Management of Lipids in Primary and Secondary Prevention of Cardiovascular Diseases

Transcription

1 Subject Review Management of Lipids in Primary and Secondary Prevention of Cardiovascular Diseases CARL J. LAVIE, M.D., GERALD T. GAU, M.D., RAY W. SQUIRES, Ph.D., BRUCE A. KOTTKE, M.D., Division of Cardiovascular Diseases and Internal Medicine Although the frequency of cardiovascular disease is declining, it remains a major present and future threat to health in the United States. The deleterious effects of abnormal blood lipid concentrations have long been recognized, but the benefit of corrective intervention in this process has only recently been demonstrated. We review the major lipid abnormalities and the available clinical therapeutic interventions. In addition, we discuss data that address the premise that reducing low-density lipoprotein cholesterol or raising high-density lipoprotein cholesterol should decrease the progression of coronary atherosclerosis, and we summarize drug trials in which clofibrate, niacin, cholestyramine, and gemfibrozil decreased coronary heart disease events. Studies that used cholestyramine and the combination of colestipol and niacin resulted in decreased progression of coronary artery disease. On the basis of early experience with lovastatin, inhibitors of hydroxymethylglutaryl-coenzyme A reductase are likely to be effective in the treatment of hypercholesterolemia. The available information on the association of low cholesterol levels and cancer suggests that low total cholesterol is a consequence rather than a cause of carcinoma. Current data strongly support the concept of vigorous intervention directed at management of lipids, both with nonpharmacologic treatment and with drug therapy, for the primary and secondary prevention of coronary atherosclerosis. Although national statistics indicate that the morbidity and mortality from cardiovascular disease have steadily declined, cardiovascular disease remains the major present and future threat to health in the United States. The decreasing incidence of cardiovascular disease is, in part, due to a more complete understanding of the role played by risk factors (such as smoking, high blood pressure, and elevated cholesterol) in the cause and progression of atherosclerosis. 1 Smoking cessation and antihypertensive therapy have been widely promoted for primary and secondary This work was supported in part by Grant HL from the National Heart, Lung, and Blood Institute. Address reprint requests to Dr. G. T. Gau, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN Mayo Clin Proc 63: , prevention of coronary heart disease. During the past decade, progress has been made in establishing the cholesterol-coronary artery disease hypothesis and in defining the role of hypercholesterolemia in the pathogenesis of atherosclerosis. 2-9 Despite increasing evidence of the importance of abnormally elevated serum lipids and the value of lipid reduction therapy, recent studies emphasize the fact that lipids have been neglected, even in patients with known severe atherosclerosis Some authors have questioned the necessity of vigorously lowering cholesterol concentrations in the general population. 13 ' 14 In this report, we describe the types and significance of blood lipid disorders. The major clinical trials and serial angiographic studies that have dealt with reduction of cholesterol are reviewed, and the therapeutic regimens currently available for the various lipid disorders are dis-

2 606 LIPIDS AND CARDIOVASCULAR DISEASE Mayo Clin Proc, June 1988, Vol 63 cussed. A brief comment on the possible link between low serum cholesterol levels and cancer, the effect of antihypertensive therapy on serum lipids, and the possible role of fish oils in preventive cardiology is included. CLASSIFICATION OF HYPERLIPOPROTEINEMIA In the future, the classification and treatment of lipid disorders will likely be directed to specific apolipoproteins. Until that is feasible, the classification shown in Table 1 is applicable for most clinical problems. With the exception of the rare Fredrickson type III hyperlipoproteinemia, this classification can be simplified to total cholesterol and triglyceride levels (Table 2). Causes of secondary hyperlipidemia must also be sought and treated (Table 3). This report, however, deals with only primary lipid disorders. Increased Low-Density Lipoprotein Cholesterol (LDL-C) Levels. Numerous studies have demonstrated an unequivocal association between serum cholesterol and coronary heart disease that represents a continuum over a broad range of cholesterol levels. 4 Patients with d LDL-C levels, and particularly d LDL apolipoprotein B, have the greatest risk of premature atherosclerosis and present the greatest therapeutic challenge. 15 Patients with type IIA hyperlipoproteinemia usually have a relatively common genetic disease called familial hypercholesterolemia or have polygenic (multifactorial) hypercholesterolemia. 16 Familial hypercholesterolemia, which affects 1 in 500 people, is caused by a genetic defect in the LDL receptor in the liver, which impairs the normal uptake of LDL- Table 2. Simplified Classification of Hyperlipoproteinemia* Group (Fredrickson type) Increased chylomicrons (type I) Increased LDL (type IIA) Increased VLDL (types III, IV, V)t Increased VLDL and LDL (type IIB) Cholesterol Normal Increased Increasedt Increased:): Triglyceride Substantially d Normal Increased Increased *LDL and VLDL = low-density and very low density lipoprotein. tchylomicrons are also elevated in type V. ttriglycerides are more elevated (in a 5:1 ratio) except in types IIB and III (1:1). C by the liver and causes LDL-C to accumulate in plasma. The actual incidence of this autosomal dominant disease in patients with type IIA hyperlipidemia is unknown because receptor studies of large numbers of patients for the detection of heterozygous familial hypercholesterolemia have been too complex to be applied to population surveys. The gene for the LDL receptor is located on chromosome 19. Patients with heterozygous familial hypercholesterolemia inherit one copy of this chromosome with a mutant LDL receptor gene from one parent and one copy of a normal chromosome 19 from the other parent. These patients typically have cholesterol levels in the range of 350 to 400 mg/dl and have a high frequency of tendinous xanthomas, arcus corneae, and xanthelasma. Premature atherosclerosis begins in the second or third decade of life and usually produces symptoms by 30 to 40 years of age. In comparison with the relatively common Type Chylomicrons Very low density lipoproteins Low-density lipoproteins High-density lipoproteins Major apolipoproteins B, C.E B, C, E B A-I, All Table 1. Classification and Characteristics of Plasma Lipoproteins Core lipids Triglycerides Triglycerides, cholesteryl esters Cholesteryl esters Cholesteryl esters Origin Intestine Liver (intestine) Intravascular metabolism of very low density lipoproteins Intestine, liver, intravascular metabolism Destination Triglyceride storage and metabolizing cells, liver Triglyceride storage and metabolizing cells Peripheral cells, liver Liver, steroidogenic tissues Function Transport of dietary triglycerides Transport of endogenously synthesized triglycerides and some cholesterol Transport of cholesteryl esters of intravascular and hepatic origin Reverse transport of cholesterol of peripheral origin

3 Mayo Clin Proc, June 1988, Vol 63 LIPIDS AND CARDIOVASCULAR DISEASE 607 heterozygous form of familial hypercholesterolemia, the homozygous form is a rare disease (affecting 1 in 1 million people) but is much more severe. In this condition, LDL receptors are completely absent or are essentially nonfunctional, and cholesterol levels are frequently at or above 600 mg/dl. Coronary artery disease develops in childhood or adolescence and frequently results in myocardial infarctions before the age of 10 years. Deposition of cholesterol in the aortic valve and aortic root can occur, producing aortic stenosis. Polygenic hypercholesterolemia is one of the common causes of type IIA hyperlipidemia. In patients with this disorder, a combination of multiple genetic abnormalities and environmental factors causes elevations of blood cholesterol levels in the range of 250 to 325 mg/dl. These patients lack the typical features of familial hypercholesterolemia such as xanthelasma, arcus corneae, and tendinous xanthomas. Insights into the potential mechanisms of polygenic hypercholesterolemia are beginning to emerge from experimental studies in animals. These studies suggest that an acquired deficiency of LDL receptors may be partly responsible for dietaggravated hypercholesterolemia. 17 Wide variations in individual sensitivity to weight gain and a diet high in saturated fat and cholesterol with respect to total cholesterol concentrations have been noted. Some patients continue to have hypercholesterolemia even when consuming a diet low in saturated fat and cholesterol. Genetic factors seem to determine this tendency and dictate whether symptomatic atherosclerosis will develop at any given level of total cholesterol. Another reported genetic cause of d LDL-C is familial combined hyperlipidemia. Patients with this disorder and affected family members have d levels of cholesterol, triglycerides, or both. A third of these patients have s in LDL-C alone (type IIA phenotype), a third have s in very low density lipoproteins (VLDL) alone (type IV phenotype), and a third have s in both LDL and VLDL (type IIB phenotype) or VLDL plus chylomicrons (type V phenotype). Patients with familial combined hyperlipidemia lack the extravascular features of hyperlipidemia but have a considerably d risk of coronary heart disease regardless of their type of lipoprotein abnormality. Familial combined hyperlipidemia can be diagnosed by finding multiple lipoprotein phenotypes Table 3. Causes of Secondary Hyperlipidemia Hypertriglyceridemia Hypercholesterolemia Excessive alcohol or simple Excessive dietary cholesterol or sugars saturated fats (or both) Contraceptives, estrogen, Hypothyroidism pregnancy Obstructive liver disease Obesity Nephrotic syndrome Diabetes mellitus Multiple myeloma or Chronic renal failure dysglobulinemia Cushing's disease, Progestational agents and corticosteroid therapy anabolic steroids in a single family. In patients with coronary heart disease, familial combined hyperlipidemia is said to be 3 to 5 times more prevalent than is familial hypercholesterolemia. Increased VLDL and Chylomicrons. The literature contains considerable debate about the significance of elevated levels of triglycerides. Prospective studies done in the continental United States and Hawaii support the idea that serum triglyceride concentrations are not independent predictors of atherosclerosis. 18,19 Much of this debate stems from a failure to understand the lipid composition of VLDL and chylomicrons, the two lipoprotein particles that carry most of the triglycerides in plasma. It must be understood that, whereas chylomicrons contain virtually only triglycerides and little cholesterol, in the case of VLDL, both cholesterol and triglycerides are present. On the average, the cholesterol content of VLDL is approximately 20% of the triglyceride content. Thus, in patients with a rare hereditary deficiency of the enzyme lipoprotein lipase or the rare absence of the cofactor for this enzyme (apolipoprotein C-II), one will find substantially elevated triglyceride levels with only minimally elevated cholesterol levels. In these patients, the elevations of serum triglycerides are associated with major complications, particularly pancreatitis, eruptive xanthomas, and lipemia retinalis. In patients with the more common types IV and V hyperlipoproteinemia, in which the major elevations are an in VLDL particles or chylomicrons that contain larger amounts of cholesterol than ordinary chylomicrons, the situation differs considerably. These patients have elevations of triglycerides associated with elevations of cholesterol. Levels of cholesterol are approximately 20% of triglyceride levels. In this situation, levels of high-density lipoprotein cholesterol (HDL-C) are frequently

