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(Circulation. 1999;99:733-735.)
© 1999 American Heart Association, Inc.
Editorials |
Dietary Prevention of Coronary Heart Disease
The Lyon Diet Heart Study
From the Departments of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston.
Correspondence to Alexander Leaf, MD, Massachusetts General Hospital, East, Bldg 149, 4th Floor, 13th St, Charlestown, MA 02129. E-mail leaf.alexander1{at}mgh.harvard.edu
Key Words: Editorials • fatty acids • trials • coronary disease
This issue of
Circulation contains an article1 that
I believe deserves special attention from cardiologists and physicians.
It reports the 46-month mean follow-up findings on the original report
of the study on "Mediterranean 
-linolenic acid–rich diet
in secondary prevention of coronary heart disease," the
so-called Lyon Diet Heart Study. This study was undertaken because of
the interest of the investigators in explaining the very much lower
mortality from cardiovascular disease, mainly
coronary heart disease, in the countries bordering the
Mediterranean compared with that in northern Europe. The initial
report2 was published in Lancet in
1994 after the study was terminated by its Scientific and Ethics
Committee at 27 months mean follow-up time of what had been planned as
a 5-year study, because the benefits in the experimental group at that
time were so favorable. Despite the striking findings in the first
report of a 70% reduction in all-cause mortality due to a reduction in
coronary heart disease (CHD) mortality and comparable large
reductions in nonfatal sequelae, I have encountered few cardiologists
here who are aware of that study.
It is much to the credit of Dr de Lorgeril and associates that they persisted in following the original enrollees despite the official termination of the study and publication of the initial findings so that they are now able to report their more extended observations. With the mean follow-up time of 46 months per patient, the initial remarkably beneficial effects of the experimental dietary program persisted compared with the control group consuming the "prudent Western-type diet."
Let me list the several important messages I believe are inherent in the results that are clearly and modestly presented in this article.
1. At a time when health professionals, the pharmaceutical industries, and the research funding and regulatory agencies are almost totally focused on lowering plasma cholesterol levels by drugs, it is heartening to see a well-conducted study finding that relatively simple dietary changes achieved greater reductions in risk of all-cause and coronary heart disease mortality in a secondary prevention trial than any of the cholesterol-lowering studies to date. This is emphasized by the finding that the unprecedented reduction in risk of CHD was not associated with differences in total cholesterol levels between the control and experimental groups and that the survival curves showed a very early separation quite unlike what has been reported in the cholesterol reduction studies.3 This study does not contradict the importance of plasma cholesterol in the genesis of CHD—the authors measured and acknowledge its contribution to the outcomes in their study—but it indicates that there are other powerful risk factors within the realm of diet that must be considered if we are to achieve maximal dietary benefits in reducing this number 1 cause of mortality in the world today.
2. The continued high adherence of the experimental group to the program over the full 46 months of mean follow-up per patient is quite remarkable, considering that the Science and Ethics Committee had officially terminated the study when the mean follow-up time was 27 months. This occurred even though all patients in the study were informed of the outcome and despite the publicity from the initial publication of the striking benefits of the trial, which seems to have influenced some in the control group to modify their diets toward that of the experimental group. The continued good adherence to the experimental diet indicates that it was readily tolerated. The unprecedented magnitude of the benefits achieved is especially notable because the study was undertaken in a very-low-risk population. Of the 36 selected countries listed, the American Heart Association's 1998 Heart and Stroke Statistical Update4 ranks France second to the lowest in cardiovascular mortality in men, with only Japan ranked lower, and France ranked the lowest in female cardiovascular mortality.
