Issues and Opinions in Nutrition
AHA Scientific Statement: Summary of the Scientific Conference on Dietary
Fatty Acids and Cardiovascular Health1
Conference Summary From the Nutrition Committee
of the American Heart Association
Conference Planning and Writing Committee: Penny Kris-Etherton, PhD,
Stephen R. Daniels, MD, PhD, Robert H. Eckel, MD, Marguerite Engler, PhD, RN,
Barbara V. Howard, PhD, Ronald M. Krauss, MD, Alice H. Lichtenstein, DSc,
Frank Sacks, MD, Sachiko St. Jeor, PhD, Meir Stampfer, MD, DrPH
For the American Heart Association Nutrition Committee Speakers and Discussants:
Robert H. Eckel, MD, Scott M. Grundy, MD, PhD, Lawrence J. Appel, MD, MPH,
Tim Byers, MD, Hannia Campos, PhD, Greg Cooney, PhD, Margo A. Denke, MD,
Barbara V. Howard, PhD, Eileen Kennedy, DSc, Ronald M. Krauss, MD,
Penny Kris-Etherton, PhD, Alice H. Lichtenstein, DSc, Peter Marckmann, MD, DSc,
Thomas A. Pearson, MD, PhD, Gabriele Riccardi, MD, Lawrence L. Rudel, PhD,
Mike Rudrum, PhD, Frank Sacks, MD, Daniel T. Stein, MD, Russell P. Tracy, PhD,
Virginia Ursin, PhD, Robert A. Vogel, MD, Peter L. Zock, PhD
AHA Members: Terry L. Bazzarre, PhD, Julie Clark, AHA Staff
AHA Scientific Statement ● diet ● fatty acids ● risk factors ● cardiovascular diseases
The objective of this Executive Summary is to provide a
synopsis of the research findings presented at the American
Heart Association conference “Dietary Fatty Acids and Car-
diovascular Health—Dietary Recommendations for Fatty Ac-
ids: Is There Ample Evidence?” held on June 5–6, 2000, in
Reston, Va. The conference was held to summarize the current
understanding of the effects of fatty acids on risk of cardiovas-
cular disease (CVD) and cancer, as well as to identify gaps in
our knowledge base that need to be addressed. There is great
interest in learning more about the biological effects of the
individual fatty acids, their role in chronic disease risk, and
their underlying mechanisms of action. As research advances
are made, there is always the need to question how new
findings may be translated into practice. There is a long history
of research providing the basis for the modification of existing
dietary guidelines. Research findings have been used to verify
intake criteria and are considered along with practical issues of
implementation to establish new guidelines. A substantive
body of consistent evidence sufficient to defend a dietary
recommendation or a change in existing dietary guidance is
essential. The conference highlighted the progress that has
been made in understanding the biological effects of fatty acids
and also addressed the need to learn more about how different
fatty acids affect the risk of chronic disease, within the context
of refining dietary guidance to further enhance health.
EPIDEMIOLOGICAL, CLINICAL TRIAL, AND
NONHUMAN PRIMATE EVIDENCE FOR THE
RELATIONSHIP BETWEEN TYPE OF FAT AND
As study designs have become increasingly rigorous, a num-
ber of megatrends have emerged from the data (1,2). There is
increased emphasis on identifying the type of fat that best
correlates with disease end points. The classic studies of Keys
et al (3) and Hegsted et al (4) have shown that saturated fatty
acids (ie, those with a carbon chain length of C12:0 to C16:0)
raise total and low-density lipoprotein (LDL) cholesterol lev-
els, whereas C18:0 and monounsaturated fat (cis C18:1) are
neutral when substituted for carbohydrate, and n-6 polyunsat-
urated fatty acids (PUFAs) lower cholesterol (3,4). More re-
cent studies have shown that long-chain n-3 fatty acids are
1© 2001 American Heart Association, Inc. Reproduced with permission. This
statement was approved by the American Heart Association Science Advisory
and Coordinating Committee in November 2000. A single reprint is available by
calling 800-242-8721 (US only) or writing the American Heart Association, Public
Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No.
