and state-government buildings, and department stores. Mobile (restaurants on wheels) fast-food restaurants visit neighborhoods, playgrounds, and beaches. More than 50% of the population of the United States lives within 3 minutes of a McDonald's. McDonald's alone has employed more than 8 million workers, 7% of the U.S. work force, and it has replaced the U.S. Army as America's largest job-training organization. McDonald's alone is the world's largest owner of commercial real estate. The FAST FOOD GUIDE by Jacobson and Fritschner [66,67] has detailed the amounts of calories, fat, sodium, sugar, and other "nutrients" in the foods and liquids sold by the 15 largest fast-food chains in the United States. The champion hamburger at the moment is Carl's Double Western Bacon Cheeseburger, which contains 1030 calories, 14 teaspoons of fat, and 1800 mg of sodium. This dandy is truly the coronary artery bypass special! It is quickly followed by Jack in the Box Ultimate Cheeseburger and the Burger King Double Whopper with Cheese. The Burger King Chicken Sandwich, the bird champ, contains nearly 700 calories, 9 teaspoons of fat, and 1415 mg of sodium. Carl's Jr. Carl's Fish Sandwich, the champ of the fish, contains 560 calories, 7 teaspoons of fat, and 1220 mg of sodium. Arby's 5-ounce french fries contain nearly 500 calories. The Dairy Queen Health Blizzard, regular, the champ of shakes and malts, contains 820 calories, 8 teaspoons of fat, 410 mg of sodium, and 14 teaspoons of sugar. Taco Bell Taco Salad with shell, the salad champion, contains 905 calories, 14 teaspoons of fat, and 910 gm of sodium. Thus these fast foods lead to quick plaques! Mexican food. And the Mexican foods are no better. [68,69] A Chicken Burrito dinner (cheese-topped flour tortilla stuffed with chicken and refried beans) contains enough sodium for 1.5 days. A Chile Relleno dinner (cheese-stuffed, deep-fried pepper, topped with cheese and red sauce) contains as much saturated fat as 27 slices of bacon and is much fattier than a cup of Haagen-Dazs Extraans Cookie Dynamo ice cream. Two Crispy Chicken Tacos (crisp corn tortillas stuffed with chicken, cheese, lettuce, and tomato) with refried beans and rice amount to 1042 calories, 36% of which come from fat, a total of 42 gm of fat including 13 gm of saturated fat and 2260 mg of sodium. Two Soft Chicken Tacos with refried beans and rice are just as bad: 1022 calories, 38% of which come from fat; a total of 43 gm of fat including 15 gm of the saturated variety, and 2690 mg of sodium. Two Chicken Enchiladas (chicken and cheese in an oil-dipped corn tortilla) total 1264 calories, 40% of which come from fat; a total of 57 gm of fat, 19 gm of which are saturated, plus 2855 mg of sodium! Two Beef Enchiladas with beans and rice amount to 1253 calories, 42% of which come from fat, a total of 58 gm of fat, 16 gm being saturated, plus 2880 mg of sodium. The appetizers and side dishes are not much better. The Mexican Rice (3/4 cup), sauted in oil or shortening before it is cooked in sodium-soaked chicken broth, is 15% fat, and Refried Pinto Beans (3/4 cup) contains nearly 40% more calories than the rice, and 39% of the 375 calories come from fat. The only dish considered decent enough to recommend is chicken fajitas but without the beans, sour cream, and guacamole. Unlike Chinese or Italian restaurant food, it is tough to make Mexican dishes less fatty and less salty. Foods and liquids consumed in 1 day in the United States. The total quantity of calories, fat, and cholesterol eaten by American adults each day is mind-boggling. As estimated by Parker [70] 10 years ago and summarized elsewhere, [71] our daily oral intake includes some of the following (this was in 1984 when the U. S. population was 236 million, not 260 million like today): approximately 815 billion calories of food are consumed, roughly 200 billion more than we need to maintain a moderate level of activity enough extra calories to feed everyone in Mexico, a country in 1984 of 80 million people). Approximately 100 million cows live in the United States, and nearly 100,000 of them are herded into slaughterhouses, where they leave 60 million pounds of red meat and nearly 4 million square feet of hide. Every day approximately 250,000 hogs and 17,700 lambs and sheep are butchered. More than 4 million pounds of bacon are eaten every day. Every day approximately 1.5 million pounds of lard (hog fat) and 47 million hot dogs (smoked sausage of beef or beef and pork) are eaten daily. McDonald's restaurants serve the equivalent of 2250 head of cattle daily. Dairy cows in the United States produce 47 million gallons of milk daily, 19 of which are used as liquid milk, and the rest as cheese, yogurt, and other dairy products. We eat 12.5 million pounds of cheese, including 85,000 pounds of blue cheese, 700 pounds of cream cheese, 650,000 pounds of Swiss, cheese and 5.8 million pounds of cheddar cheese. Americans eat 170 million eggs and 12 million chickens every day! Americans smoke 85 million packs of cigarettes. If one cigarette deducts 5.5 minutes of life from the smoker, collectively, Americans shorten their lives by 18,000 years every day. We fill 85,000 bushels with cigarette butts. Four thousand children and teenagers take up smoking each day. Excessive body weight. The tremendous quantity of fat consumed in the United States displays itself by the largeness of our society. In 1990 60% of Americans 18 years of age and older were considered overweight, and 30% were frankly obese (> 20% above ideal body