Left ventricular function and mechanics following prolonged endurance exercise: an update and meta-analysis with insights from novel techniques

Left ventricular function and mechanics following prolonged endurance exercise: an update and... Background The cardiac consequences of undertaking endurance exercise are the topic of recent debate. The purpose of this review is to provide an update on a growing body of literature, focusing on left ventricular (LV) function following prolonged endurance exercise over 2 h in duration which have employed novel techniques, including myocardial speckle tracking, to provide a more comprehensive global and regional assessment of LV mechanics. Methods Prospective studies were filtered independently following a pre-set criteria, resulting in the inclusion of 27 studies in the analyses. A random-effects meta-analysis was used to determine the weighted mean difference and 95% confidence intervals (CI) of LV functional and mechanical data from pre-to-post-exercise. Narrative commentary was also provided where volume of available evidence precluded meta-analysis. Results A significant overall reduction in LV longitudinal strain (Ɛ ) n = 22 (− 18 ± 1 to − 17 ± 1%; effect size (d ) − 9: − 1 to − 0.5%), strain rate n = 10 (SR; d − 0.9: − 0.1.3 to − 0.5 l/s) and twist n = 5 (11.9 ± 2.2 to 8.7 ± 2.2°, d − 1: − 1.6 to − 0.3°) was observed following strenuous endurance exercise (range 120–1740 min) (P < 0.01). A smaller number of studies (n = 4) also reported a non-significant reduction in global circumferential and radial Ɛ (P > 0.05). Conclusion The meta-analysis and narrative commentary demonstrated that a reduction in LV function and mechanics is evident following prolonged endurance exercise. The mechanism(s) responsible for these changes are complex and likely multi-factorial in nature and may be linked to right and left ventricular interaction. Keywords Left ventricular mechanics · Endurance exercise · Echocardiography Abbreviations E/A Ratio of early to late diastolic transmitral blood A′ Late diastolic myocardial tissue velocity flow velocities ASR Late diastolic strain rate EDV End diastolic volume CI Confidence intervalEF Ejection fraction cTn Cardiac troponin EICF Exercise-induced cardiac fatigue DBP Diastolic blood pressure ESR Early diastolic strain rate E′ Ear ly diastolic myocardial tissue velocityƐ Strain HR Heart rate LV Left ventricle RV Right ventricle Communicated by Michael Lindinger. S′ Sy stolic myocardial tissue velocity SBP Systolic blood pressure * Rachel N. Lord SR Strain rate rnlord@cardiffmet.ac.uk SSR Systolic strain rate Cardiff Centre for Exercise and Health, Cardiff TDI Tissue Doppler imaging Metropolitan University Cyncoed Campus, Cyncoed Road, WMD Weighted mean difference Cardiff CF236XD, UK Research Institure for Sport and Exercise Sciences, Tom Reilly Building, Liverpool John Moores University, Liverpool, UK Vol.:(0123456789) 1 3 1292 European Journal of Applied Physiology (2018) 118:1291–1299 imaging technology that are providing a more “complete” Introduction picture of cardiac function, motion and mechanics in dif- ferent planes of motion as well as in specific regions of the Prolonged strenuous exercise is growing in popularity (Hoff- myocardium (Oxborough et al. 2006; George et al. 2009). man 2016). Increased participation has led to a growth in Tissue Doppler imaging (TDI) was adopted in EICF research related research including the controversial topic of a transient in an attempt to overcome some of the load-dependent reduction in cardiac function post-exercise (Middleton et al. limitations of standard 2D and Doppler echocardiographic 2006). This has been termed “exercise induced cardiac fatigue” techniques as well as providing local or regional functional (EICF) (Douglas et al. 1987). Originally proposed as a concept assessment (George et al. 2005). Despite this tissue Dop- by Saltin and Stenberg (1964), this phenomenon has received pler is influenced by translation, tethering and the angle of more attention as cardiac imaging tools have improved (Daw- insonation (Marwick 2006). The advent of myocardial strain son et al. 2008; Shave et al. 2009; Oxborough et al. 2010a, b). (ε) imaging can overcome these issues and tissue Doppler The prevalence, causes and consequences of altered cardiac ε imaging allowed the assessment of LV Eulerian ε and function after prolonged strenuous exercise have prompted on- strain rate (SR) providing regional and global assessment going empirical study and debate (Douglas et al. 1987; Lord of cardiac function (Neilan et al. 2006a, b). Because tissue et al. 2016) that has led to a number of narrative reviews (Daw- Doppler ε remains angle-dependent and cardiac mechanics son et al. 2005; Shave et al. 2008; Oxborough et al. 2010a, b) occur in mutliple planes of motion the majority of ε and SR and meta-analyses (Middleton et al. 2006; Elliott and La Ger- data acquired in EICF research has employed myocardial che 2015). In a global context, during recovery from prolonged speckle tracking technology to determine regional and global endurance exercise, heart rate and therefore cardiac output are Lagrangian ε and SR data in multiple planes. This imaging elevated, however despite this, there is evidence to suggest that tool also facilitates the estimation of LV rotation, twist and there is an intrinsic reduction in cardiac function. untwist. LV untwisting is fundamental in the development of Studies completed between the 1980s and 2006 were com- an intra-ventricular pressure gradient that drives early dias- piled within a meta-analysis undertaken by Middleton et al. tolic filling (Notomi et al. 2008) and thus provides further (2006). The outcome variables were ejection fraction (EF), insight within the post-exercise setting. a gross estimate of left ventricular (LV) contractile function, There have been no systematic or narrative reviews of the and the early to atrial (E/A) peak transmitral flow velocity LV responses to prolonged strenuous exercise since 2010 ratio, an index of global diastolic function. In a collapsed sam- (Oxborough et al. 2010a). An up-to-date review and meta- ple of 294 athletes, completing between 1 and 24 h of pro- analysis including new studies employing tissue Doppler longed exercise, there was a significant overall effect on both and ε imaging techniques provides a timely update on our EF (2% decline) and E/A (0.5 au decline) post-exercise. The knowledge as well as drive on-going discussions about the outcome for EF was partially mediated by preload, exercise potential physiological mechanism(s) underpinning EICF. duration and training level although this was not the case for Potential physiological mechanisms and new data on ven- E/A. Study-to-study heterogeneity, possibly linked to exercise tricular interaction will be reviewed after the presentation mode, training status of participants, technical measurement and discussion of data from both meta-analysis outcomes issues and study design limitations have been documented and narrative comment. in later narrative reviews (Shave et  al. 2008; Oxborough et al. 2010a, b). Whilst empirical data continues to be col- lected (Neilan et al. 2006a, b; Hart et al. 2007; Dawson et al. 2008; La Gerche et al. 2008, 2011, 2012, 2015; George et al. Methods 2009; Nottin et al. 2009; Sahlen et al. 2009; Scott et al. 2009; Shave et al. 2009; Banks et al. 2010, 2011; Chan-Dewar et al. Our initial aim was to identify all echocardiographic stud- 2010; Oxborough et al. 2010b, 2011; Oosthuyse et al. 2012; ies examining tissue Doppler and myocardial ε parameters Vitiello et al. 2013a, b; Dalla Vecchia et al. 2014; Cote et al. following a bout of endurance exercise > 120 min in dura- 2015; Stewart et al. 2015; Lord et al. 2016), the most recent tion. Relevant MeSH subject terms and keywords pertaining meta-analysis (Elliott and La Gerche 2015) focussed solely to post-endurance exercise cardiac functional response and on the right ventricular response to prolonged exercise. Con- Boolean operators were used in online database searches. sequently, this new review and meta-analysis will update our In addition to date limits (2006 onwards), the