Coronary Artery Disease and Atherosclerosis

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Coronary Artery Disease and Atherosclerosis
3/22/06
Life Extension

Atherosclerosis is perhaps the single most deadly disease in the United States, yet there is a good chance that most people, even those at high risk for heart disease, don’t really understand how it develops. The fact is, long before any symptoms are clinically evident, atherosclerosis begins as a malfunction of specialized cells that line our arteries. Called endothelial cells, they are the key to atherosclerosis, and underlying endothelial dysfunction is the central feature of this dreaded disease.

Not every person who suffers from atherosclerosis has the risk factors we commonly associate with the disease, such as elevated cholesterol, but every single person with atherosclerosis has endothelial dysfunction. It is the uniting concept through which coronary artery disease must be understood. Atherosclerosis begins with inflammation and immune cell activation at the endothelial level, and they lead to endothelial dysfunction and eventually damage to the artery and formation of plaque. This process is hastened by high cholesterol, smoking, obesity, high blood pressure, and other risk factors for coronary heart disease.

Atherosclerosis takes a huge toll on our society. According to the American Heart Association, more than 64 million Americans suffer from some form of cardiovascular disease, making it the leading cause of death in the country. In 2001, cardiovascular disease was responsible for more than 39 percent of all deaths in the United States (American Heart Association: Heart Disease and Stroke Statistics 2004).

In the world of conventional medicine, atherosclerosis is a widely misunderstood disease, perhaps because of a fundamental misconception about the nature of the arteries themselves. In this antiquated view, the arteries have been thought of as stiff pipes that gradually become clogged with excess cholesterol floating around the bloodstream. The solution recommended most often has been to reduce the dietary consumption of fats in order to lower levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) in the blood. Conventional medicine’s preferred method of reestablishing blood flow in clogged arteries is through surgery (coronary artery bypass graft surgery) or by insertion of catheters bearing tiny balloons that crush the plaque deposits against the arterial walls (angioplasty), followed by the implantation of tiny mesh tubes (stents) to keep the arteries open.

There are problems with this view, however. For one thing, the grafts used to reestablish blood flow can also develop atherosclerotic plaque deposits. The same was true for balloon angioplasty; in their early years, up to half of all angioplasty procedures “failed” when the arteries gradually closed again. Even today, with the use of improved stents, the failure rate is between 10 and 15 percent, and many people have to undergo repeat angioplasty or even surgery.

Today, our understanding of atherosclerosis has literally redefined the disease. We now understand atherosclerosis as a chronic inflammatory disease that affects the way arteries function at the most basic level. Instead of viewing the arteries as pipes through which blood flows, we now understand that arteries are muscular organs that change and adapt to their environment and contract and expand in response to multiple factors, helping to raise and lower blood pressure and distribute blood throughout the body. Finally, we have begun to unravel the biochemical processes that underlie atherosclerosis.

This new understanding of atherosclerosis has yet to filter into mainstream medicine, but the most progressive and forward-thinking researchers are already developing novel ways to correct the endothelial dysfunction that underlies coronary heart disease. Life Extension Foundation is closely monitoring the state of research regarding this epidemic disease of normal aging.

Endothelial Dysfunction: Underlying Arterial Disease
The cause and progression of atherosclerosis are intimately related to the health of the inner arterial wall. Arteries are composed of three layers. The outer layer is mostly connective tissue and provides structure to the layers beneath. The middle layer is smooth muscle; it contracts and dilates to control blood flow and maintain blood pressure. The inner lining consists of a thin layer of endothelial cells (the endothelium) that provides a smooth, protective surface. Endothelial cells prevent toxic, blood-borne substances from penetrating the smooth muscle of the artery. They also respond to changes in blood pressure and release substances into the cells of the smooth muscle that help change the muscle tone of the artery. Furthermore, endothelial cells secrete chemicals that provoke a protective response in the artery after an injury. This protective response includes signaling smooth muscle cells and white blood cells to congregate at the site of an injury.

