Markers of Inflammation and Risk of Coronary Heart Disease
Markers of inflammation and risk of coronary heart disease
Nadeem Sarwar 0 1
Alexander J. Thompson 1
Emanuele Di Angelantonio 1
0 Section of Population Health, University of Aberdeen , UK
1 Department of Public Health and Primary Care, University of Cambridge , UK
Cardiovascular disease is the leading cause of global mortality, with coronary heart disease (CHD) its major manifestation. Although inflammation, the body's response to noxious stimuli, is implicated in several stages of CHD development, the relevance of circulating levels of markers of inflammation to CHD risk remains uncertain. This review summarizes available epidemiological evidence for four emerging inflammatory markers implicated in CHD (fibrinogen, C-reactive protein, lipoprotein-associated phospholipase A2 and interleukin-6); considers their likely utility in cardiovascular risk prediction; and outlines areas of outstanding uncertainty.
inflammation; coronary; cardiovascular; prediction
Cardiovascular disease is the leading cause of
global mortality, accounting for almost one in every two
adult deaths worldwide, with coronary heart disease
(CHD) its major manifestation [
]. CHD results from
atherosclerotic narrowing of the coronary arteries and
the formation of an occlusive thrombus after plaque
]. The tendency for CHD to cluster in
families (coefficient of familial clustering [?s] estimated to
be between 2 and 7) suggests that genetic variation
importantly influences CHD risk . On the other hand,
studies of migrant populations indicate that CHD risk
increases following movement from low-risk to
highrisk regions (eg, Japanese in the USA) [
that lifestyle and environmental factors also contribute
Inflammation, the body?s response to noxious
stimuli, is implicated in several stages of CHD
development, including atherosclerosis, plaque destabilization,
plaque rupture and post-ischaemia damage to the
]. Much uncertainty remains, however,
about whether circulating levels of markers of
inflammation are related to CHD risk. In particular, it remains
unclear whether such markers are (i) causal in disease
risk; (ii) correlates of conventional cardiovascular risk
factors; (iii) markers of subclinical or prevalent disease;
or some combination of these possibilities.
This review summarizes available epidemiological
evidence for four emerging inflammatory markers
implicated in CHD development; considers their likely
utility in cardiovascular risk prediction; and outlines
areas of outstanding uncertainty.
First isolated from horse plasma in 1876, fibrinogen
is the most abundant clotting protein in circulation. A
very large (340 KDa) glycoprotein synthesized in the
liver, fibrinogen can bind to GpIIB/IIIa surface
proteins creating bridges between platelets and is the
precursor to fibrin [
]. In addition to being involved in
the coagulation cascade, fibrinogen is thought to
stimulate smooth-muscle-cell migration, promote platelet
aggregation and increase blood viscosity [
]. It has
been suggested that fibrin may bind to lipoproteins in
the vascular wall, enhancing lipid accumulation in
fibrous plaques and leading to plaque growth [
Fibrinogen is thought to be a ?downstream? marker of
the inflammatory process governed by more proximal
mediators (such as interleukin-6), reflecting observed
spikes in circulating levels of fibrinogen during periods
of inflammatory stress [
Several prospective epidemiological studies have
assessed the association of circulating fibrinogen
concentration with CHD risk, but have yielded apparently
conflicting results. In the absence of individual studies of
very large size, appropriate synthesis of the available
data by meta-analysis should provide a better indication
of the relevance of risk markers to CHD than can
individual studies typically involving just a few hundred
cases. This is because meta-analyses are less likely to
be subject to random error than single studies, which
due to their inherent statistical uncertainties may
produce false-positive and false-negative results [
Fibrinogen Studies Collaboration (FSC) is an
individual participant meta-analysis of data from 154,211
participants in 31 prospective studies, including 6944
firstever non-fatal myocardial infarctions or stroke events
and 13,210 deaths recorded during 1.38 million
personyears of follow-up (Table 1) [
]. This collaborative
re-analysis of available prospective evidence on
fibrinogen and cardiovascular disease risk demonstrated
that about 7% of the variation in fibrinogen levels is
explained by conventional vascular risk factors (notably,
positive associations with smoking and body mass
index and an inverse association with HDL-C) and a
further 10% is explained by other inflammatory
]. There were approximately log-linear
relationships of circulating fibrinogen levels with risk of
several vascular and non-vascular diseases including CHD,
stroke, other vascular mortality and cancer mortality,
with no evidence of a threshold within the range of
usual fibrinogen level at any age [
]. The risk ratio for
CHD per 1 g/L increase in long-term ?average?
