Beyond Cholesterol: How Atherosclerosis Develops

Beyond Cholesterol: How Atherosclerosis Develops

© 2006 Wellness Clubs of

Historians know that a number of significant milestones occurred in 1815. In that year Napoleon was defeated at the Battle of Waterloo. Andrew Jackson’s forces defeated the British in the Battle of New Orleans. In that year John Stevens was granted the first railroad charter in the United States. Humphrey Davy patented the miner’s safety lamp, which dramatically lowered the risk of explosions in coal mines.

The year was also significant in the history of medicine. Dr. Joseph Hodgson, a British surgeon discerned that the atherosclerotic process begins in the lining of arteries. Based on his observations he proposed that the underlying cause of atherosclerosis was not aging, as had been thought, but rather inflammation of the arterial lining. Unfortunately, 1815 was also the year in which the substance we call cholesterol was discovered. Medical research turned its attention to cholesterol and Dr. Hodgson’s inflammation hypothesis was all but forgotten for nearly 200 years.

The “cholesterol is harmful” hypothesis, however, has proven false. Heart attacks remain a leading cause of death in the United States after over thirty years of aggressive efforts to lower cholesterol levels in our society. Approximately 500,000 people die prematurely of heart attacks each year, a number that has remained relatively constant in spite of a marked decrease in the level of cholesterol deemed acceptable and a dramatic rise in the number of individuals taking cholesterol-lowering medications. As I detailed in last month’s issue, cholesterol is not harmful, it is essential for optimum health.

Medical scientists have taken great strides over the past decade in discovering the actual cause of atherosclerosis and its end products of heart attacks, strokes, aneurysms, and peripheral artery disease. As researchers have taken their focus off of cholesterol and broadened their search for the mechanism of heart disease Dr. Hodgson has slowly been vindicated. He is beginning to be recognized as a visionary who was nearly two centuries ahead of his time.

Our current understanding of the atherosclerotic process is, to very great extent, the result of the work of Dr. Russell Ross, a pathologist at the University of Washington Medical School. In 1973 Dr. Ross suggested that localized injury to an arterial wall triggers plaque formation. A year later he and his colleagues identified a substance, platelet-derived growth factor, which stimulates abnormal smooth muscle growth at sites of injury. He also guided research regarding the role of specialized white blood cells, called macrophages, in the generation of an atherosclerotic lesion.

Dr. Ross’ research confirmed Dr. Hodgson’s hypothesis. Inflammation leads to injury of the arterial lining, which triggers a cascade of events that can ultimately lead to complete blockage of the artery. Cholesterol is involved in the atherosclerotic process, but not because it is inherently harmful. It is merely a participant in the process; it is not the cause.

A team of Italian researchers led by Filippo Crea, M.D. have also contributed greatly to our current understanding of the process. In 1994 Dr. Crea and his colleagues found that a substance called C-Reactive Protein (CRP), a non-specific indicator of inflammation, was elevated in patients presenting to their hospital with unstable angina. Unstable angina is a condition that suggests that a heart attack is about to happen. Two years later they demonstrated that another inflammatory marker, interleukin-6, is also elevated in many patients with unstable angina.

The Italian researchers went on to show that white blood cells, called macrophages, are active in the artery walls when inflammation is present. They also demonstrated that patients with unstable angina have a high incidence of narrowing in their carotid (neck) arteries as well. They have found that CRP levels greater than 3 mg/l are associated with complex carotid plaques as well as unstable coronary plaques, effectively proving Dr. Hodgson’s inflammatory hypothesis.

The term atherosclerosis comes from two Greek words. Athero means “gruel” or “paste” and sclerosis means “hardness”. It is a term that describes the changes in appearance of arterial walls as plaque accumulates and their elasticity and flexibility is lost.

Artery walls are comprised of three layers. The outer layer, the adventia, is composed of strong connective tissue. The middle layer, the media, is made up of smooth muscle cells and elastic tissue. The inner layer, the intima, is made up of three layers. The inner layer of the intima is comprised of flat cells, called endothelial cells. The endothelial cells form a boundary or barrier between the blood that is circulating within the artery and the vessel wall. The area beneath the endothelial cells is called the sub-endothelial space. The sub-endothelial space is attached to the media by a basement membrane. It is within the intima that the atherosclerotic battle takes place.

Endothelial cells are the body’s first line of defense against arterial injury. They form a barrier to prevent substances within the blood from entering the arterial wall. The endothelial cells continually monitor blood pressure and blood flow and tell the muscle cells in the media to contract or relax as necessary. When an injury occurs, endothelial cells in the vicinity produce substances that direct the healing process. Some of these substances cause smooth muscle cells to migrate to the area to reinforce its strength. Others signal white blood cells to stick to the site of injury to protect it from further damage.

