Homocysteine, a revolutionary look at arteriosclerosis (Pt. 1)
Dr. Kilmer S. McCully is credited with one of the major medical and scientific breakthroughs of this century. A graduate of both Harvard College and Harvard Medical school, in 1968 he opened a new field of medicine when he discovered homocysteine, a breakdown of dietary protein with many potential health risk factors. His research opened a new pathway of medical research that relates homocysteine to arteriosclerosis, cancer, aging, normal growth and development and the degenerative diseases of aging.
His accomplishments are many and worth noting: at Harvard University, he studied cholesterol biosynthesis and pregnenolone metabolism. He was appointed Research Associate in Biochemistry at National Institutes of Health, where he studied tRNA structure. In 1963 he won an American Cancer Society Faculty Research. He studied amino acid metabolism in the laboratory of James Watson, the discoverer of the DNA structure. During 1965-1968, he served as Clinical and Research Fellow in Pathology at Massachusetts General Hospital. During which, he studied protein synthesis in organ cultures of human tumors.
Following his residency in pathology, Dr. McCully began his study of homocysteine and vascular disease in 1968 in the Pathology Department at Massachusetts General Hospital. He won a Career Development Award from the National Institutes of Health from. He was appointed Associate Pathologist at Massachusetts General Hospital and Assistant Professor of Pathology at Harvard Medical School and the Harvard-Massachusetts Institute of Technology Program in Health Sciences and Technology. After leaving Harvard in 1979, he was appointed Visiting Professor of Laboratory Medicine at the University of Connecticut. In 1981 he was appointed Pathologist at the Veterans Affairs Medical Center in Providence and Associate Professor of Pathology at Brown University. He is currently Chief of Pathology and Laboratory Medicine, Director of the Boston Area Consolidated Laboratories at the Veterans Affairs Medical Center in West Roxbury, Massachusetts, and Medical Director of the Network Consolidated Laboratories for Veterans Affairs Medical Centers in New England. He also serves as Associate Clinical Professor of Pathology at Harvard Medical School.
During his tenure at the Veterans Affairs Medical Centers in Providence and Boston, Dr. McCully continued his studies of homocysteine metabolism in arteriosclerosis, cancer and degenerative diseases. He has published over 80 research articles in peer-reviewed journals in his field of investigation from 1961 until 2012. He has also published two monographs, several book chapters, and several reviews in medical journals, two books for the general reader and a book of his scientific memoirs. He currently holds seven U.S. Patents for anti-neoplastic and anti-atherogenic derivatives of homocysteine thiolactone.
In 1998 Dr. McCully was given the Linus Pauling Functional Medicine Award by the Institute for Functional Medicine and the Norman E. Clarke, Sr. Award by the American College for Advancement in Medicine. In 1999 he was given the Burton Kallman Scientific Achievement Award by the National Nutritional Foods Association and the Kynett Foundation Cardiology Award of Excellence by the College of Physicians of Philadelphia. In 2000 he received the International Integrative Medicine Award by the International Journal of Integrative Medicine, the Dinsdale Award by the Society for Scientific Exploration, the Benjamin Franklin Literary and Medical Society Award, and the Lifetime Achievement Award in Clinical Nutrition by the International and American Associations of Clinical Nutritionists. In 2000 Dr. McCully was honored by citation to the Twentieth Century Hall of Fame by Prevention Magazine. In 2001 he was given the Gallery of Heroes Award by Men’s Journal Magazine. Also in 2001 he was given a Commendation by the Veterans Affairs Medical Center in Providence. In 2003 he was awarded the Integrity in Science Award of the Weston A. Price Foundation and the Edward Rhodes Stitt Award in Laboratory Medicine by the Association of Military Surgeons of the United States. His biography is currently listed in Marquis Who’s Who in America. (1)
In his first book, ‘The homocysteine revolution’, Dr. McCully details his research on homocysteine, opening a new understanding to the underlying cause and prevention of heart disease. Based on his findings, he proposes dietary and lifetime changes the reader can easily implement. In what follows we will look at his homocysteine theory and how it applies to heart disease and arteriosclerosis.
We will also see how all the products from the ‘Healthy Hearts Club’ are the perfect complement to the homocysteine diet.
