In
this issue of Circulation, Ridker and
colleagues1 discuss the incremental value of CRP
as a predictor of future CVD events. Their conclusion is that CRP is at
least additive to HDL and total cholesterol with respect to
risk prediction. In fact, there is some evidence that lipids and CRP
are better predictors jointly than would be expected by adding up their
individual predictive powers. CRP appeared to predict events in those
at low risk on the basis of lipids, and CRP-lipid relationships to
events were minimally altered by adjustment for other known CVD risk
factors. These findings have important implications for CVD risk
assessment and risk management.
CRP is an acute-phase reactant, the levels of which increase
dramatically (100-fold or more) in response to severe bacterial
infection, physical trauma, and other inflammatory
conditions.2 Several roles have been postulated
for CRP, including that of an opsonin, promoting the phagocytic uptake
of invading microorganisms, and that of a procoagulant, promoting the
expression of tissue factor on the monocyte surface. As a marker of
inflammation, CRP is unique among the major plasma proteins in the fold
increase that is observed and in that its levels appear to be
unaffected by hormones and anti-inflammatory drugs but are regulated
primarily by the proinflammatory cytokines, especially
IL-6.2 3 Traditionally, 10 mg/L has been used as
the cut point to signify clinically important levels, with values in
the healthy reference range at or below the lower limit of sensitivity
of most assays.
Recently, elevated levels of CRP, although still for the most part in
the healthy reference range, have been associated with increased risk
of future CVD events. Initially, Liuzzo et al4
and Haverkate et al5 established the prognostic
usefulness of CRP in the setting of angina. This was followed by
studies in otherwise healthy individuals. With the use of new,
sensitive CRP assays, CRP was identified as an independent, prospective
CVD risk factor in the higher-risk middle-aged men of
MRFIT,6 the healthy middle-aged men of the
PHS7 and the MONICA-Augsburg
cohort,8 and the healthy elderly men and women of
the CHS and the Rural Health Promotion
Project.9
CRP is known to be related to smoking,10 and the
MRFIT data indicated that although there was no confounding effect,
there was an interaction of smoking with CRP: CRP better predicted
events in smokers than in nonsmokers, independently of smoking
cessation.6 Consistent with this finding,
CRP levels were associated with lifetime exposure to cigarette smoke,
independently of cessation, in cross-sectional analyses in the
elderly.11 Interestingly, Howard et
al12 have recently shown an association of
carotid wall thickness with lifetime exposure to cigarette smoke. Taken
together, these findings raise the speculation that CRP, at least in
some people, may mark permanent underlying endothelial
damage due in part to smoking. It is important to note that in the PHS,
CRP predicted future events just as well in nonsmokers as in smokers.
However, smoking levels were relatively low in the PHS, and event
follow-up was from 1 to 7 years, whereas in MRFIT it was from 6 to 17
years.
Other important independent correlates of CRP are obesity, markers of
fibrinolytic activity, and subclinical
atherosclerosis.11 The
association of CRP with markers of fibrinolytic activity such as
plasmin-
Taken together, these data strongly support the position that CRP, as a
marker of low-level inflammation, indicates increased risk of
myocardial infarction and stroke in otherwise healthy individuals.
Other acute-phase reactants have been used to indicate increased risk
of CVD events.14 Fibrinogen has been shown in a
wide variety of studies to consistently predict future CVD
events in an independent manner.15 Factor VIII
has recently been shown to predict events in middle-aged and older
healthy adults.16 17 Plasminogen
activator inhibitor-1 predicts second
myocardial infarctions in survivors of a first
infarct18 and, owing to specificity issues of the
assays involved, is probably the reason for the important observed
association between tissue plasminogen
activator antigen and future events in
PHS.19 Markers used to estimate serum iron
(ferritin) and serum copper (ceruloplasmin) are also acute-phase
reactants and have been identified as risk factors in recent
studies.20 21 During the acute-phase reaction,
albumin levels go down, and low levels of albumin
predict future events,22 as do low levels of
bilirubin (most of which is bound to
albumin).23 Even plasma lipids are
associated with inflammation, with levels of HDL
cholesterol dropping and triglycerides
rising,24 both consistent with CVD event
prediction. The only "outlier" is total cholesterol,
which also drops with inflammation. Finally, the cytokine
mediators of inflammation themselves, specifically IL-6, are risk
factors.25
This raises several questions. First, are all of these measures
equivalent with respect to risk prediction? Although there are few
head-to-head comparisons, the answer is likely to be no, because
although they all respond to inflammation, the factors that regulate
many of these proteins are not identical.26 Some
respond to both the more "immediate" IL-1/tumor necrosis factor
cytokines as well as the more "secondary" IL-6/IL-6–like
cytokines, whereas others respond only to the latter. Some are
under major hormonal regulation, whereas other are not. Technically,
the assays for some are much better than for others, and some factors
exhibit much larger within-subject variation than do others. It is
unclear which of these is the best assay from the standpoint of
prediction, or which group would make the best panel of assays.
