- Email: [email protected]
Interactions of the major risk factors for coronary heart disease
Interactions of the Major Risk Factors for Coronary Heart Disease
ANTONIO M. GOTTO, Jr., M.D. Houston.
Texas
From the Department of Medicine, Houston, should be addressed partment of Medicine, 6536 Fannin, MS. A
48
Since cardiovascular disease accounts for more than 50 percent of all deaths in the United States today, researchers in a number of major clinical studies have attempted to determine whether this epidemic of cardiovascular deaths can be controlled by reducing the primary risk factors for coronary heart disease and atherosclerosis. Treatment of one of these risk factors, hypertension, has clearly been proven beneficial in reducing the morbidity and mortality of cardiovascular disease. These positive effects are seen at the three levels of hypertension: mild, moderate, or severe. Another risk factor, cigprette smoking, is generally accepted to be the single most preventable cause of death from coronary heart disease in the United States. The mortality rate for coronary heart disease is two to three tlmes greater In those who are heavy smokers, representing a substantial independent risk factor, and the risk is even higher when smokers are also hypertensive and hypercholesterolemic. A third risk factor, hypercholesterolemia, has come under renewed scrutiny, and several recent studies have shown that lowering cholesterol through the use of diet or drugs can reduce the progression of atherosclerotic plaque. Based on the results of various intervention trials over the years, it appears that methods of preventing cardiovascular disease in the general=population, such as emphasizing the importance of diet and exercise, should be promoted. The American Heart Association recommendations, if adopted, could effect changes in attltudes of those in the medical community, at work sites, and even in schools. In addition to prophylactic measures, an intensive effort to identify and treat persons at high risk should be undertaken.
February
of Medicine, Baylor College Texas. Requests for reprints to Dr. Antonio Gotto, Jr., DeBaylor College of Medicine, 601, Houston, Texas 77030.
14, 1986
The American
Jouinal
Hypertension, cigarette smoking, and hypercholesterolemia are clearly identified as the three major risk factors for coronary heart disease and atherosclerosis. In addition, diabetes mellitus is an important risk factor for both large-vessel and small-vessel disease. There are several other risk factors that are usually considered to be secondary, including lack of exercise, type A personality, obesity, and hypertriglyceridemia. Hypertension. It is estimated that about 20 percent of adult Americans have hypertension, which is defined as a consistent elevation of arterial blood pressure. The benefit of treating even mild hypertension has now been confirmed in the Hypertension Detection and Follow-up Program [l]. The earlier Veterans Administration Study [2] had shown a decrease in mortality in patients with moderate or severe hypertension who received treatment. In the Hypertension Detection and Follow-up Program sponsored by the National Heart, Lung, and Blood Institute, 5,485 pa-
of Medicine
Volume
80
(suppl 2A)
SYMPOSIUM
tients were treated aggressively while the same number were referred to private physicians and community facilities. The treatment was clearly beneficial in terms of reducing mortality, particularly mortality from cerebrovascular disease. Even among individuals with mild hypet-tension (diastolic blood pressure values ranging between 90 and 104 mm Hg), the mortality rate was decreased by 20 percent in the group receiving aggressive treatment. Overall, the mortality rate was decreased by 17 percent in the group of patients who were aggressively treated for hypertension [l]. Cigarette Smoking. The Surgeon General has concluded that cigarette smoking is the single most preventable cause of coronary heart disease death for both males and females in the United States [3]. Because of the large number of individuals who smoke and the risks associated with cigarette smoking, the importance of this risk factor cannot be overemphasized. Smokers have a 70 percent higher mortality rate from coronary heart disease than do nonsmokers. For heavy smokers, those who consume two or more packs per day, the mortality rate for coronary heart disease is tie to three times greater than that for nonsmokers. Although cigarette smoking is one of the three major risk factors and is an independent rjsk factor for coronary heart disease, it also acts synergistically with hypertension and hypercholesterolemia. Women who smoke and use oral contraceptives have approximately a tenfold greater risk of myocardial infarction when compared with women who are nonsmokers and who do not use oral contraceptives. Cigarette smoking also increases the risk of cerebrovascular disease and sudden death. The mortality rate for coronary heart disease in smokers is higher in younger than in older age groups. The Surgeon General has estimated that cigarette smoking is respor@ble for approximately 30 percent of &II deaths from coronary heart disease in the United States each year. It is also estimated that in the United States during the period from 1965 to 1980, there were more than 3 million premature deaths from heart disease because of cidarette smoking. If current smoking trends continue, as many as 10 percent of all persons now living may die prematurely from heart disease attributable to smoking. Hypercholesterolemia. Every epidemiologic study that has been carried out to date has shown a strong positive relationship between the concentration of serum cholesterol at the time of entry into the study and the risk of coronary heart disease. The Lipid Research Clinics Coronary Primary Prevention Trial, the most definitive study to date, was planned in the United States in the early 1970s [4,5]. The purpose of the trial was to test the lipid hypothesis and, specifically, to test whether or not lowering the concentration of low-density lipoprotein cholesterol would result in a reduction in the risk of coronary heart disease. After screening and identifying individuals who qualified
February
14, 1999
ON INITIAL ANTIHYPERTENSIVE
THERAPY-GOlTO
Figure 1. Life-table cumulative incidence
of primary end point (definite coronary heart disease death and/or definite nonfatal myocardial infarction) ii, treatment groups, computed by Kaplan-Meier method. N = total nurqber of participants in the Lipid Research Clinics Coronary Primary Prevention Trial at risk for their first primary end point at each time point. Adapted from 141, with permission.
for the study, 3,806 men were selected and randomly assigned to control and treatment groups. Both groups were treated with a diet that was aimed at lowering cholesterol levels by approximately 3 to 5 percent. The actual reduction was 4 percent. The drug used in the study was cholestyramine, a bjle acid sequestrant that is not well tolerated by patients. Nevertheless, a compliance rate of 66 percent was noted among the treatment groups over the length of the study, a period of seven years. The average chobsterol decrease was 9 percent greater in the treatment group than in the placebo group and low-density lipoprotein cholesterol was reduced by 12 percent. Reductions in low-density lipoprotein cholesterol levels resulted in a 19 percent reduction in the total number of nonfatal myocardial infarctions and coronary heart disease deaths. The reduction in the risk of coronary heart disease was also reflected by significant decreases in the incidence of angina pectoris, the incidence of positive exercise electrocardiographic results, and in the need for coronary bypass surgery in the group receiving cholestyramine. The benefits of the Lipid Research Clinics Coronary Primary Prevention Trial, in terms of reducing the risk of coronary heart disease, were solely related to the degree of cholesterol lowering; the greater the degree of lowering, the greater the reduction in risk (Figure 1). Low-density lipoprotein is the lipoprotein mqst closely associated with atherosclerosis, and concentrations of this ligoprotein are related in a curvilinear route and continuous manner with the prevalence of coronary heart disease. concentrations of high-density lipoprotein, on the
The
American
Journal
of Medicine
Volume
99 (suppl
2A)
49
SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
-
THERAPY-GOTTO
ThwshoM
for increased coronary risk
Relative number of LDL receptors
Figure 2. Low-density lipoprotein receptors and plasma low-density lipoprotein cholesterol levels. Adapted from IS], with permission. FH = familial hypercholesterolemia.
