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81


Chapter 2

Coronary Heart Disease

The heart in itself is not the beginning of life:
but it is a vessel formed of thick muszle.
vivified and nourished by the artery and vein
     as are the other muscles.
   Leonardo da Vinci ( 1452-I 5 19)
    The Notebooks of Leonardo

Introduction

Coronary heart disease (CHD) is a term used to identify several cardiac
disorders resulting from inadequate circulation of blood to local areas of
heart muscle. This deficiency is nearly always a consequence of focal
narrowing of the coronary arteries by atherosclerosis. Atherosclerosis is a
progressive disease that often begins in childhood. The earliest lesions
probably arise in the lining of the coronary arteries or in the aorta, often by
ages 10 to IS. They appear first as fatty streaks. some of which may later
progress to fatty or fibrous plaques and, eventually. large complicated
lesions (Berenson 1986). The result of the progressive narrowing of the
vessels may be angina pectoris, myocardial infarction (heart attack). or
sudden death. These are the most common manifestations of CHD. Else-
where in the body, the same process may lead to serious and sudden
decrease of the blood supply to the brain (ischemic stroke). peripheral
vascular disease, or serious problems caused by weakening of the lower
abdominal aorta. The development of CHD is a silent process generally
lasting decades before the onset of symptoms. Of the half-million heart
attack deaths that occur annually, approximately 60 percent occur sud-
denly or outside of a hospital before treatment can be administered (Kannel
and Thorn 1984). Thus, much attention is directed at the prevention of CHD
by identifying and modifying risk factors before clinical disease develops.

The causes of CHD are multifactorial. It is generally accepted that high
blood cholesterol, high blood pressure, and cigarette smoking play causal
roles in the development of atherosclerosis. which leads in turn to narrow-
ingof the arteries and development of CHD. Diet plays an important role in

a3


O Nutrition and Health

the regulation of blood cholesterol levels and influences other risk factors
for CHD as well. For millions of Americans, the most effective CHD
preventive strategies are to avoid smoking cigarettes, to control high blood
pressure, and to lower high blood cholesterol.

This chapter focuses on the influence of diet on the development, treat-
ment, and prevention of CHD. The role of diet in hypertension is reviewed
in the chapter on high blood pressure.

Historical Perspective

Interest in atherosclerosis and its relationship to dietary factors can be
traced to observations made in 18th and 19th century medicine. During that
period, the fatty nature of the plaque was described and cholesterol was
identified in the blood (see historical review, Stamler 1967). In the early
20th century, atheromatous aortas were found to contain excessive
amounts of cholesterol (Windaus 1910). These observations led to a series
of experiments to induce atherosclerosis in animals by feeding them a diet
rich in fats and cholesterol. In 1912-13, typical arterial atherosclerosis was
produced in rabbits by feeding pure cholesterol dissolved in vegetable oil
(Anitschkow 1967).

At that time, another line of investigation was based on the theory that
atherosclerosis was caused by toxic products of protein metabolism. Nutri-
tional experiments, in which large amounts of foods rich in animal protein
were fed to rabbits, produced changes in the aorta similar to those in
humans. The observed effects were later attributed to the high cholesterol
content of the experimental diets (Anitschkow 1967).

Early observations by clinicians and pathologists working in the colonies of
British India, Indonesia, Africa, and Latin America were consistent with
the pathologic and experimental findings. More than 50 years ago, these
workers observed the relative rarity of CHD among the native populations
compared with European and North American populations and associated
this finding with the nature of the habitual diets. Whereas native groups
consumed diets composed mainly of vegetable products, the Westernized
population consumed large quantities of eggs and butter (Raab 1932).

Subsequent epidemiologic studies, including long-term prospective stud-
ies, of CHD mortality among many national, occupational, racial, and

84


Coronary Heart Disease _I

religious subgroups have established three major modifiable risk factors for
developing CHD: cigarette smoking, high blood pressure. and high levels
of blood cholesterol.

Significance for Public Health

Deaths from CHD are declining in this country, and this decline has been
attributed both to improved medical care and changes in lifestyle. Thus,
from 1964 to 1985, the age-corrected CHD death rate has dropped by more
than 42 percent, resulting in 350,000 fewer deaths in 1986 than would
otherwise have occurred. A recent analysis of the effects of changes in
medical intervention and changes in lifestyle attributes 30 percent of this
decline to reductions in plasma cholesterol (Goldman and Cook 1984).

Despite this decline, however, CHD still accounts for more deaths an-
nually than any other disease or group of diseases. More than 1.25 million
heart attacks occur each year (two-thirds occur in men), and more than
500,000 people die as a result (NHLBI 1984). Death rates for CHD in men
under age 65 and in women under age 75 are higher among blacks than
among whites, the reverse being true in older persons (Tables 2-l and 2-2).
Available data show lower rates for CHD in the Hispanic population than
in non-Hispanic whites (Heckler 1985).

