Effect of Competitive Marathon Cycling on Plasma N-Terminal Pro-Brain Natriuretic Peptide and Cardiac Troponin T in Healthy Recreational Cyclists
2005; Elsevier BV; Volume: 96; Issue: 5 Linguagem: Inglês
10.1016/j.amjcard.2005.04.054
ISSN1879-1913
AutoresG Neumayr, Rudolf Pfister, Guenther Mitterbauer, Guenther Eibl, H. Hoertnagl,
Tópico(s)Cardiovascular and exercise physiology
ResumoFor a further depiction of exercise-induced cardiac dysfunction, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and cardiac troponin T (cTnT) were measured in recreational cyclists (n = 29) during the Ötztal Radmarathon 2004. In all subjects, NT-pro-BNP significantly increased from 28 ± 21 to 278 ± 152 ng/L immediately after the race (p <0.001), decreased again on the following day, and returned to baseline values 1 week later. The mean percentage increase in NT-pro-BNP was 1,128 ± 803%. CTnT, negative in all subjects before the race, increased transiently in 13 athletes (45%), with levels ranging from 0.043 to 0.224 μg/L in 8 of them (28%). One day after competition, cTnT had normalized in all athletes. Because of the typical release of kinetics, the deflection of NT-pro-BNP is considered to be the adequate volume regulatory response of a hemodynamically stressed heart to prolonged strenuous exercise. The observed kinetics of cTnT substantiate a release from the free cytoplasmatic pool due to the half-life of cytosolic cTnT. In healthy cyclists, transient increases in NT-pro-BNP and cTnT are more likely to reflect cardiac fatigue than injury. For a further depiction of exercise-induced cardiac dysfunction, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and cardiac troponin T (cTnT) were measured in recreational cyclists (n = 29) during the Ötztal Radmarathon 2004. In all subjects, NT-pro-BNP significantly increased from 28 ± 21 to 278 ± 152 ng/L immediately after the race (p <0.001), decreased again on the following day, and returned to baseline values 1 week later. The mean percentage increase in NT-pro-BNP was 1,128 ± 803%. CTnT, negative in all subjects before the race, increased transiently in 13 athletes (45%), with levels ranging from 0.043 to 0.224 μg/L in 8 of them (28%). One day after competition, cTnT had normalized in all athletes. Because of the typical release of kinetics, the deflection of NT-pro-BNP is considered to be the adequate volume regulatory response of a hemodynamically stressed heart to prolonged strenuous exercise. The observed kinetics of cTnT substantiate a release from the free cytoplasmatic pool due to the half-life of cytosolic cTnT. In healthy cyclists, transient increases in NT-pro-BNP and cTnT are more likely to reflect cardiac fatigue than injury. In past years, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) has turned out to be an excellent humoral marker for heart failure.1Lerman A. Gibbons R.J. Rodeheffer R.J. Bailey K.R. McKinley L.J. Heublein D.M. Burnett Jr, J.C. Circulating N-terminal atrial natriuretic peptide as a marker for symptomless left-ventricular dysfunction.Lancet. 1993; 341: 1105-1109Abstract PubMed Scopus (297) Google Scholar, 2Maisel A.S. Krishnaswamy P. Nowak R.M. McCord J. Hollander J.E. Duc P. Omland T. Storrow A.B. Abraham W.T. Wu A.H. et al.Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.N Engl J Med. 2002; 347: 161-167Crossref PubMed Scopus (2771) Google Scholar, 3Kruger S. Graf J. Kunz D. Stickel T. Hanrath P. Janssens U. Brain natriuretic peptide levels predict functional capacity in patients with chronic heart failure.J Am Coll Cardiol. 2002; 40: 718-722Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Data on NT-pro-BNP and exercise are very limited and inconsistent so far.4Siegel A.J. Lewandrowski E.L. Chun K.Y. Sholar M.B. Fischman A.J. Lewandrowski K.B. Changes in cardiac markers including B-natriuretic peptide in runners after the Boston Marathon.Am J Cardiol. 2001; 88: 920-923Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 5Steele I.C. McDowell G. Moore A. Campbell N.P. Shaw C. Buchanan K.D. Nicholls D.P. Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects.Eur J Clin Invest. 1997; 27: 270-276Crossref PubMed Scopus (67) Google Scholar, 6Ohba H. Takada H. Musha H. Nagashima J. Mori N. Awaya T. Omiya K. Murayama M. Effects of prolonged strenuous exercise on plasma levels of atrial natriuretic peptide and brain natriuretic peptide in healthy men.Am Heart J. 2001; 141: 751-758Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar, 8Barletta G. Stefani L. Del Bene R. Fronzaroli C. Vecchiarino S. Lazzeri C. Fantini F. La Villa G. Effects of exercise on natriuretic peptides and cardiac function in man.Int J Cardiol. 1998; 65: 217-225Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Maximal short-term exercise is not likely to cause an increase in brain natriuretic peptide (BNP),5Steele I.C. McDowell G. Moore A. Campbell N.P. Shaw C. Buchanan K.D. Nicholls D.P. Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects.Eur J Clin Invest. 1997; 27: 270-276Crossref PubMed Scopus (67) Google Scholar whereas respective data on long-term exercise reveal BNP increases to be small and to remain within the normal range.4Siegel A.J. Lewandrowski E.L. Chun K.Y. Sholar M.B. Fischman A.J. Lewandrowski K.B. Changes in cardiac markers including B-natriuretic peptide in runners after the Boston Marathon.Am J Cardiol. 