Cardiac Markers (BNP, NT-Pro-BNP, Troponin I, Troponin T, in Female Amateur Runners Before and Up Until Three Days After a Marathon

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1 120Clin. Lab. 2008;54:81-87 Copyright ORIGINAL ARTICLE Cardiac Markers (BNP, NT-Pro-BNP, Troponin I, Troponin T, in Female Amateur Runners Before and Up Until Three Days After a Marathon FRASSL W 1, KOWOLL R 1, KATZ N 2, SPETH M 2, STANGL A 3, BRECHTEL L 4, JOSCHT B 5, BOLDT LH 6, MEIER-BUTTERMILCH R 7, SCHLEMMER M 1, ROECKER L 7, GUNGA HC 1 1 Center for Space Medicine Berlin (ZWMB), Department of Physiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany 2 Department of Clinical Chemistry, Justus-Liebig-University of Giessen, Giessen, Germany. 3 Bayer Vital GmbH, Fernwald, Germany 4 Institute of Sports Science, Humboldt University of Berlin, Berlin, Germany 5 Bundeswehrkrankenhaus Berlin, Berlin, Germany 6 Charité University Medicine Berlin, Campus Virchow Clinic, Department of Cardiology, Germany 7 Labor 28, Berlin, Germany SUMMARY Purpose: Transient cardiac ventricular dysfunction or sudden cardiac deaths have been reported for male athletes participating in marathon racing. Less is known about the myocardial response in females. We examined natriuretic peptides and cardiac troponins in female athletes after a marathon. Methods: At the 31 st real,- Berlin Marathon plasma levels of NT-pro-BNP, BNP, ctni and ctnt were measured in 15 women (age 35±6 years; finishing times between 3:22 h and 5:21 h) at four different time points (before, immediately after, day one and day three). Results: An increase in [NT-pro-BNP] was observed immediately after the marathon (median [NT-pro-BNP] before: 39.6 pg ml -1, after: pg ml -1, p=0.003) with a further increase on day one. [BNP] did not increase immediately after the marathon but increased on day one (median [BNP] before: 15 pg ml -1, day one: pg ml -1, p=0.006). On day three, [NT-pro-BNP] and [BNP] returned to initial values. [ctni] was under the detection limit prior to the marathon in all runners. [ctnt] was under the detection limit before the marathon except in one runner who presented a concentration of 0.03 ng ml -1. Cardiac troponins (median [ctni] after: ng ml -1, p=0.028; median [ctnt] after: ng ml -1, p=0.012) increased immediately after the marathon and returned to initial values on day one [ctnt] and three [ctni]. Discussion: Parameters representing cardiac stress increased in females after a marathon. Different kinetics of natriuretic peptides BNP and NT-pro-BNP post-marathon could be due to their different half-lives and dependence on renal function. The increase of ctni and ctnt may result from minor myocardial lesions. (Clin. Lab. 2008;54:81-87) KEY WORDS Endurance exercise, Troponin I, Troponin T, natriuretic peptides Manuscript accepted April 1, 2008 INTRODUCTION In recent years, B type natriuretic peptides have gained importance as markers for the detection of heart failure and asymptomatic left ventricular dysfunction [2,4,12, 18,19,24,28]. The plasma concentration of these peptides is increased in diseases characterised by an increased fluid volume, such as in renal failure, primary aldosteronism, and congestive heart failure as well as in ventricular hypertrophy or strain [18]. A marked gender difference in the concentrations of B type natriuretic Clin. Lab. 3+4/

2 WALTRAUD FRASSL et al. peptide is well known with women presenting higher concentrations than men [2,27]. The question of cardiac injury and its measurement is always raised in connection with prolonged exhaustive exercise. Increased post-exercise levels of BNP and/or NT-pro- BNP have been described by various authors[6,7,8,10, 15,16,17,20,22,27]. Little is known about possible differences in reaction patterns when comparing BNP and NT-pro-BNP nor about post-exercise kinetics of these markers as most studies describe levels just up until 24 hours-post-race. Cardiac troponins are the most specific and sensitive laboratory markers of myocardial cell injury and have emerged as the gold standard for biochemical detection of myocardial cell injury. Cardiac troponins are important for risk stratification and selection of appropriate treatment