Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 2006;113:e152-e155
doi: 10.1161/CIRCULATIONAHA.105.595538
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Armstrong, E. J.
Right arrow Articles by Sabatine, M. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Armstrong, E. J.
Right arrow Articles by Sabatine, M. S.
Related Collections
Right arrow Acute coronary syndromes
Right arrowRelated Article

(Circulation. 2006;113:e152-e155.)
© 2006 American Heart Association, Inc.

Clinician Update

Inflammatory Biomarkers in Acute Coronary Syndromes

Part II: Acute-Phase Reactants and Biomarkers of Endothelial Cell Activation

Ehrin J. Armstrong, MD, MSc; David A. Morrow, MD, MPH; Marc S. Sabatine, MD, MPH

From the Department of Medicine (E.J.A.), Massachusetts General Hospital, and the TIMI Study Group (D.A.M., M.S.S.), Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Marc S. Sabatine, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail msabatine{at}partners.org


*    Introduction
up arrowTop
 *Introduction
down arrowAcute-Phase Reactants
 down arrowReferences
 
The inflammatory etiology of atherosclerosis has prompted a search for biomarkers of inflammation that predict risk for coronary artery disease and its sequelae. Within the acute coronary syndromes (ACS), inflammatory biomarkers may provide independent information regarding pathophysiology, prognosis, and optimal therapeutic strategies. On the basis of the hypothesis that different pathophysiological processes provide nonoverlapping information regarding risk stratification and disease management, this review series addresses biomarkers for each step in the inflammatory process that leads to ACS. Part I reviewed cytokines; this part reviews acute-phase reactants and biomarkers of endothelial cell activation; subsequent parts will address biomarkers of oxidative stress, angiogenesis, extracellular matrix degradation, and platelet activation.


*    Acute-Phase Reactants
up arrowTop
 up arrowIntroduction
 *Acute-Phase Reactants
down arrowReferences
 
In the acute-phase response, cytokines drive production of acute-phase reactants, defined by >25% change in circulating concentration during an inflammatory response. These markers may also remain elevated chronically because of continuing inflammatory stimuli (Table).


View this table:
[in this window]
[in a new window]
  		Inflammatory Biomarkers in ACS

C-Reactive Protein
C-reactive protein (CRP) is a pentraxin acute-phase protein, members of which are evolutionarily conserved in most vertebrates.1 Hepatocytes and possibly smooth muscle cells and macrophages transcriptionally activate production of CRP in response to inflammatory cytokines, including interleukin-1 and interleukin-6.2 CRP is a robust clinical marker because of its stability, reproducible results, and ease of assay.

Although it was originally proposed as a nonspecific marker of inflammation, several reports suggest that CRP may play a direct pathophysiological role in the development and progression of atherosclerosis. Proposed mechanisms include induction of endothelial dysfunction,3 promotion of foam cell formation,4 inhibition of endothelial progenitor cell survival and differentiation,5 and activation of complement in atherosclerotic plaque intima6 and ischemic myocardium.7

Patients with ACS have elevations in CRP in association with their presenting symptoms. There appears to be a bimodal CRP response among patients with ACS. In some patients, CRP may remain elevated for up to 3 months, whereas in others, CRP slowly declines during the hospital admission.8,9 A correlation exists between troponin elevation and CRP levels, although a significant percentage of patients without troponin elevation have elevated levels of CRP. In patients presenting with acute myocardial infarction (MI), CRP levels correlate with the presence of plaque rupture, as assessed by intravascular ultrasound.10 The cause of CRP elevations in the absence of overt myocardial necrosis is uncertain but may be related to plaque instability or myocyte necrosis below the limit of detection of standard assays.11

An early study examining CRP in ACS found that CRP identified a subset of patients with severe unstable angina at increased risk for death and MI.12 Studies of CRP elevation and short-term risk after ACS have found that CRP elevation may predict 14-day mortality.13 A meta-analysis through 2001 found that elevated CRP at admission in patients with non–ST-elevation MI (NSTEMI) or unstable angina conferred a 1.5-fold increased risk of death or nonfatal MI at 30 days.14