2001; 88: 920-923Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar We hypothesized that exercise long and strenuous enough to cause cardiac fatigue might increase NT-pro-BNP even in healthy athletes.9Dawson E. George K. Shave R. Whyte G. Ball D. Does the human heart fatigue subsequent to prolonged exercise?.Sports Med. 2003; 33: 365-380Crossref PubMed Scopus (82) Google Scholar, 10Starnes J.W. Bowles D.K. Role of exercise in the cause and prevention of cardiac dysfunction.Exerc Sport Sci Rev. 1995; 23: 349-373PubMed Google Scholar Therefore, we measured NT-pro-BNP and cardiac troponin T (cTnT) as markers of cardiac injury in healthy cyclists who underwent strenuous marathon cycling for a further depiction of exercise-induced cardiac dysfunction.Twenty-nine male volunteers of 2,303 participants in the Tyrolean Ötztaler Radmarathon held on August 29, 2004, were the subjects of the study. The workload of this race (total distance 230 km, altitude difference 5500 m) is comparable to that of the hardest mountain stages of the Tour de France. All study participants were experienced and well-trained amateur cyclists. They were free of cardiovascular risk factors and without evidence of any heart disease according to case histories and clinical investigations. Blood specimens were taken the day before, immediately after, 24 hours after, and 1 week after competition. Plasma NT-pro-BNP was determined using an Elecsys pro-BNP sandwich immunoassay (electrochemiluminescence immunoassay) on an Elecsys analyzer 2010 (Roche Diagnostics, Hoffmann-LaRoche, Inc., Basel, Switzerland). The analytic range of this test extends from 20 to 35,000 ng/L. The normal range of NT-pro-BNP is age dependent and was from 5 to 95 ng/L in our study population, with a clinical cut-off value of ≥95 ng/L. On the same analyzer, cTnT was measured using a third-generation electrochemiluminescence immunoassay method (Troponin T Stat, Roche Diagnostics, Hoffmann-LaRoche, Inc.). The analytic range of this test extends from 0.01 to 25 μg/L, with an upper reference limit of 0.04 μg/L. Creatine kinase, creatine kinase isoenzyme MB, and hemoglobin were measured by standard methods. Hematocrit and percentage changes in plasma volume were calculated according to standard equations.The Mann-Whitney test was used for the analysis of the different baseline characteristics between athletes with and without exercise-induced cTnT levels, and Wilcoxon’s signed-rank test was used for the changes of the biochemical parameters over the observation period. Regression analyses were computed to assess correlations between the variables using the SPSS software package (version 9.0, SPSS, Inc., Chicago, Illinois). Statistical significance was assumed at p <0.05.The athletes’ characteristics and race results are listed in Table 1. All of them finished the race without major problems or cardiac symptoms. In all subjects, NT-pro-BNP significantly increased from 28 ± 21 to 278 ± 152 ng/L immediately after the race (p < 0.001) and decreased on the following day to a mean value of 194 ± 115 ng/L (p < 0.001). At the control investigation 1 week later, NT-pro-BNP had returned to baseline values (28 ± 17 ng/L) in all athletes. The mean increase in NT-pro-BNP (ΔNT-pro-BNP) was calculated to be 1,128 ± 803% of the baseline value. Pre- and postrace values of NT-pro-BNP as well as the individual ΔNT-pro-BNP were significantly correlated with age (r = 0.460, p = 0.012; r = 0.509, p = 0.005; r = 0.555, p = 0.002; r = 0.477, p = 0.009, respectively). There was no correlation between ΔNT-pro-BNP and the other baseline features or the markers investigated, including cTnT. The course of NT-pro-BNP is shown in Figure 1. Before competition, cTnT results were negative in all subjects. Immediately afterward, it was elevated in 13 athletes (45%). Five subjects (17%) had cTnT increases just greater than the detection limit of 0.01 μg/L, whereas 8 athletes (28%) showed significant increases greater than the upper reference limit of 0.04 μg/L ranging from 0.043 to 0.224 μg/L (Figure 2). One day after competition, cTnT had again decreased to less than the upper reference limit in all athletes. In 2 subjects, however, it still remained greater than the detection limit. Athletes with and without exercise-induced cTnT elevation did not differ in their baseline features. All pre- and postrace values of the parameters investigated are listed in Table 2.Table 1Baseline characteristics and race results of the athletesVariableMean ± SDRangeAge (yrs)34 ± 822–52Height (cm)178 ± 5168–187Body mass (kg)70.4 ± 7.861–100Body mass loss (kg) (immediately after)−1.3 ± 0.9−3.5 to +1.1Body mass loss (kg) (24 h after)−0.5 ± 0.6−2.1 to +0.5Fluid substitution (L)5.4 ± 1.52.3–10Training km (in 2004)6,608 ± 2,8152,000–13,000Race time9 h, 10 min ± 55 min7 h, 23 min to 11 h, 14 minAverage speed (km/h)25.1 ± 2.520.5–31.2 Open table in a new tab Figure 2Plasma levels of cTnT during the cycling marathon (n = 29).View Large Image Figure ViewerDownload (PPT)Table 2Biochemical markers before and after competition (n = 29)VariableBeforeAfter24 h AfterNT-pro-BNP (5–95 ng/L)⁎Values presented as mean ± SD.28 ± 21278 ± 151‡p <0.001;194 ± 114‡p <0.001;Range8–10079–59865–583ΔNT-pro-BNP (ng/L)⁎Values presented as mean ± SD.251 ± 146‡p <0.001;166 ± 103‡p <0.001;Range56–54047–488ΔNT-pro-BNP (%)⁎Values presented as mean ± SD.1,128 ± 803‡p <0.001;702 ± 395‡p 0.04 μg/L)†Values presented as number of positive/total observations.0/29 (0%)8/29 (27.5%)1/29 (3.4%)CK (38–174 U/L)⁎Values presented as mean ± SD.158 ± 89565 ± 452‡p <0.001;1,133 ± 779‡p 6%)†Values presented as number of positive/total observations.5/29 (17.2%)19/29 (65.5%)4/29 (13.8%)Hematocrit (40–52%)⁎Values presented as mean ± SD.46 ± 246 ± 2§p = NS.43 ± 2‡p <0.001;Δ plasma volume (%)⁎Values presented as mean ± SD.