strategies [3,14]. Prolonged exercise seems to promote the appearance of cardiac specific troponins (ctnt, ctni), which indicate myocardial damage[6,9, 15,16,20,21,22,26,27,29]. The interpretation of increased post-exercise concentrations in ctnt and ctni without clinical symptoms is still controversial. Especially in amateur female runners the measurement of these parameters has been neglected. Only a small number of studies have been conducted focussing on B type natriuretic peptides and cardiac troponins T and I in women during endurance exercise [27]. Various studies have been conducted with welltrained male athletes and a small number of women during ultra endurance events. Less data is available describing a broader range of female subjects who differ in age, experience and training levels. An increasing number of female recreational marathon runners makes it necessary to focus on women and cardiac markers during endurance events. It was the aim of our study to show the response of B type natriuretic peptides and cardiac troponins in females after a marathon. MATERIALS AND METHODS Subjects 15 healthy female amateur marathon runners participated in our study during the 31 st real,- Berlin Marathon on September 26, The subjects did not present any history of cardiovascular disease, which was evaluated through a questionnaire. All runners gave their written informed consent after receiving a detailed description of the study and of potential complications. The study was approved by the ethical review board of the Charité University Medicine Berlin. Protocol Subjects arrived at the medical tent on the morning of the marathon race between 7 and 8:30 a.m. Body weight, body height, blood pressure and heart rate were measured on arrival. The race commenced at 9 a.m. with an ambient temperature between 9.7 and 12.9 C for the time of the race and a relative humidity of around 80% with periods of rain. Blood samples were collected from different antecubital veins immediately before and after the marathon in the medical tent on site as well as on the morning of day one and day three in a local laboratory. Whole blood was taken without stasis, centrifuged and serum and plasma were drawn off and frozen (-20 C) until tested. EDTA blood was taken as well. Analyses CTnT was analysed in serum using electrochemiluminescence determined in the Elecsys 2010 (Roche Diagnostics, Mannheim, Germany). CTnT analytical sensitivity was < 0.01 ng ml -1. The diagnostic cut-off for minor myocardial damage of ctnt was > 0.01 ng ml -1, with values based on the 99 th percentile. The imprecision of the ctnt assay determined at two control levels (0.16 ng ml -1 and 6.1 ng ml -1 ) was VC < 6.3 %. CTnI was evaluated using serum in the ADVIA Centaur Assay (Bayer HealthCare, Leverkusen, Germany). CTnI analytical sensitivity was 0.03 ng ml -1. A diagnostic cut-off for minor myocardial damage of 0.1 ng ml -1 was used with values based on the 99 th percentile. The imprecision for the low (0.37 ng ml -1 ), medium (14.8 ng ml -1 ) and high (35.9 ng ml -1 ) control level was VC < 7.8 %. BNP, the physiologically active form of B-type natriuretic peptide, was measured using EDTA-plasma in the ADVIA Centaur Assay (Bayer HealthCare, Leverkusen, Germany). The ADVIA Centaur has an imprecision of VC < 3.5% for three BNP control levels (44.4 pg ml -1, 450 pg ml -1 and 1870 pg ml -1 ). Diagnostic cutoff values for women are: <45 years: 36 pg ml -1, years: 57 pg ml -1 with values based on the 95 th percentile. The analytical sensitivity of the BNP assay was < 2 pg ml -1. NT-pro-BNP was analysed in serum by using electrochemiluminescence determined in the Elecsys 2010 (Roche Diagnostics, Mannheim, Germany). The analytical sensitivity was < 5.0 pg ml -1, VC is < 3% at 93.1 pg ml -1 and 3330 pg ml -1. Diagnostic cut-off values for women are: < 50 years: < 150 pg ml -1 with values based on the 97 th percentile. Hematocrit (Hct) and hemoglobin (Hb) were measured on the ADVIA 120 (Bayer HealthCare, Leverkusen, Germany) by routine automatic methods. CTnT and ctni, BNP and NT-pro-BNP values presented in this paper are all corrected for plasma volume changes according to Strauss et al [23]. Statistical Analysis Statistical calculations were carried out with the nonparametric Friedman test for multiple test attempts and Wilcoxon test for matched pairs. With a non-gaussian distribution present, results are expressed as medians rather than arithmetic means. With respect to the variation, percentile values (P 25 and P 75 ) have been given. 82 Clin. Lab. 3+4/2008

