SCOTT, JESSICA M.1; ESCH, BEN T.A.1; SHAVE, ROB2; WARBURTON, DARREN E.R.1; GAZE, DAVID2,3; GEORGE, KEITH4
There is a growing body of evidence suggesting that prolonged exercise may induce a transient reduction in left ventricular (LV) function (17). Recent scientific and media interest in this issue has heightened concern in endurance athletes, coaches, scientists, and clinicians alike. With well over 100 ultramarathon events held annually in North America, the increasing popularity of extreme endurance exercise necessitates a clear understanding of the cardiovascular consequences associated with such races. The severe duration of exercise performed during ultraendurance events (20+ h) is particularly important, as it is possible that these races require greater cardiac work and thus may result in more extensive changes in LV function compared with the previously described changes involving shorter endurance races (3-12 h) (39). Although several studies have examined cardiovascular function after ultraendurance events (22,23), these investigations were conducted 20 yr ago and furthermore used only global measures of LV function. Newer techniques such as speckle tracking assessment of tissue strain and strain rates may provide a much more sensitive assessment of both regional and global LV function.
Prolonged exercise has also been linked to the appearance of cardiac-specific biomarkers such as cardiac troponin T (cTnT), B-type natriuretic peptide (BNP), and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) (29). Investigations involving shorter endurance events such as marathons and ironman triathlons have reported up to 86.5% (36) of finishers with detectable levels of cTnT. Interestingly, in the few studies involving ultraendurance exercise, cTnT was detectable in only 21% of athletes who completed a 100-km run (37), and levels of cTnT were undetectable in athletes who completed a 216-km run (28). Similar incongruities exist regarding BNP release. König et al. (14) examined professional cyclists during a 5-d cycling race and observed BNP to remain within the normal range, whereas Ohba et al. (25) described BNP increases of up to 500% after a 100-km ultramarathon. Further cardiac biomarker data are clearly required from ultraendurance events to understand the connection between exercise duration and release of biomarkers.
Understanding of the mechanism(s) contributing to decreases in LV function is limited. One theory suggests that if myocardial damage occurs with prolonged exercise (evidenced by biomarker release), as in clinical scenarios, this damage would result in a decrease in LV function. Several studies have recently reported that exercise-induced decreases in LV function are associated with increased postexercise levels of cardiac biomarkers (15,19). However, these findings remain controversial as they often appear to be influenced greatly by one or two outliers and other confounding variables such as alterations in plasma volume. Moreover, evidence of myocardial damage has not been demonstrated using SPECT or MRI (30,33), and other investigations examining biomarkers and LV function after prolonged exercise have failed to confirm an association (10). It is apparent that additional research is required to elucidate a potential relationship between alterations in LV function and myocardial damage.
It is also possible that alterations in LV function after prolonged activity may be caused by decreases in cardiac receptor responsiveness (13) or a sudden postexercise gain in parasympathetic tone (4). Due to the increased exposure to catecholamines during prolonged exercise (8), a down-regulation of β1-receptor responsiveness may occur, prompting the decline in LV contractility in healthy athletes (13). An increase in vagal tone and the resulting cardiac muscarinic receptor stimulation may cause a decrease in chronotropic and inotropic activity (34). Evidence to support this theory is limited, and indeed some investigations have demonstrated a delayed vagal reactivation after exercise in highly trained athletes (3). As a result of these discrepancies, it is still unclear if the observed decrease in LV systolic function can be attributed to a large parasympathetic influence after prolonged exercise.
Therefore, this study was designed with two objectives. The first aim was to assess the cardiovascular consequences of a 160-km (100 mile) ultramarathon using traditional echocardiography, speckle tracking imaging, cardiac biomarkers, and heart rate variability (HRV). Second, to examine possible mechanisms contributing to exercise-induced decreases in LV function, the relationship between changes in LV function, changes in cardiac biomarkers, and changes in cardiac autonomic regulation was assessed. We hypothesized that 1) as a result of ultraendurance exercise athletes would demonstrate decreases in cardiac function (measured by traditional echocardiography and speckle tracking imaging), and 2) the changes in cardiac function after ultraendurance exercise would be related to changes in cardiac biomarkers and/or cardiac autonomic regulation.