−0.6 ± 0.5§p = NS.10.3 ± 2.5‡p <0.001;CK = creatine kinase. Values presented as mean ± SD.† Values presented as number of positive/total observations.‡ p <0.001;§ p = NS. Open table in a new tab The major finding of the study is that NT-pro-BNP and cTnT as established clinical indicators of cardiac dysfunction and cardiac injury are significantly elevated in healthy asymptomatic athletes after strenuous marathon cycling. The increase in NT-pro-BNP was significant in all athletes, whereas for cTnT, it was significant in just 28% of them. The 2 indicators showed a pattern of release kinetics characteristic for the stimulus of long-term exercise, that is, immediate increases with fast clearances in the following hours to days.11Neumayr G. Gaenzer H. Pfister R. Sturm W. Schwarzacher S.P. Eibl G. Mitterbauer G. Hoertnagl H. Plasma levels of cardiac troponin I after prolonged strenuous endurance exercise.Am J Cardiol. 2001; 87: 369-371Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12Neumayr G. Pfister R. Mitterbauer G. Maurer A. Gaenzer H. Sturm W. Hoertnagl H. Effect of the “Race Across the Alps” in elite cyclists on plasma cardiac troponins I and T.Am J Cardiol. 2002; 89: 484-486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar We consider the deflections of the 2 parameters to represent biochemical evidence for cardiac fatigue for the following considerations.BNP is a naturally occurring antagonist of the renin-angiotensin-aldosterone system that is elevated in situations of increased central blood volume (fluid overload), such as edematous disorders, heart failure, or exhaustive sport events.13Levin E.R. Gardner D.G. Samson W.K. Natriuretic peptides.N Engl J Med. 1998; 339: 321-328Crossref PubMed Scopus (2028) Google Scholar Cardiac myocytes constitute the major source of BNP, and the primary stimuli of its release are left ventricular stretch and wall tension. There is a lot of cardiac wall stress in strenuous long-term exercise: (1) the myocardial workload is impressively large with respect to the duration and intensity of exercise,14Neumayr G. Pfister R. Mitterbauer G. Gänzer H. Sturm W. Eibl G. Hörtnagl H. Exercise intensity of cycle-touring events.Int J Sports Med. 2002; 23: 505-509Crossref PubMed Scopus (19) Google Scholar and (2) exercise-induced hypervolemia is pronounced as well.15Neumayr G. Pfister R. Hoertnagl H. Mitterbauer G. Prokop W. Joannidis M. Renal function and plasma volume following ultramarathon cycling.Int J Sports Med. 2005; 26: 1-7Crossref Google Scholar The positive impact of long-term exercise on plasma volume is well established, and increases of up to 22% were seen after exercise.15Neumayr G. Pfister R. Hoertnagl H. Mitterbauer G. Prokop W. Joannidis M. Renal function and plasma volume following ultramarathon cycling.Int J Sports Med. 2005; 26: 1-7Crossref Google Scholar In the present study, plasma volume increased by 10.3%. BNP is released into the circulation as a counter-regulatory response for cardiorenal homeostasis to induce diuresis and vasodilation and hence reduces pulmonary and systemic vascular resistance. As a cardiac effect, left ventricular end-diastolic pressure is decreased, improving diastolic filling and enabling increased cardiac output, indispensable for any performance of long-term exercise. Because of the typical release of kinetics with immediate increases, fast decreases after exercise, and renormalization after 1 week, we consider the deflections of NT-pro-BNP to be the adequate volume regulatory response of a hemodynamically stressed myocardium to cardiorenal distress. Our interpretation of the finding may tend to be physiologic, especially in view of the recent role of BNP as a clinical discriminator for left ventricular dysfunction. However, the way that results are interpreted will change as clinicians gain experience with new parameters such as BNP in their various settings. Further studies on long-term exercise are needed to affirm the observed BNP increases to be the primary physiologic endocrine reaction of an exercise-stressed myocardium.Previous to this study, it was known that maximal exercise testing until exhaustion does not cause an increase in BNP.5Steele I.C. McDowell G. Moore A. Campbell N.P. Shaw C. Buchanan K.D. Nicholls D.P. Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects.Eur J Clin Invest. 