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Exp Physiol 91.3 pp 511–519

Experimental Physiology

Novel application of flow propagation velocity and ischaemia-modified albumin in analysis of postexercise cardiac function in man Natalie Middleton1 , Rob Shave1 , Keith George2 , Gregory Whyte3 , Jan Forster4 , David Oxborough4 , David Gaze5 and Paul Collinson5 1

Centre for Sports Medicine and Human Performance, Brunel University, London, UK Research Institute for Sport and Exercise Science, John Moores University, Liverpool, UK 3 English Institute of Sport, Bisham Abbey, Marlow, UK 4 Leeds General Infirmary, Leeds, UK 5 Chemical Pathology, St George’s Healthcare NHS Trust, London, UK 2

The present study employed novel echocardiographic tools and cardiac markers to obtain a greater understanding of the aetiology and time course of altered cardiac function and cardiac damage following prolonged exercise and, in particular, the possible role of transient ischaemia within these phenomena. Fourteen runners in the 2004 London Marathon were assessed pre-, immediately post-, 1 h post- and 24 h postcompletion of the race. Left ventricular function was examined echocardiographically using 2-D, M-mode, tissue Doppler imaging and flow propagation velocity (V p ). Venous blood samples were analysed for N-terminal pro-B-type natriuretic peptide (proBNP), cardiac troponin T (cTnT) and ischaemia-modified albumin (IMA). Left ventricular (LV) diastolic filling was altered on completion of the race, as indicated by significant decreases in mean early to late diastolic myocardial wave (E :A ) ratio and V p (from 1.82 ± 0.9 to 1.32 ± 0.32, and from 67.5 ± 9.3 to 60.2 ± 8.2 cm s−1 , respectively, P < 0.05), accompanied by an increase in proBNP (from 21.6 ± 11 to 47.08 ± 19.5 pg l−1 , P < 0.05). The observed reduction in LV diastolic filling following completion of a marathon, unrelated to changes in heart rate or loading parameters, indicates an intrinsically mediated change in diastolic filling. Exercise-induced elevations in cTnT in nine individuals (range, 0.023–0.37 μg l−1 ) were indicative of minor cardiac damage. A significant reduction in IMA was observed after the marathon (from 63.68 ± 9.83 to 44.94 ± 16.13 Um l−1 , P < 0.05), unrelated to the alterations in cardiac function, proBNP or cTnT. The absence of an elevation in IMA suggests that exerciseinduced myocardial ischaemia did not occur and therefore could not explain the changes in cardiac function or biomarkers. Future studies in this area should investigate alternative diagnostic tools for the detection of transient ischaemia, and other potential mechanisms, in order to extend the understanding of this phenomenon. (Received 19 October 2005; accepted after revision 13 January 2006; first published online 23 January 2006) Corresponding author N. Middleton: Brunel University, Uxbridge, Middlesex UB8 3PH, UK. Email: [email protected]

Evidence of a reduction in left ventricular (LV) function (Ketelhut et al. 1992; Whyte et al. 2000; Shave et al. 2002, 2004; George et al. 2004) and an elevation in biochemical cardiac markers indicative of cardiac damage (Rifai et al. 1999; Apple et al. 2002; Shave et al. 2004; George et al. 2004) following prolonged exercise is well documented. The time course of these exercise-induced cardiac perturbations C 2006 The Authors. Journal compilation C 2006 The Physiological Society

appears to be transient, with any changes in LV function or elevation in cardiac markers returning to baseline within 24–48 h of exercise cessation (Whyte et al. 2000; Shave et al. 2002). Marathon running has emerged as a reliable and convenient model to further the examination of exerciseinduced cardiac damage and alterations in LV function DOI: 10.1113/expphysiol.2005.032631

