C-reactive protein and other inflammatory risk markers in acute coronary syndromes
Gavin J. Blake, MB, MSc, MRCPI* and
Paul M. Ridker, MD, MPH*,*
* Center for Cardiovascular Disease Prevention, the Leducq Center for Cardiovascular Research, and the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, UK
Manuscript received May 7, 2002;
revised manuscript received October 11, 2002,
accepted November 27, 2002.
*
Reprint requests and correspondence: Dr. Paul M. Ridker, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Avenue East, Boston, Massachusetts 02215, UK.
pridker{at}partners.org
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Abstract
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Markers of myocyte necrosis such as cardiac troponin or creatine kinase-myocardial band are invaluable tools for risk stratification among patients presenting with acute coronary syndromes (ACS). Nonetheless, many patients without any evidence of myocyte necrosis may be at high risk for recurrent ischemic events. In consideration of the important role that inflammatory processes play in determining plaque stability, recent work has focused on whether plasma markers of inflammation may help improve risk stratification. Of these markers, C-reactive protein (CRP) has been the most widely studied, and there is now robust evidence that CRP is a strong predictor of cardiovascular risk among apparently healthy individuals, patients undergoing elective revascularization procedures, and patients presenting with ACS. Moreover, even among patients with troponin-negative ACS, elevated levels of CRP are predictive of future risk. Other, more upstream markers of the inflammatory cascade, such as interleukin (IL)-6, have also been found to be predictive of recurrent vascular instability. A recent report from the second FRagmin during InStability in Coronary artery disease trial investigators suggests that elevated levels of an inflammatory marker such as IL-6 may indicate which patients may benefit most from an early invasive strategy. Other inflammatory markers currently under investigation include lipoprotein-associated phospholipase A2, myeloperoxidase, and pregnancy-associated plasma protein A. Of all these novel markers, CRP appears to meet most of the criteria required for potential clinical application. Furthermore, the benefits of lifestyle modification and drug therapy with aspirin or statins may be most marked among those with elevated CRP levels.
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Abbreviations and Acronyms
| | ACS | = acute coronary syndrome(s) | | BNP | = B-type natriuretic peptide | | CAD | = coronary artery disease | | CK-MB | = creatine kinase-myocardial band | | CRP | = C-reactive protein | | IL | = interleukin | | LDL | = low-density lipoprotein | | Lp-PLA2 | = lipoprotein-associated phospholipase A2 | | MI | = myocardial infarction | | MPO | = myeloperoxidase | | PAPP-A | = pregnancy-associated plasma protein A |
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Approximately 1.4 million patients with acute coronary syndromes (ACS) without ST-segment elevation are admitted to hospital annually in the U.S. (1). Markers of myocyte necrosis such as creatine kinase-myocardial band (CK-MB) and cardiac troponin are invaluable diagnostic tools for such patients and are routinely used for risk stratification. However, even troponin, a highly specific marker of cardiac myocyte necrosis, has relatively low diagnostic sensitivity for ACS, with only 22% to 50% of patients with unstable angina having positive troponin (I or T) tests (2–5). Moreover, many patients with troponin-negative ACS who have vulnerable coronary plaques remain at high risk for future ischemic events. Thus, an additional test to improve upon risk stratification based on markers of myocyte necrosis alone could prove a valuable aid in clinical practice.
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Inflammatory markers: C-reactive protein
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Pathophysiology.
The past decade has witnessed an increasing recognition that inflammatory mechanisms play a central role in the pathogenesis of atherosclerosis and its complications (6). Recently, attention has focused on the potential role of plasma markers of inflammation as risk predictors among those at risk for cardiovascular events (7). Of these potential markers, C-reactive protein (CRP) has been the most extensively studied. Produced in the liver in response to interleukin (IL)-6, CRP is an acute phase reactant that serves as a pattern recognition molecule in the innate immune system. It was initially thought of as a downstream bystander marker of vascular inflammation, but recent data suggest that CRP may play an active role in atherogenesis. C-reactive protein opsonization of low-density lipoprotein (LDL) mediates LDL uptake by macrophages (8), and CRP also stimulates monocyte release of pro-inflammatory cytokines such as IL-1b, IL-6, and tumor necrosis factor-alpha (9). Furthermore, CRP mediates monocyte chemotactic protein-1 induction in endothelial cells (10) and causes expression of intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1 by endothelial cells (11). Recent data have shown that CRP co-localizes with the membrane attack complex in early atheromatous lesions, and CRP, complement proteins, and their messenger ribonucleic acid are all substantially upregulated in atheromatous plaque (12).