1997; 27: 270-276Crossref PubMed Scopus (67) Google Scholar Sparse data on long-term exercise revealed BNP increases to be small.4Siegel A.J. Lewandrowski E.L. Chun K.Y. Sholar M.B. Fischman A.J. Lewandrowski K.B. Changes in cardiac markers including B-natriuretic peptide in runners after the Boston Marathon.Am J Cardiol. 2001; 88: 920-923Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar König et al7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar investigated 11 professional cyclists (mean age 27 years) during a 5-day cycling race and observed BNP to remain within the normal range, with postexercise increases of just 37%. Ohba et al,6Ohba H. Takada H. Musha H. Nagashima J. Mori N. Awaya T. Omiya K. Murayama M. Effects of prolonged strenuous exercise on plasma levels of atrial natriuretic peptide and brain natriuretic peptide in healthy men.Am Heart J. 2001; 141: 751-758Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar however, described BNP increases of up to 500% in 10 Japanese runners (mean age 46 years) after a 100-km ultramarathon. In our study, we found even more pronounced increases in NT-pro-BNP in all athletes (mean age 34 years). The mean ΔNT-pro-BNP was 1,128% immediately after exercise, ranging from 243% to 3,160%. Levels of NT-pro-BNP and ΔNT-pro-BNP were associated with athletes’ ages (p = 0.009). Older athletes were more likely to have higher levels at rest and after exercise of NT-pro-BNP. This association between age and BNP was also evident in the younger and better trained professional cyclists studied by König et al.7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar We therefore conclude that BNP release is dependent on age and cardiac function not only in older hospitalized patients with heart failure3Kruger S. Graf J. Kunz D. Stickel T. Hanrath P. Janssens U. Brain natriuretic peptide levels predict functional capacity in patients with chronic heart failure.J Am Coll Cardiol. 2002; 40: 718-722Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 16Nielson O.W. Kirk V. Bay M. Boesgaard S. Nielsen H. Value of N-terminal pro brain natriuretic peptide in the elderly data from the prospective Copenhagen Hospital Heart Failure Study.Eur J Heart Fail. 2004; 6: 275-279Crossref PubMed Scopus (25) Google Scholar but even in healthy athletes. It is the young and best-trained professional cyclists who exhibit the smallest exercise-induced increases in NT-pro-BNP.7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar In contrast, older and less-trained athletes experience an enhanced liberation of BNP from “somewhat aged” myocardial cells to counteract decreasing diastolic function by increased ventricular wall stiffness in older age. ΔNT-pro-BNP was not correlated with any other baseline feature or stress marker investigated. There was no significant correlation between NT-pro-BNP and cTnT either. This makes one assume that in this athlete population, the increases in NT-pro-BNP were neither linked to nor caused by structural cardiac injury. Therefore, our data seem to support the idea that cardiac fatigue and cardiac injury are different phenomena.We found exercise-induced cTnT elevations in 13 athletes (45%), 8 of whom (28%) had cTnT elevations beyond the clinical cut-off point for myocardial infarction. This percentage of positive cTnT levels is in good accordance with previous data obtained from different study populations, which revealed percentages of 25% to 36%.11Neumayr G. Gaenzer H. Pfister R. Sturm W. Schwarzacher S.P. Eibl G. Mitterbauer G. Hoertnagl H. Plasma levels of cardiac troponin I after prolonged strenuous endurance exercise.Am J Cardiol. 2001; 87: 369-371Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12Neumayr G. Pfister R. Mitterbauer G. Maurer A. Gaenzer H. Sturm W. Hoertnagl H. Effect of the “Race Across the Alps” in elite cyclists on plasma cardiac troponins I and T.Am J Cardiol. 2002; 89: 484-486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 17Rifai N. Douglas P.S. O’Toole M. Rimm E. Ginsburg G.S. Cardiac troponin T and I, electrocardiographic wall motion analyses, and ejection fractions in athletes participating in the Hawaii Ironman Triathlon.Am J Cardiol. 1999; 83: 1085-1089Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 18Whyte G.P. George K. Sharma S. Lumley S. Gates P. Prasad K. McKenna W.J. Cardiac fatigue following prolonged endurance exercise of differing distances.Med Sci Sports Exerc. 2000; 32: 1067-1072Crossref PubMed Scopus (127) Google Scholar The study affirms once again that the exercise-associated release of cardiac troponins is small and transient, unlike that after irreversible myocardial ischemia.11Neumayr G. Gaenzer H. Pfister R. Sturm W. Schwarzacher S.P. Eibl G. Mitterbauer G. Hoertnagl H. Plasma levels of cardiac troponin I after prolonged strenuous endurance exercise.Am J Cardiol. 2001; 87: 369-371Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12Neumayr G. Pfister R. Mitterbauer G. Maurer A. Gaenzer H. Sturm W. Hoertnagl H. Effect of the “Race Across the Alps” in elite cyclists on plasma cardiac troponins I and T.Am J Cardiol. 2002; 89: 484-486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 17Rifai N. Douglas P.S. O’Toole M. Rimm E. Ginsburg G.S. Cardiac troponin T and I, electrocardiographic wall motion analyses, and ejection fractions in athletes participating in the Hawaii Ironman Triathlon.Am J Cardiol. 