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Review |
1 Department of Laboratory Medicine and Pathology, Hennepin County Medical Center, Minneapolis, MN.
2 Department of Laboratory Medicine, University of California, San Francisco, San Francisco General Hospital, San Francisco, CA.
3 Clinical Division of Cardiology, Medical University Innsbruck, Innsbruck Austria.
4 Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
5 Dipartmento di Scienze Cliniche "Luigi Sacco", Univesita degli Studi di Milano, Milan, Italy.
6 Department of Chemical Pathology, Queensland Health Pathology Service, Princess Alexandra Hospital, Brisbane, Australia.
7 Laboratorio Analisi Chimico Cliniche 1, Azienda Ospedaliera Spedali Civili, Brescia, Italy.
8 Department of Pathology, University of Maryland, Baltimore, MD.
Departments of9
Medicine and10
Cardiology, University Hospital Charite, Berlin, Germany.
11 Department of Laboratory Medicine and Cardiology, Mayo Clinic, Rochester, MN.
aAddress correspondence to this author at: Hennepin County Medical Center, Clinical Laboratories P4, 701 Park Ave., Minneapolis, MN 55415. Fax 612-904-4229; e-mail fred.apple{at}co.hennepin.mn.us.
Background: Evaluation of patients who present to the hospital with a complaint of chest pain or other signs or symptoms suggestive of acute coronary syndrome (ACS) is time-consuming, expensive, and problematic. Recent investigations have indicated that increases in biomarkers upstream from biomarkers of necrosis (cardiac troponins I and T), such as inflammatory cytokines, cellular adhesion molecules, acute-phase reactants, plaque destabilization and rupture biomarkers, biomarkers of ischemia, and biomarkers of myocardial stretch may provide earlier assessment of overall patient risk and aid in identifying patients with higher risk of an adverse event.
Approach and Content: The purpose of this review is to provide an overview of the pathophysiology and clinical and analytical characteristics of several biomarkers that may have potential clinical utility to identify ACS patients. These biomarkers (myeloperoxidase, metalloproteinase-9, soluble CD40 ligand, pregnancy-associated plasma protein A, choline, ischemia-modified albumin, unbound free fatty acids, glycogen phosphorylase isoenzyme BB, and placental growth factor) have demonstrated promise and need to be more thoroughly evaluated for commercial development for implementation into routine clinical and laboratory practice.
Summary: Specifications that have been addressed for cardiac troponins and natriuretic peptides will need to be addressed with the same scrutiny for the biomarkers discussed in this review. They include validating analytical imprecision and detection limits, calibrator characterization, assay specificity and standardization, preanalytical issues, and appropriate reference interval studies. Crossing boundaries from research to clinical application will require replication in multiple settings and experimental evidence supporting a pathophysiologic role and, ideally, interventional trials demonstrating that monitoring single or multiple biomarkers improves outcomes.
The following articles in journals at HighWire Press have cited this article:
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  M. Markovic, S. Ignjatovic, N. Majkic-Singh, and M. Dajak Placental Growth Factor in Acute Coronary Syndrome Patients with Non ST-Elevation Lab Med, November 1, 2009; 40(11): 675 - 678. [Abstract] [Full Text] [PDF]
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 N. V. Bhagavan, J.-S. Ha, J.-H. Park, S. A. Honda, C. N. Rios, C. Sugiyama, G. K. Fujitani, I. K. Takeuchi, and C.-E. Ha Utility of Serum Fatty Acid Concentrations as a Marker for Acute Myocardial Infarction and Their Potential Role in the Formation of Ischemia-Modified Albumin: A Pilot Study Clin. Chem., August 1, 2009; 55(8): 1588 - 1590. [Full Text] [PDF]
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P. N. Floriano, N. Christodoulides, C. S. Miller, J. L. Ebersole, J. Spertus, B. G. Rose, D. F. Kinane, M. J. Novak, S. Steinhubl, S. Acosta, et al. Use of Saliva-Based Nano-Biochip Tests for Acute Myocardial Infarction at the Point of Care: A Feasibility Study Clin. Chem., August 1, 2009; 55(8): 1530 - 1538. [Abstract] [Full Text] [PDF]
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 H Demir, B C Topkaya, A R Erbay, M Dogan, and D Yucel Ischaemia-modified albumin elevation after percutaneous coronary intervention reflects albumin concentration rather than ischaemia Ann Clin Biochem, July 1, 2009; 46(4): 327 - 331. [Abstract] [Full Text] [PDF]
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 Y. Makino and K. Omichi Sensitive Assay of Glycogen Phosphorylase Activity by Analysing the Chain-Lengthening Action on a Fluologenic Maltooligosaccharide Derivative J. Biochem., July 1, 2009; 146(1): 71 - 76. [Abstract] [Full Text] [PDF]
