CURRENT OPINION

European Heart Journal (2013) 34, 36873690

doi:10.1093/eurheartj/eht435

How to use C-reactive protein in acute

coronary care

Department of Cardiology B, Aarhus University Hospital, Tage Hansens Gade 2, Aarhus DK-8000, Denmark
Received 26 May 2013; revised 17 September 2013; accepted 23 September 2013; online publish-ahead-of-print 7 November 2013

Introduction
C-reactive protein is an acute phase protein and an established
marker for detection, risk stratification, and monitoring of infections
and inflammatory and necrotic processes. Because C-reactive
protein is sensitive but not specific, its values must be interpreted
in the clinical context. In patients with acute myocardial infarction
(AMI), C-reactive protein increases within 46 h of symptoms,
peaks 24 days later, and returns to baseline after 7 10 days.1
C-reactive protein has gained interest recently as a marker for risk
stratification in acute coronary syndrome (ACS) when measured by
high-sensitivity C-reactive protein assays. These assays have greater
analytical sensitivity and reliably measure C-reactive protein concentrations within the reference range with low imprecision (510%).2
Because of evidence that atherosclerosis is an inflammatory disease,
high-sensitivity C-reactive protein can be used as a biomarker of risk
in primary prevention and in patients with known cardiovascular
disease.3 The aim of this review is to evaluate the use of C-reactive
protein in patients with acute coronary disease.

Biochemical and analytical issues

C-reactive protein is a non-specific first-line host defence mechanism.4 With stimulation by cytokines (e.g. interleukins and tumour necrosis factor-alpha), C-reactive protein synthesis in hepatocytes
occurs within 46 h. Concentrations can rise 1000-fold or more
over 2448 h. C-reactive protein has been detected in atherosclerotic plaques; its possible role in atherosclerogenesis is summarized in
Figure 1, but is still a matter of debate.5 Genetic variants account for
3540% of the variability in high-sensitivity C-reactive protein.6

The in vitro stability of high-sensitivity C-reactive protein is excellent.2,7 Specific blood sampling conditions are not necessary.
However, retesting may be necessary with some assays if there is
marked lipaemia. Baseline and subsequent measures are in good
agreement for risk stratification despite biological variability of
30 60%.2,7
The upper reference limit is method-dependent but usually
,8 mg/L for standard assays.2,7 The distribution of high-sensitivity
C-reactive protein concentrations is skewed in both genders with a
50th percentile of 1.5 mg/L (excluding women on hormone replacement therapy). Race differences have been reported.8 Most
studies have reported no relationship with age but circadian and seasonal variation.9 C-reactive protein concentrations are increased by
smoking, obesity, and hormone replacement therapy and reduced by
exercise, moderate alcohol drinking, and statin use.2,3,7 Correction
for these factors is essential in reference range studies.
C-reactive protein assays are not standardized.2 We recommend
the use of third-generation high-sensitivity C-reactive protein assays
that combine features of standard and high-sensitivity C-reactive
protein assays. Required assay precision should be ,10% in the
range of 3 and 10 mg/L.

Critical clinical concepts

(1) C-reactive protein concentrations are reported in mg/L.
(2) C-reactive protein test results are method-dependent, but classification of patients into risk categories is usually comparable.
(3) Third-generation high-sensitivity C-reactive protein assays are
recommended.
(4) No specific patient preparation before blood sampling is necessary.
(5) The in vitro stability of C-reactive protein is high.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

* Corresponding author. Tel: +45 78 46 7614, Fax: +45 78 46 7619, Email: kristhyg@rm.dk
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com

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Luigi M. Biasucci, Wolfgang Koenig, Johannes Mair, Christian Mueller, Mario Plebani,
Bertil Lindahl, Nader Rifai, Per Venge, Christian Hamm, Evangelos Giannitsis,
Kurt Huber, Marcello Galvani, Marco Tubaro, Paul Collinson, Joseph S. Alpert,
Yonathan Hasin, Hugo Katus, Allan S. Jaffe, and Kristian Thygesen*, the Study Group
on Biomarkers in Cardiology of the Acute Cardiovascular Care Association of the
European Society of Cardiology

3688

L.M. Biasucci et al.

