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Ann. Rev. Med. 1983. 34:179-94

Copyright © 1983 by Annual Reviews Inc. All rights reserved

THE ROLE OF DIET IN THE

ETIOLOGY AND TREATMENT
OF ATHEROSCLEROSIS
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Paul Samuel, MD., Donald J. McNamara, Ph.D., Joseph

Shapiro, MD.
The Rockefeller University, New York, New York 10021; The Long Island
Jewish-Hillside Medical Center, New Hyde Park, New York 11042; and the
Albert Einstein College of Medicine, Bronx, New York 10461

ABSTRAcr

The role of various dietary constituents in the etiology of hyperlipidemia

and cardiovascular disease is examined in light of currently available data
from epidemiological and clinical studies. Recommendations regarding the
dietary management of the hyperlipidemic patient at risk are presented and
the advisability of generalized dietary guidelines for the public examined.
The certainties, which are few, and the uncertainties, which are numerous,
regarding the cause and effect relationship between diet, hyperlipidemia,
and cardiovascular disease suggest that dietary intervention to treat the
hyperlipidemic patient is a rational first step but that the generalization of
this approach for the public may be premature.

INTRODUCTION

In the course of the past three decades few issues have generated more
discussion, argument, and controversy in the field of medicine or public
health than the effect of diet on heart disease. Can diet prevent or even
reverse arteriosclerosis, a disease affecting practically all of us in this soci­
ety, an epidemic of unprecedented proportion in the history of the species?
The confusion of the public is apparent, the opinion of the medical profes­
sion is divided, and the public policymaker is inundated with almost daily
conflicting advice and information. What gave rise to this chaos? Where are
we, how did we get there, and where do we go from here?

179
0066-4219/83/0401-0179$02.00
 180 SAMUEL, McNAMARA & SHAPIRO

For thousands of years mankind struggled for food. During the past two
hundred years, however, the advent of modem agriculture and industry has
changed the life of Western man. A hundred years ago overnutrition (i.e.
obesity) was a status symbol; the caricature of the rich, fat banker with a
top hat and a big cigar, is familiar to all. Even today, there are still many
countries on the globe where obesity is an exterior sign of success. It is
alleged that in the Western world we are now paying the price for our
opulence: arteriosclerosis, diabetes, hypertension, and perhaps some forms
of cancer, to mention just a few. Can this idea withstand critical examina­
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tion?
The average American diet contains about 40-45% of the total calories
as fat, with a polyunsaturated-to-saturated (PIS) fat ratio of 0.4, 15-20%
of total calories as protein, and the rest as carbohydrates. The daily choles­
terol content of this diet is around 400-800 mg, and the fiber content is no
more than 2-5 grams. In the 1950s and 1960s, facing an increasing rate of
coronary heart disease, the horrified public was offered a number of modifi­
cations to this diet, especially those patients whose plasma lipids (and thus
the risk of coronary disease) were excessively elevated. The thoughtful
American Heart Association (1) and a number of other centers advanced
the concept of the "prudent diet": decrease the fat content to 35% (with
a PIS fat ratio of 1.5 or higher), decrease the daily intake of cholesterol to
250 mg or less (a single egg contains that much) with 15% as protein and
the rest as carbohydrates. On the other hand, the Food and Nutrition Board
of the National Academy of Sciences, after careful examination of the
available data, could not find sufficient supporting evidence to recommend
any dietary modifications for· the. general public, and especially to those
who are enjoying good health (2). On the other side of the debate, public
policymakers held Senate hearings and recommended a diet containing only
10--20% of the total calories as fat. Under these circumstances, how can the
practicing physician answer when a patient asks for dietary instructions?
Arteriosclerosis is a multifactorial disease: heredity, diet, hypertension,
diabetes, possible viral injury to the arterial wall, cigarette smoking, stress
and strain, and perhaps many other factors may all play a role in the
etiology and development of the disease. In the present article we consider
the possible role of diet and its influences on plasma lipid levels and heart
disease risk. The "lipid hypothesis" stipulates that increased levels of
plasma lipids (more specifically cholesterol or LDL-cholesterol) will in­
crease the degree of development of arteriosclerosis (and vice versa). We
will not defend the lipid hypothesis, but we assume that it is valid. We may
be right or wrong. Nonetheless, the following discussion and arguments are
based on the validity of this probable, but as-yet unproven, theory.
 DIET AND ATHEROSCLEROSIS 181