          Table 2-1
Death Rate for Coronary Heart Diseese
by Age, Race, and Sex, United States, 1985

Age (ye-)
Total
Under 45
454
G-74

  Death Rate per 100,000 Population=
White Men   Black Men   White Women

  180.8       164.9        82.9
   8.2        13.2         1.7
  294.5       317.8        85.1
1.132.6      990.6        SC%.0

Black Women

   100.8
    4.3
   161.1
   645.9

75 &d over

'
3,071x

2,205.o      2,010.2       1,717s

BAge-adjusted to the U.S. population, 1940.

Source: National Center for Health Statistics. In press.

85


O Nutrition and Health

         Table 2-2
Prevalence of Coronary Heart Disease
by Age, Race, and Sex, United States, tg85

Age (Years)

Prevalence per 1,000 Persons

Men       Women       White      Black

Total           32.9        24.1
Under 45         0.9a         1.e
45-64           80.9         44.4
65-74           175.6        107.0
75 and over       169.0        124.6
aFigure does not meet standards of reliability or precision.

31.8        11.3a
1.3'        l.la
65.1        46.3
143.9        62.2
154.7           a

Source: National Center for Health Statistics 1 W6a.

CHD ranks fast as the reason for Social Security disability (Social Security
Administration 1982), third after arthritis and hypertension for limitation of
activity (Collins 1986), and third after mental illness and all forms of cancer
for total hospital bed days (NCHS 1987). According to information from
the National Heart, Lung, and Blood Institute (NHLBI), morbidity and
mortality from CHD cost the United States an estimated $49 billion a year
in 1985 in direct health care expenditures and lost productivity. Further-
more, it has been estimated that unless there are reductions in risk factors
or improvements in the efficacy of therapies, CHD prevalence and inci-
dence will increase in the future because of the aging of the population,
especially with maturation of the post World War II baby boom generation
(Weinstein et al. 1987).

High Blood Cholesterol (Hypercholesterolemia) and CHD Risk
An extensive body of clinical evidence supported by animal, epidemiolog-
ic, and metabolic studies has established the relationship between high
blood cholesterol and increased CHD risk (Grundy 1986). The relationship
is strong, continuous, and graded.

Until recently, it was unclear whether this relationship held only for blood
cholesterol levels above a threshold value of about 200 to 220 mg/dl.
However, data from the 361,000 men ages 35 to 57 screened for the
Multiple Risk Factor Intervention Trial indicate that the association is
apparent at even lower levels-about 180 mg/dl (Stamler, Wentworth, and
Neaton 1986; Martin et al. 1986).

Average blood cholesterol levels for adult American men and women are
211 and 215 mg/dl, respectively (NCHS 1986b). Individuals whose choles-
terol levels are within the top 25 percent of the cholesterol distribution

86


Coronary Heart Disease 0

(above 240 mg/dl) have been defined as being hypercholesterolemic and at
substantially higher risk (Consensus Development Panel 1985).

Scientific Background

The effects of dietary factors on circulating lipids in blood were among the
earliest observations of factors influencing lipid metabolism and the ath-
erogenic process. A voluminous literature has accumulated over the past
75 years on the relationship between diet, lipoproteins, atherogenesis, and
CHD. The primary conclusions of this research are (I) that the higher the
total blood cholesterol level, the greater the severity of atherosclerosis and
the greater the risk for CHD, (2) that dietary saturated fat and cholesterol
raise total blood cholesterol and low density lipoprotein (LDL) cholesterol
levels, and (3) polyunsaturated fat lowers total blood cholesterol and LDL
cholesterol levels (Levy et al. 1979). Monounsaturated fat also appears to
lower blood cholesterol (Grundy et al. 1986).

Atherogenesis

Atherosclerosis is a combination of changes in the inner lining of arteries
that occur in response to vessel injury and repair. These changes, as well as
elevations in the blood lipids, including cholesterol, permit the excessive
entry of proteins and lipoproteins, especially LDL, from the blood into
focal regions of the artery wall. In general, LDL is thought to enter intact,
but some may have been modified by oxidation or by glycosylation (as in
diabetes). They may also undergo alteration, which makes them more
atherogenic, after entering the artery wall. Some evidence suggests that
very low density lipoproteins (VLDL) may also injure the vessel wall in
some individuals with hyperlipidemia (Bradley, Gotto, and Gianturco
1985).

Injury of the blood vessel may also allow certain cells from the blood to
adhere to its lining or to enter it, causing low-grade chronic inflammation,
which helps to stimulate the proliferation of the arterial cells. The resulting
arterial plaque is made up mostly of these modified and rapidly dividing
arterial smooth muscle cells, proteins from the blood (especially lipopro-
teins and their transported fats, including cholesterol), and other cells such
as platelets and monocyte/macrophages from the blood. Smooth muscle
cells multiply in the plaque, apparently partly in response to growth factors
carried to them by blood platelets and released at the site where the
platelets adhere when they aggregate. The proliferating cells produce an
excessive amount of collagen, elastin, and intercellular matrix. Throm-
botic processes probably also participate in the progression of the plaque,
especially when endothelial injury becomes more severe.