The mysterious case of stroke in childhood
It all started in 1968. After finishing his many years of education in chemistry, medicine, biochemistry, molecular biology, genetics and pathology, Dr. McCully was given a research laboratory at Massachusetts General Hospital in Boston. While working with the human genetics unit at the hospital, and after examining many patients with genetic diseases, he was presented with the case of a 8-year-old who, 35 years earlier, had died of a disease of old age. The official cause of death was ‘arteriosclerosis of the carotid artery with cerebral infarct (hardening of the artery leading to the brain with death of brain tissue)’. The boy’s obscure case had been published in the November 23 issue of the ‘New England Journal of Medicine’ in 1933 and forgotten. Thirty-two years later, the boy’s nine-year-old niece, presented the same symptoms as her uncle. Studying the chemical composition of her urine, doctors found it contained homocysteine, an amino acid derived from the normal breakdown of proteins in the body. She was diagnosed with homocystinuria and the doctors concluded her uncle must have died of the same disease.
Dr. McCully had never heard of this disease, it had been discovered 6 years earlier by medical investigators in Belfast, Ireland. By that time, two more cases had been discovered in the U.S. A physician named Dr. Harvey Mudd had studied several more cases and he had discovered that in this disease the liver is unable to dispose of homocysteine normally because of a genetic error in a liver enzyme called cystathionine synthase. Another doctor, George Spaeth and his associates, found that vitamin B 6 lowered the amount of homocysteine found in the urine. The liver enzyme that Dr. Mudd had discovered to be abnormal in homocystinuria needs B 6 for normal activity. This enzyme converts homocysteine into cystathionine, which is further processed in the liver to cysteine and finally excreted in the urine.
Dr. McCully recovered the tissues from the original slides and re-studied the case from 1933. He found the walls of the carotid arteries leading to the brain were severely thickened and damaged by arteriosclerosis. Blood clots prevented blood from reaching the brain of the child causing death of the right half of the brain. He also found scattered, widespread changes in all the small arteries of the body similar to those he found in many elderly patients. There was no cholesterol deposited in the walls of the child’s arteries, which prompted many questions. Was this hardening of the arteries caused by homocysteine? Was there an effect on cholesterol and fat? Why was there no cholesterol in the walls of the child’s arteries? Was this disease in children the same arteriosclerosis found in the elderly?
Other doctors in Belfast and London had studied ten cases of children affected by this disease. Many of these children had died from blood clots in the brain, heart and kidneys, hardening of the arteries resulting from fibrous plaques and loss of elasticity. All these cases were identical to the 8-year-old-boy case in 1933. It was not clear yet how homocysteine could produce changes in the arteries resembling arteriosclerosis without affecting cholesterol, lipoproteins or fats in the blood and artery walls.
Some time later, Dr. McCully found another case of homocysteine, this time in a 2-month-old baby. In addition to homocysteine, this baby had another substance related to the disease called cystathionine and a different liver enzyme being affected. This enzyme was found to be unable to transform homocysteine into methionine using B 12, which in a normal liver is performed quickly and easily. The enzyme that was found to be abnormal in the other cases was normal in the 2 month-old baby, but this baby had the same arteriosclerosis as the other children. Dr. McCully studied the organs of the diseased baby and comparing all the cases, he found that in all these rare genetic cases, the amino acid homocysteine had caused damage and hardening of the arteries by a direct effect on the cells and tissues lining the arteries.
He was so excited about his discovery, he could hardly sleep for two weeks. If homocysteine causes damage to the arteries, what could this mean for the general population with heart disease? When Dr. McCully was studying these cases (1950-60’s), heart disease was already an epidemic in America and the prevailing theory was that high cholesterol depositing in the walls of the arteries causes heart disease. He wanted to know how homocysteine could be related to high cholesterol and heart disease.