LDL-cholesterol level OWN
protein cholesterol value of approximately 25 mg/dl. The relationship between the concentration of low-density lipoprotein cholesterol and the concentration of low-density lipoprotein receptors, derived from the work of Brown and Goldstein [6], is shown in Figure 2. The higher the concentration of hepatic receptors, the lower the concentration of low-density lipoprotein cholesterol. Hepatic receptor activity is high in human newborns and in various other species that are not susceptible to arteriosclerosis. The distribution of low-density lipoprotein values in the population of the United States is slightly more skewed at the upper or higher end of low-density lipoprotein values. It seems likely that there is a critical low-density lipoprotein value, below which atherosclerosis and coronary disease do not occur. It is known that a cholesterol value of 220 to 230 mg/dl does not assure protection against arteriosclerosis. The presence of hypertension and/or cigarette smoking increases the risk associated with this level of cholesterol. At the Methodist Hospital in Houston, the average serum cholesterol concentration for patients who are undergoing coronary arteriography and who have significant obstructive disease is approximately 230 mg/dl. If the cholesterol hypothesis is accepted, then on the basis of the results of the Lipid Research Clinics Coronary Prlmary Prevention Trial and other studies, this curve must be shifted to a lower level if a further substantial reduction in the coronary mortality rate is to be made in this country. Several studies during the past year have shown that decreasing cholesterol through diet or through medication can reduce the progression of atherosclerotic plaque. These studies have been performed by using coronary arteriography to examine femoral or coronary arteries.
other hand, have been shown by population studies to be inversely related to the prevalence of coronary heart disease. Animal studies have shown that experimentally induced elevations in low-density lipoprotein can predispose to afherosclerosis; however, evidence linking elevations in high-density lipoprotein with protection against atherosclerosis is not found in these studies. In animal experiments, the induction of hypertension can accelerate the development and progression of dietary-induced atherosclerosis. Serum cholesterol levels reflect the concentration of low-density lipoprotein cholesterol but not high-density lipoprotein cholesterol. The risk of coronary disease at a given level of low-density lipoprotein depends on the concentration of high-density lipoprotein cholesterol, as well as the occurrence of other risk factors such as hyperfension and cigarette smoking. The risk for a given person with a particular cholesterol value depends on the presence of other risk factors, the sex and age of the person, and the concentration of high-density lipoprotein. Risk increases with total cholesterol and low-density lipoprotein values as a continuous function. The rate at which low-density lipoprotein cholesterol is transferred from the blood into arterial walls has been measured using radiolabeled lipoproteins [6]. It can be estimated by extrapolation that the transfer of a low-density lipoprotein particle into the artery is slight at a low-density lipoprotein cholesterol concentration below 40 to 80 mg/dl. It can also be calculated that the low-density lipoprotein receptors are half saturated when the concentration of low-density lipoprotein cholesterol in the tissue fluid is approximately 2.5 mg/dl. This corresponds to a plasma low-density lipo-
50
February
14,1986
The Amerkan
Journal
d Medklne
Volume
80
(suppl2A)
SYMPOSIUM
Duffield and co-workers [7] completed a study of 24 patients with femoral arteriosclerosis. Half of the patients received no treatment, and the other half received dietary advice and cholestyramine, nicotinic acid, or clofibrate, depending on their lipoprotein phenotypes. Treatment with diet and cholesterol-lowering drugs reduced total plasma cholesterol by 25 percent, the mean low-density lipoprotein by 28 percent, and mean plasma triglycerides by 45 percent. The progression of femoral arteriosclerosis (monitored by femoral arteriography) was significantly delayed in the treatment group when compared with the control group. In a randomized trial performed at the National Heart, Lung, and Blood Institute [8], 118 patients who were treated with either placebo or cholestyramine and who underwent repeat coronary angiography were followed for a total of five years. Patients with the greatest reduction in low-density lipoprotein levels or greatest increase in highdensity lipoprotein levels had the greatest delay in progression of coronary atherosclerosis. The rate of growth of plaques was significantly diminished in those who had more than 50 percent blockage of the lumen of a major coronary artery. Elevation of high-density lipoprotein levels was correlated with a decrease in the progression of coronary atherosclerosis and appeared to act independently of a reduction in low-density lipoprotein. The rate of growth of coronary plaque decreased in proportion to the increase in the ratio of high-density lipoprotein to total plasma cholesterol and to low-density lipoprotein cholesterol. Nikkila et al [9] treated 30 patients with hyperlipoproteinemia and two- or three-vessel coronary artery disease with diet and clofibrate or nicotinic acid. Coronary arteriography was performed before therapy was initiated and after two ano seven years. Patients with the greatest degree of cholesterol lowering showed no progression of coronary arteriosclerosis, whereas those with higher levels of cholesterol showed a marked progression. In the Leiden Intervention Trial [lo], 39 patients with stable angina pectoris were treated with a vegetarian diet alone for two years. Patients with the lowest ratios of total cholesterol to high-density lipoprotein cholesterol showed no coronary disease progression, and some even showed regression. TREATMENT
Treatment goals for the prevention of cardiovascular disease can be approached in two ways. One approach is based on the recommendation of several hygienic measures for the overall population that are aimed at a general reduction in the level of risk factors. The second approach involves identifying those persons who are particularly at high risk and undertaking an intensive effort to reduce their risk factors. The hygienic measures are similar to those that the
14,1999
THERAPY-GOTTO
American Heart Association has recommended for the general population for more than 20 years. The first measure would be the avoidance of tobacco. I cannot overemphasize the deleterious effects cigarette smoking has on the cardiovascular system, especially in the presence of diabetes or even slight elevations in serum cholesterol or blood pressure levels. One of the most important dietary recommendations is to maintain ideal body weight as closely as possible and to avoid obesity. This will favorably affect serum cholesterol and triglyceride levels, as well as blood pressure values. Reducing overall obesity would also be expected to decrease the incidence of type II diabetes in the general population. Specific dietary recommendations of the American Heart Association are to decrease the total fat consumption to no more than 30 percent of the calories, with approximately 10 percent derived from saturated fats, 10 percent from polyunsaturated fats, and 10 percent from monounsaturated fats. If these guidelines were followed, and if daily cholesterol consumption could be kept to under 300 mg per day, the serum cholesterol level of the general population could be reduced by 10 to 15 percent. In fact, over the past 20 years, the American population has moved toward adopting this diet, and the average serum cholesterol value has decreased. Furthermore, reducing the consumption of saturated fat has been shown to have a beneficial effect in lowering blood pressure. Avoiding excessive consumption of salt by not adding salt to food over and above that used in cooking, for example, may result in an overall decrease in the blood pressure in the population. In societies in which there is a high salt consumption, as in Japan and China, death from cerebrovascular disease ranks at or near the top as the cause of death. However, the incidence of atherosclerotic cardiovascular disease may be quite low in these societies, a fact presumably due to a low consumption of saturated fat and total fat in the diet. The other hygienic recommendation deals with physical exercise. This may be a useful adjunct in controlling obesity, hyperlipidemia, hypertension, and diabetes. Although these general measures are not aimed specifically at a hypercholesterolemic or a hypertensive population, if adopted, they should have an effect on all levels of cholesterol and blood pressure in the population. In the American population, as in other Western societies, both blood pressure and serum cholesterol levels tend to increase with age, especially after adolescence. It is possible that changes in dietary patterns and exercise habits might prevent these age-related increases in the level of risk factors. Age itself is the greatest single risk factor for cardiovascular disease in Western society, and although aging cannot be prevented, some of the metabolic changes associated with aging might be prevented or at least forestalled.
GOALS
February
ON INITIAL ANTIHYPERTENSIVE
The
American
Journal
ol Medicine
Volume
99 (suppl2A)
51
SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
THERAPY-GOTTO
-m-m -1-1
I
I
100
Ideal mean 160 mg/dl, SD-25 mg/dl = Feasible mean 190 mg/dl, SD-30 mg/dl Present mean 210 mg/dl, SD-35 mg/dl
I
150
I
200
250
1
300
Total Serum cholesterol (mg/dl)
I.-II ----
0
100
150
ideal mean 110 mg/dl, SD-20 mg/dl Feasible mean 140 mg/dl, SD-25 mg/dl Pmsent mean 160 mg/dl, SD-25 mg/dl
Figure 3. Ideal, feasible, and existing total serum cholesterol levels in adults (top) and children, aged 5 to 18 (bottom). Adapted from [ll], with permission.
