Rough Draft 7/8/97 "Homocysteine Can Kill You
by Glenn Tisman, M.D. and Melanie Tisman
Chapter on Coronary Heart Disease
What we are about to unfold is a story that has been years in the making, and until now, has missed the limelight of most important medical discoveries. An elevated blood homocysteine level is a powerful risk factor for coronary heart disease (CHD), and the majority of physicians in the United States do not know this. For this reason, there has been no attempt to control it . . . until now. Prominent researchers now believe that plasma homocysteine elevations may be just as important, if not more so, than cholesterol elevations in the genesis of atherosclerosis and CHD (1,2).
Coronary heart disease, also called coronary artery disease, is any abnormality of the two main blood vessels in the heart, or their branches that feed the heart muscle, that results in the interruption of blood flow. When blood flow is restricted through these arteries, usually as the result of atherosclerosis, the heart muscle becomes starved of oxygen and other nutrients.
In general, CHD is a disease associated with aging. However, the young are not immune. In fact, homocysteine may be a powerful factor in the genesis of atherosclerosis in people younger than 55 years old. Most research into the causes of CHD has concentrated on cholesterol and lipids. This is logical, since lipid-laden plaque formation seems to go hand-in-hand with CHD. Most in the medical field have followed the notion that arteries are like the body's plumbing system that, with time, experiences a gradual build-up of sludge. In fact pharmaceutical companies have embraced this concept and embarked upon the development of drugs that clear the sludgy plaque from arteries in attempt to bring cholesterol levels closer to "normal".
But with the recognition of homocysteine, the focus on cholesterol as a primary cause of CHD is shifting.
Mounting evidence says that homocysteine is a detrimental risk factor for CHD in both the elderly and the young, possibly more powerful than the effects of cholesterol. Support for this belief is documented in numerous studies published in prestigious medical journals, many of them referenced in the back of this book.
Low Cholesterol Does Not Equal Low Risk
A few months ago I had a patient, we'll call him Mr. Jones, who suffered from an advanced case of atherosclerosis. He and his wife came to me because he was afflicted with prostate cancer and my specialty is Oncology. Upon our first meeting, the Jones' told me that his second coronary artery bypass surgery was scheduled to take place later that week. Ten years prior, he said, he had undergone his first bypass surgery. Both he and his wife expressed their frustration at having to go through the trauma of a surgery again, especially since his cholesterol levels were well within the normal range.
To achieve this normal cholesterol level, Mr. Jones explained, he had rigorously followed the dietary and exercise program prescribed by a well-known cardiologist for ten straight years. Why should he now have to face the operating table again? Clearly, it was not related to his cholesterol level.
Addressing their concerns, I offered to take a look at other risk factors for atherosclerosis with the hope of identifying other possible causes for his disease. Several tests were conducted and the results were available later that week. I was electrified by the findings. I called Mrs. Jones immediately, planning to tell her what I had found. Her husband's tests were mostly normal, including his cholesterol levels. The exception was his blood homocysteine level. It was extraordinarily high and was likely causing his battle with CHD. Unfortunately, before I could relay the news, she informed me that her husband had died on the operating table.
What we all learned from Mr. Jones' tragedy is clear. It is time to dismantle the strongly believed notion that high cholesterol produces all CHD. It is absolutely, 100% incorrect. As a matter of fact, a closer look at CHD patients reveals that most with heart disease do not have abnormal cholesterol levels.
This seems almost impossible considering the urgency placed on monitoring cholesterol levels. But if cholesterol is the only key, how would we explain the development of CHD in people like Mr. Jones?
Enter Dr. Kilmer McCully. Dr. McCully is a pathologist, a Harvard Medical School graduate, who had done research in molecular biology at the National Institute of Health. In 1969, he was the first to propose that homocysteine might cause CHD. Dr. McCully worked at the Massachusetts General Hospital where he came across the strange medical case of the young boy with homocysteinuria we discussed in the introduction. This case, and his familiarity with another patient suffering from homocysteinuria and atherosclerosis, sparked his thinking. Each patient had two completely different metabolic diseases. However, they produced identically severe atherosclerotic changes in the blood vessels. Finally, he found the tie that bound these two cases. Both had elevated levels of homocysteine. Dr. McCully reasoned that if high levels of homocysteine in the blood caused arterial damage, it would explain both cases, as well as the results of other research he had reviewed.
