In the past few months, I have been trying to update you on the latest
research in heart disease. This month I want to share with you the insights
of one of the world's leading researchers. I have been following Dr. David
Kritchevsky's research since about 1972 when my interests expanded from
free radicals and the aging process to free radicals and heart disease.
I was not impressed by the popular conclusions about cholesterol and heart
disease, and I found the teachings of Dr. Kritchevsky to be very enlightening.
If you are not already familiar with Dr. Kritchevsky's research, it would
take me every page in the rest of the magazine to relate his major contributions.
The following should suffice to tell you something about the impact this
scholar and true gentleman has had on our understanding of biochemistry.
Dr. Kritchevsky was the Associate Director of The Wistar Institute from
1975-1991, where he is still a professor.
He is also a professor at the University of Pennsylvania and adjunct professor
of the Medical College of Pennsylvania.
Dr. Kritchevsky is a consultant to the FDA, served on the Food and Nutrition
Board of the National Academy of Sciences from 1976-1980, and on the Dietary
Guidelines Advisory Committee of the USDA from 1983-1985, and has served
on various NIH Advisory Committees.
Dr. Kritchevsky is the Consulting Editor to Atherosclerosis, and
is on the editorial boards of ten journals (including Journal of Nutritional
Biochemistry, Nutrition Research, and Progress in Food & Nutrition Science),
and has served on past editorial boards of twelve other scientific journals
(including the American Journal of Clinical Nutrition, Journal of Nutrition,
Nutrition Reports International and The Professional Nutritionist),
and the editorial advisory boards of five others. He has authored several
books and is the series editor for eight series of scientific monographs.
Dr. Kritchevsky's major awards include the following: 1962-Research career
award from the National Heart Institute; 1974-Borden Award in Nutrition,
American Institute of Nutrition; 1977-Philadelphia award, American Chemical
Society; 1978-American College of Nutrition Outstanding Achievement award;
1992-Herman Memorial award, American Society for Clinical Nutrition.
Passwater: Dr. Kritchevsky, you have published at least 300
articles on diet and health. Most of them seem to be involved in the area
of fats, fiber, calories, cholesterol, and antioxidants as they pertain
to cancer and heart disease. What aroused your interest in this research?
Kritchevsky: I began my scientific life as a straight organic
chemist. I was in Switzerland on a post-doctorate and working on steroid
chemistry when the cholesterol field became active. I was recruited to Berkeley
to synthesize radioactive cholesterol, which I did. [1,2] I was working
with Max Biggs, an unusually capable MD, who was going for a Ph.D. in Medical
The radioactive cholesterol was fed to rabbits and people and I became interested
in its fate.  This led me into other phases of lipid (fat) chemistry
and biochemistry. I believe my colleagues and I did (in 1954) the first
study of saturated versus unsaturated fatty acids vis--vis atherosclerosis
in rabbits.  As the work went on, it became evident to me that all nutrients
should be studied as a unit, since they interact. This is what I have been
trying to do.
My interest in fiber effects in atherosclerosis (1964) led to work on fiber
and bile acids which got me invited to cancer conferences. The work on calories
arose when I became tired of hearing fat-bashing in the cancer field recalling
Tannenbaum's work in the 1940's.  I later discovered that calorie-restriction
studies went back to 1909. 
Passwater: You are being overly modest in linking your ideas
to those of others in the distant past. Your research has always been at
the leading edge. You are not a follower of the standard party line of popular
theories, but you lead into new thought and new directions even when the
established views are deeply entrenched. How do you explain your ability
to see things more clearly than many of your colleagues? Is it that you
didn't find the existing lines of research totally convincing or did you
see new leads early?
Kritchevsky: This is an embarrassing question to answer. I
don't know that I see things more clearly, but I may see them differently.
Perhaps it's due to nervousness concerning pat answers. I have asked myself
why does this happen? What's different? This leads to going into side excursions
which make for interesting and (to me) exciting studies, but it also leads
to some difficulties in obtaining funding.
