Cardiac Troponin T and I Release After a 30-km Run

Prolonged endurance-type exercise is associated with elevated cardiac troponin (cTn) levels in asymptomatic recreational athletes. It is unclear whether exercise-induced cTn release mirrors a physiological or pathological underlying process. The aim of this study was to provide a direct comparison of the release kinetics of high-sensitivity cTnI (hs-cTnI) and T (hs-cTnT) after endurance-type exercise. In addition, the effect of remote ischemic preconditioning (RIPC), a cardioprotective strategy that limits ischemia-reperfusion injury, was investigated in a randomized controlled crossover manner. Twenty-five healthy volunteers completed an outdoor 30-km running trial preceded by RIPC (4 × 5 min 220 mm Hg unilateral occlusion) or control intervention. hs-cTnT, hs-cTnI, and sensitive cTnI (s-cTnI) concentrations were examined before, immediately after, 2 and 5 hours after the trial. The completion of a 30-km run resulted in a significant increase in circulating cTn (time: all p <0.001), with maximum hs-cTnT, hs-cTnI, and s-cTnI levels of 47 ± 27, 69 ± 62, and 82 ± 64 ng/L (mean ± SD), respectively. Maximum hs-cTnT concentrations were measured in 60% of the participants at 2 hours after exercise, compared with maximum hs-cTnI and s-cTnI concentrations at 5 hours in 84% and 80% of the participants. Application of an RIPC stimulus did not reduce exercise-induced cTn release (time × trial: all p >0.5). In conclusion, in contrast to acute myocardial infarction, maximum hs-cTnT levels after exercise precede maximum hs-cTnI levels. Distinct release kinetics of hs-cTnT and hs-cTnI and the absence of an effect of RIPC favors the concept that exercise-induced cTn release may be mechanistically distinct from cTn release in acute myocardial infarction. Prolonged endurance-type exercise is associated with elevated cardiac troponin (cTn) levels in asymptomatic recreational athletes. It is unclear whether exercise-induced cTn release mirrors a physiological or pathological underlying process. The aim of this study was to provide a direct comparison of the release kinetics of high-sensitivity cTnI (hs-cTnI) and T (hs-cTnT) after endurance-type exercise. In addition, the effect of remote ischemic preconditioning (RIPC), a cardioprotective strategy that limits ischemia-reperfusion injury, was investigated in a randomized controlled crossover manner. Twenty-five healthy volunteers completed an outdoor 30-km running trial preceded by RIPC (4 × 5 min 220 mm Hg unilateral occlusion) or control intervention. hs-cTnT, hs-cTnI, and sensitive cTnI (s-cTnI) concentrations were examined before, immediately after, 2 and 5 hours after the trial. The completion of a 30-km run resulted in a significant increase in circulating cTn (time: all p <0.001), with maximum hs-cTnT, hs-cTnI, and s-cTnI levels of 47 ± 27, 69 ± 62, and 82 ± 64 ng/L (mean ± SD), respectively. Maximum hs-cTnT concentrations were measured in 60% of the participants at 2 hours after exercise, compared with maximum hs-cTnI and s-cTnI concentrations at 5 hours in 84% and 80% of the participants. Application of an RIPC stimulus did not reduce exercise-induced cTn release (time × trial: all p >0.5). In conclusion, in contrast to acute myocardial infarction, maximum hs-cTnT levels after exercise precede maximum hs-cTnI levels. Distinct release kinetics of hs-cTnT and hs-cTnI and the absence of an effect of RIPC favors the concept that exercise-induced cTn release may be mechanistically distinct from cTn release in acute myocardial infarction. Insight into the (patho)physiology of exercise-induced cardiac troponin (cTn) release is an active and relevant topic of discussion.1Shave R. Baggish A. George K. Wood M. Scharhag J. Whyte G. Gaze D. Thompson P.D. Exercise-induced cardiac troponin elevation: evidence, mechanisms, and implications.J Am Coll Cardiol. 2010; 56: 169-176Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar The recent advent of both a high-sensitivity (hs-) assay for cTnI (cTnI) and T (cTnT) with similar analytical characteristics enables to directly compare the kinetics of both diagnostic equivalent molecules. For example in acute myocardial infarction (AMI), where cTn release results from the breakdown of the contractile apparatus after ischemic myocardial injury, peak levels of hs-cTnI and hs-cTnT are reached at similar levels after admission.2Laugaudin G. Kuster N. Petiton A. Leclercq F. Gervasoni R. Macia J.C. Cung T.T. Dupuy A.M. Solecki K. Lattuca B. Cade S. Cransac F. Cristol J.P. Roubille F. Kinetics of high-sensitivity cardiac troponin T and I differ in patients