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Exercise-Induced Cardiac Troponin T Release

A Meta-Analysis

SHAVE, ROBERT1; GEORGE, KEITH P.2; ATKINSON, GREG2; HART, EMMA1; MIDDLETON, NATALIE1; WHYTE, GREG2; GAZE, DAVID3; COLLINSON, PAUL O.3

Author Information
Medicine & Science in Sports & Exercise: December 2007 - Volume 39 - Issue 12 - p 2099-2106
doi: 10.1249/mss.0b013e318153ff78
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Abstract

The cardiovascular benefits of regular physical exercise have been well documented (24,37), but exercise also acts as a trigger of sudden death and acute myocardial infarction (AMI) in susceptible individuals (29,30). A number of recent studies have demonstrated elevations in highly specific cardiac biomarkers (cardiac troponin T and I) after prolonged exercise, suggesting that strenuous physical exertion may result in myocardial injury (34,36,39,42,44). A recent study has observed that postmarathon elevations in cardiac troponin T were associated with reduced cardiac function and were most prevalent in less-well-trained individuals (34). Reports in the popular media of this and previous studies (3,13,40) have prompted concern as to the safety of endurance exercise and, specifically, marathon running.

There is considerable methodological variation among studies that have examined the possibility of postexercise myocardial injury, making it difficult to study the factors involved or the mechanisms responsible for postexercise cardiac troponin elevations. The reported incidence of postexercise cardiac troponin release has ranged from 0 to 78% of competitors in endurance events (22,44), although differences in exercise mode and duration, as well as the training status, age, and gender of participants limit comparison among studies. Further, the small sample size in many studies has produced imprecise estimates of the incidence of postexercise cardiac troponin release (10,36,39,45).

Combining all valid data from studies that have examined postexercise release of cardiac troponins in a meta-analysis would yield the large overall sample size necessary to provide more precise statistical inference. In addition, categorization of individual studies, with reference to exercise duration, participant demographics, and exercise mode, may offer insight into factors influencing cardiac troponin after exercise. The aim of the present study was to use a meta-analysis approach to explore the phenomenon of postexercise cardiac troponin release.

METHODS

Data Sources

A literature search of peer-reviewed studies examining cardiac troponin release after exercise was conducted using the Pubmed, SportDiscus, and Embase databases (1997-2006) and the key words cardiac troponin T and exercise, exercise induced cardiac damage, and cardiac biomarkers and exercise. Reference lists from published papers were also examined to identify other relevant studies. The search criteria were limited to cardiac troponin T (cTnT) because a single assay has been available (Roche Diagnostics, Lewes, UK) since 1997. Studies investigating cTnI were not included, because several assays have been used, limiting direct comparison among studies.

Study Selection and Data Abstraction

Both published and unpublished studies were eligible for inclusion. For inclusion, studies had to meet the following criteria: 1) provide an indication of the number of participants demonstrating a postexercise elevation in cTnT above the detection limit of the assay, because cTnT is not usually detected in normal individuals; 2) use an exercise stimulus greater than 30 min in duration; 3) use either the second- or third-generation immunoassay for cTnT; 4) obtain blood samples within 12 h after completion of exercise; 5) report only data previously unpublished; and 6) if published, the study must have been published between 1997 and 2006 in an English-language journal. For a study to be included in the subgroup analysis, data on age, body mass, exercise duration, and mode of exercise were also required. When data were missing from the original manuscript, authors were contacted and asked to provide the additional information. For completeness, recognized authors in the field were also contacted and asked to provide information on any unpublished studies.

The primary (R.S.) and secondary (K.G.) authors independently selected the studies for inclusion in the meta-analysis and later met to reach a consensus. The search process identified 49 studies (48 published and 1 currently unpublished (Shave, unpublished data, 2006)) for potential inclusion. Of these studies, 23 did not meet the inclusion criteria and were eliminated. For example, some papers employed the first-generation cTnT assay (4,23,28), which has been shown to possess cross-reactivity with skeletal muscle damage (57). A number of studies obtained blood samples beyond the 12-h cutoff (25,26), whereas other studies reported results from pooled data sets (44), or did not include enough information to be considered for the analyses (27,51). Because of the specific methodological design, of the 26 studies remaining, one was subdivided into three (42), and another was split into two (45) subanalyses, providing an overall sample of 1120 cases for meta-analyses (Fig. 1).

