C-Reactive Protein test to screen for heart disease: Why Do We Need Another
Protein test to screen for heart disease: Why
Do We Need Another Test?
(This article was first printed in the February,
2003 issue of the Harvard Health Letter. For
more information or to order, please go to http://health.harvard.edu/health.)
The predictive powers of a cholesterol
test only go so far. If your LDL is low,
your C-reactive protein may be a better sign
of impending heart trouble.
The gap between knowing what's good for you
and actually doing it can be huge, especially
when it comes to something like getting exercise.
(Never underestimate the appeal of the sedentary
life.) Many of us need a warning-some might
say a bit of a kick in the pants-before we'll
change our ways and get with a heart-healthy
For decades, cholesterol testing has served
as that warning for many. An elevated level
of "bad" LDL cholesterol has been just the
warning people needed to change their ways.
It has played that role for several reasons.
People like tests because the results seem
objective. Reliable measurement of cholesterol
is easy and relatively inexpensive. It makes
sense biologically. LDL cholesterol,
a protein-wrapped package containing fat and
cholesterol, tends to slip out of the bloodstream
and lodge in blood vessel walls, forming the plaque that
leads to clots and heart attacks.
And it makes sense statistically. The correlation
between lowering your LDL and lowering your
chances of having a heart attack or developing
other forms of heart disease is well documented.
Indeed, exercise and dietary changes are good
for the heart partly because they lower LDL
The Blind Spot
But for all its virtues, cholesterol testing
is seriously flawed. Research has shown that
only about 50% of the people who have heart
attacks have high LDL. If LDL levels are supposed
to be an alarm, then it's not going off for
half of those who might benefit from a wake-up
This shortcoming presents two problems. First,
and most obviously, many people at risk are
being missed. So there's a need for a different
test that will "capture" those who slip through
the fingers of cholesterol screening.
Second, because cholesterol screening does
miss so many incipient heart attacks, it suggests
that cholesterol doesn't adequately explain
Inflammation seems to be that explanation,
and C-reactive protein (CRP), a by-product
of inflammation, may provide the test.
Causes Heart Attacks
Experts who study blood vessels, plaque, and
heart attacks in minute detail have been developing
an inflammatory explanation for heart attacks.
They've described a process quite different
from the clogged plumbing analogy. Blood vessels
aren't solid pipes, but slender tubes of layered,
living tissue, some of it quite delicate. LDL
cholesterol doesn't simply lodge in arterial
walls-it injures them. And like injuries elsewhere
in the body, this stirs up an inflammatory
response. Swarms of cytokines, macrophages,
and other cells swoop in. They enlarge and
transform deposits of LDL cholesterol into
accumulations of fat-laden foam cells sealed
by fibrous caps of collagen.
Other inflammatory molecules can so weaken
a fibrous cap that eventually it bursts open.
The contents of the plaque spill out and activate
clotting factors in the blood. A massive blood
clot forms. The result: a blocked artery and
a heart attack.
Why C-Reactive Protein?
If inflammation explains heart attacks, then
a test that helps doctors gauge inflammatory
activity inside the blood vessels might be
valuable. CRP is nothing new to medical science.
The protein was discovered over 70 years ago.
Researchers quickly figured out that it was
part of the immune or inflammatory response
because levels soared in response to Streptococcus
A infection. In fact, doctors have used
CRP measurements for decades to monitor patients
with lupus, rheumatoid arthritis, and other
conditions related to the immune system.
But as a way to screen for heart disease risk?
That was a different story. All the momentum
and much of the science used to be behind cholesterol
testing. Now, however, CRP testing seems ready
to catch on for several reasons.
have heard or read about the reasoning behind
The inflammatory explanation of atherosclerosis
and heart attacks has trickled down from rarefied
research circles to doctors and the public.
Dozens of newspaper, magazine, and newsletter
articles have been written about it. People
are more likely to get a test-maybe even demand
one-if they have some understanding of what's
being measured and why. The same goes for doctors.
a good predictor of heart disease.
