The challenges to cardiovascular health because of undertaking bouts of prolonged and strenuous exercise are currently under debate (16,24,43,46,50,51,57,58,62,67,73) and are of concern for the athlete, coach, scientist, and clinician. A specific interest in recent studies has been the potential risk of exercise-associated cardiac damage and/or dysfunction, as represented by the presence or elevation of cardiac biomarkers in the systemic circulation, assumed to be caused by events such as Ironman triathlons, marathon races, cycle races, and other endurance events. The exercise-associated appearance or increase in a range of cardiac biomarkers has been reported for elite athletes and for recreational athletes. Indeed, a quick literature search would provide ample evidence of an increase in cardiac biomarkers such as troponin(s) or B-type natriuretic peptide (BNP) (e.g., 4,5,7,11-14,17,18,21,22,26,28,29,31-35,38,39,42,44,45,50,53-59,65,69,71,72).
Many different cardiac biomarkers represent different physiological and pathologic processes. Although in cardiac patients, the presence or increase of specific biomarkers usually reflects myocardial ischemia, damage, or cardiac dysfunction, in athletes, after prolonged exercise, it is still unclear if the appearance or increase in any given biomarker represents clinically significant cardiac insult or is indeed part of the physiological response to endurance exercise. The appearance of cardiac troponins is clinically helpful to indicate myocardial infarction. The elevation of ischemia-modified albumin (IMA) has been proposed to reflect ischemic insult to cardiac tissue, but there are significant caveats and limitations of this marker at present. An elevation in BNP commonly reflects elevated myocardial wall stress in cardiovascular patients with cardiac dysfunction, chronic heart failure, acute coronary syndromes, and others; in an exercise setting, it may simply reflect an increased myocardial work (34,45,50,57,59,67,69).
Elevations in cardiac biomarkers in athletes after exercise may generate difficulties for clinicians in terms of differential diagnosis and may result in inappropriate consequences (73).Therefore, the aim of this article is to provide an overview of exercise-associated alterations of the cardiac biomarkers cardiac troponins T (cTnT) and I (cTnI), IMA, BNP, and its cleaved inactive fragment N-terminal pro BNP (NT-proBNP) for the athlete, coach, scientist, and clinician, and to point out future research directions.
Although several biomarkers of cardiac damage have traditionally been used in clinical practice (e.g., creatine kinase [CK], CK-MB, myoglobin), today the gold standard biomarkers to diagnose myocardial necrosis in patients with acute coronary syndromes are cTnT and cTnI (63). Although the proteins troponin T and I are in the troponin complex as part of the tropomyosin and actin filament in skeletal and cardiac myocytes, tissue-specific isoforms of cTnT (approximately 35 kDa) and cTnI (approximately 23 kDa) are expressed in the cardiomyocyte. Besides the structurally bound cTnT and cTnI, approximately 6-8% of cTnT and 2-8% of cTnI are in the cytosolic pool as unbound cTnT and cTnI (19). In patients with myocardial infarction, at first the cytoplasmatic unbound cardiac troponin is released, followed by the structurally bound troponin of the troponin complex (75), and elevations of cTnT and cTnI appear in the blood after 2-4 h and can persist up to 21 d (19).
For cTnT and cTnI, the 99th percentile of healthy subjects is defined as the upper reference limit (URL), and concentrations above the URL are considered as elevated (63). The URL for cTnT is <0.01 ng·mL−1, and depending on different available laboratory tests, the URL for cTnI ranges between 0.04 and 0.8 ng·mL−1 (2). Although cutoff values to define myocardial infarction have been suggested in the past (0.1 ng·mL−1 for cTnT and 0.5 ng·mL−1 for cTnI) (3), the recently published expert consensus document of the European Society of Cardiology, American College of Cardiology, American Heart Association, and the World Heart Federation defines myocardial infarction as the elevation of cardiac troponins above the URL combined with at least one of the following four criteria: 1) symptoms of ischemia, 2) ECG changes indicative of new ischemia, 3) development of pathologic Q waves in the ECG, or 4) imaging evidence of new loss of viable myocardium or new regional wall abnormalities (63). "An elevated value of cardiac troponin in the absence of clinical evidence of ischemia should prompt search for other aetiologies," and "extreme exertion" is listed as one of these (63).
