Doctors, nurses, and other health care providers who treat people needing cardiovascular prevention are often asked if it is possible to "make the atherosclerotic plaques go away." The technical term for making the plaque go away is regression of the atherosclerotic plaque. Thus far, all the attempts to demonstrate atherosclerotic regression have shown how difficult it is. Regression does occur in some cases, but it is slow and it is not very common.
In the previous section, some exciting new research was mentioned, suggesting that it might be possible to remove most of the cholesterol from atherosclerotic plaques. If that is so, then why doesn't the plaque just go away? The answer is that the bulk of an atherosclerotic plaque is made of fibrous tissue, similar to the fibrous tissue of a scar. In fact, at the microscopic level, most of the atherosclerotic plaque looks just like the tissue in a scar. Scar tissue doesn't disappear very easily. Furthermore, when cholesterol is removed from the atherosclerotic core, it might be replaced and filled in by more scarring or fibrous tissue. So the plaque tends to stay, even when cholesterol is removed.
At this time, we don't know exactly how similar an atherosclerotic plaque is to a skin scar. A scar in the skin usually results from sudden cuts or tearing of the skin. The skin scar might shrink away or even disappear within a few months after the injury. A "scar" in the inner wall of an artery - that is, a plaque - results from years or decades of damage from cholesterol and inflammation. Does this mean that the arterial scar would require years to decades to shrink away? We don't know the answer. But consider this: if the skin were continually damaged every day, the skin scar would not shrink away. Instead it would probably continue to grow. In most people, this is exactly the situation that the arterial scar faces. It's difficult to remove the damaging factors from the artery wall, especially LDL cholesterol. Yet with new understanding of appropriate diet and lifestyle, as well as new drugs, it has become possible in recent years to greatly reduce the damaging factors (which are the same risk factors already discussed). As more powerful programs of risk reduction are used by motivated patients, we may yet see meaningful atherosclerosis regression.
Atherosclerosis regression, or shrinkage of the arterial scar, is very difficult, but the good news is that it usually is not necessary. The coronary blockages can be treated by balloons, stents, and/or bypasses. The risk of heart attack and stroke can be greatly reduced by removing cholesterol from the vulnerable plaque.
There is one more way that a narrowed artery might improve with time. In the earlier section on endothelial cells, it was mentioned that endothelial cells produce nitric oxide and other chemical signals that cause smooth muscle cells to relax. Over time, the pinched arterial wall can relax and stretch, and the channel for blood flow can enlarge. This is a slow process, and it works better if LDL cholesterol in the blood is reduced. Raising HDL cholesterol may also promote the endothelial/nitric oxide/smooth muscle system, according to a recent research study. Therefore, even if the atherosclerotic plaque does not shrink at all, the entire arterial wall may stretch to allow blood to flow better past the site of blockage. This improvement may depend on lowering LDL and possibly raising HDL cholesterol.
Thus a partially blocked artery could improve, in theory, either by shrinkage of the atherosclerotic plaque or by stretching of the entire arterial wall. When researchers have performed heart catheterizations to look for improvement in blockages, they cannot say which of these two mechanisms might explain the improvement. X-ray dyes outline the channel for blood flow, but cannot determine what is happening in the artery wall. Any improvement in the channel for blood flow is called angiographic regression.
Keeping in mind that angiographic regression does not necessarily mean shrinkage of plaques, we can discuss some research trials in which coronary artery blockages improved with diet, lifestyle, and drugs. Such trials give us an idea of what is required to achieve angiographic regression. The first report of coronary angiographic regression came from a study reported from the University of Southern California in Los Angeles. People who had undergone coronary bypass surgery at least 6 months previously were divided randomly into a group that received high dose drug treatment and a group that received modest drug treatment. The high dose drug treatment was colestipol 15 grams twice a day (about a tablespoon of a powder mixed with water, swallowed as a slurry, twice a day) and niacin also given in large doses. The films from coronary angiography were presented to "blinded" reviewers ("blinded" doesn't mean that they couldn't see the films, of course, but only that they did not know which film came before treatment and which came after treatment). After 2 years and again after 4 years, one out of six patients had an overall angiographic result that was better after treatment than before. Their arteries had opened up. Although it would seem disappointing that only one out of six improved, even this modest result was cheered, because it had never been seen before.
