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Clinica Chimica Acta 367 (2006) 175 – 180 www.elsevier.com/locate/clinchim Short communication Influence of physical exercise and relationship with biochemical variables of NT-pro-brain natriuretic peptide and ischemia modified albumin Giuseppe Lippi a,*, Gian Luca Salvagno a, Martina Montagnana a, Federico Schena b, Filippo Ballestrieri b, Gian Cesare Guidi a a Istituto di Chimica e Microscopia Clinica, Dipartimento di Scienze Morfologico-Biomediche, Università degli Studi di Verona, Ospedale Policlinico G.B. Rossi, Piazzale Scuro, 10 37134-Verona, Italy b Centro Interuniversitario di Ricerca in Bioingegneria e Scienze Motorie, Rovereto (TN), Italy Received 18 October 2005; received in revised form 17 November 2005; accepted 17 November 2005 Available online 4 January 2006 Abstract Background: The diagnostic approach and the clinical management of patients presenting with suspected acute coronary syndrome or cardiac dysfunction are as yet challenging. Although ischemia modified albumin (IMA) and natriuretic peptides were recently proposed for detection of myocardial ischemia and cardiac dysfunction, little information is available on preanalytical and metabolic sources of variability of these markers. Methods: To establish the influence of a regular endurance training and the relationship with conventional biochemical variables, NT-probrain natriuretic peptide (NT-proBNP) and IMA were assayed, along with cardiac troponin T (cTnT), lactate dehydrogenase (LDH), creatine kinase (CK), creatinine and albumin, in 35 sedentary healthy individuals and 50 male professional road cyclists, 12 – 24 h following the last demanding training session. Results: Athletes displayed higher values of both LDH (299 T 61 vs. 257 T 36 U/l, P = 0.002) and CK (184 T 123 vs. 115 T 74 U/l, P = 0.011), and slightly lower concentrations of creatinine (82 T 12 vs. 87 T 9 Amol/l, P = 0.044). No athlete or sedentary control displayed cTnT concentrations exceeding the lower sensitivity limit of the assay. As compared to the sedentary controls, main IMA concentration was increased in athletes (100 T 13 vs. 94 T 6 KU/l, P = 0.035), whereas that of NT-proBNP appeared significantly decreased (2.8 T 1.6 vs. 4.3 T 34, P = 0.005). The percentage of subjects displaying values exceeding the upper reference limit for the IMA assay was significantly different between athletes and sedentary controls (50% vs. 7%; P < 0.001). Pearson correlation analysis revealed an inverse association between IMA and albumin in both athletes (r = 0.640; P < 0.001) and sedentary controls (r = 0.583; P = 0.001). Conclusions: Results of our investigation indicate that a demanding and regular aerobic training regimen, though able to trigger skeletal muscle sufferance, is not associated with any biochemical sign of severe and irreversible chronic cardiac involvement. Moreover, we suggest the adoption of specific IMA diagnostic thresholds following patients’ stratification according to serum albumin concentration and physical activity. D 2005 Elsevier B.V. All rights reserved. Keywords: Heart failure; Acute coronary syndrome; Physical exercise; Sport; Ischemia modified albumin; Natriuretic peptides 1. Introduction The diagnostic approach and the clinical management of patients presenting with acute coronary syndrome and * Corresponding author. Tel.: +39 045 8074516; fax: +39 045 8201889. E-mail address: [email protected] (G. Lippi). 0009-8981/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2005.11.018 cardiac dysfunction are as yet challenging [1]. Over the past decades, several biomarkers were proposed to identify patients with true myocardial ischemia and risk stratification of heart failure. The ischemia modified albumin (IMA) [2] and the natriuretic peptides [3] were recently proposed as reliable markers for early detection of myocardial ischemia and cardiac dysfunction, respectively. During ischemia, the generation of reactive oxygen species influences the metal- 176 G. Lippi et al. / Clinica Chimica Acta 367 (2006) 175 – 180 binding capacity of albumin for transition metals, like cobalt. It has been recently hypothesized that IMA generation in vivo might be interpreted as an efficient endogenous signal or mechanism of response to ischemia, preventing myocardial damage or limiting the burden of myocyte necrosis [4]. On this premise, any IMA increase could be interpreted as an indicator of ischemia prior to necrosis, displaying a remarkable negative predictive value at the specific diagnostic threshold [5]. Following evidences of an endocrine function