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Semin Thromb Hemost 2012; 38(02): 222-229
DOI: 10.1055/s-0032-1301419
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Degradation of Troponin I in Serum or Plasma: Mechanisms, and Analytical and Clinical Implications

Giuseppe Lippi
1   U.O. Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Italy
,
Gianfranco Cervellin
2   U.O. Pronto Soccorso e Medicina d'Urgenza, Azienda Ospedaliero-Universitaria di Parma, Italy
› Author Affiliations
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Publication History

Publication Date:
16 February 2012 (online)

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Abstract

A prolonged myocardial ischemia, which results from a total deprivation of blood supply to an area of cardiac muscle for an appreciable period of time, is the leading mechanism responsible for acute myocardial infarction (AMI). The irreversible injury of myocardiocytes and the subsequent release of a variety of intracellular components into blood is the cornerstone of the diagnosis of AMI. Cardiac troponins are advocated as the biochemical gold standards among the various biomarkers of plaque instability, plaque rupture, ischemia, reversible cellular injury, and early and late necrosis (i.e., irreversible injury). The assessment of cardiac troponins in the diagnostic approach of patients with chest pain presents, however, some specific challenges due to the complex mechanisms of release from the injured myocardium, as well as to the enzymatic degradation by cardiac and extracardiac proteases (i.e., calpains, caspases, cathepsin L, and gelatinase A) that might alter the immunoreactivity (and thus laboratory detection) of the molecules. These two aspects will be discussed in this article, with specific focus on cardiac troponin I, as a variety of immunoassays based on antibodies which recognize different epitopes on the molecule is available for the measurement of this important cardiac biomarker.