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N. Middleton and others

(Manier et al. 1991; Lucia et al. 1999; George et al. 2004, 2005; Whyte et al. 2005), with widespread participation in this event across the general population. Previous authors examining marathon running have typically been restricted to basic and load-dependent echocardiographic techniques in the assessment of LV function; only recently have more sophisticated techniques been employed (George et al. 2005; Whyte et al. 2005). Although valuable, these findings did not include any tissue Doppler imaging data regarding LV systolic function. Furthermore, the recovery time course of postmarathon alterations in LV diastolic function using this technique was not examined (George et al. 2005; Whyte et al. 2005). The integration of novel and relatively load-independent applications, such as tissue Doppler imaging and flow propagation velocity (V p ), may overcome some of the limitations associated with the standard techniques previously employed (Garcia et al. 1998). Additionally, the advanced assessment of LV function 24 h following exercise cessation, previously only measured with standard techniques, will provide unique information regarding the time course of exercise-induced alterations in function. In conjunction with LV function assessment, measurement of cardiac biomarkers, including Nterminal pro-B-type natriuretic peptide (proBNP), is routinely employed in the clinical field to assist in the diagnosis and risk stratification of cardiac dysfunction (McCullough et al. 2003; Mak et al. 2004). To date, there has been limited effort to replicate this combined strategy in the examination of LV function within an exercise context. Measurement of proBNP, together with cardiac troponin T (cTnT), a marker of cardiac damage (Collinson et al. 2001), may therefore provide an insight into the origin of altered LV function and cardiac damage following prolonged exercise. Furthermore, ischaemia-modified albumin (IMA® ), a new biomarker that is currently under clinical investigation for the detection of early ischaemia (Bhagavan et al. 2003; Sinha et al. 2003, 2004), may offer additional information regarding the aetiology of altered cardiac function and cardiomyocyte damage observed following prolonged exercise. The presence of transient myocardial ischaemia during exercise, subsequent to an elevation in circulating catecholamines (Dearman & Francis, 1983), has been postulated as a mechanism underlying these phenomena (Rowe, 1991; Siegel et al. 1997). Although IMA appears to be gaining some acceptance in the clinical field, there remains some concern regarding its cardiospecificity in certain populations (Troxler et al. 2006). It is pertinent that the viability of the IMA assay within an exercise model is investigated, since this tool could potentially provide an original insight into the possible link between transient ischaemia and exercise-induced alterations in cardiac function and damage.


The aims of the study were twofold. Firstly, a spectrum of echocardiographic indices, including tissue Doppler imaging, flow propagation velocity and standard Doppler measures, were employed in order to provide a comprehensive evaluation of LV function following a marathon. Additional collection of 24 h postexercise data, previously only reported for basic and loaddependent echocardiographic measures, also allowed a thorough examination of the time course of exerciseinduced alterations in LV function. Secondly, assessment of postexercise proBNP, cTnT and IMA provided a complete biochemical evaluation of the myocardium postmarathon and an opportunity to investigate the utility of IMA in an exercise setting. We hypothesised that alterations in LV diastolic function, in the absence of changes in systolic function, would be observed immediately postexercise with both the standard and the advanced echocardiographic tools, with any changes normalizing following a 24 h recovery period. We further hypothesised that exercise-induced increases in proBNP and cTnT would be accompanied by a concomitant postexercise elevation in IMA, implicating transient ischaemia as a possible mechanism in this phenomenon. Methods Subjects and study design

Fourteen participants (13 male, 1 female) competing in the 2004 Flora London Marathon volunteered and provided written informed consent to take part in the study (mean ± s.d. age, 29 ± 5 years; height, 1.76 ± 0.74 m; and body mass, 75.9 ± 9.2 kg). Running experience ranged from 1 to 30 years (10 ± 7 years), with previous marathon completions ranging from 0 to 16 (3 ± 4). Participants self-reported no personal or early family history of cardiopulmonary disease. The study complied with the Declaration of Helsinki, and ethical approval was obtained prior to data collection from the Brunel University Ethics Committee. The marathon took place over a relatively flat course, under mild ambient conditions with frequent rain showers and a maximum temperature of 11◦ C. The study protocol employed a repeated measures design, with testing procedures taking place on the day prior to the marathon, immediately postrace (within 30 min), 1 h postrace and 24 h postrace. Identical echocardiographic and venous blood sampling procedures were conducted at each assessment, excluding the 1 h postrace assessment, when only blood was drawn. An echocardiogram was not obtained at 1 h postrace owing to logistical constraints. Body mass was also measured pre-, immediately post- and 24 h postrace. In-event heart rate data were collected on a subset of 11 of the participants, via a Polar heart rate monitor (Polar Team System, Polar

