Arteries, which are blood vessels that carry blood from the heart out to all the tissues of the body, are formed by a remarkable interaction between lining cells - endothelial cells - and arterial wall cells - smooth muscle cells. The faster blood flows through an artery, the larger it will grow. We can take advantage of this fact by using exercise to create rapid blood flow through the coronary arteries. Exercise seems to strongly prevent coronary atherosclerosis, and a key mechanism may be the production of nitric oxide by endothelial cells exposed to rapidly flowing blood.
The intima - the innermost layer - of the artery is the place where atherosclerosis develops. Atherosclerosis is a disease in which cholesterol builds up in the intima and damages the inner lining of the artery. This disease is so dangerous to human life that it causes about one-third of all deaths in modern, industrialized countries of the world.
The arterial intima is a connective tissue. However, unlike almost all other connective tissues in the body, the intima has no lymphatic vessels to drain away excess proteins that leak across the endothelial lining. Because of the lack of lymphatics, the concentration of low density lipoproteins (LDL, sometimes called "bad cholesterol") in the arterial intima is 10 times higher than it is in any other connective tissue in the body. This sets the stage for atherosclerosis. The concentration of LDL in the intima is about equal to LDL concentration in blood. The LDL concentration in blood is a strong risk factor for atherosclerosis. Other factors that raise the risk for atherosclerosis include tobacco use, high blood pressure, diabetes, male sex, and low levels of high density lipoproteins (HDL, or "good cholesterol").
In addition to endothelial cells and smooth muscle cells, inflammatory cells enter the arterial wall from the blood in atherosclerosis. The high concentration of LDL in the intima seems to be a major reason for the entry of inflammatory cells. C-reactive protein in the blood is a marker for inflammatory stimulation in the body, and C-reactive protein is also a very strong risk factor for atherosclerosis.
The earliest lesions (abnormal spots) of atherosclerosis are fatty streaks, which contain inflammatory cells loaded with cholesterol, called foam cells. As time passes, some fatty streaks develop another kind of cholesterol deposition outside of cells in the deep intimal layer. These cholesterol deposits become the lipid-rich core of the atherosclerotic plaque. The plaque grows by fibroproliferation to become a thickened area in the inner artery wall. The deep lipid-rich core also expands, and it may undermine and erode the living artery wall tissue all the way up to the inner surface of the artery wall. If this happens, the inner surface can break or rupture. Weakening of the arterial tissue seems to be caused by a combination of cholesterol and inflammation. When flowing blood comes into contact with the lipid-rich core of a ruptured plaque, the blood can clot within one to a few minutes.
LDL are lipoproteins that carry cholesterol into the artery wall. HDL are lipoproteins that can pick up cholesterol from the artery wall and direct the cholesterol back to the liver. This is consistent with the fact that people with high levels of HDL have fewer heart attacks and strokes. The final event in the history of some atherosclerotic plaques is the blood clot that forms over the ruptured plaque. If the clot blocks enough blood flow to the heart or brain, then a fatal heart attack or stroke can happen. Certain medications, including aspirin, can help to prevent the formation of clots and thus help to prevent heart attacks and strokes.
Reversal or regression of atherosclerosis is a goal often sought by patients. Sometimes regression cannot be achieved. When it does occur, it is difficult and slow. Widening of the narrowed channel for blood flow, called angiographic regression, could happen in one of two ways. Either the plaque shrinks, or the whole arterial wall relaxes and expands. Most angiographic regression probably results from relaxation and expansion of the whole arterial wall. If only one cholesterol-modifying drug is used, angiographic regression is not achieved in most patients, but combinations of drugs can achieve regression. Two trials of diet and lifestyle have also achieved regression. Significant arterial narrowings are usually narrow the channel by 70% or more. When angiographic regression is seen, the average extent of the regression is one to a few percent. This is not enough to replace the need for coronary bypass operations and heart catheterization balloon and stent procedures.
While bypass operations and balloon-stent procedures effectively relieve anginal chest pain, they usually do not reduce the risk of heart attacks very much. One of the discoveries of the 1990s is that giving drugs such as statins to lower LDL can reduce the risk of heart attacks and strokes by 25% to 40%. Early evidence also suggests that risk can be reduced further by using drugs that raise HDL. These discoveries have led to a new idea that vulnerable atherosclerotic plaques - that is, plaques prone to rupture because of a large lipid-rich core - can be stabilized to prevent rupture. A recent research study using magnetic resonance imaging brings up the possibility that most of the cholesterol in an atherosclerotic plaque might be removed by using drugs that lower LDL and raise HDL. This could lead to stabilization of the vulnerable plaque.
Calcium is deposited in the lipid-rich core of early atherosclerotic plaques, and late atherosclerotic plaques sometimes become heavily calcified. This fact is useful in detecting coronary atherosclerosis at an early stage and in measuring the extent of coronary atherosclerosis. Special techniques of CT scanning (computed tomographic scanning) are needed to detect and measure coronary calcium deposits. Research studies today are asking how CT scanning might be used to help fight coronary atherosclerosis and prevent heart attacks. Like other ways of diagnosing heart disease, CT scanning is not foolproof. Many questions remain to be answered. The presence of calcium in coronary atherosclerosis might seem to support the idea of chelation therapy in treatment. However, on closer inspection, the evidence says that chelation therapy won't work and doesn't work.
Thousands of diseases affect humankind. It is a remarkable fact that just one disease -atherosclerosis - causes about one-third of all human deaths in modern societies, as well as much suffering and early death. Just 30 to 40 years ago, coronary heart disease and stroke were mostly accepted as facts of life, and it was thought that little could be done about them. We now have coronary care units, bypass operations, and sophisticated heart catheterization procedures that are effective in people with chest pain, but don't work very well to prevent future heart attacks and strokes. As we learn more about atherosclerosis, and especially about the roles of cholesterol and clotting, it is becoming clear that most (and someday nearly all) heart attacks and strokes can be prevented.
John R. Guyton, MD