By Richard A. Passwater, Ph.D.
The homocysteine theory of arteriosclerosis has finally been widely accepted in the scientific and medical communities. The implications of this theory are of great importance for reducing the risk of heart disease, cancer and other serious health problems. Dr. Kilmer McCully is the brilliant medical detective who elucidated this theory and directed its development over the years.
Dr. McCully has written an exciting account of his research that is being confirmed in study after study every month, along with the intrigue of being chastised for original thinking at a time when a large number of researchers were profiting from the cholesterol bandwagon. His book, "The Homocysteine Revolution," [Keats Publishing, 1997] has helped the media to finally notice the strength of his research and its health implications. Since this interview took place, Time, Newsweek, New York Times, The Today Show and 20/20 have also published or scheduled interviews. Quite a turn around for a researcher upon whom Harvard once turned its collective back.
For that very reason, I want to emphasize the wide and thorough training of Dr. McCully. Dr. McCully is a graduate of Harvard College in 1955 and Harvard Medical School in 1959, where he received degrees in chemistry, biochemistry and medicine. Following his internship in internal medicine at Massachusetts General Hospital, he received fellowship training in biochemistry, molecular biology, and genetics at National Institutes of Health, Massachusetts General Hospital, Glasgow University in Scotland and Harvard University. Following his residency in pathology at Massachusetts General Hospital, he became Associate Pathologist and Assistant Professor of Pathology at Harvard Medical School. Additional appointments were Visiting Professor of Laboratory Medicine at University of Connecticut and Associate Professor of Pathology at Brown University. He has served as a pathologist at the Veterans Affairs Medical Center in Providence since 1981.
Dr. McCully's discovery elucidates how deficiencies of certain B-complex vitamins can lead to a build up of an undesired amino acid in the blood. The homocysteine - heart disease relationship does not involve eating too much homocysteine or taking supplements of homocysteine, but optimizing dietary intake of vitamins B-6, B-12 and folic acid (folate).
Passwater: Do elevated blood levels of the amino acid homocysteine cause a separate type of heart disease or is it involved in "typical" heart disease?
McCully: Homocysteine causes the most common form of heart disease as seen in human populations, that is arteriosclerotic heart disease. Homocysteine was discovered to cause the fibrous and fibrocalcific plaques in children with homocystinuria (a rare biochemical abnormality characterized by the abnormal presence of homocysteine). It has now been implicated in the most common form of coronary heart disease in the human population.
Passwater: How does elevated homocysteine compare to elevated cholesterol for predicting or explaining common coronary heart disease?
McCully: Elevation of the homocysteine level in the blood is an independent risk factor for coronary heart disease and arteriosclerosis. What this means is that regardless of the cholesterol level, if the homocysteine level is elevated, it is associated with increased risk of arteriosclerosis and coronary heart disease. On the other hand, it is also well known that elevated cholesterol levels, particularly as carried in the low-density lipoprotein (LDL) fraction are associated with increased risk of arteriosclerosis and coronary heart disease.
Passwater: Let me repeat part of what you said to further clarify the term "independent risk factor." Some people seem to be confused by this term. This does not mean that homocysteine is the cause of another "independent" form of heart disease, but that homocysteine is a risk factor for the typical form of heart disease independent of the blood cholesterol level. Correct?
McCully: Yes, homocysteine causes coronary heart disease by injuring the lining of the coronary arteries and by thickening of the wall of the arteries, regardless of the level of cholesterol in the blood. Perhaps this diagram will help show this point.
Passwater: Have you been able to find out just how homocysteine can damage artery linings?
McCully: As I published in my second monograph in 1994, homocysteine theoretically interferes with the way cells use oxygen, resulting in a build-up of damaging free radicals. These reactive chemical forms can oxidize low-density lipoproteins (LDL), producing oxycholesterols and oxidized fats and proteins within developing plaques. Also, homocysteine stimulates growth of smooth muscle cells, causing deposition of extracellular matrix and collagen, which causes a thickening and hardening of artery walls.
Passwater: Well, I am glad to hear the part about the involvement of oxidation of LDL. This is where antioxidants such as vitamin E come into play to reduce the free-radical damage and the oxidation of LDL. You described how homocysteine injures arteries. Does it do any other harm?