weight). No society has ever been as overweight as the present U. S. one. And the percent overweight continues to increase. [72] Adults in the United States in 1993 gained 155 million pounds. A survey in 1991 showed an average weight loss of 10 pounds for adults in the United States; in 1993 a similar poll showed an average gain of 2.1 pounds. Four national surveys between 1960 and 1991 of 6000 to 13,000 adults in the United States showed that 33% were overweight (> 120% of desirable weight) during the last survey (1988 to 1991). Overweightness frequency increased 8% between the 1976 to 1980 and the 1988 to 1991 surveys. The mean body weight during this approximate 10-year period increased 8 pounds (3.6 kg)! For the first time in 15 years, neither losing weight nor stopping smoking was the number 1 New Year's resolution in 1994. Instead, people are most concerned with managing their personal finances better. According to the National Cattlemen's Association, beef production is increasing: 23 billion pounds in carcass weight in 1993 and an increase to nearly 24 billion in 1994. Per capita beef consumption in the United States, as measured by retail weight, lags behind chicken by 68.7 to 65.6 pounds. Beef consumption, however, if measured by "boneless edible weight," leads chicken consumption by a wide margin, 62.2 to 48.0 pounds. There is no better monitor for fat consumption than body weight. The first road to health is the maintenance of ideal or near ideal body weight. The more we weigh, the sooner we die. [73] All of us can identify the exception, such as Sir Winston Churchill, but he was an exception. Physicians need to set the example here. And losing weight is so difficult! A pound of body fat contains approximately 3500 calories. To lose 1 pound of fat, 3500 more calories must be burned than consumed. One pound can be lost each week by burning 500 more calories each day than consumed. Because walking or running a mile each consumes about 400 calories, combining exercise with reduced calorie consumption may speed weight reduction. Calculating the percentage of calories from fat and the grams of fat consumed daily to maintain an ideal body weight. To help maintain or achieve an ideal or near ideal body weight, it is useful to know how many calories are permissible each day. [74] Most adults in the Western world need from 11 to 18 calories per pound per day to sustain an ideal weight: 11 for the near sedentary individual (+), 13 for the moderately active (++), 15 for the moderate exerciser or physical laborer (+++), and 18 for the extremely active exerciser of physical worker (++++). Table II lists the calories needed in both women and men at the various activity levels to maintain an ideal body weight, and Table III lists the maximal grams of fat allowed with four different percentage-of-calories-from-fat diets. Because I am 6-feet-tall and like to weigh no more than 170 pounds and am moderately active (++), I need approximately 2300 calories daily: a 30%-of-calories-from-fat diet for me would be 690 calories from fat (2300 x 0.30); at 20% fat, 460 calories, (2300 x 0.20) and at 10% fat, 230 calories (2300 x 0.10). Given the new food-labeling regulations, which provide grams of fat on food labels, it is better to calculate the grams of fat rather than the percentage of calories from fat in each of the various percentage-of-calories-from-fat diets. Thus the maximal grams of fat I should consume can easily be determined by dividing by 9 (the number of calories in 1 gm of fat) the number of calories derived from fat were I to consume a 30% (690 [divided by] 9 = 75 gm), a 20% (460 [divided by] 9 = 50 gm), or a 10% (230 [divided by] 9 = 25 gm) calories-from-fat diet. Total calories is the important factor from the standpoint of body weight, but fat calories or fat grams is the important item from the standpoint of atherosclerotic disease. If all of us consumed no more than 25 gm of fat daily, none of us would have atherosclerosis of clinical significance, but unfortunately few of us are pure vegetarians, a near requirement to maintain a 25 gm fat intake. At 50 gm of fat daily (a little ---------------------------------------------- Table II. Calories needed daily to sustain ideal body weight ---------------------------------------------- ---------------------------------------------- Table III. Maximal grams of fat allowed with four different percent-of-calories-from-fat diets ---------------------------------------------- Flesh consumption. If clinically significant atherosclerosis is to be prevented or arrested, the amount of fat consumed must be diminished. An easy way to decrease fat consumption is to decrease flesh consumption. The ideal of course is a pure vegetarian-fruit diet that provides no more than approximately 10% of calories from fat. Not many persons in the Western world are desirous, however, of becoming vegetarians (either pure [vegans] or ovolacto-type), but that should be our goal. For atherosclerotic health to improve, however, at least the quantity of flesh consumed must be decreased. With 21 meals a week, we must make more of them meatless. The type of flesh consumed also must be altered. Bovine and porcine muscle are the most heavily laden with fat, and therefore their quantity must be decreased the most. In general, the higher the grade of meat is, the more fat it contains. Regardless of the grade or cut, the fat of all red meats is predominantly saturated (approximately 45% of the fat), and only 2% of the fat is polyunsaturated. Ground