C 2006 The Authors. Journal compilation C 2006 The Physiological Society


Left ventricular function and marathon running

Electro Oy, Kempele, Finland), and was downloaded using Polar Precision Performance software (version 3.0). Echocardiographic procedures

Each participant underwent echocardiographic examinations in the left lateral decubitas position. A single experienced sonographer performed all measurements with a commercially available ultrasound system (Acuson Sequoia, Siemens Medical, Mountain View, CA, USA), using a 2.5–4 MHz phased array transducer. All acquisitions were performed at end expiration, and the standard measurements were conducted in accordance with the American Society of Echocardiography guidelines (Gottdiener et al. 2004). Images were stored and analysed off-line at a later date, with an average of three to five consecutive cardiac cycles taken for the calculation of all echocardiographic measurements. At the time of the echocardiographic assessment, blood pressure was determined using standard auscultation procedures. Systolic function. Two-dimensionally guided M-mode images were recorded for measurement of LV internal diameter during diastole and systole, and left ventricular posterior wall thickness during systole. These measurements were employed in the calculation of ejection fraction (EF; Longo et al. 1975) and systolic blood pressure-to-end systolic volume (SBP/ESV) ratio (Haykowsky et al. 2001). Left ventricular meridional wall stress (LVMWS) was calculated from the M-mode and systolic blood pressure data (Reichek et al. 1982) and employed as a surrogate of afterload, whilst LV end diastolic volume (LVEDV) was used as an indirect measure of preload. Intra-observer reliability data for these standard measures within our group have been reported previously (George et al. 2004). Left ventricular systolic wall motion velocity was assessed by tissue Doppler imaging, since the potential load-independence of this tool (Pela et al. 2004) offers greater validity in the assessment of cardiac function in the face of postexercise alterations in loading. A total of five sites were interrogated using a 4 mm sample gate at the level of the mitral valve annulus: lateral wall, septal wall, inferior wall, anterior wall and posterior wall. The peak velocity of the systolic myocardial wave (S ) was measured for each segment of the LV, with the mean value representing global LV wall motion velocity in systole. Diastolic function. Diastolic filling was examined using both pulsed-wave Doppler interrogation of mitral valve inflow velocities and tissue Doppler imaging of LV wall motion at the level of the mitral valve. The pulsed-wave Doppler velocity curves were digitized to obtain peak early (E) and peak late filling (A), allowing calculation C 2006 The Authors. Journal compilation C 2006 The Physiological Society

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of the early-to-late diastolic filling ratio (E:A). Similarly, the early diastolic (E ) and end-diastolic (A ) myocardial waves obtained from the tissue Doppler imaging were measured for the calculation of the E :A ratio. Tissue Doppler imaging measures have been shown to be highly reproducible, with a typical intra-observer error of 3 ± 2, 4.6 ± 2 and 5 ± 4% for E , A and E :A, respectively (Nagueh et al. 1998). The coefficients of variation for E and A within our own group are 5.3 and 12.2%, respectively. The flow propagation velocity (V p ) of the LV was assessed via colour M-mode Doppler ultrasonography from an apical four-chamber view, with the M-mode sample taken with the plane from the apex to the tips of the mitral valve leaflets. Colour Doppler was used with optimal gain for minimal background noise, and the pulse repetition frequency was reduced to provide a Nyquist velocity of 40–60 cms−1 . A slope calliper was drawn from the mitral valve at the first aliasing velocity during early filling to 4 cm distally into the LV cavity to obtain the V p . Typical intraobserver error for V p within our own group is 8.6%. LV filling pressures. Assessment of peak pulmonary vein inflow velocity during the systolic, diastolic and atrial reversal phases was evaluated by placing a 5 mm sample volume 1 cm into the right upper pulmonary vein, with the assistance of colour flow. The percentage of left atrial filling during systole was obtained from these measurements. Pulmonary venous flow patterns, together with mitral flow velocities, can assist in the identification of impaired LV relaxation (Nishimura et al. 1990). An elevation in LV filling pressure, as a result of reduced LV compliance, is typically characterised by a blunted systolic pulmonary venous flow, and an associated increase in both diastolic and atrial reversal pulmonary venous flow (Garcia et al. 1998). Further estimates of filling pressures were derived from the diastolic data, with the E:E and E:V p ratios employed as surrogates of early left atrial pressure (Nishimura et al. 1990; Ommen et al. 2000; Firstenberg et al. 2000).

