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INTRODUCTION Strenuous exercise induces significant increases in cardiac biomarkers. However, it is still unclear whether this is caused by cardiomyocyte necrosis or secondary mechanisms such as ischemia, cardiac energy deficiency, increased inflammation, or renal dysfunction.
METHODS Therefore, we investigated cardiac biomarkers (hs-cTnT, NT-proBNP, h-FABP), inflammation markers (hs-CRP, IL-6, IL-10, TNF-Î±) and renal function (cystatin C) in 102 healthy men (age 42 (±9) y) before and after (0h, 24h, 72h) a marathon.
RESULTS Kinetics of hs-cTnT for the time period of 72h after the race revealed a peak immediately after the race (V3) rapidly decreasing to normal values within 72h (V5) (median (interquartile range IQR): V3: 31.07 (19.25-46.86) ng/L v. V5: 3.61 (3.20-6.70) ng/L, p<0.001). NT-proBNP (V3: 92.6 (56.9-149.7) ng/L v. V5: 34.9 (21.7-54.5) ng/L, p<0.001) and h-FABP kinetics (V3: 44.99 (32.19-64.42) µg/L v. V5: 7.66 (5.64-10.60) µg/L, p<0.001) showed a similar pattern. Pro-inflammatory markers such as IL-6 and hs-CRP, and renal dysfunction were significantly augmented during the race (pre-race compared to maximum post-race: IL-6: 15.5-fold, hs-CRP: 28-fold, cystatin C: 1.22-fold, all p<0.001). However, these increases were not significantly related to the increase of hs-cTnT.
Neither training history, finishing time nor exercise intensity were significantly associated with changes of hs-cTnT.
CONCLUSION Cardiac biomarker increased immediately after a marathon race but returned rapidly to normal values within 72h. These kinetics with a sharp peak indicate that cardiac necrosis during marathon running seems very unlikely, but may be explained by altered myocyte metabolism.
Key words: cardiac markers, exercise, inflammation, myocardial necrosis
ClinicalTrials.gov Number: NCT00933218
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Regular moderate physical exercise is a major prevention strategy to improve cardiovascular risk factors, delay cardiovascular disease, and decrease cardiovascular mortality.(20, 46) In contrast an increased risk of exercise-related sudden cardiac death during vigorous exercise such as marathon running has been frequently reported,(1) still the results being equivocal.(37)
Extreme exercise has shown to increase biomarkers of cardiac strain such as N-terminal pro-brain natriuretic peptide (NT-proBNP) as well as markers of cardiac injury (e.g. cardiac troponins (cTn)).(38) In addition, transient functional as well as persistent structural myocardial alterations (e.g. left and right ventricular dysfunction) and even myocardial fibrosis have been described.(5, 35) However, the underlying mechanism for these alterations first addressed as "cardiac fatigue syndrome" by Douglas et al.(14) are not yet understood.(36)
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Several hypotheses have been raised to explain this phenomenon of increased cardiac biomarkers after strenuous exercise. First, systemic inflammation or oxidative stress induced by strenuous exercise has been addressed to cause cardiac injury.(7) Exercise-induced increase of cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF-Î±) may lead to cardiomyocyte dysfunction comparable to findings in severe inflammation or sepsis.(27) Second, it has been hypothesized that stretch-related mechanisms mediated by integrins of viable cardiomyocytes may lead to exercise-related release of cTn.(21) This hypothesis of minimal membrane leakage and rapid resealing is still discussed controversially.(26) Third, ischemia has been addressed to cause exercise induced elevation of cardiac enzymes as structural cardiac damage has been demonstrated in older marathon runners.(5) Whether cell necrosis due to microvascular stenosis with subsequent increase of cTn after strenuous exercise is a potential mechanism is still under debate. Arguments against this hypothesis are that kinetics of cTn after marathon running are different than after myocardial infarction.(24, 29) Fourth, impaired renal excretion may cause elevated troponin T levels due to decreased renal elimination.(10) Likewise, an acute renal tubular dysfunction with transient oliguria caused by long-lasting strenuous exercise has been previously described.(23) Because of the differences in reported elevation of serum concentration of cTn, the different kinetics of elevation, the different reported prevalence of increased cTn per se as well as the different reported intensities and durations of exercise resulting in increased cTn,(15, 43, 44) the underlying mechanisms of cTn elevation post strenuous exercise remain unclear.(42)
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Recently, a novel and more specific and sensitive marker of cardiac cell injury, called high-sensitive cardiac troponin T (hs-cTnT) has been developed yielding more precise results and permitting analyses of cTn concentrations that are 10-fold lower than determined in previous assays.(31) Therefore a more precise and sensitive documentation of the chronological sequence is possible. This marker as well as other more established markers of cardiac ischemia, such as heart-type fatty acid binding protein (h-FABP), increases during acute myocardial infarction. The latter returns to baseline within 24 h whereas hs-cTnT remains elevated over days following myocardial injury.(48)
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To shed more light into the pathophysiology of cardiomyocyte strain and injury induced by long-distance vigorous exercise, we investigated the kinetics of specific cardiac biomarkers (h-FABP, hs-cTnT, NT-proBNP), inflammatory markers (interleukin-10 (IL-10), IL-6, high-sensitive C-reactive protein (hs-CRP) and TNF-Î±), and renal dysfunction (Cystatin C) before and up to 72 h after a marathon race in a large cohort of otherwise healthy individuals.