4 608 LIPIDS AND CARDIOVASCULAR DISEASE Mayo Clin Proc, June 1988, Vol 63 decreased, a finding associated with the presence of coronary heart disease. As mentioned, controversy about the relationship of elevated triglycerides to coronary heart disease stems primarily from a failure to appreciate the cholesterol content of VLDL. In samples from fasting patients, d chylomicrons are extremely rare. The most common reason for elevated triglyceride levels is an elevation of VLDL. Such elevations are always associated with an in plasma cholesterol because of the cholesterol content of the VLDL particles. In other words, triglycerides by themselves cannot be considered as an independent variable in multivariate analysis because they do not occur in the plasma as an independent factor. Instead, they are almost always seen in association with cholesterol. Because of this, it is not appropriate to apply the technique of multivariate analysis by first subtracting the effects of plasma cholesterol levels on the variable being measured and then looking for an additional effect of triglycerides. If one uses this procedure, the regression against cholesterol accounts for the regression due to both LDL and VLDL particles. Thus, as one would theoretically expect, no additional effect of triglycerides is found. Such an analysis is artificial and not based on the physiologic principles of the lipoprotein system. In contrast, if one uses measures of VLDL and LDL (such as their cholesterol or protein content), one is dealing with independent variables. With use of such measures, in general, VLDL will show a correlation with coronary heart disease. It is unfortunate that the misuse of multivariate regression analysis has resulted in confusion in this area. A more appropriate method for this multivariate analysis would be to analyze the effects of LDL-C separately from the effects of VLDL-C levels. Despite these limitations, some studies do support the importance of triglycerides in the epidemiologic features of atherosclerosis. Plasma triglycerides and VLDL levels were shown to be independent predictors of myocardial infarction in young men. 20 They also correlated with the severity of coronary disease in autopsy studies on patients who had died of myocardial infarction 21 and in adolescents who had died of noncardiac causes. 22 Plasma triglyceride levels were shown to be an independent risk factor for the development of coronary heart disease in men, and particularly in women, in the Framingham Heart Study. 23 Three additional prospective studies support the role of triglycerides as an independent risk factor for coronary disease Not only is diabetes an important cause of both hypertriglyceridemia and coronary heart disease but, in addition, some evidence suggests that hyperlipidemia may also be a risk factor for the development of diabetes. Low HDL-C Levels. HDL, which are rich in phospholipids as well as cholesterol and cholesteryl esters, are thought to play an important role as cholesterol acceptors for the transfer of cholesterol from peripheral cells back to the liver. 27,28 Studies have demonstrated a strong inverse relationship between HDL-C and coronary heart disease, particularly in elderly persons. HDL-C values have an r value of about 0.4 to 0.5 for the correlation with coronary heart disease in comparison with an r value of 0.3 for total cholesterol levels. 29 Patients with rare hereditary metabolic disorders (for example, Tangier disease) can have profoundly low or absent HDL- C levels. Low serum HDL-C, particularly less than 30 mg/dl, is a powerful predictor of premature coronary disease. 30 Women, blacks, and runners, who are considered to have a lower-thanaverage risk for coronary artery disease, have higher levels of HDL-C than do sedentary persons, smokers, patients with diabetes, obese persons, and middle-aged white men, who are considered to have a higher-than-average risk. 1 Recently, attention has been focused on HDL subfractions and HDL apolipoproteins, particularly apolipoprotein A-I (apo A-I). Studies have demonstrated that both aerobic exercise and ingestion of ethanol HDL-C levels, but exercise raises the cardioprotective HDL2 subfraction, whereas ethanol raises HDL3. 31 ' 32 Free cholesterol can enter the cell membrane for reverse cholesterol transport, and apo A-I on the surface of HDL serves as the acceptor protein. 27,28 The enzyme lecithin-cholesterol acyltransferase is activated by apo A-I and promotes the resynthesis of cholesteryl esters within the HDL particle. On the basis of this evidence, it seems plausible that a relative deficiency of apo A-I may play an important role in the accumulation of lipids in cells, resulting in atherosclerosis. A recent report demonstrated low apo A-I levels in survivors of myocardial infarction who had normal HDL-C levels. 33 Two recent

5 Mayo Clin Proc, June 1988, Vol 63 LIPIDS AND CARDIOVASCULAR DISEASE 609 studies from our institution demonstrated that apo A-I levels are more frequently associated with the presence (but not severity) of severe coronary artery disease than are HDL-C levels. 34,35 Investigators have suggested that exercise may the apo A-I concentration. In a recent study, however, we found no differences in apo A-I levels among sedentary control subjects, light exercisers, or marathon runners, but HDL-C concentrations were highest in marathon runners. 36 An in apo A-I may accelerate removal of cholesteryl ester and could impede the development or progression of atherosclerosis. Exercise may alter HDL composition and thereby the ability of HDL particles to accept and bind free cholesterol. DRUG TRIALS Although the deleterious effects of hypercholesterolemia have been recognized for years, data about the benefit of intervention in this process have been slow to accrue. During the past several years, major prospective trials have demonstrated the benefits of pharmacologically reducing total cholesterol and LDL-C levels in the primary and secondary prevention of coronary heart disease (Table 4). World Health Organization (WHO) Cooperative Trial. This double-blind trial of clofibrate versus placebo in 15,745 men began in the 1960s. 37 A 9% reduction of total cholesterol level was associated with a 20% reduction in nonfatal myocardial infarction (P<0.05) after 5 years, but 25% more deaths were observed in the clofibrate group (P<0.01), and clofibrate therapy was associated with a greater number of cholecystectomies (P<0.001). Despite the reduction in cardiovascular events with clofibrate therapy, the in noncardiovascular morbidity and mortality lessened enthusiasm for pharmacologic reduction of cholesterol levels, particularly with clofibrate. Coronary Drug Project (COP). This doubleblind, randomized, placebo-controlled trial was conducted between 1966 and 1975 to assess the efficacy and safety of estrogen therapy (2.5 and 5.0 mg/day), dextrothyroxine, clofibrate, and niacin in 8,341 male patients with previous myocardial infarction. 38 The two estrogen regimens and dextrothyroxine were discontinued prematurely because of excessive cancer and cardiovascular mortality with use of these regimens. 38,39,46-48 Although clofibrate therapy was associated with a 6% reduction in total cholesterol levels, the shortterm and long-term studies showed no beneficial effects on mortality or other cardiovascular events. In addition, clofibrate was associated with d adverse effects, including cholelithiasis, cardiac arrhythmias, and pulmonary emboli. Despite poor patient compliance with the niacin regimen (3 g/day), this therapy was associated with a 10% reduction in total cholesterol levels and a 27% reduction in nonfatal myocardial infarction (P<0.01), although almost identical death Trial* WHO 37 CDp38,39 LRC-CPPT 4041 Helsinki Heart Study 42 NHLBI Type II CIS 43,44 CLAS 45 Table 4. Major Clinical and Angiographic Trials of Pharmacologic Reduction of Cholesterol No. of subjects 15,745 3,908 3,806 4, Drug Clofibrate Niacin Cholestyramine Gemfibrozil Cholestyramine Colestipol + niacin Duration (yr) Mean cholesterol reduction (%) Reduction in CHD (%)f 20 (nonfatal MI) 27 (nonfatal MI) 11 (mortality, 15-yr follow-up) 19 (nonfatal MI) 24 (CHD death) 37 (nonfatal MI) 34 (CHD events) 26 (CHD death) Coronary angiographic outcome (%) No Regression change Progression Placebo 9 Drug Placebo Drug 16.2 *CDP = Coronary Drug Project; CLAS = Cholesterol-Lowering Atherosclerosis Study; LRC-CPPT = Lipid Research Clinics Coronary Primary Prevention Trial; NHLBI Type II CIS = National Heart, Lung, and Blood Institute Type II Coronary Intervention Study; WHO = World Health Organization Cooperative Trial. tchd = coronary heart disease; MI = myocardial infarction