Thirty-five athletes (25 male, 10 female) competing in the 2007 Western States 100 mile Endurance Run (WSER) (start: Squaw Valley, California, finish: Auburn, California) were recruited to participate in this study. A questionnaire was completed to obtain demographic data, training history, ultraendurance competition history, and details of cardiovascular risk factors. The participants who volunteered for this investigation were well-conditioned male and female amateur athletes (for characteristics, see Table 1). This study was approved by the Western States Endurance Run Research Committee (United States) and the Brunel University Ethics (United Kingdom) committee. Written informed consent was obtained from each participant.
Participants underwent two separate testing days: 1) prerace assessment of LV function, cardiac biomarkers, cardiac autonomic modulation, and body mass assessment 1 d before WSER; and 2) postrace assessment of LV function, cardiac biomarkers, cardiac autonomic modulation, and body mass assessment immediately after WSER. For the postrace assessment, subjects were asked to attend a testing tent adjacent to the finish area as soon as possible after completion of the race. All subjects were advised to abstain from hard training within the 48-h period before pretesting.
Assessment of LV Function
Traditional echocardiographic measurements
Participants underwent two-dimensional transthoracic and pulsed-Doppler imaging by use of a commercial ultrasound system (Vivid-i; GE Healthcare Wauwatosa, WI). Images were obtained by a single experienced sonographer in the parasternal long axis, short axis, and apical four-chamber views according to the American Society of Echocardiography guidelines (16). LV systolic function was evaluated using fractional area change (FAC), ejection fraction (EF), end-systolic pressure volume relationship (systolic blood pressure/end-systolic volume (SBP/ESV)), and stroke volume (SV). End-diastolic LV dimensions were used to calculate LV mass (9). Pulsed Doppler recordings were used to assess diastolic filling; in particular, early (E) and atrial (A) peak mitral inflow velocities were measured, and the ratio of early to late diastolic filling velocity (E:A) was calculated. LV end-diastolic volume (EDV; modified Simpson's rule from four-chamber view) and end-systolic meridional wall stress (27) (WS) [WS (g·cm−2) = 0.334 SBP end-systolic diameter/end-systolic posterior wall thickness (1 + end-systolic posterior wall thickness) / end-systolic diameter] were estimated as indices of preload and afterload, respectively. Images were analyzed off-line by a single experienced technician. On the basis of the HR differences before and after the race, it was not possible to blind the technician to this aspect of analysis. A minimum of three consecutive cardiac cycles were measured and averaged.
Speckle tracking imaging
Radial and circumferential strain data were derived from a parasternal short axis view imaged at the basal level. Specifically, this was at the level of the first appearance of the superior surface of the papillary muscle when imaged down from the mitral valve to provide a reproducible anatomical landmark for repeat scans. The focal point was positioned close to the center of the LV cavity to provide optimum beam width while reducing the effects of divergence. The apical window was used for longitudinal assessment incorporating apical two- and four-chamber orientations. The focal point was positioned at the level of the mitral valve. In both orientations, frame rates were maximized (>40 and <90 frames per second). Using the original two-dimensional images, a single experienced technician performed offline measurements of the longitudinal, radial, and circumferential planes using a dedicated software package (Echopac; GE Healthcare). This system tracks acoustic markers within the myocardium, frame-by-frame, over the entire cardiac cycle. The spatial displacement of an acoustic marker indicates local tissue movement. A tracking setting was selected with a width between endocardium and epicardium to include as much myocardium as possible. The software automatically scores the tracking quality of each segment on a scale from 1.0 for optimal to 3.0 for unacceptable. Segments with scores greater than 2.0 were excluded from the analysis. Due to limitations in scanning time as well as occasional image quality problems, we report data for basal wall segments. Sonographer-specific coefficient of variation data ranged from 4.9% to 7.1% for strain and strain rate derived in radial and circumferential planes. This rose slightly to 7.1% to 12.7% for indices derived in the longitudinal plane. On the basis of the HR differences before and after the race, it was difficult to blind the technician to this aspect of analysis. A minimum of three consecutive cardiac cycles were measured and averaged.