As we age, however, the endothelium becomes leaky, allowing lipids and toxins to penetrate the endothelial layer and enter the smooth muscle cells. As a result, smooth muscle cells gather at the site of the injury, and the artery loses some flexibility. In response, the endothelium signals white blood cells to congregate along the cell wall. These white blood cells produce pro-inflammatory substances, such as leukotrienes and prostaglandins, as well as damaging free radicals that attack the endothelium (Touyz RM 2005). Toxins soon begin to penetrate into the arterial wall, where lipids such as LDL, cholesterol, and triglycerides accumulate and become oxidized.

At this point, the atherosclerotic process has begun in earnest. In response to the oxidized lipids, the body mounts an intensive immune response that causes more white blood cells to attack the fats, producing more inflammation within the arterial wall. In an attempt to heal the injury, smooth muscle cells begin to produce collagen to form a cap over the injury site. The mixture of oxidized lipids, white blood cells, and smooth muscle cells forms a plaque deposit. Over time, calcium accumulates on the deposit and forms a brittle cap. If this calcified plaque ruptures, a blood clot can form, and the clot may result in a heart attack or stroke.

All the processes described above, in which the inner arterial wall is damaged and normal endothelial function is compromised, are collectively referred to as endothelial dysfunction. Evidence of endothelial dysfunction can even be found in adolescents who are genetically prone to atherosclerosis. While this process occurs naturally to some degree in all people, it is aggravated by the traditional risk factors for heart disease, such as smoking and obesity (two of the leading modifiable risk factors for coronary artery disease). The following are additional risk factors:

Elevated LDL cholesterol. LDL is dangerous because it can penetrate the endothelial wall and contribute to the creation of lipid foam, which forms the core of a plaque deposit. Oxidized LDL cholesterol also triggers within the endothelium an inflammatory process that accelerates atherosclerosis.
Hypertension. High blood pressure is known to aggravate endothelial dysfunction, and leading researchers have identified the endothelium as an “end organ” for damage caused by high blood pressure. Many studies have shown that high blood pressure is dangerous, and Life Extension suggests a target optimal blood pressure of 119/75 mmHg (or lower).
C-reactive protein. Inflammation is central to the endothelial dysfunction that underlies coronary artery disease. One good way to measure inflammation is through levels of C-reactive protein (CRP). Studies have shown that higher levels of CRP increase the risk of stroke, heart attack, and peripheral vascular disease (Rifai N 2001; Rifai N et al 2001). Stroke patients with the highest CRP levels (greater than 33 mg/L) are two to three times more likely to die or experience a new vascular event within a year than are patients with low levels (less than 5 mg/L) (Di Napoli M et al 2001).
Metabolic syndrome and diabetes. Metabolic syndrome is a cluster of abnormalities that, when they occur in the same person, dramatically elevate the risk of heart disease. These abnormalities include elevated triglyceride levels, insulin resistance, abdominal obesity, elevated blood pressure, and low high-density lipoprotein (HDL). According to recent data, this condition affects about 20 percent of adult Americans. Diabetes is also a significant risk factor for coronary artery disease. High circulating levels of blood glucose (and insulin) cause microvascular damage that accelerates the atherosclerotic process, partly by accelerating endothelial dysfunction (Beckman JA et al 2002).
Homocysteine. High homocysteine levels contribute to inflammation and the production of free radicals that attack endothelial cells and raise thrombotic risk (Riba R et al 2004). Mild elevations in serum homocysteine (homocysteinemia) can be caused by nutrient deficiencies, including deficiencies in folate and vitamin B12. The Life Extension Foundation identified the role of homocysteine in cardiovascular disease in its November 1981 issue of Life Extension magazine. Life Extension’s position has been confirmed by numerous studies showing that homocysteine, like cholesterol, is strongly associated with risk of heart disease (Haynes WG 2002; Guilland JC et al 2003).
Elevated fibrinogen. Fibrinogen is involved in the blood clotting process. When a blood clot forms, fibrinogen is converted to fibrin, which forms the structural matrix of a blood clot (Koenig W 1999). Fibrinogen also facilitates platelet adherence to endothelial cells (Massberg S et al 1999). People with high levels of fibrinogen are more than twice as likely to die of a heart attack or stroke as people with normal fibrinogen levels (Wilhelmsen L et al 1984; Packard CJ et al 2000). This risk goes up even more in the presence of hypertension (Bots ML et al 2002).
Life Extension Foundation was the first research group to recognize the importance of fibrinogen as an independent risk factor for cardiovascular disease. Life Extension’s innovation was later corroborated in a study that found that individuals who had suffered heart attacks had significantly higher fibrinogen levels than healthy individuals (Ma J et al 1999). Other studies have shown that fibrinogen levels have a stronger association with cardiovascular deaths than cholesterol levels (Thompson SG et al 1995).