Materials and Methods
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Study Design & Participants
This prospective study aimed to investigate blood parameters of healthy men before, during and up to 72 hours after a marathon race. The study protocol was approved by the ethics committee (approval reference number: 2384/09, University Hospital Klinikum rechts der Isar, Munich, Germany) and the investigation conforms to the principles outlined in the Declaration of Helsinki. All participants gave written informed consent before enrollment.
Participants were recruited by 1) advertisements in local newspapers as well as running journals, 2) announcement in the internet, and 3) from athletes who had presented to our out-patient clinic for pre-participation screening.
Runners were consecutively included on a participation list until the number of 150 potential study subjects was reached (estimated drop-out rate before and during marathon race of 30%, predicted number of complete data at all visits n=105). For the given sample size, bivariate correlations with a correlation coefficient of r>|0.27| were detectable with 80% power at a two-sided 0.05 level of significance.
Inclusion criteria: Age 20-60 years, history of at least one successfully finished half marathon, intention to participate at the Munich Marathon 2009 (42.195km), and written informed consent.
Exclusion criteria: Cardiac disease, pharmaceutical treatment for diabetes mellitus or arterial hypertension, musculoskeletal or psychiatric disease, neoplasia, acute or chronic infection, medication or supplementation influencing the immune status.
Participants were examined (visit V1) to assess inclusion and exclusion criteria four to five weeks before the race. Baseline data were collected during the week before the race (visit V2) including questionnaires assessing training history, physical examination, anthropometry, clinical chemistry, collection of blood samples for further analyses, electrocardiogram (custo cardio 200 with custo diagnostics 3.8.3, custo med GmbH, Ottobrunn, Germany), and echocardiography (parasternal short- and long-axis images and apical 2-, 3- and 4-chamber views in a left lateral decubitus position; iE33 imaging system equipped with a broadband S5-1 transducer (frequency transmitted 1.7 MHz, received 3.4 MHz), Philips Medical Imaging, Hamburg, Germany).
Because of the potential influence of nutrition and medication on inflammation, participants were asked to document all medication (e.g. NSAID) and were asked to minimize intake of fatty foods, large-doses of vitamins or mineral supplements, and probiotic yogurt during the whole study period. Subjects recorded food intake with a 3-day food record before visit V2 and before the marathon.
Within one hour after finishing the race (visit V3) electrocardiogram, collection of blood samples, and assessment of blood pressure were performed. Follow-up examinations 24 hours (visit V4) and 72 hours (visit V5) after the marathon race (electrocardiogram, blood samples, and blood pressure) were performed in identical settings.
Further parameters recorded extensively as part of the trial protocol but that are not reported here, include cardiovascular measurements (diastolic and systolic cardiac function, arterio-venous ratio, and electrocardiogram).
During the marathon all participants were asked to use a heart rate monitor in order to determine the individual exercise intensity. %HRmax was calculated as a ratio of mean heart rate during marathon (HRM) and maximum heart rate (HRmax). HRmax was calculated by the formula: HRmax= 208 - 0.7 x age [years].(45) 78 participants (77%) wore a heart rate monitor during the race.