for the heart, cardiac hormones and natriuretic peptides were discovered nearby 25 years ago [6]. Although the brain natriuretic peptide (BNP) was initially identified in porcine brain, myocardium was recognized thereafter as a primary site of synthesis and production, allowing modification of its original denomination to B-type natriuretic peptide. BNP is a neurohormone synthesized as a preliminary 134-amino acid polypeptide (preproBNP) in the heart ventricles, which is cleaved to produce the 108-amino-acids-long proBNP and an N-terminal signal peptide. ProBNP is further cleaved to the inactive 76-amino-acid N-terminal proBNP (NT-proBNP) fragment and the biologically active counterpart [7]. Mechanic and neurohumoral stimulation of the heart, along with ventricular myocyte stretch in response to ventricular volume expansion, appear so far the leading causes for equimolar increase of both BNP and NT-proBNP levels in plasma [8]. Although the mechanisms involved in clearance of natriuretic peptides are not fully comprehended, main catabolism seems to occur primarily by glomerular filtration, specific receptorial pathways, and degradation by neutral endopeptidases. Elimination half-life of BNP and NT-proBNP are 18 and 90– 120 min, respectively [7]. As plasma BNP correlates with hemodynamic, measurement of both BNP and NTproBNP has been proposed to identify patients with heart failure, guide the therapy and monitor treatment effectiveness [9]. It has been reported that the levels of natriuretic peptides in plasma may vary as a function of some demographic and clinical variables, chiefly race, age, sex and renal function. Therefore, identification and application of accurate and specific thresholds appears pivotal to achieve profitable clinical information in the acute care setting [10]. Although BNP kinetics during dynamic exercise in patients with chronic heart failure has been extensively investigated [11 – 14], and natriuretic peptides have been proposed to identify exercise-induced elevation of filling pressures in patients with diastolic heart failure [15], there is little information on the influence of a regular aerobic training on NT-proBNP. This latter aspect is clinically meaningful, as a strenuous endurance exercise might generate transitory ischemia, diastolic left ventricular dysfunction and trigger life-threatening cardiovascular complications not present at rest [16,17]. Additionally, the high cardiac workload in professional trained athletes might hypothetically influence IMA generation and cardiac release of NT-proBNP, requiring adoption of reliable and specific reference ranges in such a peculiar context [18]. 2. Materials and methods To establish the influence of a regular endurance training on cardiovascular function, cardiac troponin T (cTnT), NTproBNP and IMA, along with lactate dehydrogenase (LDH), creatine kinase (CK), creatinine and albumin, were evaluated in 50 consecutive male professional road cyclists and further compared with 35 consecutive sedentary healthy individuals, matched for age and sex. Athletes reached our center in the middle of the competitive season, during a regular, highworkload period of aerobic training. All subjects recruited to the study gave a preliminary informed consent for being tested and were in a fasted state and athletes had rested for a period of 12– 24 h since the last demanding training session or competition. Blood was collected in the morning in vacuum tubes containing no additives (Becton-Dickinson, Oxford, UK). After centrifugation at 1500g for 10 min at room temperature, serum was separated, stored in aliquots and kept frozen at 70 -C until measurement. cTnT and NTproBNP were assayed on Elecsys 2010 (Roche Diagnostics GmbH, Mannheim, Germany), whereas IMA, determined by a colorimetric assay (ACB, Ischemia Technologies, Denver, USA), LDH, CK, creatinine and albumin were measured on the Modular System P (Roche Diagnostics GmbH), employing proprietary reagents. The upper reference limit for the IMA assay for this study was established at 100 KU/l, as established in a previous evaluation [18]. Results of measurements and relative distribution of values were compared by Student’s t-test and chi-square analysis. The level of statistical significance was set at p < 0.05. Pearson correlation analysis was used to quantify the degree of association between variables from the population studied. 