87


O Nutrition and Health

Figure 2- 1 illustrates the microscopic appearance of arterial plaque created
as a result of the interaction of these various mechanisms. The smooth
muscle cell proliferation in conjunction with cellular accumulations of
cholesterol and fat-filled macrophages or foam cells results in a tissue mass
with a fibrous layer, or cap, on the lumen (interior) side of the artery.
Within the plaque, dead cells and lipid debris, which represent the break-
down of earlier stages of plaque growth, form acentral core. This is the soft
cholesterol ester-rich component from which the lesion derives its name
(athero-"gruel") (Wissler 1985).

Lipoprotein Metabolism

The link between high blood cholesterol and atherogenesis has been eluci-
dated through studies of lipoprotein metabolism. Lipoproteins are the
protein carriers of lipids in the blood. Four classes of plasma lipoproteins
are generally recognized. They are designated according to their density,
which depends on their relative proportions of protein and lipid; those that
contain the greatest proportion of lipid are the lightest. Chylomicrons, the
lightest lipoproteins, contain mostly triglyceride (90 percent) and originate
when dietary fats are delivered to the blood stream via the intestinal lymph.
Very low density.lipoproteins mainly manufactured by the liver, are also
rich in triglyceride (65 percent). The low density lipoproteins normally
carry 60 to 70 percent of the circulating cholesterol. High density lipopro-
teins (HDL) are the heaviest lipoprotein particles because they contain a

    Necrotic Center
   (cell debris, cholesterol
   crystals, cholesterol
;/ esters, calcium)

    Ehdothelium

Fibrous Cap
(proliferated smooth
muscle cells. collagen,
extracellular and
intracellulai lipid,
including foam cells)

Media

Adventitia

Fgure 2-1. Diagram d an athenrsclerotic plaque The advanced atherosclerotic
szr -the t2ho&Wd- and
                necroWcoreandIheiibrouscap.

Source: Conner, W.E., and Bristow, J.D., eds. 1985. Coronary heart disease: Prevention,
    complications and treatment, p. 194. Philadelphia, PA: Lippincott.
    Reprinted with permission.

88


Coronary Heart Disease 0

relatively higher proportion of protein (approximately 50 percent by
weight) (Rifkind 1982). All of these lipoproteins contain cholesterol but in
varying amounts. All contribute to the total blood cholesterol level. An
increase in any of them therefore contributes to high blood cholesterol.
Lipoproteins are generally measured in the blood as the cholesterol frac-
tion, for example, HDL cholesterol.

The metabolism of lipoproteins is largely determined by the composition of
their protein components, or apoproteins. Some apoproteins serve pri-
marily a structural role in lipid transport; others serve as functional units
that are recognized by and bind to cell receptors. Still other apoproteins
appear to act as cofactors for enzyme systems involved in catalyzing the
intravascular changes in lipoproteins or their entry or exit from cells.
Advances in techniques for measuring the composition and structure of
lipoproteins are providing new insights into mechanisms controlling lipid
metabolism and the process of atherogenesis. Although much information
is available on how diet affects circulating levels of lipoproteins and the
process of atherogenesis, less is known about its effects on the underlying
mechanisms.

Low Density Lipoproreins. Low density lipoprotein is the major atherogen-
ic lipoprotein and usually accounts for most of the CHD risk associated
with elevated plasma total cholesterol (Gordon et al. 1977b). The level of
LDL in the blood is an important determinant of the rate at which choles-
terol is deposited in the artery walls. Low density lipoprotein levels are
also influenced by other risk factors such as diabetes, cigarette smoking,
and obesity (Schwarz et al. 1982).

The level of circulating LDL is determined by specialized proteins called
LDL receptors, located on the surface of cells in the liver and other tissues
(Goldstein, Kita, and Brown 1983). The number of receptors is determined
by the cholesterol needs of the cell. Although cells are capable of making
their own cholesterol, their receptors can also bind cholesterol-rich LDL
particles and remove them from the circulation, leading to the incorpora-
tion of their cholesterol into the cell. If uptake of cholesterol by this route is
decreased, as when the number of receptors is deficient, the cell increases
its own synthesis of cholesterol. When the cholesterol is not withdrawn by
the cells, LDL accumulates in the plasma and may be taken up by the
arterial wall cells by mechanisms that do not involve LDL receptors.

Although the synthesis of cholesterol by the liver is under feedback regula-
tion from dietary cholesterol, a reduction in dietary cholesterol intake to
lower levels (~300 mg/day) will cause a net plasma cholesterol decrease

89


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despite increased endogenous synthesis (Ernst and Levy 1980). The ability
with which dietary cholesterol suppresses endogenous cholesterol syn-
thesis varies greatly among individuals (Quintao, Grundy, and Ahrens
1971). Dietary cholesterol appears to suppress LDL receptor function in
humans (Appelbaum-Bowden et al. 1984).

Much information about the consequences of diminished LDL receptor
production has come from studies of individuals with familial hyper-
cholesterolemia (FH) (Goldstein, Kita, and Brown 1983). This disease is
caused by a genetic inability to synthesize normally functioning LDL
receptor protein, causing very high circulating levels of LDL cholesterol,
severe atherosclerosis, and often death in early adulthood from heart
attack. In the most severe form of FH, accelerated and clinically cata-
strophic CHD occurs in early childhood in the absence of any other risk
factors and is caused solely by elevated LDL cholesterol. Although the
receptor defect in FH is genetically determined, other factors, such as
increasing age and high-fat diets, may also lead to diminished receptor
function in normal individuals (Brown, Kovanen, and Goldstein 1981).

