Experiments on cultured cells and animals now indicate that the trouble begins when LDLs from the blood collect in the intima, the part of the arterial wall closest to the bloodstream. At reasonable concentrations in the blood, LDLs can pass in and out of the intima, which consists mainly of the endothelial cells that line vessel walls, the underlying extracellular matrix (connective tissue), and a smattering of smooth muscle cells (matrix producers). But in excess, LDLs tend to become stuck in the matrix.
As the LDLs accumulate, their lipids undergo oxidation (similar to the processes that rust pipes and spoil butter) and their proteins undergo both oxidation and glycation (binding by sugars). Cells in the vessel wall seem to interpret the changes as a danger sign, and they call for reinforcements from the body’s defense system.
In particular, endothelial cells display adhesion molecules on their blood-facing surface. These molecules latch like Velcro onto quiescent inflammatory cells known as monocytes, which normally circulate in the blood. This interaction causes the cells to drop from the circulation and to roll along and attach to the artery wall. The modified LDLs also spur the endothelial cells and smooth muscle cells of the intima to secrete chemicals called chemokines, which attract monocytes. Much as hounds track the scent of their prey, the monocytes squeeze between endothelial cells and follow the chemical trail to the intima.
Chemokines and other substances elaborated by the endothelial and smooth muscle cells then induce the monocytes to multiply and mature into active macrophages: fully armed warriors, ready to unleash their various weapons against the body’s enemies. These warriors also set about clearing perceived invaders from the vessel wall. Reacting to proteins emitted by stimulated endothelial and intimal smooth muscle cells, the macrophages decorate their surface with molecules called scavenger receptors, which capture modified LDL particles and help the macrophages ingest them. The macrophages ultimately become so packed with fatty droplets that they look foamy when viewed under a microscope. Indeed, pathologists refer to the fat-filled macrophages as foam cells.
Just as monocytes follow adhesion molecules and chemokines into the intima, so do T lymphocytes, white blood cells that represent a different branch of the immune system. These lymphocytes also release cytokines that amplify inflammatory activities in artery walls. Together the foamy macrophages and a lesser number of T lymphocytes compose the so-called fatty streak, a precursor of the complex plaques that later disfigure arteries. Disturbingly, many Americans harbor nascent plaques as early as their teens.
Fueling Plaque Growth
WHEN AN INFLAMMATORY response in, say, a scraped knee successfully blocks an infection, macrophages release molecules that facilitate healing. A “healing” process also accompanies the more chronic, low-level kind of inflammation that operates in atherosclerosis. Instead of restoring artery walls to their original state, though, the process perversely remodels— changes the character of—the wall, eventually generating a bigger, more complicated plaque.
In recent years, biologists have learned that macrophages, endothelial cells and smooth muscle cells of the inflamed intima secrete factors that prod smooth muscle cells of the media (the tissue under the intima) to migrate to the top of the intima, replicate and synthesize components of the extracellular matrix. The cells and matrix molecules coalesce into a fibrous covering overlying the original atherosclerotic zone. As this “cap” matures, the zone underneath generally changes somewhat. Most obviously, some fraction of the foam cells die, releasing lipids. For this reason, pathologists denote the region under the cap as the lipid or necrotic core.
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Add CommentLinus Pauling wrote in 1986 that vitamin C decreases LDL and increases HDL in the blood. C binds to cholesterol and transports it to the liver, where it is converted to bile and excreted. Vitamin C is a component of collagen, an essential structural component of arteries. Dr. Pauling wrote that atherosclerotic plaque is an evolutionary adaptation to the chronically low levels of vitamin C in humans, one of the few species who do not synthesize vitamin C internally. The medical-pharmaceutical establishment does not advocate vitamin C to prevent heart disease because there is far greater profit in treating heart disease, by means of medical procedures and drugs.
Reply | Report Abuse | Link to thisAlthough most people don’t realize it, atherosclerosis is a disease which, in addition to being a lipid storage disorder, also has components of inflammatory and immunologic disease. Thanks to television commercials, the cartoon image of cholesterol plaques that most people have in their head is if a yellow cholesterol plaque stuck to a red arterial wall. The truth is that most of that yellow plaque is not make up of cholesterol; it is made up of the body’s own cells responding to an endothelial disturbance, in addition to cellular markers of inflammation such as TNF-a, IL-6, hsCRP, foam cells, among many others. One of the main differences in the effectiveness of HMG CoA reductase inhibitors or “statins” in addition to their ability to increase the metabolism of cholesterol, is their ability to decrease inflammation. The two drugs that are best at decreasing inflammation cholesterol metabolism are Lipitor (atorvastatin) and Crestor (rosuvasatin). No currently marked drug exists which can affect the immunologic or cell migration effect in atherosclerotic plaques.
Reply | Report Abuse | Link to thisI suggest a new round of actualization now in 2010. Influenza would sure receive more consideration today regarding myocardial infarction triggering. But I continue to insist that triggering not its sole contribution.
Reply | Report Abuse | Link to thisMaria Ines Azambuja, MD
see Connections Braz J Med Biol Res January 2008, Volume 41(1) 1-4
I came to this article to see what a respected institution had to say about the causes of Atherosclerosis. The lipid theory has been significantly discredited by most research untouched by big pharma. This piece while not directly advocating it is pointing to statin therapy, and relating Atherosclerosis to LDL levels. When research said that there is no difference amongst patients who have had a heart attack in terms of their cholesterol levels - the proponents say we need to lower the LDL threshold, despite the almost total lack of evidence that LDL serum levels have anything to do with MI. What is disappointing is that there is NO discussion about what causes the inflammation in the first place. The levels of MI in our society have increased steadily in the past 100 years or so. These breakthroughs (in statin therapy) have not provided any solution to this health issue. The key is understanding lies in what causes the inflammation that leads to Atherosclerosis and modifying our lifestyle and diet to suit. The information must be there somewhere - there is somehting that has changed in the past 100 yrs that have made this MI epidemic, but maybe its not in the interest of some stakeholders for us to find out. Unfortunately SA have added more fuel to the old song about cholesterol myth and I await patiently when this Stalin billion dollar scam blows open.
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