J. Nutr. 131: 1322-1326, 2001.
by guest on June 1, 2013
hypotriglyceridemic and trans fatty acids are hypercholester-
olemic. Epidemiological studies have shown that saturated fat
intake is associated with increased risk of coronary heart
disease; the greatest risk reduction is associated with PUFA
intake, and a lesser extent of risk reduction is associated with
monounsaturated fat. Both n-6 (linoleic acid) and n-3 (?-
linolenic acid) PUFAs are protective. Trans fatty acids are
strong predictors of increased coronary risk compared with
saturated fat or carbohydrates (1).
The paradigm that dietary fats act exclusively via effects on
serum lipids and lipoproteins has been challenged (5–8). The
Lyon Diet Heart Study (5) and the Indian Heart Study (6)
have both shown in clinical trials that diet can prevent fatal
and nonfatal cardiovascular events in individuals with CVD.
In both trials, saturated fats were replaced with monounsatu-
rated fats and ?-linolenic acid, an n-3 PUFA that is present in
canola (rapeseed) oil. Vegetables and fruits were increased in
the diets in these studies as well. In addition, fish and fish oil
have been shown to reduce all-cause mortality (7,8) and
cardiovascular death (8) in patients who had myocardial in-
Studies have been conducted in primates to examine the
effects of dietary fatty acids on atherosclerosis (9,10). Diets
with saturated, monounsaturated, and polyunsaturated (in-
cluding both n-3 and n-6) fatty acids have been evaluated.
Coronary artery atherosclerosis (as measured by intimal area)
was less in the polyunsaturated fat than in the saturated fat and
monounsaturated fat groups. Monkeys fed monounsaturated
fat developed equivalent amounts of coronary artery athero-
sclerosis as those fed saturated fat (9). LDL cholesterol was
similar in monkeys fed polyunsaturated and monounsaturated
fat and lower than in animals fed saturated fat. However, there
was an enrichment of cholesteryl oleate in plasma cholesteryl
esters of the monkeys fed the diet high in monounsaturated
fatty acids, which correlated with coronary artery cholesteryl
ester concentration, a measure of coronary artery atheroscle-
rosis (10). Activation of ACAT2 (the enzyme responsible for
cholesterol oleate formation and secretion by the liver) may
explain how dietary monosaturated fat promotes atherosclero-
sis out of proportion to its effects on plasma LDL cholesterol
levels. Both n-6 PUFAs (primarily linoleic acid) and n-3
PUFAs (principally eicosapentaenoic acid and docosahexa-
enoic acid) have been shown to confer protection. That a diet
rich in monounsaturated fat resulted in more atherosclerosis
than a diet rich in polyunsaturated fat even though plasma
LDL and high-density lipoprotein (HDL) cholesterol levels
were comparable also suggests that nonlipid risk factors may
play a role in atherogenesis. Thus, additional studies with
cardiovascular end points that go beyond the measurement of
surrogate markers of CVD risk (ie, plasma lipids and lipopro-
teins) are needed to evaluate the effects of fatty acids in
humans. In this regard, there is evidence in human subjects
that a single high-fat meal (high in monounsaturated fat or
saturated fat) adversely affects endothelial function, (11)
which is thought by some to be an early event in the athero-
EPIDEMIOLOGICAL AND CLINICAL TRIAL
EVIDENCE FOR A RELATIONSHIP BETWEEN
TYPE OF FAT AND CANCER RISK
There are no good biomarkers for studying the link between
cancer risk and fatty acids in the diet (12). Epidemiological
studies relating dietary fats to cancer risk have generally shown
weak and inconsistent patterns of associations. Breast cancer
risk has been shown to be unrelated to fat content of the diet
across a wide range of intake. There is limited evidence that
monounsaturated fats might be associated with reduced risk
and that trans fats might be associated with increased risk of
breast cancer, but those findings are weak and should be
regarded as preliminary. Prostate cancer has been associated
with higher dietary saturated fat, an association that may be
due to an effect of saturated fat on circulating testosterone
levels. Colorectal cancer risk is increased with higher-fat diets,
but this association may be due more to a direct effect of red
meats or carcinogens formed with high-temperature cooking of
meats than to fat per se. There is limited information from
randomized, controlled trials of cancer end points. The Polyp
Prevention Trial (13) showed that reducing the levels of fat in
the diet from 36% to 24% did not reduce the rate of new
adenoma formation over a 3-year period. However, because
the low-fat group did not show a decrease in plasma choles-
terol and HDL cholesterol, established markers of reduced
total fat intake, the lack of an effect on polyp formation may
have been due to a lack of adherence to the low-fat diet.