200
Tote1Serum cholesterol (mg/dl)
It appears that if these measures are to be successful, they would have to be adopted by the general population rather than by a group of individuals who are at highest risk based on arbitrarily defined upper limits of normal. Thus, the goals of the hygienic approach would be to reduce serum cholesterol levels and blood pressure in the general population to desirable or ideal levels. We at Baylor College of Medicine, believe that reducing serum cholesterol and blood pressure values would dramatically decrease the mortality rate for cerebrovascular disease, and, furthermore, that the adoption of such changes would pose little risk to the population. The lower limit of safety for a cholesterol value should be approximately 100 mgldl, since some patients with hypobetalipoproteinemia and values below this level have neurologic and hematologic abnormalities. Concerns for an increased incidence of cerebral hemorrhage and cancer of the colon in individuals with low cholesterol values have not been borne out. Life expectancy in Japan and Italy is slightly greater than that in the United States even though the cholesterol levels are substantially lower in those countries. This is due primarily to lower mortality from coronary heart disease. The serum cholesterol level
52
February
14,1986
The American
Journal
of Medlclne
is obviously closely related to the dietary habits of the population. In societies in which the diet is mainly vegetarian and the individual level of physical activity is high, the serum cholesterol level may range from 100 to 140 mg/dl. In Greece, Yugoslavia, Italy, the Mediterranean countries, Latin America, and urban Japan, the cholesterol values average from 180 to 200 mg/dl. The incidence of coronary heart disease in these countries is much less than that in many of the industrialized societies of the West [l 11. Based on results obtained from dietary intervention in free-living populations, the results shown in Figure 3 represent feasible cholesterol values for adults and children [ll]. Values should be calculated separately for males and females and should be adjusted for age. It may be necessary to obtain a cholesterol value of 140 mg/dl for children in order to reach the 190 mg/dl value for adults. At the end of adolescence and the beginning of adulthood, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol is approximately one to one. In primitive societies, this ratio does not change substantially during later adult life. However, the change in this ratio in Western societies is remarkable. The level of high-density lipoprotein stays about the same, but the level of low-density
Volume
80 (suppl2A)
SYMPOSIUM
THERAPY
FOR HIGH-RISK
POPULATIONS
In selecting therapy for one risk factor of coronary heart disease, it is important to study a patient’s entire profile. Each risk factor makes its own contribution and may act synergistically with other risk factors. Augmentation of coronary heart disease has occurred when more than one risk factor is present and, therefore, it may be a mistake to emphasize one factor (lack of exercise, smoking, blood pressure, or diet) to the exclusion of others. Initial treatment of risk factors should be hygienic and as physiologic as possible. If hypercholesterolemia or hypertension can be controlled by diet and/or weight loss, this obviously is a more desirable approach than using drugs. Reducing caloric intake and the saturated-fat content of the diet and restricting salt intake in hypertensive patients may be adequate therapy to control serum cholesterol or blood pressure elevations in the mild to moderate range. If these measures fail, pharmacologic therapy is required, but less medication will be needed and a greater reduction in the abnormal risk factor will be achieved if a restricted diet is followed as well. Furthermore, cigarette smoking may offset any improvement achieved with diet, exercise, or drugs. The Lipid Research Clinics Coronary Primary Prevention Trial illustrates explicitly the way in which a risk factor operates on a continuum: in that study, the greater the reduction in cholesterol and low-density lipoprotein levels,
February
14, 1986
THERAPY-GOTTO
the greater the decrease in the incidence of myocardial infarction. Thus, the benefits of cholesterol reduction could be observed even before optimal cholesterol and low-density lipoprotein levels had been achieved. Metabolic Effects of Treatment. When one risk factor is treated, it is important to be aware of both positive and negative effects on other risk factors. For example, when one stops smoking and begins a program of physical exercise, each of these changes may affect the cardiovascular system in multiple beneficial ways, including raising the concentration of high-density lipoprotein cholesterol. Conversely, in some patients, treatment of hypercholesterolemia or hypertriglyceridemia with fibric acid drugs such as clofibrate may result in an increase in the concentration of low-density lipoprotein cholesterol. In the treatment of hypertension, beta blockers increase cholesterol and triglycerides and decrease high-density lipoprotein cholesterol. Diuretics may increase the concentration of total plasma cholesterol, triglycerides, and low-density lipoprotein cholesterol. The alpha blocker prazosin does not appear to adversely affect lipid ratios and, in fact, may have a favorable effect by decreasing the concentration of low-density lipoprotein cholesterol and increasing the concentration of plasma high-density lipoprotein. Clonidine, hydralazine, and reserpine are not known to have adverse effects on lipids. Thiazide diuretics and chlotthalidone increase the concentrations of plasma cholesterol and triglycerides and decrease high-density lipoprotein cholesterol levels. In the Lipid Research Clinics Prevalence Survey, propranolol was associated with about a 15 percent reduction in high-density lipoprotein cholesterol levels in females. However, other agents, such as the alpha blocker prazosin, do not have these adverse effects on serum lipids. Cholesterol concentrations are modified by the sex hormones as follows: estrogens increase triglycerides and high-density lipoprotein and decrease lowdensity lipoprotein; progesterones increase low-density lipoprotein and decrease triglycerides and high-density lipoprotein; and androgens increase cholesterol and lowdensity lipoprotein and decrease high-density lipoprotein. The 1984 National Institutes of Health Cholesterol Consensus Conference defined levels of cholesterol risk as follows: men and women from the ages of 20 to 29 are considered at moderate risk if their cholesterol levels are above 200 mg/dl, and at high risk if their levels are above 220 mg/dl; those from the ages of 30 to 39 are considered at moderate risk if their cholesterol levels are more than 220 mg/dl, and at high risk if their levels are more than 240 mg/dl. For those men and women over 40 years of age, moderate risk is defined as a cholesterol level of more than 240 mg/dl, and high risk is a level exceeding 260 mg/dl. These values are to be used in selecting patients requiring treatment. For those at mild to moderate risk, dietary treatment should be undertaken, in most instances, using the step-
lipoprotein increases by two and one half to three times between the period of the late teens and the early thirties. Thus, clinical investigation, clinical trials, epidemiologic study, pathologic data, and laboratory data all converge to support the view that cholesterol and low-density lipoprotein values in the United States and Western Europe are too high. Values above 200 mg/dl do not lead to optimal cardiovascular health. Indeed, this figure should be even lower when other risk factors, such as high blood pressure and cigarette smoking, are considered. The best lipid indicators of a population’s risk for coronary heart disease are obtained by examining the ratio of total cholesterol or low-density lipoprotein to the concentration of highdensity lipoprotein. The risk of persons in affluent, industrialized societies such as ours is improved by considering the high-density lipoprotein value. In the United States, the high-density lipoprotein value becomes an important predictor of coronary heart disease after the age of 55. The ultimate question is whether an individual’s circulatory system benefits from treatment of the various risk factors. The effect of a reduction in blood pressure on mortality and cerebrovascular disease is well established. Recent trials, described earlier, have shown that lowering cholesterol and low-density lipoprotein levels decreases the incidence of nonfatal myocardial infarction and the rate of progression of atherosclerosis in the coronary and femoral arteries. INTENSIVE
ON INITIAL ANTIHYPERTENSIVE
The
American
Journal
of Medicine
Volume
80 (suppl
2A)
53
SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
TABLE I
THERAPY-GOTTO
Dietary Goals for Phases 1, 2, and 3 of the American Heart Association’s LipidLowerlng Diet
Bile acid sequestrants are believed to increase the number of hepatic low-density lipoprotein receptors by decreasing the intrahepatic concentration of cholesterol. Nicotinic acid blocks lipolysis in adipose tissue and decreases the flux of free fatty acids to the liver. It may also decrease the hepatic synthesis of very-low-density lipoproteins. The fibric acid derivatives have similar effects and also decrease hepatic cholesterol synthesis in animals. The precise action of probucol, as with the above listed hypochoiesteroiemic agents, is not yet clearly understood. in animal experiments, probucol has been shown to alter the structure of low-density lipoprotein, resulting in a more protein-rich particle, which may be preferentially cleared by a scavenger pathway in the liver involving the macrophage and not the low-density lipoprotein receptor mechanism. I believe that it is essential to emphasize the detection and treatment of hypercholesterolemia by physicians. One recent survey reported that only 39 percent of physicians believed that cholesterol values were significant coronary heart disease risk factors as compared with more than 80 percent who felt that hypertension was a significant risk factor. The National institutes of Health Cholesterol Consensus Conference has recommended a nationwide choiesterol education program similar to the hypertension detection and education program in the early 1970s. I fully sup port this effort. Since each person in this country visits his or her physician on the average of once a year, the physician’s office is the ideal place to begin screening for the high-risk population. A new procedure, developed by Boehringer-Mannheim (ReFlotron), that measures cholesterol levels within one to two minutes after a blood sample is obtained from a finger puncture will soon make it feasible to carry out a screening program at the work site or other sites. However, before such a screening program is undertaken, it would be essential to establish a mechanism for follow-up. Just as with blood pressure, it is of little value to tell individuals what their cholesterol values are unless there is some follow-up, i.e., interpretation of results and, if indicated, instruction on what could be done to lower a high cholesterol level. Physicians in the health care delivery system must be ready to accept and provide care for persons with moderate to severe hypercholesterolemia who are identified through such a screening program.
