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4 Current Pharmaceutical Biotechnology, 2012, 13, 4-16
1389-2010/12 $58.00+.00 2012 Bentham Science Publishers

Role of C-Reactive Protein in Acute Myocardial Infarction and Stroke:
Possible Therapeutic Approaches
Paolo Calabr
1,*
, Enrica Golia
1
and Edward T.H. Yeh
2

1
Division of Cardiology, Department of Cardiothoracic Sciences, Second University of Naples, Monaldi Hospital,
Naples, Italy;
2
Texas Heart Institute/St. Luke Episcopal Hospital and Department of Cardiology, the University of Texas
MD Anderson Cancer Center, Houston, Texas
Abstract: Myocardial infarction (MI) and stroke are relevant clinical issues in Western Countries for morbidity and mor-
tality. In the last decades, great interest has been paid to the identification of non-traditional risk factors for a better strati-
fication of patients and to recognize those at higher risk, who might particularly benefit from a more aggressive approach.
In this field, C-reactive protein (CRP) is the most extensively studied novel marker, since it seems related to several stages
of atherogenesis, from its beginning to clinical events (i.e. acute coronary syndromes - ACS). Among its possible patho-
genetic role both in coronary artery disease (CAD) and ischemic stroke, several studies have shown that CRP could be
used to predict first ever MI and stroke in healthy subjects, as well as outcome in acute settings. Moreover, a decrease of
CRP levels can be achieved by several therapies, first of all statins, and this seems to be associated with a better outcome.
Then a possible role for CRP to guide treatment of patient with ACS and stroke has been claimed and need to be specifi-
cally addressed by large randomized controlled trials.
Keywords: Vascular inflammation, CRP, cardiovascular diseases, cerebrovascular diseases.
INTRODUCTION
MI and stroke are important health issues in Western
Countries. Scientific community in the last decades has been
showing a growing interest in the early identification of sub-
jects at increased risk. Moreover, after the publication of the
J UPITER trial [1], the need to investigate the potential utility
of nontraditional markers to target therapeutic interventions
has re-emerged, since this could improve our capacity to
improve treatment results, identifying those most likely to
benefit.
Since 20% of patients, especially among women, experi-
ences cardiovascular events in the absence of an established
risk factor and, conversely, a high proportion of patients with
major risk factors do not develop cardiovascular disease
(CVD) [2], a better risk stratification could include non-
traditional risk factor assessment.
Great attention has been paid to the inflammatory re-
sponse as a determinant of the atherothrombotic disease de-
velopment, progression and complication [3].
Inflammatory markers have been studied as nontradi-
tional risk and prognostic factor. Among them, CRP, a proto-
type marker of the inflammatory process, is the most studied
both as a causal factor and in the prediction of CVDs and,
although less extensively, of cerebrovascular disease [4].

*Address correspondence to this author at the Division of Cardiology,
Department of Cardiothoracic Sciences, Second University of Naples, Mon-
aldi Hospital, Via L. Bianchi 80131 - Naples, Italy; Tel: +39-081-7062815;
Fax: +39-081-7064234; E-mail: paolo.calabro@unina2.it
Inflammation and C-Reactive Protein: Possible Causal
Role
CRP, a member of the pentraxin family, was one of the
first acute phase proteins identified. It plays a key role in
innate immune response and constitutes a stable plasma
marker of systemic inflammation. CRP is a highly conserved
plasma protein, with a half life of 19 h. During the acute
phase response, its levels may rapidly rise up to 1,000-fold
above the reference values.
The main source of plasma CRP is liver, under the regu-
lation of several cytokines, mainly interleukin (IL)-6, IL-1,
and tumor necrosis factor (TNF)-alpha [4]. Recently, other
sites of production has been reported, such as respiratory
tract epithelium and macrophages, kidney, neuronal cells.
More recently, cells in the vascular wall have been exten-
sively studied to demonstrate their ability to produce CRP.
We demonstrated that human coronary artery smooth muscle
cells but not human umbilical vein endothelial cells (HU-
VEC) synthesize CRP in response to several inflammatory
stimuli, such as IL-1, IL-6, and TNF-alpha. Also, CRP
mRNA levels increased compared to baseline and in a simi-
lar model, Venugopal and colleagues showed an upregula-
tion of CRP mRNA and protein in human aortic endothelial
cells (HAECs) after stimulation with macrophage condi-
tioned medium, but not in HUVECs, confirming our previ-
ous report [5, 6]. Indeed, following a previous report of
Ouchi et al., we demonstrated that CRP can be produced by
human mature adipocytes, but not preadipocytes, under in-
flammatory stimuli, including lipopolysaccharide (LPS),
TNF-alpha, and resistin [7-9].
CRP appears to act as causal factors in each stage of
atherogenesis, from the initial leukocytes recruitment and
C-Reactive Protein in Myocardial Infarction and Stroke Current Pharmaceutical Biotechnology, 2012 Vol. 13, No. 1 5
endothelial dysfunction to clinical events, as summarized in
Fig. (1) [4].
CRP seems to contribute to endothelial dysfunction, one
of the first recognized phases of atherogenesis, blunting NO-
related vasorelaxation and decreasing expression and bioac-
tivity of nitric oxide synthase (NOS), as demonstrated in
both in in vitro models of human aortic and coronary artery
endothelial cells (ECs) [10, 11] and of vascular smooth mus-
cle cells (VSMCs) [12]. Mononuclear cell recruitment is
another important step of athergenesis and depends upon the
induction of endothelial expression of adhesion molecules.