beef contributes more saturated fat to the average American diet than any other single food. The fat-ladened skin of chickens and turkeys must be avoided. Fish is the preferred flesh because it contains relatively little fat (and because its consumption has the least unfavorable effects on our environment.) [75-82] Fish also contains some potentially favorable fatty acids in contrast to that in the muscle of cows, pigs, chickens, turkeys, sheep, etc. Additionally, we need to avoid snacks between meals, because many of them are laden with fat and calories, and desserts, except on special occasions. Calories just before bedtime are rarely fat- or calorie-friendly. Characteristics of carnivores and herbivores. Human beings basically are not carnivores. [83] If several characteristics of carnivores and herbivores are compared, human beings clearly have more characteristics of herbivores than carnivores. The appendages of carnivores contain claws; those of herbivores, hands or hoofs. The teeth of carnivores are sharp; those of herbivores, mainly flat (for grinding). The intestinal tract of carnivores is short; that of herbivores is long. (The small intestine of humans is 26 feet long!) Carnivores lap fluids; herbivores sip them. Carnivores cool their bodies by panting; herbivores, by sweating. Carnivores make their own vitamin C; herbivores obtain their vitamin C from their diet. Most human beings believe themselves to be carnivores (we eat flesh), but fundamentally our characteristics more closely resemble the herbivores. Foods intended for homo sapiens probably are only three: starches (rice, corn, potatoes, beans, and pasta), vegetables, and fruits. Diseases infrequent in vegetarians. Human beings who eat exclusively a vegetarian-fruit diet for many decades (assuming that consumption of the fatty acids high in saturated fat are avoided--coconut oil, palm kernel oil) infrequently have the diseases so commonly observed in human meat eaters. [77] Diseases very uncommon in vegetarians include atherosclerosis; systemic hypertension (at least 60 of the 160 million persons in the United States older than 20 years of age have systemic arterial pressures > 140/90 mm Hg); cancer of the breast and colon, and possibly cancer of the prostate gland; diabetes mellitus (with onset after age 50 years); obesity; peptic ulcer, appendicitis, diverticulitis, and irritable bowel syndrome; osteoporosis and osteoarthritis; gallstones and kidney stones; and salmonellosis and trichinosis. Diets and diseases of our stone-age ancestors. Most diseases that vegetarians do not get were apparently also rare or very uncommon among our stone age or Paleolithic ancestors and also among the few remaining groups of hunters-gatherers still living on Earth. Eaton et al. [81,84] have made some observations about our stone-age ancestors, and some are summarized as follows [85]. Lack of genetic change. The gene pool has changed little since anatomically modern human beings, Homo sapiens sapiens, became widespread approximately 30,000 years ago. From a genetic standpoint current humans are still late Paleolithic preagricultural hunters-gatherers. We have stone age bodies in an atomic age. Our genetic makeup was selected, over geologic eras, ultimately to fit the lifestyle of Paleolothic humans. Enormous environmental change. The increasing industrialized affluence of the last 200 years has affected health both beneficially and adversely. Improved housing, sanitation, and medical care have ameliorated the impact of infection and trauma, the chief causes of death from the Paleolithic era until 1900. The result is that average life expectancy is now approximately double what it was for preagricultural humans. Concomitantly, the past century has accelerated the biologic estrangement that has increasingly differentiated humans from other mammals for more than 2 million years. In today's Western nations we have little need for exercise, but we consume foods quite different from those available to other mammals and expose ourselves to such harmful agents as alcohol and tobacco. We have crossed an epidemiologic boundary and entered a watershed in which disorders such as atherosclerosis, systemic hypertension, obesity, diabetes mellitus, and certain cancers have become common in contrast to their rarity or near nonexistence among remaining preagricultural humans. The late Paleolithic lifestyle. The period 35,000 to 20,000 years ago is the last time period during which the collective human gene interacted with bioenvironmental circumstances typical of those for which it had been originally selected. Thus the diet, exercise patterns, and social adaptions of that time have continuing relevance today. Nutrition. The dietary requirement of all stone age persons were met exclusively by uncultivated vegetables and wild game. The amount of protein was great, probably 33% of calories, compared with the current American diet, which derives 12% of its calories from protein. Because game animals are lean, Paleolithic people ate much less fat than Americans and Europeans do today. Stone Age people ate more polyunsaturated than saturated fat. Their cholesterol intake equaled or exceeded that now common in industrialized nations. Stone Age people ate much more dietary fiber than do most Americans. They obtained far more potassium than sodium from their food (as do all other mammals). Because they had no domesticated animals, they had no dairy foods; despite this fact, their calcium intake far exceeded that consumed today. Physical