3. Results Main results of this study are synthesized in Table 1 (values are expressed as mean T standard deviation). As Table 1 Mean values and standard deviations of serum creatinine, albumin, lactate dehydrogenase (LDH), creatine kinase (CK), cardiac troponin T, ischemia modified albumin (IMA) and NT-pro-brain natriuretic peptide (NTproBNP) in professional road cyclists compared to matched sedentary healthy controls N Age Training regimen (h/day) Creatinine (mg/dl) Albumin (g/l) LDH (U/l) CK (U/l) cTnT (ng/ml) IMA (KU/l) NT-proBNP (pmol/l) Sedentary controls Professional road cyclists 35 29.3 T 2.6 0.05 T 0.02 0.87 T 0.09 46.6 T 2.4 257 T 36 115 T 74 <0.01 94 T 6 4.3 T 34 50 28.9 T 2.9 2.95 T 0.82 0.82 T 0.12 46.1 T 3.8 299 T 61 184 T 123 <0.01 100 T 13 2.8 T 1.6 Differences are evaluated by Student’s t-test. P 0.580 <0.001 0.044 0.078 0.002 0.011 – 0.035 0.005 G. Lippi et al. / Clinica Chimica Acta 367 (2006) 175 – 180 Table 2 Pearson correlation analysis between ischemia modified albumin (IMA), NT-pro-brain natriuretic peptide (NT-proBNP) and serum creatinine, albumin, lactate dehydrogenase (LDH), creatine kinase (CK), evaluated in professional road cyclists and matched sedentary healthy controls Sedentary controls Professional road cyclists r NT-proBNP vs. IMA NT-proBNP vs. CK NT-proBNP vs. LDH NT-proBNP vs. albumin NT-proBNP vs. creatinine IMA vs. CK IMA vs. LDH IMA vs. albumin IMA vs. creatinine P 0.023 0.061 0.207 0.158 0.175 0.038 0.114 0.583 0.051 0.908 0.762 0.301 0.430 0.383 0.852 0.571 0.001 0.800 r P 0.077 0.006 0.066 0.049 0.074 0.161 0.176 0.640 0.249 0.593 0.967 0.649 0.735 0.610 0.263 0.221 <0.001 0.081 r = correlation coefficient. expected, following the high workload aerobic training, athletes displayed higher values of both CK and LDH. Mean value of serum albumin was nonstatistically different between athletes and sedentary controls, whereas that of serum creatinine was significantly lower in athletes. The concentration of cTnT was always below the lower sensitivity limit of the assay in both athletes and controls. Main IMA concentration was significantly increased in athletes, whereas that of NT-proBNP appeared significantly decreased. In multiple linear regression analysis, higher LDH ( P = 0.003) and decreased NT-proBNP ( p = 0.047) values were the only biochemical covariables that significantly discriminated professional athletes from sedentary controls. The percentage of subjects displaying IMA values exceeding our upper reference limit (100 KU/l) was significantly different between athletes and controls (50% vs. 7%; P < 0.001). No athlete or sedentary control exhibited values exceeding the age- and sex-specific NT-proBNP diagnostic threshold recommended by the manufacturer (> 14.8 pmol/l). Pearson correlation analysis between the biochemical variables tested is shown in Table 2. Beside an inverse association between IMA and albumin in both athletes (r = 0.640; P < 0.001) and sedentary controls (r = 0.583; P = 0.001), no additional significant correlation could be observed. After stratifying the population according to the albumin threshold of 46 g/l, mean IMA concentrations below or above this arbitrary threshold appeared significantly different in both sedentary controls (99 T 4 vs. 91 T 4 KU/l; P < 0.001) and professional athletes (106 T 14 vs. 93 T 8 KU/l; p < 0.001). 4. Discussion Although acute coronary syndrome and heart failure are the most frequent pathologies in western countries, diagnostic approach and differential diagnosis are as yet challenging [1]. Identification of preanalytical sources of variability is essential to avoid pitfalls in laboratory testing and becomes 177 pivotal for the management of patients in the acute care setting, admitted with suspected cardiac pathologies. It was earlier determined that the adoption of sex-, race- and agerelated reference limits is essential for clinical interpretation of results of natriuretic peptides measurement, and relative thresholds should be selected according to these demographic variables. Moreover, as renal failure is a potential cause of elevated BNP and NT-proBNP, even in the absence of left ventricular dysfunction, diagnostic thresholds of these markers should be preferably stratified according to renal function [19]. As for the natriuretic peptides, selection of accurate IMA diagnostic thresholds influences the efficient diagnosis of myocardial ischemia and prediction of cardiac outcomes [20]. Peculiarly, results of IMA measurements should be interpreted considering preanalytical sources of variations, such as the physical activity [18]. To our knowledge, this is the first study attempting to establish whether a regular and demanding aerobic physical exercise in highly trained athletes may influence baseline NT-proBNP serum concentrations, as earlier