Keywords

troponin - proteolysis - degradation - interference - preanalytical variability
 

  • References

  • 1 Mair J. Tissue release of cardiac markers: from physiology to clinical applications. Clin Chem Lab Med 1999; 37 (11-12) 1077-1084
    CrossrefPubMedGoogle Scholar
  • 2 Franchini M, Lippi G, Favaloro EJ. Coagulopathies and thrombosis: usual and unusual causes and associations, part I. Semin Thromb Hemost 2009; 35 (3) 257-259
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Lippi G, Franchini M, Favaloro EJ. Coagulopathies and thrombosis: usual and unusual causes and associations, part II. Semin Thromb Hemost 2009; 35 (7) 591-595
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Favaloro EJ, Lippi G, Franchini M. Coagulopathies and thrombosis: usual and unusual causes and associations, part III. Semin Thromb Hemost 2010; 36 (1) 1-5
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Lippi G, Favaloro EJ, Franchini M. Coagulopathies and thrombosis: usual and unusual causes and associations, part IV. Semin Thromb Hemost 2011; 37 (3) 175-180
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost 2008; 34 (8) 747-761
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Lippi G, Franchini M, Favaloro EJ. Unsuspected triggers of venous thromboembolism—trivial or not so trivial?. Semin Thromb Hemost 2009; 35 (7) 597-604
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Gawaz M, Favaloro EJ. Platelets, inflammation and cardiovascular diseases. New concepts and therapeutic implications. Semin Thromb Hemost 2010; 36 (2) 129-130
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Amabile N, Rautou PE, Tedgui A, Boulanger CM. Microparticles: key protagonists in cardiovascular disorders. Semin Thromb Hemost 2010; 36 (8) 907-916
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Lippi G, Franchini M, Targher G. Arterial thrombus formation in cardiovascular disease. Nat Rev Cardiol 2011; 8 (9) 502-512
    CrossrefPubMedGoogle Scholar
  • 11 Thygesen K, Alpert JS, White HD ; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol 2007; 50 (22) 2173-2195
    CrossrefPubMedGoogle Scholar
  • 12 Montagnana M, Lippi G, Guidi GC. [New perspectives in the diagnostic approach to acute coronary syndrome]. Recenti Prog Med 2005; 96 (4) 171-177
    PubMedGoogle Scholar
  • 13 Lippi G, Montagnana M, Salvagno GL, Guidi GC. Potential value for new diagnostic markers in the early recognition of acute coronary syndromes. CJEM 2006; 8 (1) 27-31
    PubMedGoogle Scholar
  • 14 Lippi G, Favaloro EJ, Montagnana M, Franchini M. C-reactive protein and venous thromboembolism: causal or casual association?. Clin Chem Lab Med 2010; 48 (12) 1693-1701
    CrossrefPubMedGoogle Scholar
  • 15 Lippi G, Filippozzi L, Montagnana M, Salvagno GL, Guidi GC. Diagnostic value of D-dimer measurement in patients referred to the emergency department with suspected myocardial ischemia. J Thromb Thrombolysis 2008; 25 (3) 247-250
    CrossrefPubMedGoogle Scholar
  • 16 Lippi G, Montagnana M, Guidi GC. Albumin cobalt binding and ischemia modified albumin generation: an endogenous response to ischemia?. Int J Cardiol 2006; 108 (3) 410-411
    CrossrefPubMedGoogle Scholar
  • 17 Lippi G, Targher G, Franchini M, Plebani M. Genetic and biochemical heterogeneity of cardiac troponins: clinical and laboratory implications. Clin Chem Lab Med 2009; 47 (10) 1183-1194
    CrossrefPubMedGoogle Scholar
  • 18 Benamer H, Steg PG, Benessiano J , et al. Comparison of the prognostic value of C-reactive protein and troponin I in patients with unstable angina pectoris. Am J Cardiol 1998; 82 (7) 845-850
    CrossrefPubMedGoogle Scholar
  • 19 Adams III JE, Schechtman KB, Landt Y, Ladenson JH, Jaffe AS. Comparable detection of acute myocardial infarction by creatine kinase MB isoenzyme and cardiac troponin I. Clin Chem 1994; 40 (7 Pt 1) 1291-1295
    PubMedGoogle Scholar
  • 20 Giannoni A, Giovannini S, Clerico A. Measurement of circulating concentrations of cardiac troponin I and T in healthy subjects: a tool for monitoring myocardial tissue renewal?. Clin Chem Lab Med 2009; 47 (10) 1167-1177
    CrossrefPubMedGoogle Scholar
  • 21 Lippi G, Banfi G. Exercise-related increase of cardiac troponin release in sports: An apparent paradox finally elucidated?. Clin Chim Acta 2010; 411 (7-8) 610-611
    CrossrefPubMedGoogle Scholar
  • 22 Lippi G, Montagnana M, Aloe R, Cervellin G. Highly sensitive troponin immunoassays: navigating between the Scylla and Charybdis. Adv Clin Chem ;in press
