The impact of diet on coronary heart disease

CLINICAL NUTRITION

0025-7125/93 $0.00 + .20

THE IMPACT OF DIET ON CORONARY HEART DISEASE David A. Woodard, MD, and Marian C. Limacher, MD

Because coronary heart disease (CHD) did not manifest itself in its current epidemic proportions until the modern era, major investigations into its causative factors were not undertaken before this century. By 1909, dietary factors were demonstrated to be associated with CHD when Ignatowski 1Y and later Anitschkow2 developed animal models of atherosclerosis. Using these models, cholesterol was shown to be a causative agent in atherosclerosis. Additionally, epidemiologic studies have consistently established that serum cholesterol is an independent, predictive risk factor for CHD. * What has been subjected to more debate has been the relationship between CHD and dietary intake of fats and cholesterol. This article reviews the pertinent findings of published studies which have attempted to determine whether dietary factors contribute to outcomes associated with coronary heart disease. The two major groups of studies that will be considered are the epidemiologic investigations (longitudinal observations of population cohorts whose diets and outcomes were systematically assessed) and the human clinical trials of dietary interventions. EPIDEMIOLOGIC STUDIES

One of the earliest noninterventional studies was the U.S. Western Electric study, involving 1900 men aged 40 to 55 years who were employed at Western Electric Company, Hawthorne Works in Chicago in 1957. 45 Dietary information was obtained by interviews and questionnaires administered by a nutritionist at baseline and at 1 year utilizing the methods of Burke. 4 The diet scores of Keys and coworkers22 and Hegsted and coworkers 14 were calculated and serum cholesterol was measured at the time of initial evaluation. The Keys and *References 5, 9, 11, 21, 24, 25, 33, 38, 39, 42-44, 47, 48. From the Division of Cardiology, University of Florida College of Medicine, Gainesville, Florida MEDICAL CLINICS OF NORTH AMERICA VOLUME 77 • NUMBER 4 • JULY 1993

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Hegsted scores summarize the lipid composition of the diet with a high score indicating a relatively high intake of saturated fatty acids and cholesterol and a relatively low intake of polyunsaturated fatty acids. No therapeutic suggestions were made to the participants. Vital status was determined at the 20th anniversary of the initial examination. Both the Keys and Hegsted scores were positively associated with serum cholesterol concentration at the initial exam. Serum cholesterol concentration was positively associated with dietary saturated fatty acids and cholesterol and tended to vary inversely with polyunsaturated fatty acids. When adjusted for body mass index and age, the association with saturated fatty acids was strengthened whereas the association with polyunsaturated fatty acids and dietary cholesterol decreased. Changes in the Keys and Hegsted dietary score were positively associated with change in serum cholesterol. The risk of death from CHD during 19 years of study was positively related to the baseline levels of both dietary scores. It was inversely related to the intake of polyunsaturated fatty acids and positively related to intake of dietary cholesterol. Saturated fatty acids in the diet was not significantly associated with coronary heart disease. 45 The Zutphen study was begun in 1960 as an investigation into the relationship between diet, other risk characteristics such as serum cholesterol, hypertension, tobacco, and anthropometric measures, and the incidence of CHDY The study group consisted of 871 men aged 40 to 59 years living in Zutphen, the Netherlands. Dietary intake data were collected using a crosscheck dietary history method, which estimated the usual food consumption pattern for the 6 to 12 months preceding the interview. Spouse interviews and food purchases provided the cross-checks. After 10 years, 37 men had died from coronary heart disease; 30 of these men were free of CHD at the onset of the study. Those men who initially were disease-free at the onset of the study but died from CHD during the study consumed 273 kilocalories per day less than survivors. When expressed as energy intake per kilogram of body weight, the difference was highly significant. This observation, also noted in other reports, may reflect the reduction in physical activity among patients developing CHD symptoms or, alternatively, the protective effect of increased levels of physical activity (requiring increased energy intake) among subjects free of heart disease. 27 Dietary cholesterol per 1000 kilocalories was significantly, positiyely related to CHD death. In univariate analysis, vegetable protein, polysaccharides, and dietary fiber were significantly and inversely related to death rate. When energy intake per kilogram of body weight was added to the logistic model, however, the relationships were no longer statistically significant. There was an inverse relationship between energy intake per kilogram body weight and CHD death in univariate logistic regression, but when subscapular skinfold thickness and serum cholesterol were included in the model, this relationship was statistically insignificant. The investigators concluded that energy intake per kilogram of body weight was not independently related to CHD but was important because of its role in regulating body fat and serum cholesterol which are known to be major risk characteristics for CHD. They found no relationship between intake of different fatty acids and ID-year CHD death. Dietary cholesterol was positively related to CHD death in univariate analysis; however, it too became insignificant in multivariate analysis. It was concluded that energy intake per kilogram of body weight was a stronger determinant of CHD than individual macronutrientsY When this cohort was re-examined at 25 years after the initiation of this study, the baseline serum cholesterol level remained an independent predictor of myocardial infarction but not of mortality. Impor-

