The Heart Disease Breakthrough

The average total cholesterol of people with heart disease in the original Framingham Study was actually 20 points lower than the healthy controls.

The standard tests for cholesterol, HDL, LDL, and triglyceride levels only target about 20 percent of all coronary artery disease patients. The other 80 percent can only be identified by differentiating the particle subgroups which make up the total cholesterol figure.

LDL is a particle of the cholesterol molecule. Seven or more types of LDL particles can actually be differentiated. It is the number and type of these various particles that largely determine how virulent your LDL cholesterol will be.

Like LDL particles, HDL particles are divided by size and density. There are five different types: two kinds of HDL2, a and b; and three kinds of HDL 3, a, b, and c. HDL2 particles carry away the cholesterol for disposal. Elevated levels of certain kinds of HDL 3 particles reflect abnormally increased triglyceride content of the HDL particle. This alteration renders this potentially potent protection factor almost useless as a cholesterol scavenger. High HDL3 complements the increased virulence of the high triglyceride containing LDL subclass b particles.

Isolated elevations of triglyceride levels are usually secondary to genetic defects not commonly tested for in themselves. Triglyceride levels in the low 100s range are usually not a problem in themselves, but are a manifestation of diabetes or another, more malignant underlying problem involving LDL particles. Elevations of this magnitude should trigger further testing.

Here are some further markers of patients who develop coronary artery disease. All of these require special tests, but the tests can be fairly easily done if you make a point of asking for them.

Apoprotein b , or atherogenic lipoprotein profile (ALP).
This disorder afflicts 50 percent of heart disease patients. It carries a 300 to 400 percent risk of disease, and is the product of multiple gene disorders. Along with elevated LDL cholesterol levels, ALP is the biggest cause of heart disease. The Apoprotein b test gives more accurate circumstantial evidence about the presence of small, dense, LDL particles. While the subclass b test actually measures the size and size distribution of the particles----parameters that define the LDL subclass----the Apoprotein b test measures the number of the particles.

Apoprotein E Isoform is an actual test of the gene determining the activity of the LDL receptor that attaches to the apoproteins found on various lipid particles. The Apoprotein E structure results from the pair of genes (one from each parent) coding for it. There are four variants of this gene. Each variant being an allele, one coming from each parent. An individual inherits one of six permanent isoform patterns that reflect combinations of the alleles coding for Apoprotein E. The Apoprotein E structure will determine how LDL particles are cleared from the bloodstream, and how diet will affect this clearance. It can affect heart disease risk by 30 to 40 percent.

High Lipoprotein (a) or Lp(a).
Its presence in the blood can interfere with normal clotting dynamics and promote clotting around atherosclerotic plaques. It also more readily oxidizes and migrates into the arterial wall than even the small dense LDL particle. One third of coronary artery disease patients have elevated Lp (a), and such elevations carry a 250 to 300 percent increased risk. This risk is amplified by the presence of high LDL cholesterol levels, LDL subclass b state, elevated hemocysteine, and fibrinogen levels.

An Lp (a) level above 20 indicates a risk factor, and a level of 30 in some populations is equivalent to the danger of a total cholesterol of 240! It is also a factor particularly threatening to people who have recently had their coronary arteries opened by invasive procedures like angioplasty, the opening of a blocked coronary artery by the inflation of a balloon threaded into the blockage. Forcing the artery open like this, while restoring blood flow, also damages the already injured arterial inner wall. This makes the artery particularly susceptible to reobstruction by blood clots. About one-half of your descendants will inherit this problem. Its presence cannot be predicted by any other lipid tests.

Fasting blood sugar, fasting insulin level, two hour postprandial blood sugar or insulin level, glucose tolerance test, hemoglobin A1C level.

Often, the first sign of diabetes is a heart attack. Diabetes is linked to LDL subclass B, high triglycerides, low HDL, high fibrinogen, and a range of other not as easily measurable abnormalities that so strongly predispose to atherosclerosis formation that this risk complex has been termed the cardiovascular dysmetabolic syndrome.