search was understanding of the LV response to prolonged exercise. limited to human studies and those with an English language A new systematic review and meta-analysis is timely abstract. The following search string was employed: because of; (1) the continuing interest and development of a growing and often contradictory or underpowered empirical ‘Left Ventricular Strain$ OR Mechanics$ AND Endur- database, and (2) the substantial developments in cardiac ance$ Exercise$’ 1 3 European Journal of Applied Physiology (2018) 118:1291–1299 1293 Prospective studies were filtered initially using titles and then abstracts. This process was completed independently by two authors (MB, BC) who compared decision-making and discussed disagreements. Inclusion criteria were: (1) Exercise duration over 120 min, (2) Pre-and post-exercise data provided and (3) Healthy subjects with no history of cardiovascular disease. This resulted in 27 studies for inclu- sion in the meta-analysis (Fig. 1; Table 1). All relevant cardiac data were extracted (MB, BC) directly from individual trials into a spreadsheet (Excel 2010, Micro- soft Corp). Continuous data for LV functional parameters were recorded as group mean ± SD for each study. Extracted systolic variables comprised ejection fraction (EF), systolic septal mitral annular tissue velocity (S′), longitudinal, radial and circumferential ε and systolic SR (SRS), rotation and systolic rotation rates as well as twist. Diastolic variables comprised early diastolic transmitral blood flow velocity (E ), late diastolic transmitral blood flow velocity (A), early dias- tolic mitral annular tissue velocity (E′), late diastolic mitral annular tissue velocity (A′), longitudinal, radial and circum- ferential diastolic SR (ESR and ASR) as well as untwist. Outcome variables selection was based upon physiological relevance and study-to-study reporting. Furthermore, we extracted data on heart rate, blood pressure and LV end dias- tolic volume (LVEDV) as potential mediating factors (rate, afterload, preload) for LV function. Statistical analysis A random-effects meta-analysis was used to determine the weighted mean difference (WMD) and 95% CIs of LV func- tional data between pre-exercise and post-exercise as well as data for HR, blood pressure and LVEDV. For the purposes of the meta-analytic technique we focused on specific primary LV functional variables on the basis of the number of studies containing relevant data. Where data were available for ≥ 4 studies a meta-analysis approach was completed. For variables with fewer studies narrative comparisons and comments were Fig. 1 Outline of the search and filtration process for studies included made. All statistical analyses were performed using Compre- in the meta-analysis hensive Meta-Analysis (Biostat: V 2.2.064, Englewood, NJ, USA). For comparison of moderator variables, standardised to the right. This supports further evaluation of study-to-study difference in means (Cohen’s d)/effect sizes were calculated heterogeneity. for each individual study and a summary with overall effect size recorded for each group of studies. Negative effect sizes indicated greater moderator variable at pre-exercise group, Results and commentary whereas a positive effect size identified greater value post- exercise. Heterogeneity was reported using Cochran’s Q and Loading conditions I statistic (the percentage of total variation between studies due to heterogeneity rather than chance). To address publi- Following prolonged endurance exercise, heart rate (HR) cation bias, funnel plots were calculated following Egger’s was significantly elevated from 59 ± 1 (56–61) to 78 ± 2 regression intercept. Exemplar plots for EF and longitudinal ε (76–81) whilst SBP was significantly reduced from 126 ± 2 are provided in Fig. 2a, b. The funnel plots demonstrated that (121–131) to 115 ± 3 (109–132). LV EDV was significantly fewer studies were outside of the funnel but were distributed 1 3 1294 European Journal of Applied Physiology (2018) 118:1291–1299 Table 1 Study and participant demographics, training history and exercise stimulus detail Study N Male Female Age (years) Distance (km) Duration (min) Exercise type Training Train- distance ing time (km) (min) Banks et al. (2011) 18 12 6 28 150 High-intensity exercise Banks et al. (2011) 18 15 3 52 150 High-intensity exercise Chan Dewar et al. (2010) 19 16 3 41 89 586 Ultramarathon 88 Cote et al. (2015) 17 17 0 45 160 1740 Run 86 Cote et al. (2015) 8 0 8 46 160 1554 Run 86 Dalla Vecchia et al. 35 31 4 42 160 Half marathon (2014) Dawson et al. (2008) 15 15 0 32 42 229 Marathon George et al. (2009) 19 16 3 41 89 586 Run Hart et al. (2007) 14 13 1 34 42 126 Marathon La Gerche et al. (2008) 27 20 7 32 600 Triathlon 1152 La Gerche et al. (2011) 39 35 4 36 960 La Gerche et al. (2011) 14 12 2 38 102 La Gerche et al. (2012) 40 36 4 37 Run/tri/cycle/ultra La Gerche et al. (2015) 40 36 4 37 Marathon, endurance 978 triathlon, alpine cycling race and an ultra-triathlon Lord et al. 2016 15 14 1 40 160 Ultramarathon 104 Neilan et al. (2006a, b) 60 41 42 245 Run 67.2 Nottin et al. (2009) 23 23 0 40 840 Triathlon 720 Oosthuyse et al. (2012) 11 11 0 30 Stimulated race cycling 780 Oxborough et al. (2010a, 17 17 0 33 42 209 Marathon b) Oxborough et al. (2011) 16 12 4 42 161 1470 Run 104 Sahlen et al. (2009) 15 15 0 62 30 199 Cross-country race 276 Scott et al. (2009) 25 20 5 41 160 1530 Ultramarathon 786 Shave et al. (2009) 15 14 1 32 42 213 Marathon Stewart et al. (2015) 10 10 0 27 120 480 Vitiello et al. (2013a, b) 21 21 0 40 166 2280 Ultramarathon Vitiello et al. (2013b) 16 16 0 23 180 Cycling (ergometer) reduced from 125 ± 11 to 117 ± 11 ml pre-to-post-exercise significant reduction in EF of − 0.8 (− 1.2 to − 0.5) indi- [d = − 0.53, 95% CI (− 0.8 to − 0.3, P < 0.001)]. LV systolic cating a global decrease in systolic function following pro- and diastolic functional parameters should be interpreted longed endurance exercise. This is a similar response to that with consideration of these changes in loading conditions observed by Middelton et al. (2006). As EF is heavily influ- coupled with the significant evidence of study-to-study enced by preload and afterload, recent research has focussed heterogeneity (I statistic > 75% for most variables; see more on systolic tissue velocities and/or myocardial ε as Table 2). Although both an increase in inotropic stimulation representative measures of global or regional LV systolic and a decrease in afterload are associated with an increase function. The meta-analysis outcome for S′ indicated no in systolic and diastolic functional parameters, a reduction difference pre- to post-exercise (9.5 ± 0.8–9.7 ± 0.9  cm/s, in preload may have an independent and negative impact on P = 0.9). Data from studies assessing myocardial systolic LV systolic and diastolic function. tissue velocities are equivocal with studies either reporting a reduction in S′ (Dawson et al. 2008; Scott et al. 2009; Chan- Dewar et al. 2010), no change (Oosthuyse et al. 2012) and LV systolic function even an increased S′ (Sahlen et al. 2009) following a bout of endurance exercise. S′ is partially mediated by HR and blood Meta-analysis outcomes for variables associated with LV pressure, so study-to-study differences in these actors may systolic function are presented in Table  2. There was a 1 3 European Journal of Applied Physiology (2018) 118:1291–1299 1295 marathon (Oxborough et al. 2010b) and 100 mile ultramara- thon (Oxborough et al. 2011; La Gerche et al. 2012). The results of the meta-analysis demonstrated a reduc- tion in twist of − 1.0 (− 1.6 to − 0.3) following prolonged endurance exercise. LV twist reflects the amount of energy stored in the myocardium during systolic contraction which is then subsequently released during diastole (Weiner et al. 2010). All five studies included in the meta-analysis reported a decline in LV twist following endurance exercise (Nottin et al. 2009; Oxborough et al. 2011; Vitiello et al. 2013a, b; Lord et al. 2016) that reflects reduced systolic contraction as well as reducing the elastic recoil during untwist in early diastole. This may go some may to explaining reduced early filling