WHAT ARE CHOLESTEROL, OTHER LIPIDS, AND LIPOPROTEINS?
Lipids
Lipids are the building blocks of any of the fats or fatty substances found in animals and plants. They are microscopic layered spheres of oil, which, in animals, are composed mainly of cholesterol, triglycerides, proteins (called lipoproteins), and phospholipids (molecules made up of phosphoric acid, fatty acids, and nitrogen). Lipids do not dissolve in water and are stored in the body to serve as sources of energy.
Cholesterol
Cholesterol is a white, powdery substance that is found in all animal cells and in animal-based foods (not in plants). In spite of its bad press, cholesterol is an essential nutrient necessary for many functions, including the following:
* Repairing cell membranes.
* Manufacturing vitamin D on the skin's surface.
* Production of hormones, such as estrogen and testosterone.
* Possibly helping cell connections in the brain that are important for learning and memory.
Regardless of these benefits, when cholesterol levels rise in the blood, they can have dangerous consequences, depending on the type of cholesterol. Although the body acquires some cholesterol through diet, about two-thirds is manufactured in the liver, its production stimulated by saturated fat. Saturated fats are those found in animal products, meat and dairy.
Triglycerides
Triglycerides are composed of fatty acid molecules and are the basic chemicals contained in fats in both animals and plants.
Lipoproteins
Lipoproteins are protein spheres that transport cholesterol, triglyceride, or other lipid molecules through the bloodstream. Most of the information about the effects of cholesterol and triglyceride actually concerns lipoproteins.
Lipoproteins are categorized into five types according to size and density. They can be further defined by whether they carry cholesterol (the two smaller lipoproteins) or triglycerides (the three largest lipoproteins).
Cholesterol-Carrying Lipoproteins. These are the lipoproteins commonly referred to as cholesterol.
* Low density lipoproteins (LDL). (Often called the "bad" cholesterol.)
* High-density lipoproteins (HDL), the smallest and most dense. (Referred to as the "good" cholesterol)
Triglyceride-Carrying Lipoproteins.
* Intermediate density lipoproteins (IDL). They tend to carry triglycerides.
* Very low density lipoproteins (VLDL). These tend to carry triglycerides.
* Chylomicrons (largest in size and lowest in density).
Lipoprotein(a). Lipoprotein(a), or lp(a) has a size and density somewhere between LDL and HDL. The molecules carries a protein that may deter the body's ability to dissolve blood clots and is under investigation as either a marker or cause of heart disease.
Remnant Lipoproteins. Remnant lipoproteins are byproducts of chylomicrons, very low-density lipoproteins (VLDL), or both. Some research indicates that high levels may be an important risk factor for coronary artery disease, particularly in patients who have otherwise normal cholesterol levels.
Cholesterol Guidelines
A number of studies have now suggested that reducing LDL and total cholesterol levels and boosting HDL levels have improved survival and prevented heart attacks in people with or without heart disease. In general, blood tests can easily measure both HDL and overall cholesterol levels. It is very difficult to measure LDL levels by themselves, but LDL levels can be reliably calculated by subtracting HDL levels from total cholesterol. (LDL makes up the difference.) Reducing LDL is the primary goal of most cholesterol therapy. [ See Table Cholesterol Goals.]
Cholesterol Goals
Total Cholesterol Goals
LDL Goals
HDL Goals
Triglyceride Goals
Less than 200 mg/dL is desirable.
Between 200 and 239 is borderline.
Over 240 is very high.
Below 100 mg/dl is optimal for everyone. Should be the goal for people with existing heart disease or diabetes or who have multiple heart risk factors sufficient to make their long-term survival rates equal to having heart disease.
130 mg/dl or below for people with two or more risk factors.
160 mg/dl or less for people with one or zero risk factors.
Anything over 160 is high with levels over 190 being very high.
Over 60 mg/dL is optimal.
Below 40 mg/dL is too low.
Below 150 mg/dL is normal.
150-199 is borderline high.
200-499 is high.
Over 500 is very high.
*Risk factors for heart disease include a family history of early heart problems before age 55 for men, before age 65 for women), smoking, high blood pressure, diabetes, being older (over 45 for men and 55 for women), and having HDL levels below 35 mg/dl. People with two or more of these risk factors may have a ten-year risk of heart attack that exceeds 20%, and may therefore need to aim for LDL levels of 100 mg/dL or below.
Although current guidelines as described in the table are extremely useful, they do have pitfalls. For example, the following cholesterol levels pose some dilemmas:
* Low LDL levels (protective) accompanied by low HDL, high triglycerides, or both (harmful).
* High total cholesterol (harmful) accompanied by high HDL (protective).
Would individuals with these cholesterol balances be at high risk or low risk for developing heart disease? To resolve this dilemma, experts have devised a calculation for a risk ratio simply by dividing the total cholesterol by either total HDL or LDL. It isn't clear at this point which ratio is a better predictor of heart disease, although the HDL ratio may be superior. Using this ratio, the following results indicate better to worse outlook:
* The ideal ratio is 3.5 or below.
* A ratio of 4.5 carries an average risk.
* Ratios of 5:1 or higher are potentially dangerous.
For example, if a person has a high, total cholesterol of 280 mg/dl but a high HDL level of 70 mg/dl, the risk ratio is 4, which actually carries a lower than average risk. The use of this ratio may predict coronary artery disease more accurately than total cholesterol levels.
HOW DO CHOLESTEROL, OTHER LIPIDS, AND LIPOPROTEINS AFFECT THE HEART?
Atherosclerosis and Danger to the Heart
Coronary artery disease, commonly known as heart disease, is the leading cause of death in the US and was responsible for nearly 530,000 deaths in 1999. As many as half of these deaths may be attributed to unhealthy cholesterol and lipid levels. Strong evidence points to LDL as the villain and HDL as a hero in the process. The role of other lipids, notably triglycerides, is not entirely clear.
Unhealthy cholesterol, particularly low-density lipoprotein (LDL), forms a fatty substance called plaque, which builds up on the arterial walls. Smaller plaques remain soft, but older, larger plaques tend to develop fibrous caps with calcium deposits.
The long-term result is atherosclerosis, commonly called hardening of the arteries. The heart is endangered in two ways by this process:
* Eventually these calcified and inelastic arteries become narrower (a condition known as stenosis). As this process continues, blood flow slows and prevents sufficient oxygen-rich blood from reaching the heart. This condition leads to angina (chest pain) and, in severe, cases to heart attack.
* Smaller unstable plaques may rupture, triggering the formation blood clots on their surface. The blood clots block the arteries and are important causes of heart attack.
This process is accelerated and enhanced by other risk factors, including high blood pressure, smoking, obesity, diabetes, and a sedentary life style. When more than one of these risk factors is present, a synergistic phenomenon occurs whereby the whole is more dangerous than the sum of its individual risk factors.
The effects of cholesterol on the heart may involve more than just one the arteries. There is some evidence unhealthy levels may affect the heart muscles and increase the risk for heart failure. High cholesterol levels may even inhibit the protection that aspirin provides for people with heart disease.
On an encouraging note, however, mortality rates associated with coronary artery disease have dropped by over one-half during the past 30 years. Some experts estimate that about 30% of the decline is due to better cholesterol management. Only 40% of people with high cholesterol levels actually die of heart disease, however, and experts cannot yet define which people are most at risk from high cholesterol levels.
Effect of Total Cholesterol
Studies consistently report a higher risk for death from heart disease with high (200 and over) total cholesterol levels. The higher the cholesterol the greater the risk. So, for example, according to a 2000 study, men with cholesterol levels over 240 mg/dL have a risk that is 2.15 to 3.63 of those whose cholesterol is below 200. On average, every time a person's cholesterol level drops by a point, the risk of heart disease drops by 2%.
Low Density Lipoproteins (LDL), the "Bad Cholesterol"
The primary villain in the cholesterol story is low-density lipoprotein (LDL). In a major study, the lowest incidence in heart disease was found among people with lowest LDL levels. Low-density lipoprotein (LDL) transports about 75% of the blood's cholesterol to the body's cells. It is normally harmless. However, if it is exposed to a process called oxidation, it can penetrate and interact dangerously with the walls of the artery, producing a harmful inflammatory respons e.
Oxidation. Oxidation is a natural process in the body that occurs from chemical combinations with unstable molecules called oxygen-free radical , also called oxidants .
* When LDL collects on arterial walls these oxidants are released from the wall membranes.
* Oxidants are missing an electron and tend to bind with other molecules in the body, which is the process called oxidation.
* When the oxidation process modifies LDL, it signals the immune system that a harmful molecule has appeared.
Inflammation and Plaque. In response to oxidized LDL, the body releases various immune factors aimed at protecting the damaged walls. Unfortunately, in excessive quantities they cause inflammation and promote further injury to the areas they target:
* White blood cells and other factors gather and form the fatty substance called plaque. (Of interest in this process is an enzyme called lipoprotein-associated phospholipase A2, which binds to oxidized LDL. Studies are now reporting that it may play a major role in the release of the plaque-forming inflammatory factors.)
* Other immune factors also cause inflammation and injure the endothelium, the layer of cells that line blood vessels.
* Immune factors that increase the risk for blood clots are also mobilized.
* Oxidized LDL plays another dangerous role by reducing levels of nitric oxide, a chemical that helps relax the blood vessels, allowing blood to flow freely.
Lowering LDL is the primary goal of cholesterol drug and lifestyle therapy.
High Density Lipoproteins (HDL), the "Good Cholesterol"
HDL appears to benefit the body in two ways:
* It removes cholesterol from the walls of the arteries and returns it to the liver.
* It helps prevent oxidation of LDL. In fact, it appears to have antioxidant properties on its own.
HDL then helps keep arteries open and reduces the risk for heart attack. High levels of high-density lipoprotein (HDL), above 60 mg/dl, may be as important for the heart as low levels of LDL. HDL levels below 40 mg/dl are considered to be harmful. In one study, for each 4 mg/dL decline in HDL levels there was a 10% increase in coronary artery disease.
Triglycerides
Evidence now suggests that triglycerides may be major troublemakers for the heart, possibly in the following ways:
* Triglyceride appears to interact with HDL cholesterol in such a way that HDL levels fall as triglyceride levels rise. Low HDL is known to be harmful to the heart.
* The harmful imbalance of high triglycerides with low HDL levels is also associated with obesity (particularly around the abdomen), insulin resistance, and diabetes. Insulin is a hormone essential for regulating the storage and use of glucose (sugar) and amino acids (proteins) in the body. Insulin resistance occurs when there are normal insulin levels but the body cannot use it. It is the mechanism responsible for type 2 diabetes and occurs in common forms of diabetes, and with or without diabetes, is now believed to be a major risk factor for heart disease regardless of the presence of diabetes.
* Some evidence also suggests that high triglycerides are risk factors for heart disease on their own regardless of cholesterol levels. Triglycerides, for example, may be responsible for blood clots that form and block the arteries.
Still, some experts believe there is not sufficient proof of an independent risk to warrant separate tests for triglycerides.
Lipoprotein(a)
Studies are finding an elevated risk for angina and first heart attacks in people with elevated levels of lipoprotein(a), or lp(a). This lipoprotein falls somewhere in density between HDL and LDL and may have some properties that increase the risk for blood clots. Some experts suggest, however, that high levels of lp(a) may merely be markers of late-stage atherosclerosis, not a cause.) Because concentrations of lipoprotein(a) are usually inherited, they do not respond to dietary or lifestyle changes. At this time, however, few experts are recommending drug treatments to reduce lp(a) levels. Older women, but not men, appear to be at greater risk for high lp(a) levels and their consequences. (Men may be protected by the male hormone testosterone.) High levels are almost nonexistent in Asians, while they have been observed in half of African American. Caucasians carry medium risk.
WHAT ARE THE EFFECTS OF CHOLESTEROL ON THE BRAIN?
The effect of cholesterol on the brain is complex. High cholesterol has been linked to Alzheimer's disease and a greater risk for certain strokes. Low cholesterol, however, may have some negative effects on the brain. [See Box Consequences of Low Cholesterol Levels.]
High Cholesterol and Ischemic Stroke
Having adequate levels of HDL may be the most important lipid-related factor for preventing ischemic stroke, which is a type of stroke caused by blockage of the carotid arteries, those carrying blood to the brain. The effects of high total cholesterol and LDL levels on ischemic stroke are less clear. One study suggested that the risk for ischemic stroke increases when total cholesterol is above 280 mg/dl.
HDL may even reduce the risk for hemorrhagic stroke, which is a less common stroke caused by bleeding in the brain and associated with low overall cholesterol levels. [See Box Consequences of Low Cholesterol Levels.]
High Cholesterol and Late-Onset Alzheimer's Disease (AD)
There has been research suggesting an association between high cholesterol levels and Alzheimer's disease (AD) in some people. The major target in genetic research on late-onset AD has been apolipoprotein E (ApoE), which plays a role in the movement and distribution of cholesterol for repairing nerve cells during development and after injury. People who carry a variant of this gene (ApoE4) are at significantly higher risk for AD. (Other variants may even reduce the risk.) High cholesterol may pose a risk for Alzheimer's regardless of this genetic factor, however. A number of recent studies support the link between Alzheimer's disease and cholesterol by suggesting that certain cholesterol-lowing drugs statin drugs known as statins may be protective against AD. (Of interest are studies reporting that cholesterol is important within the brain for cell communication and memory, but such benefits do not apply to high cholesterol levels in the blood.)
Consequences of Low Cholesterol Levels
The negative consequences of low cholesterol levels, whether actively lowered or naturally low, are the subject of ongoing debate. In one study, men with the lowest cholesterol levels had the highest mortality rate, generally due to cancer and other, non-heart related diseases. An analysis of this study along with additional research suggests strongly, however, that this higher death rate is almost totally due to lung cancer in smokers with low cholesterol.
Cognitive Function and Depression
Effects of Natural Low Cholesterol Levels. Some studies have found that cholesterol is important for the production of serotonin, a chemical in the brain that at low levels is associated with depression. Men with naturally low cholesterol levels also have low serotonin levels.
Some evidence has reported a link between natural low natural cholesterol levels and negative emotional states:
* One study found that male psychiatric patients with cholesterol below 160 mg/dl had twice the normal rate of suicide and that elderly men with low cholesterol levels had three times the normal risk of depression.
* Another 2000 study supported earlier work on an association between depression and chronically low cholesterol levels.
* In a large 2001 Swedish study, violent behavior was linked with naturally low cholesterol levels.
* A 2000 study of patients with depression and bipolar disorders found lower cholesterol levels during specific manic or depressive episodes. The study suggested that mood states might produce low cholesterol levels, not vice versa.
Some researchers have observed that people with low cholesterol levels due to medical conditions or alcoholism are often also deficient in dietary fats known as omega-3 fatty acids. Low levels of omega-3s, which are found in oily fish, are linked with depression and aggression. In fact, some studies in which cholesterol was lowered using diets that included omega-3 fatty acids reported less depression. Clearly, any link between low cholesterol levels and emotional disorders is uncertain.
Effects of Medication-Induced Low Cholesterol Levels. Importantly, numerous studies have reported no association between the use of cholesterol-lowering drugs and depression or rates of suicide, accidents, or violent death.
Hemorrhagic Stroke
People with overall cholesterol levels below 180 mg/dl may be at risk for hemorrhagic stroke (which is bleeding in the brain), particularly if they also have high blood pressure. It should be noted, however, that this type of stroke is much less common than ischemic stroke (which is caused by artery blockage and may be related to low HDL cholesterol).
WHO IS AT RISK FOR UNHEALTHY LIPID LEVELS?
Western Lifestyle and Obesity
About half of all American adults, regardless of ethnicity, have total cholesterol levels over 200. Over 25% have been told by doctors that they have unhealthy levels. The major risk factor for these high rates may be the Western lifestyle. The typical high-fat low-fiber American diet coupled with sedentary habits is largely responsible for this unfortunate trend.
Risk by Gender
Men. Heart disease is the major cause of death in men. On average, men develop coronary artery disease ten to 15 years earlier than women do and their risk for dying of heart disease at younger ages than women is higher.
Women. Coronary artery disease is still the number one killer of women as well. Women between the ages of 20 and 34 and after menopause, around age 55, have higher cholesterol levels than men do. Some evidence suggests HDL levels might have more significance in women than in men. In one study, at total cholesterol levels above 200, women with HDL levels below 50 had a higher death rate than those with levels above 50, regardless of their LDL cholesterol levels. Women also appear to be more susceptible to the high-triglyceride low-HDL syndrome, which may be a particular risk factor for heart disease.
Risk by Age
Children and Adolescents. It is not clear what constitutes normal cholesterol levels in children. According to one study, the current adult guidelines are accurate only for Caucasian adolescent males at age 16. They do not take into account changes in cholesterol levels that occur between the ages of 8 and 18, which, furthermore, may vary between genders and population groups. In general, cholesterol levels tend to naturally rise sharply until puberty, then decrease sharply, and then rise again.
It is increasingly clear, however, that children who are overweight are at higher risk for high triglycerides and low HDL, which many experts now believe may be directly related to later unhealthy cholesterol levels. One 2000 study reported evidence of injuries in the arteries in children aged nine to 11 with high cholesterol levels.
As in adults, primary source of unhealthy cholesterol levels in children is most likely from diets high in unhealthy fats, saturated fats (found mainly in animal and dairy products) and trans-fatty acids (found in commercial food products). One study reported that five out of six American young people consume too many fats. A certain amount of fat is important for growth, but over-consumption is a major factor in the obesity epidemic occurring in American children as it is in adults. Simply lowering fat intake in their diets may safely reduce cholesterol in young children, according to one long-term study.
Less common causes of unhealthy cholesterol levels in children are the following:
* Low-birth weight (associated with low HDL levels).
* Hypothyroidism.
* Kidney or liver diseases.
* Homozygous familial hypercholesterolemia. This is an uncommon inherited condition that, in European studies, occurs in about one in 400 people. It causes severe cholesterol imbalances and can result in very early heart disease.
* Certain medications, such as specific antiseizure agents, corticosteroids, isotretinoin (Accutane).
Young and Middle-Aged Adults. The strongest evidence of unhealthy cholesterol levels and heart disease is in middle-aged adults over 40. Research, however, is now strongly suggesting that the younger a person is unhealthy cholesterol levels develop, the greater the chance for serious heart and blood vessel problems in the future. In one important 2000 study, young men (ages 16 through 34) who had cholesterol levels at or above 240mg/dL had two to four times the risk of dying from heart attack or other cardiac problems than did men whose cholesterol was lower than 200mg/dL. Young men without cholesterol problems also had higher life expectancy, by up to eight years. Other studies have suggested similar risks from unhealthy cholesterol in young women as well.