Body mass index (BMI) was calculated as the ratio of weight and the square of height (kg/m²). Total body fat was assessed by skinfold caliper technique.(6) Hypertension was defined as previously reported.(8) An elevated cholesterol level was defined as more than 240 mg/dL.(33) Smoking was defined as current smoking or having smoked within the previous year.
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Fasting blood samples were drawn from an antecubital vein with subjects in supine position at visit 1, 2, 4 and 5. Only blood collection directly after the race was not in a fasted state. All participants were instructed to refrain from sustained or long runs and strenuous exercise for at least three days before the pre-race blood draws. Routine complete blood counts were performed by clinical hematology laboratory using a Sysmex SF-3000 Automated Hematology Analyzer (Sysmex Deutschland GmbH, Norderstedt, Germany) and provided hemoglobin, hematocrit and albumin for determination of plasma volume change using the method of Dill and Costill.(13) As albumin concentration increased significantly hs-cTnT and all other dehydration-dependent concentrations were corrected for changes in plasma volume as previously described.(12) Therefore corrected values even below the lower limit of detection (LLD) can occur.
Other blood samples were centrifuged in sodium heparin or EDTA tubes, and plasma was aliquoted and stored within 1 hour at -80°C for further analyses.
High-sensitive Troponin T
Cardiac Troponin T (hs-cTnT) was measured quantitatively with the new high-sensitive enzyme immunoassay based on electrochemiluminescence (ECLIA) technology using the cobas e 411 analyser (Roche Diagnostics, Penzberg, Germany). The measuring range of this assay is 3-10,000 ng/L. The interassay coefficient of variation (CV) under actual routine conditions is 6.5% at a concentration of 27 ng/L. The upper reference limit in healthy volunteers is 14 ng/L.
NT-proBNP was measured quantitatively with the enhanced chemiluminescence immunoassay system (ECLIA) method on a cobas e 411 analyser (Roche Diagnostics, Penzberg, Germany). The measuring range of this assay is 5-35,000 ng/L. The interassay CV under actual routine conditions is 4.2% at a concentration of 138 ng/L. The upper reference limit in healthy volunteers depends on age and sex and is 65 ng/L in 18-49 year old males, 125 ng/L in 50-59 year old males, 194 ng/L in >60 year old males.
h-FABP was determined quantitatively using a solid phase enzyme linked immunoassay (ELISA) (BioCheck Inc, Foster City, U.S.A.). The measuring range of this assay is 5-500 µg/L. Serum samples have a minimum detectability of 5 µg/L. The interassay CV is 10.9% at a concentration of 86 µg/L. The upper reference limit in healthy volunteers is 19 µg/L.
In addition to its cardiac origin h-FABP is also released from peripheral musculature during strenuous exercise because h-FABP is also produced in skeletal muscle, moreover this to a much lesser extent than in heart. Therefore the origin of the h-FABP can be discriminated by the myoglobin/h-FABP ratio (with a ratio between 2 and 10 indicating cardiac damage and between 20 and 70 for muscular injury).(48) Following this, we used only participants with a myoglobin/h-FABP ratio between 2 and 10 for the multiple regressions analysis.
TNF- Î±, Interleukin-6 and -10
TNF-Î±, Interleukin-6 (IL-6) and -10 (IL-10) were measured using a solid-phase, two-site chemiluminescent immunometric assay on the ImmuliteÒ system (Siemens Healthcare, Eschborn, Germany). Expected values in healthy individuals range from non-detectable to 8.1 ng/L for TNF-±, up to 5.9 ng/L for IL-6 and up to 9.1 ng/L for IL-10. The analytical sensitivity is 1.7 ng/L for TNF-±, 2 ng/L for IL-6 and 1 ng/L for IL-10. The measuring range is up to 1,000 ng/L for all measured parameters.
hs-CRP was measured quantitatively with an immune turbidimetric method on an AU 2700 analyser (OLYMPUS Germany, Beckman Coulter, Krefeld, Germany). The measuring range of this assay is 0.7-800 mg/L. The interassay CV under actual routine conditions is 1.4% at a concentration of 13 mg/L. The intraassay CV is 0.74% at a concentration of 5.7 mg/L. The upper reference limit in healthy volunteers is <5.0 mg/L.