6 610 LIPIDS AND CARDIOVASCULAR DISEASE Mayo Clin Proc, June 1988, Vol 63 rates were noted for niacin and placebo-treated groups in the initial report. 38 After a mean followup of 15 years, almost 9 years after termination of the trial and possibly of niacin therapy, mortality from all causes was 11% lower in the niacintreated patients than in the placebo group (P<0.002). 39 These results suggest a potential long-term benefit from a relatively short course of niacin therapy, with a significant reduction in mortality evident years after discontinuation of therapy. Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT).-The LRC- CPPT represents the most extensive effort to date to test the efficacy of reduction of cholesterol in the primary prevention of coronary heart disease. In this study, 3,806 middle-aged men with dietinsensitive type II hyperlipoproteinemia (total cholesterol of more than 265 mg/dl) were enrolled in a 7.4-year trial of cholestyramine therapy (24 g/day) versus placebo. 40 Although both groups followed a moderate cholesterol-lowering diet, dietary changes were associated with only a 5% reduction in total cholesterol levels. The cholestyramine group experienced mean total cholesterol and LDL-C reductions of 13% and 20%, respectively, which were 9% and 13% greater than the reductions with placebo therapy. The major primary endpoints (death from coronary heart disease and nonfatal myocardial infarction) were reduced by 19% (P<0.05) in the cholestyramine group, and new "positive" exercise tests, coronary bypass operations, and new angina pectoris declined by 25%, 21%, and 20%, respectively. The reduction in cardiovascular risk was greatest in those patients with the greatest decreases in total cholesterol levels. 41 It should be emphasized that despite an impressive reduction in cardiovascular events with cholestyramine therapy, total mortality was similar in the two groups, and accidental and violent deaths occurred more frequently in the cholestyramine-treated group. Helsinki Heart Study. The Helsinki Heart Study was a randomized, double-blind, 5-year primary prevention trial in which gemfibrozil, 600 mg twice daily, or placebo was used in 4,081 middle-aged men with dyslipidemia (non HDL- C more than 200 mg/dl). 42 Gemfibrozil therapy was extremely well tolerated; side effects were no more likely than with placebo therapy. In this trial, IIDL-C d 10% and total cholesterol, LDL-C, and triglyceride levels decreased 8%, 8%, and 35%, respectively. Although total deaths and cancer rates were no different in the two groups, gemfibrozil was associated with a 34% reduction in coronary heart disease events (P<0.02), and nonfatal myocardial infarction and coronary heart disease deaths were reduced by 37% and 26%, respectively. Similar to the LRC-CPPT results, total mortality during the study period was not reduced by gemfibrozil therapy. Interestingly, a trend of d accidental and violent deaths was noted with gemfibrozil therapy. National Heart, Lung, and Blood Institute (NHLBI) Type II Coronary Intervention Study. At this time, we know of 10 studies of the effects of lipid-lowering therapy on progression or regression of coronary artery disease. 43 " 45 ' 49 " 55 Only two of these diet, drug, and serial angiographic studies of coronary artery disease progression or regression were placebo controlled and randomized and consisted of more than 100 patients. 43 ' 45 The NHLBI study randomized 116 patients with type II hyperlipoproteinemia and coronary artery disease to receive either a diet low in fat and cholesterol plus a placebo or such a diet plus cholestyramine (24 g/day). 43 After a follow-up period of 5 years, coronary artery disease had progressed in 49% of placebo-treated patients in comparison with 32% of cholestyramine-treated patients (P<0.05). Independent of the specific treatment group, progression of coronary disease was inversely associated with an in HDL-C and a decrease in LDL-C levels. 44 This was the first major report to indicate that pharmacologic intervention directed at lipids and an in the HDL/LDL ratio are associated with a decreased progression of coronary artery atherosclerosis. Cholesterol-Lowering Atherosclerosis Study (CLAS). Long-term results of coronary artery bypass operations are hampered by progression of disease in the native coronary circulation and by closure of saphenous vein grafts. Data from the Montreal Heart Institute demonstrate a saphenous vein graft closure rate of 2% annually for the first 5 years and then 5.3% annually between years 5 and 10; 56 at 10 years, the patency of saphenous vein grafts is only about 50%. 56,57 In a study of 82 patients 10 years after a bypass procedure, plasma levels of LDL apolipoprotein B, HDL-C, LDL-C, and triglycerides were found to be strong predictors of both saphenous vein graft patency and progression of disease in the

7 Mayo Clin Proc, June 1988, Vol 63 LIPIDS AND CARDIOVASCULAR DISEASE 611 native circulation. A recent study (CLAS) sought to determine whether aggressive lowering of LDL C with a concomitant in HDL-C would reverse or retard the growth of atherosclerotic lesions in the native coronary arteries as well as in saphenous vein grafts. 45 In a 2-year study of 162 nonsmoking men who were treated with diet plus colestipol (30 g/day) and niacin (3 to 12 g/day) versus a less stringent diet and placebo, lipids were altered to a degree not seen in any other study involving the use of serial coronary angiography. Total cholesterol was reduced by 26%, LDL-C decreased 43%, and HDL-C d 37%, in conjunction with a 57% reduction in the LDL/HDL ratio. The treatment group had a statistically significant reduction in lesions that had progressed in the native coronary arteries and saphenous vein grafts, and deterioration in overall coronary status was less in the drugtreated patients. In addition, regression in coronary atherosclerosis occurred in 16% of the drugtreated patients in comparison with only 2% of the control subjects (P = 0.002). This is the most impressive study to date that supports the idea of aggressive management of lipids in the secondary prevention of ischemic heart disease. These excellent results, evident in only 2 years, suggested that even greater differences could be noted with a longer follow-up period. THERAPY The aforementioned studies lend support to the concept of aggressive intervention directed at lipids in the primary and secondary prevention of coronary atherosclerosis. Therapy for lipid disorders includes dietary changes, maintenance of ideal body weight, aerobic exercise, and pharmacologic agents. The selection of patients who need interventional treatment will depend on the level of the abnormal lipid values (total cholesterol, triglycerides, and HDL-C) and on the presence of substantiated atherosclerosis or risk factors for atherosclerosis. In October 1987, the National Cholesterol Education Program recommended that vigorous dietary measures be implemented for all persons with LDL C of more than 160 mg/dl or more than 130 mg/dl for those with known coronary heart disease or at least two cardiac risk factors (male sex being one). 59 Normally, vigorous dietary therapy should be tried for at least 6 months before initiation of drug therapy; pharmacologic intervention may be started earlier in patients with severe elevations of LDL-C (LDL more than 225 mg/dl) or known severe atherosclerosis. Drug therapy is recommended for patients with LDL-C of more than 190 mg/dl or more than 160 mg/dl for those with two or more cardiac risk factors or known coronary heart disease. LDL-C concentrations can easily be calculated by subtracting the HDL-C and onefifth of the triglycerides (as long as the triglyceride concentration is not more than 400 mg/dl) from the total cholesterol concentration. The recommendations of the National Cholesterol Education Program should be viewed with caution. 60 Although epidemiologic data support the role of hypercholesterolemia in coronary heart disease in most patient subgroups, the studies of treatment of hyperlipidemia have primarily been conducted in middle-aged men. Currently, no data are available to support vigorous management of lipids for prevention of coronary heart disease in women or in elderly persons. The recommendations from this program, however, were for all persons older than 20 years of age. On the basis of these recommendations, almost half the population may need vigorous dietary therapy and 20% may need pharmacologic therapy. These recommendations may be difficult to implement and extremely expensive. By strict adherence to these recommendations, overtreatment of women and elderly patients and undertreatment of young patients are possible. The treatment program must be individualized, and blanket rules are not invariably applicable. How aggressive treatment should be in women and in patients older than 65 years of age continues to be controversial. Current data suggest that management of lipids may delay further disease progression and may be beneficial toward improved health in later years. At the present time, we would not categorically exclude a patient from treatment on the basis of age or sex alone. Diet. Proper nutritional advice remains the basic initial step for most, if not all, patients with lipoprotein abnormalities. In a review of six diet studies, total cholesterol concentrations were decreased by 8 to 16%; 61 pooling of these data showed that every 1% reduction in total cholesterol translated into a 2% reduction in coronary heart disease risk. Certainly, dietary therapy can play a major role in reducing coronary heart disease events and decreasing progression of coronary atherosclerosis. 50,62 We recommend the