Homocysteine Level
Homocysteinemia (high homocysteine levels) is a build up of the amino acid, homocysteine. This is a genetic condition that aggravates almost all the mechanisms involved in atherosclerosis. About 20 to 30 percent of people with coronary artery disease have this condition. Folic acid, and to a lesser extent Vitamins B₆ and B₁₂ treatment is very simple for this lethal condition.

Fibrinogen Levels
Normally there is a wide range of the protein, fibrinogen, which circulates in the blood stream to be transformed into a delicate web of fiber lacing together a blood clot into a solid mass. However, there are many other people who consistently run high levels, and whose response to stimuli that normally boost these levels is excessively sensitive. This is a result of genetics and underlying physical conditions such as diabetes, which are known to boost fibrinogen levels. People in the upper ranges of fibrinogen have a greater than 30 percent increased risk for developing coronary artery disease.

Step Two:
Determine Your Individual Genetic Risk Profile
Genes are inherited in various complex ways and in various combinations, but most of the coronary artery disease risk factors are dominant genes.

Step Three:
Find out your LDL level and LDL Subclass
The test available to consumers to distinguish the different types of LDL particles is the LDL gradient gel electrophoresis, or LDL GGE for short. This test samples your LDL cholesterol using a chemical gel. Different sized LDL particles are separated out by the graded density of the gel. The test result reveals a distribution of different size particles in order of size. It is this distribution that determines your LDL subclass.

Depending upon which LDL subclass, and its level, you will be able to be guided as to which type of diet, such as low-fat, or not low-fat will benefit you. about one-fourth of the general population will actually increase their risk by going on the almost universally advocated low-fat diet. And, for such people, the lower the fat, the worse the effects! About 15 percent of the population actually need fat in their diet. Also, most commercially processed "low-fat" foods have high sugar content as opposed to crude, complex carbohydrates. This shift in nutrient balance causes elevations of triglycerides and the consequent deleterious changes of both LDL and HDL particles. This can increase your risk, especially if the shift in distribution is not accompanied by a large reduction in LDL cholesterol per se. In other words, too much fat-free cake and low-fat yogurt can be disastrous.

There are many conditions that can cause changes in LDL subclass pattern, and many of them aren’t usually thought of as being connected to the risk of heart disease. Your LDL level and your LDL subclass should be checked if you experience any of these changes in your life:

Step Four:
Find out your HDL (Good Cholesterol) Profile
Like LDL, HDL is a particle floating in your bloodstream. It is composed of cholesterol, triglyceride, and protein "steering" molecules called Apoprotein A-I and A-II, or Apo A-I, A-II. But unlike the LDL particles, which constitute the greatest simple threat to your life, the HDL are powerful protectors. They undo just about all the horrible things that the LDL particles do.

In assessing your HDL status, which is the third component of the standard lipid screen triumvirate, be aware that your sex has a profound impact on the evaluation of the numbers. Much more so than with LDL, and to a degree similar to triglycerides, your sex places you on one of two very different scales.

For both sexes, there is a sharp acceleration of risk below the 42 mark. A correspondingly acceptable HDL cholesterol for a woman is about 10 points higher than for a man. Moreover, HDL levels are fragile. Such things as a diet change, a new medication for some unrelated condition, or a small weight change might not dent an LDL level, but may have a surprising effect on HDL level.

Influences That Increase HDL:
Weight Loss, if overweight
Exercise
Normal or high fat diet (35%-40% fat from cold water fish or monosaturated oils)
Estrogens
Alcohol
Antiacid medications: Zantac Tagamet, Pepcid

Influences That Decrease HDL:
Weight gain from normal weight
Sedentary lifestyle
High carbohydrate diet less than 30% fat
High polyunsaturated fat diets
Progesterone
Anabolic steroids
Testosterone
Age
Smoking
Liver disease
Kidney disease
Thyroid disease
Beta-blocker cardiac medications

What Is An Adequate HDL?
As is the case with LDL, the acceptable level of HDL is an individual matter. Though an average level of HDL might be okay for someone with absolutely no risk factors, a value over 50 for men and over 60 for women is much more appropriate for most people. It is important to review the lists above of positive and negative factors and see what changes you are capable of making.