exercise. The hunter-gatherer way of life generated high levels of physical and aerobic fitness. Strength and stamina were characteristic of both sexes at all ages. The hunters-gatherers were stronger and more muscular than succeeding agriculturalists. Alcohol. Alcoholic beverages were infrequently consumed, and those available, all products of natural fermentation, were far less potent than present-day distilled liquors. Solitary, addictive drinking apparently did not occur. Tobacco. Tobacco was practically unavailable until agriculture appeared in the Americas approximately 5000 years ago. Pipes and cigars were the only methods used for smoking until approximately 1850, when cigarettes first appeared. The major impact of tobacco abuse is a postcigarette phenomenon. Effects of changes in lifestyle on disease prevalence. The three chief killers of the Stone Age humans were childbirth and diseases of infancy, infection (particularly parasitism), and trauma. Obesity. Stone Age human beings were lean, and leanness today in the Western world is nearly the exception. Most food today is calorically concentrated in comparison with the wild game and uncultivated fruits and vegetables that constituted the Paleolithic diets. In eating a given volume, enough to create a feeling of fullness, Paleolithic humans consumed fewer calories than those consumed in a similar volume in the Western world today. Most beverages consumed today provide a significant caloric load. Paleolithic human beings, in contrast, drank water. Energy expenditure, that is, calories burned by modern human beings, is much less than by the Stone Age humans. Atherosclerosis. Present-day preliterate societies have little or no atherosclerosis. Like our Paleolithic ancestors, they rarely use tobacco, are normotensive, have low serum total cholesterol levels, and are physically active. The adverse changes that occur in atherosclerotic risk factors when people from societies with little such disease become westernized recapitulate the patterns observed for other diseases of civilization. The present-day remaining hunter-gatherers and the other remaining preliterates (rudimentary horticulturists, simple agriculturists, and pastoralists) consume diets low in total fat with more polyunsaturated than saturated fatty acids (a higher polyunsaturated than saturated fat ratio) but with an amount of cholesterol similar to that in the current American diet (500 mg). Because the fibrinolytic activity of blood and platelet aggregation are enhanced by physical activity but decreased by cigarette smoking, obesity, and hypercholesterolemia, the preliterate peoples also have more such activity and less platelet aggregation than do average Westerners. Systemic hypertension. There are still several cultures on earth whose members do not have essential hypertension and whose blood pressure does not rise with age. When people living in these remaining preliterate cultures, however, adopt a Western lifestyle, either by migration or acculturation, they first have a tendency for their blood pressure to rise with age and then an increasing tendency to have systemic hypertension. The diets of these normotensive preliterates are low in sodium, high in potassium, high in calcium, and low to absent in alcohol. Diabetes mellitus. Obesity and maturity-onset diabetes are among the first disorders to appear when unacculturated people undergo economic development. The overall prevalence of noninsulin-dependent diabetes among adults in industrialized countries ranges from 3% to 10%, but among unacculturated native populations it is 0% to 2%. The most powerful risk factor to diabetes is obesity, and excessive weight gain is virtually absent in preliterate societies. Obese people have reduced numbers of cellular insulin receptors, a relative tissue resistance to insulin, and higher blood insulin levels than lean people. Conversely, high-level physical fitness, characteristic of aboriginal persons, is associated with an increased number of insulin receptors and better insulin binding, both of which enhance the body's sensitivity to insulin. Diets containing ample amounts of nonnutrient fiber and complex carbohydrates lower both fasting and postprandial blood glucose levels, and these types of diets are the rule among technologically primitive societies but the exception in Western nations. Thus the message from Eaton et al. [81,84] is this: we need to eat and exercise like the Stone Age people. If we do, our health will improve substantially, and our medical bills will decrease substantially. Effectiveness or noneffectiveness of various diets in lowering the total and low-density lipoprotein cholesterol levels. The effectiveness of diet in lowering our total and LDL-cholesterol levels is nearly directly dependent on the percent of calories from fat in the diet. The average American adult consumes a diet containing nearly 40% of the calories from fat, one third of which is of the saturated variety. The most commonly prescribed diet by physicians in the United States is the National Cholesterol Education Program Step 2 diet, which is a 30%-of-calories-from-fat diet with saturated fat less than 7% and cholesterol less than 200 mg/day. [86] This diet, however, is relatively ineffective in reducing the total and LDL-cholesterol levels. With this diet, which is a 25% reduction in percent of calories from fat, the average serum total cholesterol is reduced by only 5% (e.g., 240 --> 228 mg/dl [6.2 --> 5.9 mmol/L], and the average serum LDL-cholesterol