Elderly Adults. The effects of high cholesterol in people over 70 and how to treat them have been controversial issues. A number of studies report that in older adults, high cholesterol levels pose a significant risk for death from coronary artery disease, while some others have suggested that lowering cholesterol levels in the elderly may increase the risk for stroke or heart attack. (For example, a 2001 study reported that statin therapy reduces mortality rates in people over 65 with heart disease.) According to 2000 data, men over 70 years old with levels under 160 or over 240 were at significant risk for serious heart events. Some experts, then, now suggest that the ideal cholesterol range for older adults may be between 200 and 219 mg/dl.
Obesity
In American obesity is at epidemic levels in all age groups. The effect of obesity on cholesterol levels is complex. Although obesity does not appear to be strongly associated with overall cholesterol levels, among obese individuals triglyceride levels are usually high while HDL (beneficial cholesterol) levels tend to be low, both risk factors for heart disease. Obesity, in any case, has other effects (hypertension, increase in inflammation) that pose major risks to the heart.
Hypothyroidism
According to one 2000 study, hypothyroidism (thyroid hormone deficiency) may be the second most common cause of high cholesterol, after poor diet. Between a quarter and a half of all people with hypothyroidism may develop high cholesterol, particularly high levels of LDL and lipoprotein (a). Symptoms of hypothyroidism include slowed metabolic rate, weight gain, fatigue, and sensitivity to cold. Even those with subclinical (without symptoms) hypothyroidism may be at risk. The association is so strong between these two problems that experts recommend that people with high cholesterol also be tested for hypothyroidism. [ See, Hypothyroidism.]
Type 2 Diabetes and Syndrome X
Type 2 diabetes is a risk factor of heart disease. It is by far the more common form of diabetes, accounting for 90% of diabetes cases. About 16 million Americans have type 2 diabetes and half are unaware they have it. Type 2 diabetes is a particularly hazard when it is one of the components the metabolic syndrome, also called syndrome X. This condition is a group of disorders that also includes insulin resistance, cholesterol and lipid disorders, obesity, high blood pressure, a high risk for blood clotting, and disturbed blood flow to many organs.
Genetic Factors and Family History
Genetics play a major role in determining a person's blood cholesterol levels, and children from families with a history of premature heart disease should be tested for cholesterol levels after age two. Genes may influence whether one has low HDL levels, high LDL levels, triglycerides, or high levels of other lipoproteins, such as lipoprotein(a).
Some inherited disorders and genetic abnormalities have been identified:
* Familial hypercholesterolemia causes hazardous elevations of cholesterol. It may be more common than thought; one European study reported familial hypercholesterolemia in one out of 400 people.
* Familial lipoprotein lipase deficiency is a very rare disorder that causes depletion of lipoprotein lipase. This is an enzyme that appears to be important in the removal of lipoproteins that are rich in triglycerides. People who are deficient in it have high levels of cholesterol and fat in their blood. A very low-fat diet is essential and is an effective treatment for these individuals.
* Two studies have found a genetic mutation affecting neuropeptide Y in people with high total cholesterol and LDL levels. Neuropeptide Y is a compound in the brain that regulates appetite.
* Researchers have identified a gene called APOAV, which may help detect patients at risk for elevated levels of triglycerides.
Other Medical Conditions
Other medical conditions strongly associated with unhealthy cholesterol levels are the following:
* Polycystic ovarian syndrome. Women with this disorder, particularly those who are obese, appear to be at increased risk for high triglyceride and low HDL levels. This risk may be due to higher levels of the male hormone testosterone in these women.
* Kidney disease.
WHAT ARE THE SYMPTOMS OF UNHEALTHY LEVELS OF CHOLESTEROL?
There are no warning signs for high LDL-cholesterol levels. When symptoms finally occur, they usually take the form of angina or heart attack in response to the buildup of atherosclerotic plaque in the patient's arteries. This is definitely an affliction where it pays to invest in preventive medicine before dangerous complications occur.
HOW ARE CHOLESTEROL LEVELS DIAGNOSED AND WHO SHOULD BE SCREENED FOR THEM?
Blood Tests for Cholesterol
A blood test for cholesterol should now include the entire lipoprotein profile: LDL, total cholesterol, HDL, and triglycerides. (It is very difficult to measure LDL levels by themselves, but LDL levels can be reliably calculated using total cholesterol and HDL levels.) [For current guidelines on who should be tested see Box Screening Guidelines.]
To obtain a reliable cholesterol reading, experts advise the following:
* Avoid strenuous exercise 24 hours before the test.
* Do not eat or drink anything but water for 12 hours beforehand.
* If the test results are abnormal, a second test should be performed between one week and two months after the first test.
Tests are available for home use and in public locations, such as shopping malls and pharmacies, but they only measure total cholesterol. A laboratory test is still needed to measure individual lipid and lipoprotein levels.
Tests for Markers of Heart Disease in People with Unhealthy Lipid Levels
Eventually, blood tests for factors with inflammation in the arteries may be useful in demonstrating a higher risk for heart disease in people with unhealthy lipids:
* A high white-blood cell count.
* Elevated fibrinogen (a factor responsible for blood clotting).
* C-reactive protein. This protein is regulated by a very potent immune factor called interleukin-6 and elevated levels have been strongly associated with the inflammatory response and a higher risk for heart attack, even in people with normal cholesterol levels. It is also associated with high blood pressure, insulin resistance (the primary action in diabetes), and obesity.
* Lipoprotein-associated phospholipase A2 may be prove to be another marker for inflammation and heart disease. In fact, studies suggest that it may play some causal role in coronary artery disease.
Skin Test
A test that measures cholesterol levels in the skin is in development. (High skin levels appear to be an indicator of a high risk for serious heart disease.)
Screening Guidelines
General Screening Recommendations. In 2001, the government-sponsored National Cholesterol Education Program (NCEP) issued major new guidelines for managing and screening for cholesterol. While expert groups differ slightly on when screening should start, the following are the current recommendations by the NCEP expert panel:
* Periodic cholesterol testing in all adults starting at age 20. An adult with normal cholesterol levels does not need to have the test repeated for five years unless changes occur in his or her lifestyle, including weight gain and changes in medication or diet.
* Selective screening of children who are at risk for high cholesterol and heart disease or familial hypercholesterolemia, which is genetically elevated cholesterol. (Risk factors include having parents with total cholesterol levels greater than 240, or having a parent or grandparent who had overt heart disease at age 55 or younger.
* Patients already being treated for high cholesterol should be checked every two to six months.
Early screening is important for the following reasons:
* Evidence is accumulating on the dangers of early unhealthy cholesterol levels in both young people and older adults.
* Screening of young people will encourage them to make important lifestyle changes, possibly early enough to make significant differences.
* The obesity epidemic is increasing the numbers of young people with unhealthy cholesterol levels. One study reported that one-third of all young adult men have cholesterol levels over 200 mg/dL.
* Late screening would miss the one out of every 500 individuals with inherited familial hypercholesterolemia, for whom early treatment could be life saving.
The panel also recommends testing for the total lipoprotein profile (which includes HDL, LDL, and triglycerides) instead of merely measuring total cholesterol. Testing only for the overall cholesterol level misses specific lipids and blood proteins that are becoming increasingly important in determining an individual's particular risk for heart disease.
WHAT LIFESTYLE MODIFICATIONS IMPROVE CHOLESTEROL LEVELS?
Although most studies that prove that lowering cholesterol saves lives are done using drug therapy, the absolute mandate for improving cholesterol levels is to first make changes in life style (both diet and exercise). And, even when drugs are used healthy diet and physical activity are critical companions.
As in hypertension, people with unhealthy cholesterol levels do not experience symptoms until dangerous heart disease develops. So, changing their daily patterns is like breaking through a wall. It seems impenetrable at first, but once the patient has broken through, the rewards of these good, new habits are a sense of energy and physical freedom that few will want to relinquish.
Heart Healthy Diets
Currently, there is much controversy over the best balance of carbohydrates, fats, and protein. A number of dietary approaches for improving the heart are available, which all have benefits depending on specific risk factors. Although all the major dietary approaches differ in important aspects, they have some recommendations in common:
* Choose fiber-rich food (whole grains, legumes).
* Choose fresh fruits and vegetables.
* Choose unsaturated fats over unsaturated fats (found mostly in animal products) and transfatty acids (found in hydrogenated fats and many commercial products and fast foods).
* In selecting proteins, choose soy protein, poultry, and fish over meat.
* Weight control and exercise are essential companions of any diet program.
After embarking on any heart healthy diet, it generally takes an average of three to six months before any noticeable reduction in cholesterol occurs, although some people have reported better levels in as few as four weeks. [For detailed information see, Heart Healthy Diet .]
Therapeutic Lifestyle Changes (TLC) from the National Cholesterol Education Program. New guidelines in 2001 from the National Cholesterol Education Program have now supplanted older guidelines from the American Heart Association Diet. They are more rigorous than previous standards and include the following for preventing and managing high cholesterol levels in adults:
* Choose fiber-rich whole grains, legumes, and fresh fruits and vegetables. Soluble fiber is preferred (from cereal grains, beans, peas, legumes, and many fruits and vegetables).
* Fats can be up to 35% of daily calories, but no more than 7% should be from saturated fat. (People with high triglycerides or low HDL or both may need a higher fat intake.) Choose fats containing unsaturated fatty acids (from vegetables, fish, legumes, and nuts). Choose margarines containing sterols or stanols (e.g., (Benecol, Take Control). Dairy products should be low- or no-fat.
* Limit cholesterol intake to less than 200 mg per day.
* Maintain healthy body weight and a healthy level of physical fitness.
Mediterranean Diet. The Mediterranean diet is rich in heart-healthy fiber and nutrients, including omega-3 fatty acids and antioxidants. The diet recommends the following:
* A relatively high fat intake (about 35% to 45% of daily calories, mostly in monounsaturated and polyunsaturated fats.) The Mediterranean diet is known for its use of olive oil, but the greatest benefits found in a major study of this diet appeared to be derived from the use of canola oil, which is rich in omega-3 fatty acids. Olive oil, in fact, does not contain omega-3 fatty acids. On the other hand, olive oil, may have beneficial effects independent from those on lipids, such as improving insulin and blood glucose levels and reducing blood pressure.
* Daily glass or two of wine.
* The same protein intake as the AHA, although fish is the primary source. (It avoids high-fat dairy and meat products.) In fact, one 2001 study suggested that fish-consumption, not wine, that is the heart-protective ingredient in this diet.
* Lower carbohydrate intake than AHA. Emphasizes not only fresh fruits and vegetables, but also higher amounts of nuts, legumes, beans, and whole grains.
* Foods seasoned with garlic, onions, and herbs.
The Ornish Program and Severely Fat-Restricted Diets. The Ornish program limits saturated fats as much as possible, reduces total fat to 10%, and increases carbohydrates to 75% of calories. It is a very effective but demanding regimen:
* It excludes all oils and animal products except nonfat yogurt, nonfat milk, and egg whites.
* Foods stressed are whole grains, legumes, and fresh fruits and vegetables.
* People in the program exercise 90 minutes at least three times a week.
* Stress reduction techniques are employed.
* People do not smoke nor do they drink more than two ounces of alcohol per day.
Everyone on low fat diets should consume a wide variety of foods and take a multivitamin if appropriate.
The DASH Diet. A diet known as Dietary Approaches to Stop Hypertension (DASH) is now recommended as an important step in managing blood pressure. Evidence now also suggests that it may be a good diet for lowering LDL levels (although HDL levels also decline). This diet is not only rich in important nutrients and fiber but also includes foods that contain two and half times the amounts of electrolytes, potassium, calcium, and magnesium, as are found in the average American diet. It makes the following recommendations:
Avoid saturated fat (although include calcium-rich dairy products that are no- or low-fat).
When choosing fats, select monounsaturated oils, such as olive or canola oils. (One study reported a reduced need for anti-hypertension medication in people with a high intake of virgin olive oil, but no sunflower oil, a polyunsaturated fat.)
* Choose whole grains over white flour or pasta products.
* Choose fresh fruits and vegetables every day. Important foods include most fruits (especially potassium-rich fruits including bananas, oranges, prunes, and cantaloupes) and vegetables (especially carrots, spinach, celery, alfalfa, mushrooms, lima beans, potatoes, avocados, broccoli). Note: Grapefruit boosts the effects of calcium channel blocking drugs, which are often used for hypertension. (Regular oranges do not appear to pose any hazard, but one study suggested that Seville oranges, also called bitter oranges, may be similar to grapefruit in their effect.)
* Include nuts, seeds, or legumes (dried beans or peas) daily.
* Choose modest amounts of protein (preferably fish, poultry, or soy products). Oily fish may be particularly beneficial.
In one study, after eight weeks on the diet, subjects from a broad range of backgrounds experienced a significant reduction in blood pressure. A 2000 study reported that a combination of the DASH diet and salt restriction is very effective in reducing blood pressure. (Each approach has positive benefits, but the combination is best.) Some individuals should take particular measures to restrict salt. [For more information, see, High Blood Pressure .]
Calorie Restriction. Calorie restriction has been the cornerstone of weight-loss programs. Restricting calories also appears to have beneficial effects on cholesterol levels, including reducing LDL and triglycerides and increasing HDL levels. In fact, in a study of an African community, inhabitants had very-low calorie diets and favorable cholesterol levels in spite of a high intake of saturated fat.
The standard dietary recommendations for losing weight are the following:
* As a rough rule of thumb, one pound of fat equals about 3,500 calories, so one could lose a pound a week by reducing daily caloric intake by about 500 calories a day. Naturally, the more severe the daily calorie restriction, the faster the weight loss.
* To determine the daily calories requirements for specific individuals, multiply the number of pounds of ideal weight by 12 to 15 calories. The number of calories per pound depends on gender, age, and activity levels. For instance a 50-year old woman who wants to maintain a weight of 135 pounds and is mildly active might require only 12 calories per pound (1,620 calories a day). A 25-year old female athlete who wants to maintain the same weight might require 25 calories per pound 2,025 (calories a day).
Fat intake should be no more than 30% of total calories. Most fats should be in the form of monounsaturated fats (such as olive oil) and saturated fats (found in animal products) should be avoided.
Diets for Children. As in adults, obesity and unhealthy cholesterol levels in children appear to be due most often to diets high in unhealthy fats. Furthermore, a major study has reported that a low-fat diet is safe and effective for treating high cholesterol in adolescent children. In the study, fat restriction had no adverse effect on mental or physical development. It should be strongly noted, however, that certain amount of fat is essential in infancy and important for growth in children. Parents should always seek professional help in developing a diet plan for their children.
Exercise
Inactivity is one of the four major risk factors for coronary artery disease, on par with smoking, unhealthy cholesterol, and high blood pressure. In fact, studies suggest that people who change their diet in order to control cholesterol are successful in actually lowering their risk for heart disease only when they also follow a regular aerobic exercise program.
The following are some observations on the effects of exercise on coronary artery disease and cholesterol:
* People who maintain an active lifestyle have a 45% lower risk of developing heart disease than do sedentary people. Even moderate exercise reduces the risk of heart attack. One 2001 study of women found that just one hour of walking a week was associated with a lower risk for heart disease. The effects were similar even in women at high risk for developing heart disease.
* People who are on a cholesterol-lowering diet are successful in actually lowering their risk for heart disease only if they also follow a regular aerobic exercise program.
* Some studies suggest that for the greatest heart protection, it is not the duration of a single exercise session that counts but the total daily amount of energy expended. Therefore, the best way to exercise may be in multiple short bouts of intense exercise.
* Burning at least 250 calories a day (the equivalent of about 45 minutes of brisk walking or 25 minutes of jogging) seems to confer the greatest protection against coronary artery disease, most likely because it raises HDL levels-the so-called good cholesterol. (Note, however, moderate exercise has little effect on HDL, and it may take up to a year of sustained exercise to make any significant difference on HDL levels.)
* Aerobic exercise appears to open up the blood vessels and, in combination with a healthy diet, may improve blood-clotting factors.
* Resistance (weight) training offers a complementary benefit to aerobics by reducing LDL levels (the so-called bad cholesterol).
* Exercises that train and strengthen the chest muscles may prove to be very important for patients with angina.
[For complete information, see, Exercise.]
Quitting Smoking
Cigarette smoking lowers HDL-cholesterol levels and is directly responsible for approximately 20% of all deaths from heart disease. Once a person quits smoking, HDL cholesterol levels rise within weeks or months to levels that are equal to their nonsmoking peers. Passive smoking also reduces HDL levels in people highly exposed to smokers. The importance of breaking this habit cannot be emphasized enough. [For more information, see, Smoking.]
Alcohol
number of studies have suggested that light to moderate alcohol intake (one or two glasses a day) improve cholesterol levels and reduce the risk for heart disease in both men and women compared to not drinking. (Heavy drinking, however, is a major heart risk.) Red wine has plant chemicals called polyphenols that may have particular heart benefits, possibly by reducing the risk for blood clots. (For those who can't, or choose not to drink, purple grape juice seems to have similar positive effects.) A number of studies, however, have found heart protection from moderate intake of any type of alcohol. Some research suggests that alcohol has anti-inflammatory properties that protect arteries from injury.
On the negative side one 2001 study also found an association between alcohol and higher homocysteine levels. Another 2001 study found that middle aged men who take up moderate wine drinking for heart health had no more protection against heart disease than those who abstained. Further, they were more likely to develop other diseases, such as cancer. And, a Danish study suggested that the apparent heart protective properties in wine were due to a higher consumption of fish in wine drinkers. More studies are still needed. Pregnant women or those at risk for alcohol abuse in any case should not drink alcohol.
WHAT ARE DRUG THERAPIES AND OTHER TREATMENTS FOR UNHEALTHY LEVELS OF CHOLESTEROL?
General Guidelines for Drug Treatments
Starting Medications. Even modest lowering of cholesterol in those whose levels are high, whether through drug therapy or lifestyle changes, reduces the risk of disability and death from heart disease. Most expert clinicians now focus on lowering LDL cholesterol, the "bad" kind. Expert guidelines now recommend starting cholesterol-lowering drugs along with a diet and exercise regimen for the following groups:
* People with LDL levels of 130 mg/dL or greater if they have existing heart disease or risk factors that place them in equivalent danger. Such factors include diabetes or other diseases that suggest atherosclerosis (such as peripheral artery disease or blockage in the carotid artery). Their goal is to achieve LDL of 100 mg/dL. (Some of these individuals may actually want to start medication at LDL levels as low as 100 mg/dL.)
* People with LDL cholesterol levels of 160 mg/dL or greater who have no existing heart disease but have two or more risk factors. Their goal is an LDL of 130 mg/dL or less.
* People whose LDL is 190 mg/dL or over and have one or no risk factors. They should strive for LDL levels of 160 mg/dL or less. (Some of these individuals might consider medications if they have LDL over 160 mg/dL.)
Evidence now strongly suggests that cholesterol-lowering drugs are improving survival in heart attack patients. Nevertheless, a 2001 study of Massachusetts residents reported that only 24% of patients were tested for high cholesterol levels after a heart attack and only about 30% who showed unhealthy cholesterol were actually given cholesterol-lowering drugs.