1999; 83: 1085-1089Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 18Whyte G.P. George K. Sharma S. Lumley S. Gates P. Prasad K. McKenna W.J. Cardiac fatigue following prolonged endurance exercise of differing distances.Med Sci Sports Exerc. 2000; 32: 1067-1072Crossref PubMed Scopus (127) Google Scholar The observed kinetics substantiate a cTnT release from the free cytoplasmatic pool (approximately 5%) due to the half-life (6 hours) of cytosolic cTnT.19Chen Y. Serfass R.C. Mackey-Bojack S.M. Kelly K.L. Titus J.L. Apple F.S. Cardiac troponin T alterations in myocardium and serum of rats after stressful, prolonged intense exercise.J Appl Physiol. 2000; 88: 1749-1755PubMed Google Scholar, 20Remppis A. Scheffold T. Greten J. Haass M. Greten T. Kubler W. Katus H.A. Intracellular compartmentation of troponin T release kinetics after global ischemia and calcium paradox in the isolated perfused rat heart.J Mol Cell Cardiol. 1995; 27: 793-803Abstract Full Text PDF PubMed Scopus (116) Google Scholar As the underlying mechanism, we previously hypothesized that an exercise-induced overload of free radicals caused by oxidative long-term stress may involve a hasty cardiomyocyte-membrane leakage, leading to the egress of cytosolic cTnT into the circulation.12Neumayr G. Pfister R. Mitterbauer G. Maurer A. Gaenzer H. Sturm W. Hoertnagl H. Effect of the “Race Across the Alps” in elite cyclists on plasma cardiac troponins I and T.Am J Cardiol. 2002; 89: 484-486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 19Chen Y. Serfass R.C. Mackey-Bojack S.M. Kelly K.L. Titus J.L. Apple F.S. Cardiac troponin T alterations in myocardium and serum of rats after stressful, prolonged intense exercise.J Appl Physiol. 2000; 88: 1749-1755PubMed Google Scholar Follow-up studies are required to substantiate this assumption that even positive cardiac troponins in healthy asymptomatic athletes are more likely to reflect reversible cardiac fatigue than irreversible subclinical cardiac injury. In past years, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) has turned out to be an excellent humoral marker for heart failure.1Lerman A. Gibbons R.J. Rodeheffer R.J. Bailey K.R. McKinley L.J. Heublein D.M. Burnett Jr, J.C. Circulating N-terminal atrial natriuretic peptide as a marker for symptomless left-ventricular dysfunction.Lancet. 1993; 341: 1105-1109Abstract PubMed Scopus (297) Google Scholar, 2Maisel A.S. Krishnaswamy P. Nowak R.M. McCord J. Hollander J.E. Duc P. Omland T. Storrow A.B. Abraham W.T. Wu A.H. et al.Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.N Engl J Med. 2002; 347: 161-167Crossref PubMed Scopus (2771) Google Scholar, 3Kruger S. Graf J. Kunz D. Stickel T. Hanrath P. Janssens U. Brain natriuretic peptide levels predict functional capacity in patients with chronic heart failure.J Am Coll Cardiol. 2002; 40: 718-722Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Data on NT-pro-BNP and exercise are very limited and inconsistent so far.4Siegel A.J. Lewandrowski E.L. Chun K.Y. Sholar M.B. Fischman A.J. Lewandrowski K.B. Changes in cardiac markers including B-natriuretic peptide in runners after the Boston Marathon.Am J Cardiol. 2001; 88: 920-923Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 5Steele I.C. McDowell G. Moore A. Campbell N.P. Shaw C. Buchanan K.D. Nicholls D.P. Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects.Eur J Clin Invest. 1997; 27: 270-276Crossref PubMed Scopus (67) Google Scholar, 6Ohba H. Takada H. Musha H. Nagashima J. Mori N. Awaya T. Omiya K. Murayama M. Effects of prolonged strenuous exercise on plasma levels of atrial natriuretic peptide and brain natriuretic peptide in healthy men.Am Heart J. 2001; 141: 751-758Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar, 8Barletta G. Stefani L. Del Bene R. Fronzaroli C. Vecchiarino S. Lazzeri C. Fantini F. La Villa G. Effects of exercise on natriuretic peptides and cardiac function in man.Int J Cardiol. 1998; 65: 217-225Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Maximal short-term exercise is not likely to cause an increase in brain natriuretic peptide (BNP),5Steele I.C. McDowell G. Moore A. Campbell N.P. Shaw C. Buchanan K.D. Nicholls D.P. Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects.Eur J Clin Invest. 1997; 27: 270-276Crossref PubMed Scopus (67) Google Scholar whereas respective data on long-term exercise reveal BNP increases to be small and to remain within the normal range.4Siegel A.J. Lewandrowski E.L. Chun K.Y. Sholar M.B. Fischman A.J. Lewandrowski K.B. Changes in cardiac markers including B-natriuretic peptide in runners after the Boston Marathon.Am J Cardiol. 