CRP elevations during admission for ACS also predict long-term risk of mortality. Patients with unstable angina and CRP >3 mg/L at discharge are more likely to be readmitted for recurrent cardiovascular instability or MI within 1 year.9 In a prospective study of patients who underwent early invasive therapy for non–ST-elevation ACS (NSTE ACS), CRP >10 mg/L during admission remained associated with increased risk of death over a mean follow-up of 20 months.15 Similar results were observed in the FRISC (FRagmin during InStability in Coronary artery disease) trial, in which CRP remained an independent predictor of mortality after an average of 30 months.16

Continued elevations in CRP portend increased risk of mortality despite currently available therapeutic strategies for ACS. In the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) trial,17 patients who achieved CRP levels <2 mg/L after treatment with atorvastatin or pravastatin had a decreased rate of death or recurrent MI compared with patients who achieved CRP >2 mg/L; this effect was independent of achieved cholesterol levels. These results validate intensive statin therapy after ACS and suggest that additional interventions targeted at lowering CRP in the post-MI period may provide additive benefit in this high-risk subgroup of patients.

Serum Amyloid A
Serum amyloid A (SAA) comprises a group of 3 functionally related apolipoproteins. During the acute-phase response, SAA displaces apolipoprotein (apo) AI and apoAII from high-density lipoprotein to form larger, denser high-density lipoprotein particles that have diminished ability to catalyze cholesterol esterification and efflux. These particles may subsequently promote foam cell formation.18

During acute MI, SAA levels increase within 24 hours and peak within 3 days after the onset of chest pain.19 A TIMI 11A substudy found that elevated levels of SAA predicted risk of 14-day mortality in patients with unstable angina or NSTEMI but that SAA and CRP provided essentially identical prognostic information.20 Patients with elevated SAA at discharge after hospitalization for ACS are more likely to be readmitted and/or have recurrent angina within 1 year.9 In contrast, measurement of SAA 2 months after MI in the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) Study showed no significant association between SAA and risk of recurrent cardiovascular events over 2 years.21

Biomarkers of Endothelial Cell Activation and Leukocyte Adhesion
Endothelial cells provide the barrier between circulation and the extravascular space; endothelial activation and endothelial cell–leukocyte interactions are therefore a necessary prerequisite for initiation of inflammatory processes that predispose to ACS. Plasma-derived soluble forms of the immunoglobulin family members intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as soluble forms of E-selectin, have been studied as possible biomarkers in ACS. In addition, levels of von Willebrand factor (vWF) may reflect endothelial cell activation acutely during ACS.

von Willebrand Factor
vWF is a multimeric glycoprotein stored in preformed endothelial Weibel-Palade bodies and platelet {alpha}-granules that activates platelets and mediates clot formation via association with factor VIII. In humans, the majority of serum vWF appears to be of endothelial origin.22

In patients with ACS, vWF levels are elevated at admission, peak within &24 hours, and return to baseline within 3 days.23 In an Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events (ESSENCE) trial substudy, the magnitude of vWF increase ({Delta}vWF) over the first 48 hours in patients with NSTE ACS was an independent predictor of the composite end point of death, MI, recurrent angina, or revascularization at 14 and 30 days.24 In a study of 153 consecutive patients presenting with ST-elevation MI (STEMI), {Delta}vWF over the first 24 hours was an independent predictor of mortality at 30 days.23 In an ENTIRE-TIMI 23 (ENoxaparin and Tenecteplase with or without glycoprotein IIb/IIIa Inhibitor as REperfusion strategy in ST-elevation MI–Thrombolysis In Myocardial Infarction) substudy of patients undergoing fibrinolysis for STEMI, increased {Delta}vWF at 48 to 72 hours compared with baseline was associated with poor coronary artery flow at presentation and with increased risk of death or MI at 30 days.25

The rise in vWF during ACS may reflect impaired tissue perfusion with subsequent endothelial activation. The {Delta}vWF is an independent predictor of adverse outcomes in both NSTE ACS and STEMI, but clinical implications for an individual patient remain unclear, apart from the apparent benefit of enoxaparin relative to unfractionated heparin. In the future, early determination of endothelial activation may identify a subset of patients who would derive greatest benefit from enoxaparin relative to other anticoagulants.

Soluble ICAM-1
ICAM-1 is a transmembrane immunoglobulin superfamily protein expressed by endothelial cells, leukocytes, fibroblasts, smooth muscle cells, cardiomyocytes, and many other noncardiac cell types.26 ICAM-1 is expressed at basal levels on endothelial cells and is upregulated in response to inflammatory stimuli; the increased ICAM-1 expression promotes leukocyte adhesion and arrest.