VLDL in serum, thereby potentially participating in the mechanisms involved in plaque formation and destabilization, and shows some of the key
properties of antibodies and may contribute to immune responses by activation of antigen presenting cells. Procoagulant effects have been reported
in vitro as well. C-reactive protein induces increased expression of adhesion molecules and modulation of NO synthesis. Dashed arrow represents
weak evidence, whereas continuous arrow denotes evidence confirmed by several studies. APC, antigen presenting cell; CRP, C-reactive protein;
LDL, low-density lipoprotein; NO, nitric oxide; VLDL, very low-density lipoprotein; TF, tissue factor.

Clinical use of C-reactive protein

in acute coronary syndrome
Higher C-reactive protein concentrations are associated with
complex, vulnerable atherosclerotic plaques,10 suggesting that
high-sensitivity C-reactive protein elevations represent a marker of
systemic atherosclerotic plaque instability. Minor increases might
reflect inflammation in coronary plaques or injured coronary walls
after stenting.5,11 However, there is no association between
C-reactive protein and the extent of coronary artery disease, and
C-reactive protein has not been causally related to coronary
events.6 Nonetheless, C-reactive protein elevations are associated
with mortality but only weakly with recurrent MI.12,13
C-reactive protein measurements have no value for the diagnosis
of ST-segment elevation AMI (STEMI), since 41% of STEMI patients
have low (,2 mg/L) concentrations on admission. Furthermore, in
many, values are not significantly different in samples obtained ,2,

24, and 4 6 h after onset of symptoms.14 However, high C-reactive

protein concentrations before percutaneous coronary intervention
(PCI) in STEMI are related to recurrent MI and death rates at 1-year
follow-up.15 Moreover, C-reactive protein values correlate with infarct
size by magnetic resonance imaging,16 although markers of myocardial
necrosis, such as cardiac troponin (cTn), correlate more closely while
providing similar predictive value for mortality.16,17
C-reactive protein measurements are not useful for the diagnosis
of non-STEMI either. Its use has been advocated during the acute
phase for risk stratification but conclusive evidence for its incremental value is absent. C-reactive protein is a predictor of short- and longterm cardiovascular complications in ACS,10,13,14,17 and C-reactive
protein levels contribute incremental information over and above
clinical risk scores or other biomarkers in some but not all studies.17
19
In addition, there are few studies to date of C-reactive protein together
with more sensitive cTn assays20 and none with high-sensitivity cTn
assays.

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Figure 1 Possible pathophysiological effects of C-reactive protein in atherosclerosis. Aggregated C-reactive protein selectively binds LDL and

3689

Use of C-reactive protein in acute coronary care

C-reactive protein is not helpful in selecting an invasive or conservative strategy in ACS.21 However, an increased C-reactive protein
level is an independent prognostic indicator for death or non-fatal
MI following PCI.22 It is difficult to advocate C-reactive protein as a
primary target for therapy since drugs that specifically influence
only C-reactive protein alone do not exist. Nonetheless, in prevention studies post ACS, lower levels of C-reactive protein following
statin therapy predict greater subsequent risk reductions.23 25
Based on early studies, a decision limit for risk stratification of
10 mg/L was suggested although other limits have been proposed
as well.20 C-reactive protein has usually been tested in samples
drawn on admission, but the optimal time to assess risk has not
been systematically investigated.

Critical clinical concepts

Conclusions and outlook

Given the central role of inflammation in the pathogenesis of atherothrombosis, this is an area of active research. There are many new
inflammatory markers proposed for use, but at present none of
them has emerged as clinically more useful than C-reactive protein.
New ways of conceptualizing acute atherothrombotic diseases may
facilitate new approaches in this critical field.26
Conflict of interest: LB has been consultant for Siemens Diagnostics, Roche Diagnostics and Abbott Diagnostics; WK has received
lecture honoraria from AstraZeneca, Roche and Novartis and is a
member of the Executive Steering Committee of CANTOS; JM has
received fees from Philipps Health Care Incubator; EG received
lecture honoraria from Roche Diagnostics, Bayer Vital, Mitsubishi
Chemicals and was consultant for Roche Diagnostics; CM received
lecture honoraria from Abbott Diagnostics, Biosite, Brahms, Roche
Diagnostics, Siemens Diagnostics and he has received support from
the Swiss National Science Foundation (PP00B-102853), the Swiss
Heart Foundation, Abbott Diagnostics, Biosite, Brahms, Nanosphere, Roche Diagnostics and Siemens Diagnostics; BL has received

