Rapid Cardiac Troponin Release After Transient Ischemia
2021; Lippincott Williams & Wilkins; Volume: 143; Issue: 11 Linguagem: Inglês
10.1161/circulationaha.120.052649
ISSN1524-4539
AutoresChristopher R. deFilippi, Nicholas L. Mills,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeCirculationVol. 143, No. 11Rapid Cardiac Troponin Release After Transient Ischemia Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBRapid Cardiac Troponin Release After Transient IschemiaImplications for the Diagnosis of Myocardial Infarction Christopher R. deFilippi, MD and Nicholas L. Mills, MD, PhD Christopher R. deFilippiChristopher R. deFilippi Christopher deFilippi, MD, 3300 Gallows Road, Falls Church, VA 22042. Email E-mail Address: [email protected] https://orcid.org/0000-0002-0660-4943 Inova Heart and Vascular Institute, Falls Church, Virginia (C.R.dF.). and Nicholas L. MillsNicholas L. Mills https://orcid.org/0000-0003-0533-7991 British Heart Foundation Centre for Cardiovascular Science and Usher Institute, University of Edinburgh, United Kingdom (N.L.M.). Originally published15 Mar 2021https://doi.org/10.1161/CIRCULATIONAHA.120.052649Circulation. 2021;143:1105–1108This article is a commentary on the followingTemporal Release of High-Sensitivity Cardiac Troponin T and I and Copeptin After Brief Induced Coronary Artery Balloon Occlusion in HumansArticle, see p 1095Immunoassays for cardiac troponin (cTn) I and T have been the cornerstone of the diagnosis of myocardial infarction (MI) for 20 years, since they were recommended in the first Universal Definition of Myocardial Infarction.1 In addition, measurable cTn levels, below the diagnostic threshold for MI, identified individuals with acute coronary syndromes who benefited from therapies, such as early revascularization, even in the absence of ST-segment elevation.2 With this recognition of potential therapeutic benefit, assay manufacturers developed high-sensitivity assays that could accurately detect levels 10 to 100 times lower than the assays used 20 years ago. Today, high-sensitivity assays can measure cTn levels in most healthy individuals and identify small changes in the absence of MI.3Elevated cTn levels are considered synonymous with cardiomyocyte cell death, irrespective of the mechanism, with a rising or falling pattern accompanying signs or symptoms of ischemia diagnostic of MI. The work by Árnadóttir et al4 in this issue of Circulation exploits the analytic precision at low levels of several high-sensitivity cTn (hs-cTn) assays to provide insights that challenge these assumptions. The authors use a model of myocardial ischemia involving transient balloon occlusion of the left anterior descending artery in patients undergoing elective cardiac catheterization who were free from coronary artery disease. They randomly assigned 34 patients to a control arm or 1 of 3 arms with balloon occlusion for 30, 60, or 90 s, followed by blood sampling over the next 4 hours.There were several important observations.4 First, with only 30 s of occlusive balloon inflation, a 6-fold increase in cTn levels was measurable by 3 hours, and with 90 s of balloon inflation, a duration in which all subjects experienced chest pain, levels of cardiac troponin I (cTnI) had risen by almost 50% within 15 minutes. Second, there were marked differences in the rate of rise and peak concentrations of the 3 hs-cTn assays. Third, copeptin, which has been considered an early marker of MI in some studies, did not change from baseline following ischemia.Cellular Mechanisms of Cardiac Troponin ReleaseIs it plausible that only 30 s of ischemia could result in cardiomyocyte cell death? In a porcine model where the left anterior descending artery was transiently occluded for 10 minutes, cTn levels increased within an hour.5 This was associated with apoptosis of individual dispersed myocytes, but no evidence of myocardial necrosis or infarction. Although the majority of cTn is tightly bound to the actin-myosin contractile apparatus and is released slowly after cell death, a small proportion is less tightly bound or is free in the cytoplasm. Could the rapid release of this smaller pool account for the early increases in cTn observed here? Alternative hypotheses have been proposed to explain cTn release in the absence of infarction, including changes in cardiomyocyte membrane permeability, formation and release of membranous blebs, and the release of smaller cTn fragments following proteolytic degradation (Figure A).6 However, in the absence of robust evidence to support the relevance of these alternative mechanisms, caspase-mediated apoptosis in isolated vulnerable myocytes seems the most