Additional long-term studies of fatty acids and cancer are
EFFECTS OF FATTY ACIDS ON INSULIN
SECRETION AND ACTION
The insulinotropic effect of individual fatty acids increases
and decreases dramatically with chain length and degree of
unsaturation, respectively (14). According to studies designed
to examine the influence of individual fatty acids on insulin
secretion in the perfused rat pancreas, insulin release was as
follows: octanoate (C8:0), 3.4-fold increase; linoleate (C18:2
cis/cis), 5.3-fold increase; oleate (C18:1 cis), 9.4-fold increase;
palmitate (C16:0), 16.2-fold increase; and stearate (C18:0),
21.0-fold increase (14). Insulin release was increased 3.1-fold
by palmitoleate (C16:1 cis). Only a modest effect on insulin
release was observed with a cis 3 trans switch of the double
bond in the C16:1 and C18:1 fatty acids. Thus, there is
remarkable diversity in how individual fatty acids affect insulin
secretion. Consequently, these in vitro studies suggest that the
type and amount of circulating fatty acids may determine the
insulin secretory response. Importantly, saturated fat raises
insulin resistance. Unpublished data from a multicenter study
in Europe showed that individuals were more insulin sensitive
when consuming a diet high in monounsaturated fatty acids
than when consuming an equivalent diet high in saturated fat.
Increased intake of dietary fat reduces insulin action in
experimental animals, and this insulin resistance is associated
with the accumulation of triglyceride in muscle and liver. In
animal models, high-fat diets composed of fish oil or safflower
oil have markedly different effects on insulin action, and these
differences may depend on the ability of fatty acids in fish oil
to upregulate lipid oxidation in the liver. Mechanisms may
involve increased translocation and activation of specific pro-
tein kinase C isozymes (PKC-? and PKC-?) that phosphory-
late and reduce the activity of insulin signaling intermediates
(15,16). In C2C12 cells (a murine muscle cell line), oleate and
palmitate have different effects on insulin-stimulated glucose
conversion to glycogen and different effects on key compo-
nents of the insulin signaling pathways (17). On the other
hand, in humans, varying the total fat content of the diet does
not affect insulin-mediated glucose disposal (18). However, it
is becoming increasingly evident that specific fatty acids or
their derivatives may have roles other than as energy substrates
involving regulation of enzyme activity and gene expression in
insulin-responsive tissues. More in vivo studies in humans are
DIETARY FATTY ACIDS AND CARDIOVASCULAR HEALTH
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EFFECTS OF FATTY ACIDS ON HEMOSTATIC
FACTORS AND PLATELET FUNCTION
Thrombosis is an important aspect of CVD. The coagula-
tion system, which includes platelets and coagulation proteins,
plays a role in the evolution of atheroma and in the events
that follow rupture of a plaque that leads to thrombosis and
symptomatic disease. As the importance of hemostatic factors
has become clear, the question of whether diet may influence
them has been one focus of research.