It is always important to emphasize that cholesterol-lowering medications are used along with healthy lifestyle habits , not in place of them. In spite of these guidelines, fewer than half of people who would presumably benefit from cholesterol-lowering drugs are being given them.
Choosing the Correct Lipid-Lowering Medication . Experts now recommend that drug treatments be tailored for raising or lowering specific lipids, depending on the patient's blood lipid picture:
* Statins are now the standard agents for most people who require LDL-lowering therapy. Bile-acid binding resins are also effective in lowering LDL, but statins have additional advantages that make them the first choice. (Another LDL-lowering agent, probucol, is usually limited to people with genetic disorders that cause severely high cholesterol levels.)
* Fibrates and nicotinic acid are important agents for people who need to lower triglycerides and increase HDL.
[For more information see Table Effects of Medications on Different Lipids.]
Considerations for Children and Adolescents. Children and adolescents with high cholesterol levels should first change any lifestyle risk factors (obesity, high-fat diet, sedentary habits) that might responsible. Young people over seven or eight years old with evidence of inherited unhealthy cholesterol levels (LDL over 190 mg dl) may benefit from the following medications.:
* Statins are proving to be effective for children with genetic conditions that cause early elevations in cholesterol and is proving to be helpful in reducing long-term dangers.
* Bile-acid binding resins may be an alternative option choice, assuming the child has normal triglyceride levels. A multiple vitamin with folic acid and iron supplements may be needed in such cases.
* Nicotinic acid (niacin) may be an option for young people with high triglycerides.
Cholesterol-lowering agents are also being for some children with high cholesterol levels without evidence of genetic causes. It should be noted that there is no evidence on the long-term safety of statins or any cholesterol-lowering agents in children. Parents should discuss medications very carefully with their physicians and, in any case, should always focus on lifestyle factors.
Considerations for People with Diabetes. At this time the best agents for improving cholesterol and lipid levels in people with diabetes are the statins. Studies suggest that they can reduce the risk for adverse heart events in people with diabetes, even if their cholesterol levels are normal or if their diabetes is mild. Further, in one study, a statin was shown to reduce the risk of developing diabetes by 30% in people with high cholesterol. Fibrates may also be useful for people with type 2 diabetes. Niacin (nicotinic acid) has the best effect on the cholesterol profile of people with diabetes but it also increases blood sugar levels. One well-controlled study, however, found that diabetics who used niacin had little trouble with glucose control, and some experts believe it now may be used as an alternative to or in combination with statins.
Effects of Medications on Different Lipids
Effect on High LDL
Effect on Low HDL
Effect on High Triglycerides
Effect on Lp(a)
Statins
Decrease (18% to 55%)
Modest increase (5% to 15%)
Decrease 7% to 30%
No change
Nicotinic acid (Niacin)
Modest decreases (5% to 25%). In combination with statins, may convert more dangerous LDL type to less dangerous.
Increase (15% to 35%) Drugs of choice for improving HDL levels.
Decrease (20% to 50%) Drug of choice for lowering triglycerides
Lower
Fibrates
Effect varies, but in general has little effect or modest decrease (5% to 20%).
Modest increase (6% to 20%)
Decrease (20% to 50%)
No change
Bile acid-binding resins
Decrease (15% to 30%)
Very modest increase (3% to 5%)
No change
No change
Statins
Statins are the most effective drugs for the treatment of high cholesterol and are becoming very important agents in general. They may benefit the heart by mechanisms beyond lowering cholesterol levels but these possible effects are not yet fully understood. Some studies suggest the following:
* Statins inhibit the liver enzyme hMG-CoA reductase, which is used in the manufacturing of cholesterol. They are particularly effective for lowering LDL levels. They also reduce triglycerides, apparently in direct proportion to their LDL-lowering effects. Statins also raise HDL levels, but to a lesser extent than other anti-cholesterol drugs.
* Statins may further contribute to heart protection by increasing cells called endothelial progenitor cells (EPCs) that repair blood vessels.
* Statins appear to reduce inflammation in the arteries, which is now believed to be a major factor in blood vessel injury.
* Some early evidence suggests that statins may help curtail blood clotting, a major factor in heart attacks. More research is needed substantiate these findings.
In addition studies are suggesting they may have benefits for the bones and the brain.
Candidates. Statins are now strongly recommended as the first choice for most patients with high cholesterol levels, particularly the following:
* Patients with diabetes, existing heart disease, or both.
* Postmenopausal women with heart disease or risk factors for it. (Importantly, statins are now recommended over hormone-replacement therapy in this group.)
* Statins may be safe children and adolescents with unhealthy cholesterol levels, but long-term studies are needed to confirm their value and safety in all children.
Brands. The statins may currently be categorized into three groups:
* So-called natural statins, including lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor). The natural statins are generally administered once a day; they should be taken in the evening because most cholesterol synthesis occurs between midnight and 3 AM. If more intensive treatment is required, a second, morning dose may be administered.
* Newer statins include fluvastatin (Lescol) and atorvastatin (Lipitor). Atorvastatin reduces LDL more effectively at equal doses to the natural statins. Long-term studies are needed to demonstrate survival benefits that are comparable to the natural statins.
* So-called "superstatins" (named by the manufacturers) are in late-trials but not yet approved. They include rosuvastatin (Crestor) and itavastatin. Manufacturer studies are suggesting that Crestor is more effective in lowering LDL than Lescol or Lipitor. Furthermore, in high doses, it may increase HDL (a weak effect with other statins). Itavastatin may be even more potent. Longer and more objective research is needed, however, to confirm any of these findings as well as any long-term adverse effects.
* The longest studies have been conducted on the natural statins, including those reporting benefits not only on the heart but on other regions in the body. The comparable long-term complications and benefits of the newer statins are not yet entirely known. In one 2001 study, for example, fluvastatin, a newer statin, had only modest effects on blood flow in heart attack patients a year after the attack. Another reported a 16% reduction in mortality rates with fluvastatin, although the natural statins have shown higher survival rates. There are no long-term studies on the "superstatins."
Benefits on the Heart and Mortality Rates. Studies are reporting considerable benefits on the heart from statins:
* Evidence has reported that the natural statins effectively reduce the risk of major coronary events, including first and second heart attacks, in both women and men and in older people with evidence of heart disease.
Experts estimate a 25% to 30% reduction in mortality rates when patients take statins after a heart attack. (Some believe the decrease may even be greater.) To date most subjects have had high cholesterol levels at the time of the attack, but evidence suggests that statins may improve survival rates even in heart attack patients with normal cholesterol levels by reducing harmful inflammation in the arteries.
* Unfortunately, studies suggest that only about a third or less of appropriate patients are given statins, although as many as 90% may benefit from them. Most benefits in the studies have been obtained with the natural statins, although work on the newer ones is showing promise. Combinations with other agents may be particularly beneficial. [ See Box Combinations of Cholesterol-Lowering Agents.]
* Benefits Outside the Heart. Studies are also suggesting that the benefits of statins go beyond the heart. At this time, nearly all these studies have been conducted with the natural statins:
* Statins may protect against kidney deterioration in patients with mild kidney disorders.
* Statins may reduce the risk for ischemic stroke in high-risk patients with a wide range of cholesterol and lipid levels. (Ischemic strokes occur from blockage in the blood vessels that lead to the brain.)
* Statins are particularly helpful for patients with diabetes. In one study, statins even appeared to prevent type 2 diabetes from developing in some men with high cholesterol.
* Some studies are reporting up to 70% lower risk for Alzheimer's disease and dementia in people who take statins. (High cholesterol levels have been linked to a high risk for the disease.)
* Some studies, including one in 2002, have reported a lower risk of hip and other fractures in women who take statins, although a 2001 study did not confirm any significant benefits. Few clinical trials have been published, to date, and more work is needed to confirm early data.
* In one small 2002 study, statins appeared to help prevent macular degeneration, an age-related eye disease that can lead to blindness.
Adverse Effects. The statins tend to be better tolerated than other cholesterol-lowering drugs. In many studies the side effects reported were nearly the same as those taking placebo (inactive agents). Those reported include gastrointestinal discomfort, headaches, skin rashes, muscle aches, sexual dysfunction, drowsiness, dizziness, nausea, constipation, and peripheral neuropathy (numbness or tingling in the hands and feet). Statins can effect the liver, so periodic liver function tests should be administered. Statins should never be taken by anyone with liver problems or by women during pregnancy or breast-feeding.
Interactions with Drugs and Food. Statins may have some adverse interactions with other drugs, including other cholesterol-lowering agents. [ See Box Combinations of Cholesterol-Lowering Agents.] Patients should tell they physicians about any other medications they are taking. It should noted that one study suggested that antioxidant supplements, such as vitamin E and C, may blunt the effects of a statin-niacin combination. Grapefruit juice and sour oranges (found in marmalades and other condiments, not in juice) may increase their potency.
Combinations of Cholesterol-Lowering Agents
Benefits. Combinations of the cholesterol lowering agents may be beneficial, particularly for patients with specific lipid imbalances, such as those with the metabolic syndrome, and patients with inherited cholesterol abnormalities.
Statins, for example, can be used with bile acid-binding resins, nicotinic acid (niacin), and fibrates. Significant benefits have particularly been reported with combinations of statins and nicotinic acid. In a 2001 study, for example, patients with low HDL cholesterol and normal LDL cholesterol who took both simvastatin (Zocor) and niacin reported a significantly lower risk for stroke and heart attacks. Advicor, a single medication that combines niacin and lovastatin, has now been approved.
Complications. Combinations between statins and fibrates or niacin increase the risk for rhabdomyolysis, a serious condition that that causes muscle pain and, in rare cases, can lead to kidney failure. The only fatal events associated with rhabdomyolysis and statins have occurred with the cerivastatin (Baycol), particularly at high doses and in combination with fibrates. This statin has been withdrawn from the market.
Nicotinic Acid (Niacin)
Brands. Nicotinic acid is the active compound found in niacin, or vitamin B3. It is the first choice for patients with low HDL levels. Brands include Niacor, Nicolar, and Slo-Niacin. An extended-release form (Niaspan), administered at bedtime, may have fewer side effects, including headaches and flushing, than rapidly-acting niacin agents. Although niacin is available over the counter, the active form used for cholesterol is given in much higher doses and is available only by prescription. It is important to take this medication under a physician's direction in order to ensure its safety and effectiveness.
Benefits. When used in high doses, it has the following benefits:
* It raises HDL levels higher than any other anti-cholesterol drug.
* It is extremely effective in reducing triglyceride levels.
* It lowers LDL-cholesterol and lipoprotein(a).
* It is also the least expensive.
* Combinations with other agents, particularly statins, may be add significant benefits. [ See Box Combinations of Cholesterol-Lowering Agents]
Side Effects. Many patients find its side effects intolerable, however. About a quarter of patients taking rapid-acting forms of nicotinic acid stop taking them. The most common side effects are flushing of the face and neck, itching, headache, blurred vision, and dizziness. They usually occur between five minutes to hours after taking the drug and can last for minutes to, uncommonly, hours. The body does become tolerant to these effects eventually, and they generally subside.
Flushing and itching may be reduced with the following measures:
* Start with low doses taken at mealtime and gradually work up to the prescribed dose.
* Consider taking low-dose aspirin about 30 minutes before taking nicotinic acid, which appears to help prevent flushing.
* Avoid hot drinks.
* Choose an extended release form. (Even with this form, it is wise to gradually increase the bedtime dose over time and take a low-dose aspirin a half-hour beforehand.)
Gastrointestinal problems are common. Other side effects include dry skin and mucous membranes and darkening of the skin.
Potentially Serious Complications. About 3% to 5% of people taking nicotinic acid develop liver abnormalities, which disappear after the medication is discontinued. The extended form (Niaspan) appears to be safe for the liver, but people with chronic liver disease should not use any form of nicotinic acid. People with gout should avoid nicotinic acid, since it elevates uric acid. The role of nicotinic acid in people with diabetes is less clear. About 30% of patients experience elevated levels in blood glucose. The agent has specifically good effects on lipid levels in diabetes, however. And one well-controlled study, found that diabetics who used niacin had little trouble with glucose control. Still, at this time most physicians avoid it for this population.
Bile-Acid Binding Resins
Bile-acid binding resins work, as their name suggests, by binding to bile in the digestive tract. This reduces cholesterol in the following way:
* Bile is made in the liver and is used as one of the primary manufacturing components.
* Once the resins bind to bile in the digestive tract, the bile is excreted in feces.
* As the resins eliminate bile from the body, the liver takes more cholesterol from the circulation in order to produce more bile.
* As cholesterol is taken out of the blood stream, LDL levels drop.
When used in combination with dietary control, LDL levels are reduced by 15% to 20%. Combinations with nicotinic acid are even more effective, with reductions of 40% to 60% observed.
Brands. The bile-acid binding resins and similar agents include cholestyramine (Questran, Questran Light) and colestipol (Colestid). They are generally used in powder form, which is dissolved in liquid, or as a chewable bar (Cholybar). Colesevelam (Cholestagelm, Welchol) is a newer agent available in tablet form. It is therefore easier to administered and is proving to lower LDL without as many side effects, such as constipation.
Side Effects. None of these drugs pose major risks, but most cause constipation, heartburn, gas, and other gastrointestinal problems, side effects that many people cannot tolerate. One study found that only half the standard dose of colestipol was needed when psyllium (Metamucil, Fiberall, Perdiem), a soluble fiber supplement, was added to the drink. In addition, bloating and constipation were reduced. Colesevelam, the newer resin, appears to have significantly fewer of these side effects.
Bile-acting agents may contribute to calcium loss and therefore increase the risk for osteoporosis. Over time deficiencies of vitamins A, D, E, and K may occur, and vitamin supplements may be necessary.
Rarely, toxic effects on the liver have been reported. Patients with liver disorders should be monitored.
Drug Interactions. Bile-acid binding resins may also interfere with other medications, including digoxin (Lanoxin), warfarin, beta-blocker drugs, and a number of medications used to treat hypoglycemia. In order to prevent drug interactions, other drugs should be taken one hour before or four to six hours after taking the bile acid-binding resins.
Fibric Acid Derivatives (Fibrates)
Brands. Fibrates break down the particles that make triglycerides. Gemfibrozil (Lopid) is the standard fibrate. It is usually taken twice a day, 30 minutes before breakfast and before the evening meal. Others include fenofibrate (Tricor) and bezafibrate (Bezalip), which is in trials. Clofibrate (Atromid-S) was the first fibrate used but is rarely prescribed because of perceived serious side effects.
Benefits. Fibric acid derivatives, or fibrates, are useful in the following settings:
* They are good choices for many patients who need to lower triglyceride levels and increase HDL but who cannot take drugs ordinarily used for these purposes, such as nicotinic acid. In one study gemfibrozil, the standard fibrate, reduced the risk for adverse heart events by 22%.
* Fibrates can produce modest reductions in LDL levels, although not as effectively as statins or other drugs. In fact, LDL may increase in patients with very high triglycerides who take these drugs. Though most fibrates have been shown to lower risk of heart attack, they may not have the ability to reduce mortality rates, as other cholesterol-lowering drugs do. More research is needed.
* In a 2001 study, men with both low HDL and LDL levels had a slightly lower risk of stroke after taking gemfibrozil.
* One study reported that fenofibrate may help reduce atherosclerosis in patients with diabetes.
* Fenofibrate also seems to reduce certain clotting factors (another risk factor for heart disease) and uric acid (a risk factor for gout).
Side Effects. Side effects may include gastrointestinal discomfort, aching muscles, sensitivity to sunlight, and skin rashes. Impotence has been associated with fibrates in less than 1% of patients. Fibrates have been known to cause gallstones, so people with gallbladder problems should not use these drugs. The drugs may cause abnormal heart rhythms and can affect the liver and kidney. In one study, people who took gemfibrozil had higher rates of death from other causes, including cancer. Subsequent studies, however, have found no higher incidence of cancer, and a 1999 study found, in fact, a lower cancer rate.
Drug Interactions. They interact with a number of drugs and substances including warfarin, some oral drugs used for diabetes, certain antibiotics, and grapefruit juice.
Probucol
Probucol (Lorelco) lowers LDL-cholesterol levels by 10% to 15%. It is also an antioxidant. Unfortunately, it also lowers the beneficial HDL levels by 20% to 30%. It is generally used for certain genetic disorders that cause high cholesterol levels, or when other cholesterol-lowering drugs are ineffective or cannot be used. Common side effects include gastrointestinal discomforts such as diarrhea, bloating, nausea, and dizziness.
Hormone Replacement Therapy
In spite of estrogen's benefits on cholesterol levels and other factors that effect the heart, the most recent evidence suggests that hormone replacement therapy (HRT) may be harmful for women with existing heart disease, at least in the first few years. In July 2001, the American Heart Association sent out an advisory regarding the use of HRT in postmenopausal women. These guidelines state that women with heart disease, or women who have a heart attack while on HRT, should strongly consider stopping the therapy. In addition, they recommend that doctors stop telling women that hormone replacement therapy has any cardiovascular benefits. It is still not clear if HRT prevents heart disease in women without existing heart disease. If a woman's sole goal is to improve her cholesterol profile, statins are now the recommended first choice for most. [See Menopause, Estrogen Loss, and Their Treatments. ]
Plasmapheresis and Familial Hypercholesterolemia
Plasmapheresis is a blood-filtering procedure that is used to dramatically reduce triglycerides and may also be used to remove LDL. The procedure may be beneficial for patients with severe hereditary forms of high cholesterol that do not respond to other therapies. Studies suggest, for example, that it is particularly useful for patients with familial hypercholesterolemia. In such patients, plasmapheresis produced a significantly lower number of adverse heart events than other treatments. The process takes about three hours. If not performed regularly, its benefits last only about two weeks. People using this procedure are still advised to maintain a healthy diet and stay on any prescribed medications to control cholesterol.
Investigative Therapies
Ezetimibe. Ezetimibe (Zetia) inhibits the absorption of cholesterol in the intestines and may turn out to be a useful adjunct to statins. In fact, manufacturers are hoping to get FDA approval for a combination pill that includes both ezetimibe and a statin.
Selective Estrogen-Receptor Modulators . (SERMs) Selective estrogen-receptor modulators (SERMs) have been designed to produce the benefits of estrogen without its risks. They are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. They include tamoxifen (Nolvadex), raloxifene (Evista), and droloxifene. Any beneficial effects of the SERMs on the heart are still unclear. They have some minor benefits for cholesterol level s but they also increase the risk for deep-vein blood clots. Droloxifene may lower blood pressure. Of course, SERMs are used most frequently in women, but in an interesting study of the SERM tamoxifen (a drug used to treat and prevent breast cancer), men who took the drug had improved cholesterol levels after two months.