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tantly, serum cholesterol level was not related to incidence of nor mortality from cancer over 25 years. The impact of dietary factors on long-term outcome was not reported. 26 The Honolulu Heart Study was a prospective study of cardiovascular disease in men of Japanese ancestry who resided on the Island of Oahu in 1965. More than 8000 men underwent complete physical examinations and dietary survey using the 24-hour recall method. Of those, 918 men with inadequate or atypical diet recall, known CHD, stroke, or cancer were excluded. Nutrient intake was related to outcome measured as total CHD, myocardial infarction or CHD death, or angina pectoris/coronary insufficiency events over 10 years, during which 456 coronary heart disease deaths occurred. Men who developed CHD had lower mean intake levels of calories, carbohydrates, starch, and vegetable proteins and had higher caloric intake of calories from proteins, fat, saturated fatty acids, and polyunsaturated fatty acids than those free of CHD. This group also had significantly lower mean percentage of calories from carbohydrates and higher mean ingestion of cholesterol per 1000 calories. In multivariate analysis for total CHD, however, carbohydrates, vegetable protein, percent of calories from saturated fatty acids, and polyunsaturated fatty acids were no longer statistically significant. In multivariate analysis variables with a significant inverse relationship, with the incidence of myocardial infarction or CHD death included total calorie intake, carbohydrates, and alcohol. Those factors found to be significantly and positively related to the lO-year incidence of myocardial infarction and CHD death were percentage of calories from protein, fat, saturated fatty acids, and cholesterol per 1000 calories. 32 The Puerto Rico Heart Health Program was a long-term prospective epidemiologic study begun in 1965 to investigate the relationship of CHD risk factors to coronary heart disease in urban and rural Puerto Rican men aged 45 to 64 years. lO Approximately 8000 men were involved. Puerto Ricans had previously been noted to have roughly one half the incidence of CHD as those in the continental United States.13 Diet analyses were made using the 24-hour dietary recall method. Urban diets had higher intake of total fat but a lower intake of carbohydrates than the rural counterparts. Dietary cholesterol intake averaged less than 450 g/day in the urban men and 330 g/day for those living in rural areas. Both urban and rural men who developed myocardial infarction or CHD death had lower average caloric intake and lower intake of total carbohydrates at the baseline measurement than those who remained free of disease, although the level of association for rural men was not statistically significant. Dietary carbohydrate and starch intake was inversely related to baseline serum cholesterol in the urban men and to a lesser degree in the rural cohort. In particular, carbohydrate intake from legumes was inversely related to CHD incidence, especially for urban residents. In neither the urban nor rural group was there any indication that those who developed CHD had an increased dietary intake of total or saturated fat, although total percentage of daily calories from fat averaged 32% for rural and 36% for urban subjects in this study. 10 The Seven Country study 2! was a prospective study using 16 cohorts of men aged 40 to 59 years who lived in seven different countries. Dietary analysis for all cohorts except the Italian and the US railroad men was estimated with data recorded from randomly selected sub-samples of 30 to 50 men in each cohort. Trained dietitians recorded the weights of all foods and beverages consumed in 7 days by each man. Duplicate samples of foods eaten were sent to a laboratory for complete chemical and caloric analysis. This analysis was repeated for each season of the year; however, the dietary estimates for the US