Several hemostatic factors are influenced by dietary com-
ponents (19,20). For example, when a high-fat diet is replaced
by a lower-fat, higher-fiber diet, the activity of factor VII
decreases and the capacity of the endogenous fibrinolytic sys-
tem increases. Studies of the relationship of dietary fatty acids
and hemostatic factors generally show that hemostatic pro-
teins are not affected by changes in the type of dietary fat, such
as saturated, monounsaturated, trans, or n-6 polyunsaturated
Platelets play several roles in atherosclerosis, including ex-
acerbating the atherosclerotic process, adhering to ruptured or
eroded lesions, and participating in the formation of an occlu-
sive thrombus. Lipids are an important constituent of the
platelet membrane. Lipids are also important in the intracel-
lular signaling of platelets. Many studies have explored the
relationship of dietary fatty acids and platelet function. The
majority of studies have been performed in small numbers of
human subjects and in animal models. However, interpreta-
tion of results is difficult because different methods have been
used to estimate platelet function, there has been inconsis-
tency in assessment of platelet lipid composition, and there
have been questions regarding the relationship of in vitro
assays to in vivo activity. The composition and duration of the
dietary manipulations have been inconsistent across studies.
There are few population-based epidemiological data because
of difficulty in assessing platelet function and diet composition
in these studies.
In general, the composition of the platelet membrane ap-
pears to reflect the fatty acid composition of the diet. Diets
rich in n-3 fatty acids appear to cause platelets to aggregate less
at a fixed dose of agonist or to require more agonist to aggre-
gate. There are some data to support a deleterious effect of
dietary stearic acid on platelet aggregation. It appears that
within the context of the usual diet, there may be some effects
of dietary fatty acids on both the coagulation proteins and the
platelet membrane. However, these effects are minor, and the
clinical meaning of such effects is unclear.
EFFECTS OF FATTY ACIDS ON
Evidence from laboratory investigations, observational
studies, and clinical trials indicates that supplementation of a
diet with high doses of n-3 PUFAs (commonly found in fish
oil) can reduce blood pressure (21,22). However, large quan-
tities (eg, 3 g per day) are needed to see a minimal effect in
nonhypertensive individuals and only very modest effects in
hypertensive individuals. The most effective n-3 PUFA is
docosahexaenoic acid rather than eicosapentaenoic acid.
Given the quantities needed to achieve the desired effect, this
is not a practical treatment for lowering blood pressure. Short-
term changes in consumption of saturated fat or n-6 PUFAs
appear to have little effect on blood pressure, although there is
some suggestion that a diet rich in monounsaturated fatty acids
can lower blood pressure. Regular fish consumption may also
reduce blood pressure; in addition, the effect of fish oil con-
sumption with weight loss is additive in reducing blood pres-
FATTY ACIDS AND ENDOTHELIAL
In vitro studies have been conducted to assess the effects of
long-chain fatty acids on leukocytic-endothelial interactions
that play a role in atherogenesis and inflammation (23). These
interactions are mediated importantly by factors that regulate
expression of leukocyte adhesion molecules. There is recent
evidence that the n-3 fatty acid docosahexaenoic acid reduces
endothelial expression of vascular cell adhesion molecule-1
(VCAM-1), E-selectin, intercellular adhesion molecule-1
(ICAM-1), interleukin 6 (IL-6), and IL-8 in response to ex-
posure to IL-1, IL-4, tumor necrosis factor, or bacterial endo-
toxin (23). In contrast, saturated fatty acids had no inhibitory
effects. In addition, there was a progressive increase in inhib-
itory activity with fatty acids of the same chain length but
increasing in degree of unsaturation. Thus, n-3 fatty acids seem
to have the greatest inhibitory effect, with n-6 fatty acids
being intermediate, followed by monounsaturated fatty acids.
The emerging evidence suggests that with increasing fatty acid
unsaturation, there is an accompanying increase in inhibition
of endothelial activation.
DIETARY FAT INTAKE
The US Department of Agriculture has been monitoring
consumption patterns in the United States for over 50 years
using representative samples of the population (24). Con-
sumption trends over the past 30 years have shown a general
downward trend in energy consumption from 1965 to 1995.