Cholestin. Cholestin is a red yeast used in traditional Chinese medicine, which may have some ability to reduce cholesterol levels. One of the primary actions of the yeast is to produce lovastatin, one of the major statin agents. It is an herbal supplement, however, not a prescription drug, so the FDA has not been allowed to regulate it. Side effects are said to include mild digestive problems. It appears to be safe, but more studies are needed. Experts warn that any substance that has such strong effects on cholesterol may also have strong adverse effects, and, like all so-called natural remedies, no official standards have been developed to control its quality.
Avasimibe. This unique agent inhibits cholesterol storage and so may reduce atherosclerosis. Small early studies report reductions in triglycerides and very low density (VLDL) cholesterol but no changes in LDL or HDL.
SCAP Ligands. These drugs have been shown to reduce greatly LDL cholesterol and triglycerides in laboratory animals. Trials in humans are needed to verify their usefulness.
WHERE ELSE CAN INFORMATION ABOUT CHOLESTEROL BE OBTAINED?
National Cholesterol Education Program, Information Center, PO Box 30105, Bethesda, MD 20824-0105. Call (301-251-1222) or (http://rover.nhlbi.nih.gov/chd/
)
American Dietetic Association. 216 W. Jackson Boulevard, Chicago, Illinois 60606. Call (312-899-0040 or 800-366-1655) or (fax 312- 899-1979) or (http://www.eatright.org/ )
The organization offers a hot-line (900-225-5267) that allows people to speak to a licensed dietitian and also provides names of licensed dietitians for specific locations. Cost is $1.95 for first minute and. 95 for every additional minute. Its web site is excellent and highly recommended. It offers good, recent information on nutrition and an excellent, searchable database for dietitians within a particular locality in a desired specialty, including eating disorders and weight control.
American College of Cardiology, Heart House, 9111 Old Georgetown Rd., Bethesda, MD 20814-1699. Call (800-253-4636) or (301-897-540) or (http://www.acc.org/ )
American Heart Association, 7272 Greenville Ave., Dallas, Texas 75231-4596. Call (214-373-6300 or 800-242-8721) or (http://www.americanheart.org ).
This is a primary source of information for heart problems. They are very responsive and will send free pamphlets and reading material, including useful diet information and locations of local representatives
Offers a useful heart risk evaluation test. (http://www.heartriskevaluations.com/ )
Government link for calculating ten-year risk. http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=pub .
An extremely informative site on the heart. (http://www.heartinfo.org )
Web site for registering and treating people with familial hypercholesterolemia (FH) (http://www.medped.org/ )
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Update 10/1/04
Newer guidelines are showing that reducing the bad cholesterol LDL to 70-80 saves lives from heart attacks. Lower LDL in people with Metabolic Syndrome X, Diabetes, High Blood Pressure, Atherosclerosis in particular should have their LDL lower.
Muscle Pains from statins, the best class of cholesterol lowering drugs, occur 5-7% of people. Baycol was used in the past but people died from rhabdomyolosis: severe muscle breakdown that releases toxins to cause kidney failure. Muscle toxicity feels like muscle aches and weakness in particular to the legs. If this happens to you, get your blood drawn right away and talk to your doctor about stopping the statins. Statins combined with fibrates in particular increase the risk of muscle breakdown.
Crestor is the newest of the statins. Only 10mg has been shown to lower LDL by half. Achieving the goal of lowering LDL to <100 is easier with this dose, and there might be less muscle toxicity since it is a lower dose. For other statins such as Lipitor, Pravachol, and Zocor, doubling the dosage only lowers LDL an additional 5% and there is more risk of liver toxicity and possibly muscle toxicity.
Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. Lesser amounts of cholesterol are also found in plant membranes.
The name originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as researchers first identified cholesterol in solid form in gallstones in 1784.
Most cholesterol is not dietary in origin; it is synthesized internally. Cholesterol is present in higher concentrations in tissues which either produce more or have more densely-packed membranes, for example, the liver, spinal cord and brain, and also in atheromata. Cholesterol plays a central role in many biochemical processes, but is best known for the association of cardiovascular disease with various lipoprotein cholesterol transport patterns and high levels of cholesterol in the blood.
When doctors talk to their patients about the health concerns of cholesterol, they are often referring to "bad cholesterol", or low-density lipoprotein (LDL). "Good cholesterol" is high-density lipoprotein (HDL); this denotes the way cholesterol is bound in lipoproteins, the natural carrier molecules of the body.
Contents [hide]
1 Physiology
1.1 Function
1.2 Synthesis and intake
1.3 Regulation
1.4 Excretion
1.5 Body fluids
2 Clinical significance
2.1 Hypercholesterolemia
2.2 Hypocholesterolemia
3 Food sources
3.1 Cholesterol in plants
4 Cholesteric liquid crystals
5 See also
6 External links
7 References
[edit] Physiology
[edit] Function
Cholesterol is required to build and maintain cell membranes; it makes the membrane's fluidity - degree of viscosity - stable over wider temperature intervals (the hydroxyl group on cholesterol interacts with the phosphate head of the membrane, and the bulky steroid and the hydrocarbon chain is embedded in the membrane). Some research indicates that cholesterol may act as an antioxidant.[1] Cholesterol also aids in the manufacture of bile (which helps digest fats), and is also important for the metabolism of fat-soluble vitamins, including vitamins A, D, E and K. It is the major precursor for the synthesis of vitamin D and of the various steroid hormones (which include cortisol and aldosterone in the adrenal glands, and the sex hormones progesterone, the various estrogens, testosterone, and derivatives ).
Recently, cholesterol has also been implicated in cell signalling processes, where it has been suggested that it forms lipid rafts in the plasma membrane. It also reduces the permeability of the plasma membrane to hydrogen ions (protons) and sodium ions.[2]
Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including the caveolae-dependent endocytosis and clathrin-dependent endocytosis. The role of cholesterol in caveolae-dependent and clathrin-dependent endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane.
[edit] Synthesis and intake
The HMG-CoA reductase pathwayCholesterol is required in the membrane of mammalian cells for normal cellular function, and is either synthesized in the endoplasmic reticulum, or derived from the diet, in which case it is delivered by the bloodstream in low-density lipoproteins. These are taken into the cell by receptor-mediated endocytosis in clathrin-coated pits, and then hydrolysed in lysosomes.
Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase pathway in many cells and tissues. About 20–25% of total daily production (~1 g/day) occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands and reproductive organs. For a person of about 150 pounds (68 kg), typical total body content is about 35 g, typical daily internal production is about 1 g and typical daily dietary intake is 200 to 300 mg. Of the 1,200 to 1,300 mg input to the intestines (via bile production and food intake), about 50% is reabsorbed into the bloodstream.[citation needed]Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism.
[edit] Regulation
Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, while lower intake from food has the opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (Sterol Regulatory Element Binding Protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site 1/2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. The cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the SRE (sterol regulatory element) of a number of genes to stimulate their transcription. Among the genes transcribed are the LDL receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol.[3]
A large part of this mechanism was clarified by Dr Michael S. Brown and Dr Joseph L. Goldstein in the 1970s. They received the Nobel Prize in Physiology or Medicine for their work in 1985.[3]
The average amount of blood cholesterol varies with age, typically rising gradually until one is about 60 years old. There appear to be seasonal variations in cholesterol levels in humans, more, on average, in winter.[4]
[edit] Excretion
Cholesterol is excreted from the liver in bile and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the gallbladder, it crystallises and is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently.
[edit] Body fluids
Cholesterol is minimally soluble in water; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by lipoproteins - protein "molecular-suitcases" that are water-soluble and carry cholesterol and triglycerides internally. The apolipoproteins forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied.
The largest lipoproteins, which primarily transport fats from the intestinal mucosa to the liver, are called chylomicrons. They carry mostly fats in the form of triglycerides and cholesterol. In the liver, chylomicron particles release triglycerides and some cholesterol, and are converted into low-density lipoprotein (LDL) particles, which carry triglycerides and cholesterol on to other body cells. In healthy individuals the LDL particles are large and relatively few in number. In contrast, large numbers of small dense LDL (sdLDL) particles are strongly associated with promoting atheromatous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol".
The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the total blood cholesterol level should be: <200 mg/dl normal blood cholesterol, 200-239 mg/dl borderline-high, >240 mg/dl high cholesterol.
High-density lipoprotein (HDL) particles transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large numbers of large HDL particles correlates with better health outcomes, and hence it is commonly called "good cholesterol". In contrast, having small amounts of large HDL particles is independently associated with atheromatous disease progression within the arteries.
[edit] Clinical significance
[edit] Hypercholesterolemia
Main article: Hypercholesterolemia
In conditions with elevated concentrations of oxidized L.D.L. particles, especially small LDL particles, cholesterol promotes atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease. In contrast, HDL particles (especially large HDL) have been the only identified mechanism by which cholesterol can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression.
Of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis). Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. Conversely, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates would still be high. In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large, then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration.[citation needed]
These effects are further complicated by the relative concentration of asymmetric dimethylarginine (ADMA) in the endothelium, since ADMA down-regulates production of nitric oxide, a relaxant of the endothelium. Thus, high levels of ADMA, associated with high oxidized levels of LDL pose a heightened risk factor for cardiovascular disease.[citation needed]
Multiple human trials utilizing HMG-CoA reductase inhibitors or statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lower cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults; however, no statistically significant mortality benefit has been derived to date by lowering cholesterol using medications in asymptomatic people, i.e., no heart disease, no history of heart attack, etc.
Some of the better-designed recent randomized human outcome trials studying patients with coronary artery disease or its risk equivalents include the Heart Protection Study (HPS), the PROVE-IT trial, and the TNT trial. In addition, there are trials that have looked at the effect of lowering LDL as well as raising HDL and atheroma burden using intravascular ultrasound. Small trials have shown prevention of progression of coronary artery disease and possibly a slight reduction in atheroma burden with successful treatment of an abnormal lipid profile.
The American Heart Association provides a set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:[5]
Level mg/dL Level mmol/L Interpretation
<200 <5.2 Desirable level corresponding to lower risk for heart disease
200-239 5.2-6.2 Borderline high risk
>240 >6.2 High risk
However, as today's testing methods determine LDL ("bad") and HDL ("good") cholesterol separately, this simplistic view has become somewhat outdated. The desirable LDL level is considered to be less than 100 mg/dL (2.6 mmol/L), although a newer target of <70 mg/dL can be considered in higher risk individuals based on some of the above-mentioned trials. A ratio of total cholesterol to HDL —another useful measure— of far less than 5:1 is thought to be healthier. Of note, typical LDL values for children before fatty streaks begin to develop is 35 mg/dL.
Patients should be aware that most testing methods for LDL do not actually measure LDL in their blood, much less particle size. For cost reasons, LDL values have long been estimated using the Friedewald formula: [total cholesterol] − [total HDL] − 20% of the triglyceride value = estimated LDL. The basis of this is that Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Ordinarily just the Total, HDL, and Triglycerides are actually measured. The VLDL is estimated as one-fifth of the Triglycerides. It is important to fast for at least 8-12 hours before the blood test because the triglyceride level varies significantly with food intake.
Increasing clinical evidence[citation needed] has strongly supported the greater predictive value of more-sophisticated testing that directly measures both LDL and HDL particle concentrations and size, as opposed to the more usual estimates/measures of the total cholesterol carried within LDL particles or the total HDL concentration.
[edit] Hypocholesterolemia
Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes of this state is relatively limited, and while some studies suggest a link with depression, cancer and cerebral hemorrhage it is unclear whether the low cholesterol levels are a cause for these conditions or an epiphenomenon[2].
[edit] Food sources
Major dietary cholesterol sources are animal food products. Examples are egg yolk (~1234 mg/g), beef products (~381 mg/g), shrimp products (176 - 256 mg/g) [6]. Plant products (eg. flax seed, peanut), also contain cholesterol-like compounds, phytosterols, which are suggested to help lower serum cholesterol. [7]
[edit] Cholesterol in plants
Many sources (including textbooks) incorrectly assert that there is no cholesterol in plants. This misperception is made worse in the United States, where Food and Drug Administration rules allow for cholesterol quantities less than 2 mg/serving to be ignored in labelling. While plant sources contain much less cholesterol (Behrman and Gopalan suggest 50mg/kg of total lipids, as opposed to 5g/kg in animals), they still contain the substance.[8]
[edit] Cholesteric liquid crystals
Some cholesterol derivatives, (among other simple cholesteric lipids) are known to generate liquid crystalline phase called cholesteric. The cholesteric phase is in fact a chiral nematic phase, and changes colour when its temperature changes. Therefore, cholesterol derivatives are commonly used as temperature-sensitive dyes, in liquid crystal thermometers and temperature-sensitive paints.
[edit] See also
Triglycerides
[edit] External links
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults US National Institutes of Health Adult Treatment Panel III
Aspects of fat digestion and metabolism - UN/WHO Report 1994
American Heart Association - "About Cholesterol"
Cholesterol in Plants
Cholesterol content in food
Links to external chemical sources.
Cholesterol and Health
The Cholesterol Myths
Cholesterol Control for the Healthy Hearts. 1989. Parlay International Diet and Heart Disease.
Anderson, Jennifer and Susan R. Wang. Service in Action. Cholesterol and Fats. Colorado State. Parlay International. 4/88
[edit] References
^ Smith LL. Another cholesterol hypothesis: cholesterol as antioxidant. Free Radic Biol Med 1991;11:47-61. PMID 1937129.
^ Haines, TH. Do sterols reduce proton and sodium leaks through lipid bilayers? Prog Lipid Res 2001:40:299–324. PMID 11412894.
^ a b Anderson RG. Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology. Trends Cell Biol 2003:13:534-9. PMID 14507481.
^ Ockene IS, Chiriboga DE, Stanek EJ 3rd, Harmatz MG, Nicolosi R, Saperia G, Well AD, Freedson P, Merriam PA, Reed G, Ma Y, Matthews CE, Hebert JR. Seasonal variation in serum cholesterol levels: treatment implications and possible mechanisms. Arch Intern Med 2004;164:863-70. PMID 15111372.
^ "About cholesterol" - American Heart Association
^ [1]
^ Ostlund RE, Racette, SB, and Stenson WF (2003). "Inhibition of cholesterol absorption by phytosterol-replete wheat germ compared with phytosterol-depleted wheat germ". Am J Clin Nutr 77 (6): 1385-1589.
^ Behrman EJ, Gopalan Venkat. Cholesterol and plants. J Chem Educ 2005;82:1791-1793
Cholesterol
(READING TIPS: For fast reading, scan through the topic headings in BOLD BLACK, important conclusions in BOLD BLUE,and " Must Know " in BOLD RED. To jump to specific sections in this article, click on the respective LINKS in the Contents.)
Before You Begin
Information presented here is for general educational purposes only. Each one of us is biochemically and metabolically different. If you have a specific health concern and wish my personalized nutritional recommendation, write to me by clicking here.
Contents
Cholesterol Basics
Cholesterol and Free Radical Activity
Lipoprotein(a)
Cholesterol and Cardiovascular Disease
What is "Normal" Cholesterol Level?
Cholesterol Lowering Drugs
Diet Cholesterol and Blood Cholesterol
Sugar and Cholesterol
High Cholesterol - a Symptom and NOT a Disease
Cholesterol Lowering Protocol
1. Nutritional Supplements
2. Modified Mediterranean Diet
Diet Tips for Lowering Cholesterol
3. Exercise
4. Natural Lower Cholesterol Agents
Laboratory Standard
Summary
High total serum cholesterol and LDL cholesterol are significant risk factors of cardiovascular disease. 14 million Americans have heart disease and more than 2,600 die daily from heart attacks in the United States alone. 15% of adults in their late 30s to 40s are afflicted by cardiovascular disease, about 50% of 55 to 64 year-olds, and 65% of those will be afflicted in the next decade.
Developed countries have shown a decrease in dietary fat and cholesterol consumption in recent years. This is largely the result of on-going massive public health campaign advocating a low fat, high carbohydrate diet as ideal to bring down blood cholesterol level to prevent arthrosclerosis. Despite this effort, the number of people with elevated blood cholesterol continues to increase. Obviously there are other causative factors that have not being addressed. In America alone, over 40 million prescription was written yearly for cholesterol lowering medications.
After decades of research, nutritionists are still debated on the etiology of high cholesterol and the best way to bring it down. Let us take a closer look.
Cholesterol Basics
Cholesterol is a waxy substance consisting of fats (lipids) and proteins. It is one of the macro-nutrients necessary for life. Cholesterol is made in the liver and is carried in the blood on carrier molecules called lipoproteins. The main lipoproteins categories are very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density-lipoprotein (HDL). Once bound to the carrier HDL, the cholesterol is known as HDL cholesterol. HDL in effect transports fat from the cell to the liver. When the HDL cholesterol level is high, it is more cardio protective. Therefore, HDL cholesterol is considered "good " cholesterol. LDL is the carrier of oxidized cholesterol as LDL cholesterol from the liver to cell. Elevated LDL cholesterol is directly correlated with increased cardiovascular risk. LDL cholesterol is therefore called the "bad" cholesterol.
Cholesterol, when unoxidized, is an antioxidant and free radical scavenger in its naturally occurring state. In fact, unoxidized cholesterol guards the cell membranes' phospholipids from free radical damage and protect it against atherosclerosis, cancer, and other free radical attack. Also, cholesterol is a predecessor to many steroid hormones and vitamin D. It is produced at the liver at the rate of 3,000 to 4,000 mg a day.
Cholesterol and Free Radical Activity
While the exact mechanism of how cholesterol affects our body is still under intense investigation, it is clear that the unified theory of free radical damage caused by unhealthy foods such as processed fat and oxidized cholesterol is the most likely mechanism. Free Radical damage to our blood vessels is one of the primary causes of atherosclerosis. The most important cause of free radical pathology is the excessive dietary fat consisting of processed poly-unsaturated fatty acid (PUFA) and trans fat (frequently used in fried foods, margarine, cooking oil, and oxidized cholesterol from commercially prepared foods). In the event that dietary fat and oil is retrieved from fresh, whole, and unprocessed foods, no lipid peroxidation will take place and the cell membrane will remain healthy in a normal cis-configuration without any free radical damage.
One theory advanced by the late Nobel laureate Dr. Linus Pauling, together with his research cohort Dr. Matthias Rath, is that the total serum cholesterol is really an indicator of the amount of free radical damage in the body. Our body maintains an optimum level of total cholesterol level as well as a delicate balance among its subcomponents. A negative feedback mechanism exists within the body that decreases the rate of endogenous synthesis when the dietary intake exceeds what is needed. The total circulating cholesterol remains relatively constant between 170-200 mg/dl for the normal adult. The higher the free radical level, the higher the body needs to produce cholesterol internally from the liver to act as an antioxidant and free radical scavenger. Cholesterol level is therefore an indicator of free radical activities in the body.
Free radicals are not all bad. Some of them are definitely necessary to protect us against cancer cells and infections. In fact, a low total cholesterol level (below 150 mg/dl) has been linked with an increased risk of cancer and stroke. Too many free radicals, on the other hand, is detrimental to our health.