Baboons, rabbits, and dogs maintained on low-fat diets have a high number
of LDL receptors, and their circulating LDL levels are much lower than
those of humans. When dogs and rabbits are fed high-fat diets, receptor
activity is decreased by as much as 90 percent and circulating LDL levels
rise (Brown and Goldstein 1984). At birth, infants have blood LDL con-
centrations similar to newborns of other species, apparently because of
their ability to produce LDL receptors. In Western societies, LDL levels
rise threefold to fourfold by adulthood. Clinical studies have suggested that
this increase is attributable to a decrease in the numberof receptors (Brown
and Goldstein 1984). The cause of this receptor deficiency is not known, but
a high-fat diet may be an important contributing factor. Diets high in
saturated fat and cholesterol cause cholesterol to accumulate in cells and
the liver, which could lead to a reduction in the number of LDL receptors.
In some animals, dietary cholesterol has been reported to inhibit LDL
receptor function by 30 percent, even in the presence of added polyunsatu-
rated fat, and saturated fat may depress receptor function by as much as 90
percent (Spady and Dietschy 1985).

Experiments with cultured cells suggest that LDL receptor activity oper-
ates optimally at an LDL blood concentration of 25 mg/dl (Brown and
Goldstein 1986). Average LDL cholesterol levels of 120 mg/dl in adult
Western populations far exceed optimal levels (Goldstein and Brown 1977).
This suggests that the human LDL receptor system evolved to function at
low LDL levels and that a substantial portion of humanity may not be

90


Coronary Heart Disease 0

genetically adapted to the relatively recent introduction of high dietary fat
intake (Tiger 1980). This hypothesis is consistent with epidemiologic tind-
ings relating elevated LDL cholesterol to dietary fat intake (Brown and
Goldstein 1984).

High Density Lipoproteins. High density lipoprotein is considered to pro-
tect against CHD. Numerous epidemiologic studies have shown that the
higher the HDL cholesterol level, the lower the risk for CHD (Heiss et al.
1980). Female sex, estrogen use, exercise, moderate alcohol consumption,
and weight loss have been associated with higher levels of HDL: in con-
trast, obesity and cigarette smoking have been associated with lower levels
(Heiss et al. 1980). Some components of the HDL fraction may be involved
in removing cholesterol from cells (reverse cholesterol transport) and
inhibiting deposition of cholesterol in arteries, but the precise role of HDL
is not well understood.

Very Low Density Lipoproteins. Very low density lipoprotein consists
primarily of triglyceride of endogenous origin. The relationship between
triglyceride and CHD is complex (NIH 1983). Although triglyceride levels
are positively associated with an increased risk ofCHD in most prospective
population studies, they are closely associated with attributes such as
obesity, total cholesterol, HDL levels, hypertension, and cigarette smok-
ing and generally not independently predictive of CHD risk (Hulley et al.
1980). Elevated triglyceride may be an independent risk factor in older
women (Gordon et al. 1977a).

However, almost all case-control studies of survivors of myocardial infarc-
tion have shown higher triglyceride levels in the affected patients, and
many diseases associated with high triglyceride levels, such as diabetes
mellitus, chronic renal disease, and certain primary hyperlipidemias, are
associated with an increase in risk for cardiovascular disease (NIH 1983).
Moreover, plasma triglyceride levels between 250 and 500 mg/dl may be a
marker of lipoprotein abnormalities that are more directly associated with
atherosclerosis, such as low HDL cholesterol. Alternatively, elevated tri-
glycerides may reflect the presence of abnormal, triglyceride-rich lipopro-
tein particles or their metabolic products that may enhance atherogenesis.
Whether or not triglycerides are directly involved in the atherogenic pro-
cess, the identification of elevated levels may help to identify persons with
increased CHD risk.

Expert Reports and Recommendations
Numerous expert bodies have examined the evidence relating diet to CHD
and its implications for public health. Although there are many determi-

91


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nants of blood cholesterol levels, no modifiable factor has been shown to
influence cholesterol and LDL more profoundly than diet. The average
adult American currently consumes a diet in which about 37 percent of the
total calories is contributed by fat and 13 percent of calories by saturated
fat. Dietary cholesterol is estimated to be about 300 to 400 mg/day (USDA
1985a, 1985b). These levels of saturated fat and cholesterol, the major
determinants of blood cholesterol, exceed those in countries with low CHD
rates, indicating the need for vigorous promotion and dissemination of
appropriate dietary guidance.

Federal recognition of this need is demonstrated in the USDA/DHHS Di-
em-y Guidelinesfor Americans issued in 1980 and revised in 1985 (USDA/
DHHS 1985). The guidelines, which are being widely distributed and
promoted in the public and private sectors, emphasize the reduction of fat,
saturated fat, and cholesterol in diets for healthy Americans and suggest
some ways to reduce these components through appropriate food selec-
tion.