This downward trend in energy intake has been paralleled by
a decrease in the percent of energy provided by total fat and
saturated fat in the diet. When the period 1989 to 1991 is
compared with 1994 to 1996, the data show a slight upward
trend in energy consumption for certain age/gender groups; it
is unclear how much of this is a result of a more accurate
measurement as opposed to a true increase in kilocalorie
intake. Some differences across racial/ethnic and socioeco-
nomic groups were noted: blacks had a slightly higher intake of
total fat and saturated fat intake, and there was a modest
decrease in fat and saturated fat intake with increasing in-
Because of challenges associated with collecting accurate
food consumption data, there is a pressing need to identify
reliable markers of fat and fatty acid intake. Evidence indicates
that adipose tissue fatty acid composition is a suitable biomar-
ker for habitual type of dietary fat intake (25,26).
MODIFICATION OF OILS FOR IMPROVED
The production of genetically modified oilseed crops to
provide vegetable oils with modified lipids provides a conve-
nient mechanism to deliver healthier products to consumers
without requiring them to make significant dietary changes
(27). Examples of such modified oils include low-saturated fat
and zero-saturated fat soybean and canola oils, canola oil that
contains medium-chain fatty acids, high-stearate canola oil
(for trans fatty acid–free products), high oleic acid soybean oil,
and canola oil containing the long-chain PUFAs, ?-linolenic
(18:3 n-6) and stearidonic acids (18:4 n-3). Long-chain n-3
fatty acids in the form of stearidonic acids, the 18:4 n-3
precursor to eicosapentaenoic acid and docosahexaenoic acid,
KRIS-ETHERTON ET AL
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could provide a more effective n-3 fatty acid than ?-linolenic
acid. In addition, vegetable oil–derived stearidonic acids could
be used as an alternative to fish oil to provide long-chain n-3
fatty acids with enhanced stability and taste that can be
incorporated into a wide variety of foods.
DIETARY FAT RECOMMENDATIONS: WHERE
WE ARE AND WHERE WE COULD GO
Current dietary guidance in general recommends a diet that
contains ?30% of energy as fat, ?10% of energy as saturated
fatty acids, up to 10% of energy as PUFAs, and ?300 mg of
cholesterol per day (28-30). These recommendations are cou-
pled with guidance on physical activity and weight mainte-
nance and are distinct from those for individuals with specific
metabolic profiles that might necessitate more restrictive or
targeted regimens. In the current revisions of the recommen-
dations, increased recognition is placed on the diet as a whole
and away from segmented guidance on individual dietary com-
ponents. In effect, this shifts the emphasis from the question of
what not to consume to what to consume. A more compre-
hensive approach to dietary guidance will likely reduce the risk
of overemphasis on one component of the guidelines over
another, allow for a stronger message regarding other aspects of
lifestyle (eg, body weight maintenance and regular exercise),
and support the necessity of the dietary guidelines/lifestyle
approach to disease risk reduction as a lifelong endeavor.
Individual fatty acids have remarkably diverse effects on
risk factors for CVD. With respect to effects on lipids and
lipoproteins, we have a reasonably good understanding of the
effects of individual fatty acids. Much remains to be learned
about individual fatty acids with regard to other risk factors
such as hemostatic factors, platelet function, blood pressure,
and endothelial function, as well as the development of ath-
erosclerosis. In general, the unsaturated fatty acids (excluding
trans fatty acids) favorably affect a number of factors that are
cardioprotective. Unsaturated fatty acids lower total and LDL
cholesterol levels when substituted for saturated fatty acids
(C12:0 to C16:0). Long-chain n-3 fatty acids from fish oil
decrease triglyceride levels, favorably affect platelet function,
and decrease blood pressure slightly in hypertensive individu-
als. Oleic acid has been shown to decrease postprandial factor
VII activity. Epidemiological studies have shown beneficial
effects of unsaturated fatty acids (both polyunsaturated and
monounsaturated) compared with saturated fatty acids on in-
cidence of coronary disease. Controlled clinical trials have
demonstrated beneficial effects of diets high in n-6 and n-3
fatty acids on coronary heart disease. There is some evidence
to suggest potentially adverse effects of unsaturated fatty acids
in that monounsaturated fat has atherogenic effects in mon-
keys that are comparable to those of saturated fat.