fibrinogen concentration was 1.8 (1.6?2.1) after adjustment
for several conventional vascular risk factors and
correction for measurement error (Fig. 1), and did not vary
materially according to sex, smoking status, level of
blood pressure or blood lipids, or laboratory and study
Observational studies are limited in their ability to
help judge causality, particularly as they are
susceptible to bias by reverse association and by
] (although such distortion of associations can be
minimised, but not eliminated, by prospectively
studying initially disease-free individuals and by
appropriately adjusting risk estimates for potential known
confounders). Comparison of disease rates in groups of
individuals between whom the only difference is the
exposure of interest, with random distribution of all
other factors across the groups, should be free of such
residual confounding and provide a more reliable
assessment of the causal relevance of the exposure.
Several interventions that lower lipid levels also influence
levels of inflammatory markers. Of these, the two most
studied in relation to both their impact on circulating
inflammatory markers and rates of CHD are statin and
fibrate medications. Since both these medications are
associated with substantial changes in several
markers (particularly lipids), they cannot specifically assess
the causal relevance of any inflammatory marker to
]. In the absence of large-scale randomised
controlled trials of suitable interventions that show
specific and important changes in inflammatory markers,
the study of genetic variants can provide an alternative
approach to assess the causal relevance of such markers
to disease risk [
]. Since the presence of particular
genetic variants is effectively allocated randomly at
conception, this should render associations of such variants
with levels of risk markers or with coronary disease risk
unaffected by subsequent development of disease (i.e.
avoidance of ?reverse association? bias) and, by
analogy with randomized controlled trials, minimize the
influence of potential confounders [
]. Identification of
genetic variants that are associated with important and
specific changes in circulating levels of inflammatory
markers would, therefore, provide an opportunity to
conduct such ?Mendelian randomisation? experiments
to assess the causal relevance of inflammatory
markers to CHD. Several genetic determinants of fibrinogen
have been identified [
], including a single nucleotide
polymorphism at position ?148 in the beta-fibrinogen
gene promoter (beta ?148C/T). A meta-analysis of 20
studies of beta-fibrinogen genotypes involving a total
of 12,220 coronary disease cases and 18,716 controls
was reported in 2006 [
]. This investigation
demonstrated that for each T allele inherited, carriers of beta
?148C/T had 0.14 g/l higher mean fibrinogen
concentration, with little evidence of any important change
in levels of several conventional vascular risk factors.
Using data from the FSC, a 0.14 g/l higher usual
plasma fibrinogen concentration would be expected to be
associated with a risk ratio for MI of 1.17 (95% CI
1.14?1.19). The observed combined odds ratio for MI
per T allele of the beta -148C/T polymorphism,
however, was 1.00 (95% CI 0.95?1.04) [
finding that genotypes that produce (presumably) lifelong
and specific differences in fibrinogen concentration are
not materially associated with CHD risk, together with
the non-specific associations of fibrinogen levels with
risk of several chronic vascular and non-vascular
], suggest that fibrinogen is unlikely to be
causal in coronary disease.
Although many published prospective studies have
commented on the potential value of particular markers
in risk prediction, they have often reported on measures
of strength of association only (e.g., odds ratios, hazard
ratios), which do not directly address the accuracy of
a marker in risk prediction or stratification. Instead,
such accuracy is commonly assessed by two
independent criteria, discrimination and calibration.