A national preventive strategy to reduce the risk of CHD was enunciated in
the 1980 DHHS report Promoting Health, Preventing Disease: Objectives
for the Nation (DHHS 1981). Specific objectives are aimed at controlling
high blood pressure, stopping smoking, lowering blood cholesterol levels,
and reducing the prevalence of obesity. By 1990, the report states, the mean
cholesterol level in the adult population ages 18 to 74 should be at or below
200 mg/dl.

In 1984, the NHLBI and the National Institutes of Health Office of Medical
Applications of Research convened a consensus development conference
on Lowering Blood Cholesterol to Prevent Heart Disease (Consensus
Development Panel 1985). After reviewing much of the available data, the
consensus panel of lipoprotein experts, cardiologists, primary care physi-
cians. epidemiologists, nutrition scientists, biostatisticians, experts in pre-
ventive medicine, and lay representatives unanimously concluded, despite
consideration of some dissenting views (Ahrens 1985) that elevated blood
cholesterol is a major cause of CHD and that the risk for heart attacks due
to CHD should be reduced by lowering elevated blood cholesterol levels.
specifically, blood levels of LDL cholesterol. The panel members sug-
gested that although the benefits of blood cholesterol reduction had been
demonstrated most conclusively in men with elevated levels, the evidence
justified the conclusion that women with elevated levels would be afforded
similar protection. The panel further recommended designation of individ-
uals with blood cholesterol levels above the 75th percentile (the upper 25
percent of values) as being at special risk and requiring vigorous treatment

92


Coronary Heart Disease O

with dietary measures. It also recognized that dietary treatment of elevated
blood cholesterol in children requires special consideration to ensure
adequate nutrients for growth and development and to meet energy needs.
Older persons, who are at increased risk for malnutrition. may also require
special care to ensure adequate intake of essential nutrients.

The panel members asserted that the average blood cholesterol level in the
United States is too high. largely because of high intakes of calories,
saturated fat, and cholesterol. They recommended that all Americans,
except children under age 2, adopt a diet with total dietary fat intake of 30
percent of total calories, with less than 10 percent of calories from saturated
fatty acids; limit polyunsaturated fat intake to a maximum of IO percent of
calories; and limit daily cholesterol intake to 250 to 300 mg or less. These
dietary recommendations are compatible with food intakes of countries
with low CHD prevalence. The panel further advised that caloric intake be
reduced if necessary to correct for obesity and that it be adjusted to
maintain ideal body weight (Consensus Development Panel 1985).

Although the consensus panel considered the moderate-fat, moderate-
cholesterol diet recommended for the genera1 public to be suitable for all
members of the family over 2 years of age, special concern was expressed
about promotion of cholesterol-lowering diets for children because such
diets might inadvertently compromise their nutritional needs (Ahrens
1985). The American Academy of Pediatrics has recommended modera-
tion with respect to decreases in saturated fat and cholesterol, noting that
30 to 40 percent of calories from fat seems sensible for adequate growth and
development (AAP Committee on Nutrition 1986; see chapter on maternal
and child nutrition). Diets that avoid extremes, it states, are safe for
children for whom there is no evidence of specific vulnerability.

National Cholesterol Education Program

The NHLBI is providing the focus for a national effort to reduce cholester-
ol levels through the National Cholesterol Education Program (NCEP),
initiated in 1985. The NCEP has issued detailed guidelines for treatment of
adults with high blood cholesterol (NCEP 1988a) and recommendations for
improvements in the measurement of blood cholesterol (NCEP 1988b).
Future panel reports will provide recommendations for the general public
and for treatment of high blood cholesterol in children and adolescents
(Lenfant 1987).

The report of the NCEP Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (NCEP 1988a) defined
categories of risk according to measurement of total cholesterol and, when

93


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indicated, subsequent evaluation of LDL cholesterol (Table 2-3). Patients
with borderline high blood cholesterol (200 to 239 mg/dl) and no other risk
factors should be given cholesterol-lowering dietary information and
should be reevaluated annually. Lipoprotein analysis is recommended for
patients either with high blood cholesterol (240 mg/dl or greater) or with
borderline high blood cholesterol and CHD, or with two other risk factors
(one of which can be male sex). The LDL cholesterol is the basis for
initiating treatment. Persons with borderline high LDL cholesterol levels
(130 to 159 mg/dl) and CHD or two other risk factors and persons with LDL
cholesterol levels of 160 mg/dl or greater should be treated to lower their
cholesterol.

The report recognized that diet is the cornerstone of therapy to reduce
borderline and high-risk blood cholesterol levels whether or not drug
therapy is eventually added to the regimen; in general, drug therapy is not
recommended without at least 6 months on optimal diet. The advent of
highly effective drugs for the treatment of elevated blood cholesterol levels
may stimulate widespread use as an alternative to diet therapy. Concerns
have been raised about this potential trend because all lipid-lowering drugs
have potential side effects, and adverse effects may not become manifest
for many years (Grundy 1986). Many patients can reduce their cholesterol
levels substantially with diet alone (see Dietary Guidance, Special Popula-
tions section). When drugs are required, concomitant modification of the
diet may reduce their dosage requirements, cost, and potential side effects.
Based on the NCEP adult treatment guidelines (NCEP 1988a), it is esti-
mated that over 40 million adult Americans could be candidates for dietary
education or treatment.

