Objectives Seventeen male participants (mean (SD) (range): age 33.5 (6.5) years (46–26 years), body mass 80 (9.2) kg (100–63 kg), height 1.81 (0.06) m (1.93– 1.70 m)) ran a marathon to investigate the relationship between systolic function (using cardiac magnetic resonance (CMR)) and diastolic function (using echocardiography) against biomarkers of cardiac damage.
Methods Echocardiographic and cardiac troponin I (cTnI)/N-terminal pro-B-type natriuretic peptide (NTproBNP) data were collected 24 h premarathon, immediately postmarathon and 6 h postmarathon. CMR data were collected 24 h premarathon and at 6 h postmarathon.
Results Body mass was significantly reduced postmarathon (80 (9.2) vs 78.8 (8.6) kg; p<0.001). There was a significant E/A reduction postmarathon (1.11 (0.34) vs 1.72 (0.44); p<0.05) that remained depressed 6 h postmarathon (1.49 (0.43); p<0.05). CMR demonstrated left ventricular end-diastolic and end-systolic volumes were reduced postmarathon, with a preserved stroke volume. Left ventricular ejection fraction 6 h postmarathon significantly increased (64.4% (4.2%) vs 67.4% (5%); p<0.05). There were significant elevations in cTnI (0.00 vs 0.04 (0.03) μg/l; p<0.05) and NTproBNP (37.4 (24.15) ng/l vs 59.34 (43.3) ng/l; p<0.05) immediately postmarathon. Eight runners had cTnI elevations immediately postmarathon above acute myocardial infarction cutoff levels (≥0.03 μg/l). No correlations between cTnI/NTproBNP and measures of diastolic function (E, A, E/A, isovolumic relaxation time, E deceleration time and E/E′) or measures of systolic function (stroke volume or ejection fraction) were observed immediately postmarathon or 6 h postmarathon.
Conclusions Biomarkers of cardiac damage after prolonged exercise are not associated with either systolic or diastolic functional measures.
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A large body of research has suggested that acute bouts of ultraendurance exercise result in a depression in insdices of global left ventricular (LV) diastolic and systolic function1 and the unrelated appearance of elevations in serum markers of cardiac myocyte damage2 often above acute myocardial infarction (AMI) cutoff levels. Despite such conclusions from recent meta-analyses, this is still a controversial research area3 with many aspects of these phenomenon equivocal, lacking data or poorly understood. Two specific issues underpin the focus of this study. First, the assessment of changes in LV systolic and diastolic function after prolonged exercise has, almost uniformly, been completed using echocardiography. The changes observed in measures such as ejection fraction (EF) are often small and the resolving limits of echocardiography have been questioned. Cardiac magnetic resonance (CMR) is the reference standard for the assessment of ventricular dimensions, function and mass in terms of accuracy and reproducibility. Measurements are highly accurate and no geometrical assumptions need to be made about the ventricle.4 5 A limited number of studies have examined cardiac function after prolonged exercise using CMR,6 7 and thus the current study will generate new and informative data.
The elevation of cardiac troponin I or T (cTnI/cTnT) after prolonged exercise is widely reported,2 8,–,13 and in a recent study, 78% of runners investigated after the completion of a competitive marathon presented evidence of minor cardiac damage.14 Despite this, few studies have assessed the relationship between raised cTn and a depression in cardiac function after prolonged exercise. George et al8 15 reported no correlation between postmarathon race changes in cTnT and depressed Doppler and tissue Doppler measures of LV diastolic function. Conversely, Rifai et al16 reported that triathletes with more abnormal wall segment motion, after completing an Ironman triathlon, had higher levels of cTnT than those athletes with fewer wall motion abnormalities. More recently, Neilan et al10 at the Boston Marathon linked the increase in biomarkers after marathon completion with postrace diastolic dysfunction, although several limitations have been considered.17 This specific issue remains controversial and requires the collection of more data.