during diastole which will be discussed in the subse- quent section. LV diastolic function The meta-analysis identified a decrease in peak E flow veloc- ity of − 1.0 (− 1.4 to − 0.6) following exercise (Table 2). The meta-analysis outcomes for E, A and the E/A ratio reflect both a reduction in E and a compensation in A velocities. This provides further support for altered diastolic filling post-prolonged endurance exercise reported in a previous meta-analysis (Middleton et al. 2006) and narrative review (Oxborough et al. 2010a, b). The decline in early LV fill- ing and the compensatory increase in atrial contribution to LV filling may be mediated by a decline in preload and/or changes in intrinsic LV relaxation and compliance. The meta-analysis also noted a reduction in E′ of − 0.7 (− 0.5 to − 1.0; Table 2) following exercise. A highly con- sistent reduction in E′ has been reported in response to pro- longed endurance exercise (Nottin et al. 2009, 2012; Shave et al. 2009; Chan-Dewar et al. 2010; Vitiello et al. 2013a, b; Fig. 2 Exemplar funnel plots for (A) Ejection fraction and (B) longi- Lord et al. 2016). tudinal strain Given the small number of studies available early and late diastolic SR and LV untwist were not included in the meta- go some way to explaining the disparate response reported analysis. A decline in early diastolic SR has been reported for S′. It is also pertinent to note that S′ data are derived alongside a reduction in LV untwist following a marathon from only a small area of the basal septum and thus may not (Oxborough et al. 2010b), ironman triathlon (Nottin et al. reflect global changes in function. 2009) and 100 mile race (Oxborough et al. 2011). The meta-analysis identified a significant reduction in longitudinal ε of − 0.9 (− 1.0 to − 0.5) and systolic strain Possible mechanisms rate (SSR) of − 0.9 (− 1.3 to − 0.5). Fewer studies have investigated circumferential ε (n = 4) and radial ε (n = 4) The meta-analysis supports a growing evidence base that after endurance exercise, therefore the meta-analysis out- prolonged exercise can result in a significant and tran- comes suggesting a non-significant reduction post-exercise sient decrement in LV systolic and diastolic function and should be treated more cautiously (see Table  2). George mechanics. Since the earliest human studies in this field et al. (2009) demonstrated changes in LV ε and SSR in all there has been speculation, but very little empirical evi- planes with a greater reduction post-exercise in radial and dence, as to what combination of factors underpin this circumferential motion in their study of Comrades Mara- phenomenon (Dawson et  al. 2003). The propensity for thon runners (c. 360 min running). Similar responses were descriptive studies, largely in a field-based setting, has noted for LV longitudinal and radial ε and SSR following a meant mechanistic insight has been limited given the 1 3 1296 European Journal of Applied Physiology (2018) 118:1291–1299 Table 2 Meta-analysis of LV functional parameters pre- and post-exercise endurance exercise (> 120 min) Parameter Number Pre mean Post mean P value d 95% CI Heterogeneity of stud- Cochrane’s Q I statistic (%) P value ies Systolic function  HR (bpm) 20 59 ± 1 (56 to 61) 78 ± 2 (76 to 81) 0.01 2 2–4 52 67 0.01  SBP (mmHg) 16 126 ± 2 (121 to 115 ± 3 (109 to 0.01 − 1 − 1.5 to − 0.6 30 73 0.01 131) 132)  DBP (mmHg) 11 74 ± 1 (72 to 76) 71 ± 2 (68 to 75) 0.01 − 0.5 − 0.8 to 0.3 4 0 0.5  LVEDV 13 125 ± 11 (104 to 117 ± 11 (95 to 0.01 − 0.5 − 0.8 to − 0.3 17 28 0.2 147) 138)  EF (%) 17 63 ± 1.0 (62 to 65) 60 ± 1.0 (58 to 62) 0.01 − 0.8 − 1.2 to − 0.5 74 78 0.01  S′ (cm/s) 5 9.5 ± 0.8 (7.8 to 9.7 ± 0.9 (7.9 to 0.08 − 0.7 − 1 to − 0.4 2 0 0.2 1.1) 11.4)  Longitudinal 22 − 18 ± 1 (− 19 to − 17 ± 1 (− 18 to 0.01 − 0.9 − 1 to − 0.5 44 77 0.1 strain (%) − 17) − 16) −1  Long SSR (l s ) 10 − 0.99 ± 0.03 − 1.01 ± 0.03 0.01 − 0.9 − 1.3 to − 0.5 44 77 0.01 (− 1.04 to (− 1.07 to − 0.90) − 0.96)  Circumferential 4 − 19.2 ± 1.1 − 17.8 ± 1.1 0.2 − 1.1 − 2.8 to 0.5 42 93 0.01 strain (%) (− 21.4 to (− 19.9 to − 17.0) − 15.7)  Radial strain (%) 4 27.4 ± 13.0 (1.8 to 11.2 ± 16.8 (− 21.8 0.07 − 1 − 2.5 to 0.1 28 89 0.04 53.0) to 44.2)  Twist ( ) 5 11.9 ± 2.2 (7.7 to 8.7 ± 2.2 (4.5 to 0.01 − 1 − 1.6 to − 0.3 19 78 0.01 16.2) 13.0) Diastolic function  E (m/s) 9 0.8 ± 0.02 (0.7 to 0.7 ± 0.02 (0.6 to 0.01 − 1 − 1.4 to − 0.6 50 74 0.01 0.8) 0.7)  A (m/s) 14 0.5 ± 0.02 (0.5 to 0.6 ± 0.02 (0.5 to 0.01 − 0.6 − 0.9 to − 0.2 49 73 0.01 0.5) 0.6) E/A 18 1.6 ± 0.1 (1.5 to 1.3 ± 0.1 (1.2 to 0.01 − 1.1 − 1. to − 0.8 59 71 0.01 1.7) 1.4) E′ (cm/s) 14 10 ± 1 (9 to 11) 9 ± 1 (8 to 11) 0.01 − 0.7 − 1 to − 0.5 15 39 0.1 HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, EF Ejection fraction, SSR strain rate in systole, E early diastolic trans- mitral blood flow velocity, A late diastolic transmitral blood flow velocity, E/A ratio of early to late diastolic transmitral blood flow velocity, E′ early diastolic myocardial tissue velocity, P value < 0.05, d Cohen’s standardised difference in means/effect sizes, I (%) tau squared, CI confi- dence interval significant limitations of field-based studies. To date, there occurring at the same time. Despite this there is evidence has been suggestion that the following factors may have that point to the fact that changes in rate or loading cannot independent or synergistic roles to play; (1) post-exercise account for all of the changes in LV systolic and diastolic alterations in loading and heart rate, (2) subclinical levels function or mechanics after endurance exercise. For exam- of cardiomyocyte damage, (3) β-adrenergic desensitisa- ple, the use of preload augmentation, via the Trendelenburg tion, and/or (4) serial or parallel ventricular interaction. manoeuvre, after a marathon only normalised E/A and not We will briefly touch on all of these and detail the strength E′ suggesting some degree of intrinsic impairment in relax- or lack of evidence related to these factors. ation (Hart et al. 2007). George et al. (2009) reported on a The role of altered rate or loading has been raised since case series where ε was reduced to a greater extent in septal the earliest empirical studies, as we are aware that pro- wall segments compared to the rest of the LV wall after longed exercise will likely lead to a raised HR, a relative a 90 km run. This localised impact on cardiac function hypotension and reduced LVEDV (preload) for a signifi - suggested a localised intrinsic, rather than a global load- cant period post-exercise (Dawson et al. 2003). It is quite related mechanism. Chan-Dewar et al. (2010) reported an difficult to “unpick” the impact of changes in rate and load- increase in electro-mechanical delay (the time between the ing from each other and alternative mechanisms that are electrical signal for contraction and peak tissue velocities 1 3 European Journal of Applied Physiology (2018) 118:1291–1299 1297 in the LV wall) post-exercise that points to an intrinsic changes in relaxation but may have a role in contractile post-excitation mechanism. In addition, the approach often change following longer duration exercise where receptors used in individual studies to correlate changes in LV func- are exposed to high levels of circulating catecholamines tion post-exercise with changes in rate and loading have over a longer time period. been highly variable (Middleton et al. 2006). Whilst rate More recently, a new theory related to LV and right ven- and loading may have some small role to play in mediat- tricular (RV) interaction (serial or parallel) has emerged ing changes in LV function and mechanics after prolonged based on work from Oxborough et al. (2010b, 2011) and exercise, there is no strong evidence to suggest this is La Gerche et al. (2011, 2012). Data suggests a relatively responsible for all of the changes observed. Consequently, higher elevation of pulmonary artery pressure (PAP) and researchers have looked for other mechanistic evidence, therefore a disproportionately higher stroke work load in the largely via indirect association. RV compared to the LV during prolonged dynamic exercise Evidence of a role for myocardial damage/stunning (La Gerche et al. 2011). The thin walled RV myocardium (Shave et al. 2010; Scharhag et al. 2013) has largely involved may not able to sustain contractile force against an elevated descriptive data with the release/appearance of cardiac- afterload for a prolonged time period (La Gerche et al. 2011; specific biomarkers of myocyte damage (cardiac troponins; Oxborough et al. 2011). This could lead to a reduction in RV cTn) evident alongside changes in LV function and mechan- contractility that would reduce the volume of blood that the ics. Despite this, only two studies have demonstrated rela- RV is able to eject and, therefore downstream or “serially” tionships between the degree of LV dysfunction and mag- LA preload will be impaired (Oxborough et al. 2010b). A nitude of troponin release following prolonged endurance drop in LA preload will lead to a reduced LV filling and exercise (Rifai et al. 1999; Neilan et al. 2006a, b). Most evi- subsequently impact upon LV systolic function and mechan- dence does not support a direct temporal correlation of these ics. Landmark studies by Oxborough et al. (2011) and La two phenomena and therefore a causative effect of localised Gerche et al. (2012) reported RV dilatation and reduced RV subclinical levels of cardiomyocyte damage on changes in ε with a concomitant reduction in LV EDV following pro- function and mechanics is improbable and this is likely a longed exercise. There may also be a “parallel” component benign response to elevated myocardial stress during pro- to ventricular interaction. In patients with a chronically ele- longed endurance exercise (Shave et al. 2010). vated RV afterload the RV is dilated (Olson et al. 2010) and Β-adrenergic receptor downregulation in response to RV pressure may be elevated. The RV dilatation places an sustained elevations in circulating catecholamines has unbalanced volume overload on the interventricular septum been suggested as an alternative mechanism to explain LV and causes septal flattening or displacement, specifically in dysfunction following prolonged endurance exercise. A diastole (Ryan et al. 1985). A flattened interventricular sep- number of studies have suggested that the increased cir- tum may affect the structural integrity of the LV and impact culating catecholamines during prolonged exercise may on LV longitudinal and twist mechanics. This could also result in decreased cardiac β-receptor function or desen- reduce the suction effect and pressure gradient caused by sitisation via downregulation and/or uncoupling with the early LV relaxation and reduce LV filling. Evidence of septal subsequent reduction in LV inotropic and chronotropic displacement is reported by both La Gerche et al. (2012) response explaining LV dysfunction (Eysmann et al. 1996; and Oxborough et al. (2011) following prolonged endur- Douglas et al. 1998; Welsh et al. 2005; Hart et al. 2006). ance exercise, highlighting the likelihood of both a serial and Whilst β-adrenergic receptor responsiveness cannot be parallel impact of the RV response to a relative elevation in directly assessed in athletes, previous studies have dem- pulmonary afterload. onstrated a significant increase in the dose of both chrono- tropic and inotropic stimulant drugs required to generate the same change in heart rate or contractility pre- to post- Limitations prolonged endurance exercise inferring a reduction in car- diac β-receptor response following prolonged strenuous This meta-analysis focused on LV mechanics and did not exercise (Eysmann et al. 1996; Douglas et al. 1998; Welsh include a comprehensive review of global cardiovascular et  al. 2005; Scott et al. 2007). This downregulation has parameters (e.g., total peripheral resistance) whose reporting been related to systolic functional changes post-exercise in ultra-endurance exercise studies is inconsistent. Future (Welsh et al. 2005; Banks et al. 2010); however, it is not empirical work may address the interaction of cardiac clear if any relationship exists with changes in diastolic mechanics within a holistic assessment of global cardiovas- function (Hart et al. 2006). As diastolic changes are preva- cular function, as this may help unpick the implications (if lent following exercise of shorter duration than included any) of exercise-induced changes in cardiac mechanics. in this meta-analysis (Hart et al. 2006), this would suggest that β-adrenergic downregulation may not fully explain 1 3 1298 European Journal of Applied Physiology (2018) 118:1291–1299 echocardiographic evidence of reduced diastolic function of the Conclusion heart. Eur J Appl Physiol 94:305–309 Dawson EA, Whyte GP, Black MA, Jones H, Hopkins N, Oxborough There is a growing body of evidence in support of a tran- D, Gaze D, Shave RE, Wilson M, George KP, Green DJ (2008) sient decline in LV systolic and diastolic function and Changes in vascular and cardiac function after prolonged strenu- ous exercise in humans. J Appl Physiol (1985) 105:1562–1568 mechanics following a period of ultra-endurance exercise. Douglas PS, Otoole ML, Hiller WDB, Hackney K, Reichek N The current meta-analysis and narrative commentary add to (1987) Cardiac fatigue after prolonged exercise. Circulation this database with the key outcomes from the meta-analysis 76:1206–1213 supporting a global reduction in LV systolic and diastolic Douglas PS, O’Toole ML, Katz SE (1998) Prolonged exercise alters cardiac chronotropic responsiveness in endurance athletes. J mechanics following prolonged endurance exercise. Whilst Sports Med Phys Fitness 38:158–163 the magnitude of this change is large enough to have a Elliott AD, La Gerche A (2015) The right ventricle following pro- significant impact on function, this does not reach a level longed endurance exercise: are we overlooking the more important indicative of pathology; however, the clinical relevance of side of the heart? A meta-analysis. Br J Sports Med 49:724–729 Eysmann SB, Gervino E, Vatner DE, Katz SE, Decker L, Douglas PS this diminished function after repeated bouts of endurance (1996) Prolonged exercise alters beta-adrenergic responsiveness exercise is not fully understood. The mechanism(s) respon- in healthy sedentary humans. J Appl Physiol (1985) 80:616–622 sible for these changes are complex and likely multi-facto- George K, Oxborough D, Forster J, Whyte G, Shave R, Dawson E, rial in nature. Newer echocardiographic assessments may Stephenson C, Dugdill L, Edwards B, Gaze D (2005) Mitral annu- lar myocardial velocity assessment of segmental left ventricular be able to provide some insight into these mechanism(s) in diastolic function after prolonged exercise in humans. J Physiol humans. Further studies are required in this complex and 569:305–313 often contradictory field. George K, Shave R, Oxborough D, Cable T, Dawson E, Artis N, Gaze D, Hew-Butler T, Sharwood K, Noakes T (2009) Left ventricular Author contribution statement RL, VU and KG conceived and wall segment motion after ultra-endurance exercise in humans designed research. BC and MB conducted data filtration and extrac- assessed by myocardial speckle tracking. Eur J Echocardiogr tion. VU carried out meta-analysis. RL, VU and KG interpreted and 10:238–243 analysed data. RL provided narrative commentary. All authors read and Hart E, Dawson E, Rasmussen P, George K, Secher NH, Whyte G, approved the manuscript. Shave R (2006) Beta-adrenergic receptor desensitization in man: insight into post-exercise attenuation of cardiac function. J Physiol 577:717–725 Open Access This article is distributed under the terms of the Crea- Hart E, Shave R, Middleton N, George K, Whyte G, Oxborough D tive Commons Attribution 4.0 International License (http://creat iveco (2007) Effect of preload augmentation on pulsed wave and tissue mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- Doppler echocardiographic indices of diastolic function after a tion, and reproduction in any medium, provided you give appropriate marathon. J Am Soc Echocardiogr 20:1393–1399 credit to the original author(s) and the source, provide a link to the Hoffman MD (2016) Injuries and health considerations in ultramara- Creative Commons license, and indicate if changes were made. thon runners. 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J Physiol 569:325–330 WF (1985) An echocardiographic index for separation of right 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Applied Physiology Springer Journals