CRP as a predictor of risk
Numerous large-scale epidemiological studies among apparently healthy men and women have found that CRP is a strong independent predictor of future cardiovascular risk (13–22). In the setting of ACS, a landmark study by Liuzzo et al. (23) showed that patients presenting with unstable angina who had elevated plasma levels of CRP ( 3 mg/l) and serum amyloid A had a higher rate of death, acute myocardial infarction (MI), and need for revascularization compared with patients without elevated levels (Table 1).
The Thrombolysis In Myocardial Infarction (TIMI) investigators have since shown that the increased risk associated with high CRP levels may be evident as early as 14 days after presentation with an ACS (24). The Chimeric c7E3 AntiPlatelet Therapy in Unstable angina Refractory to standard treatment (CAPTURE) trial investigators found that, although only troponin T was predictive in the initial 72-h period, both CRP and troponin T were independent predictors of risk at six months (25), while the FRagmin during InStability in Coronary artery disease (FRISC) investigators reported that the risk associated with elevated CRP levels at the time of index event continues to increase for several years (26). In each of the above studies, the predictive value of CRP was independent of, and additive to, troponin (Table 1). Most importantly, CRP has been found to have prognostic value among patients without evidence of myocyte necrosis; specifically, even among patients with negative troponin T, an elevated CRP is predictive of future adverse events (24–26). Recent data also confirm that CRP is a strong independent predictor of short-term and long-term mortality among patients with ACS who are treated with very early revascularization (27).
The exact source of elevated CRP levels among patients with unstable coronary syndromes remains unclear. Data suggest that plaque rupture per se may not be the cause but, rather, that elevated CRP levels may be a marker of the hyper-responsiveness of the inflammatory system to even small stimuli. The CRP levels do not change after balloon angioplasty in patients with stable or unstable angina who have normal pre-procedural levels, but they do increase after angioplasty in unstable patients with elevated CRP at baseline (28). Moreover, even diagnostic angiography without intervention caused an increase in CRP levels among patients with elevated levels at baseline.
Other inflammatory markers
Further data regarding upstream mediators of CRP production suggest that this pathway may reflect inflammatory processes that convey increased cardiovascular risk. Elevated levels of IL-1 receptor antagonist and IL-6 at 48 h after presentation are associated with an adverse in-hospital prognosis among patients with ACS, even without a rise in troponin T (29). A recent report from the FRISC II study group has found that circulating levels of IL-6 are a strong independent marker of increased mortality among patients with unstable coronary artery disease (CAD) and may be useful in directing subsequent care (30). For example, randomization to an early invasive strategy led to a 65% relative reduction in 12-month mortality among patients with elevated IL-6 levels. By contrast, among those with low IL-6 levels, an early invasive strategy did not confer any significant benefit over a non-invasive strategy. Furthermore, among patients randomized to the non-invasive arm, the risk associated with elevated IL-6 levels was markedly attenuated if they were assigned to therapy with dalteparin rather than placebo (30). Similar data were observed for CRP. Thus, the use of an inflammatory marker for risk stratification appears to identify patients at high risk for future events, but most importantly, it appears to identify individuals who might benefit most from targeted interventional or intensive medical therapy.
Other novel inflammatory markers have been studied in cardiovascular risk prediction. Lipoprotein-associated phospholipase A2 (Lp-PLA2) circulates in association with LDL-cholesterol and may contribute to atherogenesis by hydrolyzing oxidized phospholipids into pro-atherogenic fragments and by generating lysolecithin, which has pro-inflammatory properties. The West of Scotland study group reported that baseline levels of Lp-PLA2 were a strong independent predictor of risk for incident coronary heart disease in a cohort of high-risk hyperlipidemic men (31). Among a lower-risk cohort of normocholesterolemic women, baseline levels of Lp-PLA2 were also higher among cases than controls (32). However, in adjusted analyses, baseline levels of Lp-PLA2 were not a significant predictor of future cardiovascular risk, while CRP remained a strong predictor (32). Lp-PLA2 levels are highly correlated with LDL-cholesterol, which may in part explain these different results. The predictive value of Lp-PLA2 among patients with ACS is currently unknown.