Blood sampling procedures

A 15 ml whole blood sample was drawn from an antecubital vein on each occasion. An aliquot was obtained for the determination of haematocrit and haemoglobin, which were analysed via a GENS coulter counter (Beckman Coulter). The remaining blood was left to clot, centrifuged, and the serum drawn off and stored (−80◦ C) for subsequent analysis of cTnT, proBNP, IMA and total albumin. Cardiac troponin T. Cardiac troponin T (cTnT) was analysed using the third generation TROP T STAT assay

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by ECLIA technology, employed within the Elecsys 1010 automated batch analyser (Roche Diagnostics, Lewes, UK). Assay imprecision was 5.5% at 0.32 μg l−1 and 5.4% at 6 μg l−1 , with a detection limit of 0.01 μg l−1 . Values exceeding the detection limit of the assay of 0.01 are considered to represent myocardial damage (Collinson et al. 2001). N-terminal pro-B-type natriuretic peptide. N-terminal pro-BNP (proBNP) concentrations were determined with an Elecsys proBNP electrochemiluminescent immunoassay (ECLIA) on the Roche Elecsys 1010 (Roche Diagnostics), with an analytical range of 5–35 000 ng l−1 and intra-assay and interassay imprecision of 0.7–1.6 and 5.3–6.6%, respectively (Collinson et al. 2004). Ischaemia-modified albumin (IMA). Ischaemia-modified

albumin (IMA® ) was measured by the Albumin Cobalt Binding (ACB® ) test on the COBAS MIRA Plus (Ischaemia Technologies, Denver, CO, USA). The analytical sensitivity of the ACB test is 14 Um l−1 , with a within-run coefficient of variation of 7.3% (Christenson et al. 2001). The 95th percentile of 85 Um l−1 represents the diagnostic cut-off for myocardial ischaemia (Sinha et al. 2004). Total albumin. Total albumin concentration was determined via a bichromatic digital end-point Bromocresol Purple (BCP) methodology using SYNCHRON LX Albumin Reagent on the SYNCHRON LX System (High Wycombe, UK). This assay has a sensitivity of 10 g l−1 , and within-run precision of 2.0% at 100 g l−1 (SYNCHRON LX Systems).

Statistical analysis

All pre-, immediately post- and 1 h postmarathon blood variables, excluding the cTnT data, were analysed with a repeated measures ANOVA using pairwise comparisons with a Bonferroni correction. Cardiac troponin T was analysed descriptively owing to the likelihood of undetectable prerace values. Student’s paired t tests were used to compare pre- and postrace echocardiographic variables. Correlations between the changes in pre- versus postrace values for each variable were determined via Pearson’s Product-Moment correlation analysis. Key variables were also correlated to participant age, finish time and in-event HR data. All analyses were performed using SPSS (SPSS version 11.5 for Windows; SPSS Inc., Chicago, IL, USA), with α set at 0.05. Data are reported as means ± s.d. Results Participants completed the marathon in a mean time of 212 ± 36 min. All returned for postrace testing procedures,


Table 1. Pre- and postrace echocardiograph data Index

Prerace

Postrace

75.9 ± 6.7 4.3 ± 2.2 79.5 ± 14.1 43.4 ± 8.0 1.9 ± 0.5 27.5 ± 3.2 15.6 ± 3.0 1.8 ± 0.4 67.5 ± 9.3

75.6 ± 7.7 4.9 ± 2.8 68.5 ± 13.9† 60.5 ± 10.6† 1.2 ± 0.3† 24.1 ± 3.4† 19.0 ± 4.4∗ 1.3 ± 0.3† 60.2 ± 8.2†