Cholesterol in its natural state is therefore actually good for us. During commercialization, lipid (including fat and cholesterol) peroxidation takes place as soon as fats and oils are extracted from the foods in which they naturally occur. This commercialization process is sped up by metallic ions, particularly iron and copper. Extensive lipid peroxidation can occur without an apparent stale or flavor, like in peanut butter, the making of salad and cooking oil, and also in so-called cold-pressed oils. During the processing of PUFAs to make cooking oil, rapid peroxidation can take place and free radicals are released. This process is accelerated by heat, atmospheric oxygen, light, and trace amounts of unbound metallic elements.
Oxidized cholesterol is a free radical generator. It is attached particularly to low-density lipoproteins as LDL cholesterol as it goes from the liver to the cell. Hamburgers and other cooked and processed foods contain animal fats that are usually high in oxidized cholesterol when cooked. Foods cooked in animal fat and fried in processed PUFA (such as corn oil) also have high oxidized-cholesterol content. As a result, the higher the LDL cholesterol level, the higher the risk of cardiovascular disease. Research has shown that rabbits that consumed a small amount of oxidized cholesterol for merely 12 weeks had atherosclerosis plaques that were two times as big as the control population. Studies reveal that heart attack risk falls 2% for every 1% drop in LDL cholesterol level.
One of the most important causes of free radical pathology is the excessive dietary fat consisting of processed PUFA or trans fat frequently used in fried foods, margarine, and cooking oil. In the event that dietary fat and oil is retrieved from fresh, whole, and unprocessed food, no peroxidation will take place and cell membrane will remain healthy in a normal cis-configuration without any free radical damage. Studies have shown that 20% of dietary calories as commercially available fat will not surpass the control threshold of endogenous free radical protection. Unfortunately, the current contribution from such commercially processed fat to our diet exceeds 40 percent.
Lipoprotein(a)
Some of the natural cholesterol produced by the liver in response to free radical damage is converted into LDL cholesterol and its relative lipoprotein (a) (Lp (a)). While LDL cholesterol maybe known as the "bad" cholesterol, Lp (a) is even worse. Lp(a) is a plasma lipoprotein that structurally resembles LDL, but with an additional adhesive protein. Lp(a) is also made in the liver and transported to the cell. Studies have shown that Lp(a) holds fast to damaged blood vessel, attracting other Lp(a) molecules, and finally constituting the atherosclerotic plaques. In fact, a high Lp (a) level (more than 30 mg/dl) has been revealed to carry a 10 times greater risks for heart disease than LDL cholesterol level. Lp(a) level should be part of a routine blood screening test for cardiovascular disease risk.
Lp(a), according to Drs. Pauling and Rath, is the body's way of repairing its damaged vessel wall that has micro leakages caused at least in part by free radical damage and vitamin deficiencies (more specifically vitamin C) Humans do not make any endogenous vitamin C and have no self-repair mechanism of the vascular system. Lp(a) is used by the body as a surrogate vitamin C, so to say. Lp(a), unfortunately, has a sticky characteristic and adheres to each other, forming an atherosclerotic plaque over time. The body, at the interim, is unaware. As long as the damage persists due to free radical presence (either from improper diet, aging, pollution, lack of vitamins, or toxins), the body responds by making more cholesterol endogenously in the liver, feeding a viscous cycle of ever increasing Lp(a).
Cholesterol and Cardiovascular Disease
The notion that total blood cholesterol level alone is the key determinant of cardiovascular heath should be dispelled. Polar bears, for example, maintain total blood cholesterol of over 400 mg/dl and they seldom develop heart attacks. There is obviously a lot more to learn about cholesterol and its link to cardiovascular disease that we currently know.
It is proven that single focused dietary strategy of lowering dietary cholesterol does not reduce coronary heart disease risks. To make matters worse, "low-fat, high carbohydrate" diets are often high in the wrong type of carbohydrate. Instead of taking in complex, paleo type carbohydrates such as green leafy vegetables of low glycemic index, the ignorant consumer often ends up consuming carbohydrates of high glycemic index such as pasta, soda, processed foods, and fast foods. These types of food are rich in sugar and starch (carbohydrate). They actually lower the important "good" HDL cholesterol. A low HDL cholesterol level is inversely proportional to the cardiovascular disease risk. It should be remembered that cholesterol and fat are concentrated sources of calories and can lead to obesity if too much is consumed.
In the Framingham study for example, men and women consumed an average cholesterol intake of 700 mg and 500 mg per day respectively were studied (one egg provides 200 mg). The average serum concentration of cholesterol for men and women with higher than average cholesterol intake were found to be 237 and 245 mg/dl respectively. Subjects with lower than average intakes were found to be 237 and 241 mg/dl. The difference is statistically insignificant. Statistically, studies have shown that people who consume 4 eggs per week (one egg provides 200mg cholesterol) actually have average serum cholesterol (193 mg/dl) same than those who reported consuming only 1 egg per week (197 mg/dl). Clearly dietary cholesterol in and of itself is not the critical link to heart disease risks as we once thought.
What is "Normal" Cholesterol Level?
A low total serum cholesterol level (under 150 mg/dl) is undesirable for the healthy person. It is very difficult to lower cholesterol only without other types of fats because they are often found intermingled with each other in food. While saturated fatty acid (SFA) from animal and dairy products is not subject to lipid peroxidation, all animal fats contain some PUFA and cholesterol, both of which undergo auto-oxidation. Those who are serious in reducing total serum cholesterol level should refrain from intake of lipid peroxide-containing fats (trans fat such as margarine) with resulting reduction of free radical pathology. Like trans fat, oxidized cholesterol should be limited as much as possible.
A low fat diet may actually bring harm to health. The correct way is to discern the right type of fat and cholesterol to take and those to avoid. The overall fat intake as a percentage of dietary calories should not fall below 25-30%. One should have plenty of "good" mono-unsaturated fatty acids (MUFA) like olive oil, seeds, nuts, and cold-water fish that have high omega-3 fatty acid (N3) content.
Saturated fat is necessary for good health. It should come from free-range poultry or beef, and organic eggs. It is very important to avoid "bad" trans fat, like margarine and fried foods. Moreover, the use of processed PUFA such as corn, safflower or sunflower oil should be restricted.
The optimum level of blood cholesterol should be at the upper end of normal around 200 mg/dl.
Cholesterol Lowering Drugs
A class of drugs used to aggressively treat elevated LDL levels is the synthetically derived HMG-CoA reductase inhibitors such as Iovastatin, pravastatin, and simvastatin. They are collectively called "statin" drugs. By inhibiting the production of HMG-CoA reductase, cholesterol production in the liver is reduced. These are among the most potent lipid-lowering agents available. To compensate for the resulting reduction of cholesterol production, the liver increases absorption of LDL cholesterol, further contributing to an overall reduction of LDL cholesterol levels.
While statin drugs are effective in lowering LDL cholesterol, they have serious side effects. For years, the public was led to believe that the wonders of statin drugs not only in lowered cholesterol but possessed other health benefits as well. Millions of statin prescriptions are written yearly in the United States alone. In August 2001, however, German Pharmaceutical giant Bayer AG withdrew the cholesterol-lowering statin drug Baycol from the market because it was linked to 31 deaths. Moreover, deaths occurred at the manufacturer's recommended initial dose (0.4 mg/day) as well as at the highest dose (0.8 mg/day). The majority of deaths occurred in elderly patients and more often in women.
There are other statin drugs on the market, such as Lipitor (the best seller). Like Baycol, these drugs are linked to the same rare muscle weakness, known as myositis, which occurs in about 1 in 1,000 statin users. Myositis occasionally progresses to rhabdomyolysis -- a complete breakdown of muscle cells that can lead to kidney failure and death. Some experts believe that pravastatin (Pravachol) and fluvastatin (Lescol) may have less potential for this deadly drug interactions. The data at this time are not sufficient to declare one statin drug safer or more dangerous than the others.
Statin drugs also inhibits the intrinsic biosynthesis of Coenzyme Q10 (CoQ10), a central compound in the mitochondrial respiratory chain. CoQ10 is indispensable for optimum cardiac function. Reduction of CoQ10 constitutes new risk of cardiac disease, especially for those whose cardiac function is compromised, such as those with congestive heart failure or cardiomyopathy.
Furthermore, statin drugs have been linked to various forms of cancer in laboratory animals. It will be years before we know the full side effects of statin drugs.
Using statin drugs on a short-term basis to normalize blood cholesterol is a reasonable alternative if a drug-free approach fails. Anyone on long term statin type cholesterol lowering drug would be wise to get regular checkups, especially on liver function.
Questions? Ask me.
Diet Cholesterol and Blood Cholesterol
The trend to reduce serum total and LDL cholesterol started in the past two decades when studies linked high dietary saturated fat intake to increased serum cholesterol level. Furthermore, studies have convincing shown that a high LDL cholesterol level is a definite risk factor and increases chances of cardiovascular disease. Furthermore, cholesterol lowering statin drugs such as Lipitor is effective to reduce LDL cholesterol. The solution therefore appears simple - reduce dietary cholesterol on the presumption that high dietary cholesterol leads to high LDL cholesterol. If that fails, prescribe cholesterol-lowering medication.
The reality is that studies have shown that a diet high in cholesterol will not lead to high blood cholesterol if the subject is healthy. Blood cholesterol level only increases by 3 mg/dl after ingestion of one egg day for a continuous period of 6 weeks (one egg contains about 230 mg of cholesterol) in repeated studies. Clearly, dietary cholesterol is not the main culprit.
Sugar and Cholesterol
Sugar consumption has been increasing for the past 100 years and this upward trend remains unabated. Increased rates of cardiovascular disease have a direct correlation to the increase in sugar intake and not fat and cholesterol intake. Sugar includes grains such as wheat and rice. Also included are starchy underground vegetables such as potato, yam and carrot that convert quickly into sugar once inside the body.
High sugar intake is linked to an increased risk of heart disease. Simple sugars are the primary source of high triglycerides, a type of blood fat, and very low-density lipoproteins (LDL), which are an independent risk factor for atherosclerosis. Sugar lowers good HDL cholesterol and raises bad LDL cholesterol and blood pressure levels. It is estimated that a high sugar intake may account for as many as 150,000 premature deaths from heart disease in the US each year.
Sugar increases triglyceride storage and cellular oxidative damage. This assaults the vascular wall, leading to micro-leakages in the endothelial wall of blood vessels, leading to the self-repair mechanism of cholesterol and lipoprotein (a) production described above. Sugar is therefore a significant contributory factor of oxidative stress. Simple logic dictates that reduction of sugar intake will reduce oxidative stress. This in turn will reduce cholesterol production from the liver.
Studies have been conducted to support this. In one research trial, 18 male subjects received normal food followed by a rigorously specified diet in which protein and carbohydrate requirements were met by amino acids, essential fat, and glucose. The average concentration of cholesterol in the initial period, on normal food, was 227 mg/dl. After two weeks on the restricted glucose diet, it had dropped to 173. Two weeks later, the level was at 160. When the diet was altered by replacing 25 percent of the glucose with sucrose (while all other dietary constituents kept constant), the average cholesterol level rose from 160 to 178 within one week and to 208 within two weeks. The researchers carried the study one step further. The sucrose was replaced with glucose again. With this change, the cholesterol concentration dropped back to 175 within one week and the decline continued. It finally leveled off at 150 mg/dl, which was 77 mg/dl less than the initial value. This research finding links the consumption of sucrose (table sugar) directly to increased cholesterol. The exact mechanism is still under research.
In addition to glucose, fructose from fruits also raises blood triglyceride level. In a clinical trial conducted at the University of Minnesota, researchers followed 24 healthy adults who received one of 2 diets assigned randomly for a period of 6 weeks and then switched back to the other diet for 6 weeks. One diet provided 17% of energy as fructose and the other diet was sweetened with glucose and was absent of fructose. Both diets contain common foods and contained nearly identical amounts of the macronutrients. The researchers found that in men, the fructose diet raised plasma triglyceride levels by 32%, although there was no effect seen with the women being studied.
Elevated triglyceride blood level of in itself is a strong and independent risk factor for heart attack among middle-aged and elderly men. In fact, studies have shown that blood triglyceride level was a stronger risk factor than total cholesterol alone. It is not known why women appear to be immune to this other than postulations that the high level of estrogen acts as a protective factor. The exact mechanism is still under investigation.
High Cholesterol - a Symptom and NOT a Disease
Elevated cholesterol is a symptom and not a disease. The real problem is oxidative damage from excessive free radical damage caused by excessive metabolism of oxygen and sugar. Humans lack the endogenous capacity to produce vitamin C, a natural anti-oxidant. Instead, the body produces cholesterol as a surrogate. If you understand this concept, it is easy to appreciate that high cholesterol and a host of other age-related diseases such as arthrosclerosis is nothing more than a series of symptoms reflective of the body's response to imbalanced oxygen and sugar metabolism. The first and most important step to normalizing cholesterol level permanently is, in addition to exercise, proper control of your oxygen load (through reduction of oxidative stress by taking anti-oxidants) and sugar load (by avoiding foods that are high in sugar and concentrate on low glycemic index food).
Attention
Because of tremendous individual variation, the use of nutritionals should therefore be personalized for your body. One person’s nutrient can be another person’s toxin. If you have a specific health concern and wish my personalized nutritional recommendation, write to me by clicking here.
Cholesterol Lowering Protocol
Unless you have high cholesterol due to familial factors, lowering plasma LDL cholesterol can be achieved effectively by eliminating the two key causative factors - excessive oxidation and sugar overload. This is best done through a combination of nutritional supplementation, diet, and lifestyle modifications.
Steps 1,2, and 3, when taken concurrently, will lower your cholesterol within 30 to 60 days. These three steps can be continued on an on-going basis.
Step 4 contains specific natural cholesterol lowering agents that can be used for the short term reduction of cholesterol if you desire a more potent action. It can be added if steps 1,2, and 3 fail. This is not a mandatory step but an option. Long term use of this step should be supervised by a knowledgeable health professional.
1. Nutritional Supplements
A. Coenzyme Q10 (CoQ10) is a foundation formula which enhances mitochondrial function. CoQ10 supports healthy HDL and prevents the excess oxidation of LDL. Statin drugs reduce the level of CoQ10 in the body. Dosage: 30-90 mg daily.
B. L-carnitine, works synergistically with CoQ10 to support healthy cholesterol and improves transportation of nutrients from the extra-cellular space to the intra-cellular space. Dosage: 250 -1,000 mg daily.
C. Garlic reduces triglycerides and LDL cholesterol. In addition to using fresh garlic in your cooking (best to let it sit for 20 minutes in open air before eating), you can also take a therapeutic dose of garlic in supplement form. Dosage: varies, depending on the product. Look for garlic supplements standardized to 12,000-ppm allicin potential, and aim for at least 6,000 mcg of allicin per day. This is equivalent to about 4 cloves a day. Garlic has a blood-thinning effect, and should not be taken in large amounts if you are on blood thinners.
D. Digestive Enzymes including lipase and amylase help breakdown food and aid in digestion. Bowel transit time is also reduced, resulting in less stasis and absorption of fat.
E. Probiotics or "friendly bacteria" such as L. Acidophilus help promote healthy cholesterol by converting it into a less absorbable form and sending it down the gastro-intestinal tract for emptying. It also increase enzyme production such as proteases that digest proteins and lipases that digest fats. Dosage: 1- 2 capsules a day, between meals.
F. Milk Thistle (Silybum marianum) known as silymarin, is a group of flavonoid compounds. Silymarin prevents damage to the liver by acting as an antioxidant. It is much more effective than vitamin E and vitamin C. Liver is the major detoxification center of the body, and silymarin protects this organ against these toxins. Silymarin also works by preventing the depletion of glutathione. The higher the glutathione content, the greater the liver's capacity to detoxify harmful chemicals. In human studies, silymarin has been shown to exhibit positive effects in treating liver diseases of various kinds including cirrhosis, chronic hepatitis, fatty infiltration of the liver, and inflammation of the bile duct. Dosage: 70 to 200 mg one to three times a day.
G. Herb Tea. Enhanced intestinal motility is a key factor to optimum digestive health. Herbal ingredients and commonly used ingredients that enhance intestinal motility include: senna leaf, peppermint leaf, stevia leaf, buckthorn bark, damiana leaf, RED peel, chamomile flower, and uva ursi leaf. As a routine practice, it is always good to fortify your regular meals with digestive enzymes (to enhance the breakdown of food in the gastro intestinal tract). After your evening meal, you can begin drinking tea. Start slowly. You should begin by steeping the tea 2 minutes (in 1-2 cups of water) for the first 3-5 days. As your system adjusts, you may increase steeping to 5 minutes. Most individuals will experience increased bowel movements, or slight cramping, during the first few days. This is due to the initial cleansing of the body system and is normal.
H. Pantethine and pantothenic acid, 400 to 900 mg each per day. The use of pantethine to reduce total cholesterol, LDL cholesterol, and triglyceride level, while raising the good HDL cholesterol at the same time, is well documented. Bertolini et al treated a series of 65 adults suffering from hypercholesterolemia alone or associated with hypertriglyceridemia (types IIa and IIb of Fredrickson's classification). Pantethine 1200 mg daily for adults was used for 3 years. In adult population with type IIa hyperlipoproteinemia, the study showed a 25% decrease in total cholesterol, a 39% decrease in LDL-cholesterol, a 34% decrease in Apo-B, and a modest increase in HDL-cholesterol were observed. In adult patients with type IIb hyperlipoproteinemia, total cholesterol was reduced by 19.8%, LDL-cholesterol by 37%, triglycerides by 31%, and Apo-B by 6%. In this subgroup, a 23% increase of HDL-cholesterol and a 15% increase in apolipoprotein A-I were also observed. In another double-blind placebo-controlled study, 29 people with high cholesterol and triglycerides were followed for 8 weeks. The dosage used was 300 mg 3 times daily, for a total daily dose of 900 mg. In this study, subjects taking pantethine experienced a 30% reduction in blood triglycerides, a 13.5% reduction in LDL ("bad") cholesterol, and a 10% rise in HDL ("good") cholesterol. Typically, a daily dose of 900 mg pantethine has been shown to reduce triglyceride by 20-30%, total cholesterol by 10-20%, LDL cholesterol by 10-20%, and a rise in HDL cholesterol by 10-20% in many studies.
I. Polycosinol 5-10 mg a day. Policosanol is a complex mixture of compounds usually extracted from sugar cane - but sometimes from beeswax - that reduces blood cholesterol levels. The purified extract from these two are slightly different. The active ingredient is called octacosanol, and it is more abundant in the extract form sugar cane. Studies since 1993 have consistently shown policosanol effectiveness as a cholesterol-lowering agent. In one of the earlier trials, 10 mg of policosanol administered once a day for 24 weeks caused total cholesterol levels to decrease by 22.1%.