Other Reports

A compilation of 47 major reports addressing the public health issues of
habitual diet and CHD risk issued since 1968 reveals a common theme-
recommendations for less total fat, less saturated fat, and control of

         Table 2-3
National Cholesterol Education Program
Adult Treatment Panel Classification

                 Total Cholesterol
                mg/dl
Desirable               <200
Borderline high           2W239
High                  >240
                         -
Source: National Cholesterol Education Program 1988a.

LDL Cholesterol
  mg/dl
   Cl30
  130-159
   >160
    -

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Coronary Heart Disease 0

obesity-and most of the reports also recommend a reduction in dietary
cholesterol and partial replacement of saturated with polyunsaturated fat
(Truswell 1983).

In response to a congressional directive, DHHS and USDA jointly spon-
sored an assessment of the existing evidence relating dietary cholesterol to
blood cholesterol and human health, as well as recommendations for
further research. Their report to Congress, The Relationship Between
Dietary Cholesterol and Blood Cholesterol and Human Health and Nutri-
tion (1986). concluded that high blood cholesterol is one of the major risk
factors for CHD and that cholesterol in the diet, but even more the amount
and types of fat in the diet, affect blood cholesterol; dietary cholesterol
raises blood cholesterol in most people; in some there is a small response
and in others the increase is more pronounced. The prevalence of different
degrees of response in the population is not known. A broad program of
research was recommended.

The National Research Council of the National Academy of Sciences
recently conducted a 3-year review of the role of animal products in the
American diet (NRC 1988). Its report, Designing Foods. Animal Product
Options in the Marketplace, concluded that nutrition-related health prob-
lems affect nearly every American family and recommended measures to
reduce the quantity of animal fat in the diet and to increase consumers'
access to fat and cholesterol information.

Key Scientific Issues

o Role of Dietary Fat and Cholesterol in CHD
o Role of Other Dietary Factors in CHD
o Efficacy of Dietary Interventions in CHD

Role of Dietary Fat and Cholesterol in CHD

Of the many dietary factors that have been studied, the strongest and most
consistent evidence relates to dietary fat. Systematic examination of the
diet-blood cholesterol-CHD link through clinical, epidemiologic, and ani-
mal research implicates both the amount and nature of dietary fats as
important determinants of plasma cholesterol levels.

Clinical Studies
Clinical studies have addressed the role of dietary fat and cholesterol upon
CHD through their effects upon blood cholesterol and by their effects upon

95


13 Nutrition and Health

development and severity of heart disease. The latter type of clinical
studies is summarized in the section on Efficacy of Dietary Interventions in
CHD, while studies on blood cholesterol are summarized below.

A variety of clinical studies carried out over the past several decades have
shown that the type of fat and amount of cholesterol in the diet affect blood
cholesterol levels. In these studies, the composition of the diet is controlled
so that the effects of single constituents can be tested. Fatty acid sources
examined include butter fat, olive oil, cottonseed oil, sunflower oil, hy-
drogenated coconut oil, sardine oil, safflower oils, margarines, and cocoa   1
butter(Keys, Grande, and Anderson 1974). Typically, saturated fatty acids
were shown to raise and polyunsaturated fatty acids to lower plasma
cholesterol levels in comparison with monounsaturated fatty acids, which
were considered to be neutral. The degree of response to saturated fatty
acids depends on the individual fatty acid content. Myristic (14 carbon
atoms, C:14) and lauric acids (C:12) have a more powerful effect than
palmitic acid (C: 16), but palmitic acid is more abundant in the food supply.
Saturated fatty acids with more than 18 or fewer than 10 carbon atoms
appear to have little or no effect on plasma cholesterol levels (Keys 1967).
Likewise, stearic acid (C: 18) has been reported not to raise blood choles-
terol levels or, when substituted for palmitic acid, to lower blood cholester-
ol levels (Bonanome and Grundy 1988). Trans fatty-acids are isomers of
naturally occurring cis unsaturated fatty acids. They are produced in fats as
a result of commercial hydrogenation of cooking oils and also occur in
ruminant fats, including milk fat, beef fat, and lamb fat. Trans fatty acids as
consumed in hydrogenated vegetable oil appear to be the equivalent of
oleic acid in their cholesterolemic properties in humans. In this respect,
they are similar to stearic acid, but dissimilar to palmitic, myristic, and
lauric acids (LSRO 1985).

Equations to estimate the change in serum cholesterol from changes in
dietary fats and cholesterol (Keys, Anderson, and Grande 1965; Hegsted et
al. 1965) derived from such clinical experiments are presented in Table 2-4.
They show that saturated fatty acids are about twice as powerful in raising
plasma cholesterol levels as polyunsaturated fatty acids are in lowering
them, while dietary cholesterol has a smaller effect (Blackbum 1979). It has
been estimated that increasing the dietary cholesterol intake by 100
mg/1,000 kcal increases the plasma total cholesterol by about 10 mg/dl
(Grundy et al. 1988). Thus, if a person consuming 2,000 calories per day
increases his or her dietary cholesterol from 300 to 500 mg/day, plasma
cholesterol will rise about 10 mg/dl.