Technologies are emerging that will enable the production
of designer fats and oils that have a modified fatty acid profile
that provides both nutritional and processing benefits. Based
on a large body of evidence, it is apparent that the optimal diet
for reducing risk of chronic diseases is one in which saturated
fatty acids are reduced and trans fatty acids from manufactured
fats are virtually eliminated. Because of the growing health
benefits recognized for unsaturated fatty acids, it is likely that
a mixture of these fatty acids in the diet will confer the greatest
health benefits within the context of a total fat intake that is
considered moderate. Given the limited amount of evidence
to date on the effect of individual fatty acids on many of the
variables discussed in this meeting summary, it is not possible
to incorporate specific advice on all the points raised into
population-wide dietary guidelines. As the evidence base
strengthens, it will be important to reevaluate the current
guidelines on a regular basis and modify them, if necessary, in
light of substantive new findings.
Fatty Acids Conference, June 5 to June 6, 2000, Reston,
Welcome/Opening Remarks, Discussant: Penny Kris-Etherton,
PhD, Distinguished Professor of Nutrition, Penn State Uni-
versity, University Park, Pa.
Welcome/Opening Remarks, Discussant, and Conference Dis-
cussion (Closing): Robert H. Eckel, MD, University of Colo-
rado, Health Sciences Center, Division of Endocrinology,
Overview: Rationale for Dietary Fat Guidelines: Scott M.
Grundy, MD, PhD, University of Texas Southwestern Medical
Center at Dallas, Dallas, Tex.
Analysis and Interpretation of the Epidemiological and Clinical
Trial Scientific Evidence for Fatty Acid Relationships/Effects on
Disease End Points: Thomas A. Pearson, MD, PhD, Depart-
ment Chair, Community and Preventive Medicine, Albert D.
Kaiser Professor, University of Rochester, Rochester, NY.
Epidemiological and Clinical Trial Evidence for the Relationship
Between Type of Fat and CVD Risk: Frank Sacks, MD, Asso-
ciate Professor of Nutrition, Harvard School of Public Health,
Department of Nutrition, Boston, Mass; Tim Byers, MD, Pro-
fessor, Department of Preventive Medicine and Biometrics,
University of Colorado School of Medicine, Denver, Colo.
Fatty Acids in Atherosclerosis: Lawrence L. Rudel, PhD,
Department of Pathology, Wake Forest University School of
Medicine, Section of Comparative Medicine, Winston-Salem,
Effects of Fatty Acids on Lipids and Lipoproteins: Margo A.
Denke, MD, Associate Professor, University of Texas South-
western Medical Center at Dallas, Dallas, Tex.
General Discussion and AHA Dietary Guidelines: Ronald M.
Krauss, MD, Senior Scientist and Head of the Molecular
Medicine Department, University of California at Berkeley,
Lawrence Berkeley National Laboratory, Berkeley, Calif.
Insulin Secretion: Daniel T. Stein, MD, Albert Einstein
College of Medicine, Bronx, NY.
Insulin Action: Greg Cooney, PhD, Senior Research Fellow,
Metabolism and Diabetes Program, Garvan Institute of Med-
ical Research, St. Vincent’s Hospital, Sydney, Australia.
Hemostatic Factors: Peter Marckmann, MD, DSc, Associate
Professor, Research Department of Human Nutrition, The
Royal Veterinary and Agricultural University, Frederiksberg,
Platelet Function: Russell P. Tracy, PhD, Professor of Pa-
thology and Biochemistry, Director, Laboratory for Clinical
Biochemistry Research, University of Vermont, Colchester,
Vascular Reactivity: Robert A. Vogel, MD, Herbert Berger
Professor of Medicine and Head, Division of Cardiology, De-
partment of Medicine, University of Maryland School of Med-
icine, Baltimore, Md.