A soluble form of ICAM-1 (sICAM-1) is released into the circulation, probably owing to shedding and the action of neutrophil elastase and matrix metalloproteinases on membrane-bound ICAM-1. sICAM-1 levels are elevated within 10 hours of chest pain onset in ACS and remain elevated above control levels for months.27

A prospective study of 119 patients presenting with chest pain suggestive for ACS failed to reveal any association between sICAM-1 and the risk of a serious cardiac event during hospital admission.28 Although sICAM-1 remains a robust predictor of cardiovascular disease incidence, larger prospective studies will be necessary for the study of secondary prevention. On the basis of studies in the acute setting, it does not currently appear that sICAM-1 has immediate use in risk stratification of patients with ACS.

Soluble VCAM-1
VCAM-1 is a transmembrane immunoglobulin superfamily protein expressed by activated endothelial cells and smooth muscle cells. VCAM-1 binds to VLA-4, an integrin expressed by monocytes, lymphocytes, and eosinophils; this interaction promotes firm cell-cell adhesion and eventual transmigration of inflammatory cells.29

Like ICAM-1, transmembrane VCAM-1 is cleaved to a soluble form (sVCAM-1). Patients with ACS have higher circulating levels of sVCAM-1 relative to healthy patients or patients with stable angina. Patients with in-hospital adverse coronary events are more likely to have higher admission levels of sVCAM-1; this association is independent of CRP.30 In a prospective study of patients with NSTEMI, sVCAM-1 levels were significantly higher at presentation in patients who had a major adverse cardiovascular event at 6 months.31

These initial studies suggest that sVCAM-1 may be a useful marker to predict medium- to long-term risk in patients with ACS. More prospective studies in the acute setting will be necessary before sVCAM-1 can be validated as a marker of in-hospital risk.

Soluble E-Selectin
E-selectin is an endothelial cell–specific selectin that stabilizes leukocyte-endothelial cell interactions by promoting cell-cell adhesion. E-selectin is not expressed on quiescent endothelial cells but is upregulated over the course of hours in response to inflammatory stimuli. Like ICAM-1 and VCAM-1, E-selectin is cleaved to a soluble form (sE-selectin) that may be a surrogate marker for the extent of microcirculatory endothelial cell activation.

Studies have conflicted on measurements of sE-selectin in ACS, with some studies suggesting an association between E-selectin levels and ACS, whereas others found no relationship.31 The major utility of sE-selectin and other markers of endothelial cell activation may be in predicting risk of developing coronary artery disease and risk of death in patients with stable coronary artery disease, rather than as a risk stratification marker in ACS.32


*    Acknowledgments
 
Disclosures

Dr Morrow receives research grant support from Bayer Diagnostics, Beckman-Coulter, Biosite, Dade-Behring, and Roche Diagnostics; receives honoraria for educational presentations from Bayer, Beckman, and Dade-Behring; and serves on the advisory board of OrthoClinical Diagnostics. Dr Sabatine receives research grant support from Roche. Dr Armstrong reports no conflicts.


*    Footnotes
 
This article is Part II of a 4-part article. Part I appeared in the February 14, 2006, issue of Circulation (Circulation. 2006;113:e72–e75). Part III will appear in the February 28, 2006, issue, and Part IV will appear in the March 7, 2006, issue.


*    References
up arrowTop
 up arrowIntroduction
 up arrowAcute-Phase Reactants
 *References
 