investigations focalized mainly on healthy untrained individuals or patients with established heart failure. IMA and NT-proBNP levels were additionally related to conventional biochemical parameters, which are supposed to mirror renal (creatinine), liver (albumin) and muscle (CK, LDH) function. In agreement with previous investigations, we confirm that IMA generation might be slightly increased 12 – 24 h following a demanding physical exercise, in a percentage up to 50% of athletes subjected to a regular and demanding aerobic training (Fig. 1). Nevertheless, such an increase is on overall moderate, as most of these values are still comprised within the interval 100 –115 KU/l. No significant association could be observed between IMA and conventional markers of muscular injury (Table 2). Therefore, increased IMA generation appears more justifiable with a transitory ischemic condition of the skeletal muscle during a vigorous training regimen, rather than with irreversible muscular damage or necrosis. Unfortunately, we cannot provide data on exercise ECG testing, dobutamine stress echography or scintigraphy. Therefore, although unmeasurable concentrations of cTnT at 24 – 48 h postexercise rule out irreversible myocardial injury as the primary cause of increased IMA generation in athletes, the possibility of a reversible cardiac ischemia cannot be definitively excluded. Owing to heterogeneity in study design, clinical setting and timing of blood sampling after exercise, controversial observations emerged from IMA measurement in athletes [21 –23]. Some previous investigations already showed a characteristic biphasic IMA response to strenuous exercise. In the first-period postexercise, there is a transient reduction, which has been primarily related to increased lactate generation and hemoconcentration. It has been demonstrated that increased lactate in the specimen generates an analytical interference on ACB testing; in particular, as lactate concentrations increased, IMA values decreased [22]. Accordingly, hemoconcentration increases several plasma 178 G. Lippi et al. / Clinica Chimica Acta 367 (2006) 175 – 180 NT-proBNP (pmol/L) 15 10 5 0 Sedentary controls Pro cyclists Sedentary controls Pro cyclists 150 IMA (Kunits/L) 140 130 120 110 100 90 80 Fig. 1. NT-pro-brain natriuretic peptide (NT-proBNP) and ischemia modified albumin (IMA) values distribution in sedentary healthy controls and professional road cyclists. The central horizontal line indicates the mean value. proteins, including albumin, and changes in albumin within the physiologic range produce an opposite change of IMA values. As the ACB test quantifies the nonbound portion of a fixed amount of cobalt added to albumin, acute postexercise albumin reduction might be responsible for lower IMA measurable values [24]. The acute and transient IMA reduction is followed by a 24 – 48-h gradual increase postexercise, which likely results from either gastrointestinal or skeletal muscle ischemia [21]. Accordingly, it was recently observed that only acute and severe ischemic triggers might be capable to impair significantly IMA metabolism in patients with chronic peripheral vascular disease, thus impairing the ability of this marker to detect myocardial ischemia [23]. Additionally, owing to the significant inverse association with serum albumin in both athletes and controls, we suggest that IMA measurement should be interpreted with caution and appropriate or specific diagnostic thresholds should be adopted after patients’ stratification according to preanalytical variables, such as physical activity and serum albumin. Mechanic and neurohumoral stimulation of the heart, along with ventricular myocyte stretch in response to ventricular volume expansion, appear so far the main causes for equimolar increase of both BNP and NT-proBNP levels in plasma [25]. In a recent investigation, Kragelund et al. identified NT-proBNP as a marker of increased risk of left ventricular systolic dysfunction in patients with stable coronary artery disease [26]. Exercise-induced ischemia, or its associated regional wall-motion abnormalities, trigger the release of natriuretic peptides; measurement of plasma levels of both NT-proBNP and BNP before and immediately after symptom-limited exercise can help to distinguish patients with and without ischemia of cardiac origin with a high degree of accuracy [27]. There is as yet controversy on the potential onset of myocardial damage and diastolic left ventricular dysfunction following strenuous endurance exercise. Acute and significant postexercise increase of natriuretic peptides