LV loading and filling pressures Heart rate (beats min−1 ) 57 ± 6 Peak S PV flow velocity (m s−1 ) 0.61 ± 0.14 Peak D PV flow velocity (m s−1 ) 0.62 ± 0.11 Peak Ar PV flow velocity (m s−1 ) 0.27 ± 0.04 Left atrial systolic filling (%) 53.9 ± 10.5 E:E ratio 2.9 ± 0.6 1.18 ± 0.17 E/V p ratio Systolic BP (mmHg) 135 ± 5 LVMWS (g cm−1 ) 47.8 ± 1.8 LVEDV (ml) 158.1 ± 47.7

82 ± 11† 0.65 ± 0.13 0.59 ± 0.12 0.31 ± 0.05∗ 59.8 ± 7.7∗ 2.9 ± 0.5 1.14 ± 0.17 125 ± 5† 44.3 ± 1.9† 135.3 ± 48.3†

LV function EF (%) SBP/ESV (mmHg ml−1 ) E (cm s−1 ) A (cm s−1 ) E:A ratio Mean E (cm s−1 ) Mean A (cm s−1 ) E :A ratio V p (cm s−1 )

Values are presented as means ± S.D. S, systole; D, diastole; PV, pulmonary vein; Ar, atrial reverse. significant differences from prerace are shown as ∗ P < 0.05 and †P < 0.01.

which were conducted within 30 min of race finish. Owing to logistical difficulties, one participant did not provide a postrace blood sample and another participant did not provide an echocardiogram. Twenty-four hour postrace blood and echocardiograph data were collected on a subset of nine and six athletes, respectively. Despite ingesting fluid ad libitum during the race, body mass significantly decreased postrace (from 75.9 ± 9.2 to 73.4 ± 8.8 kg). Mean heart rate was 161 ± 9 beats min−1 throughout the race (85 ± 4% of predicted maximum heart rate). Echocardiographic data

Echocardiographic data obtained pre- and postrace are displayed in Table 1. No postrace alterations in the systolic function indices of EF or SBP/ESV were detected; however, mean S significantly increased following the marathon (from 16.9 ± 1.6 to 18.7 ± 2.7 cm s−1 , P < 0.05). A significant (P < 0.001) reduction in LVMWS was observed postrace, indicating a decrease in afterload (Table 1). A postexercise reduction in preload was also apparent, as measured by a significant (P < 0.01) decrease in LVEDV (Table 1). As expected, there was an increase in heart rate and a reduction in systolic blood pressure during the postexercise assessment (Table 1), although these changes were unrelated to any of the alterations in LV function. A significant (P < 0.01) postrace decrease in mitral E:A was demonstrated by the standard Doppler methods (Table 1), and this finding was further supported by C 2006 The Authors. Journal compilation C 2006 The Physiological Society



tissue Doppler imaging data, with a significant (P < 0.01) postrace reduction in the mean E :A ratio (Table 1). The greatest decrease was evident in E :A in the lateral (2.08 ± 0.74 versus 1.45 ± 0.4, P < 0.01) and posterior walls (2.17 ± 0.68 versus 1.47 ± 0.47, P < 0.01). Figure 1 illustrates the subset of mean E :A data 24 h postmarathon, which demonstrated a significant (P < 0.05) increase in E :A compared to the immediate postexercise assessment. The time course of changes in the E :A ratio was mirrored by a trend towards a reduction in V p following the marathon and subsequent return to baseline following a 24 h recovery (Fig. 1). No significant relationships were observed between the LV loading indices and the changes in pre- versus postrace values of E:A, E :A and V p , indicating that the changes in preload and afterload did not contribute significantly to the observed impairment in diastolic filling. Furthermore, there was no relation between heart rate and changes in diastolic parameters (E :A and HR, r = 0.36). Finally, despite no alteration in E:E or E:V p , there was a significant elevation in the postexercise atrial reversal pulmonary vein flow velocity (Table 1). Again, this was

Figure 1. Mean flow propagation velocity (V) and E :A ratio pre-, immediately post- and 24 h postmarathon (n = 6) Significant difference from pre-, ∗ P < 0.05; significant difference from post-, †P < 0.05. C 2006 The Authors. Journal compilation C 2006 The Physiological Society

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unrelated to any of the changes in loading or heart rate, and may therefore indicate impairment of LV relaxation.