Phase DietaryComponent Fat (percent) Carbohydrate (percent) Protein (percent) Cholesterol (mg) Polyunsaturated/saturated
1
fats
30 55 15 300 1
2 25 60 15 200-250 1
3 20 65 15 100-150 l-2
wise phase approach of the American Heart Association (Table I). The objective should be to reduce cholesterol levels to below 200 mg/dl if possible. Phase 2 and phase 3 diets may be attempted if the cholesterol levels remain above the desired range and if patients are able to adhere to an exceedingly strict dietary regimen. For the upper 25th percentile who are at high risk for coronary heart disease on the basis of hypercholesterolemia, a restricted diet, pursued to the degree that patients are able to comply with it, should be the first step in the treatment program. The major drugs for treating hypercholesterolemia may be divided into four categories: bile acid sequestrants; nicotinic acid; fibric acid derivatives; and probucol. Cholestyramine, the drug used in the Lipid Research Clinics Coronary Primary Prevention Trial, is the only cholesterollowering drug that has received approval from the Food and Drug Administration to list as an indication for use the reduction of a risk for myocardial infarction. Bile acid sequestrants, as a group, reduce cholesterol and lowdensity lipoprotein cholesterol, have little effect on trigiycerides, and, surprisingly, according to the Lipid Research Clinics Coronary Primary Prevention Trial [5] and the National Heart, Lung, and Blood institute Type II Intervention Trial [12], slightly increase high-density lipoprotein. Nicotinic acid decreases low-density lipoprotein and total plasma cholesterol, decreases triglycerides, and increases high-density lipoprotein. Based on the nine-year follow-up of the Coronary Drug Project, it has been claimed that the use of nicotinic acid resulted in a decreased mortality rate in the group taking this drug. The fibric acid derivatives include clofibrate and gemfibrozil. Because of increased overall mortality in the World Health Organization study on clofibrate-despite a decrease in incidence of nonfatal myocardiai infarctions-the Food and Drug Administration has limited the indicated use of this drug to type iii hyperiipoproteinemia. Gemfibrozil has little effect on overall plasma cholesterol levels, but it increases high-density lipoprotein and decreases triglycerides. Probucoi decreases both low- and high-density lipoproteins. The mechanisms of action of these drugs are diverse.
64
February
14,lSM
The American
Journal
of Medklne
HYPERTENSION Caloric restriction (when the patient is overweight) and salt restriction contribute to the control of hypertension and, in cases of mild hypertension, may result in sufficient control without the use of drugs. In addition to dietary restriction, exercise, relaxation, and stress reduction may have benefits for some individuals. Patients who are unusually excited or nervous at the prospect of having
Volume
80
(suppl PA)
SYMPOSIUM
their blood pressure measured at a physician’s office should have it measured elsewhere, and measurements should be repeated before treatment is started. Such patients could also learn to monitor their blood pressure at home. The choice of a drug for managing hypertension must take into consideration many factors, including age, sex, race, current status of the cardiovascular system, and potential interaction with other risk factors. Drug therapy can and should be tailored to the individual. Even when a drug is used to treat hypertension, it is desirable for patients to use nonpharmacologic adjuncts including diet and, when appropriate, exercise, relaxation, and stress reduction. The use of such adjuncts may decrease the dose of a drug or the number of drugs required. In addition, diet has been shown to offset some of the adverse effects of certain drugs on lipid levels. For example, the effects of certain antihypertensive agents that raise the concentration of serum lipids may be offset by a diet restricted in animal fat and cholesterol. Agents that do not have such adverse effects on serum lipids, such as the selective alphablocker prazosin, may be preferable in long-term management as they do not interfere with the cholesterol-lowering effect of diet. In addition, a decrease in the dietary intake of saturated fat, over and above caloric reduction and
ON INITIAL ANTIHYPERTENSIVE
THERAPY-GOlTO
sodium restriction, has been shown to have a beneficial effect on reducing blood pressure. Although the mortality rate for coronary heart disease is declining, a great deal remains to be done. Cardiovascular disease still accounts for more than 50 percent of the deaths in the United States and remains this nation’s leading “killer.” The guidelines and objectives described represent a challenge for public health officials, physicians, and the American Heat-l Association. It seems that means are now available for reducing cholesterol, lowdensity lipoprotein, and blood pressure values in a broadbased way across the general population, as well as means for identifying high-risk persons for whom a special effort should be made concerning treatment. The stepwise dietary approach adopted by the American Heart Association for the treatment of hyperlipidemia should become standard practice. The American Heart Association and the National Heart, Lung, and Blood Institute are currently attempting to change the attitudes of physicians and health care professionals. From there, it would seem advisable to institute screening and educational programs at work sites and in schools. This combined approach could provide an overall strategy for reducing cholesterol and for battling the epidemic of cardiovascular deaths in our society.
REFERENCES 1.
2.
3.
4.
5.
6.
Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979; 242: 2562-2571. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension: Ill. Influence of age, diastolic pressure, and prior cardiovascular disease; further analysis of side effects. Circulation 1972; 45: 991-1004. U.S. Department of Health and Human Services: The health consequences of smoking: cardiovascular disease. A Report of the Surgeon General. No. DHHS (PHS) 84-50204. Bethesda: US. Department of Health and Human Services, 1983; 6-7. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984; 253: 351-364. 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 1984; 251: 365-374. Brown MS, Goldstein JL: How LDL receptors influence choles-
February
14, 1996
7.
8.
9.
10.
11.
12.
terol and atherosclerosis. Sci Am 1984; 251: 58-66. Duffield RGM, Lewis B, Miller NE, et al: Brunt: Treatment of hyperlipidaemia retards progression of symptomatic femoral atherosclerosis. Lancet 1963; II: 639-642. Brensike JF, Levy RI, Kelsey SF, et al: Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. Circulation 1984; 69: 313-324. Nikkila EA, Viikinkoski P, Valle M: Effect of lipid-lowering treatment on progression of coronary atherosclerosis. A sevenyear prospective angiographic study (abstr). Circulation 1983; 68: 111-188. Arntzenius AC, Kromhout D, Barth JD, et al: Diet, lipoproteins, and the progression of coronary atherosclerosis: the Leiden Intervention Trial. N Engl J Med 1985; 312: 805-811. Blackburn H: Epidemiologic evidence. In: American health foundation, plasma lipids, optimal levels for health. New York: Academic Press, 1980; 7. Levy RI, Brensike JF, Epstein SE, et al: The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: results of the HNLBI Type II Coronary Intervention Study. Circulation 1984; 69: 325-337.
