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 ofa 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.” 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.

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.

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 perform-
ing 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.”

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.

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
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 cholesterolcontaining
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. Niacin
(vitamin B3) lowers LDL particle number, it will achieve a 10-20%
reduction.
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.
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
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
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 you 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).
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 Lcarnitine
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
OTHER MEASURES OF HEART DISEASE
RISK
Several other measures are important components of a comprehensive
assessment of heart disease risk. Although not lipoproteins, these
measures are often included in cardiovascular health panels.
C-Reactive Protein
Inflammation is fuel for the fire that leads to coronary plaque
rupture, resulting in heart attack. Inflammation may also contribute
to other diseases, such as diabetes, cancer, and arthritis. A number
of proteins circulate in the blood, signaling heightened states of
inflammation. The most clinically studied of these is C-reactive
protein (CRP).
Dr. Paul Ridker of Harvard University is the nation’s foremost authority
on CRP. He has demonstrated that high CRP levels increase heart
attack risk threefold, even when LDL level is low. When elevated
CRP occurs in the company of small LDL particle size, a very high
risk for heart attack can develop—a risk that is sixfold greater.17
Scientists have developed a way to measure CRP, called “highsensitivity”
CRP, that can detect low levels of inflammation. While
highly elevated levels nearly always represent inflammation outside
the heart (e.g., arthritis) and should not be used to prognosticate
coronary risk, modestly elevated levels can be used to gauge lowgrade
inflammation that contributes to coronary plaque rupture. Lp-
PLA2 is a cutting edge indicator of vessel inflammation and where
available should be tested.
Healthy lifestyle choices, such as restricting saturated fat, choosing
low-glycemic-index foods, and engaging in regular exercise, are
the best way to lower CRP. Fish oil can be a useful adjunct in your
program for turning off inflammation and lowering CRP.44 Plant-based
compounds called flavonoids, including olive oil polyphenols, are
emerging as potentially important factors in lowering inflammation
and CRP levels, though further investigation is warranted.46,47
Fibrinogen
Our blood maintains a precarious balance between being able to
flow freely into the smallest capillaries and being capable of clotting
in response to injury. Clotting proteins circulating in the blood help
maintain this balance. Fibrinogen is a principal clotting protein. With
the appropriate stimulation (injury or stress), fibrinogen is modified
to form a smaller protein called fibrin. Thousands of strands of fibrin
accumulate at an injury site to form a blood clot.
When greater blood levels of fibrinogen are present, the balance
is tipped in favor of blood clot formation, even when it may not be
appropriate. This can happen, for instance, at the site of a ruptured
coronary plaque. The injured plaque surface causes fibrinogen to be
converted to fibrin, forming a blood clot, which may result in heart
attack. Fibrinogen can also promote atherosclerotic plaque growth,
even without blood clot formation. Elevated fibrinogen levels are
associated with an increased risk of heart attack.48-50
The modern American lifestyle of sedentary occupations and
excessive intake of high-fat foods and refined starches increases
fibrinogen. Estrogen raises fibrinogen levels, which may account
for some of the increased blood-clotting tendency observed with
estrogen replacement.
Fish oil at doses of 3000 mg or greater daily does a good job
of lowering fibrinogen.51 Combine this with a diet rich in green
vegetables and fiber, low in saturated and hydrogenated fat, and
physical activity, and fibrinogen levels usually drop into a favorable
range. For the occasional person who requires more intensive effort,
the fibric acid class of drugs, especially fenofibrate, can lower
fibrinogen by 15-40%. Niacin also helps by lowering fibrinogen by
10-30%.52
CONCLUSION
Advanced lipoprotein testing can help provide great insight into your
risks for heart disease, filling the gaping deficiencies of mainstream
cholesterol or lipid testing. The superior information provided by
lipoprotein testing can
help you to devise an
effective program to
prevent future heart
attacks.
If you have a family history of heart disease, high blood pressure,
diabetes, or any measure of coronary plaque, you should strongly
consider lipoprotein testing. If you have had coronary disease
already diagnosed—that is, if you have had a heart attack, angina, or
a heart procedure like coronary angioplasty or bypass surgery—then
lipoprotein testing can be a crucial part of your program to prevent
future cardiac catastrophes, particularly if conventional lipid testing
has failed to pinpoint the cause of your disease.
Being aware of the glycemic-index values of different foods is
very important when you have small LDL particles, low total HDL,
deficient large HDL, or increased triglycerides or VLDL. This means
choosing foods that release sugars slowly, an effect that may help
improve all of these risk factors. Abrupt spikes in sugar release help
create these abnormalities and lead to both coronary plaque growth
and diabetes. By contrast, foods that release sugars slowly or contain
little or no sugar can help correct these patterns.60,61
The glycemic index is calculated by comparing a food’s ability to
raise blood sugar to that of either white table sugar or white bread,
two foods that are processed by the body like pure sugar. The height
of the blood sugar peak is then measured. A glycemic index of 100
would be equal in sugar-release properties to sugar or white bread; an
index below 100 would mean less sugar release. In general, proteins
and fats have lower glycemic index values, while carbohydrates and
refined foods have higher values.
Carbohydrates are a potential problem for glycemic index control.
Processed foods like breakfast cereals, white bread, other white
flour products, and sweets are clearly the worst culprits, causing
big spikes in blood sugar after ingestion. Desirable carbohydrate
sources with lower glycemic indexes include foods containing oats,
whole fruits and vegetables (the pulp and fiber slow sugar release,
unlike their juices), and beans.
Healthy oils, like canola, olive, and flaxseed oils, slow the sugarrelease
effect of other foods. Foods rich in fiber, such as oat bran,
whole grains, and raw nuts (almonds, walnuts, pecans), tend to
slow sugar release. Supplements containing glucomannan and other
fibers are very viscous, which slows sugar release and also promotes
satiety, thereby supporting weight loss.
A website managed by the University of Sydney (www.glycemicindex.
com) has an excellent searchable database that allows you to enter
the food in question and obtain its glycemic index. Dr. Jennie
Brand-Miller has published extensively on the glycemic index, and
the complete glycemic index tables generated by her research are
also available in her book The Glucose Revolution (Marlowe and
Company, 1999).
Dr. William Davis is an author, lecturer, and practicing cardiologist
focusing on coronary disease regression. He is author of the book,
Track Your Plaque: The only heart disease prevention program that
shows you how to use the new
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