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Clinica Chimica Acta 367 (2006) 175 – 180
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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-
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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
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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].
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