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Coronary Heart Disease O

Table 2-4

Estimates of Serum Cholesterol Change From Given Changes in
Dietary Lipids Based on kocaMc Controlled Experknents in
                Humans

Keys (Minnesota) equation:

ACHOL = 1.35(2AS - AP) + 1.52AZ

Hegsted (Harvard) equation:

ACHOL = 2.16AS - 1.65AP + 0.0677AC - 0.53

Where A CHOL = estimated change in serum cholesterol in mg/dl; A S =
change in percent daily calories from saturated fat; A P = change in percent
daily calories from polyunsaturated fat; A 2 = change in the square root of daily
dietary cholesterol in mg/l,OOO calories; and A C = dietary cholesterol in mg/
day.

Source: Blackbum, Ii. 1979. Diet and mass hyperlipidemia: public health considerations-
   a point of view. In Nutrition, lipids, and coronary heat7 disease, ed. Ft. Levy, 8.
   Riind, 8. Dennis, and N. Ernst, pp. X9-47. New York: Raven. Reprinted with
   permission from Raven Press, New York.

Numerous studies have predicted group mean plasma cholesterol levels on
the basis of the dietary content of saturated and polyunsaturated fatty acids
and cholesterol alone (Keys, Grande, and Anderson 1974). Other clinical
studies have shown that although saturated fat raises and polyunsaturated
fat lowers plasma cholesterol levels, the magnitude of the change differs
from that predicted by the equations. Results of six European experiments
were compared with those predicted by equations such as those shown in
Table 2-4 (Grande 1983). The predicted changes in serum cholesterol were
generally in agreement with the observed changes, with some variability.
For example, in the Finnish Mental Health Study, a dietary change that
was predicted to raise cholesterol 33 mg/dl produced an average elevation
of 49 mg/dl. In another experiment, the cholesterol-lowering effect of corn
oil and olive oil were compared with a control diet. Mean serum cholesterol
reductions were 50 mg/dl and 38 mg/dl, respectively, whereas the equa-
tions predicted the same decrease for both diets, 43 mg/dl. In another
experiment, the effect of dietary cholesterol added to a diet rich in polyun-
saturated fat was in agreement with the predicted value but was underesti-
mated when cholesterol was added to a diet high in saturated fat.

More recently, the effects of high-oleic safflower oil (monounsaturated),
high-linoleic safflower oil (polyunsaturated), and palm oil (saturated) on

97


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blood cholesterol levels were compared in normal and hypertriglyceridem-
ic patients. Both the high monounsaturated and high polyunsaturated fatty
acid oils achieved similar lowering of total cholesterol (35 mg/dl), compared
with 78 mg/dl predicted for the high polyunsaturated and 45 mg/dl predicted
for the high monounsaturated fat diets (Mattson and Grundy 1985).

In another study, beef fat, coconut oil, and safflower oil were isocalorically
exchanged in the diets of healthy normal volunteers (Reiser et al. 1985).
Mean plasma total cholesterol was 21 mg/dl lower on the safflower oil diet
compared with the habitual diet. Mean plasma total cholesterol on the beef
fat diet was 14 mg/dl higher than on the diet containing safflower oil and 13
mg/dl lower than on the diet containing coconut oil. The authors suggested
that the relatively higher proportion of stearic acid in the beef fat might
contribute to these differences.

Despite some inconsistencies in the degree of plasma cholesterol re-
sponses, clinical studies have generally shown a fall in response to polyun-
saturated fat and a rise in response to saturated fat. However, the above two
experiments suggest that the interaction of dietary factors in regulating
blood cholesterol levels may be more complex than can be accounted for
solely by the amount of saturated and polyunsaturated fats and dietary
cholesterol. Other factors that might contribute to inconsistencies across
studies include differences in baseline plasma cholesterol levels, composi-
tion and form (food vs. liquid formula) of the diet, age, metabolic status of
the participants, and duration of the experiment (Mattson and Grundy
1985).

Most clinical studies have noted a high degree of individual variability in
response to dietary cholesterol, a characteristic also noted among some
animal species (Jokinen, Clarkson. and Prichard 1985). Humans are gener-
ally less sensitive to dietary cholesterol than most animal species, and the
high degree of individual variability in plasma cholesterol responses to
dietary cholesterol suggests that some people may be overly sensitive to
dietary cholesterol while others are relatively resistant. The proportion of
the population that might be cholesterol-sensitive and the factors that
contribute to that sensitivity are not well understood. The response to
dietary cholesterol may be affected by such factors as previous diet, age, or
genetic makeup (McGill 1979) and the relative proportions of other nu-
trients in the diet. For example, one controlled clinical study compared the
effects of adding three or six eggs to basal diets containing 40 percent fat
and 300 mg of cholesterol and differing ratios of polyunsaturated to saturat-
ed fat (P/S). At P/S ratios of 0.25 and 0.4, the addition of three and six eggs
raised LDL cholesterol by 16 mg/dl and 25 mg/dl, respectively. At P/S