We first demonstrated that CRP induces both in HUVECs
and human coronary artery endothelial cells (HCAECs) the
expression of ICAM, VCAM, E-selectin, and MCP-1,
moreover, in HAECs, CRP upregulates IL-8 mRNA and
protein, via NFkB activation [13, 14]. CRP is also implicated
in LDL opsonisation and their subsequent uptake by macro-
phages [15]. Then macrophages recruited to intima become
foam cells, via ox-LDL phagocytosis. These cells show a
positive staining for CRP, which is thought to be taken up
via macropynocitosis, in part as a consequence of the uptake
of CRP-opsonized LDL. Lipid deposition in the intima of the
vessel wall and subsequent oxidation are amplified by CRP
through the induction of ROS production by several cells in
the atherosclerotic lesion, including macrophages, and
VSMCs [16]. Subsequently, the atherosclerotic plaque shifts
from the fatty streak to a more fibrous lesion. Main actors
in this stage are VSMCs, which accumulate in the intima and
produce extracellular matrix (ECM). In this phase CRP af-
fects both proliferation and migration of these cells, which
lead to VSMCs accumulation in the intima of the vessel [12].
Another biological function of CRP, during innate im-
mune response, is the regulation of complement activation,
which seems to be related to CVD, since complement factors
and CRP co-localize within atheroma [4]. In particular CRP
binds to C1q, initiating the complement cascade, which is
implicated in opsonisation, leukocytes recruitment and apop-
tosis [4]. Moreover, CRP and complement are found in in-
farcted human myocardial tissue. The binding of CRP to
phosphocholine groups in damaged cell membranes, leding
to complement activation, may cause further tissue damage
[17, 18]. In particular, Pepys et al. developed a small mole-
cule, 1,6-bis(phosphocholine)-hexane (abbreviated Bis(PC)-
H), that binds CRP and prevents interactions between CRP
and its various ligands, such as complement factors. They
used this molecule to demonstrate a pathogenetic role of
human CRP in myocardial infarction injury. Infarction was
induced by surgical occlusion of the left coronary artery in
rats. The average size of the infarct among rats in the control
group was 17.0 percent of the size of the left ventricle. A
second group received human CRP after surgery. The aver-
age size of the infarct in this group was 24.8 percent of the
size of the left ventricle, reflecting additional damage result-
ing from human CRP administration. A third group was pre-
treated with human CRP, but it also received Bis(PC)-H
starting two days before surgery and continuing for five days
after surgery. The average size of the infarct was not signifi-
cantly different from that in the control group. Authors con-
cluded that Bis(PC)-H almost completely abrogated the in-
crease in infarct size that resulted from human CRP. [19].
CRP also indirectly affects specific immune response,
during atherogenesis, through the increase of IL-12 produc-

Fig. (1). This cartoon synthesizes CRP functions in the atherogenetic process, from the fatty streak formation to plaque complication with
rupture and intravascular thrombosis.
6 Current Pharmaceutical Biotechnology, 2012, Vol. 13, No. 1 Calabr et al.
tion from macrophages, with the subsequent induction of
CD4+T lymphocytes differentiation and Interferon gamma
(INF-gamma) production [20]. Moreover, another mecha-
nism by which CRP modulates inflammation is influencing
the CD40/CD40-ligand (CD40L) interaction by up regulat-
ing their expression on human umbilical vein endothelial
cells [21]. Indeed, elevated levels of CD40L are detected in
ACS patients and identify patients at increased risk [22].
Once atherosclerotic plaque has developed, its destabili-
zation and rupture is thought to be an important determinant
of acute vascular events, such as ACS and acute ischemic
stroke. CRP plays a role also in this stage of the atheroscle-
rotic process. In particular, CRP up regulates metalloprote-
ases synthesis in both endothelial cells and macrophages.
These proteins have a main role in the ECM degradation,
which leads to plaque instability and rupture [23, 24]. CRP
also promotes VSMCs apoptosis, which is another critical
step in atherosclerosis progression to instability.
In another important phase, activation of the coagulation
cascade leads to intravascular thrombus formation and de-
velopment of acute clinical events. Tissue factor (TF) plays a
pivotal role in triggering the formation of intravascular
thrombi following endothelial injury. In this respect, we have
recently demonstrated that CRP induces the expression of
TF, via Nuclear Factor kappa B (NFkB) activation both in
ECs and VSMCs [25]. A previous paper, already demon-
strated the CRP-induced TF upregulation in mononuclear
cells [26]. Interestingly, CRP also impairs fibrinolytic proc-
ess, since it upregulates plasminogen activator inhibitor-1
(PAI-1) and inhibits tissue plasminogen activator (tPA) in
human aortic ECs [27].
During the course of brain ischemia, inflammatory
mechanisms are important mediators of focal injury. Apart
from its role in atherosclerosis, which can be translated to
carotid macroangiopathy, CRP seems to have a direct patho-
genic role in brain ischemia Fig. (2). In particular it was
demonstrated, in a co-culture model of blood brain barrier,
that clinically relevant CRP concentrations cause an oxida-
tive stress which disrupts the barrier [28]. Moreover, beside
the neuronal damage resulting from proinflammatory loops
which realizes during the response of the tissue to acute in-
jury, CRP shows a direct neurotoxic effect in vitro [29].
However, concerns have emerged about the direct patho-
physiological role of CRP, in particular for the presence of
contaminants in the commercial preparations of human re-
combinant CRP used in experimental models and the exis-
tence of two CRP isoforms (i.e. monomeric and pentameric),
as discussed elsewhere [4]. Moreover a recent paper from
Zacho et al. questioned this association showing that genetic
polymorphism associated with elevated CRP levels were not
related to increased cardiovascular risk [30]. Then it is still
controversial whether elevated CRP levels are an epiphe-
nomenon or a determinant of the atherosclerotic disease.
