Exercise is known to have a vast array of health benefits. It may however confer delirious effects on most body systems, with the cardiovascular system taking particular prominence. Athletes in particular are known to be at a higher risk for sudden cardiac death as a result of several cardiac adaptations which take place. Myocardial damage as a result of extreme exertional activities is thought to play a very important role in this risk. Cardiac troponin I is widely known to be an excellent diagnostic marker which is used in patients suspected of having acute coronary syndrome. Its release during exercise has been routinely studied, with many hypotheses currently being proposed as to its role and potential complications once released. Whether or not it implies that myocardial damage is taking place as a result of exercise is debatable, but its release might have some role in the development of cardiotoxic states which predisposes athletes to significant cardiac risk. This review aims to discuss the proposed mechanisms in exercise-induced troponin release, while also goes into its clinical relevance and potential early and late sequelae.
Statistics from Altmetric.com
Regular exercise has a beneficial effect on many of the established risk factors for cardiovascular disease. Non-athletic individuals who have substrates for potential cardiovascular complications are thought to be at an increased risk when they perform sporadic vigorous exercise regimens.1 Marathon running may precipitate acute coronary syndrome (ACS) and sudden death in 1 per 50 000 marathon participants.2 A number of studies support the notion that asymptomatic individuals undergoing bouts of prolonged exercise are likely to experience elevated levels of cardiac biomarkers, namely troponin I (cTnI) and troponin T (cTnT). In patients with cardiosvascular disease, cTn is presumed to reflect cardiac damage and dysfunction, with a delta change in cTn particularly important in supporting a diagnosis of ACS.3
The aim of this review is to look into the various evidence-based mechanisms currently being proposed for troponin release as a physiological response to endurance exercise.4 The review also discusses the clinical significance of troponin release after an acute and chronic endurance exercise, to contribute towards optimal management of the endurance athlete.5
Cardiac troponin elevation after exercise
A number of studies have looked into the release of cTn after prolonged physical exercise. Several studies have reported that there was no significant increase in cTn following exercise; however, the majority of studies have reported a statistically significant elevation.6 Two landmark meta-analyses consisting of 1120 cases (26 studies)7 and 939 cases (16 studies)8 clearly illustrated that more than 60% of cases had isolated elevated cTnT after exercise.8
Age and gender do not seem to play a role in exercise-induced cTnT release.7 Its release has however been shown to negatively correlate with the magnitude of the event rate and exercise duration, with levels generally higher in running events compared with cycling events.7 Lower cTnT levels in ultra-endurance events compared with marathons which are normally undertaken by recreational athletes might imply that postexercise release of cTnT may be associated with individuals who are competing at a higher intensity or less well-trained individuals.7
The wide variability in most observational study designs does not allow appropriate pooling of data to help formalise conclusions. The variability of cTn assays used, timing of the blood drawn for cTn measurement and the lack of individual patient data are some of the main limitations which need to be predetermined in future multicentre trials.3 The available pooled data of current scientific literature are however consistent with the hypothesis that cTn levels might frequently increase after endurance exercise.3
Multiple studies have individually documented cardiac dysfunction and cTn elevations after prolonged exercise; however, whether there is a relationship between raised cTn and depressed parameters of systolic or diastolic cardiac function is still uncertain and has been reported with different consensus.9 10
One study observed the echocardiographic variations after the Boston Marathon in non-elite athletes.11 Exercise-related cTnT after the race was shown to positively correspond to diastolic dysfunction, elevated pulmonary pressures and right ventricular (RV) dysfunction. Elevated cTnT was however inversely related to training mileage, suggesting that cardiac biomarkers may play some role in exercise-induced cardiac dysfunction after endurance activities, especially in participants with less endurance and when exercise is less prolonged.11 Altered left ventricular (LV) function during exercise is still, however, debatable, with a separate cohort not showing any significant correlation between cTnT elevations and changes in LV function,9 especially when taking into account that the proportion of elevated cTnT after the marathon was comparable to other cohorts.8
Cardiovascular magnetic resonance (CMR) imaging in a small separate cohort of recreational marathon runners independently showed CMR-related changes after exercise. Lower LV end-diastolic and end-systolic volumes, together with a small increase in LV ejection fraction, in the absence of inflammation or necrosis were among the observed changes.12 Postmarathon RV dysfunction was however not shown to be present. These CMR changes, together with the absence of any significant correlation with cTn release, suggest a gender-based response to exercise, with this cohort only including men, with 40% of the previously discussed cohort11 consisting of women. CMR-proven RV dilatation and impaired function was also shown to be present in a separate mixed gender cohort, consisting of recreational marathon runners.13