Assessment of Cardiac Biomarkers
For each blood sample, 5 mL of whole blood was drawn from an antecubital vein and collected in serum-gel tubes. Blood samples were left to clot, centrifuged, and the serum drawn off and stored (−80°C) for subsequent analysis of cTnT and NT-pro-BNP. cTnT was analyzed using the third generation TROP T STAT assay by electrochemiluminescent immunoassay (ECLIA) technology, used within the Elecsys 1010 automated batch analyzer (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. NT-pro-BNP concentrations were determined with an Elecsys proBNP ECLIA on the Roche Elecsys 1010 (Roche Diagnostics), with an analytical range of 5-35,000 ng/L−1 and intraassay and interassay imprecision of 0.7-1.6% and 5.3-6.6%, respectively.
Assessment of Cardiac Autonomic Modulation
To provide an indication of autonomic modulation pre- and postrace, HRV was assessed during 10 min of supine rest. HRV was sampled at 1000 samples per second with an A/D converter (Powerlab/16SP ML 795; ADInstruments, Colorado Springs, CO) from ECG to computer. The ECG segment was then evaluated according to previously established guidelines (1). Both frequency domain and time domain measures were analyzed. To assess frequency domain measures, the power spectra were estimated using a 1024-point linear fast Fourier transform algorithm. The power spectra were then analyzed for total power (0.0-0.4 Hz), as well as low-frequency (LF; 0.04-0.15 Hz) and high-frequency (HF; 0.15-0.4 Hz) power. HF power is almost entirely mediated by the vagal activity in the sinoatrial node, whereas LF power reflects the mixed modulation of vagal and sympathetic activities (1). HF and LF values at each specific frequency range were also normalized by dividing by the total spectral power (high [HFnu]- and low-frequency normalized units [LFnu]) to minimize the effect of the changes in total power on the LF and HF components (11). The square root of the mean of squared differences between successive RR intervals (RMSSD) was also computed as another index of cardiac parasympathetic activity (11).
Cardiovascular variables were compared before and after the race using paired Student's t-tests. The change in LV functional measures from pre- to postrace (delta scores) was correlated with age, finishing time, average training volume, as well as delta scores for HR, HRV indices, estimates of preload and afterload, and NT-pro-BNP by Pearson product-moment correlations. Due to the nature of cTnT data, we assessed the association with changes in cardiac function on a case-by-case basis. The level of significance was set a priori at P < 0.05. Data are presented as means ± SD at pre- and postrace, respectively. Data analysis was performed using statistical computer software (Statistica; Statsoft Ltd, Tulsa, Oklahoma).
Twenty-five athletes (20 males, 5 females) successfully completed the race with an average finish time of 25.5 h ± 3.2 h. Participant characteristics are shown in Table 1. All 25 athletes had blood drawn for the assessment of cardiac biomarkers, whereas 18 (15 male, 3 female) completed postrace echocardiography assessment and 16 (13 males, 3 females) completed postrace cardiac autonomic assessment. All athletes were assessed within 30 min of cessation of exercise.
Traditional Echocardiographic Measurements
Table 2 summarizes the echocardiographic data. There were no changes in body mass and SBP, although there was a significant increase in HR after the race (Table 2). There were no significant changes in LV WS (afterload). EDV, EF, FAC, and SV fell significantly postrace (P < 0.05, Table 2), with no change in cardiac output (prerace: 4.3 ± 0.7 L·min−1; postrace: 4.8 ± 1.0 L·min−1). SBP/ESV was reduced postrace (−8 ± 18%), but this did not reach statistical significance (P = 0.09). The peak early (E) transmitral filling velocity decreased significantly (P < 0.05, Table 2), whereas peak late (A) transmitral filling velocity remained unchanged after the race. This resulted in a significantly lower E/A ratio after the race. There were no significant correlations between changes in LV function and any alteration in loading conditions, HR, age, average training (miles·wk−1), or finish time (Table 3).
