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New Blood Test Better Predicts Heart Attack Risk

May 2006

By William Davis, MD, FACC

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