Left ventricular function and mechanics following prolonged endurance exercise: an update and meta-analysis with insights from novel techniques

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Springer Berlin Heidelberg
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Copyright © 2018 by The Author(s)
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Biomedicine; Human Physiology; Occupational Medicine/Industrial Medicine; Sports Medicine
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1439-6319
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10.1007/s00421-018-3906-z
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Abstract

Background The cardiac consequences of undertaking endurance exercise are the topic of recent debate. The purpose of this review is to provide an update on a growing body of literature, focusing on left ventricular (LV) function following prolonged endurance exercise over 2 h in duration which have employed novel techniques, including myocardial speckle tracking, to provide a more comprehensive global and regional assessment of LV mechanics. Methods Prospective studies were filtered independently following a pre-set criteria, resulting in the inclusion of 27 studies in the analyses. A random-effects meta-analysis was used to determine the weighted mean difference and 95% confidence intervals (CI) of LV functional and mechanical data from pre-to-post-exercise. Narrative commentary was also provided where volume of available evidence precluded meta-analysis. Results A significant overall reduction in LV longitudinal strain (Ɛ ) n = 22 (− 18 ± 1 to − 17 ± 1%; effect size (d ) − 9: − 1 to − 0.5%), strain rate n = 10 (SR; d − 0.9: − 0.1.3 to − 0.5 l/s) and twist n = 5 (11.9 ± 2.2 to 8.7 ± 2.2°, d − 1: − 1.6 to − 0.3°) was observed following strenuous endurance exercise (range 120–1740 min) (P < 0.01). A smaller number of studies (n = 4) also reported a non-significant reduction in global circumferential and radial Ɛ (P > 0.05). Conclusion The meta-analysis and narrative commentary demonstrated that a reduction in LV function and mechanics is evident following prolonged endurance exercise. The mechanism(s) responsible for these changes are complex and likely multi-factorial in nature and may be linked to right and left ventricular interaction. Keywords Left ventricular mechanics · Endurance exercise · Echocardiography Abbreviations E/A Ratio of early to late diastolic transmitral blood A′ Late diastolic myocardial tissue velocity flow velocities ASR Late diastolic strain rate EDV End diastolic volume CI Confidence intervalEF Ejection fraction cTn Cardiac troponin EICF Exercise-induced cardiac fatigue DBP Diastolic blood pressure ESR Early diastolic strain rate E′ Ear ly diastolic myocardial tissue velocityƐ Strain HR Heart rate LV Left ventricle RV Right ventricle Communicated by Michael Lindinger. S′ Sy stolic myocardial tissue velocity SBP Systolic blood pressure * Rachel N. Lord SR Strain rate rnlord@cardiffmet.ac.uk SSR Systolic strain rate Cardiff Centre for Exercise and Health, Cardiff TDI Tissue Doppler imaging Metropolitan University Cyncoed Campus, Cyncoed Road, WMD Weighted mean difference Cardiff CF236XD, UK Research Institure for Sport and Exercise Sciences, Tom Reilly Building, Liverpool John Moores University, Liverpool, UK Vol.:(0123456789) 1 3 1292 European Journal of Applied Physiology (2018) 118:1291–1299 imaging technology that are providing a more “complete” Introduction picture of cardiac function, motion and mechanics in dif- ferent planes of motion as well as in specific regions of the Prolonged strenuous exercise is growing in popularity (Hoff- myocardium (Oxborough et al. 2006; George et al. 2009). man 2016). Increased participation has led to a growth in Tissue Doppler imaging (TDI) was adopted in EICF research related research including the controversial topic of a transient in an attempt to overcome some of the load-dependent reduction in cardiac function post-exercise (Middleton et al. limitations of standard 2D and Doppler echocardiographic 2006). This has been termed “exercise induced cardiac fatigue” techniques as well as providing local or regional functional (EICF) (Douglas et al. 1987). Originally proposed as a concept assessment (George et al. 2005). Despite this tissue Dop- by Saltin and Stenberg (1964), this phenomenon has received pler is influenced by translation, tethering and the angle of more attention as cardiac imaging tools have improved (Daw- insonation (Marwick 2006). The advent of myocardial strain son et al. 2008; Shave et al. 2009; Oxborough et al. 2010a, b). (ε) imaging can overcome these issues and tissue Doppler The prevalence, causes and consequences of altered cardiac ε imaging allowed the assessment of LV Eulerian ε and function after prolonged strenuous exercise have prompted on- strain rate (SR) providing regional and global assessment going empirical study and debate (Douglas et al. 1987; Lord of cardiac function (Neilan et al. 2006a, b). Because tissue et al. 2016) that has led to a number of narrative reviews (Daw- Doppler ε remains angle-dependent and cardiac mechanics son et al. 2005; Shave et al. 2008; Oxborough et al. 2010a, b) occur in mutliple planes of motion the majority of ε and SR and meta-analyses (Middleton et al. 2006; Elliott and La Ger- data acquired in EICF research has employed myocardial che 2015). In a global context, during recovery from prolonged speckle tracking technology to determine regional and global endurance exercise, heart rate and therefore cardiac output are Lagrangian ε and SR data in multiple planes. This imaging elevated, however despite this, there is evidence to suggest that tool also facilitates the estimation of LV rotation, twist and there is an intrinsic reduction in cardiac function. untwist. LV untwisting is fundamental in the development of Studies completed between the 1980s and 2006 were com- an intra-ventricular pressure gradient that drives early dias- piled within a meta-analysis undertaken by Middleton et al. tolic filling (Notomi et al. 2008) and thus provides further (2006). The outcome variables were ejection fraction (EF), insight within the post-exercise setting. a gross estimate of left ventricular (LV) contractile function, There have been no systematic or narrative reviews of the and the early to atrial (E/A) peak transmitral flow velocity LV responses to prolonged strenuous exercise since 2010 ratio, an index of global diastolic function. In a collapsed sam- (Oxborough et al. 2010a). An up-to-date review and meta- ple of 294 athletes, completing between 1 and 24 h of pro- analysis including new studies employing tissue Doppler longed exercise, there was a significant overall effect on both and ε imaging techniques provides a timely update on our EF (2% decline) and E/A (0.5 au decline) post-exercise. The knowledge as well as drive on-going discussions about the outcome for EF was partially mediated by preload, exercise potential physiological mechanism(s) underpinning EICF. duration and training level although this was not the case for Potential physiological mechanisms and new data on ven- E/A. Study-to-study heterogeneity, possibly linked to exercise tricular interaction will be reviewed after the presentation mode, training status of participants, technical measurement and discussion of data from both meta-analysis outcomes issues and study design limitations have been documented and narrative comment. in later narrative reviews (Shave et  al. 2008; Oxborough et al. 2010a, b). Whilst empirical data continues to be col- lected (Neilan et al. 2006a, b; Hart et al. 2007; Dawson et al. 2008; La Gerche et al. 2008, 2011, 2012, 2015; George et al. Methods 2009; Nottin et al. 2009; Sahlen et al. 2009; Scott et al. 2009; Shave et al. 2009; Banks et al. 2010, 2011; Chan-Dewar et al. Our initial aim was to identify all echocardiographic stud- 2010; Oxborough et al. 2010b, 2011; Oosthuyse et