8 612 LIPIDS AND CARDIOVASCULAR DISEASE Mayo Clin Proc, June 1988, Vol 63 American Heart Association Step-One Diet, lowering of the total fat and saturated fat in the diet to 30% and 10% of total calories, respectively, and restricting the cholesterol intake to 300 mg/day or less. If this approach is unsuccessful after a 3-month period, the Step-Two Diet, in which saturated fats are restricted to 7% of total calories and cholesterol is restricted to 200 mg/day, should be used. Dietary recommendations must be individualized and aimed at the specific lipoprotein abnormality. Patients with isolated s in VLDL levels usually respond well to dietary changes alone. 63 Weight reduction, avoidance of large amounts of fructose and sucrose, and restriction of ethanol will usually normalize lipids in these patients. Increasing the intake of omega-9 monounsaturated fatty acids such as oleic acid (olive oil, rapeseed oil) and omega-3 fatty acids (fish oils) may also help to lower triglyceride and LDL-C levels in these patients. 63,64 Unlike the omega-6 polyunsaturated fatty acids (such as linoleic acid), these unsaturated fats do not decrease HDL-C concentrations and may actually this cardioprotective lipid fraction. Patients with s in both VLDL and LDL levels have an intermediate response to dietary changes that include those measures to reduce VLDL, restrict cholesterol and saturated fats, and possibly fiber and complex carbohydrates. 65 In particular, beans, oat bran, and other forms of soluble fiber (for example, pectins, /3-glucan gums, and psyllium) may lower LDL-C by about 15%. 66 ' 67 Those patients with isolated s in LDL levels often have a less dramatic response to weight loss and dietary restriction of cholesterol and saturated fats, as shown in several studies; however, patients with polygenic hypercholesterolemia may respond better to dietary changes than those with familial hypercholesterolemia. In general, specific dietary instructions and achievement of ideal body weight are the goals. To be achieved, such goals require innovative and careful nutritional programs with regular followup and continued encouragement by an enthusiastic and confident nutritional staff; in most cases, the skill of a ertified registered d atitian with a particular interest in heart disease is essential. Patients who do not respond adequately to dietary efforts or who have lipr protein abnormalities not likely to respond to dietary treatment alone are candidates for drug therapy. Exercise. Regular aerobic exercise training has been shown to reduce blood triglyceride concentrations and to HDL-C. Habitual exercise has small effects on total cholesterol and LDL-C. Moderate activity, carried out for 20 to 45 minutes three to five times per week, seems to have beneficial effects on the blood lipid profile. 1 ' 68 ' 69 Pharmacologic Agents. The commonly used lipid-lowering agents are summarized in Table 5. Increased LDL Levels. In homozygous familial hypercholesterolemia, the response to drug therapy is usually inadequate. Plasmapheresis every 2 weeks, which is expensive and which reduces HDL-C and plasma proteins, is necessary in these patients. 70 Selective LDL pheresis or liver transplantation, which provides a patient with normal LDL receptors, offers promise for this deadly genetic disease. In heterozygous familial hypercholesterolemia and polygenic disease, drug therapy can be effective. Currently, the initial drugs of choice for patients with high LDL-C levels are bile acid sequestrants such as cholestyramine or colestipol. 40 ' 41,43 ' 71,72 These agents promote oxidation of cholesterol to bile acids by preventing resorption of bile acids, but they stimulate synthesis of cholesterol. In addition, they substantially the number of LDL receptors and are associated with slight s in HDL-C. The major problems with bile acid-sequestering resins are the appreciable, but not life-threatening, side effects. At low doses (16 g/day), bile acid resins tend to cause constipation. At high doses (30 g/day), they are not well tolerated and can cause loose stools. In some patients, constipation or diarrhea can occur regardless of the dose. Patients also complain of the taste and the sensation of nausea and fullness due to d bulk. Most patients can tolerate 16 to 20 g/day but do not like the inconvenience or the noted side effects. These agents are also quite expensive. Nicotinic acid, 1 to 3 g/day, is a relatively inexpensive, over-the-counter vitamin that can be added to resins as a second drug or given alone as the first agent. 38 ' 39,71,72 Nicotinic acid lowers the triglyceride level, raises HDL-C, and reduces LDL-C levels. The major side effects of nicotinic acid are pruritus and flushing. Thesi side effects can be mi imized during the initial 2 to 6 weeks of therapy by ingestion of a low dose of cyclooxygenast inhibitor (aspirin or indomethacin) 30 to 45 minutes before administration of each dose

9 Mayo Clin Proc, June 1988, Vol 63 LIPIDS AND CARDIOVASCULAR DISEASE 613 Drug Cholestyramine (Questran) Colestipol (Colestid) Nicotinic acid (niacin) Gemfibrozil (Lopid) Clofibrate (Atromid-S) Probucol (Lorelco) Eicosapentaenoic acid (fish oils) Lovastatin (Mevacor) Daily dose (g) ,200 mg ,000 mg mg Table 5. Drug Therapy for Lipid Disorders* Effect on Cholesterol Increase, no change, or decrease Triglycerides decrease *GI = gastrointestinal; HDL-C = high-density lipoprotein cholesterol. fbased on the mean cost from five local pharmacies. HDL-C Increase Increase Approximate cost/yrf $625-1, , , ,080 Adverse effect Taste, bloating, nausea, gout, constipation, diarrhea Same as above Pruritus, flushing, GI distress, glucose intolerance, gout, skin rash, dizziness, liver dysfunction, atrial arrhythmias Myositis, possibly cholelithiasis, GI distress Cholelithiasis, myositis, possible in GI malignant lesions Diarrhea, prolonged QT interval, GI distress Weight gain, immune dysfunction Liver function abnormalities, myositis or by use of slow-release preparations (although these may prolong the duration of flushing). Of note, these slow-release preparations of nicotinic acid are usually 5 to 10 times more expensive than generic nicotinic acid, but newer generic slow-release tablets may be lower in price. The flushing tends to decrease with time (because of development of drug tolerance) and is less of a problem with continued use of nicotinic acid. Careful monitoring of blood glucose levels and results of liver function tests is recommended with use of niacin, especially in high doses. A third agent that can be used is gemfibrozil. This drug lowers both total cholesterol and triglyceride levels and raises HDL-C. 73,74 This agent is usually more effective in lowering LDL-C when an associated in triglycerides is present. It is not as effective in isolated LDL-C elevation but can be added to resins as a third-line agent. In the recently published Helsinki trial, the sideeffect profile of gemfibrozil was considerably better than the side-effect profile of clofibrate, bile acid sequestrants, and nicotinic acid, and the reduction in coronary heart disease events was greater with gemfibrozil than that seen in the previous lipid prevention trials. 42 This evidence generates further enthusiasm for the d use of this agent. Probucol is another agent that considerably lowers LDL-C concentrations and induces regression of xanthomas. 75 In addition, preliminary information indicates that probucol may inhibit the oxidation and tissue deposition of LDL independent of its LDL-C-lowering effect. 59,76 Despite these potential beneficial effects, the substantial (often 25%) reduction of HDL-C levels by probucol, as well as the fact that this agent prolongs the QT interval and induces arrhythmias in animals and possibly humans (Vatterott P: Unpublished data), diminishes our enthusiasm for the use of this agent. 71,72,77 A new and promising drug, lovastatin (formerly, mevinolin), a hydroxymethylglutaryl-coenzyme A reductase inhibitor, has recently been approved and released by the Food and Drug Administration. This drug, alone or in combination with bile acid sequestrants or nicotinic acid, has effectively reduced cholesterol levels (Fig. 1 and 2). 71,78 " 81 This agent inhibits the rate-determining step in synthesis of cholesterol and s LDL re-

