The Coronary Cascade - What Is Heart Disease: Heart Disease

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The coronary cascade

Researchers have learned that heart attacks aren't just the result of a buildup of fatty plaque in the arteries or of the formation of blood clots on those plaques. The emerging picture is more complex, involving inflammation of the blood vessels as well as the buildup of fatty plaque (see Figure 2). To get an accurate idea of the complex processes involved in coronary artery disease, it's helpful to look at the cascade of events that leads to a heart attack.

Figure 2: Got plaque? Plaque is the fatty substance that builds up inside your artery walls. The process begins when the endothelial cells that line your arteries are injured by oxidized LDL cholesterol, smoking, diabetes, or something else. This prompts the release of chemical messengers called cytokines (A). Next, LDL begins to build up inside the injured artery wall, causing inflammation. The cytokines call white blood cells known as macrophages to the scene (B), which ingest the LDL and swell into fat-laden foam cells (C), causing further inflammation. A thin, fibrous cap (D) forms over the fatty plaque, but it can rupture, causing clot formation and heart attack.

Stage 1: Abnormalities in blood cholesterol

Cholesterol belongs to the class of chemicals known as lipids. Cholesterol performs a number of vital functions in your body: It helps maintain cell membranes, is the backbone for the bile acids that are essential for digestion, and is an important precursor to vitamin D and a number of hormones. In fact, this substance is so important that the body can produce its own supply from raw materials such as fat, glucose, and protein when diet alone does not supply enough. The health problems begin when blood levels of cholesterol become abnormal, initiating the first event in the coronary cascade.

Cholesterol travels in the bloodstream within spherical particles called lipoproteins. There are five major classes of lipoproteins: chylomicrons (the largest and least dense), very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL, the smallest, heaviest, and least fatty).

On average, about two-thirds of blood cholesterol is in the form of LDL. The higher the level of LDL cholesterol, the greater the risk for atherosclerosis, coronary artery disease, and heart attack. That's because excess LDL cholesterol leaves the blood and lodges in the artery walls, initiating the inflammatory response that is central to coronary artery disease.

Where a villain lurks, a hero can often be found. When it comes to cholesterol, HDL is the hero. Whereas LDL deposits cholesterol in the blood vessel walls, HDL carries cholesterol away from the arteries to the liver, where it's metabolized into bile salts that are eliminated harmlessly from the body via the intestinal tract.

Stage 2: Changes in the artery wall

Once LDL penetrates the artery walls, the next step in the coronary cascade begins. Every artery wall has three layers; two are involved in atherosclerosis.

The inner layer, or intima, consists of a delicate layer of cells known as endothelial cells. Normally the endothelial cells secrete many molecules that keep blood flowing smoothly and keep just the right amount of flow headed to tissue downstream. These cells produce nitric oxide, a tiny molecule that widens the artery to allow more blood to pass through. Nitric oxide also helps keep the artery's inner lining smooth and slippery so that white blood cells and platelets, the fragmentary blood cells that initiate the clotting process, can't latch on. Endothelial cells also produce substances like endothelin, a chemical that narrows arteries, to adjust blood flow.

The middle layer of the artery wall, or the media, is where the cholesterol-laden deposits of atherosclerosis develop. Composed chiefly of smooth muscle cells, the media can increase or restrict the flow of blood in an artery. When the cells of the media relax, the artery widens. When those cells contract, the artery narrows. Nitric oxide and endothelin are among the messengers that tell the smooth muscle cells to relax or constrict. But when the arterial wall is injured by cholesterol, the smooth muscle cells enlarge, contributing to the development of plaque.

Stage 3: Adding inflammation to injury

Although endothelial cells play a role in keeping arteries healthy, they can't prevent LDL cholesterol from passing out of the blood and into the artery wall. Making matters worse, any injury to the endothelial layer (caused by high blood pressure, smoking, or diabetes, for example) speeds this process. Once in the arterial wall, the LDL triggers a harmful sequence of events.

After the LDL particles lodge in the artery wall, inflammation and injury result. Injured endothelial cells can't produce nitric oxide normally. They also send out distress signals, in the form of cytokines, which draw white blood cells to the scene. These cells, called monocytes and macrophages, gobble up the LDL cholesterol in the artery wall. In the process, they enlarge and transform into fat-laden foam cells.

The foam cells can't dispose of all the toxic LDL. Instead, the LDL injures the foam cells that ingest it, and many die, releasing a soft, fatty gruel that causes advanced atherosclerosis and provokes further inflammation. In an apparent attempt to seal off the inflammation, smooth muscle cells in the artery wall enlarge and proliferate, forming a fibrous cap over the whole mess and adding to the bulk of the plaque.

Stage 4: Pulling the trigger

Large plaques, of course, can block blood flow more than small plaques, but some smaller plaques can be the most dangerous. This is because atherosclerotic plaques are not just passive plugs that block arteries like a cork in a bottle. They are active, dynamic lesions teeming with inflammatory T cells (another type of white blood cell) and macrophages, as well as cholesterol. Large plaques tend to be covered by thick, fibrous caps that can resist breaking apart even though they are holding a fatty core in place. Smaller plaques sometimes have very thin, underdeveloped fibrous caps that rupture easily and start blood clotting, even though the plaque itself is too small to block blood flow.

About three-quarters of all heart attacks result when plaques rupture. This occurs after a two-pronged attack on collagen that degrades the fibrous cap until it breaks. First T cells tell smooth muscle cells in the fibrous caps to stop producing collagen, and then macrophages produce enzymes that degrade collagen.

Stage 5: The final insult

Once a plaque ruptures, the T cells send a signal that provokes the macrophages to release a protein called tissue factor. As tissue factor spills out and encounters circulating blood, it attracts platelets. The platelets adhere to the surface of the disrupted plaque. Once activated, the platelets trigger an interaction of the blood proteins that help create clots. The result is a thrombus — a clot of red blood cells, platelets, and other material — that completes the blockage (see Figure 5) and prevents blood from reaching the heart cells downstream. Deprived of blood and oxygen, a portion of the heart muscle dies.

Last updated:	May 03, 2007