Blood data

Individual cTnT data are illustrated in Fig. 2. Baseline cTnT values were below the assay detection limit of 0.01 μg l−1 in all participants and are reported as zero. Nine runners had detectable values for cTnT immediately postrace (range, 0.023–0.37 μg l−1 ). These values increased further in four participants 1 h postrace (range, 0.027–0.459 μg l−1 ), but returned to baseline levels in all but one runner 24 h postrace. Further results of the blood analyses are displayed in Table 2. Post- and 1 h postrace proBNP concentrations were significantly (P < 0.05) elevated compared to basal resting values. Conversely, IMA levels significantly (P < 0.05) dropped below baseline immediately post- and 1 h postrace, although this had already increased significantly towards prerace values at the time of the 1 h sample. IMA levels did not exceed the clinical cut-off of 85 Um l−1 at any sample point. Total albumin (n = 9) significantly (P < 0.05) increased immediately following the marathon compared to prerace levels, despite no significant differences between pre- and postrace haematocrit and haemoglobin. Delta changes in the echocardiographic variables were not significantly related to any of the changes in IMA levels, cTnT or pro-BNP. Additionally, there was no relationship between the changes in IMA levels and the change in total albumin levels. There was a significant correlation between proBNP and finish time (r = 0.697, P < 0.05); however, no other associations between age, finish time, in-event heart rate or years of running experience of each athlete and the changes in echocardiographic or biochemical variables were observed.

Figure 2. Individual cTnT levels pre-, immediately post-, 1 h post- and 24 h postrace

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Table 2. Pre- and postmarathon biochemical data Parameter proBNP (ng l−1 ) IMA (Um l−1 ) Total albumin (g l−1 ) (n = 9) IMA:total albumin ratio (n = 9) Haematocrit (l l−1 ) Haemoglobin (g dl−1 )

Pre

Post

1 h Post

24 h Post (n = 9)

21.6 ± 11.0 63.7 ± 9.8 47.4 ± 2.7 1.3 ± 0.3 0.45 ± 0.02 15.0 ± 0.6

47.1 ± 19.5∗ 44.9 ± 16.1∗ 51.1 ± 2.7† 0.9 ± 0.3† 0.46 ± 0.02 15.2 ± 0.6

48.6 ± 21.1∗ 51.7 ± 12.1∗ n.a. n.a. n.a. n.a.

38.2 ± 9.9 65.7 ± 6.7 46.0 ± 2.0 1.4 ± 0.2 0.44 ± 0.03 14.8 ± 0.8

Values are presented as means ± S.D. Significant differences from prerace are shown as ∗ P < 0.01 and †P < 0.001. n.a., not assessed.

Discussion The standard systolic functional parameters of EF and SBP/ESV were not altered postmarathon, which is in accordance with the findings of previous studies (Lucia et al. 1999; George et al. 2004). Despite the lack of change in the standard systolic function parameters, there was a small increase in both the lateral and septal S from the tissue Doppler imaging data, accompanied by an increase in the mean S . Improved systolic function during and following prolonged exercise has been reported previously (Palatini et al. 1994; McGavock et al. 2003) and may reflect changes in the contractile properties of the left ventricle resulting from inotropic factors, such as an increase in circulating catecholamines. Altered diastolic function following the marathon was manifest by a significant reduction in the LV diastolic filling parameters of mean E :A , E:A and V p , which were not related to changes in loading or heart rate. These findings are comparable with the work of Lucia et al. (1999) and George et al. (2005), who also demonstrated postmarathon reductions in diastolic filling parameters. Within the present study, tissue Doppler imaging was complemented by the flow propagation velocity data, both of which have been suggested as relatively load-independent indices of diastolic filling (Garcia et al. 2000; Pela et al. 2004), a contention supported by the lack of correlation between alterations in these parameters and changes in loading indices in this investigation. The resumption of a normal diastolic filling pattern 24 h postmarathon in the subset of six athletes is in agreement with the transient nature of altered diastolic filling reported previously with standard echocardiographic techniques (Rifai et al. 1999; Shave et al. 2004). The postexercise pattern of pulmonary venous flow demonstrated an increase in peak pulmonary vein atrial reversal flow velocity, suggesting an elevation in LV filling pressure as a result of delayed LV relaxation (Nishimura et al. 1990). Despite a small augmentation in the percentage atrial filling in systole, which may have increased in proportion to afterload (LVMWS and percentage atrial filling, r = 0.359), there was no alteration in either the E:E or E:V p ratio. The E:E ratio is a widely used index of early left atrial pressure in clinical populations (Ommen

