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New Blood Test Better Predicts Heart Attack Risk

May 2006

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).