EPIDEMIOLOGICAL EVIDENCE

The epidemiological data relating diet, plasma lipid levels, and coronary
heart disease (CHD) come from four primary sources: (a) analysis of
dietary patterns and disease incidences among nations; (b) analysis of
autopsy data from different countries; (c) studies of populations in various
nations; and (d) analysis of the effects of migration on dietary patterns and
CHD incidence (3). Statistical analyses of the data suggest that certain
nutrients may be involved in the development of hyperlipidemia and its
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associated risk of atherosclerosis and CHD incidence. In general these

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epidemiological studies demonstrate increased CHD in societies that have

high intakes of total calories, total fat, saturated fat, animal protein, choles­
terol, and sugar. Obviously a number of these dietary constituents are
related (saturated fat-animal protein--cholesterol), and it is often difficult to
separate out specific effects of a given nutrient on CHD incidence.
It should be noted that epidemiological studies compare populations
differing in many respects other than dietary intakes. Thus comparing
dietary patterns of an undernourished, lean, manual-laboring society to an
overweight, sedentary population may be investigating more than simply
dietary influences. Nevertheless, the epidemiological studies of the relation­
ships between what a population eats and its incidence of specific diseases
provide valuable data to guide the intrapopulation studies of nutrient intake
and disease incidence.
With these considerations in mind, the following section addresses the
findings from population studies relating dietary fat quality and quantity,
cholesterol quantity, carbohydrate intake, and dietary protein intake to the
risk of CHD.

Dietary Fat: Quantity and Quality

The Seven-Country Study of Keys and co-workers (4) is one of the most
comprehensive investigations of the relationship between dietary intake
patterns and CHD incidence in broad-based populations. This prospective
study of 12,000 men age 40-59 years in 18 cohorts has been carried out for
over ten years (5) and has demonstrated a positive correlation between the
saturated fat intake, as a percentage of total calories, and the five-year CHD
incidence. For these groups saturated fat intake was positively correlated
with serum cholesterol, which was positively correlated with CHD.
The Seven-Country Study also demonstrates that the total calories
derived from dietary fat is positively correlated to disease incidence. Similar
data were reported by the International Atherosclerosis Project (6), which
demonstrated a positive relationship between the saturation of dietary fat,
serum cholesterol leveIs, and CHD.
 182 SAMUEL, McNAMARA & SHAPIRO

The Ni Hon-San Study (7) of CUD mortality in Japanese men living in

Japan, Hawaii, and San Francisco showed that, as the populations moved
east, total fat intake in the diet, saturated fat intake, mean body weight, and
serum cholesterol levels all increased, as did the incidence of CHO deaths.
Undoubtedly other life-style factors also changed as these populations
moved and, while it may not be possible to demonstrate a clear cause and
effect relationship, the data are consistent with other epidemiological
findings.
The data of these cross-cultural studies would be strengthened if they
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could be verified within a population. Unfortunately, this has not been

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accomplished though tested in a variety of studies (8, 9) attempting to relate

plasma cholesterol levels and dietary patterns within groups. Many reasons
for this failure have been suggested, including the homogeneity of the
dietary pattern, the large degree of genetic and metabolic heterogeneity
within a population, the methods used for measuring nutrient intakes,
and/or various confounding variables such as other risk factors. Irrespec­
tive of the possible causes, the failure to verify the international findings by
intranational data suggests to some that the statistical relationships between
dietary fat intake, elevated serum cholesterol levels, and CUD incidence
may not be as straightforward as originally perceived.

Dietary Cholesterol
For the epidemiologist it has been difficult to demonstrate direct caus�
relationship between dietary cholesterol intake, hypercholesterolemia, and
CHD mortality simply because most cholesterol-rich foods also contain
large amounts of saturated fat. Thus, demonstrating independence of effect
has been virtually impossible. When the associated variables are factored
out of the statistical analysis, dietary cholesterol alone appears to have little
influence on CHD incidence (population studies) or on plasma cholesterol
levels (cross-sectional studies).