By reviewing research, he found two key discoveries that helped him understand homocysteine better. One was the work of Dr. James Rinehart, who had published a paper 20 years earlier where he discussed how a diet deficient in vitamin B 6 fed to monkeys led to arteriosclerotic changes in the arteries. The other was the findings of biochemists in Russia who discovered that the liver enzyme that converts homocysteine to cystathionine needs B 6 for its action. Could Rinehart’s monkeys with a B 6 deficiency have had a buildup of homocysteine that damaged their arteries? On the other hand, Dr. Harvey Mudd had found the enzyme cystathionine to be abnormal in children with homocystinuria. Another researcher, George Spaeth, had found that some children with this disease respond dramatically to large doses of B 6, preventing a buildup of homocysteine in their blood and urine. Dr. McCully was unable to explain how homocysteine related to cholesterol in causing damage to arteries because, in all cases, children with the disease had normal levels of cholesterol. The monkeys in Rinehart’s experiment also had normal levels of cholesterol.
While preparing his paper for publication, Dr. McCully read the work of some doctors from Toronto who had been working with choline, a component of lecithin. They found that a deficiency of choline in the diet of rats caused arteriosclerotic changes in the rats’ arteries and fat build up in the liver. This raised the possibility that arteriosclerosis was caused by a buildup of homocysteine in the rats’ blood.
With all these new findings, Dr. McCully published his paper stating that homocysteine damages the arteries by a direct effect on the arterial cells and tissues in homocystinuria caused by two different genetic defects. He also hypothesized that arteriosclerosis was caused by elevated blood homocysteine levels probably caused by vitamin B and choline deficiencies. His paper received hundreds of requests for reprints from scientists from all over the world.
Three different types of homocysteine
So far, Dr. McCully had found out that regardless of the cause, elevations of homocysteine causes arteriosclerosis by damaging the cells and tissues of the arteries. In this sense, a third type of homocystinuria confirmed his observations because they all had this element of damage regardless of the liver enzyme that was abnormal.
In type one, the most frequent case of the disease, B 6 was effective in preventing high levels of homocysteine. In type two, the next most frequent case, folic acid corrected the abnormality and lowered homocysteine. In type three, the rarest form of homocysteine, B 12 had little effect because of the difficulty of the liver to absorb this B vitamin.
The cholesterol theory vs. the homocysteine theory
As he continued with his publications and lectures, Dr. McCully encountered different reactions to his theories, but mostly skepticism. He believes due to the failure to find cholesterol in the patients. The explanation that an amino acid, not cholesterol, caused these cases of arteriosclerosis made it harder to accept.
But Dr. McCully was still trying to bring together the new research with the established knowledge. In the traditional view, excess fats and cholesterol are believed to damage the arteries. In the homocysteine theory, arteries are damaged by the effects of homocysteine on cells and tissues of arteries, leading to loss of elasticity, hardening, calcification, narrowing of the lumen and formation of blood clots inside arteries. It is an intoxification from proteins vs. an intoxification from fats. The homocysteine theory considers arteriosclerosis a result of an dietary imbalance due to the ingestion of protein and low levels of B vitamins, while the cholesterol theory considers the cause to be the ingestion of dietary fats.
Cholesterol in the body
Dr. McCully explains that cholesterol is “carefully controlled and adjusted according to the needs of the different organs of the body. If the amount of cholesterol is increased in the diet, a healthy well functioning liver makes less cholesterol for the needs of the body. If the amount of cholesterol in the diet is decreased, the liver makes more cholesterol.” In this way, the body regulates very precisely how much cholesterol is produced for its needs. Since it is so tightly regulated, Dr. McCully’s argument is, how could an excess of cholesterol induce arteriosclerosis?
He further explains that cholesterol is needed in the body for the production of sex hormones (estrogen and androgen), the production of stress and mineral hormones of the adrenal gland, it is a major constituent of the membranes of all cells of the body and it is excreted in the bile in the form of bile salts. According to Dr. McCully, there also needs to be an explanation on how cholesterol, a normal chemical constituent in the body, could, when overeaten in the diet, cause arteriosclerosis.
Cholesterol and oxidation
Early attempts to identify which components of LDL are injurious to artery walls led to the testing of many chemical relatives of cholesterol. A group of cholesterol compounds that contain extra oxygen atoms was found to be highly toxic when tested in cell cultures and in fragments of aorta maintained in culture. Several of these oxidized cholesterol compounds, called oxycholesterols, produced injury to artery walls, deposition of fat and arteriosclerotic plaques when fed to rabbits. One of the most toxic of these oxycholesterols is ‘cholestane triol’, which has three added oxygen atoms per cholesterol.