In 1987, a new drug came on the market. Lovastatin is, like penicillin, a complex chemical made by a mold or fungus. Merck pharmaceutical company developed lovastatin in the United States, following its discovery in Japan. Lovastatin (originally branded as Mevacor) continues to be an excellent drug in the statin class, along with pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor). These drugs given as small, once-daily tablets (5 to 80 mg) reduce LDL cholesterol more than any other drug, and similar to the effect of combining huge doses of colestipol and niacin as mentioned above.
Hopes were high that lovastatin and other statins might reverse atherosclerosis. But it did not happen. Research trials testing statins against placebo (sugar pill) medication showed that the usual progression of blockages (becoming more and more narrow with time) could be slowed by about half in patients given statins, but reversal occurred only in rare patients. In 2002, atorvastatin (Lipitor) given at a dose of 80 milligrams daily did lead to angiographic regression in most of a group of patients with familial hypercholesterolemia. This is an inherited condition found in 1 out of 500 people around the world, who usually have cholesterol levels of 350 milligrams/deciliter (mg/dl) without treatment. The reason for such a good response (actual regression) in these patients might have been their very high initial cholesterol levels.
Combining a statin with certain other cholesterol-modifying drugs in high enough doses might lead to angiographic regression in most people with coronary atherosclerosis. Some of the promising results have been achieved by the same research team in Seattle mentioned earlier, who showed probable removal of most of the cholesterol from atherosclerotic plaques in the carotid arteries. One treatment program included lovastatin 40 milligrams daily combined with high doses of colestipol. Another treatment program used niacin and colestipol in doses similar to those used in the Los Angeles study. The niacin-colestipol combination actually worked better in the Seattle trial than it did in the Los Angeles trial. Possible reasons are that more of the Seattle patients had high cholesterol levels or that the Los Angeles patients might have had less "active" atherosclerosis.
The Seattle research team also studied patients who had coronary atherosclerosis with low levels of HDL "good" cholesterol. LDL "bad" cholesterol levels in these patients were either normal or slightly high. Patients in the test group received simvastatin (Zocor) in a low to moderate dose and niacin in fairly high doses of 2,000 to 4,000 mg daily, usually divided into morning and evening doses. Patients who were randomly chosen to take placebo (that is, no real cholesterolmodifying medication) had the usual progression or worsening of coronary blockages. Patients in the test group showed slight angiographic regression.
Drug treatment is generally more powerful than dietary and lifestyle treatment for lowering LDL cholesterol and raising HDL cholesterol, but the research trial with the best result for angiographic regression used lifestyle and dietary training rather than drugs. An early, successful study of lifestyle treatment for anginal chest pain was actually planned and run by a medical student at Baylor College of Medicine in Houston, Texas in the early 1980s. With funding from a Houston developer, a group of people with anginal chest pain were housed together for a month in an elegant hotel, where they ate a vegetarian diet, exercised, and underwent relaxation and group therapy sessions. Their symptoms and their radionuclide stress tests improved. Later as a cardiologist in San Francisco, the same researcher refined his methods for measuring improvement in coronary blockages and ran a randomized research trial, in which 48 coronary patients were randomly chosen to enter a test group (with counseling and dietary change) or a control group (neither counseling nor dietary change). Exercise training in the test group was similar to that performed in cardiac rehabilitation programs all over the United States. Relaxation and visualization sessions had enthusiastic participation by the test patients; in fact, most patients did more than what the doctor asked. Many "vegetarian" diets include eggs and milk products, but this diet allowed only egg whites and nonfat dairy products. Thus the diet was more vegans than vegetarian. It was extremely low in fat. Both saturated and unsaturated fat added up to only 7% of total calories, compared to 35% in the usual American diet. The result of this lifestyle and dietary program after one year was angiographic regression of about 2% in the average coronary blockage. A follow-up study after 5 years showed further angiographic regression. This is as good as or better than the best drug trials.