Dietary Carbohydrate and Protein

The relationship between dietary carbohydrate intake, hypercholes­
terolemia, and CUD mortality is usually seen as a negative correlation in
population studies. This observation is probably due to the fact that soci­
eties with a high carbohydrate intake also have a low fat intake and a low
incidence of CHO. The available evidence would suggest that the negative
correlation between dietary carbohydrate intake and CUD is more a func­
tion of the decreased dietary fat content than of an increased carbohydrate
intake. Some studies suggest that a positive correlation exists between su­
crose intake and CHO; yet sucrose intake is correlated with saturated fat
intake. Once this variable is controlled for, the statistically significant rela­
tionship between sucrose and CHO is lost (3). Thus, the epidemiological
 DIET AND ATHEROSCLEROSIS 183

data do not suggest a link between dietary carbohydrate intake, either

simple or complex, and CHD risk.
A more complex problem is encountered in attempting to judge the
effects of dietary protein, animal versus vegetable, on plasma lipids and
CHD incidence since intake of animal protein usually involves intake of
saturated animal fat and cholesterol. For these reasons one cannot state
whether the sources of dietary protein in any way affect serum lipid levels
or CHD incidence from the available epidemiological data.

Clinical Trials
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There have been eight major clinical trials testing the "lipid hypothesis" by
dietary interventions (reviewed in References 10 and 11). These studies
were carried out as primary or secondary intervention trials and, with the
exception of the Oslo Heart Study, the patients did not necessarily have
hyperlipidemia. In the seven trials with an average plasma cholesterol level
of 260 mgldl, the decrease in plasma cholesterol achieved by dietary man­
agement ranged from 7 to 16% (mean 11%) and the data suggested, but
could not demonstrate. a benefit in terms of new events of CHD. The Oslo
Heart Study (average plasma cholesterol 323 mgldl) clearly demonstrated
that in healthy middle-aged men at high risk for CHD the dietary reduction
of plasma cholesterol levels (13% reduction) and decreased smoking signifi­
cantly reduced the incidence of the first event of myocardial infarction and
sudden death. This study supports the use of aggressive intervention on
multiple risk factors in high-risk individuals to decrease CHD incidence;
whether such benefits could be achieved in the general population has yet
to be demonstrated.
One unexpected finding from the epidemiological studies is that, within
various populations, CHD incidence is only increased in those individuals
having plasma cholesterol levels in the upper two quintiles of the population
(12). For subjects having plasma cholesterol levels in the first three quintiles
of the distribution there is little difference in CHD mortality; the third
quintile is the population mean. This has led to the questioning of the
rationale of generalized dietary guidelines for the general population since
there may be little value in lowering plasma cholesterol levels except in
those individuals with cholesterol concentrations in the top two quintiles
(13).

EXPERIMENTAL STUDIES
Dietary Cholesterol
One of the major controversies in the field of nutrition is the effect of dietary
cholesterol on plasma cholesterol levels and its impact on health and dis­
ease. According to some reports, plasma cholesterol levels will increase with
 184 SAMUEL, McNAMARA & SHAPIRO

increased dietary cholesterol intake (14) largely consisting of a marked

elevation ofLDL- and a moderate rise in HDL-cholesterol. (15). However,
other authorities suggest that decreasing cholesterol intake makes no sense,
since increased dietary cholesterol has no major effect on blood lipids (16,
17) primarily owing to feedback inhibition of endogenous cholesterol syn­
thesis. Should dietary cholesterol intake decrease, the same feedback mech­
anism would be released resulting in an increased cholesterol synthesis in
body tissues, thereby maintaining the same daily total input and an un­
changed plasma cholesterol level. In fact, in carefully controlled metabolic
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ward studies, increased dietary cholesterol intake resulted in plasma choles­