was observed in healthy men immediately after a marathon running [28,29], in highly trained male professional road cyclists, following one stage of a 5day professional cycling race [16] and in healthy males during bicycle exercise [30]. Accordingly, Huang et al. evaluated BNP concentration in healthy young adults at baseline and immediately, 1 h, 4 h, 24 h, and 48 h after a treadmill exercise, demonstrating that circulating BNP increases immediately after exercise, but returns to the baseline concentration 1 h thereafter [31]. However, these observations were recently disputed in recent studies involving healthy subjects performing a maximal aerobic exercise test [12] and in a heterogeneous group of welltrained healthy male endurance athletes at rest [32]. At variance with some earlier investigations, measurements were performed in a large and homogenous subset of professional top class athletes, who have rested 12– 24 h since the last competition or demanding training session, demonstrating that NT-proBNP concentrations are slightly lower when compared to a sedentary untrained population. Although these results are partially in agreement with those of Scharhag et al., the difference in NT-proBNP values reached a marginal statistical significance as a probable consequence of the greater number and the more homogenous training profile of the endurance athletes enrolled in our study. This finding is also consistent with a short halflife in plasma which, along with undetectable cTnT levels and increased CK, LDH and IMA concentrations, suggests that prolonged and vigorous endurance exercise in welltrained and apparently healthy subjects might produce skeletal muscle ischemia and injury, but it is not likely to generate irreversible or stable cardiac damage or dysfunction. Yet, we cannot provide a definitive explanation for the trend towards lower NT-proBNP values observed in trained athletes. Despite the fact that we failed to identify a significant association between serum creatinine and NTproBNP in both athletes and controls, natriuretic peptides are mainly cleared by glomerular filtration and these markers are elevated in patients with renal failure. However, unlike BNP, NT-proBNP is not cleaved by neutral endopeptidase and might be more dependent on clearance via the clearance receptor, which is located mainly in the kidney. As was earlier demonstrated that professional trained athletes display a trend towards lower serum creatinine values [33], a finding that we further confirmed in the present investi- G. Lippi et al. / Clinica Chimica Acta 367 (2006) 175 – 180 gation, we cannot rule out that lower NT-proBNP values in professional athletes might reflect a more efficient mechanism of renal clearance rather than an improved cardiac function. This is consistent with the evidence that no athlete or sedentary control displayed NT-proBNP values exceeding the age- and sex-specific upper reference limit of the assay, providing a reliable explanation for the discrepancies observed with previous investigations, especially those that have measured BNP instead of NT-proBNP. NT-proBNP is established as a reliable diagnostic and prognostic marker in patients with suspected heart failure. Chronic elevations of natriuretic peptides are a useful biochemical tool to identify and monitor cardiac dysfunction. It has been earlier suggested that a vigorous physical activity might elicit cardiovascular complications not present at rest, mainly due to haemodynamic and electrophysiological changes brought about by exercise in the susceptible individual [17]. In agreement with earlier investigations, we provide evidence that a demanding and regular aerobic training regimen, though able to trigger some apparent skeletal muscle injury, is not associated with any biochemical sign of severe and irreversible chronic cardiac involvement and NT-proBNP may be a useful tool to discriminate between physiological and pathological cardiac remodeling in well-trained endurance athletes [31,32]. References [1] Plebani M. Biochemical markers of cardiac damage: from efficiency to effectiveness. Clin Chim Acta 2001;311:3 – 7. [2] Roy D, Quiles J, Aldama G, et al. Ischemia modified albumin for the assessment of patients presenting to the emergency department with acute chest pain but normal or non-diagnostic 12-lead electrocardiograms and negative cardiac troponin T. Int J Cardiol 2004; 97:297 – 301. [3] Morimoto T, Hayashino Y, Shimbo T, Izumi T, Fukui T. Is B-type natriuretic peptide guided heart failure management cost-effective? 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