Atherosclerosis: Not Just a Man’s Disease
For years, many people believed that atherosclerosis primarily affected men. In reality, however, heart disease is the leading killer of women in the United States. Atherosclerosis tends to affect men and women differently and at different times in their lives. Before menopause, women suffer less from heart disease than men of comparable age. After menopause, however, the gap closes with age until eventually women become more likely than men to suffer from heart disease (Sans S et al 1997; LaRosa JC 1992).

Heart disease in women is often undiagnosed because its symptoms are often different from the symptoms men experience. Women are less likely to suffer from the chest pain traditionally associated with coronary artery disease in men (McSweeney JC et al 2003), and their heart attacks tend to be atypical (Sannito N et al 2002). Among women, the pain associated with reduced blood flow (ischemia) may be felt in the upper abdomen or back instead of the chest, and the symptoms of an actual heart attack (myocardial infarction) may also be different from those typically experienced by men.

The issue of women and heart disease is further complicated by conflicting messages about hormone replacement therapy sent by conventional medical research. For many years, doctors prescribed conventional hormone replacement therapy to reduce the risk of heart disease among menopausal women. In recent years, however, the wisdom of this approach has been called into question. Two arms of the large Women’s Health Initiative study were stopped early when researchers discovered that women on conventional hormone replacement therapy were at a higher risk for coronary artery disease, heart attack, stroke, and breast cancer than other women. As a result of these findings, which were reported around the world, many women stopped using hormone replacement therapy, despite the possible benefits of estrogen therapy in reducing cardiovascular risk (Rosano GM et al 2003; Benagiano G et al 2004). Unfortunately, this study examined women using conjugated equine estrogens, which are estrogens derived from the urine of pregnant mares (Rossouw JE et al 2002). Life Extension supports hormone replacement therapy for menopausal women—providing that blood tests are performed to establish proper individualized dosing and that only bioidentical hormones be used. For more information on bioidentical hormone therapy, please see Female Hormone Restoration.

Symptoms and Diagnosis of Atherosclerosis
Symptoms associated with atherosclerosis depend on the stage of the disease. In the early stages, which may last for decades, it rarely has any symptoms. In the later stages, the symptoms are caused by the obstruction of blood flow.

In the coronary arteries, the most common symptoms of atherosclerosis in men are chest pain (angina) and shortness of breath. In the arteries of the legs (peripheral arterial disease), the most common symptoms are leg pain (claudication). Unfortunately, atherosclerosis that occurs in the brain often has no symptoms; the first indication of serious vascular disease in the brain is often a stroke. So-called mini strokes, which have temporary symptoms similar to those of full-blown strokes, are sometimes an important warning sign of an impending stroke.

If a plaque deposit in an artery ruptures, the symptoms are likely to be acute, often in the form of a heart attack, stroke, or pulmonary embolism. Each of these is a critical condition that requires immediate medical supervision. People who suspect they may be suffering from one of these conditions should call 911 immediately. Symptoms include fainting, seizures, breathlessness, pain, and cognitive impairment.

Blood testing is recommended for all adults. A comprehensive blood test will measure levels of LDL, HDL, VLDL, and triglycerides, as well as levels of C-reactive protein, homocysteine, and fibrinogen. Life Extension recommends blood testing at least annually. More frequent testing might be recommended to monitor progress after a patient begins a heart-healthy supplementation program.