likely explanation for cTn elevations in response to transient myocardial ischemia.Download figureDownload PowerPointFigure. Mechanisms of the release and detection of cardiac troponin complex following transient myocardial ischemia. A, In acute myocardial infarction, hypoxic injury of the cardiomyocyte results in necrosis with cell lysis releasing all intracellular contents into the surrounding tissue. Alternative mechanisms could explain cardiac troponin release in the absence of infarction, including programmed cell death through caspase-mediated apoptosis, formation and release of membranous blebs in the absence of cell death, changes in cardiomyocyte membrane permeability, and the release of smaller fragments following proteolytic degradation. B, Shown is a complete troponin complex, although other immunoreactive forms of cardiac troponin I (cTnI) in blood may include free cTnI and cTnI bound to troponin C. Most immune assays for cTnI include a central binding capture and indicator-labeled antibody. Antibody affinity for these central epitopes may be influenced by the presence of bound troponin C and phosphorylation of cTnI. One vendor includes a third antibody that binds an epitope closer to the carboxy terminus that is potentially not subject to the same mechanisms influencing binding affinity to the central cTnI epitopes.All hS-cTn Assays are not Created EqualThe hs-cTn assays used in this study are widely used and considered to be equivalent for the diagnosis of MI.7 Yet, in this experimental model, there are notable differences between the hs-cTn assays with respect to the rate of rise and peak elevation. That this difference is obvious between 2 assays that measure cTnI is remarkable and suggests that the characteristics of the assays may be important for the early detection of troponin release. Early in the development of troponin assays, it was observed that both cTnI and cTnT were fragmented in circulation and frequently bound in dimers, trimers, or with troponin C.8,9 This led to the development of assays using capture and detection antibodies that targeted epitopes near the center of the proteins where high-affinity epitopes could be found in close proximity to maintain an immune reactive portion despite potential fragmentation. However, it was also hypothesized that antibodies targeting these central epitopes could have binding affinity influenced by concomitant binding with troponin C or by posttranslational phosphorylation changes in confirmation that could be dynamic over time (Figure B).Targeting an additional epitope some distance from the central region of cTnI could overcome some of the limitations that might influence the binding affinity of 2 adjacent epitopes. Siemens developed an assay to do this with a capture antibody targeting a central epitope at amino acids 30 to 35, a detection antibody targeting an adjacent epitope at amino acids 41 to 56, and a second detection antibody distant from the center near the carboxy terminus at amino acids 171 through 178. The Abbott assay has a capture antibody targeting an epitope at amino acids 24 to 40 and a single-detection antibody at an adjacent central epitope at amino acids 41 to 49.10 Detection of a more distant epitope could theoretically be problematic if proteolytic cleavage of cTnI occurs in circulation, where a stable cTnI concentration could be measured as declining over time as a result of the separation of the carboxy-terminal epitope from the central region. However, recent evidence suggests that cTnI identified early after the onset of MI is both the intact and fragmented molecule with 80% to 90% large enough to include all 3 epitopes, and the proportion of these fragments does not change over time, suggesting that cTnI fragmentation is predominately an intracellular process.11 Last, the observation of differences in signal between the 3 hs-cTn assays appears to be reproducible. In a study that performed measurements using the same assays before and immediately after ablation, a markedly greater rise in cTnI measured by the Siemens assay (496-fold) compared with cTnI measured by the Abbott assay (144-fold) or cTnT measured by Roche (69-fold) was observed.12Implications for the Diagnosis of Unstable Angina and Accelerated Diagnostic PathwaysThe observation that it is possible to measure a doubling in cTn concentrations within 2 hours of transient myocardial ischemia may have implications for clinical practice.One could argue that hs-cTn tests are now too sensitive and that the application of the 99th centile upper reference limit to identify those with myocardial necrosis is unhelpful in differentiating between angina