Unstable coronary disease is heterogeneous in etiology and prognosis. Different factors including inflammation can precipitate acute coronary syndromes, and a growing body of evidence supports the role of inflammation in atherogenesis and also thrombosis in some patients with acute coronary syndromes (1). Since early reports of elevation of CRP levels in AMI (2), numerous studies have investigated the prognostic value of CRP measurement at different thresholds in ACS.

Plasma CRP levels peak around 40-50 hours following a heart attack (3), and elevated CRP levels over 200 mg/L early after AMI have been associated with cardiac rupture and 1-year cardiac death (4).

CRP levels were found to be elevated above 6 mg/L in patients with unstable angina (5) and in a small study by A. Maseri's group, elevated CRP above 3 mg/L but normal cardiac troponin T levels in patients presenting with unstable angina, was associated with poor outcomes in the short-term: a significantly greater risk of angina and trends for the need for revascularization and for death/MI (6). In the larger TIMI 11A trial, elevated CRP above or equal to 15 mg/L in patients presenting with unstable angina or non-Q wave MI was predictive of 14-day mortality, including in those patients without evidence of myonecrosis by measurement of cardiac troponin T (7). Data from the FRISC trial further showed that in patients with unstable coronary artery disease, elevated high-sensitivity CRP (hs-CRP) levels above 10 mg/L were predictive of 2-year cardiac mortality at all levels of troponin T, and CRP and troponin T as independent risk markers were found to be additive in their effects (8).

The overall weight of evidence shows hs-CRP levels in ACS to have a strong relationship with short- and long-term outcomes, and the American Heart Association and Centers for Disease Control recommended in 2003 that hs-CRP measurement may be useful as an independent marker to assess the likelihood of recurrent events including death, MI, or restenosis after PCI, in patients with documented CAD or ACS; application of secondary preventive measures with proven efficacy should not however depend on hs-CRP levels (9).

In terms of short- and long-term risk assessment, the CAPTURE trial of over 400 patients with unstable angina showed elevated CRP levels to predict death or MI during 6 month follow-up, but not within the first 72 hours, although the level of risk appeared to increase with time and an early divergence was seen in risk between CRP positive patients (with CRP levels over 10 mg/L) and CRP negative patients (10). In the previously mentioned study by Maseri's group and the TIMI 11A trial, CRP was found to predict short-term outcomes in patients with unstable angina (6,7). Hs-CRP measurement in ACS seems to have a stronger predictive value for death as compared to MI/ recurrent ischaemic events (11,12).

With respect to the timing of hs-CRP measurement in patients with ACS, there is evidence to support taking the measurement early after presentation for the evaluation of prognosis (11,13,14). CRP can also be measured in ambulatory follow-up as indicated in the large PROVE-IT TIMI 22 trial, where measurement of CRP 30 days after ACS was predictive of recurrent MI/coronary death (15). Also, studies suggest that higher clinical cut-points are more appropriate for risk assessment in patients with ACS as compared to those at risk for coronary disease (10,11, 16).

Dr. Morrow concludes the presentation by discussing the pathobiology of risk with CRP in ACS and potential direct effects of CRP on atherothrombosis, as well as measures that can be taken to lower hs-CRP levels in ACS patients, and the responses to different treatment therapies in relation to hs-CRP levels in patients with ACS (10,11,15,17).

Copyright © 2005 MULTIWEBCAST "State-of-the-Art Webcast Services"

After viewing this presentation the participant will be able to discuss contemporary issues for CRP in ACS:

- Short vs Long-term risk
- Risk relationships: death versus recurrent ischemic events
- Optimal timing of measurements
- Appropriate cut-points
- Pathobiology
- Therapeutic response

1. Eugene Braunwald, MD Unstable Angina: An Etiologic Approach to Management Circulation. 1998;98:2219-2222.

2. Löfström Acta Med Scandinav Suppl 1943; 141:69.

3. Kari Pietilä MD, Wim T. Hermens PhD, Aimo Harmoinen MS, Taco Baardman MD, Amos Pasternack MD, Eric J. Topol MD and Maarten L. Simoons MDComparison of peak serum C-reactive protein and hydroxybutyrate dehydrogenase levels in patients with acute myocardial infarction treated with alteplase and streptokinaseThe American Journal of Cardiology
Volume 80, Issue 8 , 15 October 1997, Pages 1075-1077.

4. Toshihisa Anzai, MD; Tsutomu Yoshikawa, MD; Hiroto Shiraki, MD; Yasushi Asakura, MD; Makoto Akaishi, MD; Hideo Mitamura, MD; ; Satoshi Ogawa, MDC-Reactive Protein as a Predictor of Infarct Expansion and Cardiac Rupture After a First Q-Wave Acute Myocardial Infarction Circulation. 1997;96:778-784.

5. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in "active" coronary artery diseaseAm J Cardiol. 1990 Jan 15;65(3):168-72.