One example: In the late 1950's, two papers reported that there had been
establishment of atherosclerosis in rabbits by feeding saturated fat and
no cholesterol. I was one of many researchers who had fed saturated fat
to rabbits for as long as a year without affecting either cholesterolemia
or atherosclerosis. So these reports piqued my interest as to the discrepancy.
I collated the available literature and found that saturated fat was without
effect when added to a commercial diet, but was indeed atherogenic when
fed as part of a semi-purified diet. Since the fat was the same, it had
to be something else, and I speculated that it was the fiber. I put this
in a letter to the editors of the Journal of Atherosclerosis Research
and it took an awfully long time to get it published.  We later proved
the hypothesis. [8,9] To paraphrase Claude Bernard -- When the experts
say A and your data say B -- go with the data. Or as Wilson Mizner
said, "I respect faith, but it is doubt that gets you an education."
Passwater: Yes, it seems that all new ideas have trouble getting
funding -- even if you are Linus Pauling or David Kritchevsky. At least
you were able to get your ideas published eventually.
You did not seem to be enchanted with the old concept that dietary cholesterol
was the main cause of heart disease. Why weren't you convinced?
Kritchevsky: If it were as simple as dietary cholesterol equals
heart disease, the whole problem would have been resolved within a decade
after Anitschkow fed his first rabbit.  Data from so many sources suggested
to me that it had to be a problem in handling the cholesterol, rather than
one of ingestion. The very complicated nature of the disease was also impressed
on me when I wrote my book on cholesterol in 1958.  In 1950, a paper
by Gertler, Garn and White showed pretty clearly that dietary intake had
little to do with plasma cholesterol levels.  I think I'm the only one
who cites it.
Passwater: On the other hand, you do seem to see some credence
in a significant role for oxidized-LDL in heart disease. What are the primary
factors that make this theory attractive?
Kritchevsky: Science marches on the feet of methodology. The
possibility that oxidized lipids (fats) might play a role in atherosclerosis
was raised by a Danish scientist named Glavind in 1948. (or thereabouts)
Current research on oxidized LDL is exciting, but we need more demonstrations
of in vivo effects. Science advances with new research on new hypothesis.
Whether the hypotheses are true or not, a lot of new data and new ideas
As a side note to the current interest in the role of oxidized lipids and
lipoproteins, in the 1960's, we were interested in the effects of sex hormones
on linoleate oxidation. The studies were crude by current standards, but
the data suggested that estrogens inhibited oxidation compared to other
steroids.  This could have relevance to male/female differences in coronary
Passwater: What is the main evidence of the benefits of antioxidant
Kritchevsky: To date the bulk of the evidence on the effects
of antioxidant vitamins in both cancer and heart disease comes from epidemiological
data. Experiments are being proposed and possibly in progress to test the
hypothesis, but I'm not aware of many compelling data. The idea of the effects
of antioxidant vitamins illustrates the complexity of nutritional research
since we still aren't sure of what does the trick or which of the many sources
is the ideal one. As T. H. Huxley said: "The tragedy of science is
the slaying of a beautiful hypothesis by an ugly fact."
Passwater: Speaking of the complexity of nutritional research,
a recent Finnish study implicates the excess of the mineral iron in heart
disease.  Many people are now concerned about the possible role of this
pro-oxidant in heart disease. What advice would you offer people at this
stage of our knowledge?
Kritchevsky: The role of iron in heart disease? First, let's
wait for confirmation. Second, there is undoubtedly a range of benefit and/or
safety. One of the difficulties with all the trace minerals is that the
line between necessity and toxicity is not as wide as it is for macronutrients.
While the Salonen data are provocative, the ferritin levels cover an unusually
wide range (166 +- 149 micrograms per liter) 
Passwater: How about copper? It could conceivably be a pro-oxidant
under certain conditions. Yet copper is needed for a key component of our
antioxidant defense system, the enzyme superoxide dismutase, and iron is
needed for the antioxidant defense enzyme, catalase. You have published
research on the zinc-to-copper ratio. Would you comment on the most sensible
approach with dietary copper and zinc?