Speckle Tracking Imaging
Twelve participants who completed the race had echocardiographic images that were suitable for speckle tracking analysis (tracking quality better than 2.0). Basal radial and basal longitudinal (septum and lateral wall) displacements were significantly reduced postrace (P < 0.05, Table 4). Longitudinal myocardial velocity during systole and early diastole in both the basal septum and basal lateral wall were also reduced after the race (P < 0.05, Table 4). Peak radial and circumferential basal strain were diminished postrace (P < 0.05, Table 4), whereas peak longitudinal strain was only reduced in the basal septum but not the lateral wall (Table 4). Neither systolic nor early diastolic strain rates were consistently altered in a given plane of motion, although several pre- versus postrace differences existed (Table 4). The largest relative percent reduction in peak strain was seen in the circumferential plane, followed closely by reductions in radial strain, with relatively small changes longitudinally (Fig. 1). Changes in strain and strain rates were generally not associated with changes in EDV, WS, HR, age, average training (miles·wk−1), or finish time. However, change in septal longitudinal strain was negatively correlated with finish time and positively correlated to average training-such that those with the greatest training volume (miles·wk−1) and those who finished the fastest had the greatest decreases in septal longitudinal strain (Table 5).
Concentrations of serum cTnT were <0.01 ng/mL−1 in all participants at baseline. After the race, an increase in cTnT of >0.01 ng·mL−1 was recorded in five athletes (20%), ranging from 0.01 to 0.05 ng·L−1. Out of the five participants who had elevated levels of cTnT postrace, only two completed postrace echocardiography. One participant with elevated cTnT and echocardiographic measures was a 36-yr-old male and the other was a 35-yr-old female. These two athletes had moderate decreases in EF (−4.5% and −4.6% vs group: −6.1 ± 2.1%) and longitudinal strain (2.5% and 0.7% vs group: 1.3 ± 3.2).
At baseline, mean NT-pro-BNP was 28 ± 17.1 ng·L−1; after the WSER, NT-pro-BNP levels were significantly higher (795 ± 823 ng·L−1, P < 0.05), with a postrace range of NT-pro-BNP concentrations from 212 to 3427 ng·L−1). Prerace, one athlete had NT-pro-BNP concentrations, which exceed the upper reference limit for healthy subjects (125 ng·L−1) and was excluded from NT-pro-BNP analyses. All participants had levels of NT-pro-BNP above the upper limit of normal for exclusion of heart failure postrace (35). Changes in NT-pro-BNP were not significantly associated with LV mass (r = 0.07), average training volume (r = −0.05), age (r = −0.29), or finish time (r = 0.09). Changes in NT-pro-BNP were not associated with changes in most measures of LV function (Table 6). However, there was a significant correlation between change in radial strain and change in NT-pro-BNP (P < 0.05; Table 6). Interestingly, changes in NT-pro-BNP were significantly associated with changes in HFnu (P < 0.05; Fig. 2).
Cardiac Autonomic Modulation
Mean RR interval was significantly decreased postrace when compared with prerace (prerace 1081 ± 161 ms vs postrace 800 ± 123 ms; P < 0.05). Parasympathetic indices (RMSSD: prerace 88.9 ± 48.9 ms vs postrace 72.8 ± 92.5 ms; HFnu: prerace 40.4 ± 10.9 nu vs postrace 32.3 ± 11.7 nu) were reduced after prolonged exercise, although these changes were not statistically different. The sympathetic index LFnu (prerace 55.5 ± 16.2 nu vs postrace 42.9 ± 27.2 nu) was also decreased postrace, although not significantly so. There was also a nonsignificant increase in LF:HF ratio postrace with respect to preexercise values (prerace: 1.6 ± 1.0 vs postrace 2.6 ± 3.5). Change in HFnu was not associated with LV mass (r = 0.29), average training volume (r = 0.10), age (r = −0.09), or finish time (r = −0.37). Changes in the parasympathetic index HFnu were also not associated with most changes in LV function (Table 6). However, there was a significant correlation between change in radial strain and change in HFnu (P < 0.05; Table 6).
The present study comprehensively examined the cardiovascular consequences of ultraendurance exercise (25.5 ± 3.2 h) using traditional echocardiography, speckle tracking imaging, cardiac biomarkers, and HRV. This article represents the first comprehensive use of speckle tracking imaging after ultraendurance exercise and describes regional alterations in cardiac function. Confirming previous investigations (22,23), we also found a significant reduction in both LV systolic and diastolic function postrace using standard two-dimensional echocardiography measures. Relatively few athletes demonstrated increases in cTnT after the race, but there was a significant increase in plasma NT-pro-BNP in all athletes. Finally, in contrast with several recent studies (15,19), we report that echocardiographic evidence of decreases in LV function was not associated with alterations in cardiac biomarkers or cardiac autonomic regulation.