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railroad men cohort consisted of a 24-hour diet recall plus food habit questionnaire. Italian railroad men were surveyed using a 7-day recall method as well as comments concerning customary habits. After 15 years, approximately 20% of men apparently healthy at entry had died. The percent of dietary energy from saturated fatty acids strongly correlated with the IS-year death rate from CHD. No relationship was found between death rate and percentage of energy from either polyunsaturated fatty acids or alcohol. Death rate was not related to protein in the diet but was believed to be related to the ratio of monounsaturated fatty acids to saturated fatty acids in the diet. All cause and CHD death rates were noted to be low in cohorts with olive oil as the main fat source in their diet. 23 In the analysis of their data, the investigators of the Seven Country study pointed out that one of the limitations of any dietary analysis method is the tendency for dietary practices to change in some cohorts over the course of the study. For example, the rural Italian cohorts showed an increase in percent of dietary energy from animal fats over the study time period whereas the Zutphen group showed no change. In Finland, there was a trend toward a decrease in the amount of saturated fatty acids in the diet. This may have had the effect of diluting the differences among cohorts and therefore underestimating the importance of dietary factors on coronary heart disease events. There was no correlation noted between the diet of individuals and their serum cholesterol levels, possibly due to intra-individual variability.23 The Ireland-Boston Diet-Heart Study was a prospective epidemiologic study of 1001 middle aged men aged 30 to 69. 28 Dietary information recorded in the early lO60s, using the diet-history method of Burke,4 and subsequent mortality from CHD was compared among three cohorts. The first cohort (the Boston brother cohort) consisted of 563 men born in Ireland but living in the Boston area who had emigrated from Ireland at least 10 years before enrollment in the study. The second cohort (the Irish brother cohort) consisted of 572 brothers of the Boston men who were born in Ireland but remained there. The third cohort consisted of 373 men unrelated to the brothers, who were born in Boston of Irish immigrants. Four dietary scores were derived: the dietary lipid score of Keys and coworkers,22 Hegsted Lipid score,14 "vegetable foods" score, and an "animal foods" score. The Boston brothers cohort was found to have the highest mortality for CHD as compared with the other cohorts, although the difference was not statistically significant. Dietary habits of the three cohorts were significantly different at baseline with the Irish brothers showing a markedly higher energy intake. The Boston brothers had the highest dietary cholesterol levels, the highest modified Hegsted dietary lipid score and animal food score with the lowest vegetable protein intake, total carbohydrate intake, and vegetable food score. Because the mortality rates for CHD did not differ significantly among the three cohorts, the three groups were combined for analysis. Those who died consumed less total carbohydrate and fiber and also tended to consume less starch and vegetable protein. Those who died had a greater cholesterol consumption. The Keys and modified Hegsted score were positively and significantly related to the risk of CHD. Dietary cholesterol and saturated fatty acids were positively associated with the risk for CHD. The measurements of body size and energy intake were not noted to be a predictor of coronary heart disease mortality. One explanation for the lack of mortality difference between the cohorts was that the difference in mortality over the 20 years of the study between men in the United States and in Ireland essentially vanished. The

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THE IMPACT OF DIET ON CORONARY HEART DISEASE

mortality rate for CHD increased in Ireland, while it decreased in the United States, which illustrates the difficulty of performing long-term studies on populations subject to secular influence. '" Table 1 summarizes the results of these epidemiologic investigations with regard to their findings of associations of dietary intake and CHD mortality. It is important to note the heterogeneity of study design, number of subjects, and factors analyzed as well as the divergence of results. No factor was universally associated with CHD mortality in these diverse study populations, but dietary cholesterol and saturated fat intake were positively correlated with outcome in the larger and longer duration studies. Intake of polyunsaturated fat was inversely related to (protective against) CHD death in the Western Electric study, but positively associated in the Honolulu study, with no significant association in the others. When reported, total caloric intake was inversely related to CHD mortality, likely due to the reasons postulated above. The dietary score of Keys and Hegsted was positively related to outcome when it was measured in the Western Electric and Ireland/Boston studies. CLINICAL TRIALS

