Cardiac Troponin Increase After Endurance Exercise
2019; Lippincott Williams & Wilkins; Volume: 140; Issue: 10 Linguagem: Inglês
10.1161/circulationaha.119.042131
ISSN1524-4539
AutoresTorbjørn Omland, Kristin M. Aakre,
Tópico(s)Cardiac Imaging and Diagnostics
ResumoHomeCirculationVol. 140, No. 10Cardiac Troponin Increase After Endurance Exercise Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCardiac Troponin Increase After Endurance ExerciseA New Marker of Cardiovascular Risk? Torbjørn Omland, MD, PhD, MPH and Kristin Moberg Aakre, MD, PhD Torbjørn OmlandTorbjørn Omland Torbjørn Omland, MD, PhD, MPH, Department of Cardiology, Akershus University Hospital, NO-1478 Lørenskog, Norway. Email E-mail Address: [email protected] Department of Cardiology, Akershus University Hospital, Oslo, Norway (T.O.). Center for Heart Failure Research, Institute of Clinical Medicine, University of Oslo, Norway (T.O.). and Kristin Moberg AakreKristin Moberg Aakre Hormone Laboratory, Haukeland University Hospital, Bergen, Norway (K.M.A.). Department of Clinical Science, University of Bergen, Norway (K.M.A.). Originally published3 Sep 2019https://doi.org/10.1161/CIRCULATIONAHA.119.042131Circulation. 2019;140:815–818This article is a commentary on the followingExercise-Induced Cardiac Troponin I Increase and Incident Mortality and Cardiovascular EventsArticle, see p 804The introduction of high-sensitivity cardiac troponin (cTn) assays has revealed that cTn I and T are circulating at low concentrations in the normal state and that chronic myocardial injury is associated with low-grade, stable elevation of cTn concentrations.1,2 Cardiovascular magnetic resonance (CMR) studies have demonstrated higher cTn concentrations in individuals with imaging findings suggestive of the presence of class B heart failure. For instance, left ventricular hypertrophy and the presence of nonischemic myocardial scars are associated with higher cTn concentrations.1,3 In accordance with these observations, chronically elevated cTn concentrations in both patients with stable coronary artery disease and the general population are strongly associated with the risk of incident heart failure and cardiovascular death.1,4Transient increase of cTn concentrations may occur in a variety of circumstances, reflecting acute myocardial injury. In general, short-term cTn elevation has been considered to reflect harmful pathophysiological processes. One notable exception has been the rise in cTn concentration observed after endurance exercise in presumably healthy individuals, which has commonly been considered a benign phenomenon. The theory that transient elevation of cTn after exercise is a normal physiological response has been based on several lines of evidence: the clear cardiovascular health benefits of endurance exercise, the high frequency of cTn elevation after endurance exercise, and the lack of symptoms or imaging evidence suggesting acute cardiovascular disease. However, the theory has been challenged by recent observations: a higher prevalence of atherosclerotic plaques in former athletes than in control subjects, suggesting that endurance exercise over years may be associated with atherogenesis5; higher cTnI concentrations after exercise among marathon runners with CMR evidence of myocardial scar6; and an exaggerated and prolonged cTnI response after a bicycle race among participants with occult obstructive atherosclerotic coronary artery disease.7 However, definitive data relating postexercise cTn concentrations or the magnitude of the cTn response after endurance exercise to cardiovascular outcomes have been lacking.In this issue of Circulation, Aengevaeren et al8 report observations from the first large-scale study that investigates the association between cTn increase after endurance exercise and long-term cardiovascular events. The study included 726 middle-aged individuals (median 61 years) who walked a distance of 30 to 55 km at nearly 70% of predicted heart rate. Twenty-six percent of the participants had cardiovascular risk factors, and additionally, 14% had a history of previous cardiovascular disease. cTnI was measured