Dr. McCully had been so enthusiastic about the relationship of homocysteine as a cause of atherosclerosis and CHD that it may have cost him his job. His theories were far ahead of his time and the scientific community rejected them. Luckily, he was able to continue his important work at another laboratory under the auspices of the Veteran's Administration in Rhode Island.
Recently in 1990, in the continuing pursuit of evidence to implicate homocysteine as a cause of atherosclerosis in humans, Dr. McCully conducted a study. He examined 194 autopsies to determine the proportion of cases of atherosclerosis
that did not have one of the well-known risk factors for atherosclerosis, such as diabetes mellitus, hypertension, or elevated cholesterol levels. He evaluated the degree of atherosclerosis in his subjects in relation to their cholesterol levels. In his conclusion, he found that cholesterol was strongly associated with the severity of atherosclerosis in all his study groups, but this finding had an interesting twist. In 74% of all cases, cholesterol levels were well within what we define as a normal range for cholesterol, specifically 200 mg/dl or below.
The take-home message of this novel study is that CHD can and does develop without evidence of diabetes, hypertension, or elevated cholesterol.
These results further intensified McCully's belief that other factors, like high levels of plasma homocysteine, are conceivably a cause of atherosclerosis.
McCully continues to work on the relationship between homocysteine and atherosclerosis, and has been a prolific contributor to the theory that high serum homocysteine levels are a cause of atherosclerosis. Throughout the rest of this chapter, we will delve deeper into the scientific evidence that supports both McCully's and our theory that homocysteine plays a crucial role in the genesis of atherosclerosis and CHD.
The Effects of Low HDL
Dr. McCully's studies led him to conclude we should be looking at other risk factors, primarily homocysteine, to explain atherogenesis where there are low total cholesterol levels. A research team led by Genest and McNamara reported that in a group of men with CHD, more than one-third had a total cholesterol level within the so-called normal range. Nearly three-fourths of these men had low levels of HDL, the "good cholesterol". Further surveillance revealed they were all at high risk for subsequent cardiovascular disease, even though their total cholesterol levels were relatively low.
This contradicts the mainstream belief that low cholesterol assures a low risk of CHD. And at the same time, it supports the observation that HDL cholesterol protects against atherosclerosis. This is why it makes sense that low HDL levels may factor into the equation for predicting the onset of atherosclerosis. Moreover, it may partially explain why some of McCully's patients had suffered from severe atherosclerosis while concurrently maintaining normal total cholesterol levels.
Lp(a) and Coronary Heart Disease
We previously defined Lp(a) as the partial twin of plasminogen, an important element in the dissolution of blood clots. Lp(a) and plasminogen are adversaries, however, in that Lp(a) interferes with plasminogen's clot dissolving capabilities. Studies suggesting the relationship between Lp(a) and atherosclerosis prove that the relationship continues to exist even in the presence of normal cholesterol levels.
For example, Mr. Abrams, a retired engineer, came to me convinced that he simply had a bad heart. When I asked him to explain this assertion, he said that he had suffered a previous heart attack and was still experiencing anginal pains, even with a low cholesterol level of 159. His physician offered him no further alternative explanation, so he surrendered to the notion that he had a bad heart and nothing else could be done.
My studies of Mr. Abrams revealed that he had a modest elevation in his homocysteine level, and his level of Lp(a) was four times normal. Since Lp(a) is inherited and cannot be manipulated with diet or exercise, we addressed his problem by lowering his homocysteine level.
This will minimize the affinity between Lp(a) and any arterial blood clots he might have. This strategy worked. Mr. Abrams' most recent angiogram showed that the progression of his disease had ceased and no surgical intervention was required
It has been suggested that up to one quarter of all heart attacks in men younger than 60 years occur in those who have inherited high blood concentrations of Lp(a). This means that a significant portion of the genetics behind CHD that are not attributable to traditional risk factors may be caused by Lp(a) levels. This is important to note because it is homocysteine that enhances the affinity between Lp(a) and blood clots. It is homocysteine that, once again, elevates the risk for heart disease to another level.