Accordingly, this investigation aims to examine the relationship between cardiac structure and function, using gold standard measurements of systolic function (CMR) and diastolic function (echocardiography), against serum biomarkers of cardiac damage after the completion of a competitive marathon.
Following ethical approval from the Brompton, Harefield and NHLI research ethics committee, 17 recreational athletes provided written informed consent and volunteered to run a marathon (distance 42.2 km). Exclusion criteria included the presence of cardiopulmonary disease, including diagnosis and treatment for hypertension, angina, myocardial infarction and peripheral vascular diseases. Participants were asked not to run more than a total distance of 20 miles in the week leading up to the marathon, with no training in the immediate 3 days before the marathon. During the marathon, participants were permitted to consume food and fluid ad libitum. Maximum air temperature reached 10°C with approximately 40% humidity.
Echocardiographic, cTnI, N-terminal pro-B-type natriuretic peptide (NTproBNP) levels and CMR data were collected at an initial assessment approximately 24 h before marathon completion. After immediate completion of the marathon, only echocardiographic, cTnI and NTproBNP were collected. At 6 h postmarathon, CMR data were collected along with echocardiography, cTnI and NTproBNP.
A two-dimensional, M-mode, Doppler and tissue Doppler echocardiographic examination was performed in the left lateral decubitus position by a single experienced sonographer using a commercially available ultrasound system (Vivid 7; GE Medical, Horten, Norway). Echocardiographic data were collected 24 h premarathon, immediately postmarathon and 6 h postmarathon run. LV diastolic function was assessed using pulsed-wave Doppler recordings from apical four-chamber and three-chamber orientations. A 4-mm sample volume was placed at the tips of the mitral leaflets in diastole and transmitral flow was acquired to obtain peak early (E) and atrial (A) flow velocities. To assess isovolumic relaxation time (IVRT), the 4-mm pulsed wave sample was positioned between the LV inflow and outflow from an apical three-chamber orientation. Gain and filter settings were optimised to obtain best signal-to-noise ratio for all spectral Doppler flow recordings. All data were analysed offline using commercially available software (Echo-pac 6.0; GE Medical, Horten, Norway) and a minimum of three cardiac cycles were averaged for all indices. For the tissue Doppler assessment of E′, the apical four-chamber orientation was utilised and a 2-mm sample volume was positioned at the septal aspect of the mitral valve annulus ensuring the best alignment between wall motion and the ultrasound beam. The high-pass filter was bypassed and gains set to a minimal value to obtain the best signal-to-noise ratio. The Nyquist limit was set between 10 and 35 cm/s. Peak early diastolic (E′) tissue myocardial velocity was recorded and E/E′ was calculated.
Each participant had blood drawn from an antecubital vein for cTnI and NTproBNP at baseline, immediately postmarathon and 6 h postmarathon. This was allowed to clot, centrifuged and the serum drawn off and frozen (−20°C) for later analysis.
Cardiac troponin I
cTnI was determined using the TnI-Ultra assay for the ADVIA Centaur (Siemens Healthcare Diagnostics, Frimley, UK). The detection limit of the instrument was 0.006 μg/l, with upper limit of 50 μg/l. The claimed 10% coefficient of variation was 0.03 μg/l with a 99th centile of 0.04 μg/l. The total assay imprecision was 2.7–5.3% in the range 0.8–27.2 μg/l.
N-terminal pro-B-type natriuretic peptide
NTproBNP was determined using the Elecsys 2010 system (Roche Diagnostics, Burgess Hill, UK). The assay is an electrochemiluminescent sandwich immunoassay that uses two polyclonal antibodies directed at residues 1–21 and 39–50 of the NTproBNP molecule. The coefficient of variation of the assay is 3.2% to 2.4% from 20.7 to 585.5 pmol/l (175–4962 ng/l) with an analytical range of 0.6–4138.6 pmol/l (5–35 000 ng/l).