10 614 LIPIDS AND CARDIOVASCULAR DISEASE Mayo Clin Proc, June 1988, Vol 63 ceptors; thus, LDL-C levels are lowered by 30 to 50%. Lovastatin also decreases triglycerides by 25%) and may or may not raise HDL-C. In comparison with those who have familial hypercholesterolemia, patients with polygenic hypercholesterolemia have a slightly greater reduction in LDL-C and a significantly greater in HDL-C with lovastatin therapy. 71 Lovastatin has been extremely well tolerated in early trials. With experience in approximately 1,000 patients during a 4-year period, only 1% discontinued the drug because of side effects. 79 Concern persists over possible adverse side effects, such as cataracts (produced with very high doses of lovastatin in animal studies but not with clinical doses in human studies), liver dysfunction, and myositis, and possible long-term teratogenetic effects. The drug is not recommended for women of childbearing age, and recent reports cause concern for use in patients receiving immunosuppressive drugs (cyclosporine) or in combination with gemfibrozil. In the first 2,000 patients treated with lovastatin in clinical trials, myopathy (sometimes severe) developed in 13 in 5 of 15 patients (33%) who received lovastatin and cyclosporine, in 6 of 80 patients (7.5%) who received lovastatin and gemfibrozil, and in only 0.2% of patients who received neither immunosuppressive drugs nor gemfibrozil. 82 Myopathy has also occurred in about 2% of patients who received lovastatin and niacin (Tobert JA: Personal communication). Careful monitoring for cataracts, liver dysfunction, and myositis has been recommended. The substantial expense of this agent (more than $2,000 per year with the most effective [maximal] dose) must also be considered. Some patients, however, will show dramatic responses with low doses of the drug, such as 20 mg at nighttime. The cost of this dose is similar to that of the older pharmacologic agents (Table 5). This drug is the most powerful lipid (LDL-C)-lowering agent available; if prospective studies demonstrate a reduction in coronary heart disease and long-term safety is proved, it will likely become the drug of choice for initial drug therapy in patients with elevated LDL-C levels. Currently, we still recommend the bile acid resins, nicotinic acid, and gemfibrozil for single or combination therapy as the first-line agents. Lovastatin should be reserved for those patients who do not respond to these agents or who cannot tolerate the older, established drugs. Supplemental estrogens have also been reported to have beneficial effects on lipids (lowering LDL- C and raising HDL-C) and to decrease cardiovascular morbidity and mortality in women. 83,84 At present, however, gynecologists recommend the addition of progestin therapy to cyclic estrogen therapy in order to prevent gynecologic carcinoma. Progestational agents are known to in " E 300 -jf T I o 280 \ \ Ö 260 r. 240 (0 o V I I I I I mg b.i.d. ^ - ^ ^ - ^ - ^ I I I I I Weeks ~f- I 14 I : - -ί-ri I I ' Placebo en E 300 o JÜ 280 v> CD c 240 CO : i I-4 -* Γλ I I I I \ 10 mg b.i.d. \i? f I I 2 4 I ^v. 20 mg bid. 40 mg bid _ ^~^w* : x~^4- i Weeks _ Fig. 1. Effect of lovastatin (20 mg twice a day) on plasma cholesterol levels in patients with nonfamilial hypercholesterolemia. (From Lovastatin Study Group II. 78 By permission of the American Medical Association.) Fig. 2. Effect of increasing doses of lovastatin on plasma cholesterol levels in patients with nonfamilial hypercholesterolemia. (From Lovastatin Study Group II. 78 By permission of the American Medical Association.)

11 Mayo Clin Proc, June 1988, Vol 63 LIPIDS AND CARDIOVASCULAR DISEASE 615 crease LDL-C and lower HDL-C. Currently, we would not routinely recommend supplemental estrogens for protection against coronary heart disease except in those women with premature menopause due to bilateral oophorectomy. 85 Increased VLDL and LDL Levels. When dietary changes do not produce sufficient results in patients with d VLDL and LDL levels, pharmacologic therapy with nicotinic acid or gemfibrozil can be initiated. The use of bile acid sequestrants is relatively contraindicated in these patients because these agents may actually triglyceride levels. 71,72 In selected patients, bile acid resins can occasionally be used in conjunction with nicotinic acid or gemfibrozil. In this setting, lovastatin may play a larger role in the future. Increased VLDL Levels. If patients with d VLDL levels comply with dietary recommendations, drug therapy will rarely be needed; however, if patients are noncompliant or if dietary changes are ineffective, niacin (1.5 g/day) or gemfibrozil may be added to normalize lipid levels. Low HDL-C Levels. Although no reported studies have proved that increasing HDL-C levels will decrease coronary heart disease, attempts to do so seem reasonable, especially in patients with very low HDL-C levels and multiple cardiac risk factors or known atherosclerosis. In general, epidemiologic studies show that for every of 10 mg/dl in HDL-C, the risk of a coronary heart disease event decreases by about 50%. Therefore, nonpharmacologic measures to HDL-C should be implemented, including smoking cessation, control of blood glucose levels, weight reduction, regular aerobic exercise, and avoidance of anabolic steroids and progestational agents. Increasing dietary intake of omega-3 and omega-9 fatty acids may also HDL-C. 64 Drug therapy with nicotinic acid or gemfibrozil should be considered for patients with very low HDL-C levels (less than 30 mg/dl) or for patients with inadequate response to nonpharmacologic intervention. Frequently, patients with low HDL-C levels are refractory to both nonpharmacologic and drug therapy and have persistently low HDL-C values. Because of the risk of development of progressive coronary artery disease, consideration should be given to a trial of bile acid resins or lovastatin to reduce further the normal LDL-C levels and thereby alter the LDL/HDL ratio. No documented data have shown that this approach will alter the progression of coronary disease, but in high-risk patients, it seems theoretically sound. LOW CHOLESTEROL LEVELS AND CANCER Although low total cholesterol concentrations are associated with a decreased risk of coronary heart disease, several studies have suggested that an inverse relationship exists between levels of total cholesterol and death from several types of cancer If a low total cholesterol level is a cause of d carcinoma, then efforts to lower total cholesterol in the general population in order to decrease atherosclerosis could be questioned. Recent reports, however, suggest that a low total cholesterol level is a consequence rather than a cause of carcinoma. In the Framingham Study, no consistent association was found between cancer mortality and total cholesterol levels. 92 Recent data from the Multiple Risk Factor Intervention Trial confirmed the inverse relationship between total cholesterol levels and cancer mortality in men. 86 Both this report 86 and another study, 93 however, suggested that the relationship between total cholesterol and death from carcinoma decreases appreciably with time from the measurement of total cholesterol. In addition, the Multiple Risk Factor Intervention Trial demonstrated that in patients with subsequent development of carcinoma, total cholesterol levels began to decline 2 years before death from cancer. 86 These findings are consistent with the idea that the association between low total cholesterol and cancer is at least partially due to an effect of preclinical cancer on total cholesterol levels. In addition, dietary fat has, in fact, been implicated as a possible cause of colorectal and breast carcinoma in humans. 94 Two recent reports indicate a direct correlation between total cholesterol levels and risk of cancer of the colon and rectum. 95 ' 96 Although the occurrence of carcinoma must be carefully monitored in all lipid intervention trials, the risk of carcinoma should not be used as a reason for avoiding reduction of cholesterol in the primary and secondary prevention of atherosclerosis. LIPIDS AND ANTIHYPERTENSIVE AGENTS Antihypertensive therapy has had a dramatic influence on the risk of stroke and cerebrovascu-