Attention
Because of tremendous individual variation, the use of nutritionals should therefore be personalized for your body. One person’s nutrient can be another person’s toxin. If you have a specific health concern and wish my personalized nutritional recommendation, write to me by clicking here.
2. Modified Mediterranean Diet
The surest way to reduce cholesterol is by reducing sugar intake and not reducing dietary cholesterol alone.
While we cannot live without sugar, excessive sugar leads to increased oxidative stress, triglyceride formation and rising cortisol level. In addition to causing an increased cholesterol production from the liver; these are all pro-aging factors as well.
The anti-aging pyramid is a simple graphic format, based on the modified Mediterranean Diet. It will reduce blood cholesterol levels by reducing unnecessary sugar intake while supplying optimum nutrition. This food choice program consists of 50-55% complex carbohydrates of low glycemic index type food (such as legumes, nuts, whole-wheat, and whole fruits), 20-25% protein (preferably from plant sources), 25-30% fat, and 5% sweets, candies and dessert. This is in sharp contrast to the typical American diet where 46% comes from simple carbohydrate such as white bread and pasta, and 43% of calories come from fat (most saturated and trans-fat)
There are three major layers to the Anti-Aging Food Pyramid. They are divided into daily intake layers, 2-3 times a week, and once a week layers. Imagine a pyramid with three groups of layers, each layer getting much narrower as it gets closer to the top.
The broad base layers of the pyramid start with 10 glasses of pure filtered water a day and complex carbohydrates supplying up to 55% of the calories. These carbohydrates are low glycemic index type - barley, cereal, legumes, and above ground green leafy vegetables.
A limited amount of nuts, which is a fatty food, is also included in this first base layer. Three servings of vegetables should be taken daily. High glycemic index complex carbohydrates such as wheat, rice, and corn should be restricted. A moderate amount is acceptable if it is mixed with fat and protein.
Egg forms also part of the base layers. It is a good protein source. One egg per day is acceptable (including those used in cooking and baking). Organic eggs are the best.
Olive oil and fats from fish; nuts are part of this daily layer. 25-30% of the calories in your comes from fats. The fats in the diet should come mainly from olive oil, which is high in monounsaturated fats and also a good source of antioxidant. Some come from the fish, poultry and meat consumed.
The second group of layers is a much smaller layer contains protein food from fish and poultry. You should eat from this group 2-3 times a week. Fish should be those that live in deep and cold water, such as salmon and tuna. Poultry should preferably come from free-range chicken.
The third group of layers, which is very small, contains foods that one should eat 1 time a week. These include sweets, red meat (lean).
Diet Tips for Lowering Cholesterol
a. Reduce overall fat, especially trans-fat commonly found in fried foods and margarine. Use oil or food that are high in Omega-3 fatty acid, such as olive, rapeseed oil, flaxseed and flaxseed oil. Omega-3 fatty acid increase serum HDL Cholesterol. Avoid polyunsaturated and saturated oil, as they increase the cholesterol and triglycerides levels. Stay with mono-unsaturated fat such as olive oil for all cooking needs.
b. Eliminate refined carbohydrates and sugar from your diet and substitute complex carbohydrates that have lots of fiber. Fruit should be the major source of sweetness in your diet. Fruits are filled with pectin and fiber, which work wonders in lower serum cholesterol.
c. Foods that have been shown to lower LDL cholesterol include oat bran, oatmeal, and dry beans out of a can. Oat bran has been shown to reduce LDL cholesterol by up to 20%. Grapefruit - segments and membranes, not the juice - drives down cholesterol. Also fresh oranges, apples, garlic, onions, barley, ginger, and shitake mushrooms.
d. Eat lots of raw onion - at least half a medium onion a day. This has been shown to raise the good HDL cholesterol by up to 30%. Oat bran has also been shown to increase HDL cholesterol by up to 20%.
If you want a step by step dietary approach, My Detox Diet Protocol will help you to lower your cholesterol gradually.
You can also pick up many tips on how to change to a healthier lifestyle by reading my over 100 Anti-aging Strategies.
3. Exercise
No diabetes program is complete without a well-balanced exercise program. While most people think of exercise as a way to reduce body weight , exercise does much more, including reducing insulin resistance and impotence.
A well-balanced exercise must include three components:
a. Flexibility training
b. Cardiovascular training.
c. Strength training.
Ideally, about 2000 calories should be burned per week. Working out with 30 minutes of aerobics exercise at moderate intensity 5 times a week plus 15-20 minutes of strength training 3 times a week will accomplish this goal.
4. Natural Lower Cholesterol Agents
A. Soluble Fiber. Psyllium (Metamucil), a natural, water-soluble, gel-reducing fiber, which is extracted from the husks of blond psyllium seeds (plantago ovata), is a member of a class of soluble fibers referred to as mucilage.
Psyllium's total dietary content - 86 percent - is made up of 71 percent soluble fiber and 15 percent insoluble fiber. This compares to 15 percent total fiber and only five percent soluble fiber for oat bran. The soluble fiber in one tablespoon of psyllium is equal to 14 tablespoons of oat bran, another soluble fiber. For this reason, in contrast to oats, psyllium is added in relatively small quantities to other cereal grains to make food products.
Numerous studies have found that patients with mild to moderately elevated cholesterol levels can achieve a sustained reduction of about 10% in cholesterol level by consuming psyllium twice a day and adhering to the American Heart Association's (AHA) Diet.
Numerous landmark studies have been conducted to validate this. One is cited in the December 1, 1996 issue of the publication OBGYN News. This study was led by Dr. James Anderson, professor of medicine at the University of Kentucky College of Medicine in Lexington. For six months, Dr. Anderson followed 248 patients who were all instructed to follow the AHA diet. Some patients were given Psyllium while others were given a placebo. The average cholesterol level for the study population was 229 mg/dl, with an LDL cholesterol of 154 mg/dl. After six months, members of the Psyllium plus diet group lowered their total cholesterol by 8.6% and their LDL cholesterol by 11.1%, versus those in the diet group who showed only a 4% reduction in both these levels. The researchers further note that the Psyllium worked best for those people with the highest cholesterol levels, with reductions of up to 25%.
Another well-designed controlled study, followed more than 100 adults with high blood cholesterol (levels greater than 220 mg/dl). The study followed men and women who ate a high-fat diet (40 percent or more of total calories) in comparison to those who ate a low-fat diet (no more than 25 percent of total calories). Researchers then compared the effects of adding 1 1/2 packets of Psyllium (Metamucil) twice a day on blood cholesterol levels with the effects of not taking the soluble fiber supplement.
After eight weeks, supplementation with Psyllium showed a small but significant decrease in total cholesterol and LDL cholesterol levels, regardless of the type of diet. Total cholesterol levels dropped a weighted average of 4.7 percent; LDL cholesterol levels showed a 6.6 percent decrease.
Soluble fiber causes loose bowel movements and may reduce gastro-intestinal motility on chronic use. Long term use should be directed under the supervision of a physician. Dosage: 2 times a day.
B. Niacin is very effective normalizing cholesterol and Lp(a), the relative of LDL cholesterol and another independent and proven risk factor for heart disease. Since therapeutic levels of niacin is high and can cause an unpleasant flushing sensation and headache, gradually increase your dosage over several weeks or use the flush-free form of niacin, inositol hexaniacinate. Dosage: 100 mg twice daily, increasing to 500 mg daily. More may be needed under the supervision of a physician.
C. Fish oil lowers blood triglyceride levels, may elevate HDL, and helps support heart health. Most research studies are based on a high dosage of 3,000 mg. daily. At this dose, most people developed a harmless fishy burp after consumption of fish oil pills. If you take at least 12 ounces of fish a week, fish oils are not needed. Dosage: 2,000- 3,000 mg
Laboratory Standard
From a laboratory test perspective of controlling cholesterol, the following parameters should be considered optimum:
· Maintain a healthy total cholesterol level at the upper limit of normal at around 200 mg/dl.
· High HDL level (more than 50 mg/dl) and a low LDL level (less than 130 mg/dl).
· Total cholesterol /HDL cholesterol ratio of less then 4.
· LDL/HDL cholesterol ratio of less then 2.5.
· Triglyceride level of under 150 mg/dl.
The best way to succeed is to limit the amount of simple refined carbohydrates (sugar), processed polyunsaturated fats (corn oil), and trans fats (donuts and fast foods), while maintaining a balanced diet of complex carbohydrates of low glycemic index type (green leafy vegetables that are grown above the ground), saturated fat from free-range animals (as in meat and butter), and moderate amount of cholesterol (in meat and eggs)
Summary:
Elevated blood cholesterol is a symptom of rising oxidative stress and sugar overload. Normalization of cholesterol level to the upper end of normal range around 200 mg/dl should be the goal. Too low (below 150 mg/dl) a cholesterol level is undesirable.
A three pronged concurrent approach is best, consisting of specific nutritional supplementation, a modified Mediterranean diet focused on low glycemic index foods, and a well-rounded anti-aging exercise program. Additional natural agents such as niacin, fiber, and fish oil in high dose can be added as an adjunct for short term use.
Message from Dr. Lam
I hope you have enjoyed reading this article. If you have areas you don’t understand, comments (good or bad), or if you have a specific health concern, feel free to write to me by clicking here.
About The Author
Michael Lam, M.D., M.P.H., A.B.A.A.M. is a specialist in Preventive and Anti-Aging Medicine. He is currently the Director of Medical Education at the Academy of Anti-Aging Research, U.S.A. He received his Bachelor of Science degree from Oregon State University, and his Doctor of Medicine degree from Loma Linda University School of Medicine, California. He also holds a Masters of Public Health degree and is Board Certification in Anti-aging Medicine by the American Board of Anti-Aging Medicine. Dr. Lam pioneered the formulation of the three clinical phases of aging as well as the concept of diagnosis and treatment of sub-clinical age related degenerative diseases to deter the aging process. Dr. Lam has been published extensively in this field. He is the author of The Five Proven Secrets to Longevity (available on-line). He also serves as editor of the Journal of Anti-Aging Research.
For More Information
For the latest anti-aging related health issues, visit Dr. Lam at www.LamMD.com. Feel free to email Dr. Lam at dr@LamMD.com if you have any questions.
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What is cholesterol?
Cholesterol is a waxy, fat-like substance that is present in all animals, but not in plants (phytosterols are present in plants instead).
Every cell in our body contains cholesterol; we cannot live without it.
Cholesterol is a vital component of cell membranes. According to the Weston Price Foundation, it is a potent antioxidant that protects against free radical damage to the cell membrane.
Cholesterol is the biochemical precursor to some hormones, vitamin D, and bile acids.
93% of cholesterol in the body is found in the cells of the body, 7% in the blood.
Cholesterol alone is not very soluble in blood, so it is carried in the bloodstream by molecules called lipoproteins.
Lipoproteins are named based on their density.
We know from the careful study of cholesterol metabolism that high density lipoprotein (HDL) is "good" - it transports cholesterol to the liver.
Low density lipoprotein (LDL) is "bad" - oxidized LDL gets deposited in the walls of arteries, contributing to arteriosclerosis.
Triglycerides are another fat like substance in the body.
What is the source of cholesterol in the blood?
The liver makes cholesterol.
In general, the higher the saturated fat content of the diet, the more cholesterol made by the liver.
Approximately 80% of total body cholesterol is synthesized in the liver.
Most cells can make cholesterol – high insulin levels signal cells to make cholesterol instead of taking up cholesterol from the bloodstream.
The cholesterol in the food we eat contributes little to the blood cholesterol level. Current average cholesterol intake estimated at 430 mg/day, prehistoric intake estimated at 520 mg/day.
Why is the blood cholesterol level important?
Consistent evidence links increased cholesterol levels to an increased risk of coronary heart disease (CHD)
Data gathered in The Seven Countries Study linked blood cholesterol levels to coronary mortality (Keys A, et al. Acta Med Scand. 1966. 460 [suppl]. 1-392).
Japanese who moved to Hawaii and San Francisco had higher blood cholesterol levels and coronary event rates than Japanese who did not migrate (Am J Cardiol. 1977. 39. 239-243).
Epidemiologic data from the Framingham study confirms the link between cholesterol levels and CHD risk (Ann Epidemiol. 1992. 2. 23-28).
Data from the ARIC study, a prospective study with 15 year follow up, shows that a that each 1% increment in LDL is associated with a 2-3% increment in cardiovascular risk (N Engl J Med. 2006.354. 1264-1272 and 1310-1312)
A long-term outcome study in 3277 healthy Finnish businessmen aged 30-45 at baseline who were followed for 39 years found that above a total cholesterol of 5 mmol/L (194 mg/dl), higher total cholesterol was associated with a higher total mortality and a worse physical quality of life, as assessed by the RAND-36 questionnaire (J Am Coll Cardiol. 2004. 44. 1002-1008, as abstracted in Cardiology Review. 2006. 23 (1). 13-16).
Note: For reasons that are not yet understood, population studies show that the blood cholesterol level in people over age 70 is not correlated very strongly with the risk of heart attack (JAMA. 1994. 272. 1335-1340).
Note: The total cholesterol level in the blood is not as important as the ratio of total cholesterol (TC) to HDL cholesterol.
Recent data indicate that this ratio predicts the risk of heart attack independent of the level of LDL cholesterol in the blood (Ann Intern Med. 1994. 121. 641-647).
The higher the ratio of TC: HDL, the higher the statistical risk of plaque building up on the walls of the coronary arteries which supply the heart with blood.
Note that despite convincing evidence from clinical trials that statins reduce the risk of stroke, the data from epidemiologic trials with regard to the relationship between serum cholesterol and stroke risk is mixed (Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet. 1995. 346. 1647-1653).
What are the other risk factors for heart attacks?
The level of triglycerides in the blood stream - the statistical correlation between blood triglyceride level and heart attack risk is not as strong as the statistical correlation between the blood cholesterol level and heart attack risk.
Smoking.
High blood pressure.
Diabetes.
Obesity.
Sedentary lifestyle.
Family history (defined as a male relative with a heart attack under age 55 or a female relative with a heart attack under age 65).
What other blood measurements are risk markers for heart attacks? (See the end of this outline for more information on these risk markers)
ADMA
GGT
Homocysteine
hs-CRP
Lipoprotein (a)
WBC
What is a good blood cholesterol level?
In general, the lower the better, at least down to a cholesterol level of 140.
The normal LDL cholesterol amongst hunter-gatherers, healthy human neonates, and free living primates is 50-70 (J Am Coll Cardiol. 2004. 43. 2142-2146).
For total cholesterol, the upper limit of normal used to be defined arbitrarily as the level two standard deviations above the average cholesterol level for Americans - approximately 360 on most lab reports.
Based on this definition, only 5% of the population had an abnormal cholesterol level.
In the 1980's, as researchers learned more about the dangers of high cholesterol levels, the upper limit of normal was arbitrarily redefined as 200 on most lab reports.
HDL should be greater than 35 - this can be measured along with total cholesterol in a nonfasting state.
LDL should be less than 130 - a valid measurement requires a 12 hour fast.
In diabetics, or in people with a previous history of heart attack, stroke, or peripheral vascular disease, LDL should be less than 100.
Triglycerides should be less than 150 - a valid measurement requires a 12 hour fast.
Note on terminology and pathophysiology - there is only one type of cholesterol in the diet, but in the blood cholesterol is carried by proteins and these are called lipoproteins and HDL refers to high density lipoprotein and LDL refers to low density lipoprotein. We know that HDL carries cholesterol back to the liver whereas LDL deposits cholesterol in the walls of arteries.
What are the benefits of lowering the blood cholesterol level?
Current data in aggregate indicates that at least in middle aged men, lowering LDL cholesterol by 1% (either by lifestyle changes or medications) decreases coronary events by approximately 1%.
Note that early intervention trials to reduce coronary events by lowering blood cholesterol levels yielded mixed results (Steinberg D. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans (J Lipid Res. 2005. 46. 179-190), such that at least one review concluded in 1992 that “lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease” (BMJ. 1992. 305. 15-19).
One early positive trial was the Lipid Research Clinics Primary Prevention Trial in which 3806 asymptomatic middle aged men with hypercholesterolemia were randomized to placebo or cholestyramine and followed for a mean of 7.4 years, a 13% greater reduction in LDL was associated with a 19% reduction in the primary end point, a composite of cardiac death or MI (JAMA. 1984. 251. 351-364).
The statin trials, the first of which was published in 1994 (4S Trial), in aggregate have shown conclusively that lowering serum cholesterol reduces not just cardiovascular mortality, but also total mortality, at least in secondary prevention trials.
What are the risks associated with lowering the cholesterol level?
A scientific statistical meta-analysis of six major primary prevention trials (BMJ. 1993. 306. 1367-1373) shows that the 15% decrease in deaths from heart disease in the cholesterol lowering treatment groups is offset by increases in deaths from gallbladder disease, cancer, and injuries.
The cause of this recurrent finding of increased noncardiac death rates in patients on cholesterol lowering medication is unclear, but it suggests that in young, otherwise healthy adults, the risks of medication treatment for high cholesterol may outweigh the benefits.
Noncardiovascular mortality was NOT statistically significantly increased in any of the large statin trials.
There is some animal data indicating that some cholesterol lowering drugs (fibric acid derivatives such as Lopid and Atromid, and possibly the HMG CoA reductase inhibitors) may cause cancer.
Anecdotally, lowering cholesterol can cause memory impairment.
There does not seem to be a risk of lowering cholesterol by lifestyle changes; the risk seems to be seen only when medications are used.
Should a high cholesterol level be lowered in seniors (>age 65) without known atherosclerosis?
This is controversial – from a statistical standpoint elevated cholesterol in seniors is not as strong a predictor of heart disease as elevated cholesterol in middle aged individuals.
Anecdotally, lowering cholesterol in seniors may cause memory impairment.
There is statistical data that low cholesterol levels in seniors is associated with increased all-cause mortality, with a prospective study of 2277 individuals showing that this association is independent of comorbid illnesses (J Am Geriatr Soc. 2005. 53. 219-226).
How often should the blood cholesterol level be measured?
The National Cholesterol Education Project (NCEP) and some other authorities call for measuring a blood cholesterol level for screening purposes in all adults over age 20, every 5 years.
The United States Preventative Services Task Force (USPSTF) and the American College of Physicians (ACP) currently recommend every 5 year screening only in males over age 35 and females over age 45, in the absence of other risk factors for heart disease (see the list above).
The basis of this recommendation is data which suggests that most of the cardiovascular risk associated with a high cholesterol can be reversed within two years of starting treatment in a middle aged, high risk population.
Note: Policy documents formulated by groups consisting mostly of clinical epidemiologists (USPSTF) recommend initiation of screening at a later age than documents formulated by groups consisting mostly of lipid specialists NCEP).
Anytime cholesterol is measured for screening purposes, HDL should also be measured.
It is debatable as to whether screening cholesterol levels should be measure in adults over age 70, since the statistical correlation between cholesterol levels and heart disease risk is either very weak or non existent after age 70.