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 U. Hanusch-Enserer, G. Zorn, J. Wojta, C. W. Kopp, R. Prager, W. Koenig, M. Schillinger, M. Roden, and K. Huber Non-conventional markers of atherosclerosis before and after gastric banding surgery Eur. Heart J., June 2, 2009; 30(12): 1516 - 1524. [Abstract] [Full Text] [PDF]
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G. Lippi, G. L. Salvagno, A. M. Minicozzi, M. Montagnana, C. Cordiano, G. De Manzoni, and G. C. Guidi Biomarkers of Myocardial Infarction in Patients Undergoing Gastrointestinal Cancer Surgery Lab Med, February 1, 2009; 40(2): 91 - 95. [Abstract] [Full Text] [PDF]
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F. S. Apple, S. W. Smith, L. A. Pearce, and M. M. Murakami Assessment of the Multiple-Biomarker Approach for Diagnosis of Myocardial Infarction in Patients Presenting with Symptoms Suggestive of Acute Coronary Syndrome Clin. Chem., January 1, 2009; 55(1): 93 - 100. [Abstract] [Full Text] [PDF]
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A. H.B. Wu Novel Biomarkers of Cardiovascular Disease: Myeloperoxidase for Acute and/or Chronic Heart Failure? Clin. Chem., January 1, 2009; 55(1): 12 - 14. [Full Text] [PDF]
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 A Mentese, U Mentese, S Turedi, A Gunduz, S C Karahan, M Topbas, A Turan, T Patan, S Turkmen, G Okur, et al. Effect of deep vein thrombosis on ischaemia-modified albumin levels Emerg. Med. J., December 1, 2008; 25(12): 811 - 814. [Abstract] [Full Text] [PDF]
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 A. V. G. Edwards, M. Y. White, and S. J. Cordwell The Role of Proteomics in Clinical Cardiovascular Biomarker Discovery Mol. Cell. Proteomics, October 1, 2008; 7(10): 1824 - 1837. [Abstract] [Full Text] [PDF]
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 P O Collinson and D C Gaze Ischaemia-modified albumin: clinical utility and pitfalls in measurement J. Clin. Pathol., September 1, 2008; 61(9): 1025 - 1028. [Full Text] [PDF]
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A. S. Jaffe Key Issues in the Developing Synergism between Cardiovascular Imaging and Biomarkers Clin. Chem., September 1, 2008; 54(9): 1432 - 1442. [Abstract] [Full Text] [PDF]
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B. Yue, E. Pattison, W. L. Roberts, A. L. Rockwood, O. Danne, C. Lueders, and M. Mockel Choline in Whole Blood and Plasma: Sample Preparation and Stability Clin. Chem., March 1, 2008; 54(3): 590 - 593. [Abstract] [Full Text] [PDF]
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 U Ekelund and J L Forberg New methods for improved evaluation of patients with suspected acute coronary syndrome in the emergency department Postgrad. Med. J., February 1, 2008; 84(988): 83 - 86. [Abstract] [Full Text] [PDF]
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U Ekelund and J L Forberg New methods for improved evaluation of patients with suspected acute coronary syndrome in the emergency department Emerg. Med. J., December 1, 2007; 24(12): 811 - 814. [Abstract] [Full Text] [PDF]
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 G. Onder, E. Capoluongo, M. Cesari, P. Lulli, R. Liperoti, B. Giardina, A. Russo, R. Bernabei, and F. Landi Association of Calcium Channel Blocker Use and Pregnancy-Associated Plasma Protein-A Among Older Adults With Hypertension: Results From the ilSIRENTE Study J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2007; 62(11): 1274 - 1278. [Abstract] [Full Text] [PDF]
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 J. K. Dunnick, K. A. Thayer, and G. S. Travlos Inclusion of Biomarkers for Detecting Perturbations in the Heart and Lung and Lipid/Carbohydrate Metabolism in National Toxicology Program Studies Toxicol. Sci., November 1, 2007; 100(1): 29 - 35. [Abstract] [Full Text] [PDF]
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 R. Latini, S. Masson, I. S. Anand, E. Missov, M. Carlson, T. Vago, L. Angelici, S. Barlera, G. Parrinello, A. P. Maggioni, et al. Prognostic Value of Very Low Plasma Concentrations of Troponin T in Patients With Stable Chronic Heart Failure Circulation, September 11, 2007; 116(11): 1242 - 1249. [Abstract] [Full Text] [PDF]
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S. Bagwe, R. Sachdeva, and J. L. Mehta High-risk ACS patients and cardiac biomarkers in the emergency department: any role for new biomarkers of myocardial ischaemia? Reply Eur. Heart J., September 2, 2007; 28(18): 2297 - 2298. [Full Text] [PDF]
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 M. York, C. Scudamore, S. Brady, C. Chen, S. Wilson, M. Curtis, G. Evans, W. Griffiths, M. Whayman, T. Williams, et al. Characterization of Troponin Responses in Isoproterenol-Induced Cardiac Injury in the Hanover Wistar Rat Toxicol Pathol, June 1, 2007; 35(4): 606 - 617. [Abstract] [Full Text] [PDF]
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F. S. Apple, L. A. Pearce, A. Chung, R. Ler, and M. M. Murakami Multiple Biomarker Use for Detection of Adverse Events in Patients Presenting with Symptoms Suggestive of Acute Coronary Syndrome Clin. Chem., May 1, 2007; 53(5): 874 - 881. [Abstract] [Full Text] [PDF]