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terol levels that rose in some and fell or remained unchanged in others (18,
19). It was completely impossible to define or to predict the individual
patient's response to this "cholesterol challenge."
Can we explain these discrepancies, and how can we attempt to define
the operative mechanisms? Figure I shows the "balance" of cholesterol in
the plasma-pool of the body; in the adult human the mass of this pool is
about 6 gm. Input occurs through the two top faucets: diet (-300 mg/day,
50% absorbed of 600 mg) and synthesis (-800 mg/day). In order to main­
tain the steady state (and plasma cholesterol levels are remarkably con­
stant), the exact amount entering the pool must leave it day after day. The
only excretion of cholesterol or its end products from the body is in the feces
(we have no enzymes to decompose the cholesterol ring system). Indeed,
about 800 mg of neutral sterols (unabsorbed cholesterol and its bacterial
conversion products) appear daily in the stools, and about 250 mg of bile
acids (converted from cholesterol by the liver) are excreted. (See two bottom
faucets in Figure 1). The remaining 50 mg are used for steroid hormone
production and/or are excreted through the skin. However, a third faucet
on the bottom of Figure 1 communicates with the tissues. We know that
tissue cholesterol is constantly exchanged with the plasma, and tracer ex-

Figure 1 Cholesterol balance in the plasma pool (see text for explanation).
 DIET AND ATHEROSCLEROSIS 185

periments show that it takes about a year for most "tissue pools" to become
equilibrated with the plasma pool (20, 21).
A careful inspection of Figure 1 indicates that reduction of plasma cho­
lesterol levels by whatever means (diet, drug therapy, etc) can only be
achieved by one of the following mechanisms:

1. Reduction of dietary cholesterol or its absorption;

2. Reduction of cholesterol synthesis;
3. Increase of the fecal excretion of cholesterol end products (neutral ste­
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rols and/or bile acids);

4. Transfer of cholesterol from the plasma pool to the tissues.

There is evidence that a feedback control mechanism may be operative

between these four functions. However, the degree and effectiveness of the
feedback control varies from individual to individual; in some it is extremely
effective, in others it is practically absent. With presently available technol­
ogy the effectiveness of this mechanism can be tested. The method consists
of measuring cholesterol absorption, synthesis, and excretion during the
feeding of a low-cholesterol diet and comparing the results to those of a
regimen of markedly increased dietary cholesterol. What will be the reac­
tion of the individual to this cholesterol load, and which of the four func­
tions, if any, will be activated?
The exact mechanism of the absorption of cholesterol through the brush
border of the gut wall is not completely understood, in spite of the enlight­
ened efforts of many excellent laboratories over the past decades. Only
about 50% of the intraluminal cholesterol is absorbed from the gut, con­
trary to many other dietary components such as neutral fats or carbohy­
drates, which have a nearly complete (>90%) single-passage absorption.
The rate of cholesterol absorption remains around 50% from an intake of
a few milligrams up to about 2000 mg per day (18). Above this level the
rate of percentage absorption begins to fall and settles around 25% (at levels
of 2000-3 - 000 mg of daily dietary cholesterol) (18). It is peculiar that within
the physiologic range of dietary intake of this compound the rate of absorp­
tion remains constant, and even at relatively low levels it is incomplete. We
measured the rate of cholesterol absorption in a group of 41 outpatients on
a low cholesterol diet ("'240 mg daily). The mean absorption was "'145
mg/day (60%). When the daily cholesterol intake was increased to -830
mg, the rate of absorption showed no change: about the same percentage,
"'435 mg/day (53%), was absorbed (22). Therefore, when daily dietary
cholesterol intake is increased, let us say, from 300 to 1000 mg, we are
loading the system, increasing the daily input from the diet from -150 to
 186 SAMUEL, McNAMARA & SHAPIRO

-500 mg. What happens to cholesterol synthesis, excretion, and tissue

transfer?
It should be emphasized that to answer this question the study of each
individual patient necessitates several months of hospitalization on the
metabolic ward, controlled feeding by a diet of exactly known constituents,
the attainment of the metabolic steady state, and the precise monitoring and
analysis of the daily fecal neutral sterol and bile acid excretion., Conse­
quently, the total number of patien�s studied and the data published in the
world literature are extremely limited: 15 patients, from three laboratories.
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(18, 19, 23). In these 15 subjects the response to an increased dietary