Cardiac magnetic resonance
CMR data were collected 24 h premarathon and 6 h postmarathon. Each scan was performed by the same operator on a 1.5-T Siemens Avanto scanner (Siemens, Erlangen, Germany) using a four-channel body array coil. After an initial scout images, cine imaging of the heart was performed using steady-state free precession breath-hold cines (echo time/repetition time 1.6/3.2 ms, flip angle 60°) in long-axis planes and sequential 7-mm short-axis slices (3-mm gap) from the atrioventricular ring to the apex. Ventricular volumes, function and mass were quantified using customised analysis software (CMRtools, Imperial College, London, UK) by a blinded single experienced investigator. Papillary muscles were included in the mass and excluded from the volume. Wall motion was analysed based on the 16-segment American Heart Association/American College of Cardiology model.18 CMR right ventricular (RV) measurement was performed using a standard internationally accepted protocol tracing endocardial segments in diastole and systole for all short-axis slices from base to apex and performing an accurate Simpsons method summing of discs without any geometrical assumptions.
All values were presented as means (SD). Premarathon, postmarathon and 6-h postmarathon differences in body mass (BM), heart rate (HR) and LV diastolic functional measures (echocardiography) and LV systolic functional measures (CMR) were analysed using repeated-measures analysis of variance, with Bonferroni post hoc test. Relationships between data indices of echocardiographic and CMR measures of LV diastolic and systolic function against serum biomarkers of cardiac damage were examined via Pearson's product–moment correlation analysis. The critical α level was set at 0.05 and all analyses were carried out on SPSS V.16.0 software (SPSS, Chicago, Illinois, USA).
The participants included 17 men (mean (SD) (range): age 33.5 (6.5) years (46–26 years), BM 80 (9.2) kg (100–63 kg) and height 1.81 (0.06) m (1.93–1.70 m)). All 17 runners returned for postmarathon evaluation having successfully completed the study protocol (209 (19) min; range, 171–240 min). The average time of 209 min for the protocol completion would have placed the participants in the top 17% (total runners; 23 680) from the 2008 London Marathon. Postmarathon testing commenced within 15 min of marathon completion in all participants. BM was significantly reduced postmarathon (80 (9.2) vs 78.8 (8.6) kg, p<0.001). HR was significantly increased postmarathon (57 (8) vs 80 (12) beats/min; p<0.001) and remained significantly elevated 6 h postmarathon (68 (11) beats/min; p<0.001).
Left ventricular internal diameter during diastole was mildly but significantly reduced postmarathon (54 (1) vs 53 (1) mm, p<0.001). The mitral E wave was not reduced postmarathon, whereas A wave increased significantly postmarathon, remaining significantly elevated 6 h postmarathon. This resulted in a significant E/A reduction postmarathon (1.11 (0.34) vs 1.72 (0.44); p<0.05) that remained depressed 6 h postmarathon (1.49 (0.43); p<0.05). IVRT was not significantly increased immediately postmarathon but became significantly reduced 6 h postmarathon (76 (5) vs 66 (4); p<0.008). E deceleration time and E/E′ were not significantly different immediately postmarathon or 6 h postmarathon (table 1). No correlations were observed between BM and LV internal diameter during diastole and measures of diastolic function (E/A, IVRT, E deceleration time and E/E′).
CMR systolic function
The LV end-diastolic and end-systolic volumes were reduced postmarathon but the stroke volume was preserved (135.4 (20.7) vs 135.5 (21.8) ml, p=1.000) and a corresponding small increase in LV EF 6 h postmarathon reached significance (64.4% (4.2%) vs 67.4% (5%); p<0.05). No significant difference in the RV volumes, RV stroke volume (SV) or RV EF was seen postmarathon (table 2).
There were significant elevations in cTnI and NTproBNP immediately postmarathon, which remained significantly elevated 6 h postmarathon (table 3). There were no correlations between elevations in cTnI and NTproBNP premarathon (r=0.186, p=0.475), postmarathon (r=0.281, p=0.274) and 6 h postmarathon (r=0.148, p=0.570). Eight participants were found to have cTnI elevations immediately postmarathon (table 4) above the cutoff level for AMI (≥0.03 μg/l), which in turn gave a large SD. cTnI was further elevated at 6 h postmarathon in 11 of the 17 runners in this study, whereas NTproBNP remained significantly elevated above baseline values but was falling at 6 h postmarathon.