If serum cholesterol is an independent risk factor for CHD and if the epidemiologic studies outlined above suggest that diet composition influences and determines serum cholesterol and CHD risks, does dietary intervention have a role in the primary and secondary prevention of CHD? The major questions are (1) does dietary change effectively lower cholesterol levels? and (2) does this translate into decreased incidence of coronary heart disease events? Critics of the diet and CHD relationship argue that the definitive trial of serum cholesterol reduction by diet and its effect on CHD has not been conducted.? 8 There are multiple reasons for not having such a trial as highlighted in 1968 by the Arteriosclerosis Task Force of the National Heart Institute when it was decided that a diet-heart trial was not feasible due to near impossibility of maintaining a blinded study of diet with a large group of participants over a long-term period, the probable mobility of the participants, and the difficulty of recruiting a control group to ingest a constant diet for many years, in addition to an extremely high projected cost. 36 Therefore, the likelihood of ever embarking on a conclusive randomized, blinded, dietary intervention, clinical trial to reduce cardiovascular morbidity and mortality is remote; however, an Table 1. ASSOCIATION OF DIETARY INTAKE AND CHD MORTALITY IN SIX EPIDEMIOLOGIC STUDIES

Study

n

Years F/U Dietary cholesterol Polyunsaturated fat Saturated fat Keys score Caloric intake

Western

Electric45 Zutphen 27

2107 19 + NS

+

NR

857 10 NS NS NS NR

Honolulu 32

8006 10 + + + NR

Puerto Rico'"

Countries23

Seven

Ireland/ Boston2B

5729 6

11,570 15

1001 20 +

NS NS NS NR

NR NS

+

NR NR

NS

+ +

NS

CHO ~ coronary heart disease, n ~ number of partiCipants, FlU follow-up, + ~ positive association with CHO mortality, - ~ negative (inverse) association with CHO mortality, NS ~ no Significant association with CHO mortality, NR ~ not reported in reference cited.

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ambitious trial of women's health, the Women's Health Initiative, is currently in the planning stages and intends to include just such a large-scale, long-term dietary intervention. A feasibility study has been completed in 303 selected volunteers to determine if a dietary regimen reducing fat intake from the current average of 40% of energy from fat to approximately 20% could be undertaken as a large-scale multicenter randomized trial. Subjects were randomized to either an interventional group consisting of a low-fat eating plan or a control group consuming a customary diet. The intervention group received nutrition instruction, behavioral counseling, primarily in large permanent support groups meeting regularly, as well as stringent dietary intervention. All participants were asked to return for frequent and regular follow-ups. At 6 months, the interventional group had substantially reduced the mean proportion of total energy from fat from 39% to 20% whereas the control group had a nonsignificant reduction. In the intervention group, this reduction was sustained at 12 and 24 months. In addition, the women in the intervention group showed a significant reduction in total serum cholesterol levels at 6month follow-up. It was concluded from this study that selected women with strong motivation could, in fact, make a significant change in their dietary habits and maintain this change over a prolonged period of time. They were able to substantially alter the make-up of their diet and significantly reduce their percentage total calories by fat in their daily diet. It was also noted that the dietary changes were made using foods that are readily available in the market place. 20 Even if a large-scale "definitive" trial is not yet available, there have been multiple smaller-scale studies of specific, usually short-term, dietary intervention with clinical or surrogate end points which bear examining. A brief overview of some of the major studies and their conclusions follow. In 1969, Day ton and associates 7 published the results of a controlled trial in an institutional setting (the Los Angeles VA Domicile) of a diet high in unsaturated fat. The study attempted to answer the question whether substitution of unsaturated fat for saturated fat in an experimental daily diet would decrease the CHD and atherosclerotic complication rate in a selected population. In the Los Angeles domicile, 846 middle aged to elderly male veterans volunteered to be randomly designated to either a control group ingesting a conventional diet (n = 422) or an experimental group (n = 424) .given a diet prepared with two-thirds of the animal fat substituted by vegetable oils. Both diets maintained a total fat content of 40%. The experimental diet was lower in cholesterol, 365 mg/day compared with 653 mg/day in the control group, but still permitted consumption of seven egg yolks per week. The end points were CHD events defined as sudden death or acute myocardial infarction. After 8 years, the adherence rate to the assigned diets, computed for each individual from assignment to date of death or termination of the study, was 56% for the control subjects and 49% for the experimental group. Nonetheless, the mean reduction in serum cholesterol was 20% for the experimental group and 7.3% for the control group. Only the combined fatal atherosclerotic endpoints (fatal myocardial infarction, sudden death, fatal cerebral vascular events, fatal arterial events) were significantly different between the two groups. There was no difference, however, in the number of total end point events between groups and there was an increase in nonatherosclerotic causes of death in the experimental group, yielding no difference between groups in total mortality. 7 Among the limitations from the study were the low adherence rate to the study diet, the small number of participants, the age of participants (increasing the likelihood of competing causes of mortality), the high fat content of the