3. This study points to the inadequacy of the "Phase One" or
"Step One" dietary management of CHD (10-10-10, as the percentages
of energy from saturated, monounsaturated, and
polyunsaturated fatty acids5 ) promoted by both
the National Cholesterol Educational Program of our
National Heart, Lung, and Blood Institute and the American Heart
Association, which is quite similar, with regard to the total fat
intake of 30% of energy, to that of the experimental diet for the
present study. The Step One diet, however, has too high an intake
of saturated fats. Furthermore, although the Step One diet indicates an
adequate intake of polyunsaturated fatty acids (PUFAs), it makes no
additional recommendation for the need to lower intake of the n-6
(
6) class of the essential PUFA, linoleic acid, which is high in
most vegetable oils, and to increase the intake of the other essential
n-3 (3) class, -linolenic acid, which is present in
only a few vegetable oils, notably canola oil (low-erucic-acid rapeseed
oil, 
10% to 11% -linolenic acid) as recommended to the
experimental group, soybean oil (7%), and flaxseed oil (50%
-linolenic acid). The even more highly unsaturated fatty
acids in fish oils are also of the n-3 class of essential fatty acids.
The authors make the telling point that clinical dietary trials that
lowered saturated fatty acids and raised PUFA intake in an effort to
lower cholesterol failed to improve the overall clinical
prognosis of their experimental groups; only the trials that also
lowered intake of n-6 PUFAs and increased n-3 fatty acids successfully
lowered cardiovascular and all-cause mortality in the
experimental cohort.
4. With the high costs of drugs and invasive procedures, which are the mainstay of management of CHD in the United States, promotion of the experimental diet could lead to very considerable savings in the cost of health care.
5. Because there has been considerable morbidity and some mortality from drug and invasive management of CHD, these adverse effects of current treatments could be largely avoided by an effective dietary approach.
6. The authors' plea for a large-scale prevention trial based on the dietary modifications pursued in this trial deserves attention. I would not, however, follow their suggestion that the possible additional benefits from adding drug therapy to their experimental diet be tested, at least not until the full benefits from their experimental program alone are carefully assessed in their own right.
The reason why secondary prevention trials like this one are so useful in testing the efficacy of potentially beneficial programs is that they limit the subjects for study to those already marked for a high incidence of adverse outcomes and eliminate from the study those in the population who are destined to avoid the adverse effects of CHD. Thus, smaller numbers of subjects and much lower costs are required to demonstrate significant benefits than is true when a population-based primary prevention trial is attempted. In the case of CHD risks, however, beneficial results may be extrapolated to the entire population in Western industrialized countries, in which nearly 50% of the population is fated to die of cardiovascular diseases. Because most of us do not know for certain into which 50% of the population we fall, all would be prudent to adopt dietary habits similar to those promulgated in this trial, especially if the striking benefits are confirmed.
Although the authors indicate some deficiencies in their study, it is nevertheless clearly a thorough, serious, and rigorous effort, within the almost unavoidable limitations of dietary studies in free-living populations, and it was conducted very successfully. There were many differences between the control and experimental diets, as the authors indicate, and purists will complain. However, it is necessary to first show a beneficial effect of a diet before embarking on a dissection of the differences to learn which might be providing possible causative roles. Furthermore, anyone seeking a single causative agent for CHD is undoubtedly chasing a will-o'-the-wisp. As a piece of evidence, this study is certainly superior scientifically (and nutritionally) to the soft pap we are constantly being offered from most epidemiological studies.