The American
Journal
of Medicine
Volume
99 (suppl
2A)
55
ANTONIO M. GOTTO, Jr., M.D. Houston.
Texas
From the Department of Medicine, Houston, should be addressed partment of Medicine, 6536 Fannin, MS. A
48
Since cardiovascular disease accounts for more than 50 percent of all deaths in the United States today, researchers in a number of major clinical studies have attempted to determine whether this epidemic of cardiovascular deaths can be controlled by reducing the primary risk factors for coronary heart disease and atherosclerosis. Treatment of one of these risk factors, hypertension, has clearly been proven beneficial in reducing the morbidity and mortality of cardiovascular disease. These positive effects are seen at the three levels of hypertension: mild, moderate, or severe. Another risk factor, cigprette smoking, is generally accepted to be the single most preventable cause of death from coronary heart disease in the United States. The mortality rate for coronary heart disease is two to three tlmes greater In those who are heavy smokers, representing a substantial independent risk factor, and the risk is even higher when smokers are also hypertensive and hypercholesterolemic. A third risk factor, hypercholesterolemia, has come under renewed scrutiny, and several recent studies have shown that lowering cholesterol through the use of diet or drugs can reduce the progression of atherosclerotic plaque. Based on the results of various intervention trials over the years, it appears that methods of preventing cardiovascular disease in the general=population, such as emphasizing the importance of diet and exercise, should be promoted. The American Heart Association recommendations, if adopted, could effect changes in attltudes of those in the medical community, at work sites, and even in schools. In addition to prophylactic measures, an intensive effort to identify and treat persons at high risk should be undertaken.
February
of Medicine, Baylor College Texas. Requests for reprints to Dr. Antonio Gotto, Jr., DeBaylor College of Medicine, 601, Houston, Texas 77030.
14, 1986
The American
Jouinal
Hypertension, cigarette smoking, and hypercholesterolemia are clearly identified as the three major risk factors for coronary heart disease and atherosclerosis. In addition, diabetes mellitus is an important risk factor for both large-vessel and small-vessel disease. There are several other risk factors that are usually considered to be secondary, including lack of exercise, type A personality, obesity, and hypertriglyceridemia. Hypertension. It is estimated that about 20 percent of adult Americans have hypertension, which is defined as a consistent elevation of arterial blood pressure. The benefit of treating even mild hypertension has now been confirmed in the Hypertension Detection and Follow-up Program [l]. The earlier Veterans Administration Study [2] had shown a decrease in mortality in patients with moderate or severe hypertension who received treatment. In the Hypertension Detection and Follow-up Program sponsored by the National Heart, Lung, and Blood Institute, 5,485 pa-
of Medicine
Volume
80
(suppl 2A)
SYMPOSIUM
tients were treated aggressively while the same number were referred to private physicians and community facilities. The treatment was clearly beneficial in terms of reducing mortality, particularly mortality from cerebrovascular disease. Even among individuals with mild hypet-tension (diastolic blood pressure values ranging between 90 and 104 mm Hg), the mortality rate was decreased by 20 percent in the group receiving aggressive treatment. Overall, the mortality rate was decreased by 17 percent in the group of patients who were aggressively treated for hypertension [l]. Cigarette Smoking. The Surgeon General has concluded that cigarette smoking is the single most preventable cause of coronary heart disease death for both males and females in the United States [3]. Because of the large number of individuals who smoke and the risks associated with cigarette smoking, the importance of this risk factor cannot be overemphasized. Smokers have a 70 percent higher mortality rate from coronary heart disease than do nonsmokers. For heavy smokers, those who consume two or more packs per day, the mortality rate for coronary heart disease is tie to three times greater than that for nonsmokers. Although cigarette smoking is one of the three major risk factors and is an independent rjsk factor for coronary heart disease, it also acts synergistically with hypertension and hypercholesterolemia. Women who smoke and use oral contraceptives have approximately a tenfold greater risk of myocardial infarction when compared with women who are nonsmokers and who do not use oral contraceptives. Cigarette smoking also increases the risk of cerebrovascular disease and sudden death. The mortality rate for coronary heart disease in smokers is higher in younger than in older age groups. The Surgeon General has estimated that cigarette smoking is respor@ble for approximately 30 percent of &II deaths from coronary heart disease in the United States each year. It is also estimated that in the United States during the period from 1965 to 1980, there were more than 3 million premature deaths from heart disease because of cidarette smoking. If current smoking trends continue, as many as 10 percent of all persons now living may die prematurely from heart disease attributable to smoking. Hypercholesterolemia. Every epidemiologic study that has been carried out to date has shown a strong positive relationship between the concentration of serum cholesterol at the time of entry into the study and the risk of coronary heart disease. The Lipid Research Clinics Coronary Primary Prevention Trial, the most definitive study to date, was planned in the United States in the early 1970s [4,5]. The purpose of the trial was to test the lipid hypothesis and, specifically, to test whether or not lowering the concentration of low-density lipoprotein cholesterol would result in a reduction in the risk of coronary heart disease. After screening and identifying individuals who qualified
February
14, 1999
ON INITIAL ANTIHYPERTENSIVE
THERAPY-GOlTO
Figure 1. Life-table cumulative incidence
of primary end point (definite coronary heart disease death and/or definite nonfatal myocardial infarction) ii, treatment groups, computed by Kaplan-Meier method. N = total nurqber of participants in the Lipid Research Clinics Coronary Primary Prevention Trial at risk for their first primary end point at each time point. Adapted from 141, with permission.
for the study, 3,806 men were selected and randomly assigned to control and treatment groups. Both groups were treated with a diet that was aimed at lowering cholesterol levels by approximately 3 to 5 percent. The actual reduction was 4 percent. The drug used in the study was cholestyramine, a bjle acid sequestrant that is not well tolerated by patients. Nevertheless, a compliance rate of 66 percent was noted among the treatment groups over the length of the study, a period of seven years. The average chobsterol decrease was 9 percent greater in the treatment group than in the placebo group and low-density lipoprotein cholesterol was reduced by 12 percent. Reductions in low-density lipoprotein cholesterol levels resulted in a 19 percent reduction in the total number of nonfatal myocardial infarctions and coronary heart disease deaths. The reduction in the risk of coronary heart disease was also reflected by significant decreases in the incidence of angina pectoris, the incidence of positive exercise electrocardiographic results, and in the need for coronary bypass surgery in the group receiving cholestyramine. The benefits of the Lipid Research Clinics Coronary Primary Prevention Trial, in terms of reducing the risk of coronary heart disease, were solely related to the degree of cholesterol lowering; the greater the degree of lowering, the greater the reduction in risk (Figure 1). Low-density lipoprotein is the lipoprotein mqst closely associated with atherosclerosis, and concentrations of this ligoprotein are related in a curvilinear route and continuous manner with the prevalence of coronary heart disease. concentrations of high-density lipoprotein, on the
The
American
Journal
of Medicine
Volume
99 (suppl
2A)
49
SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
-
THERAPY-GOTTO
ThwshoM
for increased coronary risk
Relative number of LDL receptors
Figure 2. Low-density lipoprotein receptors and plasma low-density lipoprotein cholesterol levels. Adapted from IS], with permission. FH = familial hypercholesterolemia.