3 CARDIAC MARKERS IN FAMALE AMATEUR RUNNERS Table 1: Participants parameters. valid cases min P 25 median P 75 max age (years) body height (cm) body mass (kg) BMI (kg m -2 ) previous marathons marathon finishing time 15 3:22:55 3:58:59 4:16:52 4:38:27 5:21:26 Results are presented as followed: (median, p 25, p 75 ). In the figures, results are shown in boxplots. The lower edge of the box is the 25 th percentile, the upper edge the 75 th percentile. The line in the box indicates the median value of the data. The whiskers indicate the minimum and maximum data values, the points outside the end of the whiskers are outliers. The zero hypothesis was rejected when p<0.05. For statistical calculations, ctnt concentrations <0.01 ng ml -1 (diagnostic cut-off) were set as ng ml -1, ctni concentrations <0.1 ng ml -1 (diagnostic cut-off) were set as 0.00 ng ml -1. Statistical analyses were performed using SPSS 12.0 Software (SPSS GmbH Software, Munich, Germany). RESULTS All runners finished the marathon without complaints or presenting clinical symptoms. Anthropometric data, previous marathon experience and marathon finishing times are presented in Table 1. BNP [pg ml -1 ] Pre-marathon concentrations were under the cut-off level (15.0, p 25 : 8.0, p 75 : 22.0). Immediately after the marathon, no changes could be seen for BNP concentrations ([BNP]). BNP levels increased on day one (27.35, p 25 : 18.5, p 75 : 39.2; p = 0.006); four runners (max: 50.30) at this time point presented increased concentrations above the cut-off level. On day three, [BNP] decreased and reached pre-marathon levels. The changes in BNP concentrations are shown in Figure 1a. NT-pro-BNP [pg ml -1 ] NT-pro-BNP concentrations ([NT-pro-BNP]) were under the cut-off level in all participants pre-race (39.6, p 25 : 29.6, p 75 : 65.0). Immediately after finishing the marathon, the runners displayed increased NT-pro-BNP concentrations (138.6, p 25 : , p 75 : 256.0; p = 0.003); four runners presented increased concentrations above the cut-off level with one woman showing a concentration of pg ml -1. On day one, concentrations were still increased (143.45, p 25 : 73.95, p 75 : ) and six women (max: pg ml -1 ) showed concentrations above the cutoff level. On day three, [NT-pro-BNP] decreased and reached pre-marathon levels. Increased NT-pro-BNP values did not account for increased BNP values at the same time points in the individual runners. No correlations could be made between the changes in BNP and NT-pro-BNP concentrations. The changes in NTpro-BNP concentrations are shown in Figure 1b. ctnt [ng ml -1 ] ctnt concentrations ([ctnt]) were under the detection limit before the marathon except in one runner who presented a concentration of 0.03 ng ml -1. Immediately after the marathon, concentrations increased (0.032; p25: <0.01, p75: 0.061, p = 0.012). Seven runners displayed concentrations within the so-called borderline range of minor myocardial damage ( ng ml -1 ) and one runner was above that range displaying a concentration of ng ml -1. On day one, concentrations returned to pre-marathon levels. [ctnt] was also under the detection limit on day three after the marathon. The course of ctnt is shown in Figure 2a. ctni [ng ml -1 ] ctni concentrations ([ctni]) pre-marathon were under the detection limit in all runners. Immediately after the marathon, [ctni] increased (0.098, p 25 : < 0.1, p 75 : 0.178, p = 0.028). Five runners displayed concentrations within the so-called borderline range ( ng ml -1 ) of minor myocardial damage (0.106; 0.174; 0.217; 0.178; 0.218); on day one, four runners were within that borderline range (0.102; 0.299; 0.206; 0.122). On day three, all concentrations were not detectable as during pre-marathon conditions. Increased ctni values did not account for increased ctnt values at the same time points in the individual runners. No correlations could be made between the changes in ctni and ctnt concentrations. The course of ctni is shown in Figure 2b. Clin. Lab. 3+4/