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chOlesterol load was as follows: In 5 patients cholesterol synthesis was

suppressed or markedly reduced; in 6 patients the fecal excretion of choles­
terol end pfoducts (neutral sterols and bile acids) was increased; and in 4
patients the ingested cholesterol was stored' in the tissues.
What characterizes the 4 patients unable to compensate? Can we define
their clinical or biochemical characteristiCs and' eventually predict who can
eat cholesterol and who should not? On the basis of the available informa­
tion we cannot define this: segment of our population. Undoubtedly, many
more studies wilr be necessary to obtain this very important information.
Thus, both sides of the dietary cholesterol debate are right. Some of us
can neutralize increased dietary cholesterol intake by precise compensating
mechanisms, namely reduced cholesterol synthesis' andlor increased fecal
excretion. ofcholesterol end products. However, in some others,these mech­
anisms are' apparently lacking. It seems to us, that one of the most impor­
tant areas for future research in this field is to work out fast, precise,
inexpensive, and reliable methods to define these variables and their impor­
tance in health and disease.

Dietary Fat and Carbohydrate'

The argument concerning the fat content of the diet involves two major
issues: quantity and quality; Will a, low-fat diet reduce plasma lipids? It is
almost impossible to answer this question directly, inasmuch as in most
available experimental studies reduced fat content coincided with markedly
decreased dietary: cholesterol intake.' When both dietary fat and cholesterol
are reduced, serum cholesterol levels tend to decrease (24, 25). In one study,
switching from an approximate fat content of 40-45% afthe'tatal calories
(with a PIS fat ratio of 0.5, thus mostly saturated) to a practically fat-free
diet (rice diet) reduced serum cholesterol levels by an average of 22%, and
in some patients by as much as 30% (25). Some investigators ascribed this
effect to the reduced fat content (24), whereas others thought it was due
purely to reduced' cholesterol intake (23). It is interesting that as early as
1955 Hatch and associates (24) noted'that the isocaloric exchange of dietary
 DIET AND ATHEROSCLEROSIS 187

fats for carbohydrates induced hypertriglyceridemia in about one [Link]:dfthe

patients studied.
The effect of dietary exchange of carbohydrates for fats was investigated
by Schreibman et a1 (26) under [Link] controlled metabolic ward condi­
tions in hyperlipidemic patients fed liquid-formula diets. The daily dietary
cholesterol content was kept very low «45 mg/day), and was identical
during the low- and high-fat regimens. Dextrose was exchanged isocalori­
cally for polyunsaturated fats, and the fat content of the diet ranged from
70% of the total calories to 45%, 40%, 20%, and fat free. Carbohydrates
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. caused an increase of plasma triglycerides in each ,patient, and a rise in

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plasma cholesterol in 7 of 10 subjects; plasma cholesterol decreased only in

one patient and remained unchanged in two. In these last 3 patients, fecal
steroid excretion increased; in the others it remained unchanged or even
decreased. During the administration of high-carbohydrate diets LDL­
cholesterol increased and HDL-cholesterol decreased (26).
It seems to us that the exchange of dietary saturated fats (together with
cholesterol) for carbohydrates may be beneficial; however, exchanging'car­
bohydrates for polyunsatured fats isocalorically may cause a shift toward
a more atherogenic lipid profile. Some authors disagree with this concept
(15), and argue that the hypertriglyceridemic effect of high dietary carbohy­
drate is only transitory. They .report a return to baseline triglycerides after
4 weeks, following a short period of elevated levels (15). However, in
Schreibman'S experiments the high-carbohydrate feeding was maintained
for40--70 days and triglyceride levels remained high throughout the study
(26). It is, nonetheless, a fact that populations conswriing a high-carbohy­
drate, low-fat, low-cholesterol diet over a lifetime have no elevated plasma
triglyceride levels. Whether the determining factor in these populations is
the diet or some other component of a markedly different life-style is not
known at present.
The second question is the qualitative difference between fats, more
specifically the well-known effect of saturated (animal) vs polyunsaturated
(vegetable) fats on plasma cholesterol levels. In 1956 Sinclair (27) proposed
that the degree of saturation or unsaturation of dietary fatty acids had a
considerable influence in health and disease in general, and on plasma lipid
levels in particular. Since then, as is well known, a massive array of litera­
ture has appeared on this subject.
The point that fats high in polyunsaturated fatty acids reduce plasma
lipid levels was conclusively proved by Ahrens and co-workers in 1957 (28).
However, the mechanism of action in reducing plasma cholesterol levels is
still disputed. Connor et a1 (29) and Neste1 et al (30) claim that polyunsatu­
rated fats increase excretion of fecal steroids, but other workers have not
been able to demonstrate this effect (31). Thus, the mechanism of plasma
 188 SAMUEL, McNAMARA & SHAPIRO