Even if heart attacks were caused by inflammation,
CRP testing wouldn't be useful unless it's
proved to be a good predictor. In other words,
studies have to show that there's a tight correlation
between high C-reactive protein levels and
the chances of having a heart attack.
To make a long story short, that's just what
a series of studies published in prestigious
journals has shown. One, in the Nov. 14, 2002, New
England Journal of Medicine , concluded
that CRP outperforms LDL cholesterol as a predictor
of cardiovascular risk. In addition, the authors
found that the two tests identify different
high-risk groups, so using both is better than
relying on either alone. (If you're interested
in the details of this and other CRP studies,
visit our Web site at http://www.health.harvard.edu/health.)
a better predictor than other measures of
There are other ways to measure inflammation.
But a study in the March 23, 2000, New England
Journal of Medicine concluded that C-reactive
protein was a better predictor of cardiovascular
events (heart attacks, strokes, bypass surgery,
or angioplasty) than other inflammatory markers.
Until fairly recently, the test available
to doctors couldn't reliably measure low (below
10 milligrams per liter) CRP levels. Tests
are now sensitive enough to measure levels
of 1 milligram per liter or less. That's a
crucial development because it's fairly minor
differences at those lo w levels that sort
out cardiovascular risk.
The test costs $12-$16, and it takes only
a small amount of blood. In fact, the same
blood sample could be sent to a lab for both
cholesterol and C-reactive protein testing.
cutoffs have already been established.
Without preset cutoffs, doctors wouldn't know
how to interpret CRP test results. Dr. Paul
Ridker, a Harvard researcher, was principal
investigator on most of the crucial CRP studies
and is co-inventor on related patents. He says
it's now possible to classify CRP levels in
terms of low, moderate, or high risk.
Less than 1 milligram per liter of blood corresponds
to a low risk for heart attack or other cardiovascular
problems; 1-3 milligrams per liter corresponds
to moderate risk; and over 3 milligrams, to
high risk. These cutoffs might change with
more research (as have those for cholesterol),
but they're a starting point.
can do something about high levels.
Imagine your doctor telling you that a newfangled
test of inflammation shows that you have a
worrisome level of a telltale protein, but,
um, there isn't much you-or she-can do about
it. That wouldn't be a popular or helpful test,
even if it were a perfect prognosticator of
A big reason behind the growing enthusiasm
for C-reactive protein tests is that levels
can be lowered. The statin drugs (Lipitor,
Zocor, other brands) made their name by lowering
LDL; research has shown that they also lower
C-reactive protein levels. Exercise is a great
way to bring down your CRP level; losing weight
also seems to work.
C-reactive protein "hawks" think the time
has come when everyone should get the test
and that it may eventually supplant cholesterol
testing. "Doves" say that there just isn't
enough evidence about how doctors should treat
high levels, even if there is a link to cardiovascular
As we went to press (2003), neither the American
Heart Association (AHA) nor the American College
of Cardiology had made a formal recommendation
on C-reactive protein. Published comments from
AHA leaders hint that it might stake out a
middle ground and suggest testing people who
fall into an intermediate-risk group because
of their age (60 and older), weight, or blood
pressure. AHA and other guidelines will influence
how doctors will use the CRP test during the
next year or so. Ultimately, though, the fate
of the test rests with prospective, randomized
studies of CRP-lowering interventions still
Dr. Ridker's November 2002 study comparing
C-reactive protein and LDL found that cardiovascular
risk was actually greater for people in the
high CRP/low LDL group than for those in the
low CRP/high LDL group. Clearly, cholesterol
testing would have missed people in the high
CRP/low LDL group.
If these results hold up, CRP testing might
be most advisable for people with low LDL levels.
Because the test is inexpensive, doctors might
just order both tests right off the bat rather
than wait for the cholesterol results.
No test, no matter how good it is, changes
anyone's health. It's what we do in response
that matters. Statins have put a pharmaceutical
face on heart disease prevention, but the old
truths about getting exercise, eating right,
and not smoking still hold. If the CRP test
gets more people to follow that advice, then
it may be worthwhile.