2001; 88: 920-923Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar We hypothesized that exercise long and strenuous enough to cause cardiac fatigue might increase NT-pro-BNP even in healthy athletes.9Dawson E. George K. Shave R. Whyte G. Ball D. Does the human heart fatigue subsequent to prolonged exercise?.Sports Med. 2003; 33: 365-380Crossref PubMed Scopus (82) Google Scholar, 10Starnes J.W. Bowles D.K. Role of exercise in the cause and prevention of cardiac dysfunction.Exerc Sport Sci Rev. 1995; 23: 349-373PubMed Google Scholar Therefore, we measured NT-pro-BNP and cardiac troponin T (cTnT) as markers of cardiac injury in healthy cyclists who underwent strenuous marathon cycling for a further depiction of exercise-induced cardiac dysfunction. Twenty-nine male volunteers of 2,303 participants in the Tyrolean Ötztaler Radmarathon held on August 29, 2004, were the subjects of the study. The workload of this race (total distance 230 km, altitude difference 5500 m) is comparable to that of the hardest mountain stages of the Tour de France. All study participants were experienced and well-trained amateur cyclists. They were free of cardiovascular risk factors and without evidence of any heart disease according to case histories and clinical investigations. Blood specimens were taken the day before, immediately after, 24 hours after, and 1 week after competition. Plasma NT-pro-BNP was determined using an Elecsys pro-BNP sandwich immunoassay (electrochemiluminescence immunoassay) on an Elecsys analyzer 2010 (Roche Diagnostics, Hoffmann-LaRoche, Inc., Basel, Switzerland). The analytic range of this test extends from 20 to 35,000 ng/L. The normal range of NT-pro-BNP is age dependent and was from 5 to 95 ng/L in our study population, with a clinical cut-off value of ≥95 ng/L. On the same analyzer, cTnT was measured using a third-generation electrochemiluminescence immunoassay method (Troponin T Stat, Roche Diagnostics, Hoffmann-LaRoche, Inc.). The analytic range of this test extends from 0.01 to 25 μg/L, with an upper reference limit of 0.04 μg/L. Creatine kinase, creatine kinase isoenzyme MB, and hemoglobin were measured by standard methods. Hematocrit and percentage changes in plasma volume were calculated according to standard equations. The Mann-Whitney test was used for the analysis of the different baseline characteristics between athletes with and without exercise-induced cTnT levels, and Wilcoxon’s signed-rank test was used for the changes of the biochemical parameters over the observation period. Regression analyses were computed to assess correlations between the variables using the SPSS software package (version 9.0, SPSS, Inc., Chicago, Illinois). Statistical significance was assumed at p <0.05. The athletes’ characteristics and race results are listed in Table 1. All of them finished the race without major problems or cardiac symptoms. In all subjects, NT-pro-BNP significantly increased from 28 ± 21 to 278 ± 152 ng/L immediately after the race (p < 0.001) and decreased on the following day to a mean value of 194 ± 115 ng/L (p < 0.001). At the control investigation 1 week later, NT-pro-BNP had returned to baseline values (28 ± 17 ng/L) in all athletes. The mean increase in NT-pro-BNP (ΔNT-pro-BNP) was calculated to be 1,128 ± 803% of the baseline value. Pre- and postrace values of NT-pro-BNP as well as the individual ΔNT-pro-BNP were significantly correlated with age (r = 0.460, p = 0.012; r = 0.509, p = 0.005; r = 0.555, p = 0.002; r = 0.477, p = 0.009, respectively). There was no correlation between ΔNT-pro-BNP and the other baseline features or the markers investigated, including cTnT. The course of NT-pro-BNP is shown in Figure 1. Before competition, cTnT results were negative in all subjects. Immediately afterward, it was elevated in 13 athletes (45%). Five subjects (17%) had cTnT increases just greater than the detection limit of 0.01 μg/L, whereas 8 athletes (28%) showed significant increases greater than the upper reference limit of 0.04 μg/L ranging from 0.043 to 0.224 μg/L (Figure 2). One day after competition, cTnT had again decreased to less than the upper reference limit in all athletes. In 2 subjects, however, it still remained greater than the detection limit. Athletes with and without exercise-induced cTnT elevation did not differ in their baseline features. All pre- and postrace values of the parameters investigated are listed in Table 2. CK = creatine kinase. The major finding of the study is that NT-pro-BNP and cTnT as established clinical indicators of cardiac dysfunction and cardiac injury are significantly elevated in healthy asymptomatic athletes after strenuous marathon cycling. The increase in NT-pro-BNP was significant in all athletes, whereas for cTnT, it was significant in just 28% of them. The 2 indicators showed a pattern of release kinetics characteristic for the stimulus of long-term exercise, that is, immediate increases with fast clearances in the following hours to days.11Neumayr G. Gaenzer H. Pfister R. Sturm W. Schwarzacher S.P. Eibl G. Mitterbauer G. Hoertnagl H. Plasma levels of cardiac troponin I after prolonged strenuous endurance exercise.Am J Cardiol. 2001; 87: 369-371Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12Neumayr G. Pfister R. Mitterbauer G. Maurer A. Gaenzer H. Sturm W. Hoertnagl H. Effect of the “Race Across the Alps” in elite cyclists on plasma cardiac troponins I and T.Am J Cardiol. 