Novel Troponin Fragmentation Assay to Discriminate Between Troponin Elevations in Acute Myocardial Infarction and End-Stage Renal Disease
2022; Lippincott Williams & Wilkins; Volume: 146; Issue: 18 Linguagem: Inglês
10.1161/circulationaha.122.060845
ISSN1524-4539
AutoresJuhani Airaksinen, Rami Aalto, Tapio Hellman, Tuija Vasankari, Akseli Lahtinen, Saara Wittfooth,
Tópico(s)Cardiac Imaging and Diagnostics
ResumoHomeCirculationVol. 146, No. 18Novel Troponin Fragmentation Assay to Discriminate Between Troponin Elevations in Acute Myocardial Infarction and End-Stage Renal Disease Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBNovel Troponin Fragmentation Assay to Discriminate Between Troponin Elevations in Acute Myocardial Infarction and End-Stage Renal Disease K.E. Juhani Airaksinen, Rami Aalto, Tapio Hellman, Tuija Vasankari, Akseli Lahtinen and Saara Wittfooth K.E. Juhani AiraksinenK.E. Juhani Airaksinen Correspondence to: K.E. Juhani Airaksinen, MD, PhD, Heart Center, Turku University Hospital, Turku, Finland, Hämeentie 11, PO Box 52, 20521 Turku. Email E-mail Address: [email protected] https://orcid.org/0000-0002-0193-568X Heart Center (K.E.J.A., T.V.), Turku University Hospital and University of Turku, Finland. , Rami AaltoRami Aalto Biotechnology Unit, Department of Life Technologies, University of Turku, Finland (R.A., A.L., S.W.). , Tapio HellmanTapio Hellman https://orcid.org/0000-0001-9453-5687 Kidney Center (T.H.), Turku University Hospital and University of Turku, Finland. , Tuija VasankariTuija Vasankari Heart Center (K.E.J.A., T.V.), Turku University Hospital and University of Turku, Finland. , Akseli LahtinenAkseli Lahtinen Biotechnology Unit, Department of Life Technologies, University of Turku, Finland (R.A., A.L., S.W.). and Saara WittfoothSaara Wittfooth https://orcid.org/0000-0002-7886-3477 Biotechnology Unit, Department of Life Technologies, University of Turku, Finland (R.A., A.L., S.W.). Originally published31 Oct 2022https://doi.org/10.1161/CIRCULATIONAHA.122.060845Circulation. 2022;146:1408–1410There is a clinical need for a simple troponin assay with better specificity to segregate between type 1 myocardial infarction (MI) and troponin elevations caused by myocardial injury attributable to other causes such as renal failure. Heavily truncated small fragments of cardiac troponin T (cTnT) seem to be responsible for the cTnT elevations in renal failure and after strenuous exercise, whereas intact and long forms of cTnT have been detected early after MI.1–3 The commercial cTnT assay measures intact, mildly truncated and heavily truncated cTnT forms.1–3 In the present study, we assessed the ability of a novel immunoassay targeted for long cTnT forms (including intact and mildly truncated cTnT) to discriminate troponin elevations caused by type 1 MI and end-stage renal disease (ESRD).We collected heparin plasma samples from 46 patients with non–ST-segment–elevation MI (NSTEMI), 71 patients with ST-segment–elevation MI (STEMI), and 40 patients with ESRD on maintenance hemodialysis.We developed a novel, simple time-resolved, fluorescence-based sandwich immunoassay to measure the long forms of cTnT. The capture antibody (HyTest monoclonal antibody 7E7) binds to an epitope at the C-terminal part of cTnT (amino acid residues 223-242 according to UniProt entry P45370-6) and 3 tracer antibodies (Hytest monoclonal antibodies 7G7, 329cc, and 1C11) bind different areas of the central part of cTnT (amino acid residues 67–86, 119–138, 174–190, respectively). Thus, the assay detects intact and only mildly truncated cTnT forms. The setup of the assay is similar to a previously published time-resolved immunofluorometric assay.4The plasma samples were analyzed with our new assay and with a commercial high-sensitivity cTnT assay (Roche Diagnostics). This assay targets epitopes very close to each other in the middle of the central part of cTnT (amino acid residues 125–130 and 136–147) and detects intact, mildly truncated and also heavily truncated short forms of cTnT and, thus, we call it the total cTnT assay. For this assay and our novel assay, the limit of detection was 3 ng/L and 11 ng/L, the limit of quantitation (10% coefficient of variation) 13 ng/L and 25 ng/L, and the measuring range high end 10 000 ng/L and 50 000 ng/L, respectively. We assessed the ratio of long cTnT forms/total cTnT in the samples as a measure of fragmentation. Details of the patients, methods, and data supporting the present findings are available from the corresponding author on reasonable request. The study protocol (Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04465591) was approved by the local Medical Ethics Committee. All participants provided written informed consent.Total cTnT did not differ between the patients with NSTEMI and ESRD, but was higher in patients with STEMI. The ratio of long/total cTnT was higher in both MI groups than in patients with ESRD (Figure A). The ratio was also higher in patients with a ≤24-hour sample delay after symptom onset than in those with longer delays both in the NSTEMI (median, 0.29 versus 0.15) and STEMI groups (median, 0.62 versus 0.22; P 24 hours between symptom onset and sampling. Statistics: Mann-Whitney U test. C, Total cTnT, long cTnT forms, and ratio of long cTnT forms/total cTnT in patients with ESRD and in patients with NSTEMI with ≤24-hour delay between symptom onset and sampling. Statistics: Mann-Whitney U test. cTnT indicates cardiac troponin T; Long cTnT, intact and mildly truncated forms of cTnT; ESRD, end-stage renal disease; MI, myocardial infarction; NSTEMI, non–ST-segment–elevation MI; and STEMI, ST-segment–elevation MI.Despite the use of rapid cTnT algorithms, problems may arise when patients with ESRD or chronic kidney disease present to the emergency department with chest discomfort and troponin elevations.5 We provide the first evidence that an immunoassay targeting long cTnT forms (and especially the long/total cTnT ratio) separates cTnT elevations in NSTEMI and ESRD in a single sample with high accuracy and remarkably outperforms commercial high-sensitivity cTnT tests. Our study confirms with a new method that the intact and mildly truncated cTnT forms are typical for type 1 MI in the early hours of myocardial damage, whereas small fragments are the main components of cTnT elevation in ESRD.1,3 Our study also supports the view that fragmentation of cTnT is a continuous process after MI and leads to dilution of the observed differences later after MI.1 Serial sampling to document whether the ratio changes over time and external validation of the present findings is desirable and should be the subject of future studies.Our immunoassay approach is much simpler and more sensitive than laboratory methods previously used for studying cTnT fragmentation. The principle of our assay could be applied on automated platforms to allow implementation in clinical care to improve the accuracy and rapidity of laboratory diagnostics of MI. Ongoing studies will evaluate the value of this assay in other patient groups with myocardial injury.Article InformationRegistration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04465591.AcknowledgmentsThe authors thank J. Rosenberg from the University of Turku for providing the biotin isothiocyanate and europium chelate label. The authors also acknowledge Hytest Ltd for providing the antibodies for the long cardiac troponin T assay.Sources of FundingThis work was supported by the Finnish Foundation for Cardiovascular Research, Helsinki, Finland; Clinical Research Fund (EVO) of Turku University Hospital, Turku, Finland; and the Finnish Society of Clinical Chemistry, Helsinki, Finland.Disclosures K.E. Juhani Airaksinen has received research grants from the Finnish Foundation for Cardiovascular Research and Clinical Research Fund of Turku University Hospital, Turku, Finland; and fees for lectures from Astra Zeneca, Bayer, Boehringer Ingelheim, and Bristol-Myers-Squibb-Pfizer. S. Wittfooth received a research grant from the Finnish Society of Clinical Chemistry. The remaining authors have no conflicts to declare.Footnotes*K.E. Juhani Airaksinen and R. Aalto contributed equally.Circulation is available at www.ahajournals.org/journal/circFor Sources of Funding and Disclosures, see page 1410.Correspondence to: K.E. Juhani Airaksinen, MD, PhD, Heart Center, Turku University Hospital, Turku, Finland, Hämeentie 11, PO Box 52, 20521 Turku. Email juhani.[email protected]fiReferences1. Vylegzhanina AV, Kogan AE, Katrukha IA, Koshkina EV, Bereznikova AV, Filatov VL, Bloshchitsyna MN, Bogomolova AP, Katrukha AG. Full-size and partially truncated cardiac troponin complexes in the blood of patients with acute myocardial infarction.Clin Chem. 2019; 65:882–892. doi: 10.1373/clinchem.2018.301127CrossrefMedlineGoogle Scholar2. Vroemen WHM, Mezger STP, Masotti S, Clerico A, Bekers O, de Boer D, Mingels A. Cardiac troponin T: only small molecules in recreational runners after marathon completion.J Appl Lab Med. 2019; 3:909–911. doi: 10.1373/jalm.2018.027144CrossrefMedlineGoogle Scholar3. Mingels AM, Cardinaels EP, Broers NJ, van Sleeuwen A, Streng AS, van Dieijen-Visser MP, Kooman JP, Bekers O. Cardiac troponin T: smaller molecules in patients with end-stage renal disease than after onset of acute myocardial infarction.Clin Chem. 2017; 63:683–690. doi: 10.1373/clinchem.2016.261644CrossrefMedlineGoogle Scholar4. Tuunainen E, Lund J, Danielsson J, Pietilä P, Wahlroos V, Pudge K, Leinonen I, Porela P, Ilva T, Lepäntalo M, et al. Direct immunoassay for free pregnancy-associated plasma protein a (PAPP-A).J Appl Lab Med. 2018; 3:438–449. doi: 10.1373/jalm.2018.026096CrossrefMedlineGoogle Scholar5. Twerenbold R, Badertscher P, Boeddinghaus J, Nestelberger T, Wildi K, Puelacher C, Sabti Z, Rubini Gimenez M, Tschirky S, du Fay de Lavallaz J, et al. 0/1-Hour triage algorithm for myocardial infarction in patients with renal dysfunction.Circulation. 2018; 137:436–451. doi: 10.1161/CIRCULATIONAHA.117.028901LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Katrukha I, Riabkova N, Kogan A, Vylegzhanina A, Mukharyamova K, Bogomolova A, Zabolotskii A, Koshkina E, Bereznikova A and Katrukha A (2023) Fragmentation of human cardiac troponin T after acute myocardial infarction, Clinica Chimica Acta, 10.1016/j.cca.2023.117281, 542, (117281), Online publication date: 1-Mar-2023. November 1, 2022Vol 146, Issue 18 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.060845PMID: 36315607 Originally publishedOctober 31, 2022 Keywordsmyocardial infarctionnon-ST elevated myocardial infarctionkidney failure, chronicST elevation myocardial infarctiontroponin TPDF download Advertisement SubjectsBiomarkersChronic Ischemic Heart DiseaseClinical StudiesIschemiaMyocardial Infarction
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