For quantitative determination of cystatin C in plasma a particle enhanced immunoturbidimetric assay run on a Cobas Integra 800 analyser (Roche Diagnostics, Penzberg, Germany) was used. The measuring range of this assay is 0.4-8.0 mg/L. Expected values for healthy adults are between 0.5 and 1.09 mg/L.
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Data analysis was performed using PASW Statistics 18.0.2 (SPSS Inc., Chicago IL, USA). For quantitative data, the mean, standard deviation and range or if more appropriate (non-normally distributed data) the median and interquartile range (IQR: 25th/75th percentile) was reported for descriptive purpose. Assumption of normal distribution of data was verified by using descriptive methods (skewness, outliers and distribution plots) and inferential statistics (Shapiro-Wilk test).
Due to the non-normal skewed distribution of main outcome parameters transformation by natural logarithm was applied prior to parametric data analysis (linear regression). Thus, relative effects of potential explanatory variables were modeled. Particularly, back-transformation of regression coefficients (using simple exponential function) gives an estimate for the median relative change of outcome measure by a one-unit increment of the corresponding explanatory variable. Based on evidence of recent literature, the variables age, body composition (25) and FABP (11) were considered as relevant confounding and/or explanatory factors in the multivariable analysis. The variance inflation factor (VIF) was used to assess multicolinearity of multivariable explanation factors. Higher VIF values reflect a stronger dependency of a single predictor variable in association to the remaining explanatory variables included in a regression model.
To evaluate changes in serum biomarkers between two time points Wilcoxon-signed rank test was used. A p-value <0.05 was considered to indicate statistical significance and Bonferroni correction of p-values was applied variable-wise within any multiple comparison. Testing was performed two-sided.
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Participants' characteristics: From the 150 runners originally a total of 102 were eligible for analysis (Fig. 1). Baseline characteristics are given in Tab. I.
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Kinetics of high-sensitive cardiac troponin T and marathon running: hs-cTnT was measured in all 102 marathon runners at all 5 visits. In the pre-marathon visits the hs-cTnT concentrations were higher than the lower limit of detection (LLD) in approximately half of the samples (51%). Three days after the marathon race hs-cTnT concentrations were above the LLD in 43 participants (42%). In the pre-race samples the 99th-percentile value for hs-cTnT was 18 ng/L. At the first visit two otherwise healthy participants (2%) had an hs-cTnT concentration above the upper reference limit (values of 18 ng/L and 44 ng/L). This increase above the clinical threshold of 14 ng/L was observable in 91 participants (89%) immediately after the race, in 27 participants (27%) 24 hours and in 4 participants (4%) 72 hours post-race.
Immediately after the marathon hs-cTnT increased significantly with an average of 10.8-fold (p<0.001) compared to pre-race (V2) (Tab. II, Fig. 2). Three days after the marathon race the levels of hs-cTnT concentrations were increased above pre-race levels in most runners (p<0.001).
The five participants with the highest hs-cTnT concentrations immediately after the race (hs-cTnT 147 to 631ng/L) were 29 to 51 years old, free of cardiovascular risk factors (non-smoker, mean BMI 24.6 kg/m², mean blood pressure 117/78 mmHg) and completed between one to fife marathon races before. Their hs-cTnT concentrations showed prolonged elevation over the reference limit in V4 and V5 (mean hs-cTnTV4: 52.5ng/L, mean hs-cTnTV5: 16.5 ng/L). Further cardiac examinations of these participants (also post-exercise) showed normal results.
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Levels of additional myocardial markers: All additional myocardial markers showed a significant increase immediately and 24 hours post-race (all p<0.001 compared to pre-race, Tab. II).
Regarding h-FABP, within 72 hours post-race no significant changes were seen compared to pre-race (p=0.09). To discriminate between h-FABP, from skeletal muscle and from cardiac origin, the myoglobin/h-FABP ratio was calculated.(48) The results regarding the origin of h-FABP are shown in figure 3.
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Levels of inflammation markers: There were significant changes in all markers of inflammation between the examination one week pre-race, immediately after the race and one day post-race (Tab. II). At the pre-race visits and the visits 24 and 72 hours post-race cytokines were mainly below the LLD. Only at the investigation directly post-race the majority of participants had measurable cytokine levels with a significant increase immediately post-race (IL-6 and IL-10: p<0.001).