In a series of studies of oxycholesterols, medical scientists at Albany Medical College showed that purified cholesterol, freed from all traces of oxycholesterols and protected from the oxygen of air, does not produce arteriosclerosis when administered on animals. These oxycholesterols have been discovered in arteriosclerotic plaques of human arteries and in the LDL fraction of human blood plasma coming from dietary fats of animal sources, specially those that have been heated in the presence of air.
Shortcomings of the cholesterol/fat approach
During the 80 years of its existence, the cholesterol/fat approach to arteriosclerosis became the favorite of the medical community. Because of his deep research on arteriosclerosis, Dr. McCully thinks the cholesterol/fat approach to arteriosclerosis has many shortcomings. One of the biggest ones according to him is that it fails to explain a correlation between fat and cholesterol and the major changes produced by arteriosclerosis. Especially taking into account that the fat and cholesterol content of the American diet has changed very little in the recent decades.
He also feels that it fails to consider the potent effects of the oxycholesterol contaminants found in feeding experiments with animals.
Furthermore, the author sees a major flaw with the cholesterol approach because a majority of people with severe or fatal arteriosclerosis, myocardial infarction, kidney failure or gangrene of the toes have normal cholesterol and lipoprotein levels. He even asserts: “At a practical level, physicians know that the majority of their patients with coronary heart disease have no incidence of elevated cholesterol or LDL levels”. He considers that in all of the very intensive clinical investigations done through the decades on cholesterol lowering drugs, there has not been a noticeable reduction in heart disease mortality and arteriosclerosis remains the leading cause of death in America.
What is more, he asserts that no comprehensive theory has been developed which satisfactorily explains how arteriosclerosis risk factors affect cholesterol levels or how elevated LDL and decreased HDL initiate formation of arteriosclerotic plaques.
To support his arguments, Dr. McCully did a research of 194 autopsy studies of male veterans with severe arteriosclerosis and found only 8% of them had high cholesterol, diabetes or hypertension. According to him, the cholesterol/fat approach has yet to provide a coherent scientific theory which explains how cholesterol, a normal constituent of the body, or excess dietary fat produces arteriosclerosis.
He also found that a diet abundant in vitamin E, a potent fat-soluble antioxidant vitamin, keeps LDL from being oxidized by oxygen, therefore it is of benefit in reducing the risk of coronary heart disease in both men and women.
Dr. McCully sees the need for a new, comprehensive and effective approach for prevention and treatment of arteriosclerosis, since it is still the leading cause of deaths in the US. He considers the discovery of homocystinuria in young children is a great opportunity to understand arteriosclerosis better.
The homocysteine theory of arteriosclerosis
The homocysteine theory is based on the results of animal experiments and the study of human subjects at risk of arteriosclerosis. In essence, it relates the underlying cause to a buildup of homocysteine in the blood caused by dietary, genetic, toxic, hormonal and aging factors. Specifically, an imbalance between the methionine of dietary protein and the dietary intake of vitamins B 6, B 12 and folic acid needed to prevent accumulation in the cells and tissues of the body. The importance of this theory is that it explains many aspects of the disease that cannot be explained by the cholesterol/fat hypothesis. It also explains why the diet of developed countries accelerate its progression.
The dietary factors that determine high blood homocysteine levels are the total methionine content of dietary protein and the content of vitamins B 6, B 12 and folic acid in the diet. The only source of homocysteine in the body is from the methionine of dietary proteins: meats, seafood, dairy products, eggs, etc.
Methionine is an amino acid containing sulfur that is present in all proteins. It is an essential amino acid because all animals including man require it for proper growth and maintenance of all cells and tissues of the body. B 12 and folic acid help convert homocysteine to methionine. B 6 converts homocysteine to cystathionine, which in turn is converted into cysteine and excreted through urine. In this way, these vitamins protect arteries from homocysteine.
Dietary proteins vary in the amounts of methionine they provide. Animal sources like meat, eggs, milk are abundant in it. Proteins from plant sources are more limited in it (1/3 to 1/2 less of that found in animal sources). Fruits and vegetables contain much less, which means that eating a vegetarian diet vs. a meat/dairy diet might protect from homocysteine because there is less need by the body to convert homocysteine to methionine. From this we can also infer that diets high in meat and dairy will need more of the B vitamins to make this conversion and keep homocysteine to safe levels.