98


Coronary Heart Disease- 0

ratios of 0.8 and 2.5, the addition of three eggs had little effect, but the
addition of six eggs at the P/S ratio 0.8 raised LDL cholesterol 17 mgidl. On
the diet with a P/S of 2.5, neither three nor six eggs produced significant
changes. Thus, both the cholesterol content and the P/S ratios were impor-
tant in determining LDL level (Schonfeld et al. 1982). Another example
suggests that type of protein may influence response to dietary cholesterol.
In a controlled dietary study in Type II hypercholesterolemia patients.
substitution of soybean for animal protein caused a reduction in serum
cholesterol concentrations, and the decrease was about the same with or
without the addition of 500 mg of cholesterol to the diet (Sir-tori, Gatti. and
Mantero 1979).

A total of 75 studies were carried out in 50 male outpatient volunteers fed
high cholesterol (approximately 800 mg/dl) versus low cholesterol (approx-
imately 250 mg/dl) in a diet containing 35 percent of calories as either
polyunsaturated or saturated fat. In 69 percent of the studies. participants
compensated for the increased dietary cholesterol by decreasing cholester-
ol absorption or endogenous synthesis. The type of dietary fat had a larger
and more consistent effect on plasma cholesterol (McNamara et al. 1987).

The main effect of dietary cholesterol on lipoproteins is to raise LDL
levels, but it also affects other lipoprotein fractions. For example, human
volunteers who ate three to six eggs per day showed increased binding
activity of an HDL subfraction that might be associated with increased risk
for the development of atherosclerosis (Mahley et al. 1978). It is hypothe-
sized that dietary cholesterol might increase the cholesterol content of
chylomicron and VLDL remnants, making them more atherogenic; these
changes would not be detected in fasting blood samples. indicating the need
for information on postprandial lipoproteins (Grundy et al. 1988).

Epidemiologic Studies

Extensive evidence relating diet to high blood cholesterol has been
amassed in a variety of observational-epidemiologic studies. These investi-
gations involve comparisons of different populations, comparisons of mi-
grant with native populations, and comparisons of groups within popula-
tions.

Between-Population Studies (International Comparisons). In one type of
international analysis, nutrient and food commodity data from Food and
Agriculture Organization food balance sheets have been compared with
World Health Organization CHD mortality data for sets of countries
(Stamler 1983). Univariate analyses consistently showed statistically sig-

99


O Nutrition and Health

nificant positive associations of CHD mortality with calories, total fat,
animal fat, saturated fat, dietary cholesterol, total protein, animal protein,
animal products (dairy products, meat, poultry, and eggs), and refined
sugars. Similar analyses have also shown an inverse association between
vegetable products and CHD mortality. Since many of these variables
occur together, the independent effect of a single nutrient cannot be
determined in such analyses. When the data were reanalyzed, combining
the saturated and polyunsaturated fatty acids and dietary cholesterol into a
single score based on defined equations (see Table 2-4) and using analysis
of variance to control separately for the influence of sugar, vegetable
products, and fat, the significant effects of dietary fats persisted while
sugar and vegetable products no longer related to CHD mortality (Liu et al.
1982).

In a second type of international comparison, autopsy records were used to
compare the degree of atherosclerosis with dietary data. The most system-
atic study was the International Atherosclerosis Project (McGill 1%8), in
which severity of atherosclerosis was quantified in autopsies of 23,000
people in 12 countries. The percent of calories consumed as fat ranged from
10 to I5 percent in Costa Rica and Guatemala to nearly 50 percent in the
United States. Dietary composition was estimated from available survey
data and subjective judgment. The countries were ranked on the basis of
severity of disease, dietary indices, and serum cholesterol. The results
showed that the percentage of calories from dietary fat was related to the
severity of the atherosclerosis (r = 0.67) and to population levels of blood
cholesterol (r = 0.74).

A third type of international comparison involves the direct measurement
of cardiovascular risk factors and dietary assessment. These epidemiologic
surveys provide further descriptive data on dietary factors associated with
the prevalence of heart disease in the populations studied. For example,
the Seven Countries Study (Keys 1970) has involved 12,000 men from I8
populations sampled in Finland, Greece, Italy, Japan, the Netherlands, the
United States, and Yugoslavia. Fourfold differences in prevalence and
incidence of CHD were shown among these populations. The highest
incidence rates were recorded for Finland and the United States and the
lowest for Japan and three populations in Greece (Co&, Crete, and
Dalmatia). Seven-day food records supplemented by chemical analyses of
the diets consumed by study participants showed wide variability across
population samples in both amount and type offat. Saturated fat intake was
highest in Finland, the United States, and the Netherlands (I7 to 22 percent
of calories, compared with 5 to 9 percent of calories in the other countries).
Saturated fat intakes and 5-year CHD incidence rates for these populations
were highly and significantly correlated (r = 0.84), as were saturated fat and

100