cholesterol reduction was explained in these studies by a shifting of choles­

terol from the plasma pool into the tissues (31). It was assumed that the shift
occurs into "bulk tissue," namely to muscle, adipose, or connective tissues.
The calculated mass of cholesterol thus shifted from the plasma pool varies
from 200 to 4000 mg. The estimated size of the mass of cholesterol in bulk
tissue is about 50 g, thus the shift produces only an insignificant increase
(31). Nevertheless, it has not been shown that this "shifted cholesterol" does
not go to the intima of the arterial wall. There is general agreement that
dietary polyunsaturated fatty acids reduce LDL-cholesterol; HDL-choles­
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terol may go up or down or may remain unchanged (32).

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Recently, a series of papers appeared expressing some reservation on the

use of fats high in polyunsaturated fatty acids. In most instances the authors
expressed their fears that these substances may be carcinogenic or have
cancer-potentiating effects (33). In our opinion, the evidence at hand con­
necting polyunsaturated fats to carcinogenesis is weak and insufficient to
warrant discontinuation of the present trend. However, this concept has
had its impact in that current dietary recommendations suggest a dietary
fat intake of 30% of the calories; 10% of each type of fat, saturated,
monounsaturated, and polyunsaturated. Until further data are obtained, a
definitive statement cannot be made.
A word about refined carbohydrates is in order. In the early 19608 several
groups reported that the exchange of starch for sucrose in the diet resulted
in increased serum lipids (34). However, in later investigations this finding
was not always reproduced. Again, only further studies will answer the
question.

Dietary Protein
The exchange of mixed dietary protein, mainly of animal origin, for soybean
protein was reported to reduce serum cholesterol levels moderately but
significantly (35). LDL-cholesterol decreased, HDL-cholesterol remained
unchanged or slightly diminished. The fat, carbohydrate, and sterol content
of the diet remained unchanged in these experiments. Although in one
report no difference was found in serum lipids when animal proteins were
exchanged for soybean protein (36), in the majority of these studies the
experimental data again seem to suggest the detrimental effects of car­
nivoricity.

Dietary Fiber
In 1954 Walker & Arvidsson (31) proposed that one of the important
factors responsible for low plasma lipid levels in some indigenous African
populations was the fiber content of their diet. In a later article Burkitt et
a1 (38) generalized this theory, and proposed that high dietary fiber can
 DIET AND ATHEROSCLEROSIS 189

prevent a number of diseases, particularly of the large bowel, and some

other ailments like atherosclerosis that have become prevalent in Western
society. Indeed, the average daily fiber content of the Western diet is esti­
mated to be 2-5 g, whereas an 18-35-glday intake is reported in more
primitive cultures (38).
On the basis of the available experimental evidence it is difficult to assign
a central role to dietary fiber alone in keeping plasma lipid levels at a very
low plateau. Reports from a number of laboratories failed to show any effect
of dietary bran, pectin, cellulose, wheat fiber, mixed cereals, or bagasse (39).
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On the other hand, a number of authors reported significant reductions of

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serum cholesterol and triglyceride levels with the use of bran, pectin, and,
particularly, guar gum (40, 41). This coincided with decreased levels of
LDL- and no change in HDL-cholesterol concentrations. Increased intesti­
nal transit times with larger stool weights and decreased bacterial transfor­
mation of intraluminal bile acids were reported (38).
In our hands, the daily administration of 30 gm of guar gum in strictly
controlled metabolic ward studies decreased plasma cholesterol levels by
14%, plasma triglycerides by 19%, cholesterol absorption from 66 to 49%,
and significantly increased fecal neutral and acidic steroid excretions (p.
Samuel, unpublished data). However, guar gum mix is a bad-tasting glue­
like mixture, with a very poor patient acceptance. Perhaps in the form of
"crispbread" as proposed by Jenkins (41) it could become more acceptable
for ingestion.