McCully: As we understand it at the present time, homocysteine is involved in virtually all of the pathogenic processes that result in arteriosclerotic plaques. It is crucially involved in blood clotting. Blood platelets, the smallest cells in blood, are a major factor in the clotting process. When clots form in a coronary artery the blood supply to the heart itself is reduced or stopped. This is called a coronary thrombosis which results in the death of heart tissue which is called myocardial infarction. Homocysteine in its reactive form, homocysteine thiolactone (see figure 3), affects the reactivity of platelets and is extremely active in causing platelet aggregation which can lead to clot formation. When freshly synthesized in test tube experiments, this form of homocysteine causes aggregation of normal human platelets.
Also, homocysteine causes the binding of lipoprotein (a) [Lp(a)] to fibrin in very low concentrations. Lipoprotein(a) has also been linked to the thrombotic events in coronary heart disease. In addition to these findings, homocysteine is involved in other important clotting factors including protein C, factor 7, factor 12, and other clotting factors. As far as the participation and the formation of the plaques is concerned, it is well demonstrated that homocysteine in vivo damages the endothelial cells which line the arteries of animals and causes a proliferation of the smooth muscle cells in the walls of the arteries. This damaging effect can also be demonstrated in cell cultures of endothelial cells. Homocysteine also has the ability to stimulate the growth of cultured smooth muscle cells. The production of fibrous tissues of sulfated glycosaminoglycans and the destruction of elastin fibers in the wall of the artery lead to the formation of fibrous plaques. In addition to this, when homocysteine is given to the animals, and cholesterol and fats are fed in the diet simultaneously, the lesions in the arteries accumulate a great deal of fat and cholesterol, producing fibrolipid plaques.
Passwater: Aside from homocysteine being an independent risk factor, is there any relationship, dependent or otherwise, between the blood levels of homocysteine and cholesterol?
McCully: In a few studies published in the literature, there is a weak correlation between elevated homocysteine and elevated cholesterol levels, but this is not seen in all studies. There are reasons to think that the LDL and cholesterol in the blood help to carry homocysteine to the cells and tissues of the artery where the damage is caused, leading to arteriosclerotic changes. So, the two substances appear to work together in the pathogenic process.
Passwater: Is one more important than the other? Is an elevated homocysteine level a greater predictor of heart disease risk than an elevated cholesterol?
McCully: The majority of patients who have severe coronary heart disease and arteriosclerosis have cholesterol levels in the normal range. I did a study of our Providence Veterans population in 1990 and I analyzed just this point. In a consecutive series of 194 autopsies, the degree of arteriosclerosis was carefully assessed based on the autopsy findings. The records were then examined for the cholesterol levels in these veterans who had died. It was very surprising to me to find that in the group with the most severe coronary heart disease about 85 percent of these veterans had levels lower than 250 milligrams per deciliter. Only about 15 percent had distinctly elevated cholesterol levels above 250, and the mean level for that group was 186 milligrams per deciliter, well within the recommended guidelines of several of the major agencies. In looking at the group as a whole, among those with severe arteriosclerosis, about two-thirds of the veterans had no evidence of elevated cholesterol, diabetes, or elevated blood pressure.
Passwater: You of course did not know what their homocysteine level was?
McCully: This was before a homocysteine test was widely available. There are more recent studies but I don't think any of them have addressed this exact point.
Passwater: What is the normal level of homocysteine for a middle-aged male and would he be at risk for heart disease if his homocysteine level were 50 percent above normal?
McCully: The normal level of homocysteine in the blood for a middle aged man is about 8 to 12 micromoles per liter, so a 50 percent increase in this would be up to 17 micromoles per liter. In different human studies, this level of homocysteine in the blood has been shown to be associated with an increased risk of development of myocardial infarction, as shown by the Physicians Health Study, and for thickening of the carotid arteries, as shown by the Tufts Nutrition Center and Framingham Heart study, and also for increased risk of coronary cerebral and peripheral vascular disease throughout the body.
Passwater: What causes homocysteine levels to build up?
McCully: There are many different factors that are related to elevation of the homocysteine level. As we understand it now, perhaps the single most important factor is a dietary imbalance between too much methionine from dietary protein and too little of the three B vitamins which are needed to break down or get rid of excess levels of homocysteine; namely vitamin B-6, vitamin B-12 and folic acid.