F1-2
FIGURE 1:
Summary of study assessment and exclusion stages.

Statistical Analysis

Power analysis.

The outcome variable in all the relevant studies is a simple event rate (%). The median number of subjects in our sample of studies was 19. When the sample size is 19, a two-sided 95% confidence interval for a single proportion using the large sample normal approximation would extend approximately ± 22.5% from the observed proportion for a delimited proportion of 50%, making the precision of estimate relatively low (i.e., it could merely be claimed that the true population event rate is likely to lie between 22.5 and 72.5%). We can perform a simple, unweighted statistical power estimation to support the relevancy of our meta-analysis, using the number of cases we have analyzed; for a meta-analyzed sample size of 1120 cases, the two-sided 95% confidence interval can be estimated to extend only approximately ± 2.9% from a delimited event rate of 50%, thus providing our study with a substantial improvement in statistical power compared with a single investigation.

Derivation of outcome statistics.

The dichotomous outcome for each study was an event rate defined as the proportion of individuals in the sample that indicated a detectable or "positive" cTnT value for the presence of myocardial injury. Because cTnT is not present in serum of normal, healthy individuals, we chose to define the event rate as any postexercise cTnT above the 0.01-μg·L−1 detection limit of the cTnT assay. All studies included in the analyses comprised a single-group, pre-post design, with no control group. The number of research participants in any one study who provided a positive cTnT concentration before exercise was ≤ 1 (< 0.1% of total sample of research participants studied). Therefore, it was appropriate that the postexercise event rates and the associated standard errors were meta-analyzed.

Pooling of results.

Using version 2 of the Comprehensive Meta-Analysis software package (Biostat, Englewood, NJ), a random-effects meta-analysis of dichotomous outcomes was conducted (12,19). A 95% confidence interval (95% CI) was calculated for the event rate derived from each study. A pooled event rate was then calculated on the basis of weighted standard errors calculated from the standard error for each study event rate. Statistical significance was determined if the 95% CI did not overlap zero (P < 0.05).

Exploration of heterogeneity.

Heterogeneity of study event rates was examined with the Q-test and I2 value associated with the fixed-effects model (19). A Q statistic was deemed statistically significant if P < 0.10 and I2 values of 25, 50, and 75% were deemed small, medium, and large, respectively.

Exploration of publication bias.

The presence of publication bias was first explored with a standard funnel plot of study event rates versus the standard error of event rates. Quantitative explorations of publication bias were performed using Kendall's tau and Egger's regression test.

Sensitivity analysis.

All studies involved the same research design and primary outcome variables. Nevertheless, two main sensitivity analyses were deemed relevant. First, the pooled event rate was calculated both with and without the study results of Fortescu et al. (14), which were derived from an unusually large sample (N = 482). Second, the pooled event rate and the meta-regression analysis were calculated both with and without the study results of Neumayr et al. (36), which were collected before and after an event that was unusually long (1342 min).

Exploratory subgroup and meta-regression analyses.

The presence of significant heterogeneity was followed up with preplanned ANOVA-like subgroup analyses for the categorical moderator variables (11) and weighted fixed-effect meta-regression methods for the continuous moderator variables (54). The hypothesized categorical moderator variable in the subgroup analysis was mode of exercise (cycling only, running only, and triathlon). The hypothesized moderator variables in the meta-regression analysis were the mean duration of exercise (min), the proportion of males in the sample (%), the mean age of participants (yr), and the mean body mass of participants (kg). Any colinearity between these continuous moderator variables was investigated with Kendall's correlation. To control for asymmetry in the outcome scale, event rates were logarithmically transformed (base E) before the subgroup and meta-regression analyses.

RESULTS

Overall synthesis of event rates.

The overall event rate for the detection of cTnT after exercise was 0.47 (95% CI = 0.39-0.56, Fig. 2). This event rate changed only slightly to 0.46 (0.37-0.54) after removal of the study by Fortescu et al. (14), and to 0.49 (0.41-0.57) after removal of the study by Neumayr et al. (36). Therefore, the true incidence of postexercise cTnT release in the population of athletes is likely to lie somewhere between 39 and 56%. Nevertheless, there was evidence of large, statistically significant heterogeneity between studies (Q25 = 105.4, P < 0.0005; I2 = 76%). Consequently, the investigation of possible moderating variables on the heterogeneity of event rates is relevant.