Discrimination is the ability to separate individuals at higher
risk from those at lower risk, while calibration is the
ability to correctly estimate the risk or probability of a
future event [
]. Each of these approaches may
impart somewhat different information. To date,
prospective studies that have used such methods to assess the
potential improvement in vascular risk prediction upon
measurement of fibrinogen levels in addition to
conventional vascular risk factors have yielded conflicting
]. Relevant investigations in the FSC
should help provide a more robust assessment about
whether measurement of circulating fibrinogen
concentration can help better identify individuals at increased
risk of CHD than measurement of conventional risk
3. C-reactive protein (CRP)
CRP, a nonglycosylated 224-residue plasma protein,
is probably the most studied circulating marker of
inflammation. Produced by hepatocytes, CRP
synthesis is closely regulated by upstream pro-inflammatory
cytokines (such as interleukin-6) and resultantly
massive spikes in circulating CRP levels are observed in
response to inflammatory stimuli [
]. Whereas older
less sensitive assays were only able to identify such
acute phase responses of CRP (during which levels of
CRP can rise up to several-thousand fold), more
recent ?high sensitivity? immunoassay methods have
enabled measurement of circulating ?baseline? levels and
assessment of chronic low-grade inflammation [
The first population-based prospective study of
circulating CRP concentration and incident CHD risk,
reported in 1996, was a nested case-control comparison
of 246 CHD cases and 491 controls within The Multiple
Risk Factor Intervention Trial [
]. Since this study,
more than 40 such studies of CRP and CHD risk have
been reported. A literature-based meta-analysis of 22
prospective epidemiological studies published by 2004,
involving a total of 7068 incident CHD cases, reported
a combined risk ratio for CHD of 1.6 (1.5?1.7) in a
comparison of individuals in the top third with those
in the bottom third of the baseline distribution of CRP
concentration in the population [
] (Fig. 1). It remains
unclear, however, whether associations of CRP levels
with incident CHD risk are ?independent? from
conventional vascular risk factors and other inflammatory
markers, specific to CHD (or vascular disease), or
importantly modified under different circumstances (such
as by age, sex, smoking status or different levels of
conventional vascular risk factors). The Emerging Risk
Factors Collaboration (ERFC) is an individual
participant meta-analysis of data from 110 prospective
cohorts which builds on the FSC [
]. It has established a
central database in which individual data records from
over 1.1 million participants have been harmonised to a
consistent format, including from large subsets of
participants with information on inflammatory (including
CRP) and other emerging risk markers, lipids and
other conventional risk factors and characteristics, as well
as major cardiovascular morbidity and cause-specific
mortality (Table 1) [
]. Information on repeat
measurements on relevant characteristics has been
collected in approximately 320,000 participants to enable
estimation of and adjustment for within-person variability
in measured values. This collaborative initiative should
enable more precise and detailed characterisation than
has previously been possible of the shape and strength
of the age- and sex-specific associations of circulating
CRP levels with incident CHD outcomes under a wide
range of circumstances [
Several genetic variants in the CRP gene that control
CRP concentration have been identified [
metaanalysis of studies of the +1444C>T polymorphism
in the CRP gene assessed the association of this
variant with circulating CRP concentration and CHD in a
total of 18,637 participants, including 4610 CHD
]. This meta-analysis reported that the combined
geometric mean CRP was 1.14 (1.11?1.18) higher per
each T allele inherited, with negligible difference in
levels of several conventional vascular risk factors [
The association of the same variant with CHD risk was
0.96 (0.90?1.03) per T allele [
]. A separate study
assessed associations of 4 different variants in the CRP
gene (1081G>A, 223C>T, ?390C>T>A, 3678T>G)
in a total of over 50,000 participants (including 6545
with CHD) [
]. A combination of these 4 variants
was associated with a 64% increase in circulating CRP
concentration and, based on the observed association
of CRP levels with CHD risk, was predicted to be