LDL-cholesterol level OWN
protein cholesterol value of approximately 25 mg/dl. The relationship between the concentration of low-density lipoprotein cholesterol and the concentration of low-density lipoprotein receptors, derived from the work of Brown and Goldstein [6], is shown in Figure 2. The higher the concentration of hepatic receptors, the lower the concentration of low-density lipoprotein cholesterol. Hepatic receptor activity is high in human newborns and in various other species that are not susceptible to arteriosclerosis. The distribution of low-density lipoprotein values in the population of the United States is slightly more skewed at the upper or higher end of low-density lipoprotein values. It seems likely that there is a critical low-density lipoprotein value, below which atherosclerosis and coronary disease do not occur. It is known that a cholesterol value of 220 to 230 mg/dl does not assure protection against arteriosclerosis. The presence of hypertension and/or cigarette smoking increases the risk associated with this level of cholesterol. At the Methodist Hospital in Houston, the average serum cholesterol concentration for patients who are undergoing coronary arteriography and who have significant obstructive disease is approximately 230 mg/dl. If the cholesterol hypothesis is accepted, then on the basis of the results of the Lipid Research Clinics Coronary Prlmary Prevention Trial and other studies, this curve must be shifted to a lower level if a further substantial reduction in the coronary mortality rate is to be made in this country. Several studies during the past year have shown that decreasing cholesterol through diet or through medication can reduce the progression of atherosclerotic plaque. These studies have been performed by using coronary arteriography to examine femoral or coronary arteries.
other hand, have been shown by population studies to be inversely related to the prevalence of coronary heart disease. Animal studies have shown that experimentally induced elevations in low-density lipoprotein can predispose to afherosclerosis; however, evidence linking elevations in high-density lipoprotein with protection against atherosclerosis is not found in these studies. In animal experiments, the induction of hypertension can accelerate the development and progression of dietary-induced atherosclerosis. Serum cholesterol levels reflect the concentration of low-density lipoprotein cholesterol but not high-density lipoprotein cholesterol. The risk of coronary disease at a given level of low-density lipoprotein depends on the concentration of high-density lipoprotein cholesterol, as well as the occurrence of other risk factors such as hyperfension and cigarette smoking. The risk for a given person with a particular cholesterol value depends on the presence of other risk factors, the sex and age of the person, and the concentration of high-density lipoprotein. Risk increases with total cholesterol and low-density lipoprotein values as a continuous function. The rate at which low-density lipoprotein cholesterol is transferred from the blood into arterial walls has been measured using radiolabeled lipoproteins [6]. It can be estimated by extrapolation that the transfer of a low-density lipoprotein particle into the artery is slight at a low-density lipoprotein cholesterol concentration below 40 to 80 mg/dl. It can also be calculated that the low-density lipoprotein receptors are half saturated when the concentration of low-density lipoprotein cholesterol in the tissue fluid is approximately 2.5 mg/dl. This corresponds to a plasma low-density lipo-
50
February
14,1986
The Amerkan
Journal
d Medklne
Volume
80
(suppl2A)
SYMPOSIUM
Duffield and co-workers [7] completed a study of 24 patients with femoral arteriosclerosis. Half of the patients received no treatment, and the other half received dietary advice and cholestyramine, nicotinic acid, or clofibrate, depending on their lipoprotein phenotypes. Treatment with diet and cholesterol-lowering drugs reduced total plasma cholesterol by 25 percent, the mean low-density lipoprotein by 28 percent, and mean plasma triglycerides by 45 percent. The progression of femoral arteriosclerosis (monitored by femoral arteriography) was significantly delayed in the treatment group when compared with the control group. In a randomized trial performed at the National Heart, Lung, and Blood Institute [8], 118 patients who were treated with either placebo or cholestyramine and who underwent repeat coronary angiography were followed for a total of five years. Patients with the greatest reduction in low-density lipoprotein levels or greatest increase in highdensity lipoprotein levels had the greatest delay in progression of coronary atherosclerosis. The rate of growth of plaques was significantly diminished in those who had more than 50 percent blockage of the lumen of a major coronary artery. Elevation of high-density lipoprotein levels was correlated with a decrease in the progression of coronary atherosclerosis and appeared to act independently of a reduction in low-density lipoprotein. The rate of growth of coronary plaque decreased in proportion to the increase in the ratio of high-density lipoprotein to total plasma cholesterol and to low-density lipoprotein cholesterol. Nikkila et al [9] treated 30 patients with hyperlipoproteinemia and two- or three-vessel coronary artery disease with diet and clofibrate or nicotinic acid. Coronary arteriography was performed before therapy was initiated and after two ano seven years. Patients with the greatest degree of cholesterol lowering showed no progression of coronary arteriosclerosis, whereas those with higher levels of cholesterol showed a marked progression. In the Leiden Intervention Trial [lo], 39 patients with stable angina pectoris were treated with a vegetarian diet alone for two years. Patients with the lowest ratios of total cholesterol to high-density lipoprotein cholesterol showed no coronary disease progression, and some even showed regression. TREATMENT
Treatment goals for the prevention of cardiovascular disease can be approached in two ways. One approach is based on the recommendation of several hygienic measures for the overall population that are aimed at a general reduction in the level of risk factors. The second approach involves identifying those persons who are particularly at high risk and undertaking an intensive effort to reduce their risk factors. The hygienic measures are similar to those that the
14,1999
THERAPY-GOTTO
American Heart Association has recommended for the general population for more than 20 years. The first measure would be the avoidance of tobacco. I cannot overemphasize the deleterious effects cigarette smoking has on the cardiovascular system, especially in the presence of diabetes or even slight elevations in serum cholesterol or blood pressure levels. One of the most important dietary recommendations is to maintain ideal body weight as closely as possible and to avoid obesity. This will favorably affect serum cholesterol and triglyceride levels, as well as blood pressure values. Reducing overall obesity would also be expected to decrease the incidence of type II diabetes in the general population. Specific dietary recommendations of the American Heart Association are to decrease the total fat consumption to no more than 30 percent of the calories, with approximately 10 percent derived from saturated fats, 10 percent from polyunsaturated fats, and 10 percent from monounsaturated fats. If these guidelines were followed, and if daily cholesterol consumption could be kept to under 300 mg per day, the serum cholesterol level of the general population could be reduced by 10 to 15 percent. In fact, over the past 20 years, the American population has moved toward adopting this diet, and the average serum cholesterol value has decreased. Furthermore, reducing the consumption of saturated fat has been shown to have a beneficial effect in lowering blood pressure. Avoiding excessive consumption of salt by not adding salt to food over and above that used in cooking, for example, may result in an overall decrease in the blood pressure in the population. In societies in which there is a high salt consumption, as in Japan and China, death from cerebrovascular disease ranks at or near the top as the cause of death. However, the incidence of atherosclerotic cardiovascular disease may be quite low in these societies, a fact presumably due to a low consumption of saturated fat and total fat in the diet. The other hygienic recommendation deals with physical exercise. This may be a useful adjunct in controlling obesity, hyperlipidemia, hypertension, and diabetes. Although these general measures are not aimed specifically at a hypercholesterolemic or a hypertensive population, if adopted, they should have an effect on all levels of cholesterol and blood pressure in the population. In the American population, as in other Western societies, both blood pressure and serum cholesterol levels tend to increase with age, especially after adolescence. It is possible that changes in dietary patterns and exercise habits might prevent these age-related increases in the level of risk factors. Age itself is the greatest single risk factor for cardiovascular disease in Western society, and although aging cannot be prevented, some of the metabolic changes associated with aging might be prevented or at least forestalled.
GOALS
February
ON INITIAL ANTIHYPERTENSIVE
The
American
Journal
ol Medicine
Volume
99 (suppl2A)
51
SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
THERAPY-GOTTO
-m-m -1-1
I
I
100
Ideal mean 160 mg/dl, SD-25 mg/dl = Feasible mean 190 mg/dl, SD-30 mg/dl Present mean 210 mg/dl, SD-35 mg/dl
I
150
I
200
250
1
300
Total Serum cholesterol (mg/dl)
I.-II ----
0
100
150
ideal mean 110 mg/dl, SD-20 mg/dl Feasible mean 140 mg/dl, SD-25 mg/dl Pmsent mean 160 mg/dl, SD-25 mg/dl
Figure 3. Ideal, feasible, and existing total serum cholesterol levels in adults (top) and children, aged 5 to 18 (bottom). Adapted from [ll], with permission.