In addition to this dietary factor, genetic factors or inherited factors are extremely important. It has been estimated that as many as one out of eight of the population in general carries a hidden genetic defect in a reductase enzyme that causes them to require more folic acid than normal people would require to prevent elevation of homocysteine levels. In addition to the dietary and genetic factors, we know that homocysteine is related to the aging process. Over the age of about 60 the homocysteine level increases about one micromole per liter for every ten years of age.
Moreover, homocysteine levels are controlled by hormones. A premenopausal woman has a level of about 2 micromoles per liter lower than men of the same age. Normal women have homocysteine levels of 6-10 micromoles per liter, compared to normal men of the same age who have 8-12. After the menopause, the level of homocysteine rises in the blood to approach that of men of the same age. Another very important hormonal relation is to thyroid hormone. In a chronic partial thyroid hormone deficiency, the homocysteine level can rise and lead to increased risk of vascular disease.
In addition to these other factors -- diet, genetic, aging and hormonal factors — there are toxic factors. Cigarette smoke for example. Smokers have a higher level of homocysteine than non-smokers. Exercise is also related to homocysteine. Those who exercise strenuously have a lower level of homocysteine than those who are sedentary. There are also a number of important drugs which can elevate the homocysteine level, such as methotrexate, nitrous oxide, and azaribine.
Passwater: Let's focus on the dietary component. What levels of B-6, B12, and folic acid are recommended for minimizing homocysteine levels?
McCully: The best evidence in the literature indicates that 350-400 micrograms a day of folic acid is required to keep the homocysteine level in the normal range. As far as vitamin B-12 is concerned, most members of the population consume adequate vitamin B-12, about 5 - 15 micrograms per day. In the elderly, absorptive problems may cause a marginal vitamin B-12 deficiency. In the case of vitamin B-6, there is perhaps a little less certainty about the exact figure. The current RDA for vitamin B-6 is 2 milligrams per day but in the elderly cohort of the Framingham survivors, approximately 30-40 percent of them had an intake that was significantly lower than the RDA, in the range of 1.6 to 1.7 milligrams per day. Now, in extrapolating from the data of Dr. James Rinehart on vitamin B-6 deficiency in monkeys, he found that in order to prevent arteriosclerotic plaques in these experimental animals (monkeys), he had to give the equivalent of about 3.5 milligrams per day of vitamin B-6 to prevent arteriosclerosis. I think the current RDA of 2 milligrams per day is too low and should be 3.5 milligrams per day, based on Rinehart's studies and the Framingham studies.
Passwater: How about individuals who have had poor diets and aren't aware of this association, would it benefit them to take supplements that are higher in order to make up for lost time? How about if a woman has the reductase enzyme abnormality and doesn't know it? Would larger amounts than you just mentioned be of value to anyone?
McCully: Well, I think that in a person who has a history of chronic nutritional depletion and nutritional abuse, such as a chronic alcoholic, higher levels of these vitamins given as supplements may be helpful. These vitamins are quite non-toxic. In spite of the fact that there is some question about folic acid masking vitamin B-12 deficiency, this is quite a rare occurrence and does not ordinarily happen — happens only in a minuscule fraction of the people who receive folic acid. Giving folic acid in the range of 1 milligram per day is probably entirely safe for all but a tiny fraction of the population. In the case of vitamin B-6, there have been claims that rarely when megadoses of vitamin B-6 are given (1 - 2 grams per day), a few individuals can experience mild sensory neuropathy. This is a very rare occurrence since in extensive studies with vitamin
B-6 in thousands of patients by Dr. John Ellis of Texas, levels of 50 to 200 milligrams per day were given safely without any cases of peripheral neuropathy. Vitamin B-6 in this dose range is very well-tolerated, safe, and non toxic. Vitamin B-12 is also quite safe. In cases of prolonged, severe nutritional depletion and nutritional abuse, I think that supplements do have a role in helping to replete the body's supply. B-vitamins of course are water soluble and any excess vitamin beyond the body's requirement is excreted quite rapidly in the urine.
Passwater: Would you include smokers in your category of nutritionally deprived?