Relationships between blood markers and LV function
There were no significant correlations between cardiac biomarkers (cTnI and NTproBNP) and measures of diastolic function (E, A, E/A, IVRT, E deceleration time and E/E′) immediately postmarathon or 6 h postmarathon. This included immediate postmarathon diastolic function against 6-h postmarathon cTnI and NTproBNP results, and immediate postmarathon cTnI and NTproBNP results against 6-h postmarathon diastolic function (E, A, E/A, IVRT, E deceleration time and E/E′). Finally, there were no significant correlations between biomarkers of cardiac damage (cTnI and NTproBNP) and measures of CMR systolic function (SV or EF) postmarathon or 6 h postmarathon.
The present investigation observed a significant reduction in LV diastolic function (E/A ratio) immediately after a marathon run that remained depressed 6 h postexercise. Data indices of systolic function using gold standard assessment, namely, CMR, demonstrated a significant increase in EF 6 h postmarathon. A concomitant but unrelated elevation in cardiac biomarkers (cTnI and NTproBNP) was observed immediately postmarathon that remained elevated or increased further after 6 h of recovery.
The release of cardiac troponins (cTnT and cTnI) after prolonged exercise has been extensively documented.2 12,–,14 The high prevalence of cTnI and NTproBNP in the current cohort is consistent with previous marathon studies.8 10 11 The relationship between cardiac biomarkers, systolic and diastolic function after prolonged exercise has been an area of controversy in the literature. A large number of studies have reported a lack of association between troponin release and diastolic functional changes, suggesting that they are distinctly separate phenomena.19 Our data concur with these studies demonstrating no significant relationship between cTnI and NTproBNP and measures of diastolic function (E, A, E/A, IVRT, E deceleration time and E/E′) postmarathon or 6 h postmarathon. These data support the hypothesis that alterations in cardiac function and the presence of cardiac biomarkers are unrelated.
Most of the previous papers have examined cardiac biomarkers immediately postexercise and/or 24 h postexercise. Our time course findings of cTnI immediately after a marathon contrasts research by Middleton et al9 who documented a significant elevation in cTnT immediately postmarathon, which remained significantly elevated 6 h postmarathon (please note Middleton et al measured cTnT and not cTnI as within the present investigation) (see table 2). Middleton et al reported that during a marathon, between 60 and 120 min, cTnT increased in all participants. However, at race completion, or within 1 h of marathon completion, cTnT had returned to baseline values in all subjects. All but one subject showed a further release of cTnT within the 24-h recovery period, with five of these subjects having an elevated cTnT 24 h after exercise.9 The reasons for the absence of cTnT at marathon completion in the study of Middleton et al are unclear; however, these contrasts with findings in most previous studies.
In light of the continued rise of cTnI at 6 h postmarathon in the present study, in addition to examining concomitant time points for cardiac biomarkers and LV diastolic function, we examined the relationship between cTnI measured 6 h postexercise with LV diastolic function immediately postexercise. The rationale for this interrogation was the potential that a delayed release of cardiac troponin may be associated with alterations in LV diastolic function. Our data suggest no relationship between cTnI and LV diastolic function at these time points therefore offering further support of a separate aetiology for these two phenomena.