If the total cholesterol is over 240 in an adult without other risk factors for heart disease, or is over 200 in an adult with at least two other risk factors for heart disease, NCEP recommends repeating screening cholesterol levels every year.
Cholesterol should be rechecked after 6-8 weeks in somebody on treatment (either lifestyle changes or medications).
How can one improve ones cholesterol: HDL cholesterol ratio?
Smoking cessation lowers cholesterol and LDL cholesterol, and raises HDL cholesterol.
Relaxation techniques (meditation, yoga) lower cholesterol and LDL cholesterol.
Weight loss raises HDL cholesterol.
Aerobic exercise
Raises HDL cholesterol, but the mean HDL response in exercise studies is small (1.2 mg/dl) and the increase is only observed at high exercise levels (the equivalent of running 10-15 miles per week).
Consistent aerobic exercise lowers the cholesterol: HDL cholesterol ratio by 15% (Circulation. 1995. 92. 773-777).
Alcohol (1-2 drinks per day) raises HDL cholesterol.
Ultraviolet light (i.e. sunlight) -in one experiment, 97% of subjects experienced a 13% decrease in serum cholesterol two hours after exposure to ultraviolet light, and 86% maintained the drop in cholesterol 24 hours later (Circulation. 1953. 8. 438).
Dietary modification:
A diet low in saturated fat lowers cholesterol and LDL cholesterol.
Studies show that a population based educational approach is associated with a 1-11% reduction in cholesterol levels.
Other studies show that an individual counseling approach is associated with a 5-14% reduction in cholesterol levels (75-80% of the reduction seen in "metabolic ward studies" in which the individual is in a controlled environment in which dietary intake of saturated fat is accurately determined by a professional).
In 4 RCTs in which individuals started with diets high in saturated fat and reduced saturated fat intake by 10% of energy intake, a 12-15% decrease in total cholesterol was seen, and this was associated with a significant reduction in cardiovascular disease (Circulation. 1969. 60. 111S-163S; Circulation. 1970. 42. 935-942; Int J Epidemiol. 1979. 8. 99-118 as cited in the Comment section of JAMA. 2006. 295. 655-666).
A diet low in trans fats lowers cholesterol and raises HDL - Return to Home Page, click on "Nutrition" and scroll to trans fats for more detail.
A diet low in simple sugars and high glycemic index carbohydrates may raise HDL.
A diet with 2-10 grams/day of soluble fiber lowers cholesterol levels 15-18% (Am J Clin Nutr. 1999. 69. 30-42).
More information below under the heading of herbs – see konjac root and psyllium.
There is some data that rye fiber lowers cholesterol and blood sugar more than wheat fiber (Am J Clin Nutr. 2003. 77. 385-391).
A plant-based diet – in a 4 week outpatient feeding study in 120 adults, the group that incorporated more vegetables, legumes, and whole grains into a low fat diet (AHA Step I guidelines) achieved an average 17.6 mg/dl drop in total cholesterol compared to an average 9.2 mg/dl drop in the low fat control group (P=0.01)and an average 13.8 mg/dl drop in LDL compared to an average7.0 mg/dl drop in the low fat control group (P=0.02). The HDL dropped an average of 3.8 mg/dl in the plant group compared to an average of 2.5 mg/dl in the control group (P=0.13) and the triglycerides increased an average of 0.1 mg/dl in the plant group compared to 1.2 mg/dl in the control group (P>0.2). The two diets in this study were designed to have identical levels of total fat (30%), saturated fat (10%), and cholesterol (<300 mg/day) [Ann Intern Med. 2005. 142. 725-733].
A diet rich in foods sometimes referred to as functional foods which are known individually to lower cholesterol. This has been shown to lower LDL 28.6% and CRP by 28.2% (JAMA. 2003. 290. 502-510).
Certain foods (reference is Food: Your Miracle Medicine by Jean Carper):
Almonds – FDA actually now allows health claim for heart disease risk reduction.
Apples (soluble fiber)
Avocados
Beans (pintos, kidney, black, navy, lentils, chickpeas), one cup/day, may lower LDL as much as 20% and, after 1-2 years, raise HDL as much as 9%.
Carrots (soluble fiber)
Chili peppers
Chocolate (dark) improves the HDL: LDL cholesterol ratio (Brit J Nutr. 2002. 88. 479-488).
Cordyceps sinensis mushrooms lower cholesterol – also available as a dietary supplement (see dosing information below).
Fatty fish (salmon, sardines, herring, mackerel, whitefish, and bluefin tuna) raise HDL and lower triglycerides. Fish oil capsules do the same.
Flax meal or flax oil
Grape seed oil raises HDL.
Margarine lowers cholesterol, but the trans fatty acids created by the chemical process of hydrogenation by which margarine is converted from a liquid into a solid are now clearly associated with significant health risks which offset the benefits of stick margarine with regard to cholesterol lowering. Newer margarines made from plant sterols or plant stanols seem to be a safe and effective way of lowering cholesterol.
Oat bran lowers cholesterol and LDL and raises HDL. In one study, two ounces of oat bran per day was associated with a 16% lowering of LDL and, after 3 months, an increase in HDL of as much as 15% (JAMA. 1991. 285. 1833-1839).
Olive oil raises HDL, lowers LDL, and interferes with the oxidation of LDL cholesterol.
Onions (half a raw onion/day) may raise HDL as much as 30%.
Plant sterols and stanols (Am J Cardiol. 2005. 96 [supplement])
Effectiveness at lowering LDL cholesterol as much as 10-20 % in doses of approximately 2-3 grams/day documented in more than 20 published studies. Based on data from short term studies, equivalent amounts of plant sterol and stanol esters are equally effective at lowering LDL cholesterol. Data indicates lack of further benefit with doses higher than 3 grams/day. Effect at cholesterol lowering is additive to that of prescription statins.
Presumed mechanism of action – block absorption of cholesterol in the intestinal tract (similar mechanism of action as the prescription drug Zetia). This is accomplished by competing with cholesterol for incorporation into mixed micelles required for cholesterol absorption and by increasing the flux of cholesterol from the enterocyte back into the lumen of the intestine. Note that dietary intake of cholesterol is only 50-750 mg/day, biliary cholesterol input to the intestine is 500-2400 mg/day.
The FDA in 2000 authorized the use of a therapeutic label claim for foods containing at least 0.65 grams of plant sterols per serving or at least 1.7 grams of plant stanols per serving. The claim states that "Diets low in saturated fat and cholesterol that include at least 1.3 grams of plant sterol esters or 3.4 grams of plant stanol esters, consumed in two meals with other foods, may reduce the risk of heart disease." Note that average dietary intake of plant sterols is only 150-350 mg/day and average dietary intake of plant stanols is only 50 mg/day, so achieving therapeutic intake for purposes of LDL lowering requires supplementation.
Take Control is a margarine spread which contains plant sterols derived from soybeans. A portion containing 1.7 grams of plant sterols when consumed twice a day lowered LDL by up to 17%.
Benecol is a margarine spread which contains plant stanols derived from soy, beans, and corn. A portion containing 1.7 grams of plant sterols when consumed three times a day lowered LDL by up to 14%.
Benecol SoftGels contain 1.1 grams of plant stanols per serving of 2 capsules.
Cholesterol Success Plus by Twinlab and Cholest-Off by Nature Made are brand names of other supplements.
CholestePure (Emerson Ecologicals) and UltraMeal Plus (Metagenics) are other products with phytosterols.
To date (7/04) no significant side effects have been reported in numerous studies, but long term effects are unknown.
5-12% of plant sterols are absorbed into the bloodstream; 1-5% of plant stanols are absorbed into the bloodstream.
There is a theoretical concern that regular long-term consumption may interfere with absorption of fat soluble vitamins and nutrients. Current data indicates no effect on absorption of vitamins A, D, and K, but some decrease in absorption of tocopherols and carotenoids.
Plant sterols increase plasma plant sterol levels whereas plant stanols decrease plasma plant sterol levels – clinical significance uncertain.
Absorption of plant sterols downregulates bile acid synthesis, which attenuates their cholesterol-lowering efficacy, so plant stanols may be preferable for long-term management of hypercholesterolemia (Am J Cardiol. 2005. 96. 29D-36D).
Reishi mushrooms lower cholesterol – also available as a dietary supplement (see dosing information below).
Shiitake mushrooms lower cholesterol – also available as a dietary supplement (see dosing information below).
Soybeans (raw soybeans, soy milk, soy nuts, tempeh, and tofu but not soy sauce, soy oil, or many brands of soy burgers, soy cheeses, or soy hotdogs) are as potent as the other beans above at lowering LDL and raising HDL.
A meta-analysis of 29 articles on the effects of ingesting 31-47 grams of soy protein on serum cholesterol levels found that soy on average was associated with a 9.3% decrease in total cholesterol, a 12.9% decrease in LDL cholesterol, a 2.4% increase in HDL cholesterol, and a 10.5% decrease in triglycerides (New Engl J Med. 1995. 333. 276-282).
Based on a number of published studies (New Engl J Med. 1995. 333. 276-282; Am J Clin Nutr. 1998. 68. 1375S-1379S; Am J Clin Nutr. 1998. 68. 1385S-1389S), the FDA in 10/99 approved a "health claim" label for soy products, stating that "Diets low in saturated fat and cholesterol that include at least 25 grams of soy protein may reduce the risk of heart disease." The cholesterol lowering benefits of soy protein require consumption of at least 25 grams per day, based on a literature review.
A meta-analysis of 41 RCTs published between 1996 and 2005 and using soy protein supplementation found a mean reduction of 5.26 mg/dl in serum total cholesterol and 4.25 mg/dl in LDL and 6.26 mg/dl in triglycerides, and a mean increase of 0.77 mg/dl in HDL (Am J Cardiol. 2006. 98. 633-640).
Presumed mechanism of action – reduced hepatic cholesterol synthesis. It has been proposed that only the 1/3 of individuals who convert daidzein to equol benefit from soy with regard to the lipid profile. The ability to convert daidzein to equol appears to be related to specific gut flora.
Walnuts
Certain herbs:
Artichoke – in one 6 week trial 1800 mg of artichoke extract, total cholesterol was lowered 18.5% in the treatment group vs. 8.6% in the placebo group (Arzneimittelforschung. 2000. 50. 260-265). In another trial, artichoke extract reduced LDL, reduced LDL oxidation and improved endothelial function (Life Sci. 2004. 76. 775-782).
Fenugreek - lowers cholesterol and triglycerides along with lowering blood sugar (Prostaglandins Leukot Essent Fatty Acids. 1997. 56. 379-384).
Garlic 300 mg 3 times a day
A meta-analysis of the effect of garlic on serum total cholesterol found a significant decrease of 22.8 mg/dL or 9% compared to placebo. This figure was based on four statistically homogenous trials including a total of 324 participants (Ann Intern Med. 1993. 119. 599-605).
A subsequent meta-analysis of 16 trials including 952 persons reported a reduction in total cholesterol of 29.7 mg/dL or 12% (J R Coll Physicians Lond. 1994. 28. 39-45).
A more recent meta-analysis of 13 RCT's with 796 persons, all with baseline total cholesterol greater than 200 mg/dL, showed a reduction in total cholesterol of 15.7 mg/dL [confidence interval -25.6 mg/dL to -5.7 mg/dL]. However, 6 diet-controlled trials with the highest scores for methodologic quality revealed a non-significant difference between garlic and the placebo groups. An additional 21 trials of garlic were identified by a literature search but excluded because either they were not placebo-controlled, not randomized, not double-blind, or did not use a garlic monopreparation. Ten of the 13 trials used Kwai garlic powder, one used spray-dried powder, and two used oil. (Ann Intern Med. 2000. 133. 420-429).
Note that garlic oil in one published study did not lower cholesterol (JAMA. 1998. 279. 1900-1902).
Guggulipid
This is a standardized extract of the herb Commiphora mukul, used in India for 2000 years.
In one study, 200 mg four times a day lowers cholesterol 14% - 27% and lowers triglycerides 22% - 30% with no side effects noted (Cardiovasc Drugs Ther. 1994. 8. 659-664).
Numerous other studies (approximately 20) suggested beneficial effects.
An 8 week RCT in 85 hypercholesterolemic subjects who received either placebo, guggulipid 1000 mg three times a day, or guggulipid 2000 mg three times a day failed to show benefit (JAMA. 2003. 290. 765-772). HOWEVER re-analysis of the data for other endpoints showed an association of guggulipid with reductions in glucose, serum insulin, systolic blood pressure, and hs-CRP (Internal Medicine News. 1/15/04. 49).
Usual dose is 500 mg three times a day of a product standardized to 5% guggulsterone.
Herb-drug interactions - stimulates a PXR cell receptor, which riggers a liver enzyme which accelerates metabolism of many prescription drugs, including AZT, some anticancer drugs, and statins (J Pharmacol and Exp Ther).
Gummar (Gymnema sylvestre) – trials in diabetics show a cholesterol lowering effect.
Konjac root – contains a very viscous water-soluble fiber called glucomannan, which is 5 times more potent than psyllium, oat fiber, or guar gum in lowering cholesterol, secondary to its high viscosity.
Psyllium (Metamucil)
15 cc (one tablespoon) twice a day lowers cholesterol 15% and LDL cholesterol 20% in adults on a Step I American Heart Association Diet (Arch Intern Med. 1988. 148. 292-296).
A meta-analysis of 5 studies using a total of 10.2 grams per day of psyllium seed husk as an adjunct to Step I AHA diet found that psyllium was associated with significant reductions in total cholesterol and LDL cholesterol (Am J Clin Nutr. 2000. 71. 472-479).
In an 8 week trial in 68 hyperlipidemic adults, psyllium fiber 15 grams + simvastatin 10 mg is as effective at lowering LDL cholesterol as 20 mg of simvastatin (Arch Intern Med. 2005. 165. 1161-1166).
Presumed mechanism of action – increases excretion of cholesterol by increasing excretion as opposed to enterohepatic recirculation of bile acids.
FDA allows health claim for heart disease risk reduction.
Vitamins, minerals, and non-herbal dietary supplements
Bifidobacterium – binds cholesterol in the intestine.
Calcium citrate – 1000 mg per day of calcium citrate lowered LDL by a mean of 6% and raised the LDL: HDL ratio by 16% in a study in 223 postmenopausal women (Am J Med. 2002. 112. 343-347).
Chromium (picolinate or GTF) may raise HDL cholesterol and lower LDL cholesterol, with positive studies (Am J Clin Nutr. 1981. 34. 2670-2678; West J Med. 1990. 152. 41-45) and a negative study (J Gerontol A Biol Sci Med Sci. 2000. 55. M260-M263).
Cordyceps sinensis mushroom extract 400 mg hot water extract with 14% beta glucan, 6% cordycepic acid, 0.15% adenosine, 1-3 capsules bid - in a large study of Cordyceps for the treatment of high cholesterol (excluding those patients whose high cholesterol resulted from diabetes mellitus, liver and liver-related diseases, kidney disease, and hypothyroidism) involving 273 patients at nine hospitals in China, patients received 1 gram of Cordyceps three times a day. After 4 to 8 weeks, it was found that their cholesterol levels had dropped by an average of over 17% (http://www.lifestreamgroup.com/Atherosclerosis.html - reference not cited).
DHEA (J Clin Endocrinol Metab. 1988. 66. 57-61) and 7-keto-DHEA (Physiol Res. 2001. 50 9-18).
Inositol hexaniacinate – less flushing than niacin, presumed to be effective at lowering cholesterol, but no clinical trials. Suggested dose is 600 mg 1-3 capsules three times a day.
Krill oil (NKO)
In a 12 week human trial, 1 gram of NKO reduced TC by 13.4%, 2-3 grams of NKO reduced TC 18% and triglycerides 28% (Alternative Medicine Review. 2004. 9. 420-428).
In unpublished data from McGill Univ 6/06, 1-1.5 gm/day lowers LDL 34% and raises HDL 43%.
Magnesium - 500 mg daily lowers total cholesterol and raises HDL (Br J Nutr. 1997.78. 737-750).
Manganese 4 mg daily (based on anecdotes)
Lactobacillus acidophilus – assimilates cholesterol, inhibiting absorption.
Lactobacillus sporogenes – binds cholesterol in the intestine, inhibiting absorption. May also interfere with cholesterol synthesis.
Niacin (nicotinic acid) in high doses (3-6 grams per day in divided doses) lowers cholesterol and LDL and raises HDL (Archives of Biochemistry and Biophysics. 1955. 54. 558-559).
Inhibits the mobilization of free fatty acids from peripheral tissues, thereby reducing hepatic synthesis of triglycerides. At high doses also inhibits HDL catabolism.
In the Coronary Drug Project, reduced the 5-year incidence of nonfatal reinfarction in men with a prior MI by 27% (JAMA. 1975. 231. 260-281). After a mean follow up of 15 years, reduced all cause mortality by 11% compared to placebo (p<0.001) [J Am Coll Cardiol. 1986. 8 1245-1255].
Therapeutic doses (1.5-3 grams) lower LDL by 5-25%, triglycerides by 20-50%, lipoprotein (a)by 34%, and increase HDL by 15-35%.
BEWARE doses this high can cause liver toxicity, can raise blood sugar, and can exacerbate gout.
Immediate release niacin costs approximately $7.10 per month for 2000 mg/day.
Sustained release niacin costs approximately $9.76 per month for 2000 mg/day, but BEWARE that milligram for milligram, long acting niacin preparations appear to be more hepatotoxic.
No flush niacin costs approximately $21.70 per month for 2000 mg/day.
In the study which determined the above average costs of OTC products, 10 no-flush products were analyzed and none contained nicotinic acid; they all contained inositol hexaniacinate, an ester of nicotinic acid (Ann Intern Med. 2003. 139. 996-1002).
Inositol hexaniacinate – see separate listing just above in this outline.
Pantothenic acid (vitamin B5) - 300 mg three times a day in a trial in 24 patients lowers total cholesterol 17% and triglycerides 49% and raises HDL cholesterol 15% (Clin Ther. 1986. 8. 537-545).
Phosphatidylcholine - no clinical trials. Potential to reduce cholesterol by decreasing absorption, decreasing synthesis, initiating conversion into bile salts.
Policosanol
Product is a mixture of alcohols extracted from either from the wax of sugar cane, honeybees, wheat germ, or rice bran. Most of the published research has been done with the sugarcane product.
Shown in a meta-analysis of 29 RCT's in 1528 individuals to have significant cholesterol lowering effects (Pharmacotherapy. 2005. 25. 171-183). 28 of the 29 studies were done in Cuba by the same research group, and sponsored by Dalmer Laboratories, a commercial enterprise.
Studies show a 15% to 25% decrease in total cholesterol, 20% to 30% decrease in LDL cholesterol, and 5% to 15% increase in HDL cholesterol (Alternative Medicine Alert. 2004. 7. 37-41). The lipid lowering effect is believed to be dose-dependent.