McCully: Smokers have subjected themselves to hundreds of toxic compounds that are known to be present in cigarette smoke. Probably the most important of these toxic compounds is carbon monoxide which combines with vitamin B-6 to inactivate pyridoxamine phosphate, one of the active co-enzymes for many different enzymes in the body. It has been shown quite clearly that smokers tend to have a lower level of vitamin B-6 and they have a higher requirement for vitamin B-6. In smokers a case can be made for increasing the vitamin B-6 intake through supplementation.
Passwater: How important are dietary methyl donors, such as trimethylglycine (betaine)?
McCully: Methyl donors have been studied mainly in experimental animals. For example in choline-deficient rats, the homocysteine level in the blood rises. In addition to that, it is well known that there is an alternative pathway for conversion of homocysteine to methionine in man involving betaine. This methyl donor function of betaine has a supplementary action in lowering elevated homocysteine levels both in chronic renal failure and also in patients with homocystinuria. The exact role of these methyl donors in human populations in controlling homocysteine levels is really largely unknown at the present time.
Passwater: Will these inexpensive nutrients protect against heart disease more effectively than expensive cholesterol lowering drugs?
McCully: We anticipate that this approach to controlling homocysteine levels will be successful in prevention of vascular disease and the catastrophic complications of vascular disease, heart attack, stroke and gangrene. However, at the present time, there are no prospective studies that have been published to demonstrate this effect conclusively. These studies are desperately needed. What we have at present are just a few tantalizing clues to suggest that this approach may be successful in the future. One of the first clues was obtained from treating patients with homocystinuria with large doses of vitamin B-6. About half of these patients with the most common form of this disease respond quite well to vitamin B-6 in large doses. In studying the survivors of homocystinuria, it has been shown that this amount of vitamin B-6 will actually decrease the risk of thrombosis in vascular complications. So that is one clue.
The second clue is that in Dr. Ellis's patients with carpal tunnel syndrome, doses of vitamin B-6 in the range of 50-200 milligrams per day over a period of years, appeared to be associated with a 75 percent reduction in the risk of angina pectoris and myocardial infarction. Of course this was a retrospective study, and he compared his patients to other patients in the community who did not receive vitamin B-6.
The third tantalizing clue is that in the recently reported European Concerted Action Project on homocysteine from 16 medical centers in Europe found a small fraction of the 750 patients who took supplements appeared to have a two-thirds reduction in risk of vascular events (one-third of the normal risk). The researchers did not conclude that this was a definite finding because of the "small numbers" of individuals out of a total of 750 subjects studied. These are some tantalizing clues, but I must say the final evidence that lowering homocysteine levels will prevent vascular events has not been conclusively proven. However, I would project that this approach will in the future be found to have a larger effect on reduction of vascular disease risk than the cholesterol lowering drug therapy that is currently being promoted by the pharmaceutical companies.
Passwater: You had been reporting this relationship since 1969. What was your first clue?
McCully: The observation that led to this homocysteine approach was a discovery that children with this inherited disease, homocystinuria, have arteriosclerosis. The original index case was published in 1933. The patient was an 8-year old boy with dislocated lenses, some mild developmental abnormalities, and mental retardation. He was admitted to the hospital with symptoms and signs of a stroke and died of a stroke three days later. In the analysis of the case, the pathologist reported severe arteriosclerosis of the carotid arteries with thrombosis and cerebral infarction. This child appeared to have abnormalities of the arteries resembling the arteriosclerotic changes one ordinarily sees in an elderly individual. In reviewing a case of homocystinuria that was discovered at the Massachusetts General Hospital in 1965, the pediatricians were told by the mother of the child that the uncle of this little girl had died in 1933 of a similar disease in the same hospital. This was the case that I reviewed because it was from the pathology department where I was working.
I was intrigued by the appearance of the arteries which showed that these arteriosclerotic changes were scattered throughout arteries in other organs of the body. At the time it was known that children with homocystinuria had an increased risk of thrombosis, and the leading theory was that the platelets were abnormally reactive because of this genetic defect. However, in the illustration of these publications one could see changes in the arteries that resembled arteriosclerosis of the usual kind. It was plausible that homocysteine could somehow lead to these changes, but it was not entirely clear how this could happen. These previous authors did not interpret the arterial changes as arteriosclerosis.