The many differences between the diets of the control and experimental
groups indeed confound any attempts to assign a singular role to the
-linolenic acid that is highlighted in this study. However,
numerous publications have reported biochemical and
physiological effects of the n-3 class of essential
fatty acids in humans and animals that would be expected to prevent or
ameliorate CHD (for reviews, see References 6 through 86 7 8 ). In addition,
studies have reported potent antiarrhythmic effects of long-chain
PUFAs, especially of the n-3 class, manifested by prevention of
ischemia-induced fatal ventricular
arrhythmias in rats, marmosets, and dogs, and there is
suggestive evidence that these n-3 fatty acids may prevent sudden
cardiac death in humans. This has been the focus of research by my
laboratory group, who have found that a concentrate of free fatty acids
of fish oils, but also the pure individual n-3 PUFAs
eicosapentaenoic acid (EPA), docosahexaenoic
acid (DHA), and -linolenic acid (LNA), all prevent
fatal ventricular arrhythmias in a reliable dog
model of sudden cardiac death with a very high
probability.9 10 11 We have found the mechanism for this
protection to result from the
electrophysiological effects of the free,
nonesterified, PUFAs when they are simply partitioned into the
phospholipids of the sarcolemma without covalently bonding to any
constituents in that cell membrane.12 Once
covalently incorporated into the phospholipids of the cell membrane,
they are no longer antiarrhythmic until they are liberated again as
free fatty acids13 in the sarcolemma by
phospholipases, a lipolytic action that occurs promptly with increased
sympathetic activity, as with ischemia, unusual physical
effort, or emotional stress. The presence of the free form of the PUFAs
partitioned in the hospitable hydrophobic milieu of the acyl chains of
phospholipid membranes stabilizes each contractile
cardiomyocyte, ventricular and atrial,
electrically by requiring a stronger electrical stimulus just to elicit
an action potential and markedly prolonging the relative refractory
period of the myocytes.14 These effects in turn
result from an action of the PUFAs to modulate ion currents in the
myocyte sarcolemma. The currents due to several ions are affected, but
so far it seems that the very potent inhibitory effects of
the PUFAs on the fast sodium current,
INa,15 16 and the
L-type calcium current,
ICa,L,17 are the
major contributors to their antiarrhythmic actions in ischemia,
whereas the inhibition of the ICa,L may be
of major importance in preventing triggered arrhythmias caused
by excessive cytosolic calcium fluctuations.17
The effects of the PUFAs are to shift the steady-state inactivation
potential to more negative values. Once we knew that the PUFAs were
affecting ion currents in the heart, an excitable tissue, we suspected
that they must be affecting all excitable tissues, which all use the
same electrical communicating system—and they do. We have found very
similar effects on INa and
ICa,L in hippocampal
neurons18 and an anticonvulsant effect in an
electrical threshold model of epilepsy in rats.19
Much more remains to be learned about how these fatty acids interact
with the ion channel proteins to produce these effects, but the
findings increase our appreciation of the potential
cardiovascular benefits that these PUFAs may offer.
The initial report of the Mediterranean -linolenic acid diet
recorded a complete prevention of cardiac sudden death in the 302
subjects in the experimental group but 8 deaths in the 303 subjects on
the control diet.1 This effect of the diet was
perhaps supported by the finding of an increased concentration of n-3
PUFAs in the plasma lipids of the experimental compared with the
control groups. Although prevention of sudden cardiac death may be
contributing to the striking reduction in mortality in the present
report, the numbers are small, as the authors note, and this effect
seems not to account for the total benefit, for 2 reasons. First, the
overall reduction of mortality of 70% reported exceeds the percentage
of deaths, 50% to 60%, reported to occur within 1 hour of acute
myocardial infarction,4 and the total
cardiovascular deaths in this study were not limited to
sudden cardiac deaths after acute myocardial infarctions. Second, the
study reports markedly beneficial effects on nonfatal
cardiovascular morbidity, which must be attributed to
other effects of the diet (antiatheromatous?) rather
than its antiarrhythmic effects.
In conclusion, we should anticipate that as research increases our
understanding of the pathogenesis of coronary
atherosclerosis, it will reveal to open and alert minds
many possibilities for preventing this now ubiquitous malady of CHD.