Blood Pressure: Lawrence J. Appel, MD, MPH, The Johns
Hopkins University, Baltimore, Md.
Fatty Acids in the Diet and Food Supply: Eileen Kennedy,
DSc, United States Department of Agriculture, Office of Re-
search, Education & Economics, Washington, DC.
Biomarkers to Assess Fatty Acid Intake: Hannia Campos,
DIETARY FATTY ACIDS AND CARDIOVASCULAR HEALTH
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PhD, Assistant Professor, Harvard School of Public Health, Download full-text
Department of Nutrition, Boston, Mass.
New Technologies to Manipulate Dietary Fatty Acids: Virginia
Ursin, PhD, Nutrition Sector, Monsanto Company, Calgene
Campus, Davis, Calif.
Technologies to Modify Fatty Acids: Mike Rudrum, PhD,
Unilever Research Vlaardingen, Vlaardingen, The Nether-
lands. Discussant: Barbara V. Howard, PhD, President, Med-
lantic Research Institute, Washington, DC.
Dietary Recommendations for Fatty Acids: Peter L. Zock,
PhD, Wageningen Center for Food Sciences, Nutrition and
Health Program, Wageningen University, Wageningen, The
Dietary Recommendations for Fatty Acids: Gabriele Riccardi,
MD, Institute of Internal Medicine and Metabolic Diseases,
Second Medical School, University of Naples, Napoli, Italy.
Recommendations for Dietary Fat: Where We Are and Where
We Could Go: Alice H. Lichtenstein, DSc, Professor of Nu-
trition, HNRC/Tufts University, Boston, Mass.
1. Hu FB, Stampfer MJ, Manson J, et al. Dietary fat intake and the risk of
coronary heart disease in women. N Engl J Med. 1997;337:1491–1499.
2. Sacks FM. Dietary prevention trials. In: Hennekens CH, Buring JE,
Manson JE, Ridker PM, eds. Clinical Trials in Cardiovascular Disease: A Com-
panion to Braunwald’s Heart Disease. Philadelphia, Pa: WB Saunders Co; 1999:
3. Keys A, Anderson JT, Grande F. Serum cholesterol response to changes
in diet, IV: particular saturated fatty acids in the diet. Metabolism. 1965;14:776–
4.Hegsted DM, McGandy RB, Myers ML, et al. Quantitative effects of
dietary fat on serum cholesterol in man. Am J Clin Nutr. 1965;17:281–295.
5. De Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional
risk factors, and the rate of cardiovascular complications after myocardial infarc-
tion: final report of the Lyon Heart Study. Circulation. 1999;99:779–785.
6. Singh RB, Rastoqi SS, Verma R, et al. Randomised controlled trial of
cardioprotective diet in patients with recent acute myocardial infarction: results of
one year follow up. BMJ. 1992;304:1015–1019.
7. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish and
fibre intakes on death and myocardial reinfarction: Diet And Reinfarction Trial
(DART). Lancet. 1989;2:757–761.
8. GISSI Investigators. Dietary supplementation with n-3 polyunsaturated
fatty acids and vitamin E after myocardial infarction: results of the GISSI-Preven-
zione TRIAL: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto mio-
cardico. Lancet. 1999;354:447–455.
9. Rudel LL, Parks JS, Sawyer JK. Compared with dietary monounsatu-
rated and saturated fat, polyunsaturated fat protects African green monkeys from
coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol.1995;15:2101–
10. Rudel LL, Hains JL, Sawyer JK, et al. Hepatic origin of cholesteryl oleate
in coronary artery atherosclerosis in African green monkeys: enrichment by di-
etary monounsaturated fat. J Clin Invest. 1997;100:74–83.