et al. 2000) that retains accuracy even under altered loading conditions (Sundereswaran et al. 1998; Nagueh et al. 1998). Similarly, the E:V p ratio has been shown to be highly correlated with pulmonary capillary wedge pressure in healthy individuals (Firstenberg et al. 2000). The alteration in diastolic filling may therefore indicate a reduction in LV pressure decay resulting from an intrinsic impairment of LV relaxation and/or compliance, rather than changes in left atrial pressure as a result of altered haemodynamic loading. This finding appears paradoxical in light of the present systolic TDI data; however, it is possible that LV relaxation may be altered independently of changes in systolic function, for example, by increased intracellular calcium as a result of impaired calcium re-uptake by the sarcoplasmic reticulum (Galderisi, 2005). Postrace elevations in cTnT levels, representative of minor myocardial damage (Collinson et al. 2004), were observed in 69% of the marathon runners, unrelated to any of the changes in LV function. The cTnT elevations within the present study are similar to those reported previously from our group following marathon running (George et al. 2004). However, the proportion of runners exhibiting positive troponins was considerably higher than the 26% reported by Rifai et al. (1999) following the Hawaii Ironman Triathlon, possibly reflecting a training-induced cardioprotective mechanism within the elite ultra-endurance athlete population. Alternatively, the observed discrepancy could be explained by the longer exercise duration, and therefore lower exercise intensity, within the study by Rifai et al. (1999). The cTnT levels found within the present study are markedly lower than the typical troponin elevations following an acute myocardial infarction; however, seven participants exhibited elevated cTnT levels above the 0.03 μg l−1 cut-off for increased risk of coronary events in cardiac patients (James et al. 2003). Troponin released from tissue damaged in acute myocardial infarction requires up to 4 h to enter the circulation (Wu et al. 1999). Although the precise time course of cTnT release following exerciseinduced cardiac damage has not yet been examined, the further increase in cTnT levels 1 h postrace in the present investigation indicates that there may be a similar lag in troponin release compared to that observed in clinical cases. Recent findings by Urhausen et al. (2004), who C 2006 The Authors. Journal compilation C 2006 The Physiological Society



reported higher cTnT levels in blood samples taken 2.5– 3.5 h following prolonged endurance events in contrast to the 15 min postexercise sample, lend support to this theory. A rapid return of cTnT to baseline 24 h postmarathon values in the majority of athletes observed within the present study and in previous reports (Whyte et al. 2000; Shave et al. 2004), however, may reflect troponin release from the cytosolic fraction (Koller, 2003) rather than necrosis of the contractile apparatus (Wu & Ford, 1999). Future investigators in this area should attempt a more thorough investigation of the cTnT release pattern following prolonged exercise, to assist in the differential diagnosis of exercise-induced cardiac damage and acute myocardial infarction in an athletic population. Concomitant to the increases in cTnT, proBNP levels were significantly elevated postexercise in the present study, indicative of an increase in either LV wall stress or end-diastolic pressure (McCullough et al. 2003; Mak et al. 2004). Similar elevations in proBNP and BNP following marathon running have been previously documented (Ohba et al. 2001; Niessner et al. 2003), although not in conjunction with assessment of LV function. It is likely that an increase in end-diastolic pressure during the race over a prolonged period of time, due to augmented venous return, may have facilitated the proBNP release. Accordingly, the relationship between proBNP and marathon completion time within in the present investigation may be accounted for by the greater LV wall stress sustained by individuals taking longer to complete the race. Elevated BNP levels have 85% sensitivity in predicting diastolic dysfunction in patients with normal systolic function (Lubien et al. 2002). In the present study, there was a moderate negative correlation (r = −0.469) between the change in mean E :A and proBNP level, which may have reached statistical significance with a larger sample size. No relationships were noted between proBNP and cTnT, or between E :A and cTnT, supporting the theory that postexercise reductions in LV function and exerciseinduced cardiac damage are separate phenomena (Shave et al. 2004). The absence of elevated IMA following the marathon suggests that myocardial ischaemia did not occur during the exercise period. In fact, marathon IMA levels were significantly decreased immediately following the marathon, with a return towards prerace levels 1 h postrace. This finding concurs with that of Apple et al. (2002), who demonstrated a similar pattern in IMA levels following a marathon race. Although not related to any of the changes in function or markers of cardiac damage, the observed reduction in IMA in the present study, and that of Apple et al. (2002), may be explained by the interaction of various factors associated with prolonged exercise. It has been postulated that the decrease in IMA may be accounted for by the relationship between total C 2006 The Authors. Journal compilation C 2006 The Physiological Society

