The most common factor leading to blockage of the coronary arteries is atherosclerosis, a leading cause of death in Western, developed countries.

The initial causes of atherosclerosis are still not well-understood. Apparently, the process begins with damage to the endothelium lining the arterial walls. Atherosclerosis can then be viewed as a subsequent, nonadaptive response of the blood vessel to the damage. Increasingly, atherosclerosis is viewed as a disorder of chronic inflammation.

At the site where atheroclerosis is to develop, small lipoprotein particles cross the endothelium and accumulates in the tunica intima. This is usually said to be LDL cholesterol, although it may be more accurate to say that it is lipoprotein particles with the apolipoprotein apoB molecule. Oxygen radicals oxidize the apoB molecule and other molecules, making the particles particularly likely to be phagocytized by macrophages.

Macrophages also are accumulating at the site of atherosclerosis. This occurs as monocytes and platelets adhere to the endothelium at the site of damage, with the monocytes migrating through the endothelium and becoming the macrophages. The macrophages bind the oxidized lipoprotein using their innate receptors to bind apoB, take up the lipoprotein by phagocytosis, and unfortunately lose their mobility.

Normally macrophages would transfer their phagocytized lipid to HDL. But for whatever reason, the lipid is not effectively cleared from the macrophages in this way.

Eventually the macrophages take up so much cholesterol they are termed foam cells. These accumulate in the expanding plaque in the tunica intima of the artery. At this point, the wall of the artery is at the fatty streak stage.

The macrophages, platelets and epithelial cells release growth factors that stimulate the growth of nearby smooth muscle cells and fibroblasts. Smooth muscle cells migrate from the tunica media into the intima. Some of these deposit additional connective tissue, and as the abnormal region grows it becomes a fibrous plaque. As the plaque expands in size, the central region tends to become necrotic, with the degenerating cells releasing cholesterol crystals. The term fibrous cap refers to the fibrous region lying between the necrotic core and the blood.

With growth, the plaque slowly begins to occlude the artery. Surprisingly, about three-quarters of the cross-sectional area of the coronary artery must be blocked before symptoms begin to appear. With time the plaques tend to become calcified. The stability of different plagues can vary, depending apparently on the thickness of the fibrous cap overlying the main portion of the plaque. A calcified plaque with a thick fibrous cap tends to be the most stable.

Symptoms Due to Inadequate Blood Flow

As the lumen of the vessel narrows, at some point there may be ischemia, which is the term for inadequate blood flow due to an obstruction. All arteries are not affected uniformly by atherosclerosis, but rather just those in certain places, depending on the individual.

If a coronary artery is too narrow, pain will occur with exertion when the heart requires more blood. This pain, of course, is referred to the body surface, and in this case is called angina pectoris.

Another common location for atherosclerosis is the distal aorta, the iliac arteries and femoral artery. This may reduce flow to the legs enough that a person may feel pain in the calves with even mild exercise. This is called claudication and is the main reason for measuring the ankle-brachial index.

The common carotid is another major location where atherosclerosis may occur. Someone constriction here may cause marginal blood flow to the brain, so that the person has a tendency for syncope, which is fainting due to low cerebral blood flow. But there are other causes of syncope, which we will discuss later.

Symptoms Due to Infarction

Atherosclerotic plaques may be reasonably stable, so that any symptoms are due to ischemia. This tends to be the case if the fibrous cap is thick. Such a plaque may also be calcified.

On the other hand, if the fibrous cap is thin, it may rupture. This exposes the necrotic core to the blood, including the extracellular lipids, which strongly promote clotting. As the clot grows larger, it may break free and lead to an infarction. In a coronary artery, a myocardial infarction results when the clot breaks free and clogs the artery. On the other hand, in the common carotid, a clot forming and breaking free leads to a stroke.


Another type of problem in arteries is an aneurysm, which is a localized dilation of an artery at a point of weakness in the wall. Often these are congenital. For example, small, spherical aneuryms of a cerebral artery, called berry aneurysms, are a possible location for a hemorrhagic stroke, which is a stroke that occurs due to a break in the wall rather than a clot. An aneurysm clip is in one of the brains in the lab.

The term aneurysm can also be used for a circumscribed dilation of the wall of a chamber of the heart due to damage to the wall. (But the term is not used for a generalized dilation, such as might occur in systolic heart failure.)

But in other situations an aneurysm may be due to atherosclerosis. An especially common type is an abdominal aneurysm at the distal end of the aorta. Sometimes the dilation is fist-sized or larger.

Risk Factors in Atherosclerosis.

As anyone who reads the popular press is aware, there are many divergent, yet still authoritative, opinions about the risk factors for atherosclerosis. Definite, major risk factors include hypertension, cigarette smoking, obesity, and diabetes mellitus. Moreover, high levels of cholesterol in the blood correlate with a more rapid progression of atherosclerosis. Most cholesterol in the blood is found in the low density lipoprotein fraction, and it is this cholesterol that accumulates in atherosclerosis. By contrast, cholesterol is removed from tissues via high density lipoprotein, and increased levels of this lipoprotein correlate with a reduced incidence of atherosclerosis. We will go a little further into hyperlipidemia in lecture.

Risk calculating tools are available for estimating a person's risk for a myocardial infarction or stroke. The calculation is based on long-term epidemiological studies with large populations. The results are used to estimate a person's risk of a myocardial infarction or stroke in the next 10 years. The factors usually included are the person's age, gender, weight and height, total cholesterol, HDL cholesterol, blood pressure, and the presence or absence of diabetes and smoking. Various calculators are on the web, for example, a recent one is at risk calculator.

Attempts have been made to improve the accuracy of this risk calculation by adding other factors. For example, the plasma level of C-reactive protein, which is a marker for inflammation, has had some success. Also, adding the ankle-brachial index, which we measured in lab, improves the accuracy of the prediction, presumably because a low ratio reveals that significant atherosclerosis is already present.


Here is the link to the page from last quarter on Cholesterol, Lipoproteins & the Liver. You are responsible once again for the information under "Disorders and Drug Treatments".