associated with a 32% increase in CHD risk [
]. The same
genetic combination, however, was not significantly
associated with CHD [
]. These findings from studies of
CRP genotypes do not support a causal association of
CRP in CHD. However, as any associations of common
genetic variants with disease risk are likely to be
modest, genetic studies require information from upward of
15,000 patients with coronary disease to reliably
evaluate the likelihood and magnitude of any causal
association between CRP and CHD risk [
]. The CRP CHD
Genetics Collaboration (CCGC) has established a
central database containing individual data on CRP
polymorphisms, circulating CRP levels and major coronary
outcomes as well as several other relevant
] (Table 1). This collaboration comprises a total
of over 37,000 CHD outcomes and over 120,000
controls in 35 studies and should help clarify whether CRP
is involved in the pathogenesis of CHD [
]. Study of
interventions that specifically modify circulating CRP
levels may help directly assess whether CRP is likely
to be causal in CHD. Although such interventions are
in development, these interventions currently focus on
whether anti-CRP agents may have a role in minimising
tissue damage subsequent to an MI (rather than help
prevent development of CHD) [
Several prospective studies have reported on the
potential utility of CRP measurements for CHD risk
prediction. A recent review assessed the predictive
performance of CRP in two prospective cohort studies
(involving a total of 309 CHD outcomes) and reported a
systematic review of relevant data from 31 published
prospective studies (involving a total of 11,252 CHD
]. This review concluded that although
raised circulating CRP levels are consistently
associated with increased CHD risk, measurement of CRP
levels provides little improvement in CHD risk
prediction when assessed using several metrics of predictive
]. Despite such reservations stemming from
findings from observational studies, there has been
substantial interest in whether measurement of CRP
levels should be used for risk stratification and
prioritization of preventative treatment in individuals who,
according to current clinical guidelines, would otherwise
be ineligible for such treatment [
Justification for the Use of Statins in Prevention: an
Intervention Trial Evaluating Rosuvasatin (JUPITER) trial
randomly assigned 17,802 men and women with LDL-C
levels < 3.4 mmol/L (ie, below thresholds for
treatment according to current clinical guidelines) and
highsensitivity CRP levels 2.0 mmol/L to receive 20 mg
rosuvastatin or placebo [
]. The trial was stopped
after a median follow-up of 1.9 years, with an observed
reduction in LDL-C and CRP of 50% and 37%,
respectively, in people receiving rosuvastatin. The hazard
ratio for MI in this trial was 0.46 (0.30?0.70) in
people receiving rosuvastatin compared to people
receiving placebo [
]. A separate report from the JUPITER
trial reported that compared to participants receiving
placebo, the hazard ratio for a combination of any of
non-fatal MI, non-fatal stroke, unstable angina,
revascularization or cardiovascular death in participants
allocated to receive rosuvastatin was: 0.45 (0.34?0.60)
in people who achieved LDL-C < 1.8 mmol/L; 0.38
(0.26?0.56) in people who achieved CRP < 2 mg/L;
and 0.35 (0.23?0.54) in people who achieved LDL-C
< 1.8 mmol/L and CRP < 2 mg/L [
acknowledged in this report, however, such assessments are no
longer randomized and, therefore, potentially
susceptible to distortion by confounding [
]. Assessment of
the relevance of CRP levels in other long-term trials of
statin medications are ongoing [
4. Lipoprotein-associated phospholipase A2
Originally named platelet-activating factor
acetylhydrolase after its ability to catalyse the hydrolysis
of platelet-activating factor in vitro, Lp-PLA 2 appears
to link arterial retention and oxidative modification of
LDL in the coronary artery wall with localised
inflammation and subsequent plaque destabilization [
Expressed by hematopoietic cells, around 70?80% of
LpPLA2 is carried on LDL [
]. By virtue of this
association, Lp-PLA2 is carried into the arterial wall where it
can hydrolyze the sn-2 fatty acids in the phospholipids
of LDL as they become truncated by oxidation [
For example, Lp-PLA2 mediates the oxidative
modification of phosphatidylcholine (a common phospholipid
in LDL) and its subsequent hydrolysis to
lysophosphatidylcholine and oxidized free fatty acids. These
products elicit several potentially proinflammatory and
proatherogenic effects [