11. Vogel RA. Brachial artery ultrasound: a noninvasive tool in the assess-
ment of triglyceride-rich lipoproteins. Clin Cardiol. 1999;22(6 suppl):II34–II39.
12. Willet WC. Diet and health: what should we eat? Science. 1994;264:532–
13. Schatzkin A, Lanza E, Corle D, et al. Lack of effect of a low-fat, high-fiber
diet on the recurrence of colorectal adenomas: Polyp Prevention Trial Study
Group. N Engl J Med. 2000;342:1149–1155.
14. Stein DT, Stevenson BE, Chester MW, et al. The insulinotropic potency
of fatty acids is influenced profoundly by their chain length and degree of
saturation. J Clin Invest. 1997;100:398–403.
15. Griffin ME, Marcucci MJ, Cline GW, et al. Free fatty acid-induced insulin
resistance is associated with activation of protein kinase C theta and alterations
in the insulin-signaling cascade. Diabetes. 1999;48:1270–12741.
16.Schmitz-Peiffer C, Browne CL, Oakes ND, et al. Alterations in the
expression and cellular localization of protein kinase C isozymes epsilon and
theta are associated with insulin resistance in skeletal muscle of the high-fat-fed
rat. Diabetes. 1997;46:169–178.
17. Schmitz-Peiffer C, Craig DL, Biden TJ. Ceramide generation is sufficient
to account for the inhibition of the insulin-stimulated PKB pathway in C2C12
skeletal muscle cells pretreated with palmitate J Biol Chem. 1999;274:24202–
18.Howard BV. Diet, insulin resistance, and atherosclerosis. In: Baba S,
Kaneko T, eds. Diabetes. New York: Elsevier Science BV; 1995:446–450.
19. Pearson TA, LaCava J, Weil HF. Epidemiology of thrombotic-hemostatic
factors and their associations with cardiovascular disease. Am J Clin Nutr. 1997;
20. Marckmann P. Diet, blood coagulation and fibrinolysis. Dan Med Bull.
21. Appel LJ, Miller ER III, Seidler AJ, et al. Does supplementation of diet with
“fish oil” reduce blood pressure? A meta-analysis of controlled clinical trials. Arch
Intern Med. 1993;153:1429–1438.
22. Morris MC, Sacks FM. Dietary fats and blood pressure. In: Swales JD,
ed. Textbook of Hypertension. Oxford, UK: Blackwell; 1994:605–618.
23.De Caterina R, Liao JK, Libby P. Fatty acid modulation of endothelial
activation. Am J Clin Nutr. 2000;71(suppl 1):213S–223S.
24. Kennedy ET,Bowman SA, Powell R. Dietary-fat intake in the US popu-
lation. J Am Coll Nutr. 1999;18:207–212
25. FarquharJW, Ahrens EH Jr. Effects of dietary fats on human erythrocyte
fatty acid patterns. J Clin Invest. 1963;42:675–685.
26. Dayton S, Hashimoto S, Dixon W, et al. Composition of lipids in human
serum and adipose tissue during prolonged feeding of a diet high in unsaturated
fat. J Lipid Res. 1966;7:103–111.
27. Knutzon DS, Knauf V. Manipulating seed oils for polyunsaturated fatty
acid content. In: Harwood J, ed. Plant Lipid Biosynthesis: Fundamentals and
Agricultural Applications. Cambridge, UK: University Press; 1998:287. Society for
Experimental Biology Seminar Series 67.
28.Summary of the second report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA. 1993;269:3015–3023.
29. Nutrition and Your Health: Dietary Guidelines for Americans, 2000. Avail-
able at: http://www.usda.gov/cnpp/DietGd.pdf. Accessed December 22, 2000.
30. Krauss RM, Eckel RH, Howard B, et al. AHA dietary guidelines: revision
2000: a statement for healthcare professionals from the Nutrition Committee of
the American Heart Association. Circulation. 2000;102:2284–2299.
KRIS-ETHERTON ET AL
by guest on June 1, 2013