Kritchevsky: I have published one (count it) one paper on
the zinc/copper ratio, and that was with Dr. Les Klevay who knew we had
samples of tissue from a primate study and offered to do the analysis. 
I can't come up with a sensible approach to dietary copper and zinc except
for what has been my approach to diet in general -- moderation not martyrdom.
Everyone now seems to be joining the BMV club -- balance, moderation, variety.
Passwater: Speaking of balanced diet, have you given thought
to the possible role of antioxidant nutrients beyond basic nutritional needs
-- such as possible prophylactic uses in limiting excesses of free radicals?
Kritchevsky: You have raised a good point and it may get down
to a semantics question. Nutritionists become apprehensive when people talk
about high doses of vitamins. This is due, in part, to the fact that vitamins,
as catalysts, act in minute quantities. At higher levels they are really
pharmacological agents which are being ingested at pharmacologic doses.
So that when you talk about intermediate metabolism, it's vitamin C; but
at quantities suggested for the common cold, for instance, it should be
called ascorbic acid.
Passwater: You have also discussed trans fats in your research
publications. Dr. Mary Enig of the University of Maryland used to stop off
at the Solgar Nutritional Research Center and study the latest literature
on vitamins while her family visited the beach, and she would tell me interesting
things on trans fats. Her research group was having trouble getting funds
for trans fats research. Would you tell us a little about trans fats --
what they are and their possible adverse effects?
Kritchevsky: Trans fats (by which we mean fats containing
trans unsaturated fatty acids) have been studies since 1960. [16,17] In
general and until recently, the best advice has been to regard them as quasi-saturated
fats. In rabbits, for instance, they have been shown to raise cholesterol
levels but do not increase the severity of atherosclerosis.  Generational
studies in rats have also shown no adverse effects. The new studies
in man show trans fat to lead to a small increase in total and LDL cholesterol.
Two new factors have arisen -- one, that they also lower HDL, and the other,
that they may raise Lp(a). That is worrisome. [19,20]
The major studies, to date, have been carried out in the Netherlands using
levels of trans fat that are considerably higher than those ingested in
the USA. There are ongoing American studies and those results will be of
great interest, especially as they relate to Lp(a) levels.
Passwater: In your 1992 Herman Award Lecture, you made an
interesting review of the popular thinking about dietary fats and heart
disease.  You stated that "since 1950 we have gone from believing
that the amount of dietary fat was the primary stimulus for hyperlipidemia
to looking at amounts of saturated and unsaturated fatty acids in the diet.
Advice concerning recommended amounts of dietary unsaturated fatty acids
has gone from 'the more the better' to 'no more than one-third of total
fat energy.' This change was made with virtually no explanation." You
have found that specific fatty acids may have specific effects that can
be manifested in total cholesterolemia or lipoproteinemia. Where do you
see lipid research going?
Kritchevsky: We are at the threshold of reexamining the influences
of fats and specific fatty acids on apolipoproteins, mRNA concentrations,
and LDL receptors in addition to measurement of plasma lipids. In time,
we may again find that total fat is the main factor.
The field of lipoprotein research is expanding. Lipoproteins are defined
by their physical, not chemical, characteristics, and it is becoming evident
that agglomerates with the same density may differ in size or in composition.
The amount of esterified cholesterol in LDLs may influence its atherogenic
properties, and this may, in turn, be affected by the nature of the cholesterol
ester fatty acids. The size of lipoproteins particles within the same density
class appears to affect their metabolic pathways and research in polymorphism
of apolipoproteins is yielding new explanations for lipoprotein effects.
New discoveries and possibly alterations in hypothesis lie ahead.
Passwater: And many people thought that heart disease was
simply a matter of eating too much cholesterol. I think you have adequately
shown that heart disease and diet is a complex issue and that you have much
more research to do for us all. We will be eagerly awaiting your publications.
Thanks for giving us an insight into your outstanding research.