Traditional echocardiographic measurements
The present data support the findings of Niemela et al. (23), suggesting that the completion of an ultraendurance event results in a reduction in LV systolic function and an alteration in diastolic filling. Previous investigations have suggested that decreases in LV function are related to alterations in loading conditions (12), and acute reductions in preload such as during the Valsalva maneuver have been shown to alter diastolic and systolic parameters (18). However, the general lack of significant correlation between LV function and HR, preload, and afterload in this investigation (Table 3) suggests that an alteration in intrinsic LV function occurred postrace. Furthermore, although recent studies have indicated that decreases in LV function are associated with training volume (19), and/or age (14), our data would suggest that both of these variables had little impact on LV function in the current cohort.
Speckle tracking imaging
Our results also support the findings of Neilan et al. (20) who reported decreases in both peak systolic strain and strain rate after a marathon run. However, Neilan et al. (20) used tissue Doppler-derived strain and strain rate, which is even more angle-dependent than Doppler flow measures (24). We have used speckle tracking imaging, which is less dependent on transducer orientation and found both strain and strain rate to be decreased after a 100-mile running race. Importantly, there were also differential alterations in the basal longitudinal, radial, and circumferential planes of motion after the race. The largest relative percent reduction in peak strain was seen in the circumferential plane (32.3%), followed closely by reductions in radial strain (28.3%), with relatively small changes longitudinally (7.1%) (Fig. 1). This is interesting to note considering that Notomi et al. (24) have recently shown that with exercise the largest proportional increase in myocardial velocity from rest to exercise occurs in the circumferential plane, followed by the radial and lastly changes in the longitudinal plane. Therefore, it is possible that the planes of myocardial contraction that increase the most during exercise will result in the greatest impairments of function after prolonged exercise.
Although our results indicate that age, finish time, and training volume had little impact on both traditional echocardiography and most speckle tracking-derived measures, finish time and training volume were related to changes in longitudinal strain. That is, the more miles an individual ran per week in training, the faster they finished the race and the greater their reduction in longitudinal strain. This finding may be suggestive of an intensity-dependent contribution to the decrease in LV function. Although speculative, this point requires further study.
In the present investigation, cTnT results were negative in all subjects prerace, whereas postrace, five runners (20%) presented with cTnT values above the lower detection limit of the assay. This percentage of positive cTnT levels is lower than data obtained from studies involving exercise ranging from 3 to 12 h, which revealed percentages of 56% to 86.5% (15). Similar to our results, other investigations involving extreme endurance events (over 20 h) have reported few, if any, cases of positive cTnT values (28,37). It is possible that troponin release is related to exercise intensity, as athletes in shorter endurance events may exercise at higher intensities than those racing for 20 or more hours. Interestingly, Neilan et al. (19) reported that postexercise alterations in cardiac biomarkers were strongly influenced by the level of preparation undertaken by participants, such that the majority of the most marked abnormalities in cardiac structure or function, as well as cardiac biomarker changes, were seen in those athletes training less than 35 miles·wk−1 before a marathon race. Although George et al. (10) found no such relationship in a diverse group of recreational runners, it is possible that high training volumes could act to prevent myocardial damage and the release of cardiac troponins. Participants in the present investigation trained an average of 53.8 ± 16.7 miles·wk−1, and this high training volume may account for the relatively low percentage of athletes who demonstrated cTnT levels above the assay detection limit.
The fact that the majority of participants exhibited reduced LV function despite nondetectable troponin release, coupled with only moderate decreases in LV function observed in two athletes with elevated cTnT, together suggest that the decline in LV function after prolonged exercise is due to mechanisms other than myocardial damage. A remaining question becomes what causes the postexercise biomarker release? Several authors (21,29,30) have theorized that an exercise-induced overload of free radicals caused by long-term oxidative stress may involve cardiomyocyte membrane leakage, leading to the leakage of cytosolic cTnT into the circulation. The concept of cytosolic leakage fits with the low levels of cTnT present in the circulation as well as their rapid appearance and clearance compared with clinical cases (21,29,30).