CRP and Cardiovascular Event
It has been noted that CRP is one of the most suitable
candidates as non-traditional risk factor. It is a highly stable
analyte, with no diurnal variation and there is no significant
difference in the distribution curve between men and women.
Moreover, serum levels are independent from age and eth-
nicity [31]. Then, in addition to in vitro and in vivo studies, a
large number of studies on the utility of CRP as a clinical
marker for CVD have been performed (Table 1).
Accurate and high-sensitivity CRP (hs-CRP) assays to
detect its plasmatic concentration have become available in
the last 10 years with a relative low cost, contributing along
with the CRP biological profile to the interest in this mole-
cules biology. In particular, commercially available hs-CRP
assays with a detection limit down to 0.3 mg/L are the only
validated assays for risk stratification [32].

Fig. (2). Proposed role of CRP in stroke. Beside its role in carotid macroangiopathy, CRP seems to have also a direct pathogenetic role in
brain ischemia. Clinically relevant CRP concentrations cause an oxidative stress which disrupt the barrier. It is involved in the unfavourable
loops of the inflammatory response, which produce tissue damage. Moreover CRP shows a direct neurotoxic effect in vitro.
Table 1. hs-CRP in the Prediction of the First Ever CV Event
Study Population Main Findings
Physicians health study 543 Apparently Healthy (AH) men Higher hs-CRP levels predicted Stroke and MI Ridker et al. 1997
Womens health study 28263 AH postmenopausal women
hs-CRP levels are associated with higher risk
of CV events also when LDL<130 mg/dl
Ridker et al. 2000
Monica study 936 AH men (45-64 years old) hs-CRP levels predicted firt ever ACS Koenig et al. 1999
Aric study 12819 AH men and women
hs-CRP predicted CAD even with LDL<130
mg/dl
Ballantyne et al. 2004
Reykjavik study
2459 patients from the Reykjavik cohort of
AH men and women who suffered non fatal
MI vs 3969 control subjects
hs-CRP predicted CV events Danesh et al. 2005
Cardiovascular health study 3971 healthy men and women aged over 64
Higher hs-CRP levels were associated with of
CV risk
Cushman et al. 2005
Nurses health study and
health professionals follow-
up study
32,826 women and 18225 men from the study
cohort of middle aged AH subjects
Higher hs-CRP levels were associated with of
CV risk
Pai et al. 2004
8 year follow up of AH
American women
hs-CRP and LDL evaluated in 27939 AH
women followed for the occurrence of CV
events
hs-CRP is stronger than the LDL in the predic-
tion of CV events and adds information to
Framingham risk score
Ridker et al. 2002
8 year follow up of AH
American women
14719 AH women, 24% with metabolic syn-
drome at the study entry
CRP identifies patients with metabolic syn-
drome at higher risk of CV events
Ridker et al. 2003
J upiter
17802 AH men and women with LDL<130
mg/dl and hs-CRP>2 mg/L treated with rosu-
vastatin vs placebo
Reduction of the primary endpoint of MI,
hospitalization for UA, arterial revasculariza-
tion, stroke and CV death in the treatment
group
Ridker et al. 2008

Along with experiences in CVD, several studies have
been conducted to evaluate the utility of hs-CRP in the pre-
diction of stroke (Table 2). However, it has to be noted that it
is not possible to transfer concept valid for CVD directly to
stroke. Although atherosclerosis represents a common sub-
strate for MI and some stroke subtypes, the risk factor profile
of these two entities clearly differ in some aspects: different
populations are affected (stroke patients are usually older)
and hypercholesterolemia is more important in CAD,
whereas hypertension is a stronger risk factor in stroke. Most
notably, atherosclerosis is the main but not the only causal
factor in stroke, which is often poorly phenotyped and while
in carotid disease several evidence exists on the causal role
of the inflammatory process, less evident and inconsistent
data are available for other types of stroke, such as lacunar
syndrome and cardioembolic stroke [33]. Among ischemic
stroke only 20% are related to large arteries disease, and
therefore only this group can be considered analogous to
CVD [34].
The utility of hs-CRP as a predictor of future cardiovas-
cular events was first described by Ridker et al. in 1997 [35].
In this study, baseline serum hs-CRP levels were higher
among apparently healthy men who developed MI or stroke
than among subjects who remained free of disease, inde-
pendent of other traditional risk factors, such as hyperlipi-
daemia. A three-fold increase in the risk of MI and 1-fold
increase in the risk of stroke were registered among patients
in the highest quintile of hs-CRP concentration. Similar re-
sults came from the Womens Health Study [36], the Athero-
sclerosis Risk in Communities (ARIC) Study [37], the
Nurses Health Study and Health Professionals Follow-Up
Studies [38], the MONItoring of Trends and Determinants in
CArdiovascular Disease (MONICA)-Augsberg cohort [39],
the Reykjavik Heart Study [40] and the Cardiovascular
Health Study [41]. In particular, hs-CRP resulted in a
stronger predictor of cardiovascular events than the LDL
cholesterol level, with additive prognostic information to that
provided by the Framingham risk score, even in patient with
metabolic syndrome [42]. However in 30-40% of patients
with myocardial infarction no hs-CRP elevation is noted.