before and 10 minutes after completion of exercise using a contemporary assay with a limit of detection of 0.006 μg/L and an upper reference limit (ie, the 99th percentile) of 0.040 μg/L. After a median of 8 hours of walking, 9% of participants showed values above the 99th percentile for cTnI. During a median follow-up time of 43 months, 29 deaths and 33 major adverse cardiovascular events (defined as myocardial infarction, stroke, heart failure, acute or elective revascularization, or sudden cardiac arrest) occurred. Twenty-seven percent of participants in the group with postexercise cTnI concentrations above the 99th percentile experienced an end point compared with 7% of participants with values below this level (P<0.001). The association remained significant after adjustment for traditional risk factors and baseline cTnI concentrations. Moreover, larger changes from before to after exercise were significantly associated with the primary outcome. The association seemed to be driven by the incidence of major adverse cardiovascular events rather than all-cause mortality. Although the study results seem robust and convincing, the observations of Aengevaeren et al8 raise several questions, in particular concerning the underlying mechanisms of cTn release after strenuous physical activity and the potential clinical implications of exercise-associated cTn elevation.The physiological mechanisms underlying exercise-induced cTn elevation remain incompletely understood. The current paradigm of transient, exercise-induced cTn release is based on the concept that a small proportion of cTnI and cTnT molecules circulate freely in the cytosol or are weakly bound to the myofilaments of the cardiomyocyte and may be released into the extracellular space after reversible cell injury.9 In contrast to the prolonged cTn response observed after cardiomyocyte necrosis, the current theory suggests that stretching of the cell membrane, oxygen supply-demand mismatch, or toxic neurohormonal or inflammatory influences may be potential inducers of reversible cell injury leading to a transient cTn increase during and after exercise.9 Subsequent formation of membranous blebs, extracellular vesicles, and cell wounds may permit leakage of cTn through the cell membrane (Figure). In contrast to the case in cell necrosis, recent data suggest that reversible myocardial injury may preferentially be characterized by the presence of circulating cTn fragments rather than intact cTn molecules.10 Finally, a transient reduction in clearance could theoretically also contribute to the cTn increase observed after endurance exercise.Download figureDownload PowerPointFigure. Potential mechanisms for cardiac troponin release and expected cardiac troponin dynamics after endurance exercise. A, Cardiac troponins may be released from reversibly injured cardiomyocytes after formation of cell wounds, membranous blebs, or extracellular vesicles. B, The magnitude of the short-term cardiac troponin response after reversible myocardial injury induced by a given exercise load is likely greater and more prolonged in individuals with underlying long-term myocardial injury.Short- and long-term myocardial injury leads to distinct cTn patterns: long-term injury is characterized by stable elevated troponin concentrations, whereas short-term injury shows a rapid increasing/decreasing pattern returning to baseline within hours. The magnitude of cTn release after exercise seems to vary according to both the intensity and duration of exercise, although some data suggest that exercise intensity may be the stronger determinant.11 Accordingly, cardiorespiratory fitness may also impact on the cTn response to exercise in that low cardiorespiratory fitness appears to be related to an augmented cTn response. Other studies (including the current study by Aengevaeren et al8) suggest that baseline cTn concentration is an important predictor of the magnitude of the cTn response8,12,13 (Figure), compatible with the theory that long-term subclinical myocardial injury may be associated with less tolerance to short-term myocardial stress.The presence of asymptomatic