    PubMedGoogle Scholar
  • 23 Plebani M, Zaninotto M. Cardiac troponins: what we knew, what we know - where are we now?. Clin Chem Lab Med 2009; 47 (10) 1165-1166
    CrossrefPubMedGoogle Scholar
  • 24 Wu AH, Feng YJ, Moore R , et al. Characterization of cardiac troponin subunit release into serum after acute myocardial infarction and comparison of assays for troponin T and I. American Association for Clinical Chemistry Subcommittee on cTnI Standardization. Clin Chem 1998; 44 (6 Pt 1) 1198-1208
    PubMedGoogle Scholar
  • 25 Morjana NA. Degradation of human cardiac troponin I after myocardial infarction. Biotechnol Appl Biochem 1998; 28 (Pt 2) 105-111
    PubMedGoogle Scholar
  • 26 Labugger R, Organ L, Collier C, Atar D, Van Eyk JE. Extensive troponin I and T modification detected in serum from patients with acute myocardial infarction. Circulation 2000; 102 (11) 1221-1226
    CrossrefPubMedGoogle Scholar
  • 27 McDonough JL, Arrell DK, Van Eyk JE. Troponin I degradation and covalent complex formation accompanies myocardial ischemia/reperfusion injury. Circ Res 1999; 84 (1) 9-20
    CrossrefPubMedGoogle Scholar
  • 28 Feng J, Schaus BJ, Fallavollita JA, Lee TC, Canty Jr JM. Preload induces troponin I degradation independently of myocardial ischemia. Circulation 2001; 103 (16) 2035-2037
    CrossrefPubMedGoogle Scholar
  • 29 McDonough JL, Labugger R, Pickett W , et al. Cardiac troponin I is modified in the myocardium of bypass patients. Circulation 2001; 103 (1) 58-64
    CrossrefPubMedGoogle Scholar
  • 30 Madsen LH, Christensen G, Lund T , et al. Time course of degradation of cardiac troponin I in patients with acute ST-elevation myocardial infarction: the ASSENT-2 troponin substudy. Circ Res 2006; 99 (10) 1141-1147
    CrossrefPubMedGoogle Scholar
  • 31 Labugger R, Organ L, Collier C, Atar D, Van Eyk JE. Extensive troponin I and T modification detected in serum from patients with acute myocardial infarction. Circulation 2000; 102 (11) 1221-1226
    CrossrefPubMedGoogle Scholar
  • 32 Guiheneuf R, Vuillaume I, Mangalaboyi J , et al. Pneumatic transport is critical for leukaemic patients with major leukocytosis: what precautions to measure lactate dehydrogenase, potassium and aspartate aminotransferase?. Ann Clin Biochem 2010; 47 (Pt 1) 94-96
    CrossrefPubMedGoogle Scholar
  • 33 Lippi G, Favaloro EJ, Franchini M. Laboratory diagnostics and therapy in thrombosis and hemostasis: from bedside to bench to bedside. Semin Thromb Hemost 2009; 35 (1) 3-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Lippi G, Chance JJ, Church S , et al. Preanalytical quality improvement: from dream to reality. Clin Chem Lab Med 2011; 49 (7) 1113-1126
    CrossrefPubMedGoogle Scholar
  • 35 Lippi G, Guidi GC, Mattiuzzi C, Plebani M. Preanalytical variability: the dark side of the moon in laboratory testing. Clin Chem Lab Med 2006; 44 (4) 358-365
    CrossrefPubMedGoogle Scholar
  • 36 Favaloro EJ, Lippi G, Adcock DM. Preanalytical and postanalytical variables: the leading causes of diagnostic error in hemostasis?. Semin Thromb Hemost 2008; 34 (7) 612-634
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Lippi G, Blanckaert N, Bonini P , et al. Haemolysis: an overview of the leading cause of unsuitable specimens in clinical laboratories. Clin Chem Lab Med 2008; 46 (6) 764-772
    CrossrefPubMedGoogle Scholar
  • 38 Katrukha AG, Bereznikova AV, Filatov VL , et al. Degradation of cardiac troponin I: implication for reliable immunodetection. Clin Chem 1998; 44 (12) 2433-2440
    PubMedGoogle Scholar
  • 39 Spitznagel JK, Dalldorf FG, Leffell MS , et al. Character of azurophil and specific granules purified from human polymorphonuclear leukocytes. Lab Invest 1974; 30 (6) 774-785
    PubMedGoogle Scholar
  • 40 Prabhu SD. Cytokine-induced modulation of cardiac function. Circ Res 2004; 95 (12) 1140-1153
    CrossrefPubMedGoogle Scholar
  • 41 Legendre JL, Jones HP. Purification and characterization of calpain from human polymorphonuclear leukocytes. Inflammation 1988; 12 (1) 51-65
    CrossrefPubMedGoogle Scholar
  • 42 Di Lisa F, De Tullio R, Salamino F , et al. Specific degradation of troponin T and I by μ-calpain and its modulation by substrate phosphorylation. Biochem J 1995; 308 (Pt 1) 57-61
    CrossrefPubMedGoogle Scholar
  • 43 Xu PT, Song Z, Li Q, Zhang L, Wang YY, Yu ZB. [Calpain mediates cardiac troponin I degradation in tail-suspended rats]. Sheng Li Xue Bao 2010; 62 (5) 415-420