200
Tote1Serum cholesterol (mg/dl)
It appears that if these measures are to be successful, they would have to be adopted by the general population rather than by a group of individuals who are at highest risk based on arbitrarily defined upper limits of normal. Thus, the goals of the hygienic approach would be to reduce serum cholesterol levels and blood pressure in the general population to desirable or ideal levels. We at Baylor College of Medicine, believe that reducing serum cholesterol and blood pressure values would dramatically decrease the mortality rate for cerebrovascular disease, and, furthermore, that the adoption of such changes would pose little risk to the population. The lower limit of safety for a cholesterol value should be approximately 100 mgldl, since some patients with hypobetalipoproteinemia and values below this level have neurologic and hematologic abnormalities. Concerns for an increased incidence of cerebral hemorrhage and cancer of the colon in individuals with low cholesterol values have not been borne out. Life expectancy in Japan and Italy is slightly greater than that in the United States even though the cholesterol levels are substantially lower in those countries. This is due primarily to lower mortality from coronary heart disease. The serum cholesterol level
52
February
14,1986
The American
Journal
of Medlclne
is obviously closely related to the dietary habits of the population. In societies in which the diet is mainly vegetarian and the individual level of physical activity is high, the serum cholesterol level may range from 100 to 140 mg/dl. In Greece, Yugoslavia, Italy, the Mediterranean countries, Latin America, and urban Japan, the cholesterol values average from 180 to 200 mg/dl. The incidence of coronary heart disease in these countries is much less than that in many of the industrialized societies of the West [l 11. Based on results obtained from dietary intervention in free-living populations, the results shown in Figure 3 represent feasible cholesterol values for adults and children [ll]. Values should be calculated separately for males and females and should be adjusted for age. It may be necessary to obtain a cholesterol value of 140 mg/dl for children in order to reach the 190 mg/dl value for adults. At the end of adolescence and the beginning of adulthood, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol is approximately one to one. In primitive societies, this ratio does not change substantially during later adult life. However, the change in this ratio in Western societies is remarkable. The level of high-density lipoprotein stays about the same, but the level of low-density
Volume
80 (suppl2A)
SYMPOSIUM
THERAPY
FOR HIGH-RISK
POPULATIONS
In selecting therapy for one risk factor of coronary heart disease, it is important to study a patient’s entire profile. Each risk factor makes its own contribution and may act synergistically with other risk factors. Augmentation of coronary heart disease has occurred when more than one risk factor is present and, therefore, it may be a mistake to emphasize one factor (lack of exercise, smoking, blood pressure, or diet) to the exclusion of others. Initial treatment of risk factors should be hygienic and as physiologic as possible. If hypercholesterolemia or hypertension can be controlled by diet and/or weight loss, this obviously is a more desirable approach than using drugs. Reducing caloric intake and the saturated-fat content of the diet and restricting salt intake in hypertensive patients may be adequate therapy to control serum cholesterol or blood pressure elevations in the mild to moderate range. If these measures fail, pharmacologic therapy is required, but less medication will be needed and a greater reduction in the abnormal risk factor will be achieved if a restricted diet is followed as well. Furthermore, cigarette smoking may offset any improvement achieved with diet, exercise, or drugs. The Lipid Research Clinics Coronary Primary Prevention Trial illustrates explicitly the way in which a risk factor operates on a continuum: in that study, the greater the reduction in cholesterol and low-density lipoprotein levels,
February
14, 1986
THERAPY-GOTTO
the greater the decrease in the incidence of myocardial infarction. Thus, the benefits of cholesterol reduction could be observed even before optimal cholesterol and low-density lipoprotein levels had been achieved. Metabolic Effects of Treatment. When one risk factor is treated, it is important to be aware of both positive and negative effects on other risk factors. For example, when one stops smoking and begins a program of physical exercise, each of these changes may affect the cardiovascular system in multiple beneficial ways, including raising the concentration of high-density lipoprotein cholesterol. Conversely, in some patients, treatment of hypercholesterolemia or hypertriglyceridemia with fibric acid drugs such as clofibrate may result in an increase in the concentration of low-density lipoprotein cholesterol. In the treatment of hypertension, beta blockers increase cholesterol and triglycerides and decrease high-density lipoprotein cholesterol. Diuretics may increase the concentration of total plasma cholesterol, triglycerides, and low-density lipoprotein cholesterol. The alpha blocker prazosin does not appear to adversely affect lipid ratios and, in fact, may have a favorable effect by decreasing the concentration of low-density lipoprotein cholesterol and increasing the concentration of plasma high-density lipoprotein. Clonidine, hydralazine, and reserpine are not known to have adverse effects on lipids. Thiazide diuretics and chlotthalidone increase the concentrations of plasma cholesterol and triglycerides and decrease high-density lipoprotein cholesterol levels. In the Lipid Research Clinics Prevalence Survey, propranolol was associated with about a 15 percent reduction in high-density lipoprotein cholesterol levels in females. However, other agents, such as the alpha blocker prazosin, do not have these adverse effects on serum lipids. Cholesterol concentrations are modified by the sex hormones as follows: estrogens increase triglycerides and high-density lipoprotein and decrease lowdensity lipoprotein; progesterones increase low-density lipoprotein and decrease triglycerides and high-density lipoprotein; and androgens increase cholesterol and lowdensity lipoprotein and decrease high-density lipoprotein. The 1984 National Institutes of Health Cholesterol Consensus Conference defined levels of cholesterol risk as follows: men and women from the ages of 20 to 29 are considered at moderate risk if their cholesterol levels are above 200 mg/dl, and at high risk if their levels are above 220 mg/dl; those from the ages of 30 to 39 are considered at moderate risk if their cholesterol levels are more than 220 mg/dl, and at high risk if their levels are more than 240 mg/dl. For those men and women over 40 years of age, moderate risk is defined as a cholesterol level of more than 240 mg/dl, and high risk is a level exceeding 260 mg/dl. These values are to be used in selecting patients requiring treatment. For those at mild to moderate risk, dietary treatment should be undertaken, in most instances, using the step-
lipoprotein increases by two and one half to three times between the period of the late teens and the early thirties. Thus, clinical investigation, clinical trials, epidemiologic study, pathologic data, and laboratory data all converge to support the view that cholesterol and low-density lipoprotein values in the United States and Western Europe are too high. Values above 200 mg/dl do not lead to optimal cardiovascular health. Indeed, this figure should be even lower when other risk factors, such as high blood pressure and cigarette smoking, are considered. The best lipid indicators of a population’s risk for coronary heart disease are obtained by examining the ratio of total cholesterol or low-density lipoprotein to the concentration of highdensity lipoprotein. The risk of persons in affluent, industrialized societies such as ours is improved by considering the high-density lipoprotein value. In the United States, the high-density lipoprotein value becomes an important predictor of coronary heart disease after the age of 55. The ultimate question is whether an individual’s circulatory system benefits from treatment of the various risk factors. The effect of a reduction in blood pressure on mortality and cerebrovascular disease is well established. Recent trials, described earlier, have shown that lowering cholesterol and low-density lipoprotein levels decreases the incidence of nonfatal myocardial infarction and the rate of progression of atherosclerosis in the coronary and femoral arteries. INTENSIVE
ON INITIAL ANTIHYPERTENSIVE
The
American
Journal
of Medicine
Volume
80 (suppl
2A)
53
SYMPOSIUM
ON INITIAL ANTIHYPERTENSIVE
TABLE I
THERAPY-GOTTO
Dietary Goals for Phases 1, 2, and 3 of the American Heart Association’s LipidLowerlng Diet
Bile acid sequestrants are believed to increase the number of hepatic low-density lipoprotein receptors by decreasing the intrahepatic concentration of cholesterol. Nicotinic acid blocks lipolysis in adipose tissue and decreases the flux of free fatty acids to the liver. It may also decrease the hepatic synthesis of very-low-density lipoproteins. The fibric acid derivatives have similar effects and also decrease hepatic cholesterol synthesis in animals. The precise action of probucol, as with the above listed hypochoiesteroiemic agents, is not yet clearly understood. in animal experiments, probucol has been shown to alter the structure of low-density lipoprotein, resulting in a more protein-rich particle, which may be preferentially cleared by a scavenger pathway in the liver involving the macrophage and not the low-density lipoprotein receptor mechanism. I believe that it is essential to emphasize the detection and treatment of hypercholesterolemia by physicians. One recent survey reported that only 39 percent of physicians believed that cholesterol values were significant coronary heart disease risk factors as compared with more than 80 percent who felt that hypertension was a significant risk factor. The National institutes of Health Cholesterol Consensus Conference has recommended a nationwide choiesterol education program similar to the hypertension detection and education program in the early 1970s. I fully sup port this effort. Since each person in this country visits his or her physician on the average of once a year, the physician’s office is the ideal place to begin screening for the high-risk population. A new procedure, developed by Boehringer-Mannheim (ReFlotron), that measures cholesterol levels within one to two minutes after a blood sample is obtained from a finger puncture will soon make it feasible to carry out a screening program at the work site or other sites. However, before such a screening program is undertaken, it would be essential to establish a mechanism for follow-up. Just as with blood pressure, it is of little value to tell individuals what their cholesterol values are unless there is some follow-up, i.e., interpretation of results and, if indicated, instruction on what could be done to lower a high cholesterol level. Physicians in the health care delivery system must be ready to accept and provide care for persons with moderate to severe hypercholesterolemia who are identified through such a screening program.