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diets (reducing the likelihood of achieving a major change with the intervention), and the limited generalizability of this older, institutionalized, male population to the general public. Yet, this design permitted a blinded dietary intervention to be conducted on a long-term basis. Another design has been outlined by the National Diet-Heart Study, which enrolled 2032 men at six clinical centers, into a randomized feasibility study of dietary intervention. 36 The dietary changes were offered by nutritionists, to subjects and spouses, and were monitored frequently by interviews with the nutritionist. In addition, prepared meals were provided to subjects and their families to maintain a double-blind assignment to control and altered component diets. Of note is the observation that 41 % of participants of the first year study did not choose to volunteer for an extended (additional 4 years) trial. In 1981, the Oslo study group published the results of a trial of diet and smoking intervention on the incidence of CHD.15 In this primary prevention trial, 1232 40 to 49-year-old healthy, normotensive males at high risk for CHD were enrolled in a 5-year trial. The objective of the trial was to determine if lowering serum lipids and cessation of smoking could decrease CHD. Serum cholesterol ranged from 290 to 380 mg/dL at entry. The endpoints were defined as fatal or nonfatal myocardial infarction, sudden death, or cerebral vascular accident. Intervention consisted of dietary advice recommending a decrease in saturated fatty acid intake and slight increase in polyunsaturated fatty acid intake for those with elevated serum cholesterol only and a reduction in total calories for those who also had elevated triglyceride levels. Other dietary modifications suggested were fiber-rich bread, little margarine, use of skim milk, and intake of approximately one egg weekly. Fish, low-fat meat, polyunsaturated fatty acid oil for cooking, decreased sugar, sweetened drinks, and alcohol were also suggested. Smoking advice was given individually. Wives of participants were invited to join the group presentation. After 5 years, there were measurable reductions in cholesterol levels and smoking levels in the intervention group, with a 17% reduction in serum cholesterol from initial screening and a mean difference between groups of 13%. Most (90%) of the men in the intervention group experienced a decrease in the serum cholesterol level. Tobacco consumption fell approximately 45% more in the intervention group than control, although only 25% of smokers completely stopped smoking in the intervention group and 17% in the control group. Changes in serum cholesterol correlated with incidence of CHD incidence, and in a multivariate statistical model, accounted for nearly 60% of the reduction in CHD. The intervention group had a significantly lower incidence of cardiovascular events. Total mortality was 33% lower (16 deaths versus 24 deaths) and cardiac mortality 55% lower (8 versus 15 deaths) in the intervention group, but these differences were not statistically significant, using a two-tailed test, except in the category of sudden cardiac death. 15 Additional results from the Oslo study were published in 1985 indicating that the net difference of 10% in the serum cholesterol between groups was the main cause for a significant reduction in incidence of first major CHD events and that the reduction in smoking contributed to a lesser degree. The overall results indicated a 47% reduction in incidence of first major CHD event in the intervention group compared with the control group. These significant reductions involved all social strata. 18 Another large, well-publicized trial was the Multiple Risk Factor Intervention Trial (MRFIT), a randomized, primary prevention trial involving 12,866 men aged 35 to 57 years who were believed to be at high risk of having CHD although no clinical evidence existed. 34 Increased risk was defined by the