Myeloperoxidase (MPO) levels may be elevated among individuals with CAD (33). Myeloperoxidase is an enzyme secreted by a variety of inflammatory cells, including activated neutrophils, monocytes, and certain tissue macrophages, such as those found in atherosclerotic plaque. The enzyme is not released until leukocyte activation and degranulation. Myeloperoxidase may convert LDL into a high-uptake form for macrophages, leading to foam cell formation, and may also deplete nitric oxide, contributing to endothelial dysfunction. In a recent case-control study, increasing levels of leukocyte-MPO and blood-MPO were significant predictors of the risk for CAD, such that after adjustment for white blood cell count and Framingham risk score, individuals in the highest quartile of blood-MPO had a 20-fold higher risk of CAD than individuals in the lowest quartile (33). Prospective studies are thus needed to test this interesting hypothesis directly.
Recent ACS data have also been presented for pregnancy-associated plasma protein A (PAPP-A) (34). This zinc-binding metalloproteinase enzyme is a specific activator of insulin-like growth factor I, a mediator of atherosclerosis. Among eight patients who died suddenly from cardiac causes, PAPP-A was abundantly expressed in ruptured and eroded unstable plaques, but PAPP-A was absent or minimally expressed in stable plaques. In plaques with large lipid cores and cap rupture, staining for PAPP-A revealed that the enzyme occurred mostly in the inflammatory shoulder region. In a small case-control study, circulating levels of PAPP-A were higher among patients with unstable angina or acute MI than among patients with stable angina and controls (34). Levels of CRP were also higher among those with acute MI and unstable angina than those with stable angina. Among patients with ACS, levels of PAPP-A and CRP were highly correlated (r = 0.61), but there was no association between PAPP-A and CK-MB (r = 0.07) or troponin I (r = 0.1). As with MPO, these data require assessment in larger cohorts.
Non-inflammatory markers
de Lemos et al. (35) have also recently reported data regarding the potential prognostic utility of B-type natriuretic peptide (BNP) among patients with ACS in the Orbofiban in Patients with Unstable coronary Syndromes (OPUS)-TIMI 16 study. Unlike inflammatory markers, BNP is a neurohormone synthesized in ventricular myocardium and released in response to pressure overload and ventricular dilation. Baseline levels of BNP, drawn on average 40 h after the onset of ischemic symptoms, correlated with the risk of death, heart failure, and MI at 30 days and 10 months. This association was significant across the full spectrum of ACS, including patients presenting with ST-segment elevation MI, MI without ST elevation, and unstable angina. Although it was statistically significant, the correlation between BNP and CRP was weak (r = 0.2; p < 0.001). After being adjusted for other independent predictors of risk of death, including the presence or absence of heart failure in patients, the odds ratio for death at 10 months for the top quartile of BNP compared with the lowest was 5.8, BNP also remained a significant predictor of death when analyses were restricted to an investigation of the presence or absence of elevated troponin levels. Non-CRP inflammatory and non-inflammatory biomarker results are summarized in Table 2.
Clinical utility
Three major questions must be answered before routine clinical application of inflammatory markers is advocated (36,37). First, does the marker independently predict risk beyond conventional tools? Second, are specific therapies available to reduce levels of the inflammatory marker, and third, do therapies that lower plasma levels of inflammatory markers also reduce cardiovascular risk? To this list could also be added the need for a widely available reliable biochemical assay.
Of the inflammatory markers discussed in the previous text, CRP currently meets most, if not all, of these criteria. C-reactive protein has been shown to predict risk in a wide variety of clinical settings; it has incremental value in addition to standard lipid screening for primary prevention (18,19,38) and in addition to cardiac troponin testing among patients with ACS (24–26). Furthermore, a recent analysis by Chew et al. (39) shows that CRP predicts the risk of death or MI at 30 days among patients undergoing percutaneous coronary intervention. In this setting, the risk associated with elevated CRP was independent of, but additive to, the effect of an increased American College of Cardiology/American Heart Association lesion score.