Given the evidence of its prediction role, an important
step in incorporating hs-CRP into the risk stratification strat-
egy of CV diseases was made by The American Heart Asso-
ciation and the Center for Disease Control and Prevention
Consensus, with the publication in 2003 of a Report about
inflammatory markers as risk predictors in patients with
CVDs [43]. Reviewing available evidences in this field, it
has been recommended that the entire adult population
should not be screened for serum hs-CRP levels for the pur-
pose of CV risk assessment (class of recommendation III,
level of evidence - LoE C); however measurement of se-
rum hs-CRP, with a cut off of 3 mg/L, was considered rea-
sonable for assessing absolute risk for coronary disease in
intermediate-risk individuals. Indeed, in patients with the
Framingham score of 10% to 20% risk, the hs-CRP level
should help direct future evaluation and therapy in the pri-
mary prevention of CVD (class of recommendation IIa, LoE
B). However, the committee considered hs-CRP measure-
ments to be less useful in the absence of other risk factors
(class of recommendation IIb, LoE C) [43]. In patient with
known CAD, the workgroup recommended to use hs-CRP at
discretion of physician in global risk assessment, with a cut-
off value of <3 mg/L, as a marker of high risk (Class IIa,
LoE B) [43].
Moreover, Ridker et al. recently made an attempt to
evaluate non-traditional risk factors in prediction of cardio-
vascular events, including non fatal stroke, in a cohort of
24558 healthy US women [44]. Authors developed a risk
prediction algorithm that reclassified 40% to 50% of women
at intermediate risk into higher- or lower-risk categories. In
particular a simplified algorithm, including hs-CRP (the
Reynolds Risk Score), greatly improved accuracy comparing
to models based on ATP-III prediction scores. This score
significantly improves global cardiovascular risk prediction
even in men, as demonstrated later [45].
In the field of acute cardiovascular syndromes (i.e. ACS),
CRP has been consistently shown to be a prognostic marker
of adverse clinical cardiac events, such as death, acute MI,
and urgent revascularization. First Liuzzo et al. in the 1990s
[46] demonstrated that hs-CRP levels above 3 mg/L can pre-
dict clinical outcome of patients with unstable angina (UA),
with an approximately five fold increased risk of recurrent
events. More recent large studies have supported the finding
that high serum hs-CRP levels are predictors for short term
mortality in patients with ACS [47-49]. In particular a
GUSTO IV ACS trial sub-group analysis, in patients not
undergoing early invasive strategy, hs-CRP and Troponin T
were measured [48]. They were both independently related
to 30 day mortality and the combined strategy in risk stratifi-
cation was better than either marker alone. A similar predic-
tive synergy were noted in the Thrombolysis In Myocardial
Infarction (TIMI) 11A [49] and Fragmin during Instability in
Coronary artery disease (FRISC) trials [50] enrolling patients
with unstable angina or non-Q-wave MI. Moreover, Foussas
et al found that an elevated plasma hs-CRP level provides
additional prognostic information to the validated Throm-
bolysis In Myocardial Infarction (TIMI) risk score in patients
with ACS [51].
The utility of serial hs CRP measurements in ACS pa-
tients were evaluated in two recent studies. Nakachi et al
[52] found that patients with Non ST Elevated (NSTE) ACS
and both admission hs-CRP elevation and increase at 24 h
had higher rates of ST segment depression and positive tro-
ponin T at admission (cut-off of >3 mg/L). Interestingly, at
the multivariate analysis, an elevated hs-CRP on admission
and increase at 24 h were both independent predictors of 30-
Table 2. hs CRP in the Prediction of Stroke in Apparently Healthy Subjects
Study Population Main Findings
Physicians health study
543 cases of CVD and 543 control subjects
(healthy subjects at the enrollment)
Higher hs-CRP concentration predicted
incidence of Ischemic Stroke
Ridker et al. 1997
Womens health study
158 cases of ischemic stroke among a cohort of
healthy postmenopausal women
cerebrovascular events
Ridker et al. 2000
Health abc 936 AH men (45-64 years old) No association of hs-CRP levels with stroke Cesari et al. 2003
Nhanes iii
Cross sectional study of 8850 non-
institutionalised US individuals
Association of hs-CRP levels with self re-
ported stroke
Ford et al. 2000
Honolulu heart program
259 cases of ischaemic stroke and 1348 controls
from the Honolulu Heart program cohort
Association of hs-CRP levels with stroke Curb et al. 2003
Cardiovascular health study
5417 healthy men and women aged over 64
without stroke or atrial fibrillation
stroke
Cao et al. 2003
Framingham
1462 participants (mean age 69,7 years) without
stroke or TIA from the Framingham study
ischemic stroke
Rost et al. 2001
Leiden 85 p
Cross sectional study of 599 inhabitants of
Leiden, 85 yo at the enrollment
Association of hs-CRP levels with ischemic
stroke (WHO definition at baseline)
van Exel et al. 2002
Rotterdam study 6430 participants
CRP is associated with the risk of any stroke
and ischemic stroke
Bos et al. 2006
Prosper
260 new ischemic stroke in an elderly population
at risk of vascular events
Higher hs-CRP concentration were predic-
tive of incident stroke in univariate analyses,
but not after adjustment for conventional
risk factors
Sattar et al. 2007

d events (e.g. death, MI, or refractory angina). Bogaty et al
conducted a more recent large trial of 1210 patients [53]. hs-
CRP was measured in the acute setting, at discharge and one
month later in ACS patients. They found that hs-CRP has
only a modest predictive ability, which disappeared after
adjustment for common clinical variables. However, in this
study authors included the whole spectrum of ACS from
Braunwalds class IB unstable angina to ST-segment eleva-
tion MI and did not exclude patients with acute or chronic
inflammatory diseases. This could mask the ability of a sen-
sitive but nonspecific marker like hs-CRP and confound the
interpretation of the results from the study.