]. In turn, inflammatory cells
attracted to the arterial wall by the products of Lp-PLA 2
activity express further Lp-PLA2, potentially creating
a positive feedback loop [
]. On the other hand,
LpPLA2 has also been proposed to play a protective role
against atherosclerosis, based on the observation that
its substrates (rather than the products it generates)
can show proinflammatory and proatherogenic
Despite ongoing debate over the role of Lp-PLA 2
in atherosclerosis, several prospective epidemiological
studies have reported generally positive associations
between circulating levels of Lp-PLA2 and subsequent
risk of cardiovascular disease. A literature-based
metaanalysis of 14 observational studies reported a relative
risk of 1.5 (1.3?1.8) for Lp-PLA 2 and cardiovascular
disease risk [
] (Fig. 1). The validity of that
metaanalysis was limited, however, because it combined
information from prospective and retrospective studies
(increasing the potential for selection and reverse
association biases); considered heterogeneous populations,
disease outcomes and Lp-PLA2 exposures (potentially
conflating any divergent associations); and did not
standardize reported risk estimates to a consistent
]. The relevance of Lp-PLA 2 to CHD risk
remains uncertain. In particular, the magnitude and shape
of any dose-response relationships, the extent of any
coronary or vascular specificity, and the degree of
independence from conventional cardiovascular risk
factors (particularly the lipoproteins on which Lp-PLA 2
is carried) have yet to be characterized in detail. The
Lp-PLA2 Studies Collaboration (LSC) is a consortium
of investigators of prospective studies of Lp-PLA 2 and
cardiovascular disease [
] (Table 1). The LSC will
include data from 32 prospective studies involving a total
of approximately 15 000 patients with major
cardiovascular disease outcomes and should help to determine
more reliably than previously possible the strength and
shape of any independent association, the magnitude of
associations in different circumstances, and sources of
heterogeneity between studies [
Family studies have suggested that around half of the
variation in Lp-PLA2 activity may be heritable [
and several common variants in the Lp-PLA 2 gene
(PLA2G7 on chromosome 6) have now been
identified. One such variant, V279F is found almost
exclusively in East Asian populations and results in
LpPLA2 activity being significantly reduced in
heterozygotes and almost undetectable in individuals
homozygous for the T allele [
]. In contrast to V279F which
has only been reported in East Asian populations,
other common PLA2G7 variants have been found in all
] and Mendelian randomization
experiments (such as those described above) involving study
of these variants may provide a framework to help judge
whether Lp-PLA2 is causal in CHD.
Because circulating Lp-PLA2 levels have generally
been positively associated with cardiovascular diseases
in published prospective studies, a consensus panel
recently recommended the incorporation of Lp-PLA 2
mass measurement into risk assessment guidelines for
individuals at ?intermediate? risk of CHD . As
noted above, however, assessments of the magnitude and
independence of associations with disease outcomes do
not directly address the potential utility of a risk marker
in classifying or predicting disease risk. The few
previous studies to have directly assessed the predictive
ability of Lp-PLA2 in vascular disease have reported
generally modest improvements in risk prediction on
addition of Lp-PLA2 to conventional risk factors [51?55].
Interpretation of these findings has been complicated,
however, by the fact that these relatively few studies
have used different population settings and endpoints;
have added Lp-PLA2 to risk prediction models that
include different sets of conventional cardiovascular risk
factors; have typically involved fewer than 10 years of
follow-up; and have generally used the area under the
receiver-operator characteristic curve (AUROC) to
assess discrimination, a technique that is only appropriate
for binary data and does not consider time to event or
allow for censoring. Furthermore, these previous studies
did not evaluate the ability of Lp-PLA 2 measurements
to reclassify predicted CHD risk; analyses that may
be more clinically informative than discrimination per
se. Future prospective studies with long-term
followup in large numbers of initially healthy participants are
therefore needed to help clarify the value of Lp-PLA 2
measurements to cardiovascular risk prediction.