C-reactive protein levels are higher among smokers, diabetics, and obese subjects. Adipose tissue is a potent source of IL-6, the main hepatic stimulus for CRP production. Thus, intensification of dietary measures and exercise programs would seem to be appropriate for these individuals. Statin therapy may have powerful anti-inflammatory effects (40), and in recent clinical studies, statin therapy has been shown to lower CRP levels, an effect that is independent of lipid lowering (19,41–44). Recent data suggest that baseline levels of CRP and IL-6 are strong independent predictors of the risk of developing type II diabetes (45). In this regard, intriguing data from the West of Scotland study suggest that pravastatin therapy, compared with placebo, reduced the risk of development of type II diabetes (46).
Further data suggest that the benefits of statin therapy may be greatest among those with elevated CRP levels, either among post-MI patients (47) or in the primary prevention setting (19). In the Cholesterol And Recurrent Events (CARE) trial population, patients with persistent low-grade vascular inflammation, as evidenced by high CRP and serum amyloid A levels, were at increased risk of recurrent events. Randomization to pravastatin therapy prevented 54% of recurrent events among those with persistent inflammation, compared with 25% among those without (47). Similarly, in the primary prevention Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), individuals with low LDL levels (<149 mg/dl) but high CRP levels (>0.16 mg/dl) were at high risk for future cardiovascular events, and they derived substantial benefit from lovastatin therapy (relative risk compared with placebo = 0.58; 95% confidence interval, 0.34 to 0.98) (19).
Current clinical practice should not be based on these post-hoc analyses (16,43), and there are currently no prospective data that prove that lowering CRP decreases cardiovascular events or improves survival, or that establish defined targets for treatment. Thus, although substantial gains may be made by targeting statin therapy at those with heightened vascular inflammation (48), prospective randomized trials to test these hypotheses directly are needed.
The effect of aspirin on CRP levels is controversial (49,50), but the benefit of aspirin therapy in preventing future MI appears to be greatest among those with elevated CRP levels (16). As noted above, data from the FRISC-II study suggest that the benefits of an early invasive approach may be greatest among those with evidence of a heightened inflammatory response (30). In the absence of an elevated inflammatory response, a less invasive approach may prove equally effective. Again, prospective randomized studies are required to test these hypotheses directly. The possibility of novel anti-inflammatory interventions targeted at specific mediators of vascular inflammation is also appealing.
The optimal cutoff point for defining high CRP levels among patients with ACS remains to be determined. The CAPTURE group found that a threshold of 10 mg/l maximized the predictive value of CRP (25). Several other investigators have used a cutoff point of 3 mg/l for patients with ACS, while the reference ranges for primary prevention populations are lower (16,18,19). The precise cause of these different thresholds remains unclear, but it is probably related to heightened vascular inflammation at the time of presentation with ACS.
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Conclusions
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In summary, the use of CRP and other novel inflammatory markers may significantly add to our ability to correctly identify patients presenting with ACS who are at high risk for future cardiovascular events. The predictive value of CRP appears to be independent of, and in addition to, troponin. Individuals with evidence of heightened inflammation may benefit most from an aggressive modification of lifestyle and an intensification of proven preventive therapies such as aspirin and statins. Moreover, the benefits of an early invasive strategy may also be greatest among those with elevated levels of inflammatory biomarkers.
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Footnotes
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Please refer to the Trial Appendix at the back of this supplement for the complete list of clinical trials.
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F. Dentali, E. Romualdi, and W. Ageno
The metabolic syndrome and the risk of thrombosis
Haematologica,
March 1, 2007;
92(3):
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D. N. Tziakas, G. K. Chalikias, C. O. Antonoglou, S. Veletza, I. K. Tentes, A. X. Kortsaris, D. I. Hatseras, and J. C. Kaski
Apolipoprotein E Genotype and Circulating Interleukin-10 Levels in Patients With Stable and Unstable Coronary Artery Disease
J. Am. Coll. Cardiol.,
December 19, 2006;
48(12):
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[Abstract]
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P. Secchiero, R. Candido, F. Corallini, S. Zacchigna, B. Toffoli, E. Rimondi, B. Fabris, M. Giacca, and G. Zauli
Systemic Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Delivery Shows Antiatherosclerotic Activity in Apolipoprotein E-Null Diabetic Mice
Circulation,
October 3, 2006;
114(14):
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[Abstract]
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E. Lopez-Garcia, R. M van Dam, L. Qi, and F. B Hu
Coffee consumption and markers of inflammation and endothelial dysfunction in healthy and diabetic women.