also is reduced an average of 5% (e.g., 160 --> 152 mg/dl [4.1 --> 3.9 mmol/L]). [87,88] Some individuals lower their serum total and LDL cholesterol by up to 30% by this modest diet, and in other patients the serum cholesterol levels actually increase by up to 20%. The average change, however, is a 5% decrease. A reduction in the percent of calories from fat from 40% to 20% (The American Heart Association phase III diet) decreases the serum total cholesterol by approximately 20% (e.g., 240 --> 192 mg/dl [6.2 --> 5.0 mmol/L] and the LDL-cholesterol also about 20% (e.g., 160 --> 128 mg/dl [4.1 --> 3.3 mmol/L]). [89] Most Americans, however, are not willing to reduce their percent of calories from fat to the 20% level. A reduction of the percent of calories from fat from 40% to 10% can reduce the serum total cholesterol level in persons without familial hypercholesterolemia to the 150 mg/dl (3.9 mmol/L) area, a level achieved for practical purposes only by those following a vegetarian-fruit diet, but a level where atherosclerotic plaques do not form and where those present shrink in size. Incidently, the diet of the Japanese historically has consisted of a 10%-of-calories-from-fat diet, and significant atherosclerosis has seldom been observed. [12] Today the Japanese are consuming a diet averaging approximately 23% of calories from fat, and the consequence has been a significant increase in the frequency of symptomatic atherosclerosis. Thus for diets to be very effective in lowering the serum total and LDL-cholesterol levels, the percentage of calories from fat must be reduced to 20% and ideally to 10%. If all adults in the United States were to reduce their percentage of calories from fat by 25% (40% --> 30% of calories from fat), the frequency of symptomatic and fatal atherosclerosis and the extent of atherosclerosis would decrease for the population. For an individual, however, the percentage of calories from fat must be reduced to approximately 20% before the risk of a first or subsequent atherosclerotic event will be substantially reduced. And in individuals who have already had an atherosclerotic event, in whom the challenge is to decrease the chances of a subsequent atherosclerotic event, a reduction of 50% of the percentage of calories from fat (and also of direct cholesterol) is necessary to significantly reduce the risk of a further event. For Americans who have consumed approximately 40% of their calories from fat for 40 years to suddenly reduce that percentage by half is a burden most are not willing to tackle. Thus lipid-lowering drugs have a major role in cholesterol lowering in the United States. Lipid-lowering drugs. For persons with familial hypercholesterolemia, diet alone will not be adequate to lower the total and LDL-cholesterol levels sufficiently to substantially reduce the risk of having an atherosclerotic event. Furthermore for persons who have had an atherosclerotic event, lipid-lowering drug therapy is recommended, unless the person is willing to reduce the percent of calories from fat to approximately 10%. [90] Additionally, for persons with very high serum total and LDL-cholesterol levels not produced by an identifiable cause such as a drug (e.g., diuretic), hepatic disease, renal disease, or hypothyroidism and unassociated with an atherosclerotic event, a lipid-lowering drug may be required if diet therapy is ineffective. Primary prevention. Except for the person with familial hypercholesterolemia, the first and ideally the only step required to lower the total and LDL-cholesterol levels adequately is diet, followed by diet, and then more diet. Each succeeding step of diet means further lowering of the quantity of fat and cholesterol consumed. If the diet alone does not lower the total and LDL-cholesterol levels adequately, the lipid-lowering (altering) drugs are useful. Secondary prevention. In my view persons who have had an atherosclerotic event should be on one or more cholesterol-lowering drugs irrespective of the serum or plasma lipid levels, because whatever the levels are in those with events, they are too high. [90] This recommendation is not made lightly, because approximately 7 million persons in the United States alone have symptomatic myocardial ischemia, and many others have limb or cerebral ischemia from atherosclerosis. Nevertheless there is increasing evidence that lipid-lowering medicines after heart attacks may be even more beneficial than aspirin, beta blockers, angiotensin-converting-enzyme inhibitors, and calcium antagonists in preventing subsequent atherosclerotic events. Furthermore lipid-lowering drugs, if they can bring the serum total cholesterol down to the 150 mg/dl area and the LDL-cholesterol level to less than 100 mg/dl, can prevent or at least retard atherosclerotic progression and produce some regression. Neither lack of progression nor initiation of regression, however, appears to occur unless the serum total cholesterol is lowered to the range enjoyed by pure or nearly pure vegetarians. The use of lipid-lowering drugs, of course, does not negate the use of a low-cholesterol, low-fat diet, because each appears to work synergistically. Even in patients who refuse to follow the low-cholesterol, low-fat diet, however, the lipid-lowering drugs nevertheless produce substantial reductions in the serum cholesterol levels [87] and decrease the chances of first and subsequent events (Figure 3). ---------------------------------------------- Figure 3. Effects of serum total cholesterol reduction on risk of