F2-2
FIGURE 2:
Forest plot showing event rate, sample size (total), and 95% confidence limits for each study. Studies are ranked in ascending magnitude of event rate within in each subgroup of studies (cycling, running, triathlon). The overall random-effects event rate and associated 95% confidence limits for the 1120 research participants are shown in the bottom row of the plot. * Indicates data that were unavailable. Gender is quantified according to the proportion (%) of males in the study sample.

Publication bias investigation.

The funnel plot for investigation of publication bias demonstrated asymmetry in the distribution of study event rates, but in the opposite direction from that expected if publication bias existed (Fig. 3). A significant, negative correlation was found between study standard error and the magnitude of study event rate (Kendall's tau = −0.41, P = 0.004), suggesting that the event rate increased with sample size. Egger's regression intercept was found to be −2.42 (95% CI = −1.64 to −3.19, P < 0.0005). Publication bias exists because small studies are more likely to be published when they show a relatively large treatment effect, which is not the case for the present data.

F3-2
FIGURE 3:
Funnel plot of logit event rates vs standard error. Large standard errors are indicative of a small sample size. A logit event rate that is positive in sign corresponds to an actual event rate that is larger than 0.5 (50%), and vice versa.

Subgroup analysis.

The number of studies involving cycling, running, and triathlons was 6, 15, and 5, respectively. The pooled event rates (95% CI) for the studies involving cycling, running, and triathlon were 0.27 (0.15-0.45), 0.52 (0.42-0.62), and 0.53 (0.36-0.7), respectively. The difference in pooled event rates between studies involving cycling and running was statistically significant (Q1 = 6.07, P = 0.014), and that between triathlon and cycling approached statistical significance (P = 0.059).

Meta-regression analyses.

The frequency of cTnT detection was influenced by exercise duration (P = 0.022) and mean body mass (P = 0.0033), but not mean age (P = 0.309) (Figs. 4 and 5). The detection of cTnT postexercise decreased very slightly (mean slope of meta-regression line = −0.007) as the proportion of male participants in the study sample increased (P = 0.028).

F4-2
FIGURE 4:
Scatterplot showing the negative relationship between the duration of an exercise bout and the study logit event rate. The slope of the regression line is −0.00116 (95% CI = −0.00017 to −0.00216).
F5-2
FIGURE 5:
Scatterplot showing the positive relationship between the body mass of research participants and the study logit event rate. The slope of the regression line is 0.0686 (95% CI = 0.0234 to 0.114).

The relationship between exercise duration and cTnT detection was slightly negative, suggesting that cardiac damage was less prevalent among athletes who competed in longer events. This relationship was also present when only the running studies were considered (P = 0.016), although differences in event rates through the range of exercise durations remained low in terms of clinical significance. The event duration studied by one research group (Neumayr et al. (36)) was more than two times greater than the next-longest duration that was studied. When this study was removed from the meta-regression in a sensitivity analysis, the slope remained slightly negative, but it was not statistically significant (P = 0.26). The relationship between mean body mass of research participants and magnitude of study event rate was slightly positive, suggesting that the heavier athletes were somewhat more likely to demonstrate cardiac damage. There was, however, significant colinearity between the moderator variables of duration of exercise and mean body mass (Kendall's tau = −0.346, P = 0.0207), suggesting that the athletes who competed in shorter-duration events were heavier.

DISCUSSION

Our results demonstrate that approximately 47% of the participants who have been studied in endurance events have finished with a serum cTnT greater than 0.01 μg·L−1. The proportion of troponin-positive participants in each study was inversely related to exercise duration and was positively related to body mass. Nevertheless, the clinical significance of these relationships was low in terms of the difference in event rates through the range of exercise duration/body mass that has been studied. Interestingly, neither the age nor the gender of the participants had a statistically or clinically significant influence on the number of cTnT-positive subjects. The incidence of cTnT release after exercise was, however, much greater in running compared with cycling events.

The funnel plot and quantitative assessment of publication bias demonstrate that the studies with the largest samples possessed the greatest incidence of postexercise cTnT release, rather than the smaller studies, as would be expected if publication bias were evident. These data suggest that there may actually be a bias for researchers not to publish the results of small studies with findings of high event rates. Therefore, we maintain that it is unlikely that our estimate of overall event rate is an overestimation attributable to publication bias.