Previous investigations have reported increases in BNP levels after prolonged exercise. König et al. (14) examined professional cyclists during a 5-d cycling race and observed BNP to remain within the normal range, with postexercise increases of just 37%. Differing results were revealed by Ohba et al. (25), who described BNP increases of up to 500% after a 100-km ultramarathon. Similar to Ohba et al. (25), there was an even more pronounced increase in NT-pro-BNP in the current investigation. We found nearly a 30-fold increase in NT-pro-BNP immediately after exercise. In contrast with several other investigations (14,19), we found no associations between changes in NT-pro-BNP and athletes' ages or finish times.
The cause of the observed dramatic increase in NT-pro-BNP is intriguing. NT-pro-BNP is a hormone produced by the ventricles in response to pressure and volume load and works as a counterregulatory mechanism against the renin-angiotensin-aldosterone system (6). The renin-angiotensin-aldosterone system is elevated in situations of increased central blood volume, such as during exercise (5). Because renal blood flow is dependent on the duration and intensity of exercise (32), pronounced reductions in renal blood flow would be expected to occur, particularly given the duration (20+ h) of exercise used in this study. Therefore, it is possible that the increase in NT-pro-BNP observed after exercise in the present investigation could in fact be part of a regulatory response to significant increases in sympathetic activity and renin secretion (21). This would suggest that these responses are purely physiological and regulatory and not of any pathological relevance. It is interesting to note that although NT-pro-BNP was unrelated to changes in systolic and diastolic function, it was significantly related to indices of vagal tone (Fig. 2). Our results demonstrate that after an ultraendurance run, those with the greatest increase in parasympathetic indices also have the greatest increase in NT-pro-BNP. Further research is required to elucidate this possible link.
Cardiac Autonomic Modulation
There has been relatively little information on the recovery of cardiovascular autonomic function after various types of physical exercise. Arai et al. (2) assessed the dynamics of autonomic nervous activity during and after a maximal bicycle exercise test with HRV and reported that both HF and LF variables returned to baseline within few minutes after exercise. We also found no significant differences between prerace and postrace HRV indices. Some investigators have suggested that a decreased LV function after prolonged exercise could be caused by strong vagal reactivation after exercise (34). However, unlike these recent reports involving shorter endurance events, we found little evidence of association between alterations in echocardiographic measures and changes in cardiac biomarkers or changes in cardiac autonomic modulation. Given this lack of relationship after the WSER, it is likely that factors other than myocardial damage or strong vagal reactivation contributed to postexercise decreases in LV function (7). Many other underlying mechanisms have been presented in the literature, which may have contributed to the decreases in LV function. These mechanisms could include a down-regulation of cardiac β-receptors mediated by elevated catecholamines during prolonged exercise (13,31), changes in biochemical homeostasis caused by elevated levels of free fatty acids (38), alterations in myofilament sensitivity to calcium (26), and abnormal sarcoplasmic reticulum calcium reuptake caused by a decrease in sarcoplasmic reticulum calcium ATPase (40).
Several limitations should be considered when interpreting the results of the present study. This study included ultraendurance athletes under the age of 50. With the increasing number of older individuals participating in ultraendurance events, future studies should aim to investigate the impact of age on alterations in cardiovascular function after ultraendurance races. Additionally, although our results provide more support for the role of an extraordinarily prolonged duration (e.g., greater than 20 h), as being pivotal in the development of decreases in LV function, the interplay and importance of exercise duration, intensity, and volume on the development of decreases in LV function require further research.
Evidence from the present study indicates that based on traditional echocardiography and novel speckle tracking imaging, both systolic and diastolic functions are mildly reduced immediately after a 100-mile ultraendurance race. Furthermore, levels of NT-pro-BNP are increased in all participants, whereas levels of cTnT are increased in very few athletes. Although we found no association between traditional echocardiography, strain, NT-pro-BNP, and cTnT, further study is needed to confirm these data possibly in older athlete groups. It appears that factors other than myocardial damage or strong vagal reactivation contributed to postexercise decreases in LV function after an ultramarathon.
The authors would like to thank the participants for their time and enthusiasm and the leadership of the Western States Endurance Run for facilitating and partial funding of the research. We would also like to acknowledge the generous support of Dr. Jack Taunton (Chief Medical Officer, Vancouver Organizing Committee for the 2010 Olympic and Paralympic Winter Games (VANOC)) and GE Healthcare. This research project was funded by the Canada Foundation for Innovation, the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, and the Michael Smith Foundation for Health Research. The results of the present study do not constitute endorsement by ACSM.
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