A conclusion drawn by investigators in an ongoing study called the Framingham Heart Study says that a high level of Lp(a) ranks among the most prevalent inherited risks for heart attacks.
A given quantity of Lp(a) in the blood may confer as much added risk as does ten times the quantity of LDL. This has powerful implications for heart disease patients like Mr. Abrams and explains another reason that homocysteine is a detriment to our health.
Homocysteine's Graded Relationship: The Clue to Cause and Effect
You are certainly familiar with the basic concept of cause and effect. A mixture of atmospheric elements is a cause, rain, snow, or other precipitation is the effect. Eating too much over the holidays is a cause, not being able to button your pants the next week is the effect. When observers were able to link the severity of atherosclerosis to the degree of elevated plasma homocysteine, it was a monumental moment in which a cause-effect relationship between the two was strongly implied.
Yet cause and effect is only the surface of the relationship between homocysteine and CHD. A study by an important researcher named Robinson published in the journal Circulation in 1995 revealed that simple, incremental changes in homocysteine levels cause corresponding incremental changes in risk for CHD. As one value goes up, so does the other and by a seemingly fixed amount. This positive correlation gives evidence of a "dose-effect" relationship between homocysteine and atherosclerosis/CHD. Robinson's group also determined that this dose-effect relationship is much more profound than the simple correlation between cholesterol and CHD. What does that mean?
To illustrate the strength of this relationship, let's look further into Robinson's work. Robinson's studies revealed an increased risk for CHD when homocysteine levels were at a relatively low concentration of 4.5 micromole/L (a measurement of concentration). Each time your blood homocysteine concentration is increased by another 5 micromoles/L, the chances of developing CHD increases by 240%. This is of immense importance, because the overwhelming majority of the presumed normal U.S. population has plasma homocysteine levels greater than 4.5 micromole/L. To put this assertion to the test, I challenged my associates to measure the homocysteine levels of the next approximately fifty patient to walk through the door of our practice. They did so, and found that the average homocysteine level was three times greater than the 4.5 micromoles/L mark. Robinson's study and studies conducted by others tell us that a majority of the U.S. population is at a greater risk of homocysteine-induced atherosclerotic damage than ever imagined.
An important study by Pancharuniti from the Department of Epidemiology, University of Alabama in 1994 revealed a progressively increasing risk for the development of CHD based on homocysteine levels. Pancharuniti divided homocysteine levels into quartiles. As can be seen in the figure below, the odds ratio for developing CHD varied between 1 and 6.7, increasing with each consecutive increase in homocysteine quartile level. This study further confirms the depth and strength of the positively correlated relationship between homocysteine and CHD.
Taking the dose-effect theory one step further, a similarly graded association can be made between homocysteine levels and the total number of blocked coronary arteries in the CHD patient.
Ubbink from South Africa, a prolific researcher of the relationship between homocysteine and atherosclerosis, initiated a study in which he analyzed total serum homocysteine and cholesterol levels in 163 men with CHD. Each patient was subjected to a coronary angiogram, which is considered the gold standard in revealing the degree of CHD. 41.9% had hyperhomocysteinemia, or elevated fasting plasma homocysteine levels. Furthermore, homocysteine levels were significantly elevated in patients with major blockages in two or three coronary arteries.
Remarkably, Ubbink found that the preponderance of blood homocysteine elevations correlated quantitatively and directly with the number of blocked coronary vessels. We can illustrate this point with two patients from my own practice:
Mr. Epstein suffered from exercise-related chest pain for five years. Finally submitting to his wife's urging, he sought medical attention. His blood homocysteine level was elevated to 13.6 micromoles/L. He was given a coronary angiogram, which revealed partial blockage of only one coronary artery. Mr. Felding, another patient sought help for his own exercise-related chest pain. He was found to have an elevated homocysteine level of 18.2 micromoles/L, a measurement significantly higher than Mr. Epstein's. Mr. Felding's coronary angiogram revealed significant blockage of three of his major coronary arteries. As you can see, Mr. Felding had the higher homocysteine level and a corresponding increase in the number severely affected arteries. These cases help illustrate the quantitative association that Ubbink demonstrated between homocysteine and the degree of CHD.