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weighted presence of three risk factors: cigarette smoking, serum cholesterol, and blood pressure. Serum cholesterol and blood pressure had to be in the upper 10% of risk score distribution at the initial screening but could not exceed a level of 350 mg/dL for cholesterol or a diastolic blood pressure of 115 mm Hg. The baseline serum cholesterol at entry for both groups in MRFIT was approximately 253 mg/dL. Approximate dietary energy consumption for both groups was 2,400 kilocalories per 24 hours. Saturated fatty acids comprised approximately 14% of calories and polyunsaturated fatty acids 6.4% of calories. Dietary cholesterol was approximately 450 mg/day. The men were randomly divided into two groups, one designated the special intervention (SI) group which targeted cessation of cigarette smoking and reduction of elevated serum cholesterol and blood pressure levels. The other group was designated the usual care (UC) group and was referred to local physicians for treatment of their risk factors as determined individually appropriate. The dietary aspect of this trial was aimed at lowering serum cholesterol by counseling and fostering the development of shopping, cooking, and eating patterns rather than a specific prescribed diet. Dietary recommendations also consisted of decreasing the saturated fat content to less than 8% of total calories, decreasing the dietary cholesterol to less than 250 mg/day, and recommending weight loss for those who were 115% or greater of desirable weight. The four defined end points of this trial included (1) death from CHD, (2) death from cardiovascular disease, (3) death from any cause, and (4) the combination of fatal CHD and nonfatal myocardial infarction. Subjects were followed up over an average of 7 years. Risk factor levels declined in both groups, but to a much greater degree in the SI group. The mortality from CHD was 17.9 deaths per 1000 in the SI group (n = 115) and 19.3 per 1000 in the UC group (n = 124), whereas total mortality rates were 41.2 per 1000 in the SI group (n = 265) and 40.4 per 1000 in the UC group (n = 260). Both figures were essentially no different. The number of deaths in the UC group fell far short of predicted, leading the investigators to conclude that substantial contemporary alterations in lifestyle choices and medical management led to the inconclusive results. Indeed, cigarette smoking in the UC subjects decreased from 59% to 46%, diastolic blood pressure was reduced from 90.9 to 83.6 mm Hg, and serum cholesterol levels decreased from 253 to 240 mg/dL. In the SI group, the intensive intervention resulted in a reduction of smokers from 64% to 32%, of diastolic blood pressure from 91 to 80.5 mm Hg, and of serum cholesterol from 253.8 to 235.5 mg/dL. Thus, a greater degree of reduction was demonstrated for SI than UC groups, but both experienced improvement in risk factor profile. 34 Also noted was the fact that hypertensive patients with resting electrocardiographic abnormalities treated in the SI group had 15 more deaths than in UC, suggesting an unfavorable outcome related to the choice of antihypertensive agents for SI. 6 In 1965, a small study was published in the Lancet, in which 264 males under the age of 65 who had recovered from a first myocardial infarction were enrolled in a randomized trial and either placed on a low-fat diet or continued on their normal diet. 40 The dietary regimen for the intervention group consisted of an allowance of up to 40 g of fat daily with no alteration in the type of fat consumed. Assessment of dietary consumption over 5 years of follow-up demonstrated that the diet group maintained an average fat intake of 45 g/day whereas the control group consumed between 110 and 130 g/day. Patients did not have to meet an entry level of elevated serum cholesterol. Over the 4-year course of the study period, the low-fat diet group showed a decrease in mean

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serum cholesterol from 260 mg/dL at entry to 216 mg/dL. The control group had an initial cholesterol level of 266 mg/dL which decreased to 241 mg/dL. Less than one half of all patients, however, had measurements obtained at each 3-month visit. After 4 years, the cumulative death and reinfarction rate was 38% for the low-fat group and 40% for the control group.40 A similar trial conducted by the same research group was published in 1968 in which 393 males under the age of 60 who had recently survived their first myocardial infarction were randomized to either an experimental group given a diet low in saturated fats containing 85 g of soybean oil daily or a control group consuming their ordinary diet.'! The trial lasted a range of 2 to 7 years. The men on the test diet lowered their serum cholesterol from a mean initial level of 272 to 213 mg/dL at 6 months, a 22% decrease compared with a reduction in the control group from 273 to 259 mg/dL, a 6% fall. At the end of the study period, there were no significant differences in the reinfarction or death rate between the two groups. From these two studies, it was concluded that a low-fat diet following myocardial infarction did not affect overall occurrence of cardiovascular events. The lack of clinical benefit in these secondary prevention studies could be expected due to incomplete assessment of subjects, small numbers of patients, short follow-up, subjective assessment of events, small numbers of endpoints, and a decrease in cholesterol level occurring even in the control group. In 1983 the World Health Organization European Collaborative Group published the results of a multifactorial trial in the prevention of CHD.50 This study attempted to determine to what extent the main coronary risk factors can be modified in middle-aged men and what effect these changes would have on the incidence of and mortality due to CHD. A total of 60,881 men aged 40 to 59 employed in factories in the United Kingdom, Belgium, Italy, and Poland were enrolled with 49,784 comprising the basis for reporting. Randomization took place by factory, rather than by individual. The community-wide effort targeted high-risk males by utilizing group interaction, media intervention, and personal interaction with minimal intensive medical intervention. The intervention factors were cholesterol lowering by dietary change, cessation of smoking, weight reduction, daily exercise, and hypertension control. The primary end points were defined as (1) fatal CHD, (2) fatal CHD plus nonfatal myocardial infarction, and (3) total mortality. At the onset of the trial, the mean plasma cholesterol level in the intervention group was 216 mg/ dL whereas the control group had a level of 217 mg/dL. There was an 11 % reduction in combined risk estimate and although only a 1.2% net average reduction in plasma cholesterol and modest reductions in the other risk factors. The high-risk subjects experienced an even greater net reduction of 19.4% in the combined risk estimate. Among CHD rates, there was a 7.4% net overall reduction for deaths and a 3.9% net overall reduction for fatal CHD plus nonfatal myocardial infarction. Among men aged 40 to 49 years, the reduction for this end point was 15%. There was an overall 2.7% reduction in all cause death rate. The change in CHD among the different centers correlated with the degree of change in risk factors. Only in Belgium, where the reduction in CHD incidence decreased 24% and reduction in total mortality reached 17%, were these changes significantly different. Investigators concluded that risk for CHD in middle-aged men is reducible and cost effective when used in the work setting with the support of additional staff.50 Although primarily a drl1g intervention trial, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) also utilized a cholesterol lowering diet, the effects of which can be demonstrated within the control group.3D The 1900 men in the "placebo" arm of the trial were instructed in a