People who have suffered a heart attack or stroke or who have symptoms indicative of coronary artery ischemia (such as chest pain) should see a physician. They may be required to undergo additional testing to determine the health of their coronary arteries. Additional tests include the following:

Angiography. During this test, a catheter is inserted through a large artery, usually in the groin, and guided into the heart, where it is used to deliver contrast material into the coronary arteries. This contrast material is visible under x-ray. The test allows physicians to identify the location and degree of vascular occlusion.
Electrocardiogram. This is an electronic readout of heart function that can reveal ischemic damage as a result of restricted blood flow.
Intima-media thickness. This test uses ultrasound imaging to estimate the thickness of the intima, or inner layer of the arteries. An increase in intima-media thickness over time indicates that atherosclerotic vascular disease is worsening. This technique can also be used to measure the effectiveness of cardiovascular intervention therapies.
Computed tomography scanning. This technique can assess the degree of calcification in the coronary arteries, which correlates strongly with atherosclerosis. Because of the risks associated with radiation exposure, Life Extension does not recommend computed tomography scanning unless absolutely necessary.
The National Institutes of Health, together with the National Cholesterol Education Program, also offers an easy-to-use online test to help people determine their risk of a major cardiovascular event. The test relies on commonly used parameters such as age and weight to determine a 10-year Coronary Risk Profile. The Coronary Risk Profile can be accessed at http://www.nhlbi.nih.gov/guidelines/cholesterol/.

Conventional Treatment of Atherosclerosis
The treatment of atherosclerosis depends on the stage of the disease. Severe disease, in which an artery has significant blockage or unstable plaque deposits, may require intensive care. In most cases, however, less severe disease is treated with a combination of lifestyle changes (including dietary changes) and medication. The following dietary and lifestyle changes have been shown to slow, or even reverse, the effects of atherosclerosis:

Reduce dietary saturated fats, cholesterol, and trans-fatty acids.
Increase intake of fiber to at least 10 g daily.
Consume at least five servings of fruits and vegetables daily.
Ensure adequate intake of folic acid (400 to 1000 mcg daily) to reduce homocysteine levels.
For obese people, lower weight and increase physical activity to reduce the risk factors for metabolic syndrome and to help control blood pressure and reduce cardiac workload.
For people with hypertension, limit sodium intake and maintain adequate intake of potassium, calcium, and magnesium.
Stop smoking. This is essential.
In addition to lifestyle changes, a number of medications may be used to control individual risk factors. These include the following:

Cholesterol-lowering drugs. When cholesterol levels remain high despite adequate dietary changes, weight loss, and regular exercise, cholesterol-lowering drugs are often prescribed. The drugs most commonly used to lower LDL are the statin drugs: pravastatin (Pravachol®), simvastatin (Zocor®), and atorvastatin (Lipitor®). A new drug, Vytorin®, has recently gained popularity. Vytorin® is a combination pill containing ezetimibe (Zetia®) and simvastatin. It has been shown to lower cholesterol more effectively than either Lipitor® or Zocor® alone. Bile acid sequestrants are another class of drugs prescribed for reducing LDL. These include cholestyramine (Locholest®, Questran®) and colestipol (Colestid®). Other drugs used to lower cholesterol include gemfibrozil (Lopid®), clofibrate (Atromid-S), and probucol (Lorelco) (American Heart Association: Cholesterol-Lowering Drugs 2005). For more information, please see the chapter titled Cholesterol.
Antihypertensive drugs. Drugs used to lower high blood pressure include beta blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers, and diuretics. For more information on each class of drug, please see the chapter titled High Blood Pressure.
Antithrombotic drugs. These drugs reduce the blood’s ability to clot, thus reducing the risk of heart attack and stroke. The most common antiplatelet drug today is aspirin. Clopidogrel (Plavix®) is a popular antiplatelet prescription medication. However, many other drugs are prescribed to prevent thrombosis. Some are indicated for preventing stroke, deep vein thrombosis following surgery, or blood clots following arterial revascularization. The leading antithrombotic drugs include adenosine-diphosphate-receptor inhibitors, anticoagulants such as warfarin, thrombin inhibitors, glycoprotein IIa/IIIb inhibitors, phosphodiesterase inhibitors, and Pentoxifylline. For more information on reducing the risk of blood clots, please see the chapter titled Blood Clots.
People with advanced coronary artery disease may be recommended for a surgical or “minimally invasive” procedure. In general, there are two main interventional treatments aimed at reestablishing blood flow in diseased coronary arteries: coronary artery bypass grafting and catheter-based procedures such as angioplasty and coronary artery stenting. Unfortunately, neither surgery nor catheter-based procedures can stop the underlying disease progression, and patients might end up needing additional procedures, plus the use of expensive pharmaceuticals for life. Obviously, early intervention through dietary supplementation, exercise, and careful monitoring of risk factors is preferable. Even if surgery or angioplasty is necessary, patients should do everything possible to slow the progression of the disease and support a healthy endothelial layer.

