~ New Blood Test Better Predicts Heart Attack Risk

By William Davis, MD, FACC

Marc, a successful architect, had rigorously monitored his cholesterol levels every six months since his mother’s difficult recovery from a coronary bypass operation at the age of 63.

Over the years, Marc’s low-density lipoprotein (LDL), a component of a standard cholesterol panel, wavered within a narrow range that never exceeded 95 milligrams per deciliter (mg/dL). “Your cholesterol profile is excellent, as always,” his family doctor declared.

Nevertheless, a heart attack struck Marc down without warning at the age of 54, leaving him breathless and exhausted from performing the most ordinary activities. Demoralized and frightened, Marc pressed his doctor to explain why he had a heart attack despite his excellent cholesterol values. “Marc, some people have heart attacks because of genetics,” his doctor replied. “There’s not a whole lot we can do about that.”

If you ask your doctor whether heart disease lurks silently within you, chances are your doctor will have no idea. Too often, an attempt will be made to predict your future by evaluating standard cholesterol tests. As a result, your risk, like Marc’s, may be frightfully misjudged.

The shocking reality is that heart disease is the number-one killer of men and women in the US, yet most physicians have no idea how to diagnose the presence of hidden heart disease. If you go to an emergency room having suffered a heart attack, the doctor will usually make the correct diagnosis. But most heart disease is silent and unsuspected. The first symptom is often the last: sudden death. If you rely on your doctor to detect hidden heart disease, you may not get an accurate assessment. It does not have to be this way.

Limits of LDL Testing

The patient previously described suffered a heart attack despite having an LDL level of 95 mg/dL. Is this unusual? Consider 100 other heart attack survivors. What would you predict their cholesterol levels to be? You would probably expect them to be high. The average LDL level in heart attack survivors is 140 mg/dL. Compare this to the average LDL for all Americans, which is 134 mg/dL.1-3 These values are so close, it is no wonder that predicting heart attack risk based on LDL values is an imprecise science at best.

There is tremendous overlap in LDL values between people destined to have a heart attack and those who will never have one. Except at the extremes, I challenge anyone to distinguish who has hidden heart disease and who does not — and who will suffer a heart attack and who will not — just by looking at cholesterol values.

Relying on cholesterol values to identify the presence of hidden heart disease is about as good as tossing a coin to do so. If we focus only on people with LDL levels greater than 130 mg/dL, for example, we will miss half of all those who will suffer a heart attack. Should we treat you to prevent a future heart attack—heads or tails? Since it is foolish to gamble with the precious asset of health, we must dig deeper to identify the factors that accurately predict heart disease.

Limitations of Standard Lipid Testing

For years, physicians have relied on the standard lipid panel—including total cholesterol, LDL, high-density lipoprotein (HDL), and triglycerides—to assess their patients’ cardiovascular disease risk. It is increasingly apparent that this approach fails to detect many individuals at risk for heart disease.

This focus on standard lipid testing causes individuals and doctors to neglect all the other causes of heart disease, some of which are more important than cholesterol. Can you have a heart attack if you have low cholesterol? You sure can. Can you survive to the age of 95, outlive all your neighbors, and never have a heart attack despite high cholesterol? Absolutely. Can you suffer a debilitating or fatal heart attack with “normal” cholesterol? It happens every day—1,152 times a day nationwide, to be exact, according to a 2004 report by the American Heart Association.

Yet most of the time, doctors attempt to assess heart disease risk by looking only at a standard cholesterol panel. The truth is, many risk factors are involved in the development of heart disease. Most people with coronary disease do not have just one contributing cause but rather five, six, or more contributing factors. High cholesterol is, at best, just one item on this list.

Cholesterol can be a useful tool in risk assessment. Several large studies have demonstrated that cholesterol levels are related statistically to the risk of heart disease. The higher your cholesterol levels (total and LDL), the greater the likelihood of heart disease. The Multiple Risk Factor Intervention Trial, or MR FIT, showed that the likelihood of heart attack in the people with cholesterol levels in the highest 20% was three times that of people whose levels were in the lowest 20%.4 The well-known Framingham trial also illustrated this phenomenon.5

In both studies, however, a significant number of heart attacks still occurred in people with low or “normal” cholesterol values. In the Framingham study, four of five people fell into a large middle range of cholesterol levels, whether or not they developed heart disease. Those with extremely low total cholesterol (less than 150 mg/dL) had low (though not zero) risk for heart attack; those with extremely high cholesterol (greater than 300 mg/dL) had high risk for heart attack (threefold higher). But the great majority of people fell in between these extremes, and the greatest number of heart attacks developed in people with cholesterol levels in this middle range.