Triglyceride level and LDL subclass status are half of the influences of HDL level. All of the factors appearing on the lists above will have variable and often unpredictable effects, depending on the state of your metabolism. High triglyceride levels can cause HDLs to fall. This is part of the picture of the subclass B state. Falling triglycerides may signal a rise in HDLs, just as they may signal a conversion from the LDL subclass B to subclass A state.

Because triglycerides, HDLs, and LDLs are all linked, many of the same interventions are effective in optimizing all three. But in some cases, the effects are antagonistic: What raises an HDL level (like more fresh high fat fish in the diet) may promote the subclass B state and raise LDL levels. This can be very tricky to manage---even with professional help. Just when we think we’ve got it all figured out, more convolutions erupt. For example, let’s look at diet.

A low-fat, high-carbohydrate diet that is not intended to gain or lose weight may cause a fall in HDL levels. You’ve learned that the effect of various diets on LDL, however, is highly variable, depending on subclass and, in some cases, on your Apoprotein E test results.

Low HDL
Having a persistently low HDL is a serious problem. If after making all the lifestyle adjustments you can, your HDL is still in the unacceptable range, the two most likely possibilities are that you are an LDL subclass B (more likely), or you have a condition called hypoalphalipoproteinemia, or Hypo A (less likely). In other words, the problem is in your genes. If this is the case, you need some help in the form of medication. In the case of resistant low HDL associated with subclass B, the first line medication treatments for subclass B are potent HDL boosters. Niacin is a powerful HDL stimulant, and fibrates will prove particularly helpful if triglycerides are above 200.

Low HDL and the Apoprotein A-I Test
The Apoprotein A-I test can be used to confirm the low HDL condition due to Hypo A, which is a genetic disorder, and is very deadly. 40% of people who develop heart disease before the age of sixty have this problem either alone or in combination with other factors.

It is believed that Hypo A exists in less than 10 percent of the general population, so it’s uncommon, but not rare. It is present in about 20 percent of all coronary artery disease patients. Fifty percent of the children of an affected parent can be affected, so when this condition is discovered, it is absolutely crucial to go up and down the genetic ladder, testing parents and children.

As with most genetic disorders, its sensitivity to being turned on and off by other factors varies from person to person. All the factors, both metabolic and behavioral, that can cause HDLs to fall can radically amplify this condition. So, treatment starts with clearing your lungs of tobacco smoke, and your blood of triglycerides. Despite this, most true Hypo A-Is won’t appreciably improve without medication.

That’s when niacin should be tried, but unlike all the other situations for which niacin seems like a miracle drug, against the Hypo A-I gene (or genes), it often finds its match; they don’t respond. Postmenopausal women have another option: estrogen therapy.

If there is no response, the best advice medicine has to offer at the present time is to optimize every other metabolic and behavioral risk factor. In short, your goals are identical to those I advise for the person with active coronary artery disease.

What Your "Average" Laboratory Test Doesn’t Tell You About Your HDL.
As there are with LDL, there are different kinds of HDL. However, their relative significance as atherosclerotic risk factors are not nearly as well understood as are the LDL subtypes.

Analogous to the LDL-GGE test, which separates different LDL particles, the HDL-GGE test separate the HDL fraction of cholesterol into two families of particles, HDL2 and HDL3. In the Finnish study where men with HDL levels below 42 had over a three times risk of having a heart attack, those with HDL2 had half the risk of those with HDL3, and it was found to be even more protective than the total HDL level itself. Thus, HDL2 seems to be the most important protective factor against coronary artery disease, so much so that a decreased level was more dangerous than elevations of LDL cholesterol, smoking, or high blood pressure.

Still, there is no general agreement about the exact relative significance of these families of HDL. Some studies have shown that HDL3 is more important. Nevertheless, there is no debate about the protective value of HDL2.

The major task of the HDL particle is to melt atherosclerotic lesions. HDLs float by in the bloodstream, target a cholesterol deposit down in the lining of the artery wall, and carry it back to the liver for disposal. HDL3s are thin, hungry HDL particles that when they become engorged with cholesterol become HDL2s. It’s the HDL2s then that are actually bringing the cholesterol away for disposal. This is called reverse cholesterol transport. It is probably the single most important event occurring in your body ensuring longevity---it is the biological antidote to atherosclerosis.