Several months later I was fortunate enough to examine a two-month baby boy who had died of a different disease, also with homocystinuria. This little boy had a disease which we now know to be cobalamin C disease, an exceedingly rare genetic disease in which an abnormality of vitamin B-12 metabolism prevents the methylation or conversion of homocysteine to methionine. In this disease, cystathionine is also excreted in the urine. When I examined this case, I looked in the autopsy protocol for a description of the arteries. As described in my book, there was no description of any changes in the arteries. When I restudied this second case, I discovered that this two-month old infant had a form of rapidly progressive arteriosclerosis. Because of the different enzyme defects in these two children, I was able to conclude that the homocysteine itself was damaging the artery wall.
Several years later, a case was reported from Chicago in which there was a third enzyme defect that led to homocystinuria. In this case with methylenetetrahydrofolate reductase deficiency, the researchers found arteriosclerotic changes identical to the changes I had found in my two cases. From the study of these interesting cases, it is clear that the elevation of the homocysteine level in the blood damages the arteries regardless of any particular enzyme defect.
Passwater: Sherlock Holmes would be proud of your detective work. What was the reaction of the medical community to your first papers showing this?
McCully: I was astonished to receive 300 or 400 reprint requests within about a month or two of publishing my first paper. Evidently there were people all over the world who were looking for a new way to study arteriosclerosis and understand the genesis of this disease in the population. However, the current thinking at the time was that these arteriosclerotic changes were likely to be of importance only in these children with rare diseases. Furthermore, since the cholesterol level was normal in these children, the findings were not considered to be of importance in the population as a whole.
So for many years the theory was ignored by the vast majority of the medical community. Most investigators believed that cholesterol must somehow be involved in arteriosclerosis. It was clear that these children did not have abnormal cholesterol levels and furthermore the plaques in the arteries were of the fibrous and fibrocalcific type. Many investigators, therefore, felt that this causal relationship between homocysteine and vascular disease was not representative of the disease in the population as a whole. It wasn't until human studies began to show the atherogenic potential of mild elevations of homocysteine that the medical community began to pay attention to the significance of this theory.
Passwater: It's for that very reason that I constantly have been quoting your research over the years. Nearly everyone was pushing the cholesterol bandwagon, but that theory just had too many holes in it. Researchers could not pay attention to the major causes of heart disease if they would not look beyond the relatively minor factor. As you continued to publish on your clues and your theory, what was the reaction at Harvard?
McCully: The immediate reaction when I first started was supportive. I had a number of colleagues who were interested, and the chairman of my department was interested for a period of about five or six years. I was able to publish the basic elements of the theory until about 1975, when the chairman of my department retired. The new chairman informed me that I would have to support my work in some way but no he made no effort to help obtain this support. My laboratory was removed from the department to another part of the hospital. It was made clear to me that I should look elsewhere for support. The Director of the hospital told me that Harvard Medical School believed that I hadn't proven my theory. I left Harvard at the end of December of 1978 and came to Providence VA Medical Center in 1981 where I have worked ever since.
Passwater: What kept your new theory from dying on the vine? Did you continue publishing? Did others join in and if so, what piqued their interest?
McCully: I continued to work as best I could. There were also some crucial studies that were published by other investigators. I helped to plan the first human study by Drs. Bridget and David Wilcken of Australia. In 1976 they showed that patients with coronary heart disease had a higher elevation of homocysteine in their blood following an oral dose of methionine, compared with controls without coronary heart disease. This first small human study was very important.
Another important study in 1976 was reported from Seattle, Washington, in which the investigators showed that infusion of homocysteine into baboons caused arteriosclerotic plaques and thrombosis. Their results completely confirmed what I had already found by using subcutaneous injections of homocysteine in rabbits.
So, these were two crucial points. After that, I published my first review monograph on this subject in 1983. After 1984, other human studies began to be published from all over the world including reports from Sweden, Netherlands, Japan, Ireland, New York and other centers. These studies showed that patients with vascular disease on the average had higher homocysteine levels than those of normal controls. These human studies really began to set in motion a world-wide effort to follow up on the homocysteine theory of arteriosclerosis.