Am. J. Clinical Nutrition,
October 1, 2006;
84(4):
888 - 893.
[Abstract]
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C. M. Westerhout, Y. Fu, M. S. Lauer, S. James, P. W. Armstrong, E. Al-Hattab, R. M. Califf, M. L. Simoons, L. Wallentin, E. Boersma, et al.
Short- and Long-Term Risk Stratification in Acute Coronary Syndromes: The Added Value of Quantitative ST-Segment Depression and Multiple Biomarkers
J. Am. Coll. Cardiol.,
September 5, 2006;
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Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al.
ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death)
J. Am. Coll. Cardiol.,
September 5, 2006;
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Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al.
ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society
Europace,
September 1, 2006;
8(9):
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M. Juonala, J. S.A. Viikari, T. Ronnemaa, L. Taittonen, J. Marniemi, and O. T. Raitakari
Childhood C-Reactive Protein in Predicting CRP and Carotid Intima-Media Thickness in Adulthood: The Cardiovascular Risk in Young Finns Study
Arterioscler Thromb Vasc Biol,
August 1, 2006;
26(8):
1883 - 1888.
[Abstract]
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T Kilic, D Ural, E Ural, Z Yumuk, A Agacdiken, T Sahin, G Kahraman, G Kozdag, A Vural, and B Komsuoglu
Relation between proinflammatory to anti-inflammatory cytokine ratios and long-term prognosis in patients with non-ST elevation acute coronary syndrome
Heart,
August 1, 2006;
92(8):
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[Abstract]
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A. Yilmaz, J. Weber, I. Cicha, C. Stumpf, M. Klein, D. Raithel, W. G. Daniel, and C. D. Garlichs
Decrease in Circulating Myeloid Dendritic Cell Precursors in Coronary Artery Disease
J. Am. Coll. Cardiol.,
July 4, 2006;
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K. Niu, A. Hozawa, S. Kuriyama, K. Ohmori-Matsuda, T. Shimazu, N. Nakaya, K. Fujita, I. Tsuji, and R. Nagatomi
Dietary long-chain n-3 fatty acids of marine origin and serum C-reactive protein concentrations are associated in a population with a diet rich in marine products
Am. J. Clinical Nutrition,
July 1, 2006;
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A. M. Gori, F. Sofi, A. M. Corsi, A. Gazzini, I. Sestini, F. Lauretani, S. Bandinelli, G. F. Gensini, L. Ferrucci, and R. Abbate
Predictors of Vitamin B6 and Folate Concentrations in Older Persons: The InCHIANTI Study
Clin. Chem.,
July 1, 2006;
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A. Tedgui and Z. Mallat
Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways
Physiol Rev,
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C. J. Boos, R. A. Anderson, and G. Y.H. Lip
Is atrial fibrillation an inflammatory disorder?
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D. Rothenbacher, S. Muller-Scholze, C. Herder, W. Koenig, and H. Kolb
Differential Expression of Chemokines, Risk of Stable Coronary Heart Disease, and Correlation with Established Cardiovascular Risk Markers
Arterioscler Thromb Vasc Biol,
January 1, 2006;
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M. B. Clearfield
C-Reactive Protein: A New Risk Assessment Tool for Cardiovascular Disease
J Am Osteopath Assoc,
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M. M. Chavan, P. D. Kawle, and N. G. Mehta
Increased sialylation and defucosylation of plasma proteins are early events in the acute phase response
Glycobiology,
September 1, 2005;
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Y. Michowitz, E. Goldstein, A. Roth, A. Afek, A. Abashidze, Y. Ben Gal, G. Keren, and J. George
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M. Panteghini
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Eur. Heart J.,
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I. A. Arenas, Y. Xu, P. Lopez-Jaramillo, and S. T. Davidge
Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-{alpha}
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D. B Panagiotakos, C. Pitsavos, C. Chrysohoou, E. Tsetsekou, C. Papageorgiou, G. Christodoulou, and C. Stefanadis
Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA study
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W. A. Hsueh and D. Bruemmer
Peroxisome Proliferator-Activated Receptor {gamma}: Implications for Cardiovascular Disease
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Top
Abstract
Inflammatory markers: C-reactive...