al. 2012; ies examining tissue Doppler and myocardial ε parameters Vitiello et al. 2013a, b; Dalla Vecchia et al. 2014; Cote et al. following a bout of endurance exercise > 120 min in dura- 2015; Stewart et al. 2015; Lord et al. 2016), the most recent tion. Relevant MeSH subject terms and keywords pertaining meta-analysis (Elliott and La Gerche 2015) focussed solely to post-endurance exercise cardiac functional response and on the right ventricular response to prolonged exercise. Con- Boolean operators were used in online database searches. sequently, this new review and meta-analysis will update our In addition to date limits (2006 onwards), the search was understanding of the LV response to prolonged exercise. limited to human studies and those with an English language A new systematic review and meta-analysis is timely abstract. The following search string was employed: because of; (1) the continuing interest and development of a growing and often contradictory or underpowered empirical ‘Left Ventricular Strain$ OR Mechanics$ AND Endur- database, and (2) the substantial developments in cardiac ance$ Exercise$’ 1 3 European Journal of Applied Physiology (2018) 118:1291–1299 1293 Prospective studies were filtered initially using titles and then abstracts. This process was completed independently by two authors (MB, BC) who compared decision-making and discussed disagreements. Inclusion criteria were: (1) Exercise duration over 120 min, (2) Pre-and post-exercise data provided and (3) Healthy subjects with no history of cardiovascular disease. This resulted in 27 studies for inclu- sion in the meta-analysis (Fig. 1; Table 1). All relevant cardiac data were extracted (MB, BC) directly from individual trials into a spreadsheet (Excel 2010, Micro- soft Corp). Continuous data for LV functional parameters were recorded as group mean ± SD for each study. Extracted systolic variables comprised ejection fraction (EF), systolic septal mitral annular tissue velocity (S′), longitudinal, radial and circumferential ε and systolic SR (SRS), rotation and systolic rotation rates as well as twist. Diastolic variables comprised early diastolic transmitral blood flow velocity (E ), late diastolic transmitral blood flow velocity (A), early dias- tolic mitral annular tissue velocity (E′), late diastolic mitral annular tissue velocity (A′), longitudinal, radial and circum- ferential diastolic SR (ESR and ASR) as well as untwist. Outcome variables selection was based upon physiological relevance and study-to-study reporting. Furthermore, we extracted data on heart rate, blood pressure and LV end dias- tolic volume (LVEDV) as potential mediating factors (rate, afterload, preload) for LV function. Statistical analysis A random-effects meta-analysis was used to determine the weighted mean difference (WMD) and 95% CIs of LV func- tional data between pre-exercise and post-exercise as well as data for HR, blood pressure and LVEDV. For the purposes of the meta-analytic technique we focused on specific primary LV functional variables on the basis of the number of studies containing relevant data. Where data were available for ≥ 4 studies a meta-analysis approach was completed. For variables with fewer studies narrative comparisons and comments were Fig. 1 Outline of the search and filtration process for studies included made. All statistical analyses were performed using Compre- in the meta-analysis hensive Meta-Analysis (Biostat: V 2.2.064, Englewood, NJ, USA). For comparison of moderator variables, standardised to the right. This supports further evaluation of study-to-study difference in means (Cohen’s d)/effect sizes were calculated heterogeneity. for each individual study and a summary with overall effect size recorded for each group of studies. Negative effect sizes indicated greater moderator variable at pre-exercise group, Results and commentary whereas a positive effect size identified greater value post- exercise. Heterogeneity was reported using Cochran’s Q and Loading conditions I statistic (the percentage of total variation between studies due to heterogeneity rather than chance). To address publi- Following prolonged endurance exercise, heart rate (HR) cation bias, funnel plots were calculated following Egger’s was significantly elevated from 59 ± 1 (56–61) to 78 ± 2 regression intercept. Exemplar plots for EF and longitudinal ε (76–81) whilst SBP was significantly reduced from 126 ± 2 are provided in Fig. 2a, b. The funnel plots demonstrated that (121–131) to 115 ± 3 (109–132). LV EDV was significantly fewer studies were outside of the funnel but were distributed 1 3 1294 European Journal of Applied Physiology (2018) 118:1291–1299 Table 1 Study and participant demographics, training history and exercise stimulus detail Study N Male Female Age (years) Distance (km) Duration (min) Exercise type Training Train- distance ing time (km) (min) Banks et al. (2011) 18 12 6 28 150 High-intensity exercise Banks et al. (2011) 18 15 3 52 150 High-intensity exercise Chan Dewar et al. (2010) 19 16 3 41 89 586 Ultramarathon 88 Cote et al. (2015) 17 17 0 45 160 1740 Run 86 Cote et al. (2015) 8 0 8 46 160 1554 Run 86 Dalla Vecchia et al. 35 31 4 42 160 Half marathon (2014) Dawson et al. (2008) 15 15 0 32 42 229 Marathon George et al. (2009) 19 16 3 41 89 586 Run Hart et al. (2007) 14 13 1 34 42 126 Marathon La Gerche et al. (2008) 27 20 7 32 600 Triathlon 1152 La Gerche et al. (2011) 39 35 4 36 960 La Gerche et al. (2011) 14 12 2 38 102 La Gerche et al. (2012) 40 36 4 37 Run/tri/cycle/ultra La Gerche et al. (2015) 40 36 4 37 Marathon, endurance 978 triathlon, alpine cycling race and an ultra-triathlon Lord et al. 2016 15 14 1 40 160 Ultramarathon 104 Neilan et al. (2006a, b) 60 41 42 245 Run 67.2 Nottin et al. (2009) 23 23 0 40 840 Triathlon 720 Oosthuyse et al. (2012) 11 11 0 30 Stimulated race cycling 780 Oxborough et al. (2010a, 17 17 0 33 42 209 Marathon b) Oxborough et al. (2011) 16 12 4 42 161 1470 Run 104 Sahlen et al. (2009) 15 15 0 62 30 199 Cross-country race 276 Scott et al. (2009) 25 20 5 41 160 1530 Ultramarathon 786 Shave et al. (2009) 15 14 1 32 42 213 Marathon Stewart et al. (2015) 10 10 0 27 120 480 Vitiello et al. (2013a, b) 21 21 0 40 166 2280 Ultramarathon Vitiello et al. (2013b) 16 16 0 23 180 Cycling (ergometer) reduced from 125 ± 11 to 117 ± 11 ml pre-to-post-exercise significant reduction in EF of − 0.8 (− 1.2 to − 0.5) indi- [d = − 0.53, 95% CI (− 0.8 to − 0.3, P < 0.001)]. LV systolic cating a global decrease in systolic function following pro- and diastolic functional parameters should be interpreted longed endurance exercise. This is a similar response to that with consideration of these changes in loading conditions observed by Middelton et al. (2006). As EF is heavily influ- coupled with the significant evidence of study-to-study enced by preload and afterload, recent research has focussed heterogeneity (I statistic > 75% for most variables; see more on systolic tissue velocities and/or myocardial ε as Table 2). Although both an increase in inotropic stimulation representative measures of global or regional LV systolic and a decrease in afterload are associated with an increase function. The meta-analysis outcome for S′ indicated no in systolic and diastolic functional parameters, a reduction difference pre- to post-exercise (9.5 ± 0.8–9.7 ± 0.9  cm/s, in preload may have an independent and negative impact on P = 0.9). Data from studies assessing myocardial systolic LV systolic and diastolic function. tissue velocities are equivocal with studies either reporting a reduction in S′ (Dawson et al. 2008; Scott et al. 2009; Chan- Dewar et al. 2010), no change (Oosthuyse et al. 2012) and LV systolic function even an increased S′ (Sahlen et al. 2009) following a bout of endurance exercise. S′ is partially mediated by HR and blood Meta-analysis outcomes for variables associated with LV pressure, so study-to-study differences in these actors may systolic function are presented in Table  2. There was a 1 3 European Journal of Applied Physiology (2018) 118:1291–1299 1295 marathon (Oxborough et al. 2010b) and 100 mile ultramara- thon (Oxborough et al. 2011; La Gerche et al. 2012). The results