Viewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?

Abstract

ViewpointViewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?Mark R. Boyett, Alicia D'Souza, Henggui Zhang, Gwilym M. Morris, Halina Dobrzynski, and Oliver MonfrediMark R. BoyettInstitute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, Manchester, United Kingdom, Alicia D'SouzaInstitute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, Manchester, United Kingdom, Henggui ZhangInstitute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, Manchester, United Kingdom, Gwilym M. MorrisInstitute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, Manchester, United Kingdom, Halina DobrzynskiInstitute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, Manchester, United Kingdom, and Oliver MonfrediInstitute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, Manchester, United KingdomPublished Online:01 May 2013https://doi.org/10.1152/japplphysiol.01126.2012This is the final version - click for previous versionMoreSectionsSupplemental MaterialPDF (56 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat it is well known that athletes have a low resting heart rate, i.e., a resting bradycardia and heart rates below 30 beats/min have been reported (7). For example, Wikipedia states that the Tour de France cyclist, Miguel Indurain, had a resting heart rate of 28 beats/min when race fit. The resting bradycardia in athletes is most often attributed to high vagal tone, i.e., high parasympathetic nerve activity (e.g., Ref. 1). However, over the years doubt about this explanation has been expressed (e.g., Ref. 26). Here we take a critical look at the two lines of evidence said to favor the high vagal tone hypothesis: 1) little or no change in the intrinsic heart rate in athletes and 2) an increase in heart rate variability in athletes.Effect of training on intrinsic heart rate in humans.Jose and Taylor (9) investigated the effect of autonomic blockade in conscious human subjects and concluded that injection of 0.2 mg/kg propranolol (β-adrenergic receptor blocker) and 0.04 mg/kg atropine (M2 muscarinic receptor blocker) effectively blocks autonomic influence on the resting heart rate in the human. They obtained dose-response curves for both drugs to ensure that there was complete blockade (9). This pioneering study established a technique that can be used to study the nature of the resting bradycardia in athletes. Since the effect of athletic training on the resting heart rate before and after autonomic blockade has been extensively investigated in the human and these studies are summarized in Table 1. In three studies (1–3 in Table 1), only the parasympathetic activity to the heart was blocked. In all three studies, there was a significant resting bradycardia as expected in the athletes [see heart rate (HR) data for studies 1–3 in Table 1]. The resting heart rate after parasympathetic blockade was also lower in the athletes (see HRab data for studies 1–3 in Table 1), and in all studies the difference in the heart rate after parasympathetic blockade was greater than the difference in the normal heart rate (compare ΔHR and ΔHRab data for studies 1–3 in Table 1). This suggests that high vagal tone is not the cause of the resting bradycardia in the athletes in these three studies at least. Instead it could be the result of either a decrease in sympathetic tone or a decrease in the intrinsic heart rate in the athletes.Table 1. Summary of the effect of athletic training on the resting HR under normal conditions and after HRab in human subjects in different studiesStudyAuthorsSex, Age, Number of SubjectsType of StudyType of Athlete or TrainingAutonomic Blockade, mg/kgHR of Untrained Subjects, beats/minHR of Trained Subjects, beats/minΔHR, beats/minHRab of Untrained Subjects, beats/minHRab of Trained Subjects, beats/minΔHRab, beats/minΔHRab/ΔHR, %1Maciel et al. (14)Male; 24–34; n = 7I/E10 wk cycling0.04 atr; block not confirmed69.0 ± 1.958.0 ± 1.7*11.0121.0 ± 4.6105.0 ± 4.6*16.01452Katona et al. (10)Male; approximately 21–22; n = 9/8C/ENational/international rowers0.04 atr; block confirmed by dose-response curve63.2 ± 2.153.6 ± 1.4*9.6117.1 ± 3.993.9 ± 2.6*23.22423Stein et al. (26)Male; approximately 28–29; n = 6/groupC/ERunners (≥50 km/week)0.04 atr; block not confirmed65.7 ± 5.958.3 ± 5.7*7.591.9 ± 5.781.4 ± 6.0*10.51404Dickhuth et al. (5)Not specifiedC/not specifiedNot specified0.2 pro + 0.04 atr; not known whether block confirmed67.1 ± 10.253.0 ± 8.8*14.1108.0 ± 7.185.2 ± 12.8*22.81625Lewis et al. (12)Male; approximately 21–26; n = 8/groupC/EElite cyclists (450–700 km/week for 5–11 yr)0.25 pro or 0.5 met +0.04 atr; block not confirmed70.0 ± 7.353.0 ± 7.5*17.0103.0 ± 6.984.6 ± 7.5*18.41086Katona et al. (10)Male; approximately 21–22; n = 9/8C/ENational/inter-national rowers0.2 pro + 0.04 atr; block confirmed by dose-response curve63.2 ± 2.153.6 ± 1.4*9.699.8 ± 3.379.8 ± 2.3*202087Lewis et al. (11)Male; approximately 22; n = 5I/R11 wk leg training0.2 pro + 0.04 atr; block not confirmed58.3 ± 9.152.1 ± 8.6*6.293.0 ± 9.089.3 ± 8.7NS3.7608Smith et al. (23)Male; 20–31; n = 10/groupC/EEndurance exercise trained for >2 yr0.2 met + 0.04 atr; block confirmed by Valsalva manoeuvre and injection of isoproterenol70.0 ± 4.054.0 ± 2.0*16.087.0 ± 2.080.0 ± 3.0*7.0449Smith et al. (24)Male; approximately 25; n = 10/groupC/ERunners (running competitively for several years; >50 miles/week)0.2 met + 0.04 atr; block confirmed by Valsalva manoeuvre only70.2 ± 3.154.7 ± 3.0*15.586.6 ± 2.579.5 ± 2.8*7.14610Shi et al. (22)Male; approximately 28; n = 8I/E8 mo walk/jog training0.2 met + 0.04 atr; block confirmed by Valsalva manoeuvre and