with ST-segment elevation myocardial infarction treated by primary coronary intervention.Eur Heart J Acute Cardiovasc Care. 2015; (Epub ahead of print)Google Scholar, 3Solecki K. Dupuy A.M. Kuster N. Leclercq F. Gervasoni R. Macia J.C. Cung T.T. Lattuca B. Cransac F. Cade S. Pasquie J.L. Cristol J.P. Roubille F. Kinetics of high-sensitivity cardiac troponin T or troponin I compared to creatine kinase in patients with revascularized acute myocardial infarction.Clin Chem Lab Med. 2015; 53: 707-714Crossref PubMed Scopus (30) Google Scholar A direct comparison of exercise-induced hs-cTnI and hs-cTnT release could provide more insight into the underlying (patho)physiology. In addition, remote ischemic preconditioning (RIPC), a powerful noninvasive cardioprotective strategy, can be applied to study the contribution of an imbalance between oxygen supply and demand in exercise-induced cTn release. RIPC describes the application of brief episodes of nonlethal ischemia and reperfusion to a tissue or an organ, resulting in protection of the same or another visceral organ against an injurious ischemic insult in the future.4Hausenloy D.J. Yellon D.M. Remote ischaemic preconditioning: underlying mechanisms and clinical application.Cardiovasc Res. 2008; 79: 377-386Crossref PubMed Scopus (407) Google Scholar In line with the cardioprotective effect of RIPC in various settings of tissue ischemia, we hypothesize that if an oxygen demand-supply imbalance contributes to exercise-induced cTn release, application of an RIPC stimulus would result in reduced postexercise cTn levels. The aim of this study was a head-to-head comparison of the release kinetics of hs-cTnT and hs-cTnI after prolonged endurance-type exercise. In addition, we examined the effect of RIPC on exercise-induced cTn release using a randomized controlled single-blind crossover design. Twenty-nine healthy runners (age range 18 to 65 years) were recruited with posters at local running clubs. Before testing, all participants were informed about the study procedures and method but remained naïve to the study rationale. This study was carried out according to the principles of the Declaration of Helsinki and approved by the local Institutional Review Board and Ethics Committee of Maastricht University Medical Center. All subjects provided written informed consent before participation. This study was conducted from March 2013 to June 2013 and was registered at clinicaltrials.gov as NCT01774461. In a randomized controlled single-blind crossover design, participants completed 2 identical outdoor 30-km running trials, either preceded by an RIPC or control intervention. Both experimental test days started in the morning and were separated by at least 2 weeks. Before each trial, participants were instructed to refrain from any strenuous physical labor and sports activities for 24 hours and to standardize their breakfast on both experimental days. The running trials were organized in a research setting on paved (bicycle) lanes with a minimal number of cross sections with the start and finish ≈ 1 km from Maastricht University Medical Center. While running, participants were individually followed by a researcher on a bicycle and allowed to drink water and Isostar sports drink ad libitum. Before the first running trial, a comprehensive 2-dimensional and 3-dimensional transthoratic echocardiogram at rest was recorded from all participants. No abnormalities were observed. Temporal unilateral upper arm ischemia was achieved by inflating a blood pressure cuff to 220 mm Hg. Circulatory occlusion lasted 5 minutes and was followed by 5 minutes of reperfusion by deflation of the cuff. This sequence was repeated for a total of 4 cycles and resulted in a total procedure time of 40 minutes (4 × [5 minutes of circulatory occlusion + 5 minutes of nonocclusion]). The control intervention followed an identical protocol, except for the blood pressure cuff being inflated to only 20 mm Hg, allowing uninterrupted perfusion. The order of testing (RIPC vs control) was randomized and counterbalanced between participants. Blood samples were collected in serum and ethylenediaminetetraacetic acid-containing tubes at baseline (preceding the RIPC intervention), immediately after exercise, 2 and 5 hours after exercise. Within 1 hour of collection, hematology parameters were analyzed on a Sysmex XE-5000 (Kobe, Japan) analyzer. In addition, serum tubes were centrifuged, and aliquots were stored at −80°C until analysis. Serum cTnT was measured using the high-sensitivity assay of Roche Diagnostics (Basel, Switzerland); the clinical reference limit (99th percentile of a