Since the risk of cerebrovascular events and stroke pa-
tients received less attention in the CDC/AHA 2003 docu-
ment, a statement in 2005 was published to address this topic
[54]. In this document it has been reported how several per-
spective studies demonstrated that a single hs-CRP meas-
urement is a predictor of cerebrovascular events in appar-
ently healthy subjects [35, 36, 55-55], in most cases inde-
pendently of age, smoking, blood pressure, diabetes and cho-
lesterol levels, thus providing relative risk estimation. The
Third National Health And Nutrition Examination Survey
(NAHNES III) and the Leiden 85-Plus Study are two cross-
sectional study in which was demonstrated an association
between the history of stroke and raised plasma concentra-
tion of hs-CRP [55-61]. Some perspective studies assessed
the incidence of cerebrovascular disease in healthy adults.
Authors in the Physicians Health Study [35], the
Framingham Study [56], the Cardiovascular Health study
[59] and the Honolulu Heart Program [57] followed large
cohorts of middle-aged healthy subjects; interestingly, they
all found higher rates of stroke in those patients with the
highest concentration of hs-CRP. In particular hs-CRP ap-
pear to have a stronger relation to the risk of stroke when
compared to total cholesterol levels and LDL concentration
[60]. The Health ABC study did not found a significant as-
sociation between hs-CRP and the incidence of stroke, but
the follow up period was relatively short (3,6 years)[61].
However, less data were reported about absolute risk of
cerebrovascular disease and predictive value and, moreover,
it was unclear if the same hs-CRP tertiles used for CVD
stratification could be used in cerebrovascular diseases, al-
though studies demonstrated a concentration dependent rela-
tionship between hs-CRP levels and risk of stroke. The more
recent Rotterdam Study of 6430 participants demonstrated
that high hs-CRP levels were significantly associated with
the risk of any stroke and ischemic stroke, although without
improving individual stroke risk prediction, in contrast with
results of the WHS [62]. Similar findings were reported from
the PROSPER study of elderly patients, in which hs-CRP
levels at the multivariate analysis failed to add predictive
information to traditional risk factors [63].
When this issue has been analysed in patients with
stroke, the authors reported controversial findings. Several
small studies reported that hs-CRP appear to be related to
infarct size and stroke severity, and then to mortality [64,
65]. Some authors reported an association with recurrent
cardiovascular events, independently of conventional prog-
nostic markers [66-76], such as age and stroke severity. Ap-
propriate cut-off was not clearly determined: however, in
most studies values of hs-CRP related to poor outcome were
>6-7 mg/L [66-76]. Interestingly, perspective studies sug-
gested that hs-CRP is an important predictor of outcome
after stroke in a dose dependent manner and that the risk
persisted even after adjustment for traditional risk markers.
Potential pitfalls in CRP measurements, especially in the
acute setting of stroke, are represented by the common coex-
istence of infections (often unrecognized) and other inflam-
matory triggers, such as deep venous thrombosis which were
not in the exclusion criteria in most studies. Another impor-
tant issue is the timing of hs-CRP sampling in the setting of
stroke. Plasma concentration of hs-CRP increases early after
stroke and remains high at 3 months after index event [66].
Most studies measure hs-CRP within 12 to 72 hours [69, 75-
77], but a re-evaluation at discharge and 1-3 months later
might be useful as better predictor of the mid and long-term
outcome and of the risk of recurrent events in patients with
persistently high concentrations, whereas peak measure-
ments (first week) are more related to infarct volume and
clinical outcome [54, 65, 77].
Di Napoli et al., in the 2005 statement concluded that
patients should be stratified primarily by the evaluation of
traditional risk factors, which should suffice in most cases to
determine risk and guide appropriate measures to optimizing
primary and secondary prevention (Class I LoE A) [54]. Ele-
vated hs-CRP was recognized as an independent marker of
ischemic stroke risk (Class IIa LoE B) and an independent
predictor of recurrent vascular events after stroke, but there
is insufficient evidence to justify a routine use of its meas-
urement in cerebrovascular disease (Class IIb LoE B) [54].
A recent metanalysis published in Lancet [78], raised
concern about the independent association between CVD and
stroke with CRP. This is an individual participant analysis
that is an individual record analysis of 160309 people with-
out a history of vascular disease from 54 long-term prospec-
tive studies. Authors found that Log CRP concentration was
linearly associated with several conventional risk factors and
inflammatory markers, and nearly log-linearly with the risk
of ischemic vascular disease and non-vascular mortality.
CRP concentration showed continuous associations with the
risk of coronary heart disease, ischemic stroke, vascular mor-
tality; however these associations seem to depend considera-
bly on conventional risk factors and other markers of in-
flammation.
Inflammation as a Therapeutic Target
If inflammation is implicated in causing and exacerbating
CAD and stroke, limiting inflammatory response has been
claimed to be a possible therapeutic target.
For MI and stroke inflammation might be relevant for its
relation to the underlying vascular disease and as a precipi-
tating factor in the acute setting; once the tissue damage has
developed, inflammation represents an obvious response to
the injury. However it starts unfavourable loops which exac-
erbate the injury itself; away from the acute event, as previ-
ously noted, a chronic inflammatory activation could repre-
sent a marker of the risk of recurrent events. Any of these
points justify the need to investigate inflammatory markers,
and specifically hs-CRP, as a target of therapy.
The use of hs-CRP to improve patient selection for car-
diovascular therapies is best shown with regard to statins.