That exercise can induce increases of cTnT or cTnI in obviously healthy athletes has been demonstrated in several studies in the past and has been the subject of a recent meta-analysis in Medicine & Science in Sports & Exercise ® (56). The initial studies used first-generation immunoassays with apparent cross-reactivity between skeletal and cardiac troponins, and therefore, these assays could not differentiate myocardial from skeletal muscle release. In more recent studies using newer assays (second and third generations) without cross-reactivity, significant elevations of cTnT and cTnI have been reported after prolonged and competitive endurance exercise bouts such as marathon and ultramarathon running, ultratriathlon, road cycling, long-distance mountain bike races, or cross-country skiing in adult athletes (16,57). Recently, elevations in cTnT and cTnI have been reported in junior male runners after a 21-km run (in 6 of 10 athletes) (64). Current unpublished data in our laboratories have observed cardiac troponin elevations after as little as 60 min of treadmill running at a marathon running pace. In addition, elevated cTnT and cTnI concentrations after a basketball game (in 4 of 10 athletes) have been described recently (36). Of interest, this is not an exclusive human phenomenon because increases in cardiac troponins have also been documented for well-trained sled dogs and horses after endurance exercise (15,23). In contrast to endurance exercise, strength training does not appear to induce elevations in cardiac troponins (60), although these data are very limited.
In a meta-analysis, an overall postexercise cTnT incidence rate of 47% in 1120 athletes after endurance exercise (running, cycling, and triathlon) was shown (56). Unfortunately, the incidence rate of exercise-induced increases in cTnI cannot be calculated by a meta-analysis because of different immunoassays with different standards and incomparable cTnI values. However, the postexercise cTnI incidence rate may be similar or even somewhat higher than for cTnT. In a study that examined cTnT and cTnI in 105 endurance athletes after a marathon run, a 100-km ultramarathon, or a long-distance mountain bike race (Fig. 1), the URL of cTnI (0.04 ng·mL−1; AccuTnI, Beckman Coulter) was exceeded by 74%, whereas 47% of the athletes exceeded the URL of cTnT (coefficient of correlation between cTnT and cTnI: r = 0.79, P < 0.001) (45). In contrast to cardiovascular patients with myocardial infarction, in athletes exercise-associated elevations of cardiac troponins typically decrease significantly within 24 h after exercise and usually reach normal values within this period (14,27,33,34,45,57,64). A relation between exercise-associated elevations of cardiac troponins and cardiovascular risk factors seems not to exist (45), whereas a relation to the amount of prerace endurance training has been reported by Neilan et al. (31): after a marathon, higher increases in cTnT concentrations were seen in nonelite runners with a training distance of ≤35 miles·wk−1 (≤56 km·wk−1) when compared with nonelite runners with higher training distances. Fortescue et al. (11) reported that less marathon experience and younger age were associated with troponin increases after the Boston marathon. However, this has not been confirmed in the London marathon (12,13) or after other endurance events (45).
The relation between raised cardiac troponins and depressed parameters of systolic or diastolic cardiac function has been reported in some studies with little consensus. Of recent interest is the study by Neilan et al. (31) who performed echocardiographic measurements 20 min after completion of the Boston marathon and reported greater changes in cardiac function in those with elevated troponins (62). To elucidate the possible relation between exercise-induced increases in cardiac troponins and cardiac dysfunction in obviously healthy athletes and its clinical significance, one requires further studies.
Despite several authors making the assumption that exercise-associated elevations in cTnT or cTnI represent cardiomyocyte damage (22,26,31,32,38,39,42) and, as a consequence, athletes with elevated cardiac troponins after exercise would have required further clinical examination, only a few studies have reported on clinical or cardiovascular follow-ups in these athletes (50,59,67,69). Siegel et al. (59) reported on normal postrace SPECT sestamibi myocardial imaging scans in five runners after the Boston marathon, of whom two presented exercise-induced elevations in cTnI. In a more recent study, 34 endurance athletes with elevated cardiac troponins after endurance exercise (marathon, 100-km run, mountain bike marathon; ranges of cTnT and cTnI: 0.01-0.56 and 0.08-1.93 ng·mL−1, respectively) were evaluated within a few months after the competitions by physical examination, routine blood parameter screening, ECG evaluation at rest and during exercise, and echocardiography at rest and during exercise including tissue Doppler imaging (50,67). In only one athlete that prior unknown coronary artery disease was diagnosed (left coronary artery main stem and descending artery stenosis) (47). In all other athletes, no cardiovascular abnormalities explaining the exercise-induced increases in cardiac troponins were detected (50,67). Even contrast-enhanced magnetic resonance imaging, performed in 20 of the abovementioned athletes, revealed neither causal cardiac abnormalities nor delayed enhancement as a proof of myocardial necrosis or infarction (50). In addition, 1 h of intensive and 3 h of extensive standardized endurance exercise could not reproduce an increase in cardiac troponins in these athletes (50). This observation is further confirmed by Middleton et al. (28) who also did not find a reproducible exercise-induced cardiac troponin release in eight participants of the 2004 and 2005 London marathons.
Because of the aforementioned findings, it is suggested that exercise-associated increases in cardiac troponins do not necessarily reflect irreversible cardiomyocyte damage or myocardial necrosis as it does in cardiovascular patients with myocardial infarction. The circumstances leading to a release of cardiac troponins during endurance exercise are not yet fully known. Besides exercise duration, exercise intensity is suggested as an important factor to trigger the release of cardiac troponins in endurance exercise bouts (46). As already mentioned, the meta-analysis of Shave et al. (56) demonstrated higher postexercise cTnT incidence rates in "shorter" endurance exercise events, which presumably are performed with higher exercise intensities when compared with longer endurance exercise events. The negative cTnT results reported for participants of the Death Valley Badwater Ultramarathon (216 km; median running time: 44 h 30 min; averaged running velocity of the first marathon distance: approximately 7.2 km·h−1) (43) may have resulted from a low exercise intensity and, hence, a low release of stress hormones and metabolic substrates, although the athletes exercised under extreme environmental conditions. In future studies, exercise intensities should be quantified to examine its possible influence on the exercise-induced release of cardiac troponins.
The mechanisms of the exercise-induced release of cardiac troponins are also not yet known. As with cardiovascular patients with acute coronary syndromes, an explanation could be an irreversible injury with myocardial damage and necrosis (16). However, if so, athletes should encounter cardiac failure after several years of practice and competition. After the reversible injury concept (16,75), an explanation for the exercise-induced release of cardiac troponins in obviously healthy athletes could be an exercise-induced reversible increase in the membrane permeability of the cardiomyocytes, with a transitory release of unbound cTnT and cTnI of the cytoplasmic pool (34,45,50,75). This reversible membrane leakage could also explain differences between cTnT and cTnI kinetics due to an earlier and prolonged release of the smaller molecule cTnI and to a higher postexercise incidence rate of cTnI in comparison with cTnT (14,45).
Other possible causes of an exercise-associated release of cardiac troponins may be intracellular calcium overload with activation of calpains, effects of free radicals, elevated catecholamines, alterations in glucose and fat metabolism, or mechanically induced disruptions of the membrane of the cardiomyocytes with rapid resealing (25,45,50,68). In addition, exercise-induced ischemia or coronary vasospasms are discussed as underlying causes. Clearly, caution is warranted in the transfer of findings from cardiovascular patients with acute coronary syndromes to healthy athletes because there is only a limited direct evidence of myocardial ischemia in prolonged exercise. Although Chen et al. (6) demonstrated an increase in cTnT in rats after 5 h of forced swimming, with histologic foci of cardiomyocyte injury by interstitial inflammatory infiltrate, the histologic evidence of ischemic myocardial changes was missing. In addition, even patients with ischemic heart disease who exercised up to 60 min at an intensity that induced myocardial ischemia documented by significant ST-segment depression (1.0 to 2.1 mm) did not present elevations in cTnT (37). Moreover, evidence of myocardial ischemia by values of IMA (see next paragraphs) is still missing in endurance athletes.
For clinicians, it is important to know that serum or plasma concentrations of cardiac troponins can be elevated after prolonged and strenuous endurance exercise, which do not necessarily seem to reflect irreversible myocardial damage in asymptomatic and obviously healthy athletes. Typically, elevations of cardiac troponins decrease significantly within 24 h after exercise and usually reach normal values within this period. Therefore, in asymptomatic and obviously healthy athletes without electrocardiographic or echocardiographic abnormalities, a 24-h observation or follow-up seems to be sufficient. In doubtful cases, noninvasive diagnostic measures are recommended at first (exercise-ECG, exercise-echocardiography, exercise-scintigraphy, and cardiovascular magnetic resonance imaging). Immediate invasive diagnostic examinations in clinically and noninvasively unsuspicious athletes with only an exercise-associated elevation of cardiac troponin seem not to be indicated by the present knowledge.
Only a few studies of exercise-associated alterations on cardiac biomarkers have additionally examined IMA (4,27,31,57). During ischemia and acidosis, the N-terminal end of albumin is changed by free radicals, and the ability of IMA to bind cobalt is reduced. IMA can be determined by the albumin cobalt binding test (ACB® Test), and in cardiovascular patients with myocardial ischemia, IMA is elevated (57).
Prolonged endurance exercise has been demonstrated to alter IMA, but in contrast to cardiovascular patients with myocardial ischemia, a decrease in the mean concentration of IMA was found 30 min after a marathon in 19 recreational athletes, followed by a mild increase above the mean preexercise value 24 to 48 h after exercise (4). Mild decreases of mean IMA concentrations after marathon runs have also been reported by others (27,31,57). The underlying mechanisms of changes in IMA during exercise have not yet been clarified. Possible confounders such as an exercise-induced increase in circulating albumin, a possible peripheral ischemia in tissues other than the myocardium, or the influence of blood lactate on the assay have to be considered (57). Therefore, it seems justified by the consistency of results to date that prolonged endurance exercise does not result in any or in profound myocardial ischemia. However, some care must be observed in assuming homogeneous individual responses when group data are presented (57).
BNP AND NT-proBNP
Primarily synthesized by cardiomyocytes, elevated blood concentrations of BNP and its cleaved inactive fragment NT-proBNP reflect elevated myocardial wall stress due to myocyte stretch caused by volume or pressure overload and to neurohumoral activation in cardiac dysfunction, chronic heart failure, cardiomyopathy, acute coronary syndromes, and other cardiac diseases. As a marker of cardiac dysfunction, BNP and NT-proBNP have garnered increasing attention as helpful tools in cardiovascular diagnostics, guidance of drug therapy, and risk stratification.
As a counter-regulatory hormone, BNP reduces myocardial wall stress by an increase in natriuresis, vasodilation, and sympathoinhibitory effects as an opponent of the renin-angiotensin system. Furthermore, cytoprotective and growth-regulating properties of BNP have also been demonstrated. BNP inhibits hypertrophy in cultured cardiomyocytes and angiotensin II-stimulated collagen synthesis by cardiac fibroblasts (8,9). In mice, BNP gene knockout led to multifocal cardiac fibrosis (61), and deletion of the natriuretic peptide receptor NPR-A caused hypertension with cardiac hypertrophy (20). BNP is cleared via the natriuretic peptide clearance receptor C and proteolysis by peptidase. In healthy young men, kidneys extract BNP and NT-proBNP to a similar extent without an effect from short-term exercise (52). The half-lives of BNP and NT-proBNP are approximately 20 and 60-120 min, respectively. Although URLs of 100 pg·mL−1 for BNP and 125 pg·mL−1 for NT-proBNP in healthy adults have been suggested by manufacturers, sex- and age-dependent higher URLs in women and older subjects have to be considered (40,41).
Despite some contradictory evidence (30), resting BNP and NT-proBNP concentrations in athletes with or without athlete's heart are not elevated when compared with untrained and age-matched subjects (1,48). In strength-trained athletes, BNP and NT-proBNP values are not elevated either (49). Only strength-trained athletes and body builders with a history of anabolic steroid abuse had somewhat higher concentrations of BNP and NT-proBNP than endurance athletes with athlete's heart or untrained controls (Fig. 2), and this might be the expression of possible myocardial damage by chronic abuse of anabolic steroids (66).
Physical exercise can induce acute alterations in serum or plasma BNP and NT-proBNP concentrations in healthy athletes. Indeed, after prolonged and strenuous endurance exercise, increases in BNP and NT-proBNP concentrations above URLs have been documented (14,18,27,31,34,38,45,59,69). Increases in BNP and NT-proBNP have been related to endurance exercise duration and athlete's age (18,34,45). In 105 athletes examined for alterations in NT-proBNP concentrations after endurance exercise events (marathon, 100-km run, and mountain bike marathon), elevations above the URL (males: 88 pg·mL−1; females: 153 pg·mL−1) were found in 77% of athletes (Fig. 1) (45). Shorter but more intense exercise bouts between 30 and 60 min (in particular, above the individual anaerobic threshold) also resulted in increases in BNP and NT-proBNP in healthy athletes and untrained individuals in an unpublished study of the principal author of this review. However, these increases were less pronounced than after prolonged endurance exercise and did not exceed the URL in healthy athletes.
The relationship between BNP and cardiac troponins after endurance exercise has been the target of some interest. A relationship between exercise-associated increases in BNP and cTnT in healthy athletes was reported by Ohba et al. (38) but could not be substantiated in a larger study for NT-proBNP and cTnT or cTnI (45). This provides some support for the concept that the increases in different cardiac biomarkers are the result of different mechanism(s) (45,50).
It has been hypothesized that the exercise-associated immune response could contribute to postexercise alterations in BNP or NT-proBNP concentrations (24). Although this seems unlikely, future studies are needed to answer this question (51). A more feasible explanation for the exercise-associated increase in BNP and NT-proBNP can be derived from the physiological significance of the active hormone BNP with its natriuretic, vasodilating, and sympathoinhibitory effects, which, via reducing preload and afterload, can reduce the myocardial wall stress. Thus, it is obvious to suppose that the exercise-associated increase in myocardial wall stress with an increase in exercise duration-analogous to the time-dependent increase in BNP expression in stretched cardiomyocytes in vitro (74)-leads to an increasing release of BNP and NT-proBNP, respectively. In addition, catecholamines seem to induce the myocardial BNP expression (74). Furthermore, cytoprotective and growth-regulating effects demonstrated in vitro and in animal models for BNP can also be assumed in healthy athletes with exercise-associated elevations in BNP.
It is plausible that myocardial response or adaptation both during and after exercise might be regulated by the release of BNP in healthy athletes. This assumption is supported by the data from Neilan et al. (31) who demonstrated that higher increases in NT-proBNP concentrations were present in nonelite runners with lower training distances (≤35 miles·wk−1 or 56 km·wk−1) after a marathon. A similar result with a negative correlation between the increase in NT-proBNP and the amount of endurance training per week was also reported for endurance exercise bouts under standardized conditions (50). Higher resting values of BNP in healthy male British Army recruits with an increase in left ventricular mass (LVM) after 10 wk of exercise training (30) may reflect the acute myocardial stress and the beginning of myocardial adaptation to the training stimulus (acute effect of myocardial adaptation). In endurance athletes with a longer history of endurance training, the myocardium might be already adapted to endurance exercise, and thus, BNP or NT-proBNP concentrations are not elevated in such athletes at rest (1,48). However, further studies are needed to examine this concept.
Although there is evidence that exercise is associated with an increase in BNP or NT-proBNP in obviously healthy athletes, this increase should not be confounded with elevated resting values or exercise-associated elevations in cardiovascular patients, reflecting pathologic regional wall motion abnormalities that can be enhanced by myocardial ischemia (10,70). For clinicians, it is important to know that BNP and NT-proBNP values are not elevated under resting conditions in healthy athletes and that intensive, strenuous, and prolonged endurance exercise can induce transient elevations above the URL.
Increases in cardiac troponins are commonly reported after strenuous and prolonged endurance exercise in elite and recreational endurance athletes. In contrast to acute myocardial infarction, increases in cardiac troponins are only mild and of short duration and, therefore, likely reflect a reversible membrane leakage of cardiomyocytes with troponin release from the free cytosolic pool (not bound in the contractile apparatus). In healthy athletes, exercise-associated elevations in cardiac troponin typically decrease significantly within 24 h after exercise and usually reach normal values within this time. Changes in IMA with prolonged exercise have been examined in only a few studies, which demonstrated a decrease immediately after exercise. These consistent findings argue against myocardial ischemia, but significant caution is advised because of confounding variables that appear during exercise. BNP or NT-proBNP concentrations under resting conditions are not elevated in healthy athletes (with or without athlete's heart), but after intensive, strenuous, and prolonged endurance exercise, short-term elevations of BNP or NT-proBNP in elite athletes and in nonelite and recreational athletes can be present.It is suggested that these increases are not of pathologic nature as in cardiovascular patients, even when clinical cutoff values are exceeded, but may have cytoprotective and growth-regulating effects on the athletes' heart. Additional research is required to elucidate further some of the associations between cardiac biomarker and prolonged exercise.
The results of this article do not constitute endorsement by the American College of Sports Medicine.
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