healthy reference population) is 14 ng/L, with a 10% analytical variation at 13 ng/L.5Giannitsis E. Kurz K. Hallermayer K. Jarausch J. Jaffe A.S. Katus H.A. Analytical validation of a high-sensitivity cardiac troponin T assay.Clin Chem. 2010; 56: 254-261Crossref PubMed Scopus (853) Google Scholar Serum cTnI was measured with the following 2 assays: the STAT high-sensitive troponin I assay (Abbott Diagnostics, Abbott Park, IL) and the Access AccuTnI+3 assay (Beckman Coulter, Brea, CA) According to the package insert, the 99th percentile limit of the Abbott hs-cTnI assay is 26.2 ng/L with a corresponding coefficient of variation of 4%. The Beckman Coulter assay has a 99th percentile limit of 40 ng/L and a corresponding 10% imprecision, as specified by the manufacturer. Complementary cardiovascular or skeletal biomarkers; N-terminal pro–B-type natriuretic peptide (NTproBNP), creatine kinase (CK), CK muscle and brain fraction (CK-MB), and lactate dehydrogenase were measured using assays of Roche Diagnostics. In addition, creatinine (Roche Diagnostics) and cystatin C (Gentian, Moss, Norway) were measured to calculate the estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.6Inker L.A. Schmid C.H. Tighiouart H. Eckfeldt J.H. Feldman H.I. Greene T. Kusek J.W. Manzi J. Van Lente F. Zhang Y.L. Coresh J. Levey A.S. CKD-EPI InvestigatorsEstimating glomerular filtration rate from serum creatinine and cystatin C.N Engl J Med. 2012; 367: 20-29Crossref PubMed Scopus (2508) Google Scholar Sample size estimation was based on hs-cTnT as the primary outcome variable. We aimed to include 29 runners to detect a 30% reduction in exercise-induced hs-cTnT release due to RIPC (from 40 ± 32 ng/L to 28 ± 32 ng/L, mean ± SD) with a statistical power of 0.8 at an alpha error probability of 0.05. An estimated postexercise hs-cTnT concentration of 40 ng/L was based on our previous studies of marathon-induced hs-cTnT release.7Mingels A. Jacobs L. Michielsen E. Swaanenburg J. Wodzig W. van Dieijen-Visser M. Reference population and marathon runner sera assessed by highly sensitive cardiac troponin T and commercial cardiac troponin T and I assays.Clin Chem. 2009; 55: 101-108Crossref PubMed Scopus (253) Google Scholar, 8Mingels A.M. Jacobs L.H. Kleijnen V.W. Laufer E.M. Winkens B. Hofstra L. Wodzig W.K. van Dieijen-Visser M.P. Cardiac troponin T elevations, using highly sensitive assay, in recreational running depend on running distance.Clin Res Cardiol. 2010; 99: 385-391Crossref PubMed Scopus (35) Google Scholar The expected effect size of 30% was derived from the reports, where a 40% reduction of cTn release by RIPC preceding cardiac and vascular surgery has been observed.9Hausenloy D.J. Mwamure P.K. Venugopal V. Harris J. Barnard M. Grundy E. Ashley E. Vichare S. Di Salvo C. Kolvekar S. Hayward M. Keogh B. MacAllister R.J. Yellon D.M. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial.Lancet. 2007; 370: 575-579Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar, 10Hoole S.P. Heck P.M. Sharples L. Khan S.N. Duehmke R. Densem C.G. Clarke S.C. Shapiro L.M. Schofield P.M. O'Sullivan M. Dutka D.P. Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP stent) study: a randomized control 2009; PubMed Scopus Google Scholar, V. D.J. A. Di Salvo C. Kolvekar S. J. D. J. Yellon D.M. Remote ischaemic preconditioning myocardial injury in patients undergoing cardiac surgery with a randomised controlled 2009; PubMed Scopus Google Scholar a similar effect in endurance-type exercise, we that a reduction would a relevant contribution of ischemia-reperfusion in the setting of exercise-induced cTn release. are as mean ± A (time × was to in In addition, trial order or RIPC was into the statistical as a out this of not In the of a were by All statistical were and a p of was were using for Twenty-nine participants and were in the participants the study due to a injury or to the study and were not in the analysis. was after study completion of highly elevated hs-cTnT hs-cTnI and sensitive cTnI concentrations and ng/L, before running trial. In the absence of clinical were highly for exercise-induced troponin release in the 24 hours and for to a of the study of exercise in the 24 hours preceding the participants and with an of 40 ± 13 (mean ± SD) were in the were to highly with an of running 20 to runners completed at least marathon or trial. of the subjects a of cardiovascular assessed by characteristics ± or are as mean ± or mean in a are as mean ± or mean The exercise trials were separated by a of 2 2 to All participants completed both trials a time of to of myocardial was in the completion time between the control