Because these vitamins are so sensitive to destruction by food processing, refining and conservation, the less processed the food is, the more it will keep its vitamins. In milling wheat into white flour, for example, 50-90% of the B 6 is lost. B 12 is only obtained from foods of animal origin. The small amount required (3 micrograms) is easily supplied in most diets. This means that strict vegetarians can suffer from B 12 deficiencies. Elderly people because of inflammation of the stomach can have problems absorbing it.
The process by which homocysteine causes arteriosclerosis is as follows: In the liver, methionine, obtained from the breakdown of proteins is continually converted to homocysteine and back to methionine. This process is known as remethylation and it is dependent on vitamin B 12 and folic acid. Deficiencies of these vitamins will lead to the build up of homocysteine.
A second process, transulfuration, converts homocysteine to cystathionine, cysteine, etc for excretion in the urine. It requires B 6. Deficiency of B 6 leads to buildup of homocysteine because the body has no other way to eliminate excess homocysteine by excretion in the urine. Vitamins B 6, B 12 and folic acid need to be obtained from the diet because they are not made in the body. The homocysteine theory attributes the origin of the disease to the inadequate dietary intake of vitamin B 6 and folic acid and the subsequent failure to prevent the damage to arteries caused by elevated blood levels of homocysteine.
Consequently, populations that consume food of animal origin abundant in methionine and highly processed foods depleted of key vitamins are at higher risk for arteriosclerosis.
Other factors such as advanced age, elevated blood cholesterol, male gender, menopause, diabetes, kidney failure, thyroid deficiency, hypertension, etc – play a role too:
Homocysteine and aging
One of the strongest risk factors for arteriosclerosis is aging, especially the 7th, 8th and 9th decades. The aging process affects the ability of the body to dispose of excess homocysteine, therefore it causes an increase in homocysteine in this age range. There is also a parallel increase in cholesterol at this age, peaking at 70-80 and declining after that.
What is more, as one ages, the ability to consume food and burn calories gradually declines, and the decrease in levels of vitamin B 6 is significant. Supplementation with this vitamin is partially effective, suggesting that absorption of the B vitamins is also affected by the aging process. This is the reason why many health professionals recommend B 12 shots.
Dr. Edward Group, in his article ‘Does the vitamin B 12 shot have side effects?’ asserts: “Those who cannot digest or absorb B 12 as a result of inherited genetics or damage to the stomach and small intestine require more than can be absorbed from sublingual supplementation. In situations where a high dose is needed, or where injection is the only option, the B 12 shot is used. In some cases, B 12 shots are used as an energy booster, since B 12 plays a critical role in cellular energy production…the doctor or healthcare professional delivers the shot directly into muscle, usually into the thigh or upper arm, for easy absorption into the bloodstream.” (2)
Homocysteine and elevated blood cholesterol
Limiting the intake of animal foods high in methionine and increasing the intake of B vitamins can help lower homocysteine and cholesterol, how is this so? Experiments with animals have shown that homocysteine in its reactive tiolactone form, is capable of increasing the formation of fats in the form of triglycerides and cholesterol as low density lipoprotein (LDL) in the liver.
Processed fats and sugars are examples of highly processed foods with no vitamins, minerals or proteins. A diet high in both will lead to a deficiency in the B vitamins that keep homocysteine low and exacerbate the tendency of blood cholesterol and lipoprotein. On the other hand, a diet high on protein of plant origin, high in B vitamins and raw foods will lower it.
The male gender, menopause and hormones
The difference between men and women when it comes to coronary heart disease is men typically are affected in the 5th and 6th decade while women are affected on the 6th decade, after menopause. Studies have consistently shown that women have slightly lower levels of homocysteine in the blood than men. After menopause, however, these levels are similar to those of men of the same age. In the eighth and ninth decades of life, the levels of homocysteine increase in both sexes.
The author believes the higher levels of estrogen in women protect them from heart disease, while the administration of synthetic estrogens and contraceptives has been shown to increase homocysteine and have a subsequent increase in blood clots and arteriosclerotic plaques. This risk in even greater in smokers who take hormones. The reason for this is that these hormones oppose the functions of B 6 in the body, requiring higher levels of this vitamin to correct the imbalance. Cigarette smoke also antagonizes B 6 in its vital functions in the body.