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(1) C-reactive protein is an established marker for diagnosing and

monitoring infection, inflammation, and tissue injury.
(2) C-reactive protein measurement in primary prevention predicts
future cardiovascular events with significance similar to that of
total and HDL cholesterol.
(3) C-reactive protein measurement in secondary prevention predicts risk of recurrent MI, stroke, and cardiovascular death.
(4) C-reactive protein measurements have no value for diagnosing
AMI.
(5) C-reactive protein release is related to infarct size and risk in
STEMI patients.
(6) C-reactive protein is not helpful for the choice of an invasive or
conservative strategy in ACS.
(7) C-reactive protein measurement after ACS and after PCI can be
used to identify patients in whom an intensive risk factor modification is useful.
(8) For cardiovascular prevention, a C-reactive protein value of
.3 mg/L is considered high risk but a limit 10 mg/L seems
more appropriate in ACS patients.

research grants from Roche Diagnostics and Radiometer A/S, lecture

fees from Roche Diagnostics and Siemens Healthcare Diagnostics
and has been member of the scientific advisory boards of Philips
Healthcare, Siemens Healthcare, Beckman Coulter, FIOMI and bioMerieux; HK holds a patent on the cardiac troponin T assay jointly
with Roche Diagnostics; ASJ has received consulting honoraria
from most of the major diagnostic companies including BeckmanCoulter and Siemens; MT has been member of the advisory boards
of Roche Diagnostics and Abbott Diagnostics and he has received
lecture honoraria from Biosite/Inverness, Abbott Diagnostics and
Dade Behring; JA received lecture honoraria from Roche Diagnostics
and Siemens Diagnostics; PC is member of the Diagnostics Advisory
Committee of the National Institute of Clinical Excellence in the UK;
CH has been consultant for Abbott Diagnostics and Roche Diagnostics; MG has been consultant for Roche Diagnostics and he has
received research grants from Roche Diagnostics, Siemens Diagnostics and Beckman Coulter; MP received consulting honoraria from
Siemens, Roche and Abbott Diagnostics; PV has received lecture
honoraria and research grants from Abbott, Beckman Coulter,
Roche Diagnostics, Siemens and is currently consultant for Abbott,
bioMerieux, Philips and Radiometer.

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CARDIOVASCULAR FLASHLIGHT

doi:10.1093/eurheartj/eht413
Online publish-ahead-of-print 3 October 2013

.............................................................................................................................................................................

Acute myocardial infarction caused by coronary tumour embolism

Shuhei Kushiyama, Yoshihiro Ikura*, and Yasuhiro Iwai
Department of Pathology, Takatsuki General Hospital, Takatsuki 569-1192, Japan

* Corresponding author. Tel: +81 726813801, Fax: +81 726823834, Email: ikura@ajk.takatsuki-hp.or.jp

A 78-year-old male patient with advanced lung cancer and liver metastasis was admitted to our hospital because of persistent and critical
hyperkalaemia (5.17.1 mEq/L), probably caused by tumour lysis syndrome. He had a history of myocardial infarction and arteriosclerosis
obliterans. Echocardiography showed akinesis of the cardiac apex, and
severe hypokinesis of the inferior wall, reflecting old infarction. His
hyperkalaemia was accompanied by elevated levels of aminotransferases and lactate dehydrogenase. Because his disease was an incurable malignancy, palliative care was chosen for his treatment.
Although no electrocardiographic abnormalities associated with
hyperkalaemia were detected during hospitalization, he suffered
sudden death due to ventricular fibrillation. The clinicians suspected
that the uncontrolled hyperkalaemia had induced this fatal arrhythmia.
An autopsy was performed in which the lung cancer (pleomorphic
carcinoma) with extensive blood-borne metastases was confirmed.
Fresh myocardial necrosis was found to be superimposed on an area
of fibrosis corresponding to old infarction in the left anterior wall
(Panel A, arrowheads). This finding suggested that the precise cause
of death was not hyperkalaemia but rather acute myocardial infarction.
We then investigated the coronary arteries thoroughly to identify a culprit vascular lesion (Panel B). Surprisingly, a mixture of blood clot and
tumour cell aggregation (Panels C and D) occluded the left anterior descending artery (Panel B, asterisk). We surmised that coronary tumour
embolism was a primary reason for his sudden death.
Tumour embolism is an extremely rare cause of acute myocardial infarction. However, clinicians should recognize it as a potential
aetiology of acute coronary syndrome.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com

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L.M. Biasucci et al.