Alcohol Consumption
�uring the past decade a considerable number of epidemiologic studies
almost uniformly demonstrated that the consumption of moderate amounts
of alcohol increased the level of HOL-cholesterol and decreased the risk of
coronary artery disease (42). However, experimental data on the effect of
ethanol intake are rather scarce and controversial. There is general agree­
ment that alcohol further increases plasma triglyceride levels in patients
with hypertriglyceridemia, concomitant with increased VLOL concentra­
tions, with no change in other lipid parameters (43). Belfrage et al (44) in
healthy volunteers supplemented a mixed diet with 75 g of ethanol daily.
This resulted in a significant increase of HOL-cholesterol, which appeared
3 weeks after alcohol was added to the regimen. Conversely, in the study
of Glueck et al, the isocaloric substitution of ethanol for carbohydrate failed
to alter any of the lipid parameters in healthy young males (45). This was,
however, a short-term study (2 weeks), and it seems possible that the alleged
"beneficial" effects of moderate alcohol consumption are the results of
long-term perseverance.
 190 SAMUEL, McNAMARA & SHAPIRO

DISCUSSION, PRACTICAL APPROACH,

AND RECOMMENDATIONS
The State of the Art
More than half of the American population dies of cardiovascular diseases,
the majority of which are the result of the underlying process of arterio­
sclerosis. Simply put, the disease consists of the deposition of cholesterol in
the intimal wall, which in tum decreases or obstructs blood flow through
the lumen of the blood vessel. We are not born with atherosclerosis, so
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somehow this cholesterol has to get there. During the past decade a series
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of elegant experiments (46) in the laboratory of Goldstein and Brown

demonstrated the possible mechanisms of the development of this disease
in patients with familial hypercholesterolemia. Cellular cholesterol synthe­
sis, and ultimately tissue deposition of cholesterol, was found to be a func­
tion of feedback mechanisms, dependent on the binding of circulating
. LDL-cholesterol by decreased or absent cell-surface receptors in these pa­
tients. Although the theory and the model were generalized, it must be
pointed out that familial hypercholesterolemia is a relatively rare disease,
certainly affecting less than 5% of the population, compared to the numbers
affected by arteriosclerosis, namely all of us. What happens to the remaining
more than 95% of the general public?
It must be clearly stated that arteriosclerosis is not a genetic but an
environmental disease. Regardless of its primary cause or causes, it does not
develop, or develops to a much lesser extent, in popUlations having low
cholesterol concentrations, whereas its prevalence is overwhelming in those
whose cholesterol concentrations are at Western levels (see the section on
epidemiology). One. could conclude that we are all environmentally hyper­
cholesterolemic, and what we call "normal" in our population should rather
be termed "average," undoubtedly an abnormally high level for the human
species.
What causes this environmental catastrophe? Obviously, we do not have
all the answers. Diet is perhaps one of the most important components of
the environment. However, as shown in the foregoing paragraphs, the
evidence is meager to incriminate diet as the sole factor. Many components
and variables are unknown, and the little we know remains largely obscure
when it comes to explaining by what mechanisms diet and the environment
in general can affect plasma lipid levels and the development of the disease.
It seems to us, that the-bottom line concerns the whole-body metabolism
of cholesterol; namely dietary intake (or absorption), body synthesis, trans­
port in the plasma (which lipoproteins carry cholesterol), fecal excretion of
cholesterol and its end products, and possible shifts to or from the tissues
 DIET AND ATHEROSCLEROSIS 191

(See Figure 1). The final balance and outcome may well depend on these,
or on the prevalence of one of these factors in each individual.