Passwater: It is interesting how the European physicians and researchers weren't so convinced about the cholesterol theory as the American researchers. About how many publications are there now that support your thesis?
McCully: It's incredible. There is a tremendous avalanche of publications. Now about 20 to 30 publications per month are being published. One estimate I saw is there are now over 1500 publications on homocysteine and vascular heart disease.
Passwater: When did it become generally accepted?
McCully: Around 1991 or 1992. An important study from Ireland was published in 1991 and the Physicians Health Study from the Harvard School of Public Health in 1992 showed the three-fold increase risk of heart attack associated with an elevated homocysteine level in 14,000 U. S. physicians.
Passwater: It's interesting that Harvard researchers finally saw the light about homocysteine as a risk factor. I hope they acknowledged that you were the founder of this concept.
McCully: The Harvard study in 1992 of the 14,000 U.S. physicians did not refer to my research on homocysteine. The important studies from the Tufts Nutrition Center and the Framingham Heart Study have consistently referred to my original article in 1969. An important meta-analysis study from the University of Washington, summarizing the results of 207 studies in the scientific and medical literature, cited my 1969 paper as the first reference. Other researchers have cited the chapter in the textbook, "The Metabolic Basis of Inherited Disease," which discusses homocystinuria and refers to my 1969 publication and two of my experimental reports from 1970 and 1975.
Passwater: Is homocysteine damage limited to heart disease or is it involved in other problems such as cancer, nerve damage, or birth defects.
McCully: The clearest evidence in humans is that homocysteine is involved in the increased risk of neural tube defects in children that are born to mothers who are deficient in folic acid. These folate-deficient mothers tend to have a higher level of homocysteine in their blood, and the amniotic fluid itself has a higher level of homocysteine than in those in mothers who have a normal folate intake.
In the case of cancer, it has been known for many years that there is an abnormality of methionine and homocysteine processing in cancer cells. In 1976 I published my first study in this field which showed that cultured malignant cells have a very specific abnormality of homocysteine thiolactone metabolism. Malignant cells are unable to convert homocysteine thiolactone to sulfate whereas normal cells do this very well. And as a result of this observation, I have spent a number of years trying to synthesize a homocysteine compound that I believe that is present in normal cells. This compound enables normal cells to process homocysteine thiolactone normally and is lost in malignant cells.
In these synthetic studies I have discovered a compound that is formed between homocysteine thiolactone and vitamin A acid (retinoic acid), a substance called thioretinamide. This substance is anticarcinogenic and antineoplastic in animal models. Furthermore, thioretinamide forms an additional complex with vitamin B-12, a substance known as thioretinaco. This compound is also anticarcinogenic and antineoplastic in animal models. We believe, as I published in my 1994 monograph, that the activation of this thioretinaco occurs through ozone oxidation of the sulfur atoms of homocysteine. This oxidation reaction may cause it to be a highly effective anti-cancer compound.
In addition to cancer and the birth defects, it has recently been found that homocysteine levels are elevated in rheumatoid arthritis. The report from the Tufts Nutrition Center shows that rheumatoid arthritis patients do have a significantly higher homocysteine level than normal controls. These patients also have an increased requirement of vitamin B-6, although vitamin B-6 therapy does not ameliorate their arthritis. In a study from England, immune lymphocytes that react to HLA antigens altered by homocysteine were found in rheumatoid arthritis patients.
Passwater: Did writing "The Homocysteine Revolution" (Keats 1997) for the general reader help bring your research to the attention of the public? After all, it's the public that stands to benefit from your research. They should know about it now, not wait for their physicians to learn about it.
McCully: Yes, I think so. I have wanted to write such a book for some time. The publication of all these recent epidemiological studies made it possible for me to explain the homocysteine approach in a way that was convincing to the average reader. I also wanted to convey the importance of the various factors that are known to control homocysteine in controlling vascular disease risk. One of the reasons I published the book is to try to explain to general readers how they could modify their own risks and how they could use this theory to help prevent the disease as they get older.
Passwater: Thank you for sharing some of the background of your exciting research with us. There is much more interesting information that will help everyone in your book, but we have only a few pages to hit some of the highlights here.
All rights, including electronic and print media, to this article are copyrighted to Richard A. Passwater, Ph.D. and Whole Foods magazine (WFC Inc.).