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diet designed to provide 400 mg of cholesterol per day and a polyunsaturatedto-saturated (P/S) fat ratio of approximately 0.8%. The mean dietary values at entry for the placebo group were 2264 kcal per day, 309 mg cholesterol, 95 g total fat (38% of calories), 33 g saturated fat (13% total calories), and a PIS fat ratio of 0.43. After 7 years follow-up, the placebo group average intake was 2060 kcal per day, 284 mg cholesterol, 87 g fat (38% of calories), 28 g saturated fat (12.6% of calories), and a PIS ratio of 0.67. Mean plasma lipid values at baseline for the placebo group were 292 mg/dL total cholesterol and 216 mg/dL low-density lipoprotein (LOL) cholesterol. After 7 years of dietary intervention only (with the modest changes listed above), the total cholesterol had fallen to 277 mg/dL (a 5% reduction) and LOL cholesterol to 198 mg/dL (an 8% reduction).3o Although no clinical outcomes can be judged (as there was no "control" group for the placebo arm), this study demonstrated that changes in lipid levels are achievable without extreme dietary alterations. Several studies have tackled the problem of risk reduction by dietary change in patients with known CHO and are designated secondary prevention trials. The Leiden Intervention Trial attempted lowering of serum cholesterol by dietary changes in 39 patients (35 men and 4 women) with stable angina who had angiographic evidence for coronary artery obstruction of at least 50% in one artery.3 The dietary intervention consisted of a vegetarian diet which contained a PIS ratio of at least 2 and cholesterol content less than 100 mg/day. Total serum cholesterol was reduced from 267 mg/dL to 240 mg/dL over 2 years. Total cholesterol high-density lipoprotein (HOL) ratio fell from 7.1 at baseline to 6.4 at 2 years. LOL cholesterol was not determined. By visual assessment of baseline and follow-up arteriograms, there was mean progression of disease in 21 of 39 patients but no lesion increase in 18 patients. Lesion growth was strongly correlated with the total/HOL cholesterol ratio. Dietary intervention to induce an alteration in the total/HOL cholesterol ratio was suggested as a means to delay coronary artery disease progression; however, the Leiden study suffered from having no control group, loss of follow-up in 25% of the entry population, and by not assessing clinical endpoints. Only two other dietary intervention studies have been performed in patients with known coronary artery disease to determine if lesion progression could be delayed or if actual regression could be induced. The Lifestyle Heart Trial randomized 28 patients with known coronary artery disease to a very lowfat vegetarian diet, comprised of 70% to 75% carbohydrates, 15% to 20% protein, 10% of calories from fat, and less than 5 mg cholesterol. In addition, subjects in the intervention group participated in moderate aerobic exercise, stress management, and group support meetings. The experimental group experienced substantial lowering of total and LOL cholesterol and increases in total/HOL cholesterol ratio. After 1 year, regression in average percent diameter stenosis from 40% to 37.8% occurred in the experimental group but progression from 42.7% to 46.1 % occurred in the 20 patients in the control group. Despite very small numbers and use of arteriography in lieu of clinical endpoints, this aggressive lifestyle intervention produced measurable changes in coronary arteries. 37 The St. Thomas' Atherosclerosis Regression Study (STARS) rcndomized 90 men to receive usual care (U), dietary intervention alone (D), or diet plus cholestyramine (DC) in order to determine the effect of dietary lowering of plasma cholesterol on angiographic appearance of coronary artery lesions. 49 From a mean baseline plasma cholesterol level of 280, all three groups had lower levels at 39 months: 4% reduction to 268 mg/dL (U), 14.6% reduction to 239 mg/dL (0), and 23% lowering to 215 mg/dL (DC). Both intervention groups