first or subsequent atherosclerotic event. "Average risk" refers to primary prevention--person has not had atherosclerotic event. "High risk" refers to secondary prevention--person has had atherosclerotic event. Occurrence of event shifts line to left. Nevertheless wherever serum total cholesterol level is, reduction of that level by approximately 40 mg/dl (or 1 mmol/L) reduces relative risk of atherosclerotic event (either a first one or a subsequent one) in half. Thus large benefits result from reducing serum total cholesterol. ---------------------------------------------- In November 1994 the results of the Scandinavian Simvastatin Survival Study (4S) was published, [91] and this study is the best of the secondary prevention trials so far. The 4S study involved 4444 Scandinavian adult men and women who had had either an acute myocardial infarction that had healed (80%) or angina pectoris (20%) with serum total cholesterol levels from 212 to 309 mg/dL (5.5 to 8.0 mmol/L). The double-blind, randomized, placebo-controlled study was continued until 440 patients had died. One half of the patients were treated with simvastatin (20 mg [63%] or 40 mg [37%] daily) and one half with matching placebo. During the 5 years of the study in the treatment group, the serum total cholesterol fell 28%, the LDL cholesterol fell 38%, and the HDL cholesterol rose 8%. During the study period total mortality in the treatment group fell 30% (256 [placebo] vs 182 [simvastatin]), coronary mortality fell 42% (189 [placebo] vs 111 [simvastatin]), and noncardiovascular mortality was similar in both treatment and placebo groups. The risk of coronary death and nonfatal acute myocardial infarction fell 34%, the risk of survival without an atherosclerotic event was reduced 26%, and the need for coronary angioplasty or bypass was reduced 37% in the treatment group compared with the control group. This latter 37% reduction was in five Scandinavian countries where these procedures are performed far less frequently per capita than in the United States. Thus this percent reduction of need for these procedures, if applied to the United States, would probably be much higher and the cost savings substantial. No patient was lost to follow-up in the entire study, and only 10% of patients in the treatment group discontinued taking simvastatin. In summary, the 4S study provides substantial justification for initiating lipid-lowering drug therapy (and low-cholesterol, low-fat dieting) after onset of either acute myocardial infarction or angina pectoris. The study also shows that noncardiovascular mortality is not increased by simvastatin therapy. Types of lipid-lowering drugs. The first-line lipid-lowering drugs in my view should be the 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors (the statins), because they are the best LDL-cholesterol-lowering drugs, they are the only lipid-lowering drugs that can be taken only once a day, because they are well tolerated, and because they have few side effects. Four statin drugs are presently available in the United States, and more than 70% of patients taking them are taking only one tablet daily; few patients are taking the maximal recommended doses of these drugs. Equivalent doses would be 10 mg simvastatin = 20 mg lovastatin = 20 mg provastatin = 40 mg fluvastatin. [92] Not only do these drugs lower the serum LDL-cholesterol and total cholesterol, but they raise the serum HDL-cholesterol (approximately 6%) and lower the triglyceride level (approximately 20%). Side effects of the statins at the low doses are extremely uncommon. Niacin, a vitamin taken in high doses, generally approximately 1.5 gm daily, may be thought of as a poor person's HMG-CoA reductose inhibitor, because it too has favorable effects on all four lipoproteins. Niacin is the best HDL-cholesterol raiser of the lipid-lowering agents. Its side effects, flushing, itching, and head pounding, limit its use in most patients. Gemfibrozil, the only fibrate available in the United States, lowers the triglyceride level more effectively than any of the other lipid-lowering drugs, but it has only modest effect on the LDL-cholesterol, and not infrequently it raises rather than lowers the LDL-cholesterol level. Cholestyramine and colestipol, the bile-acid resins, are the safest of the lipid-altering drugs, but these medicines must be taken in huge amounts (approximately 30,000 mg/day) to have the same effects on LDL-cholesterol as do the smaller doses of the statin drugs. Furthermore these drugs raise the triglyceride level, and they have small (4% [arrow up]) effects on the HDL cholesterol. Probucol, an antioxidant, has not been demonstrated to prevent or retard atherosclerosis, and it is rarely used now in the United States. This drug also lowers (23% [arrow down]) the HDL-cholesterol, has no effect on the triglyceride level, and its LDL-cholesterol lowering is only modest. Other antioxidants, vitamin E, C, and A, have yet to be shown either to prevent or to retard atherosclerosis. Because the most common cause of ventricular arrhythmias and congestive heart failure is atherosclerotic coronary artery disease, the lipid-lowering drugs by their ability to diminish progression and initiate atherosclerotic regression may be the best antiarrhythmic and anticongestive heart failure agents, at least prophylactically. [93,94]. A major problem with the lipid-lowering drugs is compliance. Approximately 50% of persons who started taking these drugs quit taking them within a year, and this rate holds true whether