For TNF-Î± significant changes were observed during the race. TNF-Î± values were below the reference limit at the first visit in 44% of the participants, in the week before the marathon in 37% of the participants, immediately after the race in 7%, 24 hours post-race in 23% and 72 hours post-race in 31% of the participants. There was a significant increase in TNF-Î± from pre- to immediately post-race (Tab. II).
The levels of hs-CRP 24 hours post-marathon were approximately tenfold higher compared to pre-race (p<0.001) (Fig. 4, Tab. II).
Renal function: Cystatin C increased significantly immediately after the marathon race (Tab. II).
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Multiple regressions analysis revealed significant associations of increment in hs-cTnT concentration (pre-race v. immediately post-race) and hs-cTnT pre-race (n-fold change per an one unit increment: 1.11, CI: 1.04-1.19, p=0.003), pre- to post race difference in IL-6 concentration (n-fold change per a ten units increment: 1.06, CI: >1.00-1.12, p=0.046), age (n-fold change per a ten year increment: 0.70, CI: 0.59-0.83, p<0.001), body fat (n-fold change per an one unit increment: 1.04, CI: >1.00-1.08, p=0.034) and pre- to post race difference in h-FABP (n-fold change per a ten unit increment: 1.06, CI: 1.02-1.11, p=0.005). In total 32% of change of hs-cTnT concentration was explained (adjusted R²=0.29) by this multivariable model. These results were in accordance with a weak positive correlation observed between changes in IL-6 and hs-cTnT from pre- to immediately post-race (Spearman's rho: + 0.27, p=0.006). Solely the impact of body fat changed considerably within the multivariable analysis when comparing to the result of the univariable analysis (n-fold change of hs-cTnT per an one unit increment of body fat: 1.01 CI: 0.97-1.05 p=0.645). This difference in effect sizes is explained by the high inter-correlation of body fat and the other explanation factors considered in the multivariable analysis, which is reflected by the comparable high variance inflation factor (VIF) for body fat of 1.64 (VIF for all other clinical parameters <1.10)
In further bivariate correlation analyses we found no statistically significant association between renal dysfunction (represented by cystatin C), markers of cardiac stretch (such as NT-proBNP), trainings history (e.g. previously finished marathon races or training workload), finishing time or individual exercise intensity during marathon (measured by %HRmax) and the increase of hs-cTnT immediately post- compared to pre-race (all p-values >0.05).
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Several hypotheses have been raised to explain the phenomenon of increased cardiac markers particularly cardiac troponin T after prolonged strenuous exercise. To our knowledge this study is the first to describe an elevation of the novel high-sensitive cardiac troponin T in a large cohort of marathon runners and simultaneously measuring numerous other biochemical markers that have been addressed to be of pathophysiological significance. These include markers of inflammation (interleukins, TNF-Î±, hs-CRP), left ventricular strain (NT-proBNP), renal dysfunction (Cystatin C), and ischemia (h-FABP). Although all of these parameters significantly increased during the marathon, however their kinetics revealed no clear evidence for permanent structural injury or necrosis of cardiac muscle fibers induced by marathon running.
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Kinetics of serum cTn concentration released during irreversible myocyte necrosis is characterized by a steep increase and prolonged elevation for at least four to seven days. This pattern is significantly different after prolonged strenuous exercise with a distinctively faster decrease.(2) This is explained by the relatively long clinical half-life of cTn in serum of â‰¥20h due to persistent leaking of troponin from necrotic cardiac cells. In contrast to this relatively long clinical half life the true half life of cTn in the circulation is short (approximately 2h (17)) because of rapid elimination. If ischemia fails to induce necrosis, this short true half-life results in a pattern of cTn similarly seen in exercise-induced alteration. In our study we observed the latter pattern with cTnT concentrations peaking immediately after the race followed by a rapid decrease within 24h. Mingels et al. observed a similar pattern in their study investigating 85 marathon runners before and after strenuous exercise.(30) The brief peak within 24 hours might be explained by a transient injury of the cell membrane seen in reversible ischemia and myocyte metabolism alteration (decreased adenosine triphosphate availability or altered cytosolic calcium homeostasis). In this case, cTn, of which approximately 5 to 8% are unbound and soluble in the cytosol,(4) may be released due to loss of membrane integrity and shed into the bloodstream increasing systemic levels of cTn.(41) This mechanism seems to be also evident in a clinical setting of early reperfusion after ischemia in which case the troponin release is of cytoplasmic origin.(22, 24) Therefore, although still hypothetical, the cTn kinetics pattern after strenuous exercise described in previous publications (47) as well as in our study (Tab. II, Fig. 2) might be explained by this mechanism. This is in accordance with a recently published review (42) and confirmed by cardiac imaging failing to show cardiac damage by cardiac magnetic resonance (e.g. neither evidence of myocardial edema in T2 weighted imaging nor findings of delayed enhancement within the left ventricular myocardium).(32, 47) Findings of myocardial injury, as seen in older marathon runners (5) are probably independent of marathon running but rather related to cardiovascular disease or risk factors, particularly smoking.
