Nutrient Interaction in Heart Disease: An Interview With Dr. David Kritchevsky:
by Richard A. Passwater, Ph.D.
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 Physics.
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 are generated.
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 disease.
Passwater: What is the main evidence of the benefits of antioxidant vitamins?
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.
1. Preparation of tritiated cholesterol. Kritchevsky, David; Biggs, M. W. and Freeman, N. K. Univ. Cal. Rad. Lab. Rep. 644:1-5 (1950)
2. Distribution of radioactivity in the egg after feeding sodium acetate-1-C14. Kritchevsky, David; Grau, C. R.; Tolbert, B. M. and Kreuckel, B. J. Proc. Soc. Exp. Biol. Med. 76:741-3 (1951)
3. Observations with radioactive hydrogen (H3) in experimental atherosclerosis. Biggs, M. W. and Kritchevsky, David Circul. 4:34-42 (1951)
4. Effect of cholesterol vehicle in experimental atherosclerosis. Kritchevsky, DAvid; Moyer, A. W.; Tesar, W. C.; et al Amer. J. Physiol. 178:30-2 (1954)
5. The initiation and growth of tumors. Introduction I. Effects of underfeeding. Tannenbaum, A. Amer. J. Cancer 38:335-50 (1940)
6. Beziehungen zwischen ernahrung und tumorwachstum. Moreschi, C. Z. fur Immunitatsforsch. 2:651-75 (1909)
7. Experimental atherosclerosis in rabbits fed cholesterol-free diets. Kritchevsky, David J. Atheroscler. Res. 4:103-5 (1964)
8. Factors affecting atherosclerosis in rabbits fed cholesterol-free diets. Kritchevsky, David and Tepper, S. A. Life Sci. 4:1467-71 (1965)
9. Experimental atherosclerosis in rabbits fed cholesterol-free diets: Influence of chow components. Kritchevsky, David and Tepper, S. A. J. Atheroscler. Res. 8:357-69 (1968)
10. Uber die veranderung der Kaninchenaorta bei experimenteller cholesterinsteatose. Anitschkow, N. Beitr. Pathol. Anat. Allg. Pathol. 56:379-404 (1913)
11. Cholesterol. Kritchevsky, David John Wiley & Sons, NY, 291 pp. (1958)
12. Serum cholesterol and coronary artery disease. Gertler, M. M.; Garn, S. D. & White, P. D. Circulation 2:696-702 (1950)
13. Auto-oxidation of methyl linoleate: Effect of sex hormones and of nicotinic acid and related compounds. Kritchevsky, David and Tepper, S. A. Proc. Soc. Exp. Biol. Med. 115:841-3 (1964)
14. High stored iron levels are associated with excess risk of myocardial infarction in Eastern Finnish Men. Salonen, Jukka T.; et al Circulation 86:803-811 (1992)
15. Aortic sudanophilia and zinc-copper ratios in the livers of Vervet monkeys fed different types of fiber. Klevay, L. M.; Mendelsohn, D.; Vander Watt, J. J.; Davidson, L. M. & Kritchevsky, D. S. Amer. Med. J. 59:605-6 (1981)
16. Dietary fat and cancer trends -- a critique. Enig, Mary G.; Munn, R. J. and Keeney, M. Fed. Proceed. 37(9):2215-20 (Jul 1978)
17. Elaidic acid: Effect on experimental atherosclerosis. Weigensberg, B. I.; McMillan, G. C. & Ritchie, A. C. Arch. Pathol. 72:126-34 (1961)
18. Elaidinized olive oil and cholesterol atherosclerosis. McMillan, G. C.; Silver, M. D. & Weigensberg, B. I. Arch. Pathol. 76:106-12 (1963)
19. Influence of trans-unsaturated fats on experimental atherosclerosis in rabbits. Ruttenberg, H.; Davidson, L. M.; Little, N. A.; Klurfeld, D. M. & Kritchevsky, David J. Nutr. 113:835-44 (1983)
20. Effect of dietary trans fatty acid on high-density and low-density lipoprotein cholesterol levels in healthy subjects. Mensink, R. P. & Katan, M. B. N. Engl. J. Med. 323:439-45 (1990)
21. Herman Award Lecture, 1992: Lipid nutrition -- a personal perspective. Kritchevsky, David Amer. J. Clin. Nutr. 56:730-4 (1992)
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