Phase DietaryComponent Fat (percent) Carbohydrate (percent) Protein (percent) Cholesterol (mg) Polyunsaturated/saturated
1
fats
30 55 15 300 1
2 25 60 15 200-250 1
3 20 65 15 100-150 l-2
wise phase approach of the American Heart Association (Table I). The objective should be to reduce cholesterol levels to below 200 mg/dl if possible. Phase 2 and phase 3 diets may be attempted if the cholesterol levels remain above the desired range and if patients are able to adhere to an exceedingly strict dietary regimen. For the upper 25th percentile who are at high risk for coronary heart disease on the basis of hypercholesterolemia, a restricted diet, pursued to the degree that patients are able to comply with it, should be the first step in the treatment program. The major drugs for treating hypercholesterolemia may be divided into four categories: bile acid sequestrants; nicotinic acid; fibric acid derivatives; and probucol. Cholestyramine, the drug used in the Lipid Research Clinics Coronary Primary Prevention Trial, is the only cholesterollowering drug that has received approval from the Food and Drug Administration to list as an indication for use the reduction of a risk for myocardial infarction. Bile acid sequestrants, as a group, reduce cholesterol and lowdensity lipoprotein cholesterol, have little effect on trigiycerides, and, surprisingly, according to the Lipid Research Clinics Coronary Primary Prevention Trial [5] and the National Heart, Lung, and Blood institute Type II Intervention Trial [12], slightly increase high-density lipoprotein. Nicotinic acid decreases low-density lipoprotein and total plasma cholesterol, decreases triglycerides, and increases high-density lipoprotein. Based on the nine-year follow-up of the Coronary Drug Project, it has been claimed that the use of nicotinic acid resulted in a decreased mortality rate in the group taking this drug. The fibric acid derivatives include clofibrate and gemfibrozil. Because of increased overall mortality in the World Health Organization study on clofibrate-despite a decrease in incidence of nonfatal myocardiai infarctions-the Food and Drug Administration has limited the indicated use of this drug to type iii hyperiipoproteinemia. Gemfibrozil has little effect on overall plasma cholesterol levels, but it increases high-density lipoprotein and decreases triglycerides. Probucoi decreases both low- and high-density lipoproteins. The mechanisms of action of these drugs are diverse.
64
February
14,lSM
The American
Journal
of Medklne
HYPERTENSION Caloric restriction (when the patient is overweight) and salt restriction contribute to the control of hypertension and, in cases of mild hypertension, may result in sufficient control without the use of drugs. In addition to dietary restriction, exercise, relaxation, and stress reduction may have benefits for some individuals. Patients who are unusually excited or nervous at the prospect of having
Volume
80
(suppl PA)
SYMPOSIUM
their blood pressure measured at a physician’s office should have it measured elsewhere, and measurements should be repeated before treatment is started. Such patients could also learn to monitor their blood pressure at home. The choice of a drug for managing hypertension must take into consideration many factors, including age, sex, race, current status of the cardiovascular system, and potential interaction with other risk factors. Drug therapy can and should be tailored to the individual. Even when a drug is used to treat hypertension, it is desirable for patients to use nonpharmacologic adjuncts including diet and, when appropriate, exercise, relaxation, and stress reduction. The use of such adjuncts may decrease the dose of a drug or the number of drugs required. In addition, diet has been shown to offset some of the adverse effects of certain drugs on lipid levels. For example, the effects of certain antihypertensive agents that raise the concentration of serum lipids may be offset by a diet restricted in animal fat and cholesterol. Agents that do not have such adverse effects on serum lipids, such as the selective alphablocker prazosin, may be preferable in long-term management as they do not interfere with the cholesterol-lowering effect of diet. In addition, a decrease in the dietary intake of saturated fat, over and above caloric reduction and
ON INITIAL ANTIHYPERTENSIVE
THERAPY-GOlTO
sodium restriction, has been shown to have a beneficial effect on reducing blood pressure. Although the mortality rate for coronary heart disease is declining, a great deal remains to be done. Cardiovascular disease still accounts for more than 50 percent of the deaths in the United States and remains this nation’s leading “killer.” The guidelines and objectives described represent a challenge for public health officials, physicians, and the American Heat-l Association. It seems that means are now available for reducing cholesterol, lowdensity lipoprotein, and blood pressure values in a broadbased way across the general population, as well as means for identifying high-risk persons for whom a special effort should be made concerning treatment. The stepwise dietary approach adopted by the American Heart Association for the treatment of hyperlipidemia should become standard practice. The American Heart Association and the National Heart, Lung, and Blood Institute are currently attempting to change the attitudes of physicians and health care professionals. From there, it would seem advisable to institute screening and educational programs at work sites and in schools. This combined approach could provide an overall strategy for reducing cholesterol and for battling the epidemic of cardiovascular deaths in our society.
REFERENCES 1.
2.
3.
4.
5.
6.
Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979; 242: 2562-2571. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension: Ill. Influence of age, diastolic pressure, and prior cardiovascular disease; further analysis of side effects. Circulation 1972; 45: 991-1004. U.S. Department of Health and Human Services: The health consequences of smoking: cardiovascular disease. A Report of the Surgeon General. No. DHHS (PHS) 84-50204. Bethesda: US. Department of Health and Human Services, 1983; 6-7. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984; 253: 351-364. 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 1984; 251: 365-374. Brown MS, Goldstein JL: How LDL receptors influence choles-
February
14, 1996
7.
8.
9.
10.
11.
12.
terol and atherosclerosis. Sci Am 1984; 251: 58-66. Duffield RGM, Lewis B, Miller NE, et al: Brunt: Treatment of hyperlipidaemia retards progression of symptomatic femoral atherosclerosis. Lancet 1963; II: 639-642. Brensike JF, Levy RI, Kelsey SF, et al: Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. Circulation 1984; 69: 313-324. Nikkila EA, Viikinkoski P, Valle M: Effect of lipid-lowering treatment on progression of coronary atherosclerosis. A sevenyear prospective angiographic study (abstr). Circulation 1983; 68: 111-188. Arntzenius AC, Kromhout D, Barth JD, et al: Diet, lipoproteins, and the progression of coronary atherosclerosis: the Leiden Intervention Trial. N Engl J Med 1985; 312: 805-811. Blackburn H: Epidemiologic evidence. In: American health foundation, plasma lipids, optimal levels for health. New York: Academic Press, 1980; 7. Levy RI, Brensike JF, Epstein SE, et al: The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: results of the HNLBI Type II Coronary Intervention Study. Circulation 1984; 69: 325-337.
The American
Journal
of Medicine
Volume
99 (suppl
2A)
55