Diet and the Patient with Hyperlipidemia

or Proven Vascular Disease
The primary treatment of hyperlipidemia is diet. In our institution, in 1400
proven hyperlipidemic male outpatients, a carefully regulated low-fat
(35%) (high in polyunsaturated fatty acids), low-cholesterol (<250
mg/day) diet (reduced in calories when necessary) decreased plasma lipid
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levels over a 6-month period in 20% of the participants to "normal" levels

Annu. Rev. Med. 1983.34:179-194. Downloaded from [Link]

(to or below the 95th percentile) (R. Palmer, personal communication). It

is indeed the general rule that in patients with hyperlipidemia or vascular
disease, before instituting drug therapy, a 3-6-month dietary trial is in
order, possibly under the supervision of an experienced nutritionist.
But the question is: can diet induce the regression of atherosclerosis?
Again the honest answer is: we don't know. The data on the epidemiologic
trials are at best inconclusive in our view. Blankenhorn et al (41) demon­
strated regression of atherosclerotic lesions measured by sophisticated com­
puterized angiographic methods, following combined dietary and drug
treatment.
Thus, the scarce data seem to indicate that atherosclerosis can regress,
perhaps by the combination of vigorous dietary and drug therapy, perhaps
even by diet alone. It is, therefore, our opinion that strictly enforced dietary
measures are indicated in patients with hyperlipidemia or evidence of vascu­
lar disease due to atherosclerosis, in individuals with a heavy family history
of the disease, or in subjects with other major risk factors (hypertension,
diabetes, etc). The degree of success of the dietary treatment in these pa­
tients is difficult to measure. However, decreasing the levels of plasma lipids
by dietary changes should undoubtedly be a first step.

Diet and the Healthy General Population

The plethora of popular ,literature and material in the public media has
significantly changed the diet of the American population during the past
two decades (48). Concomitantly, between 1969 and 1977 mortality from
coronary heart disease has declined by 23% (48). On careful analysis one
cannot ascribe this improvement to dietary changes alone. Many other
factors enter the equation: improved coronary care units, new drugs, better
surgical and diagnostic techniques, control of hypertension, decreased ciga­
rette smoking, etc.
Should we, under these circumstances, recommend a change of diet to
the American public at large? Such recommendation would assume that
 192 SAMUEL, McNAMARA & SHAPIRO

dietary changes can prevent atherosclerosis. We showed in the foregoing

that such proof is not yet available. Should the public policymaker decide
to recommend major dietary changes, who would pay for the multibillion­
dollar expenditure that this may entail? The food industry? The public?
Probably the public. In our view at present it is not justified to make such
broad-scale recommendations.

SUMMARY
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Annu. Rev. Med. 1983.34:179-194. Downloaded from [Link]

Our knowledge of the role of diet in the prevention and treatment of

arteriosclerosis is at a crossroad. The available evidence is at best ambigu­
ous. We do not know if arteriosclerosis can be cured or prevented by
diet alone. Indeed, we have yet to demonstrate that reduction of plasma
lipid levels by any intervention can decrease cardiovascular disease
mortality. The complexity of the problem originates from the multifac­
torial etiology of the disease, the indecisiveness of epidemiological studies,
and the incompleteness of experimental data available to date. To overcome
these gaps we need to perfect experimental methods, carry out large and
carefully organized controlled trials, and foremost we need new ideas and
approaches concerning the mechanisms by which environmental factors,
such as diet, influence plasma lipids and the development of the disease.
Based on a careful review of what we know and what we don't know, we
recommend that patients with hyperlipidemia, evidence of atherosclerotic
vascular disease, heavy family history of vascular disease, and/or the pres­
ence of other major risk factors be vigorously treated with diet. However,
we feel that the evidence available is insufficient to recommend a radical
(and expensive) change in the dietary habits of the general population at this
time.
Prior to recommending any specific dietary guidelines to the general
public it should be demonstrated that (a) the diet will significantly reduce
plasma cholesterol levels in a majority of the population; (b) the risk of
cardiovascular disease can be reduced by reducing plasma cholesterol lev­
els; and (c) the proposed diet is free of any potential long-term side effects.
At this time none of these points has been answered for any of the recom­
mended diets. Under these circumstances it seems to us that the physician
should use his or her judgment in the case of each individual or family in
weighing the possible benefits of a strictly enforced prudent diet against the
inconvenience of a moderate degree of long-term discipline, and the regi­
mentation and occasional frustration such a diet may entail.
 DIET AND ATHEROSCLEROSIS 193

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