With the passage of time, an atherosclerotic core that begins as a small cholesterol-rich disruption of tissue deep in the intima will spread upward and outward. In the thickened area that makes up the atherosclerotic plaque, a well-developed atherosclerotic core will occasionally occupy 70% of more of the intimal tissue. As the core spreads upward, it can eventually erode the living tissue very close to the inner surface of the artery, next to flowing blood. The core usually does not reach the surface, but it drastically weakens the intimal tissue. At some moment, the overlying intimal tissue tears or ruptures. When this happens, pressure and flow cause blood to rush into the weakened tissue of the atherosclerotic core. In addition, the cholesterol-laden contents of the core may be expelled into the flowing bloodstream. Contact between the blood and the atherosclerotic core material is a rapid, churning event. The core material quickly causes blood clotting . This is the way that most heart attacks and strokes happen.
Cardiologists and radiologists often inject dyes into arteries to outline the area occupied by flowing blood, revealing atherosclerotic plaques as narrowings in the bloodstream shown by the dye. Sometimes an angiogram shows a plaque with a small outpouching, giving angiographic evidence of a ruptured plaque.
Pathologists have asked what characteristics make atherosclerotic plaques prone to rupture. The key characteristics fall into 3 categories: (1) extensive deposits of cholesterol and other lipids, (2) thin caps of the atherosclerotic lesions overlying the core lipids (these are called "fibrous caps"), and (3) evidence of inflammation in the fibrous caps. The inflammatory component is interesting, because it may offer the possibility of preventing plaque rupture in new ways. The number of macrophages found in the fibrous caps of atherosclerotic plaques is higher in people with many ruptured plaques. (Of course, one can only count macrophages at autopsy, in a person who has already died; this doesn't help the person being examined!) Furthermore, the macrophages make enzymes that can break down the strong fibrous proteins of the cap, and these enzymes are prominent at sites of plaque rupture. Research efforts are under way to find drugs that might reduce the numbers of macrophages in the fibrous cap or inhibit the macrophage enzymes responsible for dissolving the fibrous proteins of the cap.
Blood Clotting, Heart Attacks, and Strokes
Macrophages contribute to the clots that cause heart attacks and strokes in yet another way. Macrophages in and near the atherosclerotic core make a protein called "tissue factor," which is the primary factor that activates clotting when core material comes into contact with blood.
A tiny blood cell called the platelet, which is much smaller than red blood cells and white blood cells, participates actively in blood clotting. When platelets come in contact with atherosclerotic core material, they quickly change shape, becoming flatter and disk-shaped, and become extraordinarily sticky. If the conditions are right - that is, when tissue factor is around - blood proteins join with the platelets to make a rapidly growing clot. Most clots that cause heart attacks probably happen within a minute after the rupture of an atherosclerotic plaque.
A blood clot that causes a heart attack grows and extends across the width of the coronary artery until it completely blocks blood flow. The person in whom this occurs does not feel any pain until the clot is choking off almost all the blood flow. The heart muscle downstream, which no longer receives the oxygen it needs to continue its rhythmic contraction, sends powerful pain signals to the brain.
Sometimes a blood clot, developing over a ruptured atherosclerotic plaque, does not extend all the way across the coronary artery. If the clot goes only halfway across, the person generally will feel nothing at all. The blockage of blood flow is not enough to cause the heart muscle to cry out in pain. This kind of clot probably happens much more often than complete clots that cause heart attacks. The partial clot is not entirely harmless, however. Over a period of weeks, cells of the arterial grow into and over the clot. This kind of clot eventually becomes part of an enlarged atherosclerotic plaque. The channel for blood flow in the artery is narrowed, and the stage is set for an actual heart attack.
Almost every heart attack is caused by a blood clot forming over a ruptured or ulcerated atherosclerotic plaque. Strokes also are caused quite often by ruptured or ulcerated atherosclerotic plaques, but some strokes have causes other than atherosclerosis. For example, some strokes happen because of blood clots that form in the heart chambers and travel in the bloodstream to the brain, and some strokes are due to small blood vessels that burst and bleed into the brain. Atherosclerosis is not the cause of these strokes. One of the key jobs of the physician is to figure out whether a stroke has been caused by atherosclerosis or something else.
About 7 out of 10 strokes, nevertheless, are caused by blood clots that form over a ruptured or ulcerated atherosclerotic plaque. Usually the plaque responsible for a stroke is found in one of the large carotid arteries in the neck. You can feel the pulse of the right or left carotid artery by placing your finger in a location midway between your Adam's apple and the back of your jaw. The carotid artery has an inner diameter about 3 to 4 times larger than the diameter of a major coronary artery. When a blood clot develops over a ruptured atherosclerotic plaque in the carotid artery, the clot usually does not grow big enough to extend entirely across the large diameter of the artery. Instead, a clot may develop, only to break away from the plaque and be swept downstream by the flowing blood. The clot, which can now be called an "embolus" because it is thrown off the arterial wall, enters the smaller and smaller branches of the carotid artery within the brain. Finally it stops when it is wedged into an arterial branch smaller than the size of the embolus. Blood flow in this arterial branch stops, and tissue death occurs in the part of the brain supplied by the arterial branch.
When a plaque ruptures and exposes flowing blood to the tissue factor from the plaque core, clotting of the blood is stimulated very strongly and quickly. Is it possible to protect against the stimulation of clotting? In other words, can the blood clots be prevented, even if plaque ruptures continue to happen? The answer is that approximately one out of every 4 or 5 heart attacks and strokes can be readily prevented by aspirin, which partially blocks the clotting of blood. Aspirin does not prevent plaque rupture, but can block clotting enough that blood continues to flow, or enough that no embolus is produced. Under some circumstances, a health care provider will choose to prescribe somewhat more powerful clotting inhibitors such as clopidogrel (Plavix), dipyridamole-aspirin combination pills (Aggrenox), or warfarin (Coumadin). Whether aspirin should be used along with these prescription medications is a decision for the health care provider to make.
It is possible to completely block blood clotting, but such a strategy would have terrible consequences. Blood clotting is necessary to prevent bleeding when blood vessels are cut or stretched too far. Bleeding that occurs internally in stomach or intestines, or in the brain, can be fatal. (One type of rat poison simply causes excessive bleeding that kills the rats.) Thus there is a limit to what can be done for prevention of heart attacks and strokes by blocking blood clotting.
John R. Guyton, MD