One important note for patients about to undergo coronary artery bypass surgery is the use of coenzyme Q10. It has been shown to improve heart function if taken before surgery (Rosenfeldt F et al 2005).

Nutritional Therapy
By the time surgery or angioplasty is recommended for atherosclerosis, preventive medicine has already failed. Because atherosclerosis is such a slow process, there is ample time for intervention before symptoms develop. Dozens of clinical studies have shown that reduction of individual risk factors can help slow or even reverse the damage caused by atherosclerosis, and reversing or slowing endothelial dysfunction should be a cornerstone of therapy.

Any program aimed at reducing the risk of heart attack or slowing the progression of atherosclerosis begins with comprehensive blood testing. This step is vital to designing a program that targets an individual’s risk factors. For example, a person with high cholesterol might benefit more from a healthy nutritional program than someone with elevated risk of thrombosis. Similarly, people with high homocysteine levels should follow a program aimed at reducing homocysteine. That said, it is also important that all possible risk areas be addressed and adequate antioxidants consumed to protect against oxidant stress inside the arteries. The following chapters specifically address various risk factors for coronary artery disease:

Blood Clots
Homocysteine and Heart Disease
High Blood Pressure
High Cholesterol
Inflammation
These chapters will provide an invaluable reference to people seeking to achieve the lowest possible risk for adverse cardiovascular events and can help in the design, under the supervision of a physician, of a program closely tailored to an individual’s needs.

One nutrient that has received attention for its ability to directly improve endothelial function is propionyl-L-carnitine (PLC). PLC passes across the mitochondrial membrane to supply L-carnitine directly to the mitochondria, the energy-producing organelles of all cells. Carnitines are essential for mitochondrial fatty acid transport and energy production, which is important because heart muscle cells and endothelial cells burn fatty acids rather than glucose for 70 percent of their energy. By contrast, most cells generate 70 percent of their energy from glucose and only 30 percent from fatty acids (Kaiser KP et al 1987).

An animal study suggests PLC may help prevent or decrease the severity of atherosclerosis. In rabbits fed a high-cholesterol diet, which normally induces endothelial dysfunction and subsequent atherosclerosis, supplementation with PLC resulted in reduced plaque thickness, markedly lower triglyceride levels, and reduced proliferation of foam cells (Spagnoli LG et al 1995).

PLC also improves endothelial function by increasing nitric oxide production in animals with normal blood pressure and in animal models of hypertension. Nitric oxide is important because it helps keep arteries open. The increased nitric oxide production induced by PLC is related to its antioxidant properties; PLC reduces reactive oxygen species and increases nitric oxide production in the endothelium in the presence of superoxide dismutase and catalase (Bueno R et al 2005).

In human studies, PLC produced significant improvement in maximum walking distance with claudication (atherosclerotic peripheral vascular disease) and had no major side effects (Wiseman LR et al 1998