Elevations of blood cholesterol were found in only 34.9% of Ubbink's subjects. In contrast to homocysteine, a correlation between cholesterol and the number of blocked arteries could not be established. This is the hard evidence that homocysteine correlates more strongly to CHD than the traditionally implicated culprit, cholesterol.
Three years later, Von Eckardstein and others from the Institut fur Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfalische Wilhelms-Universitat Munster, FRG confirmed the work of Ubbink. This group studied 199 male CHD patients and age-matched control subjects ranging from 36 to 65 years old. They analyzed the role of homocysteine as a cardiovascular disease risk factor and found that the mean homocysteine levels were nearly 20% higher in patients with CHD than in control subjects. Within the CHD patients, homocysteine levels were directly proportional to the number of narrowed coronary vessels noted on their angiogram. Similar to Ubbink's results, Von Eckardstein's group could not show a correlation between serum cholesterol levels and the number of blocked coronary arteries.
The importance of Von Eckardstein and Ubbink's studies lies in the demonstration of a direct dose-effect relationship between plasma homocysteine levels and the degree of coronary atherosclerosis, and their lack of ability to show the same relationship for cholesterol.
A new investigation by Hopkins, a researcher at the Department of Internal Medicine, University of Utah School of Medicine, was the first to illustrate the dose-effect relationship of homocysteine and CHD in women. The findings showed that the relative odds for developing CHD were approximately 12.8 times higher in women with homocysteine levels of 19 micromole/L and above, versus women with levels of 9 micromole/L or less. For men, the same comparison yielded relative odds of 13.8. In this study, as in others, plasma homocysteine remained a strong, independent risk factor for CHD.
These studies and many others drive home the message that cholesterol is not the explanation for all cases of CHD, as the mainstream in medicine has come to accept.
By showing that the number of clogged coronary arteries could not be correlated to cholesterol levels, these studies clearly suggest that elevated homocysteine plays an even more significant role in atherogenesis than cholesterol.
A disturbing fact involved in this research is that homocysteine levels identified as high risk are levels that are currently accepted in mainstream medicine as "normal" (Robinson). It seems clear that the acceptable range for plasma homocysteine needs significant downward adjustment. This is not likely, unless the medical industry begins to recognize the significance of homocysteinemia.
Coronary Heart Disease And Homocysteine
We now know that all cases of CHD cannot and should not be attributed to high blood cholesterol levels.
Homocysteine plays a causative role as its established dose-effect relationship with CHD clearly depicts. An important conclusion to draw from this chapter is the extreme impact small increments of homocysteine have on the risk for developing CHD. In evaluating the work of Robinson, we learned that increases in homocysteine levels by a mere 5 micromoles/liter would increase odds for CHD by 240%. That is a tremendous effect brought about by a relatively small, incremental change in plasma homocysteine.
As we forge forward through studies that describe elevations in homocysteine in plasma, keep this gage in mind. Don't be fooled by seemingly small numbers. What at first strikes us as insignificant is indeed not, for the power behind homocysteine is beyond anything conventional medicine ever expected. Knowing this will serve as a great tool in understanding the significance of homocysteine.
1) The presence of homocysteinemia and hypercholesterolemia in angiographically defined coronary heart disease. Ubbink JB; Vermaak WJ; Bennett JM; Becker PJ; van Staden DA; Bissbort S. Klin Wochenschr (Germany), Aug 16 1991, 69(12) p527-34
2) Plasma Homocysteine as a Risk Factor for Vascular Disease
The European Concerted Action Project Graham, Ian M.,et al.
The Journal of the American Medical Association, June 11, 1997, Volume 277, Number 22, pages 1775-1781