People with low or middle-range cholesterol values vastly outnumber those with high cholesterol levels. As a result, there are at least as many heart attack victims with low and intermediate cholesterol levels as there are those with high cholesterol. The higher the cholesterol, the higher the statistical risk of heart attack, but a frightening number of heart attacks still occur in people who have favorable cholesterol values.

The lesson: Unless you belong to the minority of people who have either extremely high or extremely low levels, you will not know whether heart disease is in your future simply by relying on cholesterol alone. There is a world of causes of heart attack beyond cholesterol. Lipoproteins are one such major group of causes.

Testing Lipoproteins, Not Lipids

Cholesterol can be thought of as a passenger on a family of protein particles called “lipoproteins” (that is, lipid-carrying proteins). The protein component steers the lipoprotein particle and determines its fate — whether it interacts with the blood vessel wall to create atherosclerotic plaque, extracts cholesterol from plaque, or passes through the liver for disposal. In other words, the protein component of the particle determines the behavior of the lipoprotein particle. The cholesterol component just goes along for the ride.6

Low-density lipoprotein, routinely measured as LDL, actually comprises a varied mixture of particle types that differ in their potential to cause heart disease. You cannot assess heart disease risk simply from knowing that your LDL level is 150 mg/dL. LDL at this level could signal high risk for heart disease, or it could signal low risk. Lipoproteins can help decipher the difference.

Likewise, high-density lipoprotein (HDL) is also a heterogeneous mixture of particles. Large HDL particles are responsible for extracting cholesterol from plaque and other beneficial actions. Smaller HDL particles are essentially useless. The total HDL level provided on standard cholesterol panels lumps all HDL, large and small, together, while specialized lipoprotein testing distinguishes the various subgroups.7

Lipoprotein testing provides insight into just how likely different particles are to deposit their cholesterol in plaque, and does not rely just on the relatively passive cholesterol part of the particle. Until recently, measuring lipoproteins was a cumbersome process that was available only in research laboratories. But testing technology has advanced considerably and several methods are now widely available.

Measuring lipoproteins rather than just lipids changes the whole language of cholesterol and the factors that cause the accumulation of coronary plaque. With LDL, for example, we are concerned less with the total LDL value and more with “LDL particle number” and “LDL particle size.”

Let us now review the various measures obtained through lipoprotein testing:
  • LDL particle number
  • Small LDL
  • HDL and its subclasses
  • Intermediate-density lipoproteins (IDL)
  • Triglycerides and very low-density lipoprotein (VLDL)
  • Lipoprotein (a).
LDL Particle Number

The Quebec Cardiovascular Study was the first large study demonstrating that heart attack can occur when a person’s LDL particle number is high and LDL level is low.8 This has been repeatedly confirmed in other studies, most recently in the AMORIS study, which enrolled a remarkable 175,000 participants and demonstrated the superiority of LDL particle number (measured as apoprotein B) in predicting heart attack risk.9 This measure can be thought of as actually counting the number of LDL particles in one cubic centimeter, or one milliliter of blood.

LDL particle number is among the most powerful tools we have to predict the risk of heart attack. It can be measured directly as LDL particle number by the nuclear magnetic resonance spectroscopy method or indirectly as apoprotein B, which is a more widely available method. Apoprotein B is the major protein particle of LDL, with a single protein per LDL particle. Apoprotein B thus provides a “count” of LDL particles.

How can LDL level be low when the particle number is high? Because the amount of cholesterol contained per particle can vary widely. If you have many LDL particles that contain less cholesterol in each particle, the conventionally measured LDL level will be low, but your heart disease risk will be high. Greater numbers of cholesterol-containing particles in the blood means more cholesterol deposition in plaque. The combination of low LDL level and high LDL particle number is very common, creating a situation whereby many people are mistakenly told that they are not at risk for heart attack.

High LDL particle number responds to the same treatments as high LDL level, but this method of assessment provides greater confidence in determining who to treat and how intensively to do so. Statin prescription drugs lower LDL particle number, as does the non-statin prescription drug ezetimibe, though it is less potent. Niacin (vitamin B3) lowers LDL particle number less potently than the statins, but will achieve a 10-20% reduction. In addition to prescription medicines, many nutritional strategies can lower LDL particle number.