4 WALTRAUD FRASSL et al. (1a) (1b) Figure 1a and 1b: BNP and NT-pro-BNP concentrations on the morning before (N=15, pre), immediately after (N=11, post), on the morning of day 1 (N=14) and the morning of day 3 (N=13) after the marathon. (2a) (2b) Figure 2a and 2b: ctnt and ctni concentrations on the morning before (N=15, pre), immediately after (N=11, post), on the morning of day 1 (N=14) and the morning of day 3 (N=13) after the marathon. DISCUSSION BNP/NT-pro-BNP BNP and NT-pro-BNP have become well-accepted markers of cardiac dysfunction. These cardiac peptide hormones with natriuretic and diuretic effects as well as relaxing effects on the vascular smooth muscle are produced by cardiomyocytes [2]. Among all natriuretic peptides, BNP and NT-proBNP have proved to be the best and most powerful markers to identify patients with acute and chronic heart failure. In patients with acute coronary syndrome, both BNP and, to a greater proportion, NT-proBNP increased rapidly and peaked at 12 to 24 hours after the onset of chest pain, decreasing slightly thereafter but remaining increased for up to 12 weeks. The magnitude of natriuretic peptide increase seems to be related to the infarction 84 Clin. Lab. 3+4/2008

5 CARDIAC MARKERS IN FAMALE AMATEUR RUNNERS size. In acute coronary syndrome, NT-pro-BNP concentrations of > 400 pg ml -1 at admission are a clear sign for increased risk [5]. It is known from previous studies that immediately after a marathon race, NT-pro-BNP concentrations increase [6,15,22]. Herrmann et al. examined 40 male and six female runners after a marathon race and found increased concentrations of NT-pro- BNP 15 minutes and three hours post-race [6]. Vidotto et al. examined 13 female runners and 12 male runners who completed a half-marathon and found an increase in NT-pro-BNP concentrations 20 min and 2 hours post-race with concentrations above the URL at 120 min post-race only in female athletes [27]. Neilan et al. were able to show that females presented a post-race increase in NT-pro-BNP concentrations after a marathon more likely than males [15]. Our results correspond to these findings showing an immediate increase in NT-pro-BNP concentrations post-marathon. We also found that NT-pro-BNP concentrations were still elevated when measured on day one after the run which differs to the findings of Leers et al. [22]. BNP concentrations in our study showed a different response pattern than NT-pro-BNP. BNP did not increase immediately but did so on day one after the marathon; these findings correspond to the findings of Siegel et al. The authors found an increase in BNP concentrations 24 hours post race in 82 runners [22]. NTpro-BNP seems to display a longer lasting release which could be due to impaired renal function and different half-lives. BNP has a half-life of approximately 20 minutes; elimination is mainly done by endopeptidases. NT-pro-BNP presents a half-life of about 120 minutes; elimination is believed to happen mainly through the kidneys with a close correlation to the glomerular filtration rate [4]. A temporary impairment of the kidney function is known following strenuous exercise [25] and could lead to the accumulation of NTpro-BNP immediately after a marathon. To our knowledge, BNP and NT-pro-BNP concentrations have not previously been measured in series up until day three after a marathon. We were able to show that on day three B type natriuretic peptide concentrations had returned to pre-marathon levels. Cardiac peptides (BNP, NT-pro-BNP) are secreted from the cardiac ventricles as a response to volume overload and cardiac wall stretch. This is well known in patients with left ventricular dysfunction. Even though measured at different time points, the increase of both parameters following a marathon race could point towards transient myocardial dysfunction and be a sign of increased physiological demands [27]. ctnt, ctni Cardiac troponin testing is a new definitive laboratory standard for the diagnosis of myocardial damage [13,30]. In 50% of patients with myocardial infarction, ctnt