Diabetes and kidney failure
Diabetes mellitus is a very common condition that predisposes affected people to rapidly advancing arteriosclerosis. Sufferers are frequently affected by heart attack, stroke, kidney failure, blindness and gangrene of the toes and feet. Diabetes is marked by the insufficient production of insulin by the pancreas or the inability of insulin to transport blood sugar into cells for production of energy. As a result, all cells in the body become starved for sugar and switch into starvation mode of cellular activity. The excess blood sugar in diabetics reacts chemically with the hemoglobin of red blood cells and with the membranes around small blood vessels and capillaries, narrowing the lumen and interfering with the passage of red blood cells. In the kidney, the clogging of small arteries gradually leads to failure of kidney function. A very striking effect of kidney failure is a remarkable buildup of homocysteine in the blood. This subjects all arteries of the body to damage and rapidly progressive arteriosclerosis.
Dialysis causes a temporary drop in homocysteine levels, but after 1-2 days the blood homocysteine returns to its elevated level. Large doses of vitamin folic acid therapy (5 milligrams per day) partially decreases the levels of homocysteine. Supplementation with B 12 or B 6 does not reduce it any further.
Homocysteine and thyroid hormone
Deficiency of thyroid hormone secretion has been known to predispose to arteriosclerosis and heart disease. In a serious deficiency case, the ability of the cells to use oxygen is impaired, the basal metabolic rate is slowed and the liver begins to make increased amounts of cholesterol and triglycerides, which increases the risk for heart disease. Administration of potent thyroid hormone like thyroxine increases this risk. Insufficient dietary iodine can increase the levels of homocysteine. In cases of hyperthyroidism, on the contrary, the levels of homocysteine are lower than in normal values.
The scientific evidence for the homocysteine theory
Dr. McCully performed his own experiments on animals to simulate what he found in children with the disease. The results showed that just after three weeks of injecting homocysteine in the animals, early arteriosclerotic plaques were found in the coronary arteries. If the animals were fed cholesterol and injected homocysteine, the arteriosclerotic plaques were found to contain fat deposits too. If the animals were given a diet deficient in B 6 and injected with homocysteine, the plaques became more prominent and widespread.
With these experiments, he successfully reproduced the cases of homocysteine he found in children with the disease. When the results were presented in a national meeting, he was met with total silence. The response to what he thought was an extraordinary finding confirming his theory about the arteriosclerotic effect of an amino acid, was very disappointing. Investigators interested in the traditional approach, went back to studying cholesterol and lipoproteins and ignored his findings and some that offered to replicate his experiment, published contradictory findings, even changing the slides they sent Dr. McCully and putting pictures of a normal artery. He performed the experiment again, this time with five times more homocysteine.
In this second experiment, blood clots had formed in the veins of the legs and abdomen and went to the lungs. In the animals that were given B 6 as well as homocysteine, no blood clots had formed and the animals survived. He repeated the experiment, this time feeding the animals a high homocysteine diet rather than injecting it. When the arteries of the animals were examined, arteriosclerotic plaques were found that closely resembled those found in the children that died from the disease. Not only had he reproduced the vascular disease, he had also reproduced the complication of blood clot formation and embolism to the lungs. He also suppressed the formation of blood clots with the administration of vitamin B 6.
After publication of these findings, scientists in Japan repeated his experiments, finding the same blood clots and arteriosclerosis, also being able to reverse it with B 6. His experiments were repeated several times by different scientists around the world and the same results were found: homocysteine caused arteriosclerosis and blood clots, proving that experimental homocysteine reproduces the essential features of homocysteine observed in children with hereditary homocysteine.
Studies of cells and tissues
By growing cells in culture from the skin of children with homocystinuria, Dr. McCully was able to answer many questions about the disease. One of the early changes in arteriosclerotic plaques is an accumulation of mucoid matrix substance of decreased solubility in areas of damage to arterial tissues. Something else he observed is that the pattern of growth in arteriosclerosis resembles the pattern of growth of cancer cells in culture. Also, he observed that homocysteine induces cells to lose control of growth processes, causing growth of muscle cells in arteriosclerotic plaques. This fact explains why children with the disease grow rapidly in childhood and have long arms, legs, fingers, toes and great stature. The liver of children with homocystinuria was found to accumulate droplets of fat within the cytoplasm. Their mitochondria became enlarged, had bizarre shapes and become aggregated with one another, affecting how cells produced energy. All these facts were found to be key to how the cells became damaged and increased the formation of fats and cholesterol in arteriosclerosis.