High LDL particle number can be a source of danger even when LDL level has been reduced by treatments such as cholesterol-lowering statin drugs. This is why people who take a cholesterol-lowering medication can still suffer a heart attack. LDL particle number provides much more powerful feedback on the adequacy of treatment and is therefore a tool for further reduction of risk.10,11

Small LDL

LDL particles vary in size — big, medium, and small. The size difference is crucial. Small LDL particles are a far more destructive force than their larger counterparts. Like finely tuned weapons designed to wreak maximum damage, smaller particles more effectively penetrate the cellular barrier and enter arterial walls, contributing to atherosclerotic plaque. They also persist longer in the circulation, which allows more opportunity to cling like little magnets to tissues within the walls.

Once in the arterial wall, small LDL particles are more prone to oxidation, which stimulates the release of inflammatory and adhesive proteins. Small, dense LDL promotes endothelial dysfunction and enhanced production of pro-coagulants by endothelial cells. Small, dense LDL thus appears to be more atherogenic—that is, more likely to contribute to the build-up of plaque within arteries—than normal LDL.12,13

Small LDL can be an inherited predisposition that is activated by unhealthy lifestyles and weight gain. When the genetic factors are strong, it can occur in healthy people who are not overweight. It frequently causes heart disease and is found in more than half of all people who suffer heart attacks. Small LDL particles triple the likelihood of developing coronary plaque and suffering a heart attack.14

This one little measure also holds a world of hidden information. Not only does it indicate a higher risk for heart attack, but small LDL suggests that you are more resistant to insulin and more likely to develop metabolic syndrome, or even diabetes, if you become overweight.15 It also suggests that a very low-fat diet (deriving less than 20% of calories from fat) may paradoxically heighten your heart disease risk.16

Small LDL can augment the dangers of other cardiac risk factors, such as high total cholesterol, increased LDL particle number, or high C-reactive protein (a measure of inflammation). Researchers have noted that while elevated small LDL particle count alone can raise heart attack risk by up to 300%, heart attack risk is sixfold higher (600%) when elevated C-reactive protein is also present.17

Despite its dangers, small LDL is easy to treat. Weight loss is a powerful way to increase LDL particle size. Exercise also provides a modest benefit. Niacin in doses of 500-1500 mg daily (depending on your weight and genetic factors) effectively corrects LDL size. In doses exceeding 500 mg/day, niacin is best prescribed by a physician who is experienced with its peculiar, mostly harmless side effects, like feeling flushed or itchy. Slow-release preparations are available, but consult your doctor in choosing forms that have been shown to be safe.18,19 Exercise may also help to optimize lipoprotein profiles.20

Dietary strategies that slow or reduce sugar release into the bloodstream can be helpful. These include high-fiber foods and foods with a low glycemic index, as well as supplements such as flaxseed, glucomannan, oat bran, psyllium fiber, raw nuts like almonds and walnuts, and the “starch blocker” white bean extract.21

Oat bran is a great way not only to lower LDL particle number, but also to increase LDL particle size. Add two tablespoons daily to yogurt, fruit smoothies, cereal, or other foods.22 Omega-3 fatty acids from fish oil increase LDL size modestly, particularly if triglyceride levels are high.23

HDL and HDL Subclasses

Many people with low HDL have been told their heart disease has no known cause or that its cause is untreatable. Both statements are simply untrue. Low HDL (below 40 mg/dL) is common, affecting more than half of all people with heart disease. Deficiency of the protective subclass within HDL is even more common, affecting most people with heart disease.24,25

Like LDL, HDL comprises a family of HDL particles. The truly beneficial HDL is “large” HDL, sometimes also known as “HDL2b.” Large HDL is responsible for “reverse cholesterol transport,” or the extraction of cholesterol from plaque. Large HDL therefore plays a protective role and is crucial for regression (shrinkage) of coronary plaque.

As a rule, a deficiency of protective large HDL goes hand in hand with low total HDL levels of less than 40 mg/dL. In other words, if your HDL is less than 40 mg/dL, you are highly likely to have a marked deficiency of protective large HDL. If your total HDL is above 60 mg/dL, you probably have a favorable quantity of large HDL. If you are between 40 and 60 mg/dL, you may or may not have a deficiency of protective large HDL. Lipoprotein assessment is then necessary to measure large HDL.26,27

Strategies that increase total HDL will also increase one’s proportion of large HDL. Strict low-fat diets (less than 20% of calories from fat) lower HDL and push HDL to the undesirable smaller size. Low-fat diets are therefore not advised when total HDL is low or when large HDL is deficient. People with low HDL do better by adding dietary sources of plentiful monounsaturated fatty acids (especially raw nuts, flaxseed products, and olive and canola oils), eating unprocessed foods with a low glycemic index, and increasing lean protein intake.28 Omega-3 fatty acids from fish oil have a modest effect in raising total HDL and increasing large HDL.29 The medical treatments to raise HDL are identical to those used to treat small LDL particle size.