Originally developed solely as a drug to lower LDL choles-
terol (LDL-C), statin agents possess additional anti-
inflammatory properties [79]. These drugs may be directly
immunomodulatory, inhibiting expression of cell adhesion
molecules, inducing thrombomodulin and tissue plasmino-
gen activator and thus favourably altering haemostatic bal-
ance; furthermore, they have direct beneficial effects on
platelet activation and smooth muscle proliferation [79]. Ini-
tial observations from the CARE (Cholesterol and Recurrent
Events) trial showed clinically that statins lower CRP levels
[80]; this study involved 4159 patients with a history of a
myocardial infarction in the previous two years and showed
a significant reduction of endopoints of coronary death and
nonfatal MI, need for revascularization and stroke in the
treatment arm. The benefit of pravastatin seemed greater
among individuals with higher levels of the inflammatory
biomarkers hs-CRP or serum amyloid A protein. Similar
findings were reported in the MIRACL study of atorvastatin
in high risk ACS patients and, indeed, a recent sub-group
analysis showed that treatment with atorvastatin decreases
the early risk of stroke in ACS patients related to elevated
markers of inflammation [81]. One hypothesis which could
explain this beneficial effect of statins is that decreased CRP
levels may reflect coronary plaque stabilization, achieved by
statin therapy.
Data regarding apparently healthy patients, consistent
with the ones from the CARE trial, first came from the AF-
CAPS-TexCAPS (Air Force Coronary Atherosclerosis Pre-
vention StudyTexas Coronary Atherosclerosis Prevention
Study) primary prevention trial. This study showed that Lo-
vastatin reduced CRP levels by almost 15 percent, independ-
ently of its effect on lipid levels. Furthermore, it suggested
that individuals with low levels of LDL-C and concomitant
elevations of hs-CRP might benefit substantially from statin
treatment, in terms of reduction of MI incidence and need for
revascularization [82]. By contrast, the AFCAPS-TexCAPS
trial found no evidence of statin efficacy among individuals
with low levels of both LDL-C and hs-CRP. These analyses
led to the initiation of the recently published J UPITER, de-
scribed below [1].
Among trials showing a potential benefit targeting in-
flammation with therapies, the PROVE-IT (Pravastatin or
Atorvastatin Evaluation and Infection Therapy) TIMI 22 [83]
is one of the most important. This trial included patients
hospitalized for MI or high-risk unstable angina within the
preceding 10 days, all with cholesterol levels above 240
mg/dl. More than 4,160 patients were enrolled and were ran-
domly assigned (1:1 ratio) to pravastatin 40 mg or atorvas-
tatin 80 mg. Reported data indicate that among patients with
ACSs who are treated with a statin, achieving a target level
of hs-CRP of less than 2 mg per litre is associated with a
significant improvement in event-free survival, an effect
present at all levels of LDL-C achieved. Furthermore, pa-
tients assigned to receive 80 mg of atorvastatin daily were
significantly more likely than those assigned to receive 40
mg of pravastatin daily to have a decrease in the levels of
both LDL-C and hs-CRP to the target values. Nonetheless,
authors found little differences in outcome according to the
specific statin given, suggesting that the target levels of
LDL-C and hs-CRP were more important in determining the
outcomes than was the specific choice of statin.
With respect to stroke [84], in this trial a beneficial ef-
fects of statins in the risk of stroke was not seen, probably
due to the small number of cerebrovascular events (CVE)
registered; however the trial provided information about the
relative contributions of lipids and inflammation on CVE in
patients with an acute coronary syndrome. In contrast with
MI, there was no difference in the achieved levels of LDL
among those patients with and without a CVE, and patients
with LDL levels both above and below 70 mg/dL had similar
rates of CVE. Conversely, patients with higher levels of CRP
despite intensive or moderate statin therapy were at signifi-
cantly higher risk of subsequent CVE. This finding supports
the relevance of inflammatory processes to the risk of CVE.
Patients who achieved both an LDL level below 70 mg/dL as
well as a CRP level below 2 mg/L were at the lowest risk of
CVE.
Another recent sub-group analysis of the PROVE-IT
TIMI 22 trial has been performed to compare the prognostic
utility of apoB/AI, total cholesterol/HDL (TC/HDL) ratio,
non-HDL cholesterol (nonHDL-C), or hs-CRP as predictors
of clinical risk among patients receiving statin therapy after
ACS [85]. Authors found that in ACS patients intensive
statin therapy with atorvastatin 80 mg reduced the ratios of
apoB/AI, TC/HDL ratio, and the level of nonHDL-C at 4
months to a greater extent than moderate dose statin therapy
with pravastatin 40 mg. On-treatment levels of each lipid
parameter were associated with risk of recurrent events to a
comparable degree and provided similar information on risk
prediction to that provided by LDL-C. In contrast, the
authors observed that hs-CRP significantly improved risk
prediction models, providing independent prognostic infor-
mation to each of the lipid parameters. Moreover, hs-CRP
was only weakly correlated with each lipid parameter, sup-
porting the concept that hs-CRP provides information inde-
pendent and complementary to that provided by lipid pa-
rameters.
Moreover, the REVERSAL trial treated coronary disease
patients with the same statin agents and doses as PROVE IT
(atorvastatin 80 mg vs pravastatin 40 mg). Atherosclerotic
progression, as measured by intravascular ultrasound, slowed
primarily among individuals who lowered both LDL-C and
hs-CRP [86]. Similar to the PROVE IT trial, individuals who
achieved aggressive reductions in both LDL-C and hs-CRP
experienced the highest degree of disease regression. Taken
together, these clinical data strongly suggest that dual goals
of therapy for high-risk patients treated with statins should
include LDL-C and hs-CRP lowering.
Furthermore, a recent sub-group analysis, of the Aggra-
stat to Zocor (AtoZ) trial showed that achieved levels of hs-
CRP at 30 days and 4 months after acute coronary syndrome
are independently associated with long-term survival and
that patients treated with more aggressive statin therapy were
more likely to achieve lower levels of hs-CRP [87].