Many factors in this polygenetically based disease are interacting with
other internal and exogenous factors to cause expression of the
manifest disease state. Dietary factors must be very important, and
this study shows that they extend beyond cholesterol. As
stated, the role of n-3 PUFAs was important in the strikingly
beneficial outcomes in the experimental group. In a study included in a
published talk,20 Professor P.C. Weber and I
attempted to use the method of environmental medicine to examine the
diets of our forebears during the 2 to 4 million years that our genes
were being adapted to the environment. During all but the last 10 000
to 15 000 years (too short a period to permit genetic adaptations),
our forebears subsisted as hunter-gatherers. During that long period of
adaptation, our estimates suggest total dietary fat to be 20% of
energy, with saturated fat perhaps 7% to 8%, and the n-6 and n-3
classes of PUFAs slightly lower, with a ratio of n-6 to n-3 PUFAs of
perhaps 4 to 3. With the onset of the Industrial Revolution, saturated
fatty acids rose dramatically with the increased availability of red
meat and hydrogenation of PUFAs, largely for margarine. The plant-based
n-6 fatty acids also have increased as the public has been repeatedly
admonished to increase intake of PUFAs. Meanwhile, the n-3 fatty acids
have been largely disappearing from our diets in Western industrialized
countries, so that the ratio of n-6 to n-3 PUFAs is now estimated to be
15 to 1. Today, we are not surprised to recognize that nature has
adapted the n-6 PUFAs to important cell regulatory functions via the
arachidonic acid cascade, whereas we seem to be
surprised, to the level of disbelief, by the possibility that the n-3
class of essential fatty acids has also been adapted over the same long
time period to other essential regulatory functions, which in several
important ways balance or block the excesses of too much n-6 PUFAs, eg,
the effects of arachidonic acid
cyclooxygenase metabolites on platelet
aggregation and arteriolar vasoconstriction, the effects of
lipoxygenase metabolites of arachidonic
acid on the proinflammatory leukotrienes, and the
proarrhythmic effects of the cyclooxygenase
metabolites of arachidonic acids (except prostacyclin)
but not of the cyclooxygenase metabolites of
eicosapentaenoic acid.20
I suspect that we are just beginning to scratch the surface of the
potential biological importance to health and disease of the n-3 class
of essential PUFAs.
Acknowledgments
Studies performed in the author's laboratory were funded in part by grant DK38165 from NIDDK of the National Institutes of Health. Additional references are cited in the report of de Lorgeril et al.1
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
de Lorgeril M, Salen P, Martin J-L, Monjaud I,
Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and
the rate of cardiovascular complications after
myocardial infarction: final report of the Lyon Diet Heart Study.
Circulation. 1999;99:779–785.
2. de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin J-L, Monjaud I, Guidollet J, Touboul P, Delaye J. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;143:1454–1459.
3.
Lipids Research Clinics Program. The Lipid Research
Clinics Coronary Primary Prevention Trial Results, I: reduction
in incidence of coronary heart disease. JAMA. 1984;251:351–364.
4. American Heart Association. Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 1998.
5.
Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults. Summary of the second
report of the National Cholesterol Educational Program
(NCEP). JAMA. 1993;269:3015–3023.
6. Leaf A, Weber PC. Cardiovascular effects of n-3 fatty acids. N Engl J Med. 1988;318:549–557.[Medline] [Order article via Infotrieve]
7.
Simopoulos AP. -3 fatty acids in the
prevention-management of cardiovascular disease.
Can J Physiol Pharmacol. 1997;75:234–239.[Medline]
[Order article via Infotrieve]
8.
Leaf A, Kang JX. 3 fatty acids and
cardiovascular disease. World Rev Nutr Diet. 1998;83:24–37.[Medline]
[Order article via Infotrieve]
9.
Billman GE, Hallaq H, Leaf A. Prevention of
ischemia-induced ventricular fibrillation by n-3
fatty acids. Proc Natl Acad Sci Uß A. 1994;91:4427–4430.
10. Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturated fatty acids. Lipids. 1997;32:1161–1168.[Medline] [Order article via Infotrieve]
11. Billman GE, Kang JX, Leaf A. Prevention of fatal ischemia-induced ventricular arrhythmias by dietary pure n-3 polyunsaturated fatty acids in dogs. Circulation. 1999;99. In press.
12.
Kang JX, Leaf A. Effects of long-chain polyunsaturated
fatty acids on the contraction of neonatal rat cardiac myocytes.
Proc Natl Acad Sci U S A. 1994;91:9886–9890.
13. Weylandt KH, Kang JX, Leaf A. Polyunsaturated fatty acids exert antiarrhythmic actions as free acids rather than in phospholipids. Lipids. 1996;31:977–982.[Medline] [Order article via Infotrieve]
14.
Kang JX, Xiao Y-F, Leaf A. Free, long-chain,
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neonatal rat cardiac myocytes. Proc Natl Acad Sci U S A. 1995;92:3997–4001.
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16.
Xiao Y-F, Wright SN, Wang GK, Morgan JP, Leaf A. n-3
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