A number of factors can cause injury to the endothelium. Chemicals within tobacco smoke are known to do so. Homocysteine, an amino acid that is an intermediate step in many body reactions is toxic to endothelial cells and will cause injury if it begins to accumulate within the body. Chronic H-pylori infections in the stomach appear to trigger inflammation and injury the endothelial cells. Infections with Chlamydia and cytomegalovirus have been implicated. A link between gum inflammation (gingivitis) and heart disease is also being explored.

Whatever the cause, endothelial injury triggers a cascade of events that ultimately leads to the formation of an atherosclerotic lesion, called a plaque. This does not mean that the body is reacting inappropriately, however.

Survival is the body’s prime directive. It will respond to injury by whatever means is most likely to maintain life in the present, regardless of the long-term consequences of such an action. In the case of atherosclerosis the body’s response may be summarized as, “If I don’t fix this injury it may cause my artery wall to weaken and explode. It’s better to fix the injury today than to worry about a heart attack or stroke twenty years from now. If I don’t fix the injury today I won’t be alive to have a heart attack or stroke in the future.”

Two elements of the blood, platelets and monocytes, play critical roles in the body’s initial response to injury. Platelets are produced by the body to stop leaks in the circulatory system. They are designed to float individually though the blood stream when no injury is present, but they are to clump together at the site of an injury to plug the leak and prevent bleeding. This is why conditions in which the number of circulating platelets is too low or in which the platelets are not functioning properly are characterized by excessive bruising.

Monocytes are white blood cells that float through the system. When an injury occurs they respond by migrating into the injured tissue. There they are converted to macrophages, cells that engulf foreign substances to protect the body from invasion.

When the endothelium is injured, whether by turbulent blood flow, chemicals, homocysteine, infectious agents, or any other mechanism, platelets are attracted to the area. Under normal circumstances the platelets will form a protective barrier at the site of injury, but if the platelets are “sticky” a blood clot will form, further damaging the arterial wall.

When a monocyte is converted to an activated macrophage it begins surveying the blood flowing past the site of injury looking for foreign substances, such as bacteria or viruses, that could use the break in the endothelium to invade the artery. When it spots an invader the macrophage engulfs it so that it can be identified and other elements of the immune system alerted to its presence.

Under normal circumstances new endothelial cells replace those that were injured. The smooth lining of the artery is restored and routine blood flow is maintained. Unfortunately, abnormal circumstances often exist.

Many people in the United States consume diets that are deficient in omega-3 fatty acids.

Platelets are intended to have alternating types of fats in their membranes. When the body does not have enough omega-3 fatty acids to alternate with other fats in the platelet membrane it will still manufacture platelets, but their abnormal membranes will be sticky and they will clump together excessively. This can cause a clot to form at the site of an endothelial injury, something that can cause additional damage to the area.

Unbalanced oxygen molecules, called free radicals, are common in our environment. It has been suggested that without antioxidant activity within the body each cell would be attacked by up to 10,000 free radicals every day. The reaction between one of these unbalanced molecules and another substance is called oxidation. The substance that has been attacked by free radicals and changed in appearance has been oxidized. A common example of an oxidation reaction is the fading of a car finish. When we see a car that has lost its color or sheen, we say that the finish is oxidized.

One of the substances vulnerable to oxidation in the body is LDL cholesterol. When a LDL cholesterol molecule is oxidized it is changed in appearance. It is no longer LDL cholesterol, it is oxidized LDL cholesterol.

Most American diets are low in antioxidant nutrients such as vitamin C, vitamin E, carotenoids, and selenium. When the body’s antioxidant defense mechanisms are compromised, nearly all LDL cholesterol in the body becomes oxidized.

As macrophages stand guard at the site of endothelial injury they are ready to engulf any foreign substance that is present in the bloodstream. If a normal LDL cholesterol molecule floats by, the macrophage recognizes it as a substance that is normally present in the body and lets it pass. If an oxidized LDL cholesterol molecule approaches, however, the macrophage grabs it and pulls it into the wall of the artery as it would any other foreign substance. A macrophage that contains oxidized LDL cholesterol is called a foam cell, and it is the first stage in the development of an atherosclerotic plaque.

As foam cells begin to collect in the intima, fatty streaks develop. Foam cells cause smooth muscle cells from the media to enter the intima to replace the flat endothelial cells. These cells also begin to ingest oxidized LDL cholesterol. Some of the smooth muscle cells are converted to cells that produce connective tissue.