  1. Pepys M, Hirschfield G. C-reactive protein: a critical update. J Clin Invest. 2003; 111: 1805–1812.[CrossRef][Medline] [Order article via Infotrieve]
  2. Calabro P, Willerson J, Yeh E. Inflammatory cytokines stimulate C-reactive protein production by human coronary artery smooth muscle cells. Circulation. 2003; 108: 1930–1932.[CrossRef][Medline] [Order article via Infotrieve]
  3. Pasceri V, Willerson J, Yeh E. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165–2168.[Abstract/Free Full Text]
  4. Zwaka T, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001; 103: 1194–1197.[Medline] [Order article via Infotrieve]
  5. Verma S, Kuliszewski M, Li S, Szmitko P, Zucco L, Wang C, Badiwala M, Mickle D, Weisel R, Fedak P, Stewart D, Kutryk M. C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation. 2004; 109: 2058–2067.[CrossRef][Medline] [Order article via Infotrieve]
  6. Torzewski J, Torzewski M, Bowyer D, Frohlich M, Koenig W, Waltenberger J, Fitzsimmons C, Hombach V. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol. 1998; 18: 1386–1392.[Abstract/Free Full Text]
  7. Lagrand W, Niessen H, Wolbink G, Jaspars L, Visser C, Verheugt F, Meijer C, Hack C. C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation. 1997; 95: 97–103.[Medline] [Order article via Infotrieve]
  8. Ferreiros E, Boissonnet C, Pizarro R, Merletti P, Corrado G, Cagide A, Bazzino O. Independent prognostic value of elevated C-reactive protein in unstable angina. Circulation. 1999; 100: 1958–1963.[Medline] [Order article via Infotrieve]
  9. Biasucci L, Liuzzo G, Grillo R, Caligiuri G, Rebuzzi A, Buffon A, Summaria F, Ginnetti F, Fadda G, Maseri A. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation. 1999; 99: 855–860.[Medline] [Order article via Infotrieve]
  10. Sano T, Tanaka A, Namba M, Nishibori Y, Nishida Y, Kawarabayashi T, Fukuda D, Shimada K, Yoshikawa J. C-reactive protein and lesion morphology in patients with acute myocardial infarction. Circulation. 2003; 108: 282–285.[CrossRef][Medline] [Order article via Infotrieve]
  11. Hoffmeister H, Ehlers R, Buttcher E, Steinmetz A, Kazmaier S, Helber U, Szabo S, Beyer M, Seipel L. Relationship between minor myocardial damage and inflammatory acute-phase reaction in acute coronary syndromes. J Thromb Thrombolysis. 2003; 15: 33–39.[CrossRef][Medline] [Order article via Infotrieve]
  12. Liuzzo G, Biasucci L, Gallimore J, Grillo R, Rebuzzi A, Pepys M, Maseri A. 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]
  13. Morrow D, Rifai N, Antman E, Werner D, McCabe C, Cannon C, Braunwald E. C-reactive protein is a potent predictor of mortality independently and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. J Am Coll Cardiol. 1998; 31: 1460–1465.[Abstract/Free Full Text]
  14. Galvani M, Ferrini D, Ghezzi F, Ottani F. Cardiac markers and risk stratification: an integrated approach. Clin Chim Acta. 2001; 311: 9–17.[CrossRef][Medline] [Order article via Infotrieve]
  15. Mueller C, Buettner H, Hodgson J, Marsch S, Perruchoud A, Roskamm H, Neumann F. Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive patients. Circulation. 2002; 105: 1412–1415.[Abstract/Free Full Text]
  16. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. N Engl J Med. 2000; 343: 1139–1147.[Abstract/Free Full Text]
  17. Ridker P, Cannon C, Morrow D, Rifai N, Rose L, McCabe C, Pfeffer M, Braunwald E. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005; 352: 20–28.[Abstract/Free Full Text]
  18. Van Lenten B, Hama S, de Beer F, Stafforini D, McIntyre T, Prescott S, La Du B, Fogelman A, Navab M. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. J Clin Invest. 1995; 96: 2758–2767.[Medline] [Order article via Infotrieve]
  19. Shainkin-Kestenbaum R, Winikoff Y, Cristal N. Serum amyloid A concentrations during the course of acute ischaemic heart disease. J Clin Pathol. 1986; 39: 635–637.[Abstract/Free Full Text]
  20. Morrow D, Rifai N, Antman E, Weiner D, McCabe C, Cannon C, Braunwald E. Serum amyloid A predicts early mortality in acute coronary syndromes: a TIMI 11A substudy. J Am Coll Cardiol. 2000; 35: 358–362.[Abstract/Free Full Text]
  21. Harb T, Zareba W, Moss A, Ridker P, Marder V, Rifai N, Miller-Watelet L, Arora R, Brown M, Case R, Dwyer EJ, Gillespie J, Goldstein R, Greenberg H, Hochman J, Krone R, Liang C, Lichstein E, Little W, Marcus F, Oakes D, Sparks C, VanVoorhees L. Association of C-reactive protein and serum amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction. Am J Cardiol. 2002; 89: 216–221.[CrossRef][Medline] [Order article via Infotrieve]
  22. Ware R, Parker R, McKeown L, Graham M. A human chimera for von Willebrand disease following bone marrow transplantation. Am J Pediatr Hematol Oncol. 1993; 15: 338–342.[Medline] [Order article via Infotrieve]
  23. Collet J, Montalescot G, Vicaut E, Ankri A, Walylo F, Lesty C, Choussat R, Beygui F, Borentain M, Vignolles N, Thomas D. Acute release of plasminogen activator inhibitor-1 in ST-segment elevation myocardial infarction predicts mortality. Circulation. 2003; 108: 391–394.[CrossRef][Medline] [Order article via Infotrieve]
  24. Montalescot G, Phillipe F, Ankri A, Vicaut E, Bearez E, Poulard J, Carrie D, Flammang D, Dutoit A, Carayon A, Jardel C, Chevrot M, Bastard J, Bigonzi F, Thomas D. Early increase in von Willebrand factor predicts adverse outcomes in unstable coronary artery disease. Circulation. 1998; 98: 294–299.[Medline] [Order article via Infotrieve]
  25. Ray K, Morrow D, Gibson C, Murphy S, Antman E, Braunwald E. Predictors of the rise in vWF after ST elevation myocardial infarction: implications for treatment strategies and clinical outcome. Eur Heart J. 2005; 26: 440–446.[Abstract/Free Full Text]
  26. Niessen H, Krijnen P, Visser C, Meijer C, Hack C. Intercellular adhesion molecule-1 in the heart. Ann NY Acad Sci. 2002; 973: 573–585.[Abstract/Free Full Text]
  27. Mulvihill N, Foley J, Murphy R, Crean P, Walsh M. Evidence of prolonged inflammation in unstable angina and non-Q wave myocardial infarction. J Am Coll Cardiol. 2000; 36: 1210–1216.[Abstract/Free Full Text]
  28. Hillis G, Terregino C, Taggart P, Killian A, Zhao N, Kaplan J, Dalsey W, Mangione A. Soluble intercellular adhesion molecule-1 as a predictor of early adverse events in patients with chest pain compatible with myocardial ischemia. Ann Emerg Med. 2001; 38: 223–228.[CrossRef][Medline] [Order article via Infotrieve]
  29. Elices M, Osborn L, Takada Y, Crouse C, Luhowskj S, Hemler M, Lobb R. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell. 1990; 60: 577–584.[CrossRef][Medline] [Order article via Infotrieve]
  30. Rallidis L, Gika H, Zolindaki M, Xydas T, Paravolidakis K, Velissaridou A. Usefulness of elevated levels of soluble vascular cell adhesion molecule-1 in predicting in-hospital prognosis in patients with unstable angina pectoris. Am J Cardiol. 2003; 92: 1195–1197.[CrossRef][Medline] [Order article via Infotrieve]
  31. Mulvihill N, Foley J, Murphy R, Curtin R, Crean P, Walsh M. Risk stratification in unstable angina and non-Q wave myocardial infarction using soluble cell adhesion molecules. Heart. 2001; 85: 623–627.[Abstract/Free Full Text]
  32. Blankenberg S, Rupprecht H, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001; 104: 1336–1342.[Abstract/Free Full Text]