Another research trial using dietary change to achieve angiographic regression was performed at St. Thomas Hospital in London. The key dietary changes were strong reductions in dietary saturated fat and cholesterol from animal food products (milkfat, meat, and eggs), calorie restriction to bring overweight patients down to normal body weight, and increases in polyunsaturated fatty acids (plant oils) and omega-3 fatty acids (fish and fish oils). In the group treated with this rigorous diet, angiographic regression was achieved. The coronary blockages opened up just a little, compared with the usual result of closing further in people not treated with diet.
In every one of the successful diet and drug trials performed so far, the measurement of angiographic regression improved by 0.2% to 2% per year. But the average measurement of total blockage, at the start of treatment, was in the range of 20% to 40%. Therefore, we have to ask how meaningful the results were. Diet, lifestyle, and drugs are not likely to replace balloon catheters, stents, and bypass grafts for the treatment of coronary or other arterial blockages anytime soon. Heart catheterization and/or bypass operations remain necessary to relieve anginal chest pain in most patients. Even so, the prevention of heart attacks and strokes needs diet, lifestyle, and drugs much more than heart catheterization and surgery, as we have already discussed.
Calcium, coronary calcium scans, and a dog that won't hunt
When doctors use the term "hardening of the arteries" to refer to atherosclerosis, people may think of bony hard arteries. In many cases, this is actually correct. "Bony hard" is an accurate description of many old, advanced plaques, in which a large amount of calcium is found. The calcium mineral in these plaques is very similar to bone calcium. Recently it has been discovered that cells of the arterial wall make many of the same proteins and enzymes made by bone cells.
Another fairly new discovery is that calcium deposits are found in early atherosclerosis as well as late, advanced atherosclerosis. Tiny microscopic nodules of calcium salts are found in the lipid-rich core of both early and mature atherosclerotic plaques. What is the calcium doing there? This question is being studied in the laboratory. Perhaps the best answer so far is that calcification is part of the inflammatory process. It results from inflammation in a lipid-rich tissue. Is the calcium good or bad? Again the answer is not known. We are quite sure, for example, that cholesterol is bad. Get rid of cholesterol, and the whole arterial wall can heal and improve. But at this time, we don't know how to get rid of the calcium, nor do we know how to prevent calcium deposits forming in the lipid-rich core. So it's not possible to tell whether calcium in the artery wall is good or bad. For now, calcium should be viewed as neutral, neither harmful nor beneficial - just there.
Calcium in the coronary atherosclerosis is good in one way. It allows us to see and measure atherosclerosis in the coronary arteries long before the atherosclerosis would usually cause a heart attack or anginal chest pain. The reason is that calcium shows up in an x-ray, while cholesterol does not. Ever since we have had x-rays, radiologists have noticed calcium deposits in large atherosclerotic arteries in the body. But the small size of the coronary arteries, the fact that they are surrounded by ribs and other bones, and most of all, the constant motion of the heart and its arteries all conspired to make the job of seeing calcium in the coronary arteries very difficult. In the early 1980s, a space-age computed tomographic (CT) scanner called an electron beam CT or ultrafast CT was invented. The electron beam CT scanner forms a 3-dimensional image of the heart in only 30 to 100 milliseconds, compared to one full second for a conventional CT scanner. The difference in timing is critical, making it possible for the electron beam CT to "freeze" the motion of the heart. Instead of seeing coronary calcium only in a few elderly people, the electron beam CT can visualize and measure very small amounts of coronary calcium in half of all men by ages 50-55 and in half of all women by ages 60-65. The new technology had 2 problems, however. First, it did not produce as sharp an image as conventional scanners, and thus the electron beam CT had few real uses beyond calcium detection in the coronary arteries. Second, each electron beam CT scanner was pricey, more than $2 million each with installation. The next breakthrough occurred in the late 1990s, when software programs were developed that allowed conventional CT scanners, found in every hospital in the United States, to visualize coronary calcium deposits almost as well as electron beam CT. The conventional CT used in this way can be called a "gated CT."