2002; 89: 484-486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar We consider the deflections of the 2 parameters to represent biochemical evidence for cardiac fatigue for the following considerations. BNP is a naturally occurring antagonist of the renin-angiotensin-aldosterone system that is elevated in situations of increased central blood volume (fluid overload), such as edematous disorders, heart failure, or exhaustive sport events.13Levin E.R. Gardner D.G. Samson W.K. Natriuretic peptides.N Engl J Med. 1998; 339: 321-328Crossref PubMed Scopus (2028) Google Scholar Cardiac myocytes constitute the major source of BNP, and the primary stimuli of its release are left ventricular stretch and wall tension. There is a lot of cardiac wall stress in strenuous long-term exercise: (1) the myocardial workload is impressively large with respect to the duration and intensity of exercise,14Neumayr G. Pfister R. Mitterbauer G. Gänzer H. Sturm W. Eibl G. Hörtnagl H. Exercise intensity of cycle-touring events.Int J Sports Med. 2002; 23: 505-509Crossref PubMed Scopus (19) Google Scholar and (2) exercise-induced hypervolemia is pronounced as well.15Neumayr G. Pfister R. Hoertnagl H. Mitterbauer G. Prokop W. Joannidis M. Renal function and plasma volume following ultramarathon cycling.Int J Sports Med. 2005; 26: 1-7Crossref Google Scholar The positive impact of long-term exercise on plasma volume is well established, and increases of up to 22% were seen after exercise.15Neumayr G. Pfister R. Hoertnagl H. Mitterbauer G. Prokop W. Joannidis M. Renal function and plasma volume following ultramarathon cycling.Int J Sports Med. 2005; 26: 1-7Crossref Google Scholar In the present study, plasma volume increased by 10.3%. BNP is released into the circulation as a counter-regulatory response for cardiorenal homeostasis to induce diuresis and vasodilation and hence reduces pulmonary and systemic vascular resistance. As a cardiac effect, left ventricular end-diastolic pressure is decreased, improving diastolic filling and enabling increased cardiac output, indispensable for any performance of long-term exercise. Because of the typical release of kinetics with immediate increases, fast decreases after exercise, and renormalization after 1 week, we consider the deflections of NT-pro-BNP to be the adequate volume regulatory response of a hemodynamically stressed myocardium to cardiorenal distress. Our interpretation of the finding may tend to be physiologic, especially in view of the recent role of BNP as a clinical discriminator for left ventricular dysfunction. However, the way that results are interpreted will change as clinicians gain experience with new parameters such as BNP in their various settings. Further studies on long-term exercise are needed to affirm the observed BNP increases to be the primary physiologic endocrine reaction of an exercise-stressed myocardium. Previous to this study, it was known that maximal exercise testing until exhaustion does not cause an increase in BNP.5Steele I.C. McDowell G. Moore A. Campbell N.P. Shaw C. Buchanan K.D. Nicholls D.P. Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects.Eur J Clin Invest. 1997; 27: 270-276Crossref PubMed Scopus (67) Google Scholar Sparse data on long-term exercise revealed BNP increases to be small.4Siegel A.J. Lewandrowski E.L. Chun K.Y. Sholar M.B. Fischman A.J. Lewandrowski K.B. Changes in cardiac markers including B-natriuretic peptide in runners after the Boston Marathon.Am J Cardiol. 2001; 88: 920-923Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar König et al7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar investigated 11 professional cyclists (mean age 27 years) during a 5-day cycling race and observed BNP to remain within the normal range, with postexercise increases of just 37%. Ohba et al,6Ohba H. Takada H. Musha H. Nagashima J. Mori N. Awaya T. Omiya K. Murayama M. Effects of prolonged strenuous exercise on plasma levels of atrial natriuretic peptide and brain natriuretic peptide in healthy men.Am Heart J. 2001; 141: 751-758Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar however, described BNP increases of up to 500% in 10 Japanese runners (mean age 46 years) after a 100-km ultramarathon. In our study, we found even more pronounced increases in NT-pro-BNP in all athletes (mean age 34 years). The mean ΔNT-pro-BNP was 1,128% immediately after exercise, ranging from 243% to 3,160%. Levels of NT-pro-BNP and ΔNT-pro-BNP were associated with athletes’ ages (p = 0.009). Older athletes were more likely to have higher levels at rest and after exercise of NT-pro-BNP. This association between age and BNP was also evident in the younger and better trained professional cyclists studied by König et al.7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar We therefore conclude that BNP release is dependent on age and cardiac function not only in older hospitalized patients with heart failure3Kruger S. Graf J. Kunz D. Stickel T. Hanrath P. Janssens U. Brain natriuretic peptide levels predict functional capacity in patients with chronic heart failure.J Am Coll Cardiol. 2002; 40: 718-722Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 16Nielson O.W. Kirk V. Bay M. Boesgaard S. Nielsen H. Value of N-terminal pro brain natriuretic peptide in the elderly data from the prospective Copenhagen Hospital Heart Failure Study.Eur J Heart Fail. 2004; 6: 275-279Crossref PubMed Scopus (25) Google Scholar but even in healthy athletes. It is the young and best-trained professional cyclists who exhibit the smallest exercise-induced increases in NT-pro-BNP.7König D. Schumacher Y.O. Heinrich L. Schmid A. Berg A. Dickhuth H.H. Myocardial stress after competitive exercise in professional road cyclists.Med Sci Sports Exerc. 