In addition, homocysteine was found to activate multiple blood clotting proteins and to increase formation of thromboxane (the hormone-like fatty acid derivative causing blood clots). Homocysteine was also found to increase the binding of lipoprotein (a) to fibrin, increasing blood clots.
In his research, Dr. McCully found that components of lipoprotein homocysteine aggregates are taken up by cells of the artery wall, forming foam cells. These cells degrade and store fats and cholesterol from the LDL component, releasing them gradually to form the cholesterol crystals and fatty deposits of advanced arteriosclerotic plaques. The homocysteine component is released from foam cells and affects the oxygen utilization process of adjacent arterial cells causing increased formation of damaging free radicals. This in turn causes increased growth of muscle cells, formation of mucoid matrix from the sulfur atom of homocysteine, destruction of elastin fibers, production of fibrous collagen fibers, calcium deposits and activation of blood clotting. All of these experiments and observations explain how homocysteine causes arteriosclerotic plaques.
Many studies followed Dr. McCully’s experiments, all of which showed that elevation of blood homocysteine is a strong independent risk factor for the development of arteriosclerotic disease. The experiments revealed a three-fold increase in the risk of heart attack in a 5-year prospective study. Elevated blood homocysteine is estimated to account for at least 10% of the risk of coronary heart disease in the US population, and is estimated to be a greater risk factor than elevated blood cholesterol (22-40 fold vs. 1.2-3.1 respectively), high blood pressure (8-18 fold) and cigarette smoking (3.5 fold) in a selected group of patients with early-onset arteriosclerosis.
Another cross-sectional study showed the risk factors to be, in order of severity, male gender, age, cigarette smoking, lack of exercise, blood pressure, heart rate, blood cholesterol and triglycerides. A total of 209 published studies of the epidemiological relation between homocysteine and arteriosclerosis have been reviewed. The consensus of these studies is that elevated blood homocysteine is a strong independent risk factor for arteriosclerosis.
A detailed study of patients with angina pectoris showed the narrowing of the coronary artery by arteriosclerotic plaques correlates better with blood homocysteine than with levels of cholesterol. The same for pulmonary embolism and people with deep vein thrombosis (blood clots in the legs).
In the case of genetic transmission of homocysteine, these results have also been documented. Thankfully, since the FDA started supplementing foods with folic acid the number of babies with birth defects (neural tube defects of the brain and spine) have greatly been reduced. Recent studies have shown that these mothers have high levels of homocysteine, predisposing their babies to birth defects.
How homocysteine causes plaques. Arteriosclerosis in progress
According to Dr. McCully, “The idea that arteries in human arteriosclerosis are narrowed only by greasy deposits is simply not true for most arteries.” Only in the aorta and some large arteries, he asserts, can you find arteriosclerosis caused by deposits of fats and proteins.
According to his research, the way homocysteine causes plaques in the arteries is through a buildup of homocysteine in the body that leads to overproduction of a highly reactive form of homocysteine known as homocysteine thiolactone. This form of homocysteine causes LDL to become aggregated. These aggregates are released into the blood from the liver first and then taken up by macrophages of the artery wall to form foam cells of early arteriosclerotic plaques. These foam cells degrade the LDL homocysteine thiolactone aggregates and release fat and cholesterol into developing plaques. The foam cells also release homocysteine thiolactone into surrounding cells of the artery wall affecting the way cells handle oxygen. As a result, highly reactive oxygen radicals and deposits of calcium salts accumulate within cells damaging the lining cells of arteries, promoting blood clot formation and stimulating growth of arterial muscle cells, which form fibrous tissue, mucoid matrix and degenerative elastic tissue.
In later stages, the calcified plaques of fibrous tissue give the walls of the most affected arteries a tough, brittle, hardened consistency that is very difficult to cut either with scissors or a scalpel blade. This translates into loss of elasticity and hardening of the arteries.