At these damaged sites a vicious cycle of inflammation leading to the influx of more macrophages, smooth muscle cells, platelets, and connective tissue is established. More oxidized LDL cholesterol is incorporated into the arterial wall, additional clots form, and scarring takes place.

As the process continues calcium is often deposited in an attempt to stabilize the situation. As the plaque enlarges its inner surface may rupture. Bleeding at the site of the rupture creates a clot that completely blocks the flow of blood through the artery. The end result is a heart attack or a stroke.

Since macrophages engulf only oxidized LDL cholesterol it should be clear that attacking the body’s ability to manufacture or absorb normal cholesterol will do little to prevent the development of atherosclerotic plaques. To significantly reduce plaque development one must address the potential causes of endothelial injury and correct the nutritional abnormalities that allow plaque development to proceed.

Most of the known causes of endothelial injury can be controlled. Damage from substances in tobacco smoke can be eliminated by stopping smoking and limiting exposure to secondhand smoke. Nutritional supplementation can effectively lower homocysteine to less than 7 mmol/L, levels that are generally regarded as safe.

Gingivitis responds well to coenzyme Q-10 supplementation and to the use of essential oils, such as almond, peppermint, or tea tree. Toothpastes that contain propolis, a bee product, are also effective in stopping infection and restoring gum health.

If an elevated C-Reactive Protein level suggests that inflammation is present it is wise to check for the presence of H-pylori, which is commonly found in the stomach. If it is present, effective regimens for its eradication are available.

Normal platelet function can be restored by including omega-3 fatty acids in the diet or by taking omega-3 dietary supplements. Oxidation can be prevented by antioxidant nutrients.

This strategy has been demonstrated to dramatically reduce the risk of endothelial injury proceeding to plaque formation and rupture. Researchers in Lyon, France, looked at the effect of a Mediterranean Diet, which contains more omega-3 oils and antioxidants than other diets, on men who had suffered a heart attack. Those who followed a Mediterranean Diet reduced their risk of a second heart attack by an astounding 73 %! This is far greater than the risk reduction associated with any cholesterol-lowering regimen, including intensive drug treatment.

Omega-3 supplements obtained from cold water fish have also been shown to improve the outcome of individuals at high risk of having a heart attack. They are as effective as and far safer than aspirin in preventing platelets from clumping excessively. As little as one baby aspirin every other day will prevent platelets from adhering to each other under any circumstance. For this reason, aspirin users place themselves at risk for bruising and catastrophic events including hemorrhagic stroke (bleeding into the brain). Omega-3 oil supplementation will stop platelets from clumping when they should not do so, but the platelets will work perfectly if a situation arises in which they are needed to control bleeding.

While it is clear that oxidation of LDL cholesterol plays a critical role in plaque development, studies in which a single antioxidant nutrient, such as vitamin E, was supplemented have failed to show a consistent benefit. Many physicians have pointed to these studies as evidence that nutritional supplementation is unwarranted. The body, however, does not rely upon single nutrients to protect itself. The body requires over 100 nutrients to optimally perform maintenance and repair activities. I therefore use and recommend comprehensive nutritional supplements rather than single nutrient supplements. I have not recommended vitamin E as a stand alone supplement in over 10 years.

Although he did not live to see his theory of inflammation as the cause of atherosclerosis adopted, Dr. Joseph Hodgson deserves a prominent place in the history of medicine. Dr. Russell Ross, Dr. Filippo Crea and others who have been willing to explore alternatives to the “cholesterol is harmful” hypothesis should also be recognized for their courage and intellectual honesty.

Their efforts in defining the mechanism of the atherosclerotic process have made it possible to dramatically reduce the number of people who die year from heart attacks, strokes, and other vascular diseases. When the root causes of endothelial injury and the secondary mechanisms of plaque development are addressed heart attacks should become a rarity. When informed that someone has died of a heart attack, your immediate reaction should be, “No! You’ve got to be kidding. That just doesn’t happen!”

Just as importantly, the increase in premature deaths from cholesterol-lowering regimens should become a thing of the past. Given our current understanding of the conditions that lead to the development of atherosclerosis, accepting an increase in deaths from non-cardiac causes as a necessary evil in preventing deaths from heart attacks can no longer be justified. Neither can the increase in depression, loss of mental sharpness, muscle abnormalities, sexual difficulties and other adverse effects brought about by the use of cholesterol-lowering drugs.

It is time to take a stand against our nation’s obsession with lowering cholesterol. It is time to challenge the wisdom of pushing cholesterol to ever lower levels. It is time to turn our efforts to correcting the factors that are now known to trigger plaque development. It is time to move on.

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