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Kinetic patterns as for hs-cTnT are similar for biomarkers of ischemia (e.g. h-FABP). However, when calculating the myoglobin/h-FABP-ratio to account for the origin of the released h-FABP (cardiac v. peripheral), our analysis revealed that h-FABP after the marathon is primarily released by peripheral muscle and is not of cardiac origin. Also, the increase of markers of ventricular strain such as NT-proBNP was not correlated with the increase of cTn after the marathon, which is in concordance with previous data.(26)
In addition to the ischemia hypothesis, inflammation has been considered to be one possible pathophysiological mechanism for the increase of cTn after strenuous exercise. Like the cardiac markers, all of the pro-inflammatory markers increased during the marathon race (Tab. II). However, we could only find a correlation between changes of IL-6 and changes of cardiac markers. None of the other inflammation parameters showed a significant association with the increase of hs-cTnT concentration during the marathon. This is in accordance with the findings of Scharhag et al. who also found no relationship between exercise-induced increases in immune reactions and NT-proBNP.(40)
Of note is that in our study all potential influencing factors such as nutrition or intake of anti-inflammatory drugs (NSAIDs), were excluded. Thus our measures of inflammation were less biased by these co-factors than in previous studies.(38, 39)
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Circulating cTnT concentration is in parts dependent on renal function and excretion. We observed a distinctive increase in Cystatin C, a very sensitive marker of renal function, post-marathon and consecutively a decrease in glomerular filtration rate which is in accordance with prior studies.(28) However renal impairment was not significantly linked to the increase of cTnT concentrations, suggesting that renal elimination of cTn is not responsible for the increase in cTn after strenuous exercise.
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Other explanations for individual increases of cTn after marathon running are intensity of exercise or training status.(16, 34) However, neither previous studies investigating increases of cardiac biomarkers in relations to cardiorespiratory fitness (47) nor our data are able to confirm this. Similarly we did not find any association between finishing time, number of finished marathon runs or training history and the increase in both cardiac and inflammatory biomarkers. In contrast to our study prior studies used finishing time as a surrogate parameter for exercise intensity. Because of the varying inter-individually physical conditions this approach seems to us insufficient so we used a more direct measurement of cardiac strain (mean % HRmax). Remarkably, cTnT concentration was also not depending on individual exercise intensity during a marathon as investigated for the first time in our study. Therefore, it has to be concluded that inherent vulnerability to exercise-induced cardiac and inflammatory alterations seems to be more important than possible adaption mechanisms to training.
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Although they increase sensitivity, results attained using the new hs-cTn assays have been contested based on their supposed reduced diagnostic specificity.(3, 9) Interestingly 3 of the 102 marathon runners had baseline hs-cTnT concentrations above 14 ng/L, the 99th-percentile of the manufacturer's reference. Under the light of this finding upper reference limits should be reevaluated as there are also some other non-pathological circumstances associated with increased cTn levels.(18, 19)
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Our results suggest that the increase of cardiac troponin T after prolonged strenuous exercise is likely to be caused by transient strain or altered myocyte metabolism rather than irreversible necrosis of cardiomyocytes. Other hypotheses such as increased inflammation, renal dysfunction or cardiac stretch-related mechanisms seem to be less important. In addition, we observed no significant association between individually measured exercise intensity, training history or finishing time and changes of hs-cTnT concentration.
Acknowledgments: The authors thank Jeff Christle and Desire Wilks for careful proof-reading of the manuscript.
The results of the present study do not constitute endorsement by ACSM.
Funding: S. Braun received access to assays from Roche Diagnostics. The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
There are no other competing interests to declare.