and MI. Troponin concentrations were above the upper reference limit in 11% to 63% of patients (depending on the assay) 3 hours after balloon occlusion. However, unstable angina and MI are a consequence of the same pathogenic mechanisms and, rather than being too sensitive, hs-cTn testing may have an additional role in refining the diagnosis of unstable angina. This diagnosis is based largely on the clinical history rather than objective criteria, and, as such, it is inconsistently applied in clinical practice. If brief episodes of ischemia can induce a measurable cTn increase, could similar changes within the reference range inform diagnostic criteria for unstable angina? Further research is certainly warranted to test this hypothesis. Some caution is needed in extrapolating these observations, however, because prior studies where ischemia was induced by an exercise stress test report more modest increases in cTn levels (≈2 ng/L) in response to moderate to severe ischemia.13 It is plausible that, in patients with normal coronary arteries undergoing balloon-induced ischemia, a lack of preconditioning or collateral circulation may have contributed to a more marked cTn release than in patients with recurrent episodes attributable to obstructive coronary artery disease.Second, these observations provide insight into the timing of cTn increases following the onset of ischemia that should inform rapid diagnostic pathways. Early rule-out pathways reduce unnecessary hospital admission by using separate hs-cTn thresholds to rule out and rule in MI that avoid the need for serial testing in patients with very low cTn levels at presentation.14 Despite gains in effectiveness using these pathways, concerns remain about the safety of ruling out patients within the first few hours of symptom onset.15 The observations from Árnadóttir et al highlight why caution is required and emphasize the need for serial testing in those presenting within 2 hours of symptom onset.Last, this study questions the role of copeptin testing in the early rule-out of MI. Copeptin is not a direct measure of myocardial ischemia but is released from the hypothalamus in acute illness. However, copeptin has only been evaluated in pathways that use the same cTn threshold to rule out and rule in MI, whereas contemporary pathways use separate thresholds and recognize that small changes in cTn concentration within the reference range are important.14 Árnadóttir et al demonstrated that, after only 30 s of ischemia, an increase in hs-cTn can be reliably detected, whereas copeptin concentrations were unchanged, suggesting that the role of this biomarker in the early diagnosis of MI needs to be revisited.In summary, by conducting carefully controlled experimental studies that exploit the analytic precision of hs-cTn assays, we have gained novel insights into the pathobiology of myocardial ischemia. The findings reported by Árnadóttir et al challenge some of our assumptions, and, with further research, their observations may help shape future care pathways and the classification of acute coronary syndromes.Sources of FundingDr Mills is supported by the Butler Senior Clinical Research Fellowship (FS/16/14/32023), Program Grant (RG/20/10/34966), and a Research Excellent Award (RE/18/5/34216) from the British Heart Foundation. Dr deFilippi receives funding from the National Center for Advancing Translational Science of the National Institutes of Health Award UL1TR003015.Disclosures Dr Mills reports research grants awarded to the University of Edinburgh from Abbott Diagnostics and Siemens Healthineers, and honoraria from Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics, and LumiraDx. Dr deFilippi reports consulting fees from Abbott Diagnostics, FujiRebio, Ortho Diagnostics, Quidel, Roche Diagnostics, and Siemens Healthineers.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circChristopher deFilippi, MD, 3300 Gallows Road, Falls Church, VA 22042. Email christopher.[email protected]orgReferences1. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined–a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.J Am Coll Cardiol. 2000; 36:959–969. doi: 10.1016/s0735-1097(00)00804-4CrossrefMedlineGoogle Scholar2. Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH, Hille DA, DeLucca PT, DiBattiste PM, et al.; TACTICS-TIMI 18 Investigators. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial.JAMA. 2001; 286:2405–2412. doi: 10.1001/jama.286.19.2405CrossrefMedlineGoogle Scholar3. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018).Circulation. 