2003; 35: 1679-1683Crossref PubMed Scopus (69) Google Scholar In contrast, older and less-trained athletes experience an enhanced liberation of BNP from “somewhat aged” myocardial cells to counteract decreasing diastolic function by increased ventricular wall stiffness in older age. ΔNT-pro-BNP was not correlated with any other baseline feature or stress marker investigated. There was no significant correlation between NT-pro-BNP and cTnT either. This makes one assume that in this athlete population, the increases in NT-pro-BNP were neither linked to nor caused by structural cardiac injury. Therefore, our data seem to support the idea that cardiac fatigue and cardiac injury are different phenomena. We found exercise-induced cTnT elevations in 13 athletes (45%), 8 of whom (28%) had cTnT elevations beyond the clinical cut-off point for myocardial infarction. This percentage of positive cTnT levels is in good accordance with previous data obtained from different study populations, which revealed percentages of 25% to 36%.11Neumayr G. Gaenzer H. Pfister R. Sturm W. Schwarzacher S.P. Eibl G. Mitterbauer G. Hoertnagl H. Plasma levels of cardiac troponin I after prolonged strenuous endurance exercise.Am J Cardiol. 2001; 87: 369-371Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12Neumayr G. Pfister R. Mitterbauer G. Maurer A. Gaenzer H. Sturm W. Hoertnagl H. Effect of the “Race Across the Alps” in elite cyclists on plasma cardiac troponins I and T.Am J Cardiol. 2002; 89: 484-486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 17Rifai N. Douglas P.S. O’Toole M. Rimm E. Ginsburg G.S. Cardiac troponin T and I, electrocardiographic wall motion analyses, and ejection fractions in athletes participating in the Hawaii Ironman Triathlon.Am J Cardiol. 1999; 83: 1085-1089Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 18Whyte G.P. George K. Sharma S. Lumley S. Gates P. Prasad K. McKenna W.J. Cardiac fatigue following prolonged endurance exercise of differing distances.Med Sci Sports Exerc. 2000; 32: 1067-1072Crossref PubMed Scopus (127) Google Scholar The study affirms once again that the exercise-associated release of cardiac troponins is small and transient, unlike that after irreversible myocardial ischemia.11Neumayr G. Gaenzer H. Pfister R. Sturm W. Schwarzacher S.P. Eibl G. Mitterbauer G. Hoertnagl H. Plasma levels of cardiac troponin I after prolonged strenuous endurance exercise.Am J Cardiol. 2001; 87: 369-371Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12Neumayr G. Pfister R. Mitterbauer G. Maurer A. Gaenzer H. Sturm W. Hoertnagl H. Effect of the “Race Across the Alps” in elite cyclists on plasma cardiac troponins I and T.Am J Cardiol. 2002; 89: 484-486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 17Rifai N. Douglas P.S. O’Toole M. Rimm E. Ginsburg G.S. Cardiac troponin T and I, electrocardiographic wall motion analyses, and ejection fractions in athletes participating in the Hawaii Ironman Triathlon.Am J Cardiol. 1999; 83: 1085-1089Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 18Whyte G.P. George K. Sharma S. Lumley S. Gates P. Prasad K. McKenna W.J. Cardiac fatigue following prolonged endurance exercise of differing distances.Med Sci Sports Exerc. 2000; 32: 1067-1072Crossref PubMed Scopus (127) Google Scholar The observed kinetics substantiate a cTnT release from the free cytoplasmatic pool (approximately 5%) due to the half-life (6 hours) of cytosolic cTnT.19Chen Y. Serfass R.C. Mackey-Bojack S.M. Kelly K.L. Titus J.L. Apple F.S. Cardiac troponin T alterations in myocardium and serum of rats after stressful, prolonged intense exercise.J Appl Physiol. 2000; 88: 1749-1755PubMed Google Scholar, 20Remppis A. Scheffold T. Greten J. Haass M. Greten T. Kubler W. Katus H.A. Intracellular compartmentation of troponin T release kinetics after global ischemia and calcium paradox in the isolated perfused rat heart.J Mol Cell Cardiol. 1995; 27: 793-803Abstract Full Text PDF PubMed Scopus (116) Google Scholar As the underlying mechanism, we previously hypothesized that an exercise-induced overload of free radicals caused by oxidative long-term stress may involve a hasty cardiomyocyte-membrane leakage, leading to the egress of cytosolic cTnT into the circulation.12Neumayr G. Pfister R. Mitterbauer G. Maurer A. Gaenzer H. Sturm W. Hoertnagl H. Effect of the “Race Across the Alps” in elite cyclists on plasma cardiac troponins I and T.Am J Cardiol. 2002; 89: 484-486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 19Chen Y. Serfass R.C. Mackey-Bojack S.M. Kelly K.L. Titus J.L. Apple F.S. Cardiac troponin T alterations in myocardium and serum of rats after stressful, prolonged intense exercise.J Appl Physiol. 2000; 88: 1749-1755PubMed Google Scholar Follow-up studies are required to substantiate this assumption that even positive cardiac troponins in healthy asymptomatic athletes are more likely to reflect reversible cardiac fatigue than irreversible subclinical cardiac injury.
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