Previous authors have suggested that postexercise cardiac troponin release increases with exercise duration (5,14,39,45). This is not supported by the present findings. Conversely, we found evidence from our exploratory meta-analysis of a weak, negative relationship between duration of exercise and magnitude of event rate. It is possible that the training status of participants or the exercise intensity adopted in marathons may explain the increased incidence of cTnT release. In contrast to marathon running, ultraendurance events are completed by more highly trained individuals, usually at a lower intensity. It may be, therefore, that postexercise release of cTnT is associated with less-well-trained individuals or with those competing at a higher intensity. Lower rates of postexercise cTnT release within cycling events may also be explained by lower exercise intensities. Postural support during cycling, and the relatively smaller muscle mass used, means that heart rates are typically lower than those apparent within running events (2). Unfortunately, it was not possible to examine exercise intensity as a moderator variable in the present analysis, because relevant indicators such as heart rate were rarely reported in the literature. This is a limitation of our study; future studies examining postexercise release of cardiac troponin should attempt to report these variables.

The statistically significant relationship between body mass and the frequency of postexercise cTnT release demonstrated in the present meta-analysis has not been shown previously. It is possible that the colinearity between exercise duration and training status (i.e., those athletes with less experience likely participate in shorter events and may also be heavier) might explain the relationship between body mass and the frequency of postexercise cTnT release, rather than heavier people being predisposed to postexercise troponin release. We stress that although the slope of the meta-regression line was statistically significant, it was shallow across the range of body masses studied. Therefore, the clinical significance of this relationship is probably low.

Limitations of the data presented in the studies examined made it impossible to study the magnitude of troponin release in response to the various exercise stimuli. Within our analysis, athletes completing an event with a cTnT concentration of 0.01 or 0.3 μg·L−1 were classified in the same manner. From a clinical perspective, these two cTnT concentrations would likely represent two different populations. A troponin release above the recognized cutoff (0.05 μg·L−1) for acute myocardial infarction (AMI) (8) is of greater concern than a minor elevation above the detection limit of the assay, and it would likely result in different clinical management. Clinical management might be assisted by the differential release kinetics of cTnT after AMI and the release observed after exercise. Previous studies have shown that postexercise elevations in cTnT return to below the assay detection limit within 24 h (32,35,36), in contrast to the sustained elevation in cTnT after AMI. The kinetics of cTnT release after exercise are not clear; however, unpublished data from our laboratory demonstrate that cTnT peaks 3 h after completion of a marathon.

Earlier work suggesting that the heart may be damaged by endurance exercise was subsequently questioned (52) because the biomarkers used (e.g., creatine kinase MB) were shown to lack specificity. Although skeletal muscle contains troponin T, numerous studies have shown that the cTnT isoform detected by the third-generation immunoassay is not present in skeletal muscle (9,18,38). In addition, previous work has demonstrated a lack of cTnT release despite significant exercise-induced skeletal muscle damage (47). Therefore, whereas creatine kinase and the MB isoenzyme are not cardiac specific, cTnT is cardiospecific (53).

The mechanisms responsible for postexercise cTnT release are not known. Some have suggested that exercise-induced cardiac troponin release precedes physiologic cardiac hypertrophy (20,21,43,45). Release of acidic and basic fibroblast growth factors (αFGF and βFGF, respectively) from the cytosol of cardiac myocytes has been demonstrated, occurring in response to membrane damage caused by an increase in the rate and force of cardiac contraction (6,31). Membrane damage, subsequent to an increased rate and force of cardiac contraction during endurance exercise, may provide a mechanism by which cytosolic troponin is released into the circulation. High-intensity exercise also results in an increased production of oxygen free radicals that may lead to membrane disruption and, hence, cTnT release.

Although moderate aerobic exercise has documented health benefits (24,37), the long-term cardiac implications of repeated release of cTnT after multiple endurance events are less clear. Of interest, the autopsy of Sy Mah, who held the world record for having completed the most marathons, showed minor focal cardiac fibrosis without atherosclerosis (41). Whether postexercise cTnT release is related to microinjury of the myocardium is presently not clear. Cross-sectional and longitudinal studies are required to further examine the causes and consequences of postexercise cTnT release.

The authors thank all previous authors in the field who provided additional information when requested, specifically Drs. Siegel and Shärhag.

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      Keywords:

      HEART; EXERCISE; CARDIAC DAMAGE; CARDIAC BIOMARKERS

      ©2007The American College of Sports Medicine