12 616 LIPIDS AND CARDIOVASCULAR DISEASE Mayo Clin Proc, June 1988, Vol 63 lar mortality, but the effects on coronary heart disease are less dramatic. 97 Recently, investigators have focused attention not only on the effectiveness of lowering arterial pressure but also on left ventricular hypertrophy, 98,99 diastolic function, 100,101 ventricular ectopic activity, and lipid levels in hypertensive patients. 105,106 Various antihypertensive agents have vastly different effects on blood lipids (Table 6). We concur with the conclusions of Weinberger: 105 "Choosing the form of antihypertensive therapy least likely to worsen existent risk factors or precipitate their occurrence should enhance the benefit of blood pressure reduction in delaying or preventing cardiovascular disease." The more traditional and least expensive agents (thiazide diuretics and /3-blockers) are still acceptable agents in a given patient as long as the physician monitors the lipid profile. /3-Blockers with intrinsic sympathomimetic activity, cr-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, and diuretics with vasodilating effects (for example, indapamide) do not seem to have adverse effects on the lipid profile. Calcium entry blockers are particularly effective antihypertensive agents, especially in low-renin types of hypertension, and these agents have been shown to have beneficial effects on serum lipids 107 and to lessen atherosclerosis in animal models with hyperlipidemia, 108 " 110 as well as having antiplatelet effects, 111,112 regressing left ventricular hypertrophy, 106,113 improving diastolic function, 114 and decreasing ventricular ectopic activity (Nunez BD, Messerli FH: Unpublished data). These agents may prove to be particularly beneficial in the prevention of cardiovascular diseases. FISH OILS Two recent reports from our institution have discussed the potentially beneficial effects of fish and fish oils, which contain large amounts of omega-3 fatty acids, in preventive cardiology. 64,115 These substances have potent antiplatelet effects and beneficial lipid effects (lowering triglyceride and total cholesterol levels and raising HDLrC), and they reduce arterial pressure, decrease whole blood viscosity, erythrocyte deformability, and have been shown to be effective in animals and humans for various manifestations of atherosclerosis. In addition, epidemiologic data from the Greenland Eskimos, 116 Japan, 117 the Netherlands (Zutphen study), 118 and the Western Electric Company 119 indicate that d consumption of fish may lead to decreased mortality from ischemic heart disease. Other polyunsaturated fatty acids, such as omega-6 fatty acids (linoleic acid and arachidonic acid), have some of these beneficial effects, but they lower HDL-C and do not have potent antiplatelet effects. 63,64 On the basis of preliminary data, the lay public is being strongly encouraged to consume fish oil tablets by pharmaceutical companies, pharmacists, and health and exercise industries. To obtain the beneficial effects, a per- Drug Thiazide diuretics /3-Blockers Without ISA With ISA a-blockers Sympatholytics Calcium antagonists ACE inhibitors Table 6. Effects of Antihypertensive Agents on Lipids* Total cholesterol Increase decrease *ACE = angiotensin-converting enzyme; ISA : certain effect. Low-density lipoprotein cholesterol Increase decrease? High-density lipoprotein cholesterol decrease Increase 9 Triglycerides Increase Increase decrease decrease intrinsic sympathomimetic activity;? = un-

13 Mayo Clin Proc, June 1988, Vol 63 LIPIDS AND CARDIOVASCULAR DISEASE 617 son would have to ingest approximately 10 fish oil tablets/day (at a cost of $2 to $3 daily). This therapy has potential adverse effects, including d bleeding and possibly hemorrhagic stroke, 64 immune dysfunction, 120,121 increasing total cholesterol levels with low and moderate doses (whereas high doses reduce total cholesterol levels), 122,123 and vitamin A and D toxicity. 124 The antiplatelet and lipid effects of two over-the-counter, inexpensive agents low-dose aspirin and nicotinic acid are much more pronounced than changes induced by high-dose fish oilg 38,39,125,126 Although it seems prudent for Americans to eat less red meat and more fish (as long as it is not fried in saturated fats), we believe that supplemental fish oils should be considered experimental. Long-term controlled clinical trials that confirm both the efficacy and the lack of toxicity of fish oils are needed before these agents can routinely be recommended for either cardiac patients or the general population. CONCLUSION For prevention of cardiovascular diseases, attention must be focused on all the modifiable cardiovascular risk factors, including smoking, hypertension, obesity, diabetes mellitus, physical inactivity, and hypercholesterolemia. Smoking cessation is particularly important because it is associated with a 50 to 100% reduction in coronary heart disease events and a decrease in lung disease and cancer. The effect of smoking and hyperlipidemia on coronary heart disease, however, is more than additive; the Multiple Risk Factor Intervention Trial showed that one potentiates the other. 127 This factor may explain why coronary heart disease is relatively uncommon in Japan despite an excessive amount of cigarette smoking in that population. The current enthusiasm for management of lipids should be kept in perspective. As mentioned earlier, the clinical trials were performed primarily in middle-aged men. With use of epidemiologic data and results from the lipid intervention trials, these findings have been extrapolated to other populations (women and elderly persons); this should be done with caution. Although we would expect that aggressive management of lipids would decrease long-term mortality, this outcome has not yet been proved with the relatively short-term follow-up of the primary prevention trials with clofibrate, cholestyramine, or gemfibrozil. Long-term follow-up of the patients treated with nicotinic acid in a secondary prevention trial (CDP) did show a reduction in overall mortality. All the lipid-lowering agents are either expensive or have major side effects. Lovastatin, which may be the most promising of the lipid-lowering agents, does not yet have proven long-term efficacy and safety. Despite these reservations, we believe that the current data strongly support the concept of vigorous management of blood lipids, both with nonpharmacologic treatment and with drug therapy, for the primary and secondary prevention of coronary atherosclerosis. ACKNOWLEDGMENT We greatly appreciate the secretarial expertise of Audrey M. Schroeder and Ann M. Dahlman in the preparation of the submitted manuscript. REFERENCES 1. Lavie CJ, Squires RW, Gau GT: Prevention of cardiovascular disease: of what value are risk factor modification, exercise, fish consumption, and aspirin therapy? Postgrad Med 81:52-54; 59-62; 65-68; 70; 72, April Brown MS, Goldstein JL: A receptor-mediated pathway for cholesterol homeostasis. Science 232:34-47, Goldstein JL, Kita T, Brown MS: Defective lipoprotein receptors and atherosclerosis: lessons from an animal counterpart of familial hypercholesterolemia. N Engl J Med 309: , Grundy SM: Cholesterol and coronary heart disease: a new era. JAMA 256: , Nestel PJ: Overview: extending the indications for treating hypercholesterolemia. Am J Cardiol 57:3G-4G, Levy RI: Symposium reports on lipid regulation: a new era in the prevention of coronary heart disease (introduction). Am Heart J 112: , Ross R: The pathogenesis of atherosclerosis an update. N Engl J Med 314: , Lowering blood cholesterol to prevent heart disease (Consensus Conference). JAMA 253: , Simons LA: Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19 countries. Am J Cardiol 57:5G-10G, Amsterdam EA, Walker N, Ridgeway M, Tanji J, Baker L, Vera Z: Physician recognition of coronary risk factors: a disparity between approach to hypertension and hypercholesterolemia in patients hospitalized on a medicine service (abstract). J Am Coll Cardiol 9 (Suppl A):79A, 1987

14 618 LIPIDS AND CARDIOVASCULAR DISEASE Mayo Clin Proc, June 1988, Vol Watt P, Becker DM, Salaita K, Pearson TA: Cholesterol screening in patients undergoing coronary bypass surgery (abstract). J Am Coll Cardiol 9 (Suppl A):79A, Boekeloo B, Becker D, Yeo E, Pearson TA, Gillilan R: Post myocardial infarction cholesterol management by primary physicians (abstract). J Am Coll Cardiol 9 (Suppl A):77A, Taylor WC, Pass TM, Shepard DS, Komaroff AL: Cholesterol reduction and life expectancy: a model incorporating multiple risk factors. Ann Intern Med 106: , Becker MH: The cholesterol saga: whither health promotion? (editorial). Ann Intern Med 106: , Brunzell JD, Sniderman AD, Albers JJ, Kwiterovich PO Jr: Apoproteins B and A-I and coronary artery disease in humans. Arteriosclerosis 4:79-83, Goldstein JL, Brown MS: Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation 76: , Brown MS, Goldstein JL: How LDL receptors influence cholesterol and atherosclerosis. Sei Am 251:58-66, November Gordon T, Castelli WP, Hjortland MC, Kännel WB, Dawber TR: High density lipoprotein as a protective factor against coronary heart disease: the Framingham Study. Am J Med 62: , Hulley SB, Rhoads GG: The plasma lipoproteins as risk factors: comparison of electrophoretic and ultracentrifugation results. Metabolism 31: , Hamsten A, Walldius G, Dahl n G, Johansson B, De Faire U: Serum lipoproteins and apolipoproteins in young male survivors of myocardial infarction. Atherosclerosis 59: , Cabin HS, Roberts WC: Relation of serum total cholesterol and triglyceride levels to the amount and extent of coronary arterial narrowing by atherosclerotic plaque in coronary heart disease: quantitative analysis of 2,037 five mm segments of 160 major epicardial coronary arteries in 40 necropsy patients. Am J Med 73: , Newman WP III, Freedman DS, Voors AW, Gard PD, Srinivasan SR, Cresanta JL, Williamson GD, Webber LS, Berenson GS: Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis: the Bogalusa Heart Study. N Engl J Med 314: , Castelli WP: The triglyceride issue: a view from Framingham. Am Heart J 112: , Carlson LA, Böttiger LE: Risk factors for ischaemic heart disease in men and women: results of the 19-year follow-up of the Stockholm Prospective Study. Acta Med Scand 218: , Äberg H, Lithell H, Selinus I, Hedstrand H: Serum triglycerides are a risk factor for myocardial infarction but not for angina pectoris: results from a 10-year follow-up of Uppsala Primary Preventive Study. Atherosclerosis 54:89-97, Lapidus L, Bengtsson C, Lindquist O, Sigurdsson JA, Rybo E: Triglycerides main lipid risk factor for cardiovascular disease in women? Acta Med Scand 217: , Roheim PS: Atherosclerosis and lipoprotein metabolism: role of reverse cholesterol transport. Am J Cardiol 57:3C-10C, Kottke BA: Lipid markers for atherosclerosis. Am J Cardiol 57:11C-15C, Kannel WB: High-density lipoproteins: epidemiologic profile and risks of coronary artery disease. Am J Cardiol 52:9B-12B, Scheldt S: Lipid regulation: a clinician's view of patient management. Am Heart J 112: , Hopkins PN, Williams RR: Identification and relative weight of cardiovascular risk factors. Cardiol Clin 4:3-31, February Haskell WL, Camargo C Jr, Williams PT, Vranizan KM, Krauss RM, Lindgren FT, Wood PD: The effect of cessation and resumption of moderate alcohol intake on serum high-density-lipoprotein subfractions: a controlled study. N Engl J Med 310: , Miller NE: Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis. Am Heart J 113: , Maciejko JJ, Holmes DR, Kottke BA, Zinsmeister AR, Dinh DM, Mao SJT: Apolipoprotein A-I as a marker of angiographically assessed coronary-artery disease. N Engl J Med 309: , Kottke BA, Zinsmeister AR, Holmes DR Jr, Kneller RW, Hallaway BJ, Mao SJT: Apolipoproteins and coronary artery disease. Mayo Clin Proc 61:313^320, Squires RW, Bove AA, Kottke BA, Mao SJT, Staats BA, Menzel P: Exercise training and the apolipoprotein A-I to HDL-cholesterol ratio. J Cardiopulm Rehabil 7: , Oliver MF, Heady JA, Morris JN, Cooper J: A cooperative trial in the primary prevention of ischaemic heart disease using clofibrate: report from the committee of principal investigators. Br Heart J 40: , Coronary Drug Project Research Group: Natural history of myocardial infarction in the Coronary Drug Project: long-term prognostic importance of serum lipid levels. Am J Cardiol 42: , Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W (for the Coronary Drug Project Research Group): Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 8: , Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 251: , Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 251: , Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA: Helsinki Heart Study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipidemia; safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 317: , Brensike JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM, Loh IK, Stone NJ, Aldrich RF, Battaglini JW, Moriarty DJ, Fisher MR, Friedman L, Friedewald W, Detre KM, Epstein SE: Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. Circulation 69: , Levy RI, Brensike JF, Epstein SE, Kelsey SF, Passamani ER, Richardson JM, Loh IK, Stone NJ, Aldrich RF, Battaglini JW, Moriarty DJ, Fisher ML, Friedman L, Friedewald W, Detre KM: The influence of changes in lipid values induced by cholestyramine and diet on

