Paul Ridker MD

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Towards better screening of CV risk

• Paul Ridker MD
• Associate Professor of Medicine
• Division of Preventive Medicine and
  Cardiovascular Diseases
• Harvard Medical School
• Boston, MA

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CRP vs hs-CRP
High-sensitivityC-reactive protein tests

• Standard CRP tests
• designed to detect clinical information
• cannot predict cardiovascular event rates
• hs-CRP tests
• can detect C-reactive protein levels far below
  the lower sensitivity limits of standard clinical
  assay
• can predict cardiovascular event rates

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Plaques
Determining vulnerability

• Factors affecting the propensity of plaques to
  rupture
• lipids
• the inflammatory process
• the inflammation itself

Atherogenesis and atherothrombosis are as much
inflammatory disorders as lipid disorders.
Ross R. N Engl J Med 1999340(2)115-126
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The clinical picture
Markers of inflammation
Half of all individuals that have MI or stroke do
not have abnormalities of lipid function. For
specific markers of inflammation, hs-CRP turns
out to be the most clinically useful in
determining who is truly at risk for future heart
attacks and stroke in currently healthy
populations of men and women.
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Women's Health Study
Enhancing screening forcardiovascular disease

• NIH-funded study
• large-scale prospective cohort
• designed to determine a variety of issues in
  women's health, including the fundamental
  determinants of cardiovascular events

Ridker PM, et al. N Engl J Med 2000 342(12)
836-843
6
Physicians Health Study
CRP levels and risk of MI or stroke
study of healthy middle-aged men experimental
assay for hs-CRP used Results the higher the
level of C-reactive protein, the higher the risk
of having either a myocardial infarction or a
stroke



Ridker PM, et al. Circulation 199897(20)2007-201
1
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Women's Health Study
Markers measured
12 different putative markers of risk were
simultaneously measured in the same baseline
blood sample using a commercial assay. hs-CRP
serum amyloid A ICAM 1 interleukin-6 total
cholesterol LDL cholesterol

• HDL cholesterol
• apolipoprotein A-I
• apolipoprotein B-100
• Lp(a)
• ratio of total cholesterol to HDL
• homocysteine

Ridker PM, et al. N Engl J Med 2000 342(12)
836-843
8
Women's Health Study
Results for otherwise healthy women
The single strongest predictor of future risk of
heart attack and stroke was hs-CRP, not lipid
level. Women with the higher levels of the hs-CRP
were at nearly 4.5 times increased risk of having
a future heart attack or stroke. LDL cholesterol
levels only had a predictive value of about 2.2
(this marker is potentially better than lipid
screening). Homocysteine and Lp(a) values were
marginal at best. Homocysteine was a significant
predictor of risk but much less predictive than
the inflammatory markers.
Ridker PM, et al. N Engl J Med 2000 342(12)
836-843
9
Women's Health Study
Additive effects of CRP
hs-CRP greatly increases the predictive value of
standard lipid screening. With lipid and the
inflammatory process data, predicting future
vascular events is much more accurate.
Ridker PM, et al. N Engl J Med 2000 342(12)
836-843
10
Women's Health Study
CRP and normal lipid levels
Subgroup Only women with LDL cholesterol of 130
mg/dL (3.37 mmol/L) or less were
included. hs-CRP levels and risk hs-CRP levels
were associated with a 4-fold increase in
risk. Low levels of cholesterol may not mean low
risk if there is an enhanced propensity to
inflammatory response. Women with a propensity to
plaque rupture may be a high-risk subgroup.
Ridker PM, et al. N Engl J Med 2000 342(12)
836-843
11
CARE trial
Statins and CRP levels
The CARE trial (Cholesterol and Recurrent Events)
showed that people randomly allocated to
pravastatin therapy had significantly lower CRP
levels than those allocated to placebo. The
magnitude of risk reduction associated with
pravastatin was greatest among those who had the
inflammatory response. Research is being done to
determine if the combination of lipid screening
and hs-CRP testing will identify truly high-risk
patients who will benefit from statin therapy.
Ridker PM, et al. Circulation 1999
20100(3)230-235
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CARE trial
High CRP levels are never good

• People with low lipid levels and low CRP levels
  were the lowest-risk group.
• People with high lipid levels and high CRP level
  were the highest-risk group.

• Still at high risk
• people with low CRP levels but high lipid levels
• people with high CRP levels but low lipid levels

Ridker PM, et al. Circulation 1999
20100(3)230-235
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NHANES data
CRP in younger people
hs-CRP testing is limited to people who might
otherwise be screened for cholesterol. NHANES
research group Population studies found fairly
broad ranges of CRP levels, even in younger
patients. This suggests that the inflammatory
process may well be present in our teens and 20s.
This is not surprising, because we know that
atherosclerosis is a chronic lifelong disease and
the inflammatory process is predicting events 8,
10, 12 years down the road.
Ford ES, et al. Arterioscler Thromb Vasc Biol
200020(4)1052-1056
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Physicians Health Study
Differentiating inflammations
CRP is a very nonspecific marker of
inflammation. Infections and trauma drive CRP
levels up well into the clinical range. But,
hs-CRP testing detects very low-grade levels in
healthy patients. Still, in clinical practice,
CRP levels should be measured 2 to 3 weeks after
an acute infection.
Ridker PM, et al. Circulation 20001011767
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Physicians Health Study
CRP and obesity
CRP is elevated in obese patients. Body Mass
Index and obesity are determinants of CRP
levels. But hs-CRP is predictive among lean and
heavy individuals. Meditation through the
pro-inflammatory response may be one of the
mechanisms that make obesity so destructive in
terms of vascular function.
Ridker PM, et al. Circulation 20001011767
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CRP levels
Mediator or marker?
CRP is likely a downstream marker of a much more
sophisticated process, with no direct vascular
effects. There may be a systemic, low-grade
inflammatory response. There may be a population
distribution, where some people have more
inflammatory response, some less. The
inflammatory response in our 50s and 60s may lead
to increased vulnerability of plaques. 
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Women's Health Study
Markers associated with increased risk

• ICAM-1, one of the adhesion molecules involved in
  the adhesion and transmigration of macrophages
  and monocytes across the endothelium
• interleukin-6, one of the primary drivers of CRP
  production
• serum amyloid A, another hepatically derived
  acute-phase reactant

Ridker PM, et al. N Engl J Med 2000 342(12)
836-843
18
Women's Health Study
CRP probably a marker

• Because other markers and/or upstream modulators
  predict risk, CRP is probably a marker.
• The single strongest clinical predictor is the
  hs-CRP, likely because it gives a downstream
  overview of the whole process.
• Measuring IL-6 or ICAM 1 is difficult in a
  clinical setting.
• Advantages of hs-CRP
• it is a very hardy protein
• there is very little degradation
• it can be handled like a typical outpatient
  analyte
• it is very stable
• it is easy to measure  

Ridker PM, et al. N Engl J Med 2000 342(12)
836-843
19
Ongoing research
Data for hs-CRP
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Potential uses
The future of hs-CRP
These inflammatory markers might be used as a
method of targeting therapy or as a method of
providing entire new avenues of therapy. If this
inflammatory response is profoundly involved in
the acute coronary syndromes and in changing that
plaque from stable to unstable, we might have an
impact on the inflammatory component as well as
the thrombotic component in clinical trials.