Research studies today are asking how to use this new technology to help in the detection and treatment of coronary atherosclerosis. Every year we learn a little more, but it will likely be a decade or two before we really understand how useful it might be and how to use it best. Some facts are becoming clear, as follows: (1) The amount of calcium seen on an electron beam CT (and probably gated CT as well) gives a very good estimate of how much atherosclerosis is present in the coronary arteries. (2) Older people have more calcium than younger people. This is mostly due to older people having more atherosclerosis, but it appears that older people have more calcium than younger people for the same amount of atherosclerosis. (3) African Americans have less calcium than Caucasians and Asians for the same amount of atherosclerosis. (4) A younger person, particularly a man under age 50 or a woman under age 60, can have enough atherosclerosis to have a heart attack or heart-related death without any calcium at all seen on electron beam or gated CT. (5) Even so, the presence and amount of calcium in the coronary arteries is a very strong predictor of future heart attack or heart-related death, about as strong a predictor as LDL cholesterol, HDL cholesterol, smoking, diabetes, and high blood pressure all considered together. (6) For people who have chest pain suspected to be from coronary blockage, stress tests and heart catheterizations should be performed. They are still the best procedures to make a diagnosis of blockage. (7) Finally, whether treatment of cholesterol and other risk factors will prevent a rising amount of calcium in the coronary arteries and whether a rising amount of calcium means an even higher risk of heart attack are unanswered questions at this time.
An older friend once told me a saying that he used for any proposal that looked reasonable at first glance, but on close inspection or testing was very unlikely to work. His brief comment was "That dog won't hunt!" It might have floppy ears, a big nose, and perhaps a loud bark, but it could not point out the birds or retrieve the ducks. The dog that won't hunt here is chelation therapy. Let me point out that chelation therapy does work for lead poisoning and for certain types of iron overload in the body. It is a necessary medical procedure for those reasons. The theory of chelation therapy is that metals, including calcium, can be removed from tissue by adding fluid with a dissolved chemical that binds up the metal, makes the metal dissolve, and removes the metal as the chemical and its bound metal are washed away. In fact, you can remove calcium from atherosclerotic plaques by chelation in the laboratory. So this dog has floppy ears and a big nose. There are several problems: The strength of the chelating fluid used in laboratory experiments for removing calcium would kill any animal or person. It can only be used on dead tissue. Furthermore, as stated above, we don't know whether removing calcium from plaques would help at all in atherosclerosis. Nobody has ever reported an experiment on chelation in animals with atherosclerosis. This may be because nobody who does animal atherosclerosis research has ever figured that chelation had enough of a chance to work to make it worthwhile performing the experiment. Then again, 85% of all the calcium in an animal or human is in the bones, not in the arteries. Chelation that really removes calcium from the arteries would likely also remove much of the calcium from bones. If you could prevent heart attacks in this way, you might end up just a jelly blob lying in bed, toothless and unable to get up and walk.
The argument is made that by getting the conditions just right, you can remove calcium from the arteries, stop chest pain, and cure atherosclerosis. How can we tell if it works? One thing has been clearly learned. We cannot rely on testimonials, even if the clinic has a list of people who say, "My anginal chest pain disappeared!" Anginal chest pain can wax and wane, getter better and worse, for no apparent reason. Chelation therapy, like any other medical treatment, must be tested in a clinical trial where people are randomly chosen to receive real treatment or sham (placebo) treatment. Such trials have been done. There was no hint of benefit for real chelation treatment over sham treatment. But there is one very evident result of chelation therapy. The patient feels tingling around the lips or in the fingers, as calcium levels in the blood are mildly reduced. So this dog has a kind of bark as well. But it won't hunt.
John R. Guyton, MD