6. Giovanna Liuzzo, Luigi M. Biasucci, J. Ruth Gallimore, Rita L. Grillo, Antonio G. Rebuzzi, Mark B. Pepys, and Attilio Maseri The Prognostic Value of C-Reactive Protein and Serum Amyloid A Protein in Severe Unstable Angina NEJM Volume 331:417-424 August 18, 1994.

7. David A. Morrow MD, Nader Rifai PhD, Elliott M. Antman MD, FACC, Debra L. Weiner MD, PhD, Carolyn H. McCabe BS, Christopher P. Cannon MD, FACC and Eugene Braunwald MD, FACCC-Reactive Protein Is a Potent Predictor of Mortality Independently of and in Combination With Troponin T in Acute Coronary Syndromes: A TIMI 11A SubstudyJournal of the American College of Cardiology
Volume 31, Issue 7 , June 1998, Pages 1460-1465.

8. Bertil Lindahl, M.D., Ph.D., Henrik Toss, M.D., Agneta Siegbahn, M.D., Ph.D., Per Venge, M.D., Ph.D., Lars Wallentin, M.D., Ph.D., for The FRISC Study Group Markers of Myocardial Damage and Inflammation in Relation to Long-Term Mortality in Unstable Coronary Artery Disease
NEJM Volume 343:1139-1147 October 19, 2000.

9. Thomas A. Pearson, MD, PhD (Co-Chair); George A. Mensah, MD (Co-Chair); R. Wayne Alexander, MD, PhD; Jeffrey L. Anderson, MD; Richard O. Cannon, III, MD; Michael Criqui, MD; Yazid Y. Fadl, MD; Stephen P. Fortmann, MD; Yuling Hong, MD, PhD; Gary L. Myers, PhD; Nader Rifai, PhD; Sidney C. Smith, Jr, MD; Kathryn Taubert, PhD; Russell P. Tracy, PhD; Frank Vinicor, MD 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.

10. Christopher Heeschen MD, Christian W. Hamm MD, FACC, Jens Bruemmer MD, Maarten L. Simoons MD, FACC and for the CAPTURE Investigators Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis Journal of the American College of Cardiology Volume 35, Issue 6 , May 2000, Pages 1535-1542.

11. Cannon et al. ACC 2001.

12. Stefan K. James MD, Paul Armstrong MD, Elliott Barnathan MD, PhD, Robert Califf MD, Bertil Lindahl MD, PhD, Agneta Siegbahn MD, PhD, Maarten L. Simoons MD, PhD, Eric J. Topol MD, Per Venge MD, PhD, Lars Wallentin MD, PhD and GUSTO-IV–ACS InvestigatorsTroponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: A GUSTO-IV substudy Journal of the American College of Cardiology
Volume 41, Issue 6 , 19 March 2003, Pages 916-924.

13. Robbert J. de Winter, Johan Fischer, Radha Bholasingh, Jan P. van Straalen, Thyra de Jong, Jan G.P. Tijssen and Gerard T. SandersC-Reactive Protein and Cardiac Troponin T in Risk Stratification: Differences in Optimal Timing of Tests Early after the Onset of Chest Pain Clinical Chemistry. 2000;46:1597-1603.

14. Stefano Tommasi MD, Erberto Carluccio MD, Maurizio Bentivoglio MD, Massimo Buccolieri MD, Myriam Mariotti MD, Massimo Politano MD and Luigi Corea MDC-reactive protein as a marker for cardiac ischemic events in the year after a first, uncomplicated myocardial infarction The American Journal of Cardiology Volume 83, Issue 12 , 15 June 1999, Pages 1595-1599.

15. Paul M Ridker, M.D., Christopher P. Cannon, M.D., David Morrow, M.D., Nader Rifai, Ph.D., Lynda M. Rose, M.S., Carolyn H. McCabe, B.S., Marc A. Pfeffer, M.D., Ph.D., Eugene Braunwald, M.D., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) Investigators C-Reactive Protein Levels and Outcomes after Statin Therapy NEJM Volume 352:20-28 January 6, 2005.

16. Ernesto R. Ferreirós, MD; Carlos P. Boissonnet, MD; Rodolfo Pizarro, MD; Pablo F. García Merletti, MD; Gianni Corrado, MD; Arturo Cagide, MD; Oscar O. Bazzino, MD Independent Prognostic Value of Elevated C-Reactive Protein in Unstable Angina Circulation. 1999;100:1958-1963.

17. Derek P. Chew MBBS, Deepak L. Bhatt MD, Mark A. Robbins MD, Debabrata Mukherjee MD, Marco Roffi MD, Jakob P. Schneider RN, Eric J. Topol MD and Stephen G. Ellis MD. Effect of Clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein The American Journal of Cardiology Volume 88, Issue 6 , 15 September 2001, Pages 672-674.