the drug is easily tolerated, like the statins, or has disturbing side effects such as niacin or the bile-acid resins. Another problem with lipid-lowering drugs is that most of the persons needing them are not on them, because they have not been prescribed. Probably no more than 1 million of the 7 million persons with symptomatic myocardial ischemia in the United States are taking one or more lipid-lowering agents, and no more than 1 million of the 40 million persons in the United States with serum total cholesterol levels greater than 240 mg/dl are taking one or more lipid-lowering agents. Getting cardiologists interested in lipid-lowering drugs. Most cardiologists appear to be hesitant in prescribing lipid-lowering drugs to their patients, even those who have had one or more atherosclerotic events. Several surveys have shown that cardiologists rank only slightly above general internists, general practitioners, and the general public in considering "cholesterol" of major importance for development of atherosclerosis. It takes few fingers to name prominent cardiologists around the world who have become recognized as lipid experts or who have a major interest in lipids. Yet the data show that cholesterol causes atherosclerosis. When high cholesterol levels are lowered, clinical atherosclerotic events decrease, and the amounts of atherosclerotic plaque deposited in arteries decrease. Although there are many exceptions, cardiologists in general have relatively little interest in cholesterol and its role in atherosclerosis. Why might this be the case? [95]. 1. Cardiologists as a group are not completely convinced of the important role of cholesterol in atherosclerosis. Most patients seen by cardiologists have serum total cholesterol levels greater than 200 mg/dl (> 5.2 mmol/L), and there is not much difference in the cholesterol levels in those patients with and those without overt evidence of myocardial ischemia. Thus the actual serum total cholesterol is not very helpful in the United States in separating patients with myocardial ischemia from those without myocardial ischemia. Furthermore nearly half the patients with angiographic evidence of significant coronary arterial narrowing have serum total cholesterol levels less than 200 mg/dl ( 2. Cardiologists view cholesterol management as unexciting. Cholesterol management is long-term. Witnessed changes in outcome are rarely apparent. It is similar to the management of systemic hypertension. Cardiologists are certainly convinced of the importance of lowering elevated blood pressure, but as a group cardiologists are not interested in the management of systemic hypertension. The same goes for the management of hypercholesterolemia. Its management is relatively boring compared with the excitement of treating patients with chest pain, arrhythmias, overt congestive heart failure, heart block, etc. Cardiology focuses primarily on management of acute events, the management of which is exciting. Dramatic changes in outcome in response to therapies (drugs and procedures) are witnessed. Lowering of cholesterol or blood pressure levels do not, in contrast, produce overt changes in the patients' symptoms or appearances. Cardiologists also tend to be more excited by the acute lesions in coronary arteries than by the masses of plaque in the coronary arteries. 3. Cardiologists avoid cholesterol management because they know that successful management requires expert knowledge of nutrition, of cholesterol-lowering drugs, and a change in their own lifestyles. Cardiologists as a group are uncomfortable when nutrition is the topic. Cardiologists are not calorie counters or grocery-store shoppers. Housewives know more about calories, fats, and carbohydrates than do many cardiologists. Cardiologists as a group are not experts on lipid-lowering drugs. Cardiologists, in contrast, are comfortable with nitroglycerin, digitalis, beta blockers, calcium antagonists, angiotensin-converting-enzyme inhibitors, antiarrhythmic agents, thrombolytic agents, aspirin, heparin, warfarin, and vasopressors, but not lipid-lowering and antioxidant agents. I am afraid that we all tend to dismiss as unimportant that which we do not understand well or are not interested in. 4. Cardiologists are a bit confused by the recommendations of the lipid experts regarding whom to treat and whom not to treat with diet and lipid-lowering agents. The recommendations do change. The first U. S. recommendations, however, appeared in January 1988, [8] and the second U. S. recommendations appeared in June 1993, [86] so the argument that the recommendations are "always changing" is not valid. The recommendations may intermix primary and secondary prevention, but the importance of therapy in secondary prevention is more emphasized in the June 1993 recommendation than previously. Patients who have had atherosclerotic events should be clearly separated from those who have not, because management of the two is entirely different. I too believe that the recommendations can be simplified a bit. 5. Cardiologists resent being excluded from important roles in the cholesterol-lowering world. The adult-lipid-expert committee in the United States is composed almost entirely of persons whose subspecialty in medicine is endocrinology and metabolism. Only one cardiologist is a member of the recent adult-lipid-expert panel in the United States. [86] I suspect that cardiologists as a group are a bit uncomfortable in a situation where they are not the dominant players. Leaders in the lipid world are not physicians whose training had focused on cardiology. Yet in the real world it is the cardiologists who see patients who have had atherosclerotic events. In other words lipidologists dominate primary prevention, that is, treating persons with lipid disorders before atherosclerotic events. Cardiologists, however, because they see persons who have or have had atherosclerotic events, are the dominant forces of secondary prevention. In my view all of these patients should be on a low-fat, low-cholesterol diet, and with few exceptions, should be taking one or more lipid-lowering drugs. Cardiologists simply have no choice but to become better informed about these diets and these drugs. 