Step Five:
Discover your Lp (a) Level
The Lp (a) is an LDL particle with an extra protein, the Apoprotein A, attached to it. Here are the normal ranges of Lp(a):

What Lp(a) Does.
The structure of Apoprotein A is very similar to the structure of another protein circulating in the blood: plasminogen. This protein helps dissolve the blood clots that form around ruptured atherosclerotic plaques. Lp(a), however, with its Apoprotein A attached, can trick the receptors lining the arterial wall responsible for activating plasminogen, thus thwarting the body’s response to inappropriate clot formation. In addition, Apoprotein A seems to stimulate the movement of structural cells from the interior of the arterial wall toward the surface to help build up the growing plaque even further. And, it is extremely amenable to oxidation, making it a very effective participant in the entire range of activities that go into plaque formation. All of this makes for a very nasty particle that nobody should want to have in any appreciable concentrations.

Elevated Lp(a) is inherited. However, not all Lp(a) are alike in virulence. Unfortunately, the tests to determine genetic variants are not commercially available, so you must approach this issue as if you had all the variants.

Because of its link to the blood clotting system, Lp(a) has been implicated in causing coronary obstruction in situations that are already prone to enhance clot formation---in reocclusions of coronary arteries opened by angioplasty and in early failure of coronary artery bypass vein grafts, but not grafts made from other arteries.

High Lp(a) levels have also been associated with increased incidence of atherosclerotic obstructions of other arteries---those supplying the brain and legs, for example.

About one-third of coronary artery disease patients have elevations of Lp(a). This is now considered an independent risk factor for heart disease. High LDL levels, especially coupled with high triglyceride levels act in synergy with Lp(a) to cause cholesterol accumulation in the arterial wall. So, Lp(a) is a problem, not only late in the disease, but also at its earliest stages. Because of Lp(a)’s tight link to the blood clotting system, people with other coronary artery disease risk factors that contribute to clotting (such as high fibrinogen levels, high homocysteine levels, or elevated platelet counts) should pay particular attention to their Lp(a) levels.

Treatment
Treatment can be frustrating. It used to be believed that exercise lowered Lp(a), but that’s been proven untrue. No diet, or other lifestyle changes can directly help either. Niacin may be helpful, but it’s very hard to build up to sufficient doses without causing unpleasant side effects. While daily niacin doses in the range of 1 to 2 grams are often effective in raising HDLs or converting LDL subclass B, doses of 4 grams or more are often required to substantially lower Lp(a) levels.

Results similar to those with niacin can be obtained with estrogen therapy in postmenopausal women, and, most recently, with the estrogen-like anticancer drug tamoxifen. In men, testosterone had been shown to effectively reduce Lp(a) levels.

Of extreme importance, especially for the person with heart disease, are the other factors that increase blood clotting, homocysteine, and fibrinogen. In the presence of elevated Lp(a), you absolutely must know these levels as well, and minimize them if elevated. It’s much easier to reduce a homocysteine or fibrinogen level than it is to reduce an Lp(a) level.

Step Six:
Understand Your Blood-Clotting System
Many experts believe that the actual first moment of the atherosclerotic process has nothing to do with cholesterol at all, but with a microscopic injury to the vessel wall, an injury that can be caused by a "natural" factor like high levels of adrenaline-like hormones, or "unnatural" factors like cigarette smoke. In this conception, the first element of the atherosclerotic process is the attraction of the clotting mechanisms to the injured site of the arterial wall.

Platelets are tiny cells that are attracted to injured tissue of any kind, where they accumulate to stop the flow of blood and then chemically stimulate the clotting cascade to begin. A dozen or so clotting factors are sequentially activated to finally convert the circulating protein fibrinogen to form the weblike latticework of fibers called fibrin. This web traps red blood cells circulating through it, locking them into a tightly packed jumble, which we call a blood clot. Platelets and fibrinogen, the beginning and the end of the clotting cascade, have been found to be instrumental at every stage of the atherosclerotic process.