The report of Ridker and coworkers1 in part
addresses this issue. In the PHS, at least, CRP appears to give added
information when lipids are considered and is statistically independent
of other CVD risk factors. Similar results have been shown for
fibrinogen.5
Second, is the inflammation that these measures reflect an
epiphenomenon of atherosclerotic disease or is it in the CVD-event
causal pathway? The best current answer to this question is probably
both. Many cross-sectional studies have determined that markers such as
fibrinogen, CRP, and others have strong associations with underlying
atherosclerotic disease and, given their status as acute-phase proteins
that respond to tissue damage, probably reflect atherosclerotic damage.
However, there are many plausible mechanistic links between all the
above-mentioned variables, including increased clot formation,
lipid oxidation, and cell activation and proliferation. Taken together,
these data support the position that inflammation is not only a
response to the underlying disease process but also an integral part of
it.
Third, are these markers independent of other estimates of subclinical
CVD? Studies in the CHS were characterized by a design that matched
cases and controls on the degree of subclinical disease as assessed by
carotid wall thickness and several other
variables.9 The results suggested that
although CRP levels in part reflect underlying
atherosclerosis, prediction was not confounded by
subclinical CVD. Rather, there appeared to be effect modification,
because prediction was stronger in those with subclinical disease than
in those without it in the elderly group. This suggests there is added
benefit to measuring CRP even if noninvasive measures of
atherosclerotic burden are used as well.
Fourth, should anti-inflammatory intervention strategies use CRP
levels? Although we have limited data on this issue, the original
results from the PHS indicated that although aspirin, with respect to
incident myocardial infarction, had a protective effect in all CRP
strata, this effect was greatest in those with the highest CRP levels
at baseline.7 Although this is suggestive, we do
not known if long-term aspirin use affects CRP levels. More work is
needed on this issue.
What may we conclude from these studies? Taken together, these data
suggest that it may be time to add a marker of inflammation to the list
of CVD risk factors commonly used to assess risk in otherwise-healthy
middle-aged men. CRP is a good candidate because (1) levels appear
reasonably stable over time,27 (2) levels are
affected by little other than inflammation,2 3
(3) prediction is independent of other known CVD risk factors including
lipids,1 (4) prediction appears additive to other
noninvasive measures of subclinical atherosclerotic
disease,9 (5) CRP predicts future events in both
middle-aged and elderly healthy individuals,6 7 9
and (6) sensitive, inexpensive assays are becoming
available,27 with WHO reference material
available for assay standardization.
Before it can be put into general use, however, there are several
outstanding issues remaining. CRP levels predicted events in
middle-aged men, with no indication of an interaction with time to
event. However, in the elderly, there was a strong time-to-event
dependency, with CRP predicting events <1 year after blood collection
better than events >1 year later.9 Therefore,
more work is needed to better understand the chronological relationship
of CRP to future events in different age groups. In addition, we have
little information about CRP and middle-aged women. Other inflammatory
factors such as fibrinogen predict events in women as well as
men,28 but studies are needed of CRP in
middle-aged women, especially because in the elderly, CRP was a better
predictor of events in women than in men.9
Selected Abbreviations and Acronyms
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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© 1998 American Heart Association, Inc.
Editorial
Inflammation in Cardiovascular Disease
Cart, Horse, or Both?
Key Words: Editorials • C-reactive protein • risk factors • cholesterol • coagulation • fibrinolysis
2-antiplasmin complex provides an
important link between coagulant/fibrinolytic activity and
inflammation. The nature of the link to obesity remains unclear. A
possible mechanism may involve the association of adipose tissue with
fibrinolysis inhibition.13
CHS
=
Cardiovascular Health Study
CRP
=
C-reactive protein
CVD
=
cardiovascular disease
IL
=
interleukin
MRFIT
=
Multiple Risk Factor Intervention Trial
PHS
=
Physician's Health Study
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