Despite plenty of evidence in favour of exercise-induced cTn release, available data regarding its role in cardiac dysfunction are mostly limited to small-scale studies, at times revealing conflicting results. At present, there is no evidence which supports that transient ischaemia or infarction plays a role. Increased tension, dilatation of the RV or both may account for this biomarker phenomenon in prolonged endurance exercise,13 while changes in diastology,11 with or without changes in LV systolic function possibly also playing some role.12
Potential mechanisms of exercise-associated cardiac troponin release
More than 90% of cTn is bound to tropomyosin on the thin filament of the myofibril, with only 5%–8% being unbound in the cytosol pool. Troponin release during ACS seems to originate from the cytosol pool, with a later rise attributable to the release of the myofibril-bound cTn.1 10 Exercise-related cTn elevations do not necessarily reflect irreversible cardiomyocyte damage or myocardial necrosis. The physiological mechanisms responsible for the release of cTn during exercise are still not fully understood.9–11 Benign reversible cardiomyocyte membrane damage is thought to be the main reason for this manifestation.14 Such damage following repetitive exposure to high-intensity endurance regimes may consequently give rise to myocardial fibrosis,15 with this phenomenon in relation to chronic endurance veteran athletes currently being explored.16 Fibrotic patches may potentially serve as a substrate for malignant arrhythmias, contributing towards an alleviated risk of sudden cardiac death in endurance athletes.16
Current evidence supports the theory that cTn can be released by myocytes in the presence of ischaemia and absence of necrosis. As a result of cardiac ischaemia, there is growing evidence which confirms that plasma membrane malfunction plays a key role. It seems to contribute towards the formation of membranous blebs, getting bigger in proportion to the extent of ischaemia. cTn is then driven out of cardiac myocytes,10 similar to membrane bleb formation in hepatocytes.10 One may postulate that disparity in favour of reabsorption or release of these membrane blebs may be proportional to the intensity and/or length of exercise. High-endurance exercise may contribute towards more ischaemia, shifting the balance towards bleb release. An intact cell membrane that fails to rupture during bleb release or reabsorption may justify the low (usually <1.0 µg/L) and short-lasting (typically <24–46 hours) amount of troponin detectable with new highly sensitive assays. In the presence of inappropriate reoxygenation during vigorous exercise, cell membrane blebs may then rupture and contribute towards cell necrosis, possibly the reason why more high-endurance athletes tend to manifest higher cTn levels after exercise.10 Irrespective of the scenario, eventual reoxygenation results in only a one off release of cytoplasmic contents, in contrast to a more steady release as observed in ACS. As a result of the short half-life of cTn, it is rapidly cleared after exercise.10
Stretch-related mechanisms during exercise may also play a role in exercise-related cTn release.17 Integrins on viable cardiomyocytes seem to be linked in the formation of membrane blebs.10 There is however not enough evidence supporting this phenomenon, which is why any definite conclusions would be rather premature at this stage. Intracellular calcium overload with activation of calpains, elevated catecholamines, alterations in glucose and fat metabolism, or mechanically induced disruptions of the membrane of the cardiomyocyte with rapid resealing have also been proposed as plausible mechanisms for exercise-induced cTn release.4 Membrane leakage as a result of exercise-induced overload of free oxygen radicals is another proposed mechanism.18 Indeed, some authors have suggested that cTn release may, in part, be related to the physiological cardiac adaptation in response to exercise.5
Kinetics of troponin release following exercise
The actual kinetics which facilitate cTn release during and following exercise are not fully understood. There is a good body of evidence which supports that cTnT concentrations peak immediately after exercise, followed by a rapid decrease within 24 hours.19 Necrosis and ischaemia-related cTnT release on the other hand tends to steep after 2–4 hours, with a constant release of cytoplasmic cTnT from necrotic myocytes contributing towards a prolonged elevation for at least 4–7 days, up to 21 days in some instances. There is, on the other hand, some preliminary evidence regarding cTnT release during exercise itself.
Initial evidence suggests that cTnT seems to steadily increase during and immediately following exercise, decreasing back to baseline levels.20 This relationship implies that this manifestation might indeed be a physiological response to exercise.20 Despite a small cohort of nine participants performing a treadmill marathon, the study by Middleton et al 20 consisting data in all subjects provides a new insight into the physiology at play. That said, definite conclusions would seem premature based on these observations alone.
In a separate cohort,21 cTn release does not however seem to augment following repeated bouts of exercise. A study of 25 male adolescent runners performing two bouts of prolonged exercise (two 45 min constant-load treadmill runs, separated by 255 min of recovery) noted a progressive decline in cTn after successive bouts of exercise, rather than an augmented response as one would have expected.21 Elevations at 3 and 6 hours of the initial exercise regime were similar as observed in other cohorts,6 with interindividual variation again present in these athletes, highlighting that the current evidence does not give a holistic explanation of the underlying physiology.20
At this point in time, it is reasonable to conclude that exercise-related cTn elevations typically decrease significantly within 24 hours after exercise and reach normal values within this period.4 The true half-life for cTn is rather short (roughly 2 hours) in exercise-induced cTn elevations, provided that transient ischaemia fails to induce necrosis.19 There are otherwise limited data supporting any more conclusions at this stage.
