CORRESPONDENCE: LETTER TO THE EDITOR
Acute Coronary Syndromes: To CRP or Not to CRP?
Luigi M. Biasucci, MD, FESC, FACC*,
Giovanna Liuzzo, MD, PhD and
Filippo Crea, MD, FESC, FACC
* Institute of Cardiology, Catholic University, Largo Gemelli, 8, 00168 Rome, Italy (Email: lmbiasucci{at}virgilio.it).
We read with interest the article by Bogaty et al. (1), in which the authors failed to find an independent association between C-reactive protein (CRP) and outcome in a large, unselected population of patients presenting an acute coronary syndrome (ACS). We agree with the authors that their results do not support clinical use of CRP in patients hospitalized with an ACS. It should be made crystal clear, however, that this study does not challenge the notion that activation of inflammatory cells and mediators plays a key role in the pathogenesis of coronary instability and that the design of the study may explain the difference between plenty of data demonstrating the role of CRP in acute coronary syndromes (2). Indeed, the wide inclusion criteria adopted in this study inevitably mask the ability of a sensitive but nonspecific marker like CRP to reveal the underlying pathogenetic role of inflammation. For instance, Bogaty et al. (1) included the whole spectrum of ACS from Braunwald's class IB unstable angina to ST-segment elevation myocardial infarction. At one extreme, among patients without myocardial necrosis or with a mild elevation of troponins (as it is the case in a sizeable proportion of patients without ST-segment elevation ACS), an elevated CRP level, in the absence of systemic inflammatory diseases, is likely to reflect widespread activation of inflammatory cells and is, therefore, a marker of coronary disease activity. Accordingly, several previous studies have shown that in this setting CRP levels predict the risk of recurrent instability independently of troponin levels (2). At the other extreme among patients with ST-segment elevation myocardial infarction, CRP predominantly reflects the inflammatory response to myocardial necrosis; in this setting the predictive value of CRP is obviously related to measures of myocardial damage including cardiac enzyme levels and indexes of left ventricular dysfunction, although the association is far from linear and is influenced by the previous inflammatory condition (3). Furthermore, the authors did not exclude patients with acute or chronic inflammatory diseases, which can further confound the interpretation of the results from the study.
Finally, the statistical analysis may underestimate the predictive value of CRP. Indeed, in the logistic regression analysis, continuous levels of CRP were compared with dichotomous variables, thus reducing their ability to compete with the other variables. A further analysis was conducted to establish the predictive value of CRP levels, using a cutoff of 3 mg/l. Although this cutoff was utilized in previous studies on CRP in ACS, a scientific statement of the Centers for Disease Control and Prevention/American Heart Association proposed a cutoff of 10 mg/l as more appropriate when the predictive value of CRP is assessed in ACS (4).
Finally, the study does not provide any insight into the mechanisms responsible for the association between CRP levels and death, which has been found in this and in previous studies. In particular, why are higher levels of CRP consistently associated with a higher risk of death? What kind of cardiac deaths do these patients die? This association might be accounted for by: 1) a higher risk of recurrent instability with fatal infarctions if CRP is a marker of plaque inflammation; 2) a higher risk of sudden death if CRP is a marker of an arrhythmogenic substrate; and 3) a higher risk of early post-infarction complication if CRP plays a pathogenetic role in determining infarct size related to complement activation in the infarcted tissue.
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Footnotes
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Please note: Dr. Biasucci is a consultant for Siemens Diagnostic, Roche, Sanofi-Aventis, and Pfizer, and is a recipient of a research grant from Boehringer-Ingelheim.
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References
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1. Bogaty P, Boyer L, Simard S, et al. Clinical utility of C-reactive protein measured at admission, hospital discharge, and 1 month later to predict outcome in patients with acute coronary disease: the RISCA (Recurrence and Inflammation in the Acute Coronary Syndromes) study J Am Coll Cardiol 2008;51:2339-2346.[Abstract/Free Full Text]2. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina N Engl J Med 1994;331:417-424.[Abstract/Free Full Text] 3. Liuzzo G, Biasucci LM, Gallimore JR, et al. Enhanced inflammatory response in patients with preinfarction unstable angina J Am Coll Cardiol 1999;34:1696-1703.[Abstract/Free Full Text] 4. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association Circulation 2003;107:499-511.[Free Full Text]
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- Peter Bogaty, Serge Simard, Gilles R. Dagenais, and James M. Brophy
J. Am. Coll. Cardiol. 2008 52: 1500-1501.
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