myocardial ischemia has also been proposed as a potential underlying mechanism for exercise-associated cTn release, but existing data are conflicting. Some data suggest that in patients with suspected coronary artery disease, the increase in cTnI during stress testing is associated with the magnitude of the ischemic territory. Conversely, in a study that included both patients with and without coronary artery disease, patients with coronary artery disease had higher cTn concentrations at baseline, but the pacing-induced increase in heart rate was associated with similar increments in cTnT concentrations in the coronary sinus regardless of the presence or absence of coronary artery disease or lactate production, a surrogate of myocardial ischemia.14 In summary, although myocardial ischemia may cause short-term cTn release during exercise in individuals with significant coronary artery disease, in a population of presumably healthy individuals, physiological factors such as heart rate increase and subsequent reduction in the duration of diastole, as well as unrecognized subclinical long-term myocardial injury, may contribute more to the prevalence and magnitude of exercise-induced cTn increase.Although the study by Aengevaeren et al8 provides novel and interesting insights into the association between endurance exercise, cTn increase, and outcomes, the clinical implications are unclear. First, the 30- to 55-km walking test is obviously impractical for clinical practice, and future studies should aim at identifying briefer, standardized exercise protocols that provide reproducible results. Second, the optimal blood sampling time point for diagnostic and prognostic purposes may not be at the termination of exercise; indeed, some data suggest that samples obtained later in the recovery period may provide better discrimination.7 Third, whether the prognostic information provided by adding the delta cTn value to the baseline value, although statistically significant, is clinically important, also remains unclear. Although the hazard ratios increased with higher cTnI deltas, a goal for future studies should be to determine the delta values that provide optimal discrimination for different high-sensitivity cTn assays and investigate how the addition of postexercise cTn values impacts on C-statistics and reclassification statistics. Fourth, the study population of Aengevaeren et al8 included middle-aged individuals with a relatively high prevalence of cardiovascular risk factors and previous cardiovascular disease. To what extent the findings are generalizable to a younger population with a lower prevalence of cardiovascular risk factors and cardiovascular disease remains unclear. Finally, the clinical utility of a biomarker is greatly enhanced if its associated risk is modifiable and the biomarker reflects change in risk. Long-term cTn concentrations seem to be modifiable by lifestyle intervention, because increased physical activity in older adults has been associated with both a reduction in the age-related cTn increase and a lower incidence of heart failure.15 Whether the cTn increase after endurance exercise also is modifiable by lifestyle intervention, and whether a reduction in the magnitude of the response signals reduced cardiovascular risk, is unknown and should be addressed in future studies.Our current understanding of the causes and clinical implications of long-term stable cTn elevation and the transient increase that occurs after endurance exercise is still incomplete. The study of Aengevaeren et al8 adds another piece to the puzzle by showing that cTn measurement before and after endurance exercise can be considered a functional test of the cardiovascular system that provides prognostic information independent of conventional risk markers.DisclosuresDr Omland has received grants and personal fees from Roche Diagnostics, grants and personal fees from Abbott Diagnostics, and personal fees from Siemens Healthineers during the conduct of the study, and grants from Novartis, grants from SomaLogic, grants from Singulex, and personal fees from Bayer outside the submitted work. Dr Aakre reports personal fees from Roche Diagnostics and personal fees from Siemens Health Care outside the submitted work.