trial and the trial preceded by ischemic preconditioning: mean control trial and mean RIPC trial The between the intervention and the 30-km run was 24 minutes to and similar in the setting with and The from finish to the first postexercise blood was minutes 14 to with in the setting with and baseline of the control trial, all hs-cTnT, hs-cTnI, and s-cTnI concentrations the clinical limit of myocardial infarction and 24 The completion of a 30-km run resulted in an expected significant increase of circulating hs-cTnT, hs-cTnI, and s-cTnI (time: all p Maximum concentrations of hs-cTnT, hs-cTnI, and s-cTnI were 47 ± ng/L, 69 ± ng/L, and 82 ± 64 ng/L (mean ± control and the clinical reference of hs-cTnT, hs-cTnI, and s-cTnI in 60% and of the participants. The kinetics of hs-cTnT was from hs-cTnI and as 60% of the participants hs-cTnT maximum concentrations at 2 hours after exercise, maximum concentrations of hs-cTnI and s-cTnI were measured at 5 hours after exercise in 84% and 80% participants and respectively. of hs-cTnT, hs-cTnI, and s-cTnI measured immediately after exercise in the control trial were with each all p In addition, concentrations after the 30-km run with maximum concentrations of 14 ± (mean ± control trial, p of were not associated with hs-cTnT, hs-cTnI, or s-cTnI all p of cardiac and skeletal by a 30-km run preceded by a control or remote ischemic preconditioning Roche p ± ± ± ± ± ± ± ± Abbott ± ± ± ± ± ± ± ± Beckman ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± p ± ± ± ± p ± ± ± ± are as mean ± creatine creatine kinase muscle and brain estimated glomerular filtration hs-cTnT high-sensitivity cardiac troponin hs-cTnI high-sensitivity cardiac troponin lactate N-terminal pro–B-type natriuretic s-cTnI sensitive cardiac troponin RIPC remote ischemic in a are as mean ± CK creatine creatine kinase muscle and brain estimated glomerular filtration hs-cTnT high-sensitivity cardiac troponin hs-cTnI high-sensitivity cardiac troponin lactate N-terminal pro–B-type natriuretic s-cTnI sensitive cardiac troponin RIPC remote ischemic Application of an RIPC stimulus by 4 cycles of blood pressure cuff followed by 5 minutes of deflation did not reduce exercise-induced cTn release at and 5 hours after exercise results were for The of trial order and of the participants in the did not the results not In addition, exercise-induced of lactate and estimated glomerular filtration rate did not differ between the control and RIPC trial (time × trial: all p The study a direct comparison of the release kinetics of hs-cTnT and hs-cTnI after prolonged endurance-type exercise. after exercise, we that hs-cTnT levels peak hs-cTnI levels. we that a powerful noninvasive cardioprotective strategy in the setting of cTn release, has effect on exercise-induced cTn release. running and the in running as has in recent the cardiovascular of physical exercise are is unclear whether this is the from physical exercise to strenuous A. H. exercise the can of a PubMed Scopus Google Scholar An in this is the of exercise-induced cTn release. This is the first study that the release kinetics of both hs-cTnT and hs-cTnI after prolonged endurance-type exercise. In of the maximum concentrations of hs-cTnT, hs-cTnI, and s-cTnI the clinical reference cTnT and cTnI are equivalent for the of K. Jaffe A.S. Katus H.A. B. P.M. H. R. F. R.J. D. M. W. J.P. J. E.M. E.M. J.L. M. G. S.P. D. Wood D. S.C. D. J.L. D. M. S. for the of of myocardial 2012; PubMed Scopus Google Scholar, M. R. T. K. M. C. B. F. M. K. T. M. B. M. C. J. B. K. S. C. comparison of troponin I T for the of acute myocardial Heart J. PubMed Scopus Google Scholar we between all cTn concentrations immediately measured after exercise. we that hs-cTnT maximum concentrations at an after exercise compared with hs-cTnI hours vs This is distinct from cTn release resulting from the breakdown of the contractile apparatus after ischemic myocardial injury, where peak levels of hs-cTnT and hs-cTnI are reached the same time line after followed by cTn for days after the of myocardial G. Kuster N. Petiton A. Leclercq F. Gervasoni R. Macia J.C. Cung T.T. Dupuy A.M. Solecki K. Lattuca B. Cade S. Cransac F. Cristol J.P. Roubille F. Kinetics of high-sensitivity cardiac troponin T and I differ in patients with ST-segment elevation myocardial infarction treated by primary coronary intervention.Eur Heart J Acute Cardiovasc Care. 2015; (Epub ahead of print)Google Scholar, 3Solecki K. Dupuy A.M. Kuster N. Leclercq F. Gervasoni R. Macia J.C. Cung T.T. Lattuca B. Cransac F. Cade S. Pasquie J.L. Cristol J.P. Roubille F. 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