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albumin and IMA (Zapico-Muniz et al. 2004). Within the present study, total albumin was significantly increased immediately postrace, resulting in a significant decrease in the IMA:total albumin ratio. These parameters were not significantly correlated; however, this may be explained by the small sample employed in this analysis (n = 9). Since albumin facilitates the transportation and metabolism of free fatty acids, it is possible that the observed reduction in the IMA:total albumin ratio is a function of increased free fatty acid utilization during prolonged exercise (Convertino et al. 1980). Furthermore, the range of total albumin concentrations within the present study exceeded the upper limit of the physiological range of 35– 45 g l−1 reported by Zapico-Muniz et al. (2004), indicating hyperalbuminaemia and thereby increasing the possibility of false-negative values within the present population (Zapico-Muniz et al. 2004). An additional confounding factor, which may have affected the diagnostic utility of IMA to identify ischaemia, is the presence of circulating lactate (Roy et al. 2004). In vitro lactate concentrations of 3–11 mmol l−1 have been demonstrated to reduce IMA values by around 7–25% (Roy et al. 2004); hence the reduction in IMA within the present study may be a result of blood lactate accumulation during the marathon. Taken together, these data suggest a reduced efficacy of IMA in identifying myocardial ischaemia in the context of an exercise setting, owing to interference by a number of factors inherent to prolonged exercise (Troxler et al. 2006). Accordingly, the IMA findings from the present study cannot conclusively rule out the possible involvement of transient ischaemia in the aetiology of postexercise alterations in cardiac function and markers of cardiac damage. An increase in myocardial oxygen demand during high coronary flow situations, such as exercise, combined with reduced myocardial oxygen supply resulting from sympathetic activation and coronary vasoconstriction, has been reported to induce ischaemia-related troponin release in patients with angiographically normal coronary arteries (Bakshi et al. 2002). The clinical implications of the elevated cTnT and altered LV function in the present investigation, and whether the aetiology of these phenomena parallels that observed within clinical ischaemia, has yet to be ascertained. However, it is pertinent that exercise-induced alterations in cardiac biomarkers and cardiac function are clinically recognised in order to prevent inappropriate treatment and diagnosis in the possible event of hospital admission. Future work is required to further elucidate the clinical impact, as well as the underpinning mechanisms of these phenomena, which may include prolonged myocyte exposure to circulating catecholamines (Dearman & Francis, 1983), an increase in circulating free fatty acids (McKechnie et al. 1979) and increased production of free radicals (Venditti & Di Meo, 1996).

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In summary, postexercise reductions in a wide spectrum of LV diastolic filling indices, unrelated to changes in heart rate or loading, may indicate an intrinsically mediated change in diastolic filling patterns following a marathon. The observed alteration in LV function was accompanied by a temporary elevation in cTnT and proBNP postmarathon, indicative of exercise-induced cardiac damage, but no increase in IMA. The absence of relationships between these parameters suggests that neither the changes in cardiac function and proBNP nor cTnT elevations could be explained by IMA. Exerciseinduced increases in lactate and total albumin may reduce the efficacy of IMA in an athletic cohort, so caution should be used when employing IMA in the assessment of myocardial ischaemia within an exercise setting. Future studies in this area should investigate alternative diagnostic tools for the detection of transient ischaemia, and other potential mechanisms, in order to extend the understanding of this phenomenon.

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