Fibrinogen and Blood Clotting
Fibrinogen is the molecule that forms the actual strands of the web that traps the red blood cells and locks them into a clot. It also controls the viscosity of the blood. The more fibrinogen, the thicker blood becomes. As blood thickens, it obviously flows less easily, especially through partially blocked passages.

Seven major, well-designed studies have uniformly implicated high fibrinogen levels as a risk for cardiac disease. One study found that risk of high fibrinogen levels to be greater than that of high cholesterol levels. Fibrinogen is an accomplice, helping other risk factors do their damage through the clotting system. Smoking is a good example of this. Smoking injures artery walls, attracting fibrinogen to form clots at the injured places. High fibrinogen levels make the damage of smoking worse.

Unlike many of the circulation’s other risk factors, one does not have to have pathologically elevated levels of fibrinogen to incur a substantially increased risk from its presence---even the top third of the normal range carries increased risk.

Testing Fibrinogen Levels
Testing your fibrinogen level is easy and inexpensive. The hard part is getting a fibrinogen level that accurately represents your baseline. Concentrations of fibrinogen rise and fall rapidly in response to many stimuli. Psychological stress, an infection as mild as a cold, trauma large and small, all can cause fibrinogen levels to rise. Most confusingly, heart disease itself can cause fibrinogen level to rise. Thus, having a high fibrinogen level is, both a risk for, and a symptom of cardiac disease.

The test must be done when you have no current illness, however trivial, and no recent trauma, surgical or accidental. And, you can’t get an accurate reading until at least six months after a heart attack. For a person trying to prevent heart disease, fibrinogen is a predictive factor. For someone who already has heart disease, it is, both a disease marker, and a risk factor for aggravated illness.

To understand which diet is best for you, you first have to know which variant of the Apoprotein E gene you carry.

Apoprotein E₄ constitutes an independent risk factor for coronary artery disease. 5% of the population carry both alleles of the _e₄gene, the so called 4/4 Apoprotein E type. Since you can’t change your genes, you have to use the knowledge of you Apoprotein E type to guide you in choosing a helpful diet.

With Regards to LDL and HDL Levels:
The Apoprotein E 3/4 (about 20 percent of the population) and 4/4 person on a low fat diet will reduce LDL cholesterol twice as much as an Apoprotein E 3/3 on the same diet. The reduction of HDL will be mild, if it occurs at all.

The Apoprotein E 3/3 (about 62% of the population) person may have a modestly beneficial response to a low fat diet, but also, may have no response. HDL levels also may decline or stay the same.

The Apoprotein E 2/3 (about 10% of the population) person will probably have no response to the low fat diet and may get worse because of rising LDL levels, seriously falling HDL levels, or both.

The Apoprotein E 2/2 (1% of the population) person should never be placed on a low fat diet.

LDL Subclass and Your Diet
In addition, the effects of your LDL subclass on diet response can be contrary to those of the Apoprotein E gene. In such a situation the subclass effect will win out, but the effect will be blunted by the contrary stimulus from the Apoprotein E gene.

Generally, the subclass B metabolism responds very well to a diet of less than 30 percent fat. The lower the percent of fat the better the overall response.

By contrast, only one-third to one-half of subclass As will demonstrate a noticeable response to a low fat diet. The response will be in the range of about a 10mg drop in LDL cholesterol as compared to a 30mg drop in the subclass Bs. Furthermore, the LDL particles that fall in the subclass A person are almost exclusively the big A particles. In fact, 40 percent of subclass A men given a low fat diet actually converted from subclass A to subclass B. they actually increased their risk for heart disease as a result of the low fat diet! The tip-off for this happening is a significant increase in triglycerides, usually about 60mg.

Combining Apoprotein E and LDL Subclass Information
LDL and HDL Response to Low Fat Diet (<30% fat)

Group	LDL Response	Total HDL Response	HDL Subclass Response
Subclass A	variable	reduced levels	unfavorable
Subclass B	reduced levels	reduced levels	neutral
Apo e 2*	variable	reduced levels	unfavorable
Apo e 3*	variable	reduced levels	neutral
Apo e 4*	reduced levels	reduced levels	neutral

*Note: e₂ includes only e 2/3 people. e 2/2 people should not be on low fat diets. e ₃includes e 3/3 only. e₄ includes ¾ and 4/4 people. If a reduction in HDL cholesterol occurs, check your HDL subclasses. Often the HDL₂ is unaffected or may even rise, while the HDL₃ fraction falls. It is the HDL₂ that is considered the more protective.