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circTorbjørn Omland, MD, PhD, MPH, Department of Cardiology, Akershus University Hospital, NO-1478 Lørenskog, Norway. Email torbjorn.[email protected]uio.noReferences1. de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, Hashim I, Berry JD, Das SR, Morrow DA, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.JAMA. 2010; 304:2503–2512. doi: 10.1001/jama.2010.1768CrossrefMedlineGoogle Scholar2. Welsh P, Preiss D, Hayward C, Shah ASV, McAllister D, Briggs A, Boachie C, McConnachie A, Padmanabhan S, Welsh C, et al. Cardiac troponin T and troponin I in the general population.Circulation. 2019; 139:2754–2764. doi: 10.1161/CIRCULATIONAHA.118.038529LinkGoogle Scholar3. Seliger SL, Hong SN, Christenson RH, Kronmal R, Daniels LB, Lima JAC, de Lemos JA, Bertoni A, deFilippi CR. High-sensitive cardiac troponin T as an early biochemical signature for clinical and subclinical heart failure: MESA (Multi-Ethnic Study of Atherosclerosis).Circulation. 2017; 135:1494–1505. doi: 10.1161/CIRCULATIONAHA.116.025505LinkGoogle Scholar4. Omland T, de Lemos JA, Sabatine MS, Christophi CA, Rice MM, Jablonski KA, Tjora S, Domanski MJ, Gersh BJ, Rouleau JL, et al; Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease.N Engl J Med. 2009; 361:2538–2547. doi: 10.1056/NEJMoa0805299CrossrefMedlineGoogle Scholar5. Merghani A, Maestrini V, Rosmini S, Cox AT, Dhutia H, Bastiaenan R, David S, Yeo TJ, Narain R, Malhotra A, et al. Prevalence of subclinical coronary artery disease in masters endurance athletes with a low atherosclerotic risk profile.Circulation. 2017; 136:126–137. doi: 10.1161/CIRCULATIONAHA.116.026964LinkGoogle Scholar6. Möhlenkamp S, Leineweber K, Lehmann N, Braun S, Roggenbuck U, Perrey M, Broecker-Preuss M, Budde T, Halle M, Mann K, et al. Coronary atherosclerosis burden, but not transient troponin elevation, predicts long-term outcome in recreational marathon runners.Basic Res Cardiol. 2014; 109:391. doi: 10.1007/s00395-013-0391-8CrossrefMedlineGoogle Scholar7. Kleiven Ø , Omland T, Skadberg Ø , Melberg TH, Bjørkavoll-Bergseth MF, Auestad B, Bergseth R, Greve OJ, Aakre KM, Ørn S. Occult obstructive coronary artery disease is associated with prolonged cardiac troponin elevation following strenuous exercise [published online June 1, 2019].Eur J Prev Cardiol. doi: 10.1177/2047487319852808. https://journals.sagepub.com/doi/10.1177/2047487319852808.Google Scholar8. Aengevaeren VL, Hopman MTE, Thompson PD, Bakker EA, George KP, Thijssen DHJ, Eijsvogels TMH. Exercise-induced cardiac troponin I increase and incident mortality and cardiovascular events.Circulation. 2019; 140:804–814. doi: 10.1161/CIRCULATIONAHA.119.041627LinkGoogle Scholar9. Mair J, Lindahl B, Hammarsten O, Müller C, Giannitsis E, Huber K, Möckel M, Plebani M, Thygesen K, Jaffe AS. How is cardiac troponin released from injured myocardium?Eur Heart J Acute Cardiovasc Care. 2018; 7:553–560. doi: 10.1177/2048872617748553CrossrefMedlineGoogle Scholar10. 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.CrossrefMedlineGoogle Scholar11. Fu F, Nie J, Tong TK. Serum cardiac troponin T in adolescent runners: effects of exercise intensity and duration.Int J Sports Med. 2009; 30:168–172. doi: 10.1055/s-0028-1104586CrossrefMedlineGoogle Scholar12. Klinkenberg LJ, Res PT, van Loon LJ, van Dieijen-Visser MP, Meex SJ. Strong link between basal and exercise-induced cardiac troponin T levels: do both reflect risk?Int J Cardiol. 2012; 158:129–131. doi: 10.1016/j.ijcard.2012.04.050CrossrefMedlineGoogle Scholar13. Kleiven Ø, Omland T, Skadberg Ø, Melberg TH, Bjørkavoll-Bergseth MF, Auestad B, Bergseth R, Greve OJ, Aakre KM, Ørn S. Race duration and blood pressure are major predictors of exercise-induced cardiac troponin elevation.Int J Cardiol. 2019; 283:1–8. doi: 10.1016/j.ijcard.2019.02.044CrossrefMedlineGoogle Scholar14. Turer AT, Addo TA, Martin JL, Sabatine MS, Lewis GD, Gerszten RE, Keeley EC, Cigarroa JE, Lange RA, Hillis LD, et al. Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay: insights from a coronary sinus sampling study.J Am Coll Cardiol. 2011; 57:2398–2405. doi: 10.1016/j.jacc.2010.11.066CrossrefMedlineGoogle Scholar15. deFilippi CR, de Lemos JA, Tkaczuk AT, Christenson RH, Carnethon MR, Siscovick DS, Gottdiener JS, Seliger SL. Physical activity, change in biomarkers of myocardial stress and injury, and subsequent heart failure risk in older adults.J Am Coll Cardiol. 2012; 60:2539–2547. doi: 10.1016/j.jacc.2012.08.1006CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Hammarsten O, Ljungqvist P, Redfors B, Wernbom M, Widing H, Lindahl B, Salahuddin S, Sammantar R, Jha S, Ravn-Fischer A, Brink M and Gisslen M (2022) The ratio of cardiac troponin T to troponin I may indicate non-necrotic troponin release among COVID-19 patients, Clinica Chimica Acta, 10.1016/j.cca.2021.12.030, 527, (33-37), Online publication date: 1-Feb-2022. Martinez M, Kim J, Shah A, Phelan D, Emery M, Wasfy M, Fernandez A, Bunch T, Dean P, Danielian A, Krishnan S, Baggish A, Eijsvogels T, Chung E and Levine B (2021) Exercise-Induced Cardiovascular Adaptations and Approach to Exercise and Cardiovascular Disease, Journal of the American College of Cardiology, 10.1016/j.jacc.2021.08.003, 78:14, (1453-1470), Online publication date: 1-Oct-2021. Cirer-Sastre R, Legaz-Arrese A, Corbi F, López-Laval I, George K and Reverter-Masia J (2021) Influence of maturational status in the exercise-induced release of cardiac troponin T in healthy young swimmers, Journal of Science and Medicine in Sport, 10.1016/j.jsams.2020.06.019, 24:2, (116-121), Online publication date: 1-Feb-2021. Koppen E, Omland T, Larsen A, Karlsen T, Linke A, Prescott E, Halle M, Dalen H, Delagardelle C, Hole T, Craenenbroeck E, Beckers P, Ellingsen Ø, Feiereisen P, Valborgland T and Videm V (2021) Exercise training and high‐sensitivity cardiac troponin T in patients with heart failure with reduced ejection fraction, ESC Heart Failure, 10.1002/ehf2.13310, 8:3, (2183-2192), Online publication date: 1-Jun-2021. Le Goff C, Farré Segura J, Dufour P, Kaux J and Cavalier E (2020) Intense sport practices and cardiac biomarkers, Clinical Biochemistry, 10.1016/j.clinbiochem.2020.02.008, 79, (1-8), Online publication date: 1-May-2020. Perrone M, Macrini M, Maregnani A, Ammirabile M, Clerico A, Bernardini S and Romeo F The effects of a 50 km ultramarathon race on high sensitivity cardiac troponin I and NT-proBNP in highly trained athletes, Minerva Cardioangiologica, 10.23736/S0026-4725.20.05281-0, 68:4 Ni E, Fang Y, Ma F, Ge G, Wu J, Wang Y, Lin Y and Xie H (2020) A one-step potentiometric immunoassay for plasma cardiac troponin I using an antibody-functionalized bis-MPA–COOH dendrimer as a competitor with improved sensitivity, Analytical Methods, 10.1039/D0AY00680G, 12:22, (2914-2921) Solaro C and Solaro R (2020) Implications of the complex biology and micro-environment of cardiac sarcomeres in the use of high affinity troponin antibodies as serum biomarkers for cardiac disorders, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2020.05.010, 143, (145-158), Online publication date: 1-Jun-2020. Li F, Hopkins W, Wang X, Baker J, Nie J, Qiu J, Quach B, Wang K and Yi L (2021) Kinetics, Moderators and Reference Limits of Exercise-Induced Elevation of Cardiac Troponin T in Athletes: A Systematic Review and Meta-Analysis, Frontiers in Physiology, 10.3389/fphys.2021.651851, 12 Chaulin A (2022) Prognostic Significance and Pathophysiological Mechanisms of Increasing the Levels of Cardiospecific Troponins in Biological Fluids in Arterial Hypertension (Literature Review), Annals of the Russian academy of medical sciences, 10.15690/vramn1587, 77:1, (43-52) Related articlesExercise-Induced Cardiac Troponin I Increase and Incident Mortality and Cardiovascular EventsVincent L. Aengevaeren, et al. Circulation. 2019;140:804-814 September 3, 2019Vol 140, Issue 10 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.042131PMID: 31479313 Originally publishedSeptember 3, 2019 KeywordstroponinsEditorialsexercisebiomarkersmyocardial injurycardiovascular riskPDF download Advertisement
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