The aetiology and clinical significance of postexercise troponin release is yet to be elucidated.20 Shave et al2 suggested that postexercise release of troponin may represent either necrosis of cardiac myocytes leading to irreversible damage or may be a transient and reversible change in membrane permeability of the myocyte. The mechanisms for troponin release may come from the unbound pool found in the cardiomyocyte cytoplasm and may reflect a physiologic as opposed to a pathologic process.21 Importantly, our data demonstrated no correlation between peak troponin and NTproBNP release against diastolic function immediately postmarathon or 6 h postmarathon. It appears unlikely that the minor elevations in biomarkers of cardiac damage observed a prolonged endurance exercise indicate myocardial necrosis of sufficient magnitude to cause LV dysfunction. It is tempting to suggest that elevated cardiac troponins represent reversible cardiomyocyte membrane damage that may reflect part of a remodelling process; however, further study is required to elucidate the mechanism(s).9
Limited evidence for the relationship between cTnI and NTproBNP exists within the literature. Elevated concentrations of NTproBNP reflect elevated myocardial wall stress due to volume or pressure overload, usually observed within cardiac disease states. Our data corroborate that of Scharhag et al22 whereby no correlation was observed between cTnI and NTproBNP after an acute bout of prolonged exercise. Differing from our data, Scharhag et al observed a relationship between NTproBNP and exercise time (r=0.50, p<0.001). The authors postulated that the release of NTproBNP after prolonged exercise may not result from cardiac damage but may have a cytoprotective and growth-regulating effect. Membrane damage, subsequent to an increased rate and force of cardiac contraction during endurance exercise, may provide a mechanism by which cytosolic troponin is released into the circulation.2 However, although NTproBNP was significantly elevated postmarathon, indicating increased wall stress, it was not correlated with cTnI, suggesting that another mechanism for troponin release should be considered. Few studies have examined NTproBNP release and diastolic function after prolonged endurance exercise. Neilan et al10 document a significant relationship between NTproBNP and diastolic dysfunction after the Boston Marathon, although several limitations have been considered.17
Interestingly, E/E′ was not significantly different immediately postmarathon or 6 h postmarathon (table 1). Assuming time-dependent inhibition to be less dependent on load, the fact that both E and E′ stayed the same is surprising as both should increase with an elevated HR. The lack of rise in both could reflect a “real” depression in both due to preload drop (although minor) or an alteration in relaxation and compliance.
To our knowledge, no studies have used the gold standard technique of assessing systolic function, namely, CMR, together with standard assessment of diastolic function after a competitive marathon. A significant elevation in CMR EF (68.3% (16.7%) vs 71.4% (16.4%), p<0.05) was observed between premarathon and 6 h postmarathon, together with a preserved SV premarathon and 6 h postmarathon (131.9 (26.9) vs 131.9 (27.01) ml, p=1.000). Our CMR EF result is in contrast to that from numerous authors who have documented a reduction in EF after prolonged endurance exercise1 23 24 or a maintenance11 23 observed through standard echocardiography alone. The increase in EF 6 h postmarathon is due to a significantly reduced LV dimension. To maintain SV (which was observed), EF must increase accordingly. Whether the elevation in EF 6 h postmarathon is a systolic rebound or overloading performance issue remains to be confirmed.
Future studies should consider using T2-weighted images to investigate the potential for focal and global myocardial inflammation and oedema after endurance exercise. Furthermore, the examination of lifelong, veteran endurance athletes using late gadolinium enhancement may elucidate the impact of repeated episodes of elevated cardiac troponins in this population.
This investigation found that cTnI and NTproBNP were significantly elevated immediately postmarathon completion. cTnI was further elevated at 6 h postmarathon in 11 of the 17 runners in this study, whereas NTproBNP remained significantly elevated above baseline values but was falling at 6 h postmarathon. Evidence from the present investigation found that biomarkers of myocardial cell damage after an acute bout of prolonged exercise are not associated with either systolic or diastolic functional measures using either gold standard techniques of CMR or echocardiography, respectively.
What is already known about the topic
Acute bouts of ultraendurance exercise result in a depression in indices of global LV diastolic and systolic function and the unrelated appearance of elevations in serum markers of cardiac myocyte damage. Despite such conclusions, this is still a controversial research area, with many aspects of lacking data.
What this study adds
Biomarkers of myocardial damage after an acute bout of prolonged exercise are not associated with either systolic or diastolic functional measures using either “gold standard” techniques of CMR or echocardiography, respectively.
Competing interests None.
Ethical approval Brompton, Harefield and NHLI research ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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