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NACB WRITING GROUP MEMBERS, D. A. Morrow, C. P. Cannon, R. L. Jesse, L. K. Newby, J. Ravkilde, A. B. Storrow, A. H.B. Wu, and R. H. Christenson National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes Circulation, April 3, 2007; 115(13): e356 - e375. [Full Text] [PDF]
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NACB WRITING GROUP MEMBERS, D. A. Morrow, C. P. Cannon, R. L. Jesse, L. K. Newby, J. Ravkilde, A. B. Storrow, A. H.B. Wu, R. H. Christenson, NACB COMMITTEE MEMBERS, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes Clin. Chem., April 1, 2007; 53(4): 552 - 574. [Full Text] [PDF]
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 E. Johannsson, T. Henriksen, and P. O. Iversen Increase in matrix metalloproteinases from endothelial cells exposed to umbilical cord plasma from high birth weight newborns Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1563 - R1568. [Abstract] [Full Text] [PDF]
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T. N. Patel, M. H. Shishehbor, and D. L. Bhatt A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis Eur. Heart J., March 2, 2007; 28(6): 664 - 672. [Abstract] [Full Text] [PDF]
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M. Puls, C. Dellas, M. Lankeit, M. Olschewski, L. Binder, A. Geibel, C. Reiner, K. Schafer, G. Hasenfuss, and S. Konstantinides Heart-type fatty acid-binding protein permits early risk stratification of pulmonary embolism Eur. Heart J., January 2, 2007; 28(2): 224 - 229. [Abstract] [Full Text] [PDF]
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M. Adamczyk, R. J. Brashear, and P. G. Mattingly Choline concentration in normal blood donor and cardiac troponin-positive plasma samples. Clin. Chem., November 1, 2006; 52(11): 2123 - 2124. [Full Text] [PDF]
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 B. A. Merrick, M. E. Bruno, J. H. Madenspacher, B. A. Wetmore, J. Foley, R. Pieper, M. Zhao, A. J. Makusky, A. M. McGrath, J. X. Zhou, et al. Alterations in the Rat Serum Proteome during Liver Injury from Acetaminophen Exposure J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 792 - 802. [Abstract] [Full Text] [PDF]
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 A. S. Jaffe, L. Babuin, and F. S. Apple Biomarkers in Acute Cardiac Disease: The Present and the Future J. Am. Coll. Cardiol., July 4, 2006; 48(1): 1 - 11. [Abstract] [Full Text] [PDF]
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T. Mueller, B. Dieplinger, W. Poelz, and M. Haltmayer Increased Pregnancy-Associated Plasma Protein-A as a Marker for Peripheral Atherosclerosis: Results from the Linz Peripheral Arterial Disease Study Clin. Chem., June 1, 2006; 52(6): 1096 - 1103. [Abstract] [Full Text] [PDF]
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R. S. Vasan Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations Circulation, May 16, 2006; 113(19): 2335 - 2362. [Full Text] [PDF]
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M. Weber, B. Rabenau, M. Stanisch, A. Elsaesser, V. Mitrovic, C. Heeschen, and C. Hamm Influence of Sample Type and Storage Conditions on Soluble CD40 Ligand Assessment Clin. Chem., May 1, 2006; 52(5): 888 - 891. [Abstract] [Full Text] [PDF]
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H. M.E. Azzazy, M. M.A.L. Pelsers, and R. H. Christenson Unbound Free Fatty Acids and Heart-Type Fatty Acid-Binding Protein: Diagnostic Assays and Clinical Applications Clin. Chem., January 1, 2006; 52(1): 19 - 29. [Abstract] [Full Text] [PDF]
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R. H. Christenson, C. P. deFilippi, and D. Kreutzer Biomarkers of Ischemia in Patients With Known Coronary Artery Disease: Do Interleukin-6 and Tissue Factor Measurements During Dobutamine Stress Echocardiography Give Additional Insight? Circulation, November 22, 2005; 112(21): 3215 - 3217. [Full Text] [PDF]
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J. C. Kaski, P. Avanzas, and R. Arroyo-Espliguero Neopterin: Still a Forgotten Biomarker Clin. Chem., October 1, 2005; 51(10): 1902 - 1903. [Full Text] [PDF]
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P. M. van der Zee, H. J. Verberne, J. P. van Straalen, G. T.B. Sanders, B. L.F. Van Eck-Smit, R. J. de Winter, and J. C. Fischer Ischemia-Modified Albumin Measurements in Symptom-Limited Exercise Myocardial Perfusion Scintigraphy Reflect Serum Albumin Concentrations but Not Myocardial Ischemia Clin. Chem., September 1, 2005; 51(9): 1744 - 1746. [Full Text] [PDF]
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S. Eriksson and K. Pettersson Beliefs in Cardiac Troponin Testing Clin. Chem., September 1, 2005; 51(9): 1755 - 1756. [Full Text] [PDF]
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O. Danne, C. Lueders, C. Storm, U. Frei, and M. Mockel Whole-Blood Hypercholinemia and Coronary Instability and Thrombosis Clin. Chem., July 1, 2005; 51(7): 1315 - 1317. [Full Text] [PDF]
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