Intermediate-Density Lipoproteins (IDL)

While many health-conscious adults are familiar with low-density lipoprotein (LDL) and high-density lipoprotein (HDL), they may not be aware of intermediate-density lipoprotein, or IDL. Though intermediate in density, there is nothing “intermediate” about IDL as a risk factor for heart disease. IDL is a potent contributor to heart attack risk. Elevated IDL means that the body struggles to clear fat from the blood after eating, with many more hours required to clear the blood than normal. The longer these lipoproteins persist in the blood, the more opportunity they have to create plaque, which may ultimately lead to a heart attack.

Only about 10% of people with heart disease have elevated IDL levels. While there is no specific treatment for high IDL, it does respond to a broad variety of treatments, particularly cholesterol-lowering medicines, niacin, fish oil, and weight loss. Knowing that you have a high IDL may mean that your treatment needs to be intensified, as IDL may persist even when LDL or other parameters are corrected.30-32

Triglycerides and VLDL

For several decades, researchers have debated the question of whether triglycerides contribute to heart disease risk. The issue has been conclusively settled: while triglycerides by themselves do not cause heart attacks, they are the driving force behind lipoprotein particles that are potent causes of heart disease, such as small LDL and very low-density lipoprotein (VLDL).33 This phenomenon occurs when triglyceride levels are in the 100–400 mg/dL range. Levels over 400 mg/dL may also contribute to heart disease, but your doctor will need to consider a number of other issues, such as thyroid and kidney disease.

VLDL particles are the most densely triglyceride-packed lipoprotein. Triglycerides and VLDL particles commonly go hand in hand, but excessive VLDL can be present even when triglycerides are low. This is when specific measurement of VLDL is most helpful. When plentiful, VLDL particles circulate in the blood and interact with other lipoprotein particles such as LDL and HDL. This interaction forces triglycerides into LDL and HDL particles, and is the initial step in the formation of undesirable small LDL and deficient large HDL.34

VLDL and triglycerides respond to the same treatments. In general, aim for a triglyceride level below 100 mg/dL, as all triglyceride-rich particles (including small LDL) are minimized at this level. Fish oil in higher doses (4000–10,000 mg/day) is an effective way to lower triglycerides and VLDL by 30–50%.29 This is likely at least part of the reason fish oil has such a powerful impact on reducing death from cardiovascular events. Increasing the fiber content of your diet to 50 grams/day, adding raw nuts, maintaining healthy body weight, and avoiding foods with a high glycemic index are healthy strategies that may contribute to lowering triglycerides to the desired level of less than 100 mg/dL, thereby reducing or eliminating VLDL.35

Lipoprotein (a)

Lipoprotein (a), or Lp(a), is a powerful, much underappreciated cause of heart disease. Up to 20% of people with heart disease will have increased Lp(a), which can lead to heart attacks early in life, often in a person’s forties or fifties. Lp(a) not only is a direct cause of plaque growth and the plaque rupture that can cause a heart attack, but it also magnifies the dangers of all other risk factors, especially LDL particle size and number.36

Treatment for elevated Lp(a) is controversial. Most experts agree that, at the very least, Lp(a) should be lowered to a level no higher than 30 mg/dL, and that this significantly reduces heart attack risk.37 Niacin is the most effective direct treatment for lowering Lp(a), though higher doses are required than for other abnormalities (1000–4000 mg per day, which should be prescribed and monitored by a physician).

In females, the use of estrogen preparations may lower Lp(a), generally around 25%, though estrogen presents other issues that should be fully discussed with your doctor. Testosterone can be very helpful for men, and may lower Lp(a) by 25%. The supplement L-carnitine can be a useful adjunct; 2000 mg per day (1000 mg twice a day) can reduce Lp(a) by 7-8% and occasionally by up to 20%.38 Other nutritional strategies that help lower Lp(a) include ground flaxseed (2 tablespoons daily), raw almonds (1/4 cup daily), and vitamin C (more than 1000 mg daily), with reported reductions of approximately 7%.39-41

Continued . . .

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