of the meta-analysis demonstrated a reduc- tion in twist of − 1.0 (− 1.6 to − 0.3) following prolonged endurance exercise. LV twist reflects the amount of energy stored in the myocardium during systolic contraction which is then subsequently released during diastole (Weiner et al. 2010). All five studies included in the meta-analysis reported a decline in LV twist following endurance exercise (Nottin et al. 2009; Oxborough et al. 2011; Vitiello et al. 2013a, b; Lord et al. 2016) that reflects reduced systolic contraction as well as reducing the elastic recoil during untwist in early diastole. This may go some may to explaining reduced early filling during diastole which will be discussed in the subse- quent section. LV diastolic function The meta-analysis identified a decrease in peak E flow veloc- ity of − 1.0 (− 1.4 to − 0.6) following exercise (Table 2). The meta-analysis outcomes for E, A and the E/A ratio reflect both a reduction in E and a compensation in A velocities. This provides further support for altered diastolic filling post-prolonged endurance exercise reported in a previous meta-analysis (Middleton et al. 2006) and narrative review (Oxborough et al. 2010a, b). The decline in early LV fill- ing and the compensatory increase in atrial contribution to LV filling may be mediated by a decline in preload and/or changes in intrinsic LV relaxation and compliance. The meta-analysis also noted a reduction in E′ of − 0.7 (− 0.5 to − 1.0; Table 2) following exercise. A highly con- sistent reduction in E′ has been reported in response to pro- longed endurance exercise (Nottin et al. 2009, 2012; Shave et al. 2009; Chan-Dewar et al. 2010; Vitiello et al. 2013a, b; Fig. 2 Exemplar funnel plots for (A) Ejection fraction and (B) longi- Lord et al. 2016). tudinal strain Given the small number of studies available early and late diastolic SR and LV untwist were not included in the meta- go some way to explaining the disparate response reported analysis. A decline in early diastolic SR has been reported for S′. It is also pertinent to note that S′ data are derived alongside a reduction in LV untwist following a marathon from only a small area of the basal septum and thus may not (Oxborough et al. 2010b), ironman triathlon (Nottin et al. reflect global changes in function. 2009) and 100 mile race (Oxborough et al. 2011). The meta-analysis identified a significant reduction in longitudinal ε of − 0.9 (− 1.0 to − 0.5) and systolic strain Possible mechanisms rate (SSR) of − 0.9 (− 1.3 to − 0.5). Fewer studies have investigated circumferential ε (n = 4) and radial ε (n = 4) The meta-analysis supports a growing evidence base that after endurance exercise, therefore the meta-analysis out- prolonged exercise can result in a significant and tran- comes suggesting a non-significant reduction post-exercise sient decrement in LV systolic and diastolic function and should be treated more cautiously (see Table  2). George mechanics. Since the earliest human studies in this field et al. (2009) demonstrated changes in LV ε and SSR in all there has been speculation, but very little empirical evi- planes with a greater reduction post-exercise in radial and dence, as to what combination of factors underpin this circumferential motion in their study of Comrades Mara- phenomenon (Dawson et  al. 2003). The propensity for thon runners (c. 360 min running). Similar responses were descriptive studies, largely in a field-based setting, has noted for LV longitudinal and radial ε and SSR following a meant mechanistic insight has been limited given the 1 3 1296 European Journal of Applied Physiology (2018) 118:1291–1299 Table 2 Meta-analysis of LV functional parameters pre- and post-exercise endurance exercise (> 120 min) Parameter Number Pre mean Post mean P value d 95% CI Heterogeneity of stud- Cochrane’s Q I statistic (%) P value ies Systolic function  HR (bpm) 20 59 ± 1 (56 to 61) 78 ± 2 (76 to 81) 0.01 2 2–4 52 67 0.01  SBP (mmHg) 16 126 ± 2 (121 to 115 ± 3 (109 to 0.01 − 1 − 1.5 to − 0.6 30 73 0.01 131) 132)  DBP (mmHg) 11 74 ± 1 (72 to 76) 71 ± 2 (68 to 75) 0.01 − 0.5 − 0.8 to 0.3 4 0 0.5  LVEDV 13 125 ± 11 (104 to 117 ± 11 (95 to 0.01 − 0.5 − 0.8 to − 0.3 17 28 0.2 147) 138)  EF (%) 17 63 ± 1.0 (62 to 65) 60 ± 1.0 (58 to 62) 0.01 − 0.8 − 1.2 to − 0.5 74 78 0.01  S′ (cm/s) 5 9.5 ± 0.8 (7.8 to 9.7 ± 0.9 (7.9 to 0.08 − 0.7 − 1 to − 0.4 2 0 0.2 1.1) 11.4)  Longitudinal 22 − 18 ± 1 (− 19 to − 17 ± 1 (− 18 to 0.01 − 0.9 − 1 to − 0.5 44 77 0.1 strain (%) − 17) − 16) −1  Long SSR (l s ) 10 − 0.99 ± 0.03 − 1.01 ± 0.03 0.01 − 0.9 − 1.3 to − 0.5 44 77 0.01 (− 1.04 to (− 1.07 to − 0.90) − 0.96)  Circumferential 4 − 19.2 ± 1.1 − 17.8 ± 1.1 0.2 − 1.1 − 2.8 to 0.5 42 93 0.01 strain (%) (− 21.4 to (− 19.9 to − 17.0) − 15.7)  Radial strain (%) 4 27.4 ± 13.0 (1.8 to 11.2 ± 16.8 (− 21.8 0.07 − 1 − 2.5 to 0.1 28 89 0.04 53.0) to 44.2)  Twist ( ) 5 11.9 ± 2.2 (7.7 to 8.7 ± 2.2 (4.5 to 0.01 − 1 − 1.6 to − 0.3 19 78 0.01 16.2) 13.0) Diastolic function  E (m/s) 9 0.8 ± 0.02 (0.7 to 0.7 ± 0.02 (0.6 to 0.01 − 1 − 1.4 to − 0.6 50 74 0.01 0.8) 0.7)  A (m/s) 14 0.5 ± 0.02 (0.5 to 0.6 ± 0.02 (0.5 to 0.01 − 0.6 − 0.9 to − 0.2 49 73 0.01 0.5) 0.6) E/A 18 1.6 ± 0.1 (1.5 to 1.3 ± 0.1 (1.2 to 0.01 − 1.1 − 1. to − 0.8 59 71 0.01 1.7) 1.4) E′ (cm/s) 14 10 ± 1 (9 to 11) 9 ± 1 (8 to 11) 0.01 − 0.7 − 1 to − 0.5 15 39 0.1 HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, EF Ejection fraction, SSR strain rate in systole, E early diastolic trans- mitral blood flow velocity, A late diastolic transmitral blood flow velocity, E/A ratio of early to late diastolic transmitral blood flow velocity, E′ early diastolic myocardial tissue velocity, P value < 0.05, d Cohen’s standardised difference in means/effect sizes, I (%) tau squared, CI confi- dence interval significant limitations of field-based studies. To date, there occurring at the same time. Despite this there is evidence has been suggestion that the following factors may have that point to the fact that changes in rate or loading cannot independent or synergistic roles to play; (1) post-exercise account for all of the changes in LV systolic and diastolic alterations in loading and heart rate, (2) subclinical levels function or mechanics after endurance exercise. For exam- of cardiomyocyte damage, (3) β-adrenergic desensitisa- ple, the use of preload augmentation, via the Trendelenburg tion, and/or (4) serial or parallel ventricular interaction. manoeuvre, after a marathon only normalised E/A and not We will briefly touch on all of these and detail the strength E′ suggesting some degree of intrinsic impairment in relax- or lack of evidence related to these factors. ation (Hart et al. 2007). George et al. (2009) reported on a The role of altered rate or loading has been raised since case series where ε was reduced to a greater extent in septal the earliest empirical studies, as we are aware that pro- wall segments compared to the rest of the LV wall after longed exercise will likely lead to a raised HR, a relative a 90 km run. This localised impact on cardiac function hypotension and reduced LVEDV (preload) for a signifi - suggested a localised intrinsic, rather than a global load- cant period post-exercise (Dawson et al. 2003). It is quite related mechanism. Chan-Dewar et al. (2010) reported an difficult to “unpick” the impact of changes in rate and load- increase in electro-mechanical delay (the time between the ing from each other and alternative mechanisms that are electrical signal for contraction and peak tissue velocities 1 3 European Journal of Applied Physiology (2018) 118:1291–1299 1297 in the LV wall) post-exercise that points to an intrinsic changes in relaxation but may have a role in contractile post-excitation mechanism. In addition, the approach often change following longer duration exercise where receptors used in individual studies to correlate changes in LV func- are exposed to high levels of circulating catecholamines tion post-exercise with changes in rate and loading have over a longer time period. been highly variable (Middleton et al. 2006). Whilst rate More recently, a new theory related to LV and right ven- and loading may have some small role to play in mediat- tricular (RV) interaction (serial or parallel) has emerged ing changes in LV function and mechanics after prolonged based on work from Oxborough et al. (2010b, 2011) and exercise, there is no strong evidence to suggest this is La Gerche et al. (2011, 2012). Data suggests a relatively responsible for all of the changes observed. Consequently, higher elevation of pulmonary artery pressure (PAP) and researchers have looked for other mechanistic evidence, therefore a disproportionately higher stroke work load in the largely via indirect association. RV compared to the LV during prolonged dynamic exercise Evidence of a role for myocardial damage/stunning (La Gerche et al. 2011). The thin walled RV myocardium (Shave et al. 2010; Scharhag et al. 2013) has largely involved may not able to sustain contractile force against an elevated descriptive data with the release/appearance of cardiac- afterload for a prolonged time period (La Gerche et al. 2011; specific biomarkers of myocyte damage (cardiac troponins; Oxborough et al. 2011). This could lead to a reduction in RV cTn) evident alongside changes in LV function and mechan- contractility that would reduce the volume of blood that the ics. Despite this, only two studies have demonstrated rela- RV is able to eject and, therefore downstream or “serially” tionships between the degree of LV dysfunction and mag- LA preload will be impaired (Oxborough et al. 2010b). A nitude of troponin release following prolonged endurance drop in LA preload will lead to a reduced LV filling and exercise (Rifai et al. 1999; Neilan et al. 2006a, b). Most evi- subsequently impact upon LV systolic function and mechan- dence does not support a direct temporal correlation of these ics. Landmark studies by Oxborough et al. (2011) and La two phenomena and therefore a causative effect of localised Gerche et al. (2012) reported RV dilatation and reduced RV subclinical levels of cardiomyocyte damage on changes in ε with a concomitant reduction in LV EDV following pro- function and mechanics is improbable and this is likely a longed exercise. There may also be a “parallel” component benign response to elevated myocardial stress during pro- to ventricular interaction. In patients with a chronically ele- longed endurance exercise (Shave et al. 2010). vated RV afterload the RV is dilated (Olson et al. 2010) and Β-adrenergic receptor downregulation in response to RV pressure may be elevated. The RV dilatation places an sustained elevations in circulating catecholamines has unbalanced volume overload on the interventricular septum been suggested as an alternative mechanism to explain LV and causes septal flattening or displacement, specifically in dysfunction following prolonged endurance exercise. A diastole (Ryan et al. 1985). A flattened interventricular sep- number of studies have suggested that the increased cir- tum may affect the structural integrity of the LV and impact culating catecholamines during prolonged exercise may on LV longitudinal and twist mechanics. This could also result in decreased cardiac β-receptor function or desen- reduce the suction effect and pressure gradient caused by sitisation via downregulation and/or uncoupling with the early LV relaxation and reduce LV filling. Evidence of septal subsequent reduction in LV inotropic and chronotropic displacement is reported by both La Gerche et al. (2012) response explaining LV dysfunction (Eysmann et al. 1996; and Oxborough et al. (2011) following prolonged endur- Douglas et al. 1998; Welsh et al. 2005; Hart et al. 2006). ance exercise, highlighting the likelihood of both a serial and Whilst β-adrenergic receptor responsiveness cannot be parallel impact of the RV response to a relative elevation in directly assessed in athletes, previous studies have dem- pulmonary afterload. onstrated a significant increase in the dose of both chrono- tropic and inotropic stimulant drugs required to generate the same change in heart rate or contractility pre- to post- Limitations prolonged endurance exercise inferring a reduction in car- diac β-receptor response following prolonged strenuous This meta-analysis focused on LV mechanics and did not exercise (Eysmann et al. 1996; Douglas et al. 1998; Welsh include a comprehensive review of global cardiovascular et  al. 2005; Scott et al. 2007). This downregulation has parameters (e.g., total peripheral resistance) whose reporting been related to systolic functional changes post-exercise in ultra-endurance exercise studies is inconsistent. Future (Welsh et al. 2005; Banks et al. 2010); however, it is not empirical work may address the interaction of cardiac clear if any relationship exists with changes in diastolic mechanics within a holistic assessment of global cardiovas- function (Hart et al. 2006). As diastolic changes are preva- cular function, as this may help unpick the implications (if lent following exercise of shorter duration than included any) of exercise-induced changes in cardiac mechanics. in this meta-analysis (Hart et al. 2006), this would suggest that β-adrenergic downregulation may not fully explain 1 3 1298 European Journal of Applied Physiology (2018) 118:1291–1299 echocardiographic evidence of reduced diastolic function of the Conclusion heart. Eur J Appl Physiol 94:305–309 Dawson EA, Whyte GP, Black MA, Jones H, Hopkins N, Oxborough There is a growing body of evidence in support of a tran- D, Gaze D, Shave RE, Wilson M, George KP, Green DJ (2008) sient decline in LV systolic and diastolic function and Changes in vascular and cardiac function after prolonged strenu- ous exercise in humans. J Appl Physiol (1985) 105:1562–1568 mechanics following a period of ultra-endurance exercise. Douglas PS, Otoole ML, Hiller WDB, Hackney K, Reichek N The current meta-analysis and narrative commentary add to (1987) Cardiac fatigue after prolonged exercise. Circulation this database with the key outcomes from the meta-analysis 76:1206–1213 supporting a global reduction in LV systolic and diastolic Douglas PS, O’Toole ML, Katz SE (1998) Prolonged exercise alters cardiac chronotropic responsiveness in endurance athletes. J mechanics following prolonged endurance exercise. Whilst Sports Med Phys Fitness 38:158–163 the magnitude of this change is large enough to have a Elliott AD, La Gerche A (2015) The right ventricle following pro- significant impact on function, this does not reach a level longed endurance exercise: are we overlooking the more important indicative of pathology; however, the clinical relevance of side of the heart? A meta-analysis. Br J Sports Med 49:724–729 Eysmann SB, Gervino E, Vatner DE, Katz SE, Decker L, Douglas PS this diminished function after repeated bouts of endurance (1996) Prolonged exercise alters beta-adrenergic responsiveness exercise is not fully understood. The mechanism(s) respon- in healthy sedentary humans. J Appl Physiol (1985) 80:616–622 sible for these changes are complex and likely multi-facto- George K, Oxborough D, Forster J, Whyte G, Shave R, Dawson E, rial in nature. Newer echocardiographic assessments may Stephenson C, Dugdill L, Edwards B, Gaze D (2005) Mitral annu- lar myocardial velocity assessment of segmental left ventricular be able to provide some insight into these mechanism(s) in diastolic function after prolonged exercise in humans. J Physiol humans. Further studies are required in this complex and 569:305–313 often contradictory field. George K, Shave R, Oxborough D, Cable T, Dawson E, Artis N, Gaze D, Hew-Butler T, Sharwood K, Noakes T (2009) Left ventricular Author contribution statement RL, VU and KG conceived and wall segment motion after ultra-endurance exercise in humans designed research. BC and MB conducted data filtration and extrac- assessed by myocardial speckle tracking. Eur J Echocardiogr tion. VU carried out meta-analysis. RL, VU and KG interpreted and 10:238–243 analysed data. RL provided narrative commentary. All authors read and Hart E, Dawson E, Rasmussen P, George K, Secher NH, Whyte G, approved the manuscript. 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European Journal of Applied PhysiologySpringer Journals

Published: Jun 5, 2018

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