The recent publication of the provocative results of the
J UPITER (J ustification for the Use of statins in Primary pre-
vention: an International Trial Evaluating Rosuvastatin)
raised several questions [1]. First, about the previously rec-
ommended screen selectively policy, then about the need
to investigate therapies directed to reduce inflammation in
CVD and, moreover, in stroke. This trial was launched in
2003 and evaluated rosuvastatin versus placebo among
17,800 patients with LDL-C below the currently recom-
mended threshold for initiating pharmacologic treatment for
primary prevention (<130 mg/dl) and a hs-CRP level 2.0
mg/L as a marker of higher-risk subjects. The primary end-
point was composite of MI, stroke, unstable angina, cardio-
vascular death, or coronary intervention. Upon the recom-
mendations of an independent data-monitoring committee
and the J UPITER steering committee, the trial was stopped
prematurely after a median follow-up of 1.9 years (maxi-
mum, 5.0) due to unequivocal benefit in those assigned to
rosuvastatin. Rosuvastatin reduced LDL-C levels by 50%
and hs-CRP levels by 37%. In this trial, rosuvastatin signifi-
cantly reduced the incidence of major cardiovascular events
with a 44% relative risk reduction of the primary endpoint.
There was a similar reduction in a combination of the more
important hard outcomes: MI, stroke, or death from cardio-
vascular causes. However smokers and overweight individu-
als were included in the study, among those declared as nor-
mal healthy subjects.
Moreover a recent sub-group analysis of the study has
been published [88], which showed that rosuvastatin reduced
the incidence of stroke by 48% and that this reduction in
stroke risk was consistent across all subgroups evaluated,
including those customarily considered to be at low risk,
such as women, nonsmokers, and those without hypertension
at baseline.
Previous large trials on the use of statin in the prevention
of stroke have shown no significant effects [83, 89, 90],
however all suggested a trend toward net benefit. Ridker et
al in a random-effects metanalysis of 3 previous trial ob-
served a non significant 14% reduction in stroke risk with
statin therapy (RR, 0.86; 95% CI, 0.66 to 1.10; P 0.23). Up-
dating the metanalysis with J UPITER data, statin therapy in
primary prevention is associated with a net 25% reduction in
stroke risk, without any heterogeneity. The larger relative
and absolute benefits observed within J UPITER could reflect
the fact that, unlike the prior trials that used elevated lipid
levels as entry criteria, J UPITER targeted those with ele-
vated levels of hs-CRP, which is more closely associated
with incident stroke than elevated LDL-C. J UPITER also
used a more potent statin regimen than was used in any of
the prior trials. Thus, actively treated participants had greater
LDL-C and hs-CRP reductions.
Another recent interesting experience with statin therapy
in ACS patients came from Yun et al, who studied 445 pa-
tients referred for percutaneous coronary intervention (PCI).
Subjects were randomly assigned to 40 mg rosuvastatin load-
ing or no statin treatment before PCI. Incidence of peri pro-
cedural myocardial injury was higher in control than in rosu-
vastatin group and also hs-CRP levels after PCI were signifi-
cantly higher in control than in rosuvastatin group [91].
These findings are consistent with previous experiences with
atorvastatin in the ARMYDA trial and sub study of patients
undergoing PCI [92].The incidence of major adverse cardiac
events (MACE), including cardiac death, non-fatal MI, non-
fatal stroke, and any ischemia-driven revascularization, was
assessed after 12 month, confirming the beneficial effects of
the rosuvastatin loading dose [92].
Even when using intensive therapy with potent statins
CRP might remain elevated [93-95]. Indeed, during intensive
statin therapy, a lower CRP level was observed in patients
with the fewest coronary risk factors present, suggesting that
controlling these factors may result in lower CRP levels.
Previous evidences exist that also intensive and multiple
lifestyle changes (exercise, smoke cessation, weight loss)
and pharmacologic therapies other than statin reduce cardio-
vascular risk and lower hs-CRP levels, whereas drug thera-
pies that reduce, for example, LDL-C without affecting in-
flammation failed to reduce vascular risk, as noted above.
Diet and exercise, in particular, are known to lower the
risk of heart disease, and are associated with decreased hs-
CRP in obese and modestly overweight patients [96].
Specific rehabilitation program are of proven benefit in
patients after vascular events, and this beneficial effects
could be explained by a favourable modulation of such risk
factors as overweight, lipid profile and, most notably, the
inflammatory profile. Some studies have been published
which specifically addressed the effects on CRP levels, dem-
onstrating the ability of training programs to reduce CRP
concentration. However none of these evaluated the long-
term impact on outcome of reducing the inflammatory bur-
den with exercise [97-100]. We recently confirm this obser-
vation in a population of patients underwent PCI for both
stable angina and ACS. After revascularization patients were
randomized to a clinical follow-up or a rehabilitation period.
Trained patients showed decreased levels of hs-CRP and the
adipokine resistin, and conversely higher concentrations of
adiponectin, an anti inflammatory adipokine, comparing to
baseline and these effects were more represented in the sub-
set of patients with ACS [Calabr et al. unpublished data].
Weight loss determines a favourable effect on the in-
flammatory profile. Both when achieved with exercise and a
low-caloric diet, produces at least an improvement in body
mass composition with a dose-response relationship, in par-
ticular for the reduction in visceral adiposity and in the size
of adipocytes, known to be related to a more pronounced
inflammatory response [101-102]. Several ways to produce
weight loss can be used, and the magnitude of the decrease
in weight loss achieved seems to be the principal determinant
of this effect. Selvin et al. [103], for example, stated that 1
kg of weight loss by diet and lifestyle modification is associ-
ated with a 0.13 mg/L reduction in CRP concentration com-
pared with 0.16 mg/L by bariatric surgery. Dietary interven-
tions have been more extensively studied and the highest
rates of weight loss are seen with diet, associated or not with
exercise. Fewer studies compared different types of dietary
intervention and no significant differences were shown, with
the exception of low-glycemic-load diets, which produced
more marked reduction in inflammatory mediators [104].