6. Cardiologists view the lipid-lowering drugs as too expensive. Compared with what? In the United States in 1993, approximately $20 billion was spent on coronary bypass alone, and probably approximately half that much was spent on coronary angioplasty procedures. The lipid-lowering drugs are cheap and cost-effective in comparison. If every person in the United States with symptomatic myocardial ischemia was given a 20 mg tablet of lovastatin daily, the cost would be approximately $3 billion a year, and I suspect the benefit would be substantial. 7. Cardiologists consider cholesterol-lowering drugs to have too many side effects with too high risk/benefit ratios. The presently used lipid-lowering drugs are some of the safest of all drugs available. The EXCEL study [96,97] showed the side effects of a 20 mg tablet of lovastatin daily to be no more than that of placebo! The bile-acid resins have no systemic effects, although the quantity of them required to provide good cholesterol lowering is high. Although enormously effective, the unpleasant side effects of niacin are considerable. Thus compared with the toxic effects of atherosclerosis, the lipid-lowering drugs, in contrast, are essentially nontoxic. 8. Cardiologists view cholesterol management as financially unrewarding. Certainly in comparison to the financial rewards resulting from the various cardiologic procedures, lipid-lowering endeavors are time-consuming, often discouraging, and financially of relatively little benefit. Additionally, some cardiologists consider lipid management the purview of the referring physicians. Thus because secondary prevention is in the hands of cardiologists and because cholesterol lowering has proven benefit after atherosclerotic events, cardiologists must increase their knowledge of and use of low-fat, low-cholesterol diets and lipid-lowering agents. Retail costs of lipid-lowering drugs. Several physicians have mentioned to me that their patients cannot afford the lipid-lowering drugs. Their patients, however, seem able to afford the far more expensive procedures, angioplasty and bypass, that help relieve at least temporarily the acute consequences of severe narrowings in the coronary and peripheral arterial systems. If the 12-ounce steaks were eliminated or reduced drastically in size, there would be plenty of change left over to purchase any of the lipid-lowering agents that have been proven to decrease recurrences of atherosclerotic events and to decrease progression and cause some regression in persons who have already had atherosclerotic events. The lipid-lowering agents appear to be better than aspirin, beta blockers, and other agents for decreasing subsequent atherosclerotic events in persons who have already had an event. The retail costs (the prices the patients pay) of the four presently available statin drugs in one metropolitan area in the United States in 1 month of 1994 are tabulated in Table IV. [98]. ---------------------------------------------- Table IV. Retail costs of four 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the Dallas/Fort Worth, Tex., area, September 1994 ---------------------------------------------- SUMMARY The good news about coronary atherosclerosis is that it takes an awful lot of plaque before symptoms of myocardial ischemia occur. The bad news is that despite the need for large quantities of plaque for symptoms to occur, nevertheless nearly half of us in the United States eventually have the necessary quantity. Atherosclerosis is infrequently hereditary in origin. Most of us get atherosclerosis because we consume too much fat, cholesterol, and calories. The consequence is an elevated (> 150 mg/dl) serum total cholesterol level, and the higher the number is above 150, the greater is the quantity of plaque deposited in our arteries. If the serum total cholesterol level can be prevented from rising to more than 150 mg/dl, plaques are not laid down; if elevated levels are lowered to 150 mg/dl, further plaque does not form, and parts of those present may vanish. A fruit-vegetarian-starch diet is necessary as a rule to achieve the 150 mg/dl level in most adults. Lipid-lowering drugs are required in the patients with familial hypercholesterolemia and in most patients with atherosclerotic events. The best news about atherosclerosis is that it can be prevented in those without the hereditary form, and it can be arrested by lowering elevated serum total (and LDL) cholesterol to the 150 mg/dl level. REFERENCES 1. Roberts WC. Qualitative and quantitative comparison of amounts of narrowing by atherosclerotic plaques in the major epicardial coronary arteries at necropsy in sudden coronary death, transmural acute myocardial infarction, transmural healed myocardial infarction and unstable angina pectoris. 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