A number of studies have shown that medications
that lower lipid levels and reduce CHD risk also lower
Lp-PLA2. For example, statins lower Lp-PLA2 activity
by around 20?40% . However, because statins do
not limit secretion of Lp-PLA2 from macrophages, the
observed reductions in Lp-PLA2 activity are thought
to result from drug-induced enhanced clearance of
LDL . By contrast, darapladib (SB480848;
GlaxoSmithKline), a reversible substrate-competitive
pyrimidone, reduces Lp-PLA2 activity by around two thirds
(with more modest effects on Lp-PLA 2 mass) . In
late 2008 the STABILITY (Stabilisation of
Atherosclerotic plaque By Initiation of darapLadib TherapY)
trial was initiated . This randomised,
placebocontrolled trial will assess the impact of long-term
treatment with darapladib compared to placebo on the
composite endpoint of major cardiovascular events
(including cardiovascular death, nonfatal MI and nonfatal
stroke) in over 15,000 CHD patients receiving standard
care , and help elucidate the importance of
LpPLA2 inhibition therapy to the secondary prevention of
5. Interleukin-6 (IL-6)
IL-6, a pleiotropic 184-amino acid monomer, is
secreted by T cells, macrophages and endothelial cells
and propogates inflammatory cascades in response to
inflammatory stimuli [
]. IL-6 can either
accelerate or inhibit the inflammatory process. Part of the
role of IL-6 in the acute phase response is to
upregulate several downstream markers, including CRP [
]. IL-6 levels are also elevated in response to
muscle contraction, produced by smooth muscle cells in
blood vessels and may have a role in lipid catabolism
and insulin resistance [
]. Excess circulating IL-6
concentration has been linked to several autoimmune
disorders, especially rheumatoid arthiritis [
Although less studied than its down-stream acute
phase reactants such as fibrinogen and CRP, several
prospective studies have reported associations of
circulating IL-6 concentration with CHD risk. A
literaturebased meta-analysis of 17 prospective epidemiological
studies published by 2008, involving a total of 5730
CHD cases recorded during follow-up, reported a
combined risk ratio for CHD of 1.6 (1.4?1.8) per 2-SD
increase in baseline IL-6 measurements [
However, owing to the short half-life and substantial
withinindividual fluctuations in circulating IL-6 levels, failure
to make allowance for such within-individual variation
may substantially underestimate the magnitude of any
association of IL-6 concentration with CHD risk.
After correction for within-individual variability of IL-6,
the combined risk ratio for CHD in this meta-analysis
was 3.3 (2.5?4.6) per 2-SD increase in IL-6 levels [
(Fig. 1); potentially comparable to the strength of
observed associations of some conventional vascular risk
factors with CHD risk. Further studies of IL-6
concentration and CHD risk are warranted, therefore, to
confirm such associations and to assess whether
measurement of IL-6 levels can usefully contribute to CHD
risk prediction algorithms. Studies of genetic variants
in the IL-6 gene have predominantly focused on the
?174G>C promoter variant, but this variant does not
appear to be materially associated with circulating
IL6 concentration [
] (so is unlikely to provide any
causal inference about the relevance of IL-6 levels to
CHD). Several IL-6 receptor antagonists are under
development and are being trialed for the treatment of
rheumatoid arthritis [
]. Such trials may help
indicate whether anti-IL-6 therapy may also be a potential
therapeutic target for CHD prevention.
6. Other markers of inflammation
Several other markers of inflammation have also
been assessed in relation to CHD, including
], leukocyte count [
] (both of which are
being assessed in the ERFC), CD40 ligand [
necrosis factor alpha [
], IL-1 [
] and IL-18 [
]. Ongoing studies of
these and other related markers of inflammation should
help progress understanding of the potential relevance
of such markers to CHD.
Although it is generally accepted that inflammation
is importantly involved in the development of CHD,
it remains unclear whether circulating markers of
inflammation are causal or whether their measurement
can help improve CHD risk prediction. Ongoing
largescale epidemiological and genetic studies should help
to resolve such outstanding uncertainties.
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