Arteriosclerosis and blood clotting
The main changes in arteriosclerosis then are increased fibrous tissue and calcium deposits. But this is not all that happens. Dr. McCully further describes the arteriosclerotic process as the formation of blood clots accumulating in the damaged artery:
Human arteriosclerosis, he explains, is characterized by the formation of blood clots inside arteries (thrombosis). The injury to arterial cells and tissues in the early stages of arteriosclerosis triggers complex cellular and molecular interactions and a reaction by blood clotting factors and platelets that leads to the formation of fibrin, the principal components of blood clots. This reaction causes the platelets and arterial cells to release protein growth factors that stimulate growth of the muscle cells in artery walls. This injury also causes white blood cells to adhere to the site of injury forming more foam cells and releasing more growth factors and other cell-signaling molecules called cytokines. The result of these complex interactions is increased growth of the muscle cells of the artery wall, production of fibrous tissue and ground substance, including cholesterol, inside the place of injury in the artery.
During the progression of plaques, these clots that form in damaged areas of the arterial lining contribute to the narrowing of the artery lumen. Small blood clots that stick to the surface of the plaques gradually become incorporated into the plaque increasing its thickness. In advanced arteriosclerosis, blood clots, cholesterol and fats, fibrosis and calcium salts form complicated arteriosclerotic plaques. If this process is gradual and progressive other organs and vital functions will be affected over long periods of time. Amount of blood flow to the extremities can be compromised causing gangrene.
A similar progression of advanced arteriosclerosis commonly affects the arteries leading to the brain, heart and kidneys causing them to slowly fail. A more dramatic scenario is when a blood clot occurs in an artery that is already narrowed by plaques. In the coronary artery, this will deprive a part of the heart muscle of blood flow, causing death of that part of the heart and causing a heart attack (acute myocardial infarction). When the carotid artery to the brain is affected a stroke is the end result.
Nutritional deficiencies and arteriosclerosis
Dr. McCully further stated that over consumption of fats and cholesterol has not been proven to cause arteriosclerosis. Only oxycholesterols (a trace or contaminant associated with fat), he says is actually capable of initiating arteriosclerotic plaques. The medical community has never considered the vitamin deficiency theory (B 6, B 12 and folic acid) he proposes as possible cause for arteriosclerosis. But he thinks the overconsumption of fats, sugars and highly processed foods depleted of these vitamins, could be the single cause behind the nutritional deficiencies of these water-soluble easily destroyed vitamins.
Prevention of arteriosclerotic heart disease and the homocysteine theory
Is there proof that lowering homocysteine decreases the risk of heart disease? When Dr. McCully was doing his research, there was no information regarding this in the medical literature nor funding for trial of this kind. Government funding agencies repeatedly ignored proposals for a large scale trial of the homocysteine theory. The first piece of evidence came from the study of children with homocystinuria, who after being treated with B vitamins, showed a significant decrease in the risk of blood clots. Similarly, in 1962 Dr. John Ellis proved that high doses of B 6 given to patients with carpal tunnel syndrome reduced their risk of heart attack or chest pain by 75%.
Arteriosclerosis and the homocysteine theory
The homocysteine theory proves arteriosclerosis is caused by a toxic effect of a by-product of protein breakdown. Fats and sugars are understood to contribute because of the loss of B 6 and folic acid through processing, refining and preservation of foods, creating an imbalance between the abundant methionine from foods of animal origin and the amount of these vitamins needed to keep homocysteine from building up. In homocysteine there is a deposition of fats and cholesterol that damage the artery walls by interfering in normal oxygen processing and accumulation of free radicals. Unsaturated fish oils, together with B 6, B 12, folic acid, riboflavin, choline and troxerutin (an antioxidant of plant origin) decrease both homocysteine and LDL levels.
The homocysteine theory offers explanations for arteriosclerosis that are hard to answer with the cholesterol theory. The low incidence of arteriosclerosis in Eskimos despite the high intake of fat and cholesterol is explained by the high intake of unsaturated fatty acids and B6 from fish oil.
Concluding, Dr. McCully proved that homocysteine has a direct effect on arteriosclerosis by damaging the cells of the artery walls. High dietary intake of protein, specifically methionine, and low intake of the B vitamins cause an accumulation of homocysteine leading to arteriosclerosis.