concentrations are increased three to four hours after the onset of chest pain. The increase in ctnt after myocardial damage is known to be 100-fold. Therefore, ctnt is a very reliable marker in detecting even small necrosis areas. Two to three weeks after a major myocardial infarction ctnt can still be detected. Subacute or silent infarctions can be diagnosed one to two weeks after the cardiac event with a high reliability [11]. In our study, we found an exercise-induced increase in cardiac troponins ctnt and ctni immediately after the marathon. In some runners, markers increased to such an extent that they indicated minor myocardial damage or even exceeded cut-off values for acute myocardial infarction. These findings correspond to findings from previous studies [6,9,15,16]. It is still unclear whether this increase represents irreversible structural damage with necrosis of myocardial cells or is a physiological sign of reversible cardiac fatigue. As postulated by Scharhag, cellular leakage of cytoplasmatic free troponins across the myocytes membranes could be a reason for elevated levels of cardiac troponins [20]. Here, concentrations of elevated troponins caused by either necrosis or leakage could reach similar levels when considering that in infarction, a higher concentration of troponins could stem from a small necrosis area compared to a lower concentration of troponins coming from a larger area e.g. the whole heart in cellular leakage. Different molecular weights could explain the different kinetics of ctnt and ctni after the marathon. Increased ctni levels on day one differ from findings in other studies. Also, ctnt and ctni show different kinetics on day one when compared to each other. Even though we used the latest generation assays, another explanation for the different kinetics might be the specificity and sensitivity of these tests. Troponin I assays of various companies as well as different test versions within one company can measure very different fragments, therefore, especially in areas of minor myocardial damage, not cardiac infarction, larger discrepancies in results can emerge. In this study, we were able to show that parameters representing cardiac stress (NT-pro-BNP, BNP, ctnt, ctni) increased in healthy female runners after successful completion of a marathon. Considering the fact that an increasing number of female amateur athletes participate in such sports events, clinical staff should be aware of possible changes in cardiac markers and, together with the clinical picture, take them seriously. Treat the patient not the blood test is a case report about a highly trained athlete who presented elevated cardiac troponins with clinical symptoms following prolonged endurance exercise [29]. In this case, Whyte et al. describe the elevation as a physiological reaction and point out the difficulties the medical staff faces when dealing with highly trained athletes. They recommend that a diagnosis of myocardial injury should not be made based only on blood tests. Clinical symptoms, clinical history, experience and preparation, among others, should be taken into consideration when interpreting cardiac troponin values. Clin. Lab. 3+4/

6 WALTRAUD FRASSL et al. STUDY LIMITATIONS We could not obtain blood samples post-marathon from all subjects due to poor venous status. Therefore, we have results for N=11. Not all subjects came to the local laboratory to have their blood taken on day 1 and 3 (day 1: N=14, day 3: N=13). The number of runners in our study did not allow us to make correlations of the changes in cardiac markers with age, finishing times and experience. As we had only female runners participating in our study, we were not able to make comparisons between female and male athletes. CONCLUSIONS The major findings of this study were that parameters representing cardiac stress (NT-pro-BNP, BNP, ctnt, ctni) increased in healthy female runners after successful completion of a marathon. Cardiac peptides (BNP, NT-pro-BNP) showed a different response in regards to their kinetics. The changes in ctnt- and ctni concentrations at the measured time points did not correspond either. 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