Is this ACS? A practical approach
The presence and elevation of cTn in the systemic circulation has generated significant interest because of the clinical ramifications. cTn has been found to be elevated in a number of endurance events including Ironman triathlons, marathon races, cycle races and long-distance walking events.22 Clinicians need to be aware of alternative conditions that might cause cTn elevations. Postexercise elevations in cTn have substantial implications when faced with the situation of whether healthy individuals should be treated for ACS in the emergency department.3 A differential diagnosis should always be sought, keeping in mind that abnormal biochemistry might be in response to physiological phenomena in athletes.
Physicians must understand that the pathogenesis of cTn release is different in myocardial ischaemia (MI) versus non-MI cases. Postexercise cTn release tends to normalise within 24 hours, unlike in ACS-related levels.6 A relationship between exercise-associated elevations of cTn and cardiovascular risk factors does not seem to exist4 and cardiovascular insufficiency does not underlie the mechanism of collapse in the vast majority of collapsed runners,2 which goes to show that treating for ACS based on cTn results is not in the patient’s best interests, unless the clinical suspicion is present.
In the workup of ACS, the use of one-off measures of cTn should be viewed with caution after prolonged exercise because of different kinetics.20 Whether serial measures of cTnT and cTnI after exercise may assist in the differentiation of underling physiological versus pathological mechanisms is still uncertain and has rarely been reported.5 Shave et al 6 suggest that cTn testing may not be indicated for the evaluation of individuals who present for medical attention after participation in athletic events or significant exercise.6 Without a doubt, one has to view cTn findings in healthy athletes with caution and should not transfer these findings directly frompatients with cardiovascular disease and ACS because there is only limited direct evidence of MI in prolonged exercise.4 The misdiagnosis of MI after endurance exercise can lead to subsequent mismanagement including unnecessary hospitalisation and invasive intervention which are expensive and psychologically damaging to the athlete. Diagnosis of MI after prolonged exercise should be made on the basis of all available information and not blood tests alone.5 Immediate invasive diagnostic examinations in clinically and non-invasively unsuspicious athletes with only exercise-induced elevation of cTn do not seem to be indicated by the present knowledge.4 An algorithm has been devised to help identify or predict the likelihood of ACS after prolonged exercise (figure 1).6
Exercise has been shown to offer significant cardiovascular health benefit. High exercise regimes may however upset the balance. There is limited evidence with regard to the healthiest exercise intensity, frequency and duration. The advantages and risks brought on by exercise may show interindividual variation, with different risks brought on by different sport disciplines, exercise frequency and intensity.5 Further work is required to investigate potentially long-term risks of exercise, while also providing more evidence for the clinical implications of cTn elevations after exercise.6
Cardiac troponin release in response to vigorous exercise activity is a physiological manifestation in response to exercise related cardiac adaptations.
In the absence of typical cardiac symptoms and typical cardiovascular risk factors, post-exercise cardiac troponin elevations should not be interpreted by physicians as acute coronary syndrome, unless there are other clincial features which strongly suggest it.
Current research questions
What are the physiological mechanisms behind exercise-induced troponin elevations?
What are the clinical implications for cardiac troponin elevations in athletes after exercise?
Eijsvogels TMH, Fernandez AB, Thompson PD. Are there deleterious cardiac effects of acute and chronic endurance exercise? Physiol Rev 2016;96:99–125.
Eijsvogels TMH, Shave R, van Dijk A, et al. Exercise-induced cardiac troponin release: real-life clinical confusion. Curr Med Chem 2011;18:3457–61.
Nie J, George KP, Tong TK, et al. Effect of repeated endurance runs on cardiac biomarkers and function in adolescents. Med Sci Sports Exerc 2011;43:2081
Scharhag J, George K, Shave R, et al. Exercise-associated increases in cardiac biomarkers. Med Sci Sports Exerc 2008;40:1408–15.
Shave R, Baggish A, George K, et al. Exercise-induced cardiac troponin elevation evidence, mechanisms, and implications. J Am Coll Cardiol 2010;56:169–76.
Please answer true or false to the below statements.
Cardiac troponin elevation after exercise is a diagnostic marker of pathology.
Transient ischaemia as a result of exercise, clinically manifested as troponin elevations, might contribute towards pathology later on in life.
Exercise-related cardiac troponin elevations tend to return back to baseline within 5 days.
Troponin elevations after exercise should be treated as acute coronary syndrome in the first instance.
Integrins are thought to play a role in exercise-induced myocardial damage.
Contributors Both authors equally carried out a literature search on the literature pertaining to the subject. Both authors were also equally responsible for the writing of this review.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.