injection of isoproterenol66.0 ± 4.057.0 ± 4.0*9.085.0 ± 3.084.0 ± 3.01.01111Stein et al. (26)Male; approximately 28–29; n = 6/groupC/ERunners (≥50 km/week)0.2 pro + 0.04 atr; block not confirmed65.7 ± 5.958.3 ± 5.7*7.583.1 ± 4.772.2 ± 5.7*10.9145Values are means ± SE. atr, Atropine; C, case control study; E, endurance trained; ΔHR, difference in normal resting heart rate between trained and untrained subjects; ΔHRab, difference in resting heart rate after autonomic blockade between trained and untrained subjects; I, interventional study; iso, isoprenaline; met, metoprolol; NS, not significantly different from same heart rate measured in untrained subjects; R, resistance trained;*significantly different from same heart rate measured in untrained subjects. Values of ΔHRab/ΔHR >100% (indicating no role for high vagal tone) are in bold.In eight studies (4–11 in Table 1), the effect of complete autonomic blockade was studied. The heart rate after complete autonomic blockade is a measure of the intrinsic heart rate. In all eight studies, there was a significant decrease in the normal heart rate with training (see HR data for studies 4–11 in Table 1), and, in all but one study, the significant decrease in heart rate persisted after complete autonomic blockade (see HRab data for studies 4–11 in Table 1). The final column in Table 1 shows the decrease in the heart rate after complete autonomic blockade (ΔHRab) as a percentage of the decrease in the normal heart rate (ΔHR). In four out of the eight studies (4–6 and 11 in Table 1), the decrease in the heart rate after complete autonomic blockade was greater than the decrease in the normal heart rate (ΔHRab/ΔHR > 100%; bold in Table 1). This suggests that neither high vagal tone nor reduced sympathetic tone is the cause of the resting bradycardia in the athletes in these four studies at least and instead it is the result of a decrease in the intrinsic heart rate—in fact these data suggest that there may be a decrease in vagal tone (or an increase in sympathetic tone). However, in one of the studies (7 in Table 1) there was no significant decrease in the heart rate after complete autonomic blockade and, in three other studies (8–10 in Table 1), the decrease in the heart rate after complete autonomic blockade was less than the decrease in the normal heart rate (ΔHRab/ΔHR < 100%). In these studies (7–10 in Table 1), the decrease in the intrinsic heart rate accounts for between 11 and 60% of the decrease in the normal heart rate; it is possible, theoretically at least, that high vagal tone accounts for the remainder.However, there is a surprising variation in the intrinsic heart rate, i.e., the heart rate after complete autonomic blockade, in untrained individuals from 83 to 108 beats/min in studies 4–11 in Table 1. The largest study of the intrinsic heart rate in humans was performed by Jose and Collison (8), who measured the intrinsic heart rate (after complete autonomic blockade) in 432 healthy adult human subjects. It was age dependent and for the 152 subjects 20–30 years of age in their study it was 105.5 ± 0.7 (mean ± standard error of the mean) beats/min (8). Studies 4–11 in Table 1 are ranked according to the reported heart rate after complete autonomic blockade in untrained individuals. In studies 4–7 in Table 1, the heart rate after complete autonomic blockade is within the mean ± 2 SD, a range that will encompass 95.4% of the data, from Jose and Collison (8), i.e., from 89.4 to 121.6 beats/min. However, in studies 8–11 in Table 1, the heart rate after complete autonomic blockade is below this range. The reason for this is unclear, but it is a cause for concern. If only studies 4–7 in Table 1 are considered [in which the reported heart rate after complete autonomic blockade in young untrained individuals is within the range of the mean ± 2 SD from Jose and Collison (8)], the decrease in the heart rate after complete autonomic blockade was greater than the decrease in the normal heart rate (ΔHRab/ΔHR > 100%) in three of the four studies (4–6 in Table 1).In summary, analysis of the heart rate in athletes after autonomic blockade shows that the resting bradycardia in athletes is in part at least and perhaps even completely the result of a decrease in the intrinsic heart rate.Effect of training on intrinsic heart rate in animals.Table 2 summarizes analogous data from animal studies. In animal studies, the intrinsic heart rate can be measured either in vivo following autonomic blockade or in an isolated denervated heart preparation. In six of the nine studies summarized in Table 2, at least 90% of the resting bradycardia in the trained animals can be attributed to a decrease in the intrinsic heart rate. However, in three of the studies there is a potential role for high vagal tone (or decreased sympathetic tone).Table 2. Summary of the effect of athletic training on the resting HR under normal conditions, the HRab, and the IHR; measured in an isolated heart preparation) in animal models in different studiesStudyAuthorsSpecies, Strain, Sex, and Number of AnimalsType of StudyType of TrainingProcedure for Autonomic Blockade (mg/kg) or Determination of IHRHR of Untrained Animals, beats/minHR of Trained Animals, beats/minΔHR, beats/minHRab or IHR of Untrained Animals, beats/minHRab or IHR of Trained Animals, beats/minΔHRab or IHR, beats/minΔHRab/ΔHR or ΔIHR/ΔHR, %1De Angelis et al. (4)Mouse; male; n = 8/groupC/ETreadmill running for 4 wkIn vivo; 1 pro +1 atr612 ± 6485 ± 9*127504 ± 9473 ± 18NS3124%2Sanches et al. (19)Rat; female n = 7/groupC/ETreadmill running for 8 wkIn vivo; 4 pro +3 atr357 ± 10332 ± 7*25368 ± 8353 ± 6NS1560%3Barnard et al. (2)Rat; maