TROPONINS IN ACUTE CORONARY SYNDROMES
Cardiac isoforms of troponin I (cTnI) and T (cTnT) are highly specific markers of myocardial injury. Elevations of either of these proteins in the setting of an acute coronary syndrome (ACS) identify patients with a severalfold increased risk of death in subsequent weeks. The prognostic importance of these markers likely stems from their ability to detect microscopic amounts of myocardial necrosis that result from a severe epicardial stenosis or distal embolization of friable atherothrombotic debris overlying the unstable coronary plaque. As such, troponin-positive patients often have complex coronary lesion morphology with intracoronary thrombus and understandably derive particular benefit from platelet glycoprotein GpIIb/IIa inhibitors as well as low molecular weight heparins (25).
TROPONIN RELEASE AND PROTHROMBOTIC MARKERS AFTER VIGOROUS EXERCISE
Some studies have shown increases in cardiac troponins (e.g., 15,18,27) or selective persistence of procoagulant effects (e.g., 7,33) in endurance athletes after vigorous exercise, whereas others have not (e.g., 11,13,17,20,31,33). Based on elevations in cardiac troponins and selective persistence of procoagulant effects in endurance athletes, which are predictive of poor prognosis in patients with ACS , troponin and prothrombotic marker measurements have been vastly overinterpreted and overplayed after vigorous exercise (11,19). Some investigators have suggested that endurance athletes (e.g., marathon runners) with increased cardiac troponins may actually have an increased risk of heart attacks or other cardiac events. Other investigators have reported that a secondary hemostatic imbalance may trigger acute cardiac events after strenuous exercise (7,33). This line of reasoning leads to the recommendation by several physicians that pharmacologic intervention (low molecular weight heparins) should be considered for endurance athletes, particularly when exercising at high-altitude exposure (11). A lot of confusion and uncertainty was created by these rushed conclusions and press releases among practicing physicians and their athletes.
ANALYTICAL ISSUES
Prudence is needed in interpreting the results from articles that claim to show elevations in troponins (19,20,32,34). In addition to the problems with standardization, the precision of some of the assays is poor (for review, see Quinn and Moliterno (30)). This has not been taken into account in many authors’ analyses. Indeed, the suggested precision of many of the assays used is exaggerated. The articles by Siegel et al. (32), Whyte et al. (37), and Shave et al. (34) suggest that with modern day more sensitive assays, increases in troponins (e.g., 38) were not found.
In addition, spurious troponin elevations may be a common occurrence after strenuous exercise, and if not detected, may result in an increased number of falsely diagnosed “myocardial (micro)infarctions” (28).
Moreover, several assumptions about elevations of macromolecular markers of myocardial injury in blood require critical consideration (35). Several fallacies may obscure accurate diagnosis (35). The assumption that “cardiac” troponins are released exclusively from cardiac myocytes could possibly be violated (35). For example, inflammation may be present in the coronary vessels due to increased shear stress during vigorous exercise (33,36) and this could account for expression of troponin in cells other than cardiac myocytes, such as vascular smooth muscle cells or cellular constituents in vessels in the heart (35). Assessment of putative sites of cTnI and cTnT elaboration by immunohistochemical and in situ hybridization techniques could illuminate this possibility (35).
Spurious troponin elevations may also be a common occurrence in the presence of fibrin clots (30). It is thus important to know to what extent increases in troponins are related to the prothrombotic effects and assay artifacts related to those prothrombotic effects. This should be at least a question for which data should be generated.
All in all, the case that many authors make is severely weakened by the lack of astuteness in regard to the analytical issues, which require some degree of scrutiny before quoting the data as strongly as they do.
In addition, it should be noted that there is, as of yet, no experimental evidence supporting a link between increased cardiac troponins and acute cardiac events after vigorous exertion (14).
EXERCISE-INDUCED MYOCARDIAL DAMAGE
Although the imprecision and lack of standardization of currently available troponin assays are likely to explain elevations in troponins in athletes after vigorous exercise in most of the literature (30), exercise-induced myocardial damage as monitored by troponins cannot be excluded (e.g., 4,12).
THE IRREVERSIBILITY CONCEPT
Sudden death in asymptomatic (young) athletes is usually instantaneous and occurs predominantly on the athletic field during competition or training, substantiating that exercise is a determinant of the collapse (22). In the vast majority of these deaths, cardiovascular abnormalities can be identified at autopsy. The most common single cardiovascular abnormality among these would appear to be hypertrophic cardiomyopathy (HCM) (22). Second in importance and frequency to HCM is a spectrum of congenital vascular malformations of the coronary arterial tree (22). In approximately 2% of the cases, the standard medical examiner autopsy fails to show cardiovascular lesion that could account for sudden death (22). It is possible that death in these athletes with “normal” autopsy findings is due to other conditions such as QT syndrome, drug abuse, occult structural abnormalities of the conduction system, idiopathic ventricular fibrillation, or possibly undetected examples of segmental right ventricular dysplasia (22). In addition to the risk for sudden death in athletes due to underlying and usually unsuspected cardiovascular disease, blunt chest impact produced either by a projectile or by collision with another athlete may induce a lethal cardiac arrhythmia and instantaneous collapse (22). By far, atherosclerotic coronary artery disease is the most common form of heart disease relevant to the masters population as a cause of morbidity or sudden death (23). However, no direct experimental (histological) data are available to demonstrate that forced exercise can damage the heart. In addition, histological or cytological proof that the release of troponin indicates myocardial necrosis in humans is missing so far. It is possible that some troponin fragments could be released by reversible insults and account for small but detectable amounts of troponin in the blood. An experimental approach to this problem is difficult. In the best study done to date (8), electron microscopy was necessary to confirm that elevations of total creatine kinase detected in blood were indicative of myocardial necrosis (8).
Chen et al. (4) showed that a single bout of stressful, prolonged intense exercise induced damage as monitored by cTnT in the heart and serum in the myocardium of rats. Furthermore, an increase in exercise volume induced more myocardial damage, and training before stressful, prolonged intense exercise provided protection from myocardial damage. These findings are in agreement with recent findings in humans (15), in which strenuous endurance exercise was demonstrated to cause myocardial damage as indicated by increased cTnT and cTnI concentrations immediately after the events. Comparatively, in humans, serum cTnT concentrations returned to baseline concentrations by 24 h (15). Evidence also exists that apparently healthy individuals who are not active enough to meet a traditional exercise prescription (preconditioning) are at higher risk for subclinical necrosis caused by prolonged strenuous exercise (15) (see also Maron (21)) (Fig. 1).
;)
FIGURE 1:
Release of cardiac troponins in acute myocardial infarction and after strenuous exercise. Cardiac troponins are not detectable in the blood of highly trained athletes following extreme exercise. Any postexercise increase in cardiac troponins in untrained individuals is of very moderate magnitude and short-term duration. Cardiac troponin levels rise to approximately 20 to 50 times the upper reference limit (the 99th percentile of values in a reference control group) in patients who have a “classic” acute myocardial infarction (MI) and sustain sufficient myocardial necrosis to result in abnormally elevated levels of the MB fraction of creatine kinase (CK-MB). Clinicians can now diagnose episodes of microinfarction by sensitive assays that detect cardiac troponin elevations above the upper reference limit, even though CK-MB levels may still be in the normal reference range (not shown).
Chen et al. (4) hypothesized that the rapid return to baseline suggests that the release of cTnT from exercise-induced myocardial injury is likely from localized minor, irreversible myocyte degeneration (Fig. 1). Concordant with this hypothesis, histological evidence of localized myocyte damage demonstrated by interstitial inflammatory infiltrates consisting of neutrophils, lymphocytes, and histiocytes, as well as vesicular nuclei-enlarged chromatin patterns, was observed in left ventricle specimens. On the basis of this report (4) and recent findings in humans (15) it is tempting to speculate that stressful, prolonged intense exercise may result in minor, irreversible myocyte degeneration in humans. In agreement with the findings in rats (4), regular physical exercise (preconditioning) may protect against cardiac myocyte injury caused by vigorous endurance exercise (4,21). A model of dobutamine stress echocardiography supports the irreversibility concept (3). Whether the release of troponin indicates myocardial injury or if it could occur with myocardial ischemia alone can be answered by evaluating patients who have inducible myocardial ischemia and comparing their marker results with those of patients without ischemia. This was the approach used in a recent study (3) together with dobutamine stress echocardiography, where troponin values in those with overt myocardial ischemia were compared with those of patients with normal examinations. The findings that neither patients with normal dobutamine echocardiograms nor those with abnormal responses manifested changes in troponin values, even when highly sensitive methods and stringent criteria were used, indicates that myocardial ischemia does not result in the release of troponin (3). These data suggest that within the limits of the sensitivity tested, ischemia alone does not damage myocytes (3). On the other hand, the dogma in acute myocardial infarction is that troponin remains increased 5–7 d after myocardial injury due to gradual breakdown of myofibrils by macrophages and slow release of complexed troponin from the thin filaments (and is not the result of slow clearance of troponin once in the blood) (Fig. 1). If this is irreversible injury, how is troponin able to be cleared much faster from damaged myocytes of athletes? This is an important issue that might be the major thrust of future studies.
If the release of troponins from exercise-induced myocardial injury is from irreversible myocyte degeneration it remains to be clarified whether irreversible injury in healthy individuals as a result of physiological stress has any long-term clinical or athletic consequence or relevance (15). A recent report suggests that increases in troponin levels in a healthy individual as a result of a prolonged bout of exercise, such as a marathon, does not have any clinical or athletic consequence (12) (see also Jaffe et al. (9)). Because exercise-induced myocardial injury may be self-abating, athletes should not be excluded from participating in sports predicated solely on the presence of increased marker proteins (12). Only if a cause for a biomarker increase can be ascertained (a potentially lethal cardiovascular abnormality) should athletes be disqualified, ultimately for the purpose of protecting the health and welfare of sports participants (12). Indeed, it may well be that if reparative processes are present (for review, see Anversa and Nadal-Ginard (1)) that these increases are normal and should not be expected to be of pathophysiological significance.
On the other hand, as pointed out by Siegel et al. (33) there is an incidence of sudden death after strenuous exercise that could be related to this particular pathophysiology. Recently it has been shown (for review, see Maron (21)) that a significant increase (by a factor of up to 45) was transiently related to episodes of vigorous exercise.
Nevertheless, the absolute risk of sudden death during vigorous exertion is extremely low and equivalent to only one sudden death per 1.5 million episodes of such physical activity (21). However, the short-term increase in risk associated with vigorous exercise was significantly reduced in those who reported an active lifestyle characterized by habitual (as opposed to sporadic) vigorous exercise (21) (see also Chen et al. (4) and Koller et al. (15)). Such risks and benefits of exercise are similar to those previously reported for nonfatal myocardial infarction or primary cardiac arrest (for review, see Maron (21)). Episodes of vigorous exertion could activate the sympathetic nervous system and promote rupture of vulnerable atherosclerotic plaque or, alternatively, trigger ventricular fibrillation in the presence of susceptible myocardial substrate (which may involve exercise-induced premature ventricular depolarization) (for review, see Maron (21)). Conversely, habitual exercise would be expected to enhance the electrical stability of the myocardium by increasing vagal tone, thereby protecting against ventricular fibrillation, as well as modifying risk through favorable effects on blood lipids (21) (see also Chen et al. (4) and Koller et al. (15)). Thus, it seems quite possible that there may be a parallel increase in the risk of subclinical myocardial necrosis during or immediately after vigorous exercise (14). However, there is, as of yet, no basis for determining which individuals will develop either a major cardiac catastrophe or subclinical necrosis (14).
THE REVERSIBILITY CONCEPT
In most of the studies (as already pointed out), the increases in troponins are transient, raising the question as to whether or not the increases might be due to the release from the cytosolic pool and not to be indicative of irreversible injury but a manifestation with leak of troponin from potentially reversibly injured myocytes. In support for the reversible injury concept is the concept of in situ degradation of troponin described by Feng et al. (6) and Labugger et al. (16). However, mechanisms of stunning in the pig are radically different from the widely held concepts derived from studies in rodents and involve impaired Ca2+ handling and dephosphorylation of phospholamban but not cTnI degradation (10). In addition, recent data support a model in which a central, neural governor constrains the cardiac output to prevent myocardial damage (as a result of ischemic mechanisms) by regulating the mass of skeletal muscle that can be activated during maximal exercise (29). Noake’s model (29) (rebutted by Berg et al. (2)) argues against cardiac ischemia during vigorous exercise and consequently the concept of reversible release of troponins in cardiac ischemia. However, disruption of the cell membrane is a commonplace occurrence in many mechanically challenging, biological environments (for review, see McNeel and Terasaki (24)). Cardiac cells are known to be wounded in vivo under physiological conditions (24). A rapid resealing response, however, serves to prevent loss of vital cytoplasmic constituents and, perhaps more importantly, to block Ca2+, which would otherwise rapidly accumulate to toxic levels in the cytosol (24). Signal influx and efflux through disruptions can initiate changes in gene expression in the wounded cell or its neighbors (24). These might promote longer-term repair and adaptive responses at both the cell and tissue level (24).
HEMOSTASIS AND EXERCISE
As noted recently in a comprehensive review (5) the mechanisms responsible for and the biological significance of exercise-induced hyperfibrinolysis and hypercoagulability are not entirely understood (5). Several questions related to exercise and blood hemostasis remain unanswered and warrant future investigation (5). Available evidence suggests that moderate exercise appears to enhance blood fibrinolytic activity without a concomitant activation of blood coagulation mechanisms, whereas heavy exercise induces simultaneous activation of blood fibrinolysis and coagulation (5). However, whether activation of coagulation is associated with a high prothrombotic potential remains controversial (11).
HOW ARE WE TO INTERPRET ALL OF THIS INFORMATION, AND WHAT ARE THE IMPLICATIONS FOR (CLINICAL) PRACTICE?
cTnI and cTnT are potent tools for risk stratification and clinical decision-making with respect to the potential benefits of early invasive management for patients with non–ST-segment elevation myocardial infarction (UA/NSTEMI) (25,30). Even low-level elevations of cardiac troponins help identify patients who benefit from a strategy of early GpIIb/IIa inhibition in combination with an early invasive approach (25). These results provide an evidence-based guide for integration of cardiac troponins into critical pathways for early management of patients with non–ST-segment elevation acute syndromes (25).
Although these findings are relevant to patients with a typical clinical presentation for UA/NSTEMI (25,30), caution should be exercised in generalizing the results to athletes with a low clinical suspicion of coronary artery disease. The imprecision and lack of standardization of currently available troponin assays merit caution with the application of their findings (15,30). In addition, it may well be that if reparative processes are present and/or the release is not due to irreversible injury that increases in troponins are normal and should not be expected to be of pathophysiological significance. Due to this potential for misclassification, the crux of appropriate interpretation of troponin testing is careful consideration of the corresponding clinical scenario (9,12,30).
Most important, however, subjects should participate in vigorous exercise programs and physicians should encourage sedentary persons to enter conditioning programs even though articles claim to show exercise-induced myocardial damage as monitored by troponins (19,21,26).
On the basis of the accumulated data there is overwhelming evidence of the cardiovascular benefits attributable to consistent vigorous exercise as a primary-prevention strategy for coronary disease. These benefits include the important effect of blunting the transient risk of sudden death associated with intense exercise (21). Myers et al. (26) place valuable and readily applicable conclusions on the desk of the clinician. Absolute fitness levels (as determined by an exercise test) represent a continuum of risk, i.e., greater fitness results in longer survival. The benefits do come with some risk, particularly when vigorous exercise is undertaken abruptly by untrained or previously sedentary persons (21) (see also Chen et al. (4) and Koller et al. (15)). This concept is particularly pertinent to asymptomatic middle-aged persons (and often older) who abruptly enter or reenter the competitive athletic arena by engaging in increasingly popular and intensive masters sports programs, often after long periods of a sedentary lifestyle (21) (see also Koller et al. (15)). Importantly, there is, as of yet, no basis for determining which of these individuals will develop either a major cardiac catastrophe or subclinical necrosis as assessed by cardiac troponins (14). In the absence of procedures to detect the vulnerable, I find it hard to envision how any “tailoring” of excessive exercise by physicians can reduce such risk (14).
There is no clear evidence that a hemostatic imbalance may trigger acute cardiac events after strenuous exercise (11). While patients benefit from low molecular weight heparins (25), it may be premature and even dangerous to recommend low molecular weight heparins to endurance athletes even when exercising during high-altitude exposure (11). There might be additional factors that may further predispose athletes to thrombosis at high altitude. These include dehydration, decreased oxygen tension, and increased erythropoietin levels. In this situation, nonpharmacologic approaches such as increased water consumption may be helpful in preventing thrombosis (11).
REFERENCES
1. Anversa, P., and B. Nadal-Ginard. Myocyte renewal and ventricular remodelling. Nature 415: 240–243, 2002.
2. Bergh, U., B. Ekblom, and P. O. Astrand. Maximal oxygen uptake “classical” versus “contemporary” viewpoints. Med. Sci. Sports Exerc. 32: 85–88, 2000.
3. Carlson, R. J., A. Navone, J. P. Mcconnel, et al. Effect of myocardial ischemia on cardiac troponin I and T. Am. J. Cardiol. 89: 224–226, 2002.
4. Chen, Y., R. C. Serfass, S. M. Mackey-Bojack, K. L. Kelly, J. L. Titus, and F. S. Apple. Cardiac troponin T alterations in myocardium and serum of rats after stressful, prolonged intense exercise. J. Appl. Physiol. 88: 1749–1755, 2000.
5. El-Sayed, M. S., C. Sale, P. G. Jones, and M. Chester. Blood hemostasis in exercise and training. Med. Sci. Sports Exerc. 32: 918–925, 2000.
6. Feng, J., B. J. Schaus, J. A. Fallavolita, T.-C. Lee, and J. M. Canty. Preload induces troponin degradation independently of myocardial ischemia. Circulation 103: 2035–2037, 2001.
7. Hegde, S. S., A. H. Goldfarb, and S. Hegde. Clotting and fibrinolytic activity change during the 1 h after a submaximal run. Med. Sci. Sports Exerc. 33: 887–892, 2001.
8. Ishikawa, Y., J. E. Saffitz, T. L. Mealman, A. M. Grace, and R. Roberts. Reversible myocardial ischemic injury is not associated with increased creatine kinase activity in plasma. Clin. Chem. 43: 467–475, 1997.
9. Jaffe, A. S., J. Ravkilde, R. Roberts, et al. It’s time for a change to a troponin standard. Circulation 102: 1216–1220, 2000.
10. Kim, S.-J., R. K. Kudej, A. Yatani, et al. A novel mechanism for myocardial stunning involving impaired Ca
2+ handling. Circ. Res. 89: 831–837, 2001.
11. Koller, A. Hemostasis and exercise. Am. J. Cardiol. 89: 1242, 2002.
12. Koller, A., S. Mertelseder, and H. Moser. Is exercise-induced myocardial injury self-abating? Med. Sci. Sports Exerc. 33: 850–851, 2001.
13. Koller, A., J. Mair, W. Schobersberger, et al. Effects of prolonged strenuous endurance exercise on plasma myosin heavy chain fragments and other muscular proteins. Cycling vs running. J. Sports Med. Phys. Fitness 38: 10–17, 1998.
14. Koller, A., R. J. Shepard, and G. J. Balady. Exercise as cardiovascular therapy. Circulation 101: E164, 2000.
15. Koller, A., P. Summer, and H. Moser. Regular exercise and subclinical myocardial injury during prolonged aerobic exercise. JAMA 282: 1816, 1999.
16. Labugger, R. L., L. Organ, C. Collier, D. Atar, and J. E. Vaneyk. Extensive troponin I and T modification detected in serum from patients with acute myocardial infarction. Circulation 102: 1221–1226, 2000.
17. Laslett, L., and E. Eisenbud. Lack of detection of myocardial injury during competitive races of 100 miles lasting 18 to 30 hours. Am. J. Cardiol. 80: 379–380, 1997.
18. Laslett, L., E. Eisenbud, and R. Lind. Evidence of myocardial injury during prolonged strenuous exercise. Am. J. Cardiol. 78: 488–490, 1996.
19. Mair, J., W. Schobersberger, A. Koller, et al. Risk of exercise-induced myocardial injury for athletes performing prolonged strenuous endurance exercise. Am. J. Cardiol. 80: 543–544, 1997.
20. Mair, J., T. Wohlfarter, A. Koller, M. Mayr, E. Artner-Dworzak, and B. Puschendorf. Serum cardiac troponin T after extraordinary endurance exercise. Lancet 340: 1048, 1992.
21. Maron, B. J. The paradox of exercise. N. Engl. J. Med. 34: 1409–1411, 2000.
22. Maron, B. J. The young competitive athlete with cardiovascular abnormalities: causes of sudden death, detection by preparticipation screening, and standards for qualification. Card. Electrophysiol. Rev. 6: 100–103, 2002.
23. Maron, B. J., C. G. S. Araujo, P. D. Thompson, et al. Recommendations for preparticipation screening and the assessment of cardiovascular disease in masters athletes. An advisory for healthcare professionals from the Working Groups of the World Heart Federation, the International Federation of Sports Medicine, and the American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention. Circulation 103: 327–334, 2001.
24. Mcneil, P. L., and M. Terasaki. Coping with the inevitable: how cells repair a torn surface membrane. Nature Cell. Biol. 3: E124–E129, 2001.
25. Morrow, D. A., C. P. Cannon, N. Rifai, et al. Ability of minor elevations of troponin I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction. JAMA 286: 2405–2412, 2001.
26. Myers, J., M. Prakash, V. Froehlichert, D. Do, S. Partington, and J. E. Atwood. Exercise capacity and mortality among men referred for exercise testing. N. Engl. J. Med. 346: 793–801, 2002.
27. Neumayr, G., H. Gaenzer, R. Pfister, et al. Plasma levels of troponin I after prolonged strenuous endurance exercise. Am. J. Cardiol. 87: 369–371, 2001.
28. Ng, S. M., P. Krishnaswamy, R. Morrisey, P. Clopton, R. Fitzgerald, and A. S. Maisel. Mitigation of the clinical significance of spurious elevations of cardiac troponin I in the setting of coronary ischemia using serial testing of multiple cardiac markers. Am. J. Cardiol. 87: 994–999, 2001.
29. Noakes, T. D. Maximal oxygen uptake: “classical” versus “contemporary” viewpoints: a rebuttal. Med. Sci. Sports Exerc. 30: 1381–1398, 1998.
30. Quinn, M. J., and D. J. Moliterno. Troponins in acute coronary syndromes. More TACTICS for an early invasive strategy. JAMA 286: 2461–2462, 2001.
31. Schobersberger, W., B. Wirleitner, B. Puschendorf, et al. Influence of an ultramarathon race at moderate altitude on coagulation and fibrinolysis. Fibrinolysis 10: 37–42, 1996.
32. Siegel, A. J., E. L. Lewandrowsky, K. Y. Chun, M. B. Sholar, A. J. Fischman, and K. B. Lewandrowski. Changes in cardiac markers including B-natriuretic peptide in runners after the Boston marathon. Am. J. Cardiol. 88: 920–923, 2001.
33. Siegel, A. J., J. Stec, I. Lipinska, et al. Effect of marathon running on inflammatory and hemostatic markers. Am. J. Cardiol. 88: 918–920, 2001.
34. Shave R., E. Dawson, G. Whyte, et al. The cardiospecificity of the third-generation cTnT assay after exercise-induced muscle damage. Med. Sci. Sports Exerc. 34: 651–654, 2002.
35. Sobel, B. E., and M. M. Lewinter. Ingenuous interpretation of elevated blood levels of macromolecular markers of myocardial injury: a recipe for confusion. J. Am. Coll. Cardiol. 35: 1355–1358, 2000.
36. Wannamethee, S. G., G. D. O. Whincup, A. Rumley, M. Walker, and L. Lennon. Physical activity and hemostatic and inflammatory variables in elderly men. Circulation 105: 1785–1790, 2002.
37. Whyte, G. Is exercise-induced myocardial injury self-abating? (Response) Med. Sci. Sports Exerc. 33: 851, 2001.
38. Whyte, G., K. George, S. Sharma, et al. Cardiac fatigue following prolonged endurance exercise of differing distances. Med. Sci. Sports Exerc. 32: 1067–1072, 2000.