LDL Subclass	Apoprotein E Desirable	Percentage of Fat in Diet
A	e₂	"normal" fat: 30-40%
A	e₃	variable: start with 30%
B	e₄	low fat: 25-30%
B	e₂	low fat or variable: start with 30%
B	e₃	low fat: 25-30% (may need "normal" fat)
B	e₄	low fat: 25-30%

Tracking Diet Response
It takes at least six weeks to two months of honestly following your new diet to begin to see results. The right person on the right diet can enjoy 30 to 40mg reductions on LDL levels. It’s been shown that in populations where LDL cholesterol represents the predominant risk factor, a one percent reduction of LDL cholesterol level yields an impressive two percent reduction in risk for coronary artery disease. Of course, different combinations of subclass and Apoprotein E status will have different results.

The following table summarizes current information about what happens when you’re on a low fat diet, and what you should do about it.

Falling Apoprotein B/ LDL cholesterol ratio	Desirable
Rising Apoprotein B/ LDL cholesterol ratio	Caution
Apoprotein B/ LDL cholesterol ratio> 1:1	Check LDL subclass
Rise in triglyceride levels of about 50	Check LDL subclass
LDL subclass A changes to B	Go back to "normal" fat diet
Falling total cholesterol/HDL ratio	Desirable
Stable total cholesterol/HDL ratio (when HDL cholesterol is in "average" range)	Check HDL₂ percentage (should not fall)

Proper Diet Consumption and The Problem of the Low Fat Diet
Not all low fat diets are alike. The improper construction of the "heart-healthy" diet is often as much of the reason for poor metabolic responses, as is any inherent intolerance on the part of a particular individual.

One of the problems associated with low fat diets is their effects on HDL and LDL particles. Lack of fat and over abundance of carbohydrates are both independent and synergistic factors. On average, HDL levels drop 10 percent for every 10 percent rise in calories provided by carbohydrate rather than fat.

The problem is that many people substitute simple carbohydrates for fat instead of complex carbohydrates. Simple carbohydrates are sugar, honey, refined flour, fruit and fruit juices. These raise triglyceride levels, insulin levels, lower HDL levels, and then are stored as fat in your body. They also cause arthritis, free-radical damage, and wrinkles. Instead, stick to high fiber cruciferous vegetables, whole grain rice, beans, corn on the cob, barley, and avoid any of the above forms of simple sugars like the plague.

When choosing fat, choose monosaturated fats such as olive oil, canola oil, peanuts, fish or avocado. Avoid vegetable oils, hydrogenated fats, and saturated fats. Eat 25 to 30 grams of total fiber daily. And, there is some evidence that beer, wine and spirits each have beneficial effects against heart disease. But, alcohol is a very potent elevator of triglycerides. In any case, a drink or two a day is not a substitute for exercise, a good diet, or necessary medication. Unfortunately, some people think it is.

Small LDL particle size	High triglycerides
High LDL cholesterol levels	Reduced insulin sensitivity
LDL subclass B	Diabetes
Increased Apoprotein B	High blood pressure
Low HDL cholesterol	High fibrinogen levels
Low HDL₂	Depressed intrinsic fibrinolysis

Goal	Active Drugs
Conversion of LDL subclass B to A	Niacin Fibrates Resins Estrogen Antioxidants
Reduction of LDL cholesterol level	Statins Resins Niacin Fibrates (unreliably) Antioxidants
Elevation of HDL and HDL₂	Niacin Fibrates Estrogen Antioxidants
Reduction of triglycerides	Fibrates Niacin Atorvastatin
Reduction of fibrinogen	Fibrates Antioxidants
Reduction of homocysteine	Folate B₆Antioxidants
Reduction of Lp(a)	Niacin Estrogen Antioxidants

Sex	Average	Level of Highest 10% of the population
Male	3.8mg/dl	18mg/dl
Female	4.4mg/dl	21mg/dl