Related Article:

Issue Highlights
Circulation 2006 113: 919. [Full Text]



This article has been cited by other articles:


Home page
 HeartHome page
W Wojakowski, M Kucia, M Kazmierski, M Z Ratajczak, and M Tendera
Circulating progenitor cells in stable coronary heart disease and acute coronary syndromes: relevant reparatory mechanism?
Heart, January 1, 2008; 94(1): 27 - 33.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
R. C. Becker
Emerging Paradigms, Platforms, and Unifying Themes in Biomarker Science
J. Am. Coll. Cardiol., October 30, 2007; 50(18): 1777 - 1780.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
C. Zoccali, G. Tripepi, and F. Mallamaci
Dissecting Inflammation in ESRD: Do Cytokines and C-Reactive Protein Have a Complementary Prognostic Value for Mortality in Dialysis Patients?
J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S169 - S173.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
R. P. Giugliano and E. Braunwald
The Year in Non-ST-Segment Elevation Acute Coronary Syndromes
J. Am. Coll. Cardiol., July 18, 2006; 48(2): 386 - 395.
[Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Armstrong, E. J.
Right arrow Articles by Sabatine, M. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Armstrong, E. J.
Right arrow Articles by Sabatine, M. S.
Related Collections
Right arrow Acute coronary syndromes
Right arrowRelated Article

Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2006 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.