Bariatric surgery, as mean to achieve weight loss, and in
particular gastric bypass surgery, results, as did dietary inter-
vention, in substantial weight loss and therefore a pro-
nounced and sustained improvement in hs-CRP levels [105].
Several evidences have accumulated about agents com-
monly used to treat diabetes, including insulin, metformin,
and the peroxisome proliferator activated receptor-gamma
(PPAR-gamma) agonists rosiglitazone and pioglitazone and
their capacity to lower CRP [106]. Whether these effects
result from improvements in insulin resistance and/or do not
depend on improved glycemic control remains controversial.
Some interest in the past has been, indeed, reserved to the
anti inflammatory potential of antiplatelet agents, which are
a cornerstone of the therapy of ACS and ischemic stroke. In
the Physician Health Study [35], patients were randomly
assigned to receive aspirin or placebo. As described above,
baseline hs-CRP was higher in patients who developed MI or
stroke. Interestingly, men with the highest initial level of hs-
CRP (4th quartile) had the greatest benefit of aspirin as com-
pared with those in the lowest quartile. Furthermore, in a
study of subjects admitted for NSTE-ACS, those pretreated
with aspirin tended to have lower hs-CRP and lower troponin
I levels [107]. In this study, aspirin neutralized the adjunctive
risk of death and MI at 1 year associated with high CRP lev-
els, suggesting a potential additive effect of aspirin in car-
diovascular prevention, other than the anti platelet one.
However, subsequent trials failed to show an ability of low-
dose aspirin (75 mg 325 mg) to lower circulating levels of
hs-CRP [108-110]. These evidences do not support the initial
idea of an adjunctive beneficial effect other than the anti-
thrombotic one. With respect to the more recent inhibitors of
the P2Y12 adenosine receptor, i.e. clopidogrel, investigators
from the Cleveland Clinic Foundation showed that pre-
treatment with thienopyridine is associated with a substantial
reduction in 30-day death or MI in patients with elevated
baseline CRP undergoing PCI and stenting [111]. Most no-
tably, periprocedural treatment with clopidogrel could de-
termine an attenuation of the increase in CRP related to the
vascular injury [112].
As part of the increased renin angiotensin aldosterone
system (RAAS) activity after an ACS, angiotensin II can
create a pro-inflammatory environment via NFkB activation
and nicotinamide-adenine dinucleotide phosphate (NADPH)
oxidase-mediated superoxide production. The effects of the
renin-angiotensin system inhibition on systemic inflamma-
tion are controversial. Early studies have suggested a favour-
able effect. Di Napoli et al. [113] showed in a prospective
study of 507 patients that treatment with ACE inhibitors was
associated with lower CRP levels in patients after stroke.
However, in the earlier large Heart Outcomes Prevention
Evaluation (HOPE) trial, treatment of high-cardiovascular
risk patients with ramipril did not result in CRP reduction
[114]. Other large-scale clinical trials evaluating ACE inhibi-
tion in patients with coronary atherosclerosis have not re-
ported significant effects on CRP levels [115-117]. The
EUropean Trial on Olmesartan and Pravastatin in Inflamma-
tion and Atherosclerosis (EUTOPIA) investigators found
significant reduction (15.1%) in measured CRP levels in
hypertensive patients with micro vascular inflammation
treated with the angiotensin receptor blocker olmesartan. The
reduction was present at six weeks (as compared with base-
line levels) while there was no significant change with pla-
cebo [118]. A more recent study compared the anti inflam-
matory effect of ramipril and telmisartan in a small sample
of patients presenting with acute coronary syndrome (ACS),
who were randomized after successful percutaneous coro-
nary intervention to ramipril or telmisartan 80 mg/day (20
patients). In their experience, Telmisartan determined a sig-
nificant more pronounced reduction in hsCRP level than
ramipril [119].
CONCLUSION
Despite the large body of literature available on the in-
flammatory hypothesis in MI and stroke, it remains unknown
whether inhibition of inflammation per se will lower vascu-
lar events. J UPITER is one of the first trial to use inflam-
matory risk as an entry criterion, however cannot directly
address whether lowering inflammation alone lowers vascu-
lar risk.
Given these evidences a trial directly testing the anti in-
flammatory hypothesis in vascular diseases has been de-
signed by Ridker et al., the Cardiovascular Inflammation
Reduction Trial (CIRT) [120]. Authors choose Very Low
Doses of Methotrexate (VLDM), for its capacity to affect
inflammation without impact on other components of the
atherothrombotic process and it is known to have a good
safety profile. Methotrexate reduces several inflammatory
biomarkers, including CRP, IL-6 and TNF-alpha, as demon-
strated in population with Rheumatoid Arthritis (RA) and
psoriasis, with minimal or no effects on cholesterol levels
and platelets. Previously published experiences in RA pa-
tients showed a reduced cardiovascular mortality in those
treated with VLDM. In the CIRT, VLDM will be adminis-
tered to patients with stable CAD that is a population known
to be at higher risk with evidence of a persistent inflamma-
tory status despite traditional therapies, whereas a primary
prevention population would require an exceptionally large
sample size. Moreover, it has been considered unsafe to test
a drug with potential implication on wound healing in patient
with AMI. Patients will be followed for non-fatal MI, non-
fatal stroke and cardiovascular death. Choosing a general
anti-inflammatory drug, such as Methotrexate, instead of
developing anti-CRP therapy seems reasonable, since several
controversies exist about the actual pathogenic role of CRP.
If successful, CIRT would confirm the inflammatory hy-
pothesis and open novel therapeutic approaches of vascular
disorders.
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