15 Mayo Clin Proc, June 1988, Vol 63 LIPIDS AND CARDIOVASCULAR DISEASE 619 progression of coronary artery disease: results of the NHLBI Type II Coronary Intervention Study. Circulation 9: , Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hemphill L: Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 257: , Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease. JAMA 231: , Coronary Drug Project Research Group: The Coronary Drug Project: findings leading to discontinuation of the 2.5 mg/day estrogen group. JAMA 226: , Coronary Drug Project Research Group: Estrogens and cancer (letter to the editor). JAMA 239: , Cohn K, Sakai FJ, Längsten MF Jr: Effect of clofibrate on progression of coronary disease: a prospective angiographic study in man. Am Heart J 89: , Arntzenius AC, Kromhout D, Barth JD, Reiber JHC, Bruschke AVG, Buis B, van Gent CM, Kempen-Voogd N, Strikwerda S, van der Velde EA: Diet, lipoproteins, and the progression of coronary atherosclerosis: the Leiden Intervention Trial. N Engl J Med 312: , Buchwald H, Moore RB, Varco RL: Surgical treatment of hyperlipidemia. Circulation 49 (Suppl 1):I1-I37, Thompson GR, Myant NB, Kilpatrick D, Oakley CM, Raphael MJ, Steiner RE: Assessment of long-term plasma exchange for familial hypercholesterolaemia. Br Heart J 43: , Kuo PT, Hayase K, Kostis JB, Moreyra AE: Use of combined diet and colestipol in long-term (7-7V6 years) treatment of patients with type II hyperlipoproteinemia. Circulation 59: , Nash DT, Gensini G, Esente P: Effect of lipid-lowering therapy on the progression of coronary atherosclerosis assessed by scheduled repetitive coronary arteriography. Int J Cardiol 2:43-55, Nikkilä EA, Viikinkoski P, Valle M, Frick MH: Prevention of progression of coronary atherosclerosis by treatment of hyperlipidaemia: a seven year prospective angiographic study. Br Med J [Clin Res] 289: , Campeau L, Enjalbert M, Lesporance J, Vaislic C, Grondin CM, Bourassa MG: Atherosclerosis and late closure of aortocoronary saphenous vein grafts: sequential angiographic studies at 2 weeks, 1 year, 5 to 7 years, and 10 to 12 years after surgery. Circulation 68 (Suppl 2):II1-II7, Chesebro JH, Fuster V: Perioperative antithrombotic therapy for aortocoronary artery bypass graft operations. Curr Opinion Cardiol 1: , Campeau L, Enjalbert M, Lesperance J, Bourassa MG, Kwiterovitch P Jr, Wacholder S, Sniderman A: The relation of risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the native circulation: a study 10 years after aortocoronary bypass surgery. N Engl J Med 311: , Expert Panel: Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 148:36-69, Palumbo PJ: National Cholesterol Education Program: does the emperor have any clothes? (editorial). Mayo Clin Proc 63:88-90, Mann JI, Marr JW: Coronary heart disease prevention trials of diet to control hyperlipidemia. In Lipoproteins, Atherosclerosis, and Coronary Heart Disease. Edited by NE Miller, B Lewis. Amsterdam, Elsevier/North-Holland Biomedical Press, 1981, p Hjermann I, Velve Byre K, Holme I, Leren P: Effect of diet and smoking intervention on the incidence of coronary heart disease: report from the Oslo Study Group of a randomised trial in healthy men. Lancet 2: , Grundy SM: Dietary therapy for different forms of hyperlipoproteinemia. Circulation 76: , Lavie CJ, Squires RW, Gau GT: Preventive cardiology: what is the role of fish and fish oils in primary and secondary prevention? J Cardiopulm Rehabil 7: , Kushi LH, Lew RA, Stare FJ, Ellison CR, el Lozy M, Bourke G, Daly L, Graham I, Hickey N, Mulcahy R, Kevaney J: Diet and 20-year mortality from coronary heart disease: the Ireland-Boston Diet-Heart Study. N Engl J Med 312: , Anderson JW, Story L, Sieling B, Chen W-JL, Petro MS, Story J: Hypocholesterolemic effects of oat-bran or bean intake for hypercholesterolemic men. Am J Clin Nutr 40: , Anderson JW, Zettwoch N, Feldman T, Tietyen-Clark J, Oeltgen P, Bishop CW: Cholesterol-lowering effects of psyllium hydrophilic mucilloid for hypercholesterolemic men. Arch Intern Med 148: , Squires RW, Gau GT: Cardiac rehabilitation and cardiovascular health enhancement. In Cardiology: Fundamentals and Practice. Edited by RO Brandenburg, V Fuster, ER Giuliani, DC McGoon. Chicago, Year Book Medical Publishers, 1987, pp Superko HR, Haskell WH: The role of exercise training in the therapy of hyperlipoproteinemia. Cardiol Clin 5: , May East C, Grundy SM, Bilheimer DW: Normal cholesterol levels with lovastatin (mevinolin) therapy in a child with homozygous familial hypercholesterolemia following liver transplantation. JAMA 256: , Tikkanen MJ, Nikkilä EA: Current pharmacologic treatment of elevated serum cholesterol. Circulation 76: , Kottke BA: Apolipoprotein markers for coronary artery disease: a dissenting view. Drug Ther 16: ; ; ; ; 168; , October Kesäniemi YA, Grundy SM: Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man. JAMA 251: , Glueck C: Influence of gemfibrozil on high-density lipoproteins. Am J Cardiol 52:31B-34B, Yamamoto A, Matsuzawa Y, Yokoyama S, Funahashi T, Yamamura T, Kishino B-I: Effects of probucol on xanthomata regression in familial hypercholesterolemia. Am J Cardiol 57:29H-35H, Steinberg D: Studies on the mechanism of action of probucol. Am J Cardiol 57:16H-21H, Nestel PJ, Billington T: Effects of probucol on low density lipoprotein removal and high density lipoprotein synthesis. Atherosclerosis 38: , Lovastatin Study Group II: Therapeutic response to lovastatin (mevinolin) in nonfamilial hypercholesterolemia: a multicenter study. JAMA 256: , Tobert JA: New developments in lipid-lowering therapy: the role of inhibitors of hydroxymethylglutaryl-coenzyme A reductase. Circulation 76: , Havel RJ, Hunninghake DB, Illingworth DR, Lees RS, Stein EA, Tobert JA, Bacon SR, Bolognese JA, Frost PH, Lamkin GE, Lees AM, Leon AS, Gardner K, Johnson G, Mellies MJ, Rhymer PA, Tun P: Lovastatin