Seven RCT's comparing policosanol to prescription statins found similar effectiveness.
However, a 12 week RCT (following a 6 week open-label placebo and diet run-in phase) in 143 patients with hypercholesterolemia or combined hyperlipidemia randomized to either placebo, 10 mg/day policosanol, 20 mg/day, 40 mg/day, or 80 mg/day found no benefit beyond that of placebo at any dose. This trial was done in Germany, but nonetheless used Cuban policosanol (JAMA. 2006. 295. 2262-2269).
Another negative trial was a 12 week trial of 20 mg daily (British J Nutr. 2006. 95. 968-975).
In addition to its effects on the lipid profile, policosanol has been shown to decrease platelet aggregation, LDL peroxidation, and smooth muscle peroxidation (Alternative Medicine Alert. 2004. 7. 37-41).
The limitation of this data is that all but two studies were done by a single research group in Cuba.
Policosanol has been in common use in Cuba since 1991.
Dose is 5 - 20 mg a day - effects on the lipid profile are dose dependent.
Safety - a total of approximately 80 studies have been done, including approximately 3000 people. In addition, a post-marketing surveillance study of 27,879 patients from six major Cuban medical centers, followed for as much as 4 years (Curr Ther Res. 1998. 59. 717-722) shows excellent tolerability (only 0.31% of subjects reported adverse effects over a mean of 2.7 years) and safety.
Probiotics – see Bifidobacterium and Lactobacillus just above.
Red yeast rice
600 mg two tablets twice a day lowers cholesterol by 17%, LDL cholesterol 22%, and triglycerides by 12% after 12 weeks in a randomized, controlled trial. No significant effect on HDL cholesterol (Am J Clin Nutr. 1999. 69. 231-236).
Red yeast rice is still available over the counter, but the Pharmanex was ordered by the courts to desist from marketing its brand name product, Cholestin, because the original Cholestin contained lovastatin, which was patented by a pharmaceutical company.
Reishi mushroom extract – appears to inhibit cholesterol synthesis and absorption. Dose is 400 mg hot water extract with 10% beta glucan and 4% triterpenes, 1-5 capsules bid, ideally on an empty stomach.
Shiitake mushroom extract 400 mg hot water extract with 10% beta glucan, 1-5 capsules bid, ideally on an empty stomach.
Vitamin E – there is some data that tocotrienols, especially gamma and delta, can lower LDL cholesterol.
Medications:
Statins (Mevacor, Zocor, Pravachol, Lescol, Lipitor, Crestor) - inhibit the rate limiting enzymatic step in the biosynthesis of cholesterol in the liver (also inhibit production of Coenzyme Q 10).
Adverse effects include abnormal blood tests of liver function of unclear clinical significance, muscle pain, muscle breakdown (rhabdomyolysis), cognitive changes, mood changes, peripheral neuropathy.
There is theoretical and ancecdotal data that CoQ 10 can reverse some of the adverse effects – dose required may be as high as 200 mg daily of CoQ 10.
Statins reduce all-cause mortality by decreasing coronary heart disease mortality without increasing nonvascular mortality, based on a meta-analysis of 14 RCTs with 90,056 participants. The relative risk reduction for major coronary events was 23% for each mmol/L reduction in LDL, but the absolute risk reduction decreased from 3.8% for chol > 173 mg/dL to 1.9% for LDL < 135 (Lancet. 2005. 366. 1267-1278 as reviewed in ACP Journal Club. 2006. 144. 62).
Simvastatin (Zocor) shown to increase the AA: EPA ratio from 15.5 to 18.8 (p<0.01), an undesirable change in this ratio, in a study in 106 healthy adults with hypercholesterolemia (Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2004. 71. 263-269).
Bile acid sequestrants (Questran, Colestid, Welchol) - bind to bile acids in the small intestine, which interrupts the enterohepatic circulation of bile acids and increases the conversion of cholesterol to bile acids in the liver.
Benefit shown in the LRC-CPPT, with a statistical reduction in CHD death and nonfatal MI in the group receiving cholestyramine 24 grams/day (JAMA. 1984. 251. 351-364).
Interfere with absorption of other medications, so must be taken at a different time of the day from other medications.
Nicotinic acid - see above under 'vitamins and minerals.'
Fibrates (Lopid, Tricor) - PPAR (peroxisome proliferator-activated receptor) alpha-agonists. Statistically significant reduction in major coronary events shown in the Helsinki Heart Study, a primary prevention trial with gemfibrozol (N Engl J Med. 1987. 317. 1237-1245), the VA-HIT Trial, using Lopid 600 mg bid (N Engl J Med. 1999. 341. 410-418), and the Fenofibrate Intervention and Event Lowering in Diabetes trial, using Tricor 200 mg daily (Lancet. 2005. 366. 1849-1861).
Ezetimibe (Zetia) - intestinal cholesterol absorption inhibitor. Can be safely combined with statins. Inhibits absorption of not just dietary cholesterol but also the cholesterol released into the bowel as part of bile acids.
How can one improve ones triglyceride level
Alcohol in moderation – excess alcohol can cause very high triglyceride levels.
Blood sugar control – uncontrolled diabetes can cause very high triglyceride levels.
Exercise – both aerobic and resistance exercises are beneficial
Nutrition – reduce the amount of high glycemic index foods (i.e. sweets, pretzels, bagels, breakfast cereals)
Omega 3 fats – 2-4 grams of EPA + DHA per day recommended by the American Heart Association for individuals with marked hypertriglyceridemia
Stress reduction
Cost effectiveness of cholesterol lowering with medications (based on modeling):
Primary prevention in males and females with cholesterol greater than 300:
Age 25-34: $1,000,000 - $10,000,000/year of life saved.
Age 55-64: $100,000/year of life saved.
Note cardiac transplant only costs an estimate $50,000/year of life saved.
For more detailed statistics, see (Ann Intern Med. 2000. 132. 769-779).
Secondary prevention
In middle aged adults with established coronary artery disease, carotid artery disease, or peripheral vascular disease statins may actually be cost saving, and costs at most $10,000/QALY.
In patients over age 75 with a history of myocardial infarction, statins cost anywhere from $5400/QALY to $97,800/QALY, depending on the modeling assumptions (Ann Intern Med. 2000. 132. 780-787).
LDL - not all is created equal:
Pattern A - large particles.
Pattern B - small, dense particles.
At any given LDL value, people with pattern B are three times more prone to heart disease than those with pattern A.
Hormone replacement therapy in women seems to have a much greater impact on LDL and HDL cholesterol values in those with pattern B.
Doctors can order the test which measures LDL particle size from Berkeley Heart Lab at 1-800-HEART-89.
Oxidized LDL is the real culprit – there is data that the ratio of oxidized LDL to HDL is a more potent biomarker for discriminating between subjects with and without CAD than the lipid profile (Am J Cardiol. 2006. 97. 640-645).
NCEP II - new features (JAMA. 1993.269. 3015-3023):
Increased emphasis on total heart disease risk as a guide to treatment.
The goal for secondary prevention is LDL < 100, with a recommendation to start medication if LDL > 130 after a trial of lifestyle changes.
Age > 45 in males and age > 55 in females is added as a risk factor for heart disease.
Recommendation to use an LDL cutoff of 220 instead of 190 with regard to the threshold for starting medication treatment in low risk males under age 35 and low risk females under age 45.
Increased emphasis on HDL cholesterol as a heart disease risk factor.
Recommend include HDL measurement any time a screening cholesterol is ordered.
Designation of HDL > 60 as a negative risk factor for heart disease.
Designation of HDL < 35 as an additional positive risk factor for heart disease.
Increased emphasis on exercise and weight loss (in addition to diet).
Decision tree diagrams.
NCEP III - new features (JAMA. 2001. 285. 2486-2497):
Focus on multiple risk factors.
Persons with diabetes are considered a CHD risk equivalent.
Uses Framingham projections of 10 year absolute CHD risk.
Identifies persons with multiple metabolic risk factors as candidates for intensified therapeutic lifestyle changes.
Modifications of lipid and lipoprotein classification.
Identifies LDL cholesterol < 100 mg/dl as optimal.
Raises categorical low HDL cholesterol from <35 mg/dl to < 40 mg/dl.
Lowers the triglyceride classification cutpoints, such that triglycerides >200 mg/dl are high.
Support for implementation.
Recommends complete lipoprotein profile instead of just cholesterol and HDL cholesterol for screening.
Encourages use of plant sterols/stanols and soluble fiber as therapeutic dietary options to lower LDL cholesterol.
Presents strategies for promoting adherence to therapeutic lifestyle changes and drug therapies.
Recommends treatment beyond LDL lowering in individuals with triglycerides > 200 mg/dl.
Additional risk factors and risk markers for coronary heart disease
ADMA (asymmetric dimethyl arginine)
Naturally occurring compound that inhibits nitric oxide production and impairs endothelial function, and is an important risk factor for coronary artery disease.
Initially described in 1992 by Patrick Vallance, an endothelial cell biologist.
This is an analog of L-arginine that binds to endothelial nitric oxide synthase (eNOS) and by binding inhibits the conversion of L-arginine to nitric oxide.
This compound can be measured in the plasma. The most meaningful lab value is probably the ratio of L-arginine to ADMA, with 50:1 – 100:1 considered a healthy ratio.
If ratio is suboptimal, treatment consists of supplemental L-arginine.
GGT (gamma glutamyltransferase)
This enzyme which is mainly produced in the liver and catalyzes the antioxidant glutathione is an independent predictor of CVD death, based on data from 164,000 Australian adults followed for up to 17 years (Circulation. 2005. 112. 2130-2137).
Hypothetical mechanism – depletion of glutathione. Thus, hypothetically, supplemental NAC might offset the increased risk associated with high GGT levels.
Homocysteine
Amino acid derived from methionine which is an independent risk factor for coronary artery disease.
A meta-analysis shows that the hazard ratio for a recurrent event increases by 16% for each increase of 5 micromol/liter in serum homocysteine concentration (BMJ. 2002. 325. 1202).
Kilmer McCully first proposed in 1969 that homocysteine causes atherosclerosis.
Physiological roles are to regulate bone and tissue formation and to stimulate formation of IGF-1.
Homocysteine levels are also correlated with risk of CVA, DVT, and a variety of neurological diseases. Observational data suggest that homocysteine is neurotoxic.
Ideal homocysteine level is probably less than 6 micromol/liter, even though most labs define normal as less than 9 micromol/liter.
Hydrochlorothiazide raises homocysteine level by 16% on average (Metabolism. 2003. 52. 261-263).
In most individuals with a high homocysteine level, it can be lowered primarily by taking folate supplements, secondarily by taking B12, B6, B2, and zinc. In those with a refractory high homocysteine level, TMG, a supplement which is a biochemical precursor to SAMe, taken in doses up to 6 grams per day can help to lower homocysteine level.
The data regarding the benefits of lowering homocysteine is mixed.
A meta-analysis of prospective observational studies showed that a 25% reduction in homocysteine (approximately 3 micromol/liter) is associated with an 11% lower risk of heart disease and a 19% lower risk of stroke (JAMA. 2002. 288. 2015-2-22).
An 8 week trial in 89 men with heart disease showed that folic acid 5 mg and vitamin B12 1 mg improved vascular endothelial function (Circulation. 2000. 102. 2479-2483).
One review of published data showed that folate reduced the risk of restenosis after angioplasty from 37.6% to 19.6% (Ann Med. 2003. 35. 156-163), but in a separate study, patients with stents treated with folate, vitamin B12, and vitamin B6 had an increased rate of in-stent restenosis (N Engl J Med. 2004. 350. 2673-2681).
In the VISP trial in which 3680 patients with stroke were randomized to different daily doses of folate, vitamin B12, and vitamin B6, after two years there was a dose dependent reduction in homocysteine concentration, but no significant difference in the rates of vascular events (JAMA. 2004. 291. 565-575).
In the NORVIT trial in 3749 subjects who had had a MI within 7 days before randomization into one of four groups (placebo, folate 0.8 mg + vitamin B12 0.4 mg + vitamin B6 40 mg, folate 0.8 mg + vitamin B12 0.4 mg, or vitamin B6 40 mg), at a mean of 40 months of follow-up, and with 90% compliance, even though the homocysteine level dropped within 2 months an average of 27% in the folate + vitamin B12 group compared to placebo, the incidence of cardiovascular events in all active treatment groups (composite endpoint of recurrent MI, stroke, or sudden death attributed to CAD) was not different from placebo. There was actually a trend toward an increased risk in the composite endpoint in the treatment group administered folic acid, vitamin B6, and vitamin B12 (p=0.050 [N Engl J Med. 2006. 354. 1578-1588].
In the HOPE 2 trial in 5222 patients over age 55 with vascular disease or diabetes, those who received 2.5 mg folate daily with 50 mg vitamin B6 daily and 1 mg vitamin B12 daily had a mean decrease in homocysteine of 2.4 micromol/liter, but there was no difference in death from cardiovascular causes, MI, or any of the secondary endpoints. Risk of stroke in the active treatment group was significantly lower (RR=0.75, 0.59-0.97) but the risk of hospitalization for unstable angina was increased in the active treatment group (1.24, 1.04-1.49) [N Engl J Med. 2006. 354. 1567-1577].
Mechanisms by which folate might offset the homocysteine-lowering benefit, and thus lead to the failure to improve outcomes seen in the above trials include (1) folate may promote cell proliferation in atherosclerotic plaque, (2) folate may alter the methylation potential in vascular cells, promoting the development of plaque, and (3) folate may promote methylation of arginine to ADMA (asymmetric dimethylarginine), a substance which inhibits the activity of nitric oxide synthase (N Engl J Med. 2006. 354. 1629-1632. editorial). In addition the fact that the folate in supplements (and fortified foods) is pteroylmonoglutamate (PGA), a form that does not occur in nature, may be relevant. At doses below 0.4 mg daily, all PGA is converted into biologically active methylfolate during absorption. At higher doses, there is synthetic PGA in the blood and the long term ramifications of this are unknown (BMJ. 2004. 328. 211-214).
hs-CRP (high sensitivity C reactive protein)
This is a protein synthesized by the liver and it is a marker for inflammation, and an independent risk marker for coronary artery disease (CAD), although the magnitude of the association has been downgraded (N Engl J Med. 2004. 350. 1387-1397).
In 2006 it remains unclear whether CRP is causally related to the cardiovascular disease, or just a risk marker.
There is ongoing study and debate with regard to the extent to which measurement of hs-CRP alters cardiovascular risk assessment (Editorial. Ann Intern Med. 2006. 145. 70-72).
Data at 10 years of follow-up in the Women’s Health Study (an observational cohort study) shows that global risk assessment model that includes hs-CRP improves risk classification in women, particularly amongst those with a 10 year risk of 5-20% (Ann Intern Med. 2006. 145. 21-29).
A narrative review of the literature published prior to 1/06 concludes that there is no definitive evidence that adding CRP to models adds substantial predictive value (Ann Intern Med. 2006. 145. 35-42).
In an 8 year prospective observational cohort study in 1949 men and 2497 women from the Framingham Heart Study who did not have CAD as baseline, elevated CRP level provided no further prognostic information beyond traditional risk factor assessment (Arch Intern Med. 2005. 165. 2473-2478).
CRP can fluctuate as much as 44% over the course of a woman’s menstrual cycle.
Factors which raise hs-CRP.
High saturated fat intake raises hs-CRP.
High trans fat intake raises hs-CRP (J Nutr. 2005. 135. 562-566).
High glycemic-index foods raise hs-CRP by promoting excess production of IL-6 (Am J Nutr. 2002. 75. 492-498). Cross-sectional data in 15,033 women in the Women’s Health Study also show this association.
Oral estradiol and Premarin raise hs-CRP (topical estradiol does not).
Factors which lower hs-CRP
Alpha tocopherol and gamma tocopherol lower hs-CRP.
Alcohol in moderation lowers hs-CRP, independent of the type of alcoholic beverage consumed, based on data in 11,815 participants in the Women’s Health Study (Am J Cardiol. 2005. 96. 83-88).
Digestive enzymes lower hs-CRP.
Exercise lowers hs-CRP (Epidemiology. 2002. 13. 561-568).
Fiber lowers hs-CRP, based on NHANES data (J Nutr. 2004. 134. 1181-1185). Cross-sectional data in 15,033 women in the Women’s Health Study also show this association, and further link the association to intake of soluble fiber. In a yearlong study in 524 healthy adults, those who ate the most fiber had lower hs-CRP levels (Am J Clin Nutr. 4/06).
L-carnitine lowers hs-CRP.
Mediterranean diet lowers hs-CRP (JAMA. 2004. 292. 1440-1446).
Multivitamin lowers hs-CRP as much as 32%, based on published data from the Cooper Institute and using “Cooper Complete” (Am J Med. 2003. 115. 702-707).
TZD medications lower hs-CRP levels (p<0.0001 in a meta-analysis comparing these medications to placebo) [Am J Cardiol. 2006. 97. 655-658].
Weight loss lowers hs-CRP (Circulation. 2002. 105. 564-569)
Fish oil may or may not lower hs-CRP.
Lipoprotein (a) Cleveland Clinic Journal of Medicine. 1999. 66. 465-466.
Independent risk factor for coronary artery disease.
Levels are largely genetically determined.
Using 30 mg/dl as the upper limit of normal, it is estimated that 25% of the U.S. population has high levels.
Lifestyle modifications such as diet, weight loss, and exercise have no effect on levels.
Estrogen replacement therapy, high dose niacin, and fenofibrate lower Lp (a) but resins (Questran, Colestipol) and statins (Lipitor, Mevacor, etc.) do not.
Consider measuring the level in patients with premature coronary artery disease or patients with hypercholesterolemia resistant to statin medication.
Uric acid
Hyperuricemia (uric acid > 7.0 mg/dl in men and > 6.5 mg/dl in women) is a risk marker for cardiovascular disease, hypertension, kidney disease, metabolic syndrome, and obesity (Hypertension. 2005. 45. 18-20). Preliminary data suggests that uric acid is a risk factor, not just merely a risk marker.
Uric acid is an antioxidant.
Fructose is the only sugar that raises uric acid levels (Ann Rheum Disease. 1974. 33. 276-280).
Uric acid levels in the U.S. have steadily increased over the past 60 years, possibly due to increased fructose in the diet.
Excellent summary article in Cleveland Clinic Journal of Medicine. 2006. 73. 1059-1064.
WBC (white blood cell count)
Risk marker for coronary artery disease, based on data gathered in 2208 patients in the TACTICS-TIMI 18 trial (J Am Coll Cardiol. 2002. 40. 1761-1768).
Specifically, based on a study in which 3227 consecutive patients without a MI who had baseline angiography and were followed prospectively, a high neutrophil count and a low lymphocyte count were predictive of risk of MI and death (J Am Coll Cardiol. 2005. 45. 1638-1643).
Hypothetical mechanism – elevations occur in conjunction with inflammation.