Atherosclerosis is the single most deadly disease in the United States. At one time, researchers used to think of arteries as roughly analogous to plumbing pipes. In recent years, however, our understanding of arteries, and arterial disease, has been greatly enhanced. In fact, arteries are muscular organs that contract along with the heart to enhance blood flow and help maintain blood pressure.

Arteries are highly sensitive to a number of chemicals and hormones that help regulate their function. These chemicals act upon, and are sometimes excreted by, the inner lining of the artery, or the endothelium. Researchers have learned that long before atherosclerosis becomes clinically apparent, this thin layer of cells has already been damaged and the earliest plaque deposits have already formed. Indeed, atherosclerosis often begins in early childhood, and it rarely is limited to the coronary arteries. In most cases, if a person has atherosclerotic plaque deposits in their coronary arteries, other arteries are also affected.

The underlying defect, or cause, of atherosclerosis often remains unknown. However, researches have made great strides forward in understanding the process by which damage to the endothelial cells early in life can later evolve into a heart attack as an adult. It is now thought that the atherosclerotic process is mediated by immune-related inflammation. LDL cholesterol molecules also play an important role in the development of atherosclerosis.

According to this theory, arteries are damaged, which provokes a local immune response at the site of the injury. White blood cells gather at the site of the injury and begin to secrete chemical messengers that cause inflammation. This is a normal immune system reaction that occurs in an inappropriate place. At the same time, the protective endothelial layer has been compromised, allowing LDL "bad" cholesterol cells to migrate into the inner layer of the artery. This further aggravates the injury, which causes more white blood cells to gather. Other fatty materials in the bloodstream (e.g., triglycerides) also begin to gather at the injury. Together, these materials combine to form a lipid foam. This foam forms fatty streaks.

Over time, these fatty streaks grow larger, eventually attracting circulating blood platelets and evolving into plaque deposits on the inside of the artery wall. Not all plaque deposits pose the same threat. Some plaque deposits develop a relatively hard "shell" of minerals in a process called calcification. These types of plaque are considered to be stable plaques. They are less likely to rupture and cause a heart attack. Other types of plaque are known as unstable plaques, which, in comparison to stable plaques, have the following:

• A larger fatty core
• More white blood cells encased within
• A thinner, softer, more unpredictable coating that might be stripped off without warning

The exact trigger of a plaque rupture is unknown. However, it can occur as a result of a strong, fast blood flow, especially during heavy exertion or emotional stress, when the coating is thin and the core of fat/white blood cells is particularly full. 

During a plaque rupture, the fatty core of the plaque deposit is exposed to circulating blood, while pieces of the plaque travel downstream into the artery. At this point, several different events might occur. The site of the plaque rupture might attract platelets, which start a clotting cascade and form a blood clot (thrombosis). This blood clot may grow big enough to obstruct blood flow. Alternatively, it may break off and travel down the artery until it becomes lodged in a smaller artery. Finally, the pieces of the plaque may themselves become trapped in an artery, blocking blood flow. Any of these scenarios results in a heart attack. The severity of the attack will depend on which coronary artery is blocked, how dependent the heart muscle was on that source of blood supply and the extent of the blockage.

Researchers have found that almost 80 percent of first-time heart attack patients had ruptured plaque located both where the heart attack occurred and at other, distant sites. Researchers concluded that a heart attack is often not the result of one, discrete area of plaque damage. It may be separate areas of plaque rupture that combine to make the heart less stable and therefore vulnerable to a heart attack, a concept known as (pancoronaritis).

Heart attacks may also be caused by a coronary artery spasm, a temporary constriction of an artery in the heart.