2018; 138:e618–e651. doi: 10.1161/CIR.0000000000000617LinkGoogle Scholar4. Árnadóttir A, Pedersen S, Hasselbalch RB, Goetze JP, Friis-Hansen LJ, Bloch-Münster AM, Jensen JS, Bundgaard H, Iversen K. Temporal release of high-sensitivity cardiac troponin T and I and copeptin after brief induced coronary artery balloon occlusion in humans.Circulation. 2021; 143:1095–1104. doi: 10.1161/CIRCULATIONAHA.120.046574LinkGoogle Scholar5. Weil BR, Young RF, Shen X, Suzuki G, Qu J, Malhotra S, Canty JMBrief myocardial ischemia produces cardiac troponin I release and focal myocyte apoptosis in the absence of pathological infarction in swine.JACC Basic Transl Sci. 2017; 2:105–114. doi: 10.1016/j.jacbts.2017.01.006CrossrefMedlineGoogle Scholar6. Jaffe AS. Another unanswerable question.JACC Basic Transl Sci. 2017; 2:115–117. doi: 10.1016/j.jacbts.2017.03.002CrossrefMedlineGoogle Scholar7. Boeddinghaus J, Twerenbold R, Nestelberger T, Badertscher P, Wildi K, Puelacher C, du Fay de Lavallaz J, Keser E, Rubini Giménez M, Wussler D, et al.; APACE Investigators. Clinical validation of a novel high-sensitivity cardiac troponin I assay for early diagnosis of acute myocardial infarction.Clin Chem. 2018; 64:1347–1360. doi: 10.1373/clinchem.2018.286906CrossrefMedlineGoogle Scholar8. Katrukha AG, Bereznikova AV, Filatov VL, Esakova TV, Kolosova OV, Pettersson K, Lövgren T, Bulargina TV, Trifonov IR, Gratsiansky NA, et al.. Degradation of cardiac troponin I: implication for reliable immunodetection.Clin Chem. 1998; 44:2433–2440.CrossrefMedlineGoogle Scholar9. Apple FS, Collinson PO; IFCC Task Force on Clinical Applications of Cardiac Biomarkers. Analytical characteristics of high-sensitivity cardiac troponin assays.Clin Chem. 2012; 58:54–61. doi: 10.1373/clinchem.2011.165795CrossrefMedlineGoogle Scholar10. Apple FS, Sandoval Y, Jaffe AS, Ordonez-Llanos J; IFCC Task Force on Clinical Applications of Cardiac Bio-Markers. Cardiac troponin assays: guide to understanding analytical characteristics and their impact on clinical care.Clin Chem. 2017; 63:73–81. doi: 10.1373/clinchem.2016.255109CrossrefMedlineGoogle Scholar11. Katrukha IA, Kogan AE, Vylegzhanina AV, Kharitonov AV, Tamm NN, Filatov VL, Bereznikova AV, Koshkina EV, Katrukha AG. Full-size cardiac troponin I and its proteolytic fragments in blood of patients with acute myocardial infarction: antibody selection for assay development.Clin Chem. 2018; 64:1104–1112. doi: 10.1373/clinchem.2017.286211CrossrefMedlineGoogle Scholar12. deFilippi C, Seliger S, Latta F, Peters M, Christenson R, Dickfeld T, See VY. High-sensitivity cardiac troponin assays potentially differentiate acute from chronic myocardial injury.J Am Coll Cardiol. 2019; 73:2904–2905. doi: 10.1016/j.jacc.2019.03.487CrossrefMedlineGoogle Scholar13. Sabatine MS, Morrow DA, de Lemos JA, Jarolim P, Braunwald E. Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35.Eur Heart J. 2009; 30:162–169. doi: 10.1093/eurheartj/ehn504CrossrefMedlineGoogle Scholar14. Chapman AR, Anand A, Boeddinghaus J, Ferry AV, Sandeman D, Adamson PD, Andrews J, Tan S, Cheng SF, D'Souza M, et al.. Comparison of the efficacy and safety of early rule-out pathways for acute myocardial infarction.Circulation. 2017; 135:1586–1596. doi: 10.1161/CIRCULATIONAHA.116.025021LinkGoogle Scholar15. Bularga A, Lee KK, Stewart S, Ferry AV, Chapman AR, Marshall L, Strachan FE, Cruickshank A, Maguire D, Berry C, et al.. High-sensitivity troponin and the application of risk stratification thresholds in patients with suspected acute coronary syndrome.Circulation. 2019; 140:1557–1568. doi: 10.1161/CIRCULATIONAHA.119.042866LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Canty J (2022) Myocardial injury, troponin release, and cardiomyocyte death in brief ischemia, failure, and ventricular remodeling, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00093.2022, 323:1, (H1-H15), Online publication date: 1-Jul-2022. Hasselbalch R, Bundgaard H and Iversen K (2021) Response by Hasselbalch et al to Letter Regarding Article, "Temporal Release of High-Sensitivity Cardiac Troponin T and I and Copeptin After Brief Induced Coronary Artery Balloon Occlusion in Humans", Circulation, 144:9, (e169-e170), Online publication date: 31-Aug-2021.Related articlesTemporal Release of High-Sensitivity Cardiac Troponin T and I and Copeptin After Brief Induced Coronary Artery Balloon Occlusion in HumansÁsthildur Árnadóttir, et al. Circulation. 2021;143:1095-1104 March 16, 2021Vol 143, Issue 11 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.052649PMID: 33720770 Originally publishedMarch 15, 2021 Keywordstroponin Tmyocardial infarctionEditorialsmyocardial ischemiatroponin IPDF download Advertisement SubjectsBiomarkersIschemia
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