    PubMedGoogle Scholar
  • 44 Gao WD, Atar D, Liu Y, Perez NG, Murphy AM, Marban E. Role of troponin I proteolysis in the pathogenesis of stunned myocardium. Circ Res 1997; 80 (3) 393-399
    PubMedGoogle Scholar
  • 45 Ke L, Qi XY, Dijkhuis AJ , et al. Calpain mediates cardiac troponin degradation and contractile dysfunction in atrial fibrillation. J Mol Cell Cardiol 2008; 45 (5) 685-693
    CrossrefPubMedGoogle Scholar
  • 46 Bando Y, Kominami E, Katunuma N. Purification and tissue distribution of rat cathepsin L. J Biochem 1986; 100 (1) 35-42
    PubMedGoogle Scholar
  • 47 Ogata H, Aranishi F, Hara K, Osatomi K, Ishihara T. Proteolytic degradation of myofibrillar components by carp cathepsin L. J Sci Food Agric 1998; 76: 499-504
    CrossrefPubMedGoogle Scholar
  • 48 Fadeel B, Ahlin A, Henter JI, Orrenius S, Hampton MB. Involvement of caspases in neutrophil apoptosis: regulation by reactive oxygen species. Blood 1998; 92 (12) 4808-4818
    PubMedGoogle Scholar
  • 49 Saido TC, Sorimachi H, Suzuki K. Calpain: new perspectives in molecular diversity and physiological-pathological involvement. FASEB J 1994; 8 (11) 814-822
    PubMedGoogle Scholar
  • 50 Tschesche H. Human neutrophil collagenase. Methods Enzymol 1995; 248: 431-449
    PubMedGoogle Scholar
  • 51 Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol 2002; 37 (6) 375-536
    CrossrefPubMedGoogle Scholar
  • 52 Rouet-Benzineb P, Buhler JM, Dreyfus P , et al. Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation. Eur J Heart Fail 1999; 1 (4) 337-352
    CrossrefPubMedGoogle Scholar
  • 53 Wang W, Schulze CJ, Suarez-Pinzon WL, Dyck JR, Sawicki G, Schulz R. Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 2002; 106 (12) 1543-1549
    CrossrefPubMedGoogle Scholar
  • 54 Novogrodsky A, Quittner S, Rubin AL, Stenzel KH. Transglutaminase activity in human lymphocytes: early activation by phytomitogens. Proc Natl Acad Sci U S A 1978; 75 (3) 1157-1161
    CrossrefPubMedGoogle Scholar
  • 55 Lai TS, Liu Y, Li W, Greenberg CS. Identification of two GTP-independent alternatively spliced forms of tissue transglutaminase in human leukocytes, vascular smooth muscle, and endothelial cells. FASEB J 2007; 21 (14) 4131-4143
    CrossrefPubMedGoogle Scholar
  • 56 James S, Flodin M, Johnston N, Lindahl B, Venge P. The antibody configurations of cardiac troponin I assays may determine their clinical performance. Clin Chem 2006; 52 (5) 832-837
    CrossrefPubMedGoogle Scholar
  • 57 Panteghini M. Selection of antibodies and epitopes for cardiac troponin immunoassays: should we revise our evidence-based beliefs?. Clin Chem 2005; 51 (5) 803-804
    CrossrefPubMedGoogle Scholar
  • 58 Eriksson S, Pettersson K. Beliefs in cardiac troponin testing. Clin Chem 2005; 51 (9) 1755-1756
    CrossrefPubMedGoogle Scholar
  • 59 Shi Q, Ling M, Zhang X , et al. Degradation of cardiac troponin I in serum complicates comparisons of cardiac troponin I assays. Clin Chem 1999; 45 (7) 1018-1025
    PubMedGoogle Scholar
  • 60 Krudy GA, Kleerekoper Q, Guo XD, Howarth JW, Solaro RJ, Rosevear PR. NMR studies delineating spatial relationships within the cardiac troponin I-troponin C complex. J Biol Chem 1994; 269 (38) 23731-23735
    PubMedGoogle Scholar
  • 61 Morjana N, Clark D, Tal R. Biochemical and immunological properties of human cardiac troponin I fragments. Biotechnol Appl Biochem 2001; 33 (Pt 2) 107-115
    CrossrefPubMedGoogle Scholar
  • 62 Lippi G, Avanzini P, Dipalo M, Aloe R, Cervellin G. Influence of hemolysis on troponin testing: studies on Beckman Coulter UniCel Dxl 800 Accu-TnI and overview of the literature. Clin Chem Lab Med 2011; ; In press
    PubMedGoogle Scholar
  • 63 Hawkins RC. Hemolysis interference in the ortho-clinical diagnostics vitros ECi cTnI assay. Clin Chem 2003; 49 (7) 1226-, discussion 1227
    CrossrefPubMedGoogle Scholar
  • 64 Dasgupta A, Wells A, Biddle DA. Negative interference of bilirubin and hemoglobin in the MEIA troponin I assay but not in the MEIA CK-MB assay. J Clin Lab Anal 2001; 15 (2) 76-80
    CrossrefPubMedGoogle Scholar
  • 65 Plebani M, Lippi G. Hemolysis index: quality indicator or criterion for sample rejection?. Clin Chem Lab Med 2009; 47 (8) 899-902
    CrossrefPubMedGoogle Scholar
  • 66 Panteghini M, Bunk DM, Christenson RH , et al; IFCC Working Group on Standardization of Troponin I. Standardization of troponin I measurements: an update. Clin Chem Lab Med 2008; 46 (11) 1501-1506
    CrossrefPubMedGoogle Scholar