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showed a decrease in the proportion of patients developing lesion progression,

15% D and 12% DC compared with 46% U, over 39 months. Conversely, the

proportion of patients demonstrating an increase in coronary lumen was highest in the treated groups, 38% D, 33% DC compared with 4% of U. The changes in coronary luminal measurements correlated significantly with changes in LDL cholesterol and LDLlHDL cholesterol ratio. 49 A recent report demonstrated the benefit of adding fresh fruits and vegetables to a prudent low-fat diet in reducing cholesterol levels in a fairly large group of patients. 46 After achieving modest reductions in total and LDL cholesterol levels after 4 weeks consuming a diet based on the American Heart Association Step 1 Diet,35 the treatment group decreased total serum cholesterol and LDL cholesterol by 9.6% and 10.8%, respectively, by the addition of 522 g/day of fruits and vegetables. The additional fiber intake and possible antioxidant properties of the vitamins in fruits and vegetables appear to hold promise for long-term intervention. The impact of using available foods on cost and compliance as opposed to drug treatment adds to the attractiveness of these dietary recommendations. When the clinical trials of dietary intervention to reduce the incidence of CHD are combined in a meta-analysis, the secondary prevention trials demonstrate a significant benefit, whereas primary prevention trials and overall results show no clear benefit l6 , 17 (Fig. 1). Analysis for the effect on total mortality shows no benefit for either diet or drug treatment. 16,17 When a cost-effectiveness

PRIMARY PREVENTION 0 0 846

Day too

0.629

(7)

0.441

Oslo 0 1232 (15)

0.318

0

10.896

1

1

0.546

--+I-----l' 0.937

1-1

0.990

MRFIT 0 12,866 (34)

0.836 1

0

1

1

1.174

1.047

0.946 ~ 1.159

WHO factories (50) 0 49.764 Total 0

0.94

1.~2

r-----r 1.1

0.78 SECONDARY PREVENTION

0.63

o

0.2

0.4

1

0.6

I

0.8

1

0.96 1

1.2

1.4

Odds Ratios and 95% Cl

Figure 1. Effect of diet intervention on CHD: results of clinical trials. The odds ratios and 95% confidence intervals (Cl) are displayed for four primary prevention trials and summarized for the secondary prevention trials that used dietary intervention. The odds ratios are shown above the vertical intersecting line for each plot. The outcome of subjects receiving modified diets in studies whose Cl include 1 (dotted vertical line) are not statistically different from the control groups, Studies which have an odds ratio less than 1 and whose Cl do not reach 1 demonstrate a beneficial outcome (lower incidence of CHD than expected) in the dietary intervention group. Numbers in parentheses indicate references, (Data from Holme I: An analysis of randol1lized trials evaluating the effect of cholesterol reduction on total mortality and coronary heart disease incidence, Circulation 82:1916-1924,1990; and Holme I: Meta-analysis of cholesterol reduction trials: Coronary disease and mortality, Primary Cardiology 18:63-70,1992,)

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analysis is applied to the existing reports and current intervention guidelines, the use of aggressive means to reduce cholesterol levels in patients with existing CHD is supported. The primary prevention of coronary artery disease by cholesterol lowering is recommended to be targeted to high-risk populations. '2 Yet, with promising reports on the effectiveness of altered diet in lowering cholesterol, 20,46 the current recommendations for healthy diets for alP and for the dietary treatment of CHD'9 are prudent guidelines.

References 1. American Heart Association: Dietary guidelines for healthy American adults: A

2. 3, 4. 5, 6, 7, 8, 9. 10, 11. 12, 13. 14. 15. 16. 17, 18.

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