16 620 LIPIDS AND CARDIOVASCULAR DISEASE Mayo Clin Proc, June 1988, Vol 63 (mevinolin) in the treatment of heterozygous familial hypercholesterolemia: a multicenter study. Ann Intern Med 107: , Malloy MJ, Kane JP, Kunitake ST, Tun P: Complementarity of colestipol, niacin, and lovastatin in treatment of severe familial hypercholesterolemia. Ann Intern Med 107: , Tobert JA: Reply to letters to the editor. N Engl J Med 318:48, Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM: Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 75: , Stampfer MJ, Wille«WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH: A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 313: , Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH: Menopause and the risk of coronary heart disease in women. N Engl J Med 316: , Sherwin RW, Wentworth DN, Cutler JA, Hulley SB, Kuller LH, Stamler J: Serum cholesterol levels and cancer mortality in 361,662 men screened for the Multiple Risk Factor Intervention Trial. JAMA 257: , Beaglehole R, Foulkes MA, Prior IA, Eyles EF: Cholesterol and mortality in New Zealand Maoris. Br Med J [Clin Res] 280: , Rose G, Shipley MJ: Plasma lipids and mortality: a source of error. Lancet 1: , Williams RR, Sorlie PD, Feinleib M, McNamara PM, Kannel WB, Dawber TR: Cancer incidence by levels of cholesterol. JAMA 245: , Morris DL, Borhani NO, Fitzsimons E, Hardy RJ, Hawkins CM, Kraus JF, Labarthe DR, Mastbaum L, Payne GH: Serum cholesterol and cancer in the Hypertension Detection and Follow-up Program. Cancer 52: , Keys A, Aravanis C, Blackburn H, Buzina R, Dontas AS, Fidanza F, Karvonen MJ, Menotti A, Nedeljkoviö S, Punsar S, Toshima H: Serum cholesterol and cancer mortality in the Seven Countries Study. Am J Epidemiol 121: , Anderson KM, Castelli WP, Levy D: Cholesterol and mortality: 30 years of follow-up from the Framingham study. JAMA 257: , International Collaborative Group: Circulating cholesterol level and risk of death from cancer in men aged 40 to 69 years: experience of an International Collaborative Group. JAMA 248: , Gregorio DI, Emrich LJ, Graham S, Marshall JR, Nemoto T: Dietary fat consumption and survival among women with breast cancer. JNCI 75:37-41, Törnberg SA, Holm L-E, Carstensen JM, Eklund GA: Risks of cancer of the colon and rectum in relation to serum cholesterol and beta-lipoprotein. N Engl J Med 315: , Mannes GA, Maier A, Thieme C, Wiebecke B, Paumgartner G: Relation between the frequency of colorectal adenoma and the serum cholesterol level. N Engl J Med 315: , Hebert P, Taylor JO, Hennekens CH: An overview of trials of pharmacologic therapy of mild hypertension (abstract). J Am Coll Cardiol 7 (Suppl A):164A, Messerli FH, Devereaux RB: Introduction: left ventricular hypertrophy good or evil? Am J Med 75 (Suppl 3A):l-3, Kannel WB: Prevalence and natural history of electrocardiographic left ventricular hypertrophy. Am J Med 75 (Suppl 3A):4-11, DeMaria AN, Wisenbaugh T: Identification and treatment of diastolic dysfunction: role of transmitral Doppler recordings. J Am Coll Cardiol 9: , Lavie CJ, Amodeo C, Ventura HO, Messerli FH: Left atrial abnormalities indicating diastolic ventricular dysfunction in cardiopathy of obesity. Chest 92: , Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Fröhlich ED: Hypertension and sudden death: d ventricular ectopic activity in left ventricular hypertrophy. Am J Med 77:18-22, Lavie CJ, Nunez BD, Garavaglia GE, Messerli FH: Concentric left ventricular hypertrophy when is ventricular ectopic activity d? (abstract). J Am Coll Cardiol 9 (Suppl A):226A, Messerli FH, Nunez BD, Ventura HO, Snyder DW: Overweight and sudden death: d ventricular ectopy in cardiopathy of obesity. Arch Intern Med 147: , Weinberger MH: Antihypertensive therapy and lipids: evidence, mechanisms, and implications. Arch Intern Med 145: , Dzau VJ: Evolution of the clinical management of hypertension: emerging role of "specific" vasodilators as initial therapy. Am J Med 82 (Suppl 1Α):36-43, Pool PE, Seagren SC, Salel AF: Effects of diltiazem on serum lipids, exercise performance and blood pressure: randomized, double-blind, placebo-controlled evaluation for systemic hypertension. Am J Cardiol 56:86H- 91H, Henry PD, Bentley KI: Suppression of atherogenesis in cholesterol-fed rabbit treated with nifedipine. J Clin Invest 68: , Habib JB, Bossaller C, Henry PD: Suppression of atherogenesis in cholesterol-fed rabbit with a low-dosed calcium antagonist (PN ) (abstract). J Am Coll Cardiol 7 (Suppl A):58A, Sievers R, Rashid T, Garrett J, Blumlein S, Parmley W: Verapamil and diet halt progression of atherosclerosis in cholesterol fed rabbits (abstract). J Am Coll Cardiol 7 (Suppl A):58A, Mehta J, Mehta P, Ostrowski N: Calcium blocker diltiazem inhibits platelet activation and stimulates vascular prostacyclin synthesis. Am J Med Sei 291:20-24, Mehta J, Mehta P, Ostrowski N, Crews F: Effects of verapamil on platelet aggregation, ATP release and thromboxane generation. Thromb Res 30: , Amodeo C, Kobrin I, Ventura HO, Messerli FH, Fröhlich ED: Immediate and short-term hemodynamic effects of diltiazem in patients with hypertension. Circulation 73: , Smith V-E, White WB, Meeran MK, Karimeddini MK: Improved left ventricular filling accompanies reduced left ventricular mass during therapy of essential hypertension. J Am Coll Cardiol 8: , Ballard-Barbash R, Callaway CW: Marine fish oils: role in prevention of coronary artery disease. Mayo Clin Proc 62: , Bang HO, Dyerberg J: Lipid metabolism and ischemic heart disease in Greenland Eskimos. Adv Nutr Res 3:1-22, Kagawa Y, Nishizawa M, Suzuki M, Miyatake T, Hamamoto T, Goto K, Motonaga E, Izumikawa H, Hirata H, Ebihara A: Eicosapolyenoic acids of serum lipids of Japanese islanders with low incidence of cardiovascular diseases. J Nutr Sei Vitaminol (Tokyo) 28: , 1982

17 Mayo Clin Proc, June 1988, Vol 63 LIPIDS AND CARDIOVASCULAR DISEASE Kromhout D, Bosschieter EB, de Lezenne Coulander C: The inverse relation between fish consumption and 20- year mortality from coronary heart disease. N Engl J 124. Med 312: , Shekelle RB, Missell L, Paul O, Shryock AM, Stamler J: Fish consumption and mortality from coronary heart 125. disease (letter to the editor). N Engl J Med 313:820, Lee TH, Hoover RL, Williams JD, Sperling RI, Ravalese J III, Spur BW, Robinson DR, Corey EJ, Lewis RA, 126. Austen KF: Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med 312: , Prescott SM: The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils. J Biol Chem 259: , Thompson GR: Lipids, fish, and coronary heart disease. Curr Opinion Cardiol 1: , Sullivan DR, Sanders TAB, Trayner IM, Thompson GR: Paradoxical elevation of LDL apoprotein B levels in hypertriglyceridaemic patients and normal subjects ingesting fish oil. Atherosclerosis 61: ,1986 Sanders TAB, Naismith DJ, Haines AP, Vickers M: Cod-liver oil, platelet fatty acids, and bleeding time (letter to the editor). Lancet 1:1189,1980 Lavie CJ, Schmieder RE, Genton E: Antiplatelet therapy for cardiovascular disease. Cardiovasc Rev Rep 8:64-69, June 1987 Fuster V, Chesebro JH: Antithrombotic therapy: role of platelet-inhibitor drugs. II. Pharmacologic effects of platelet-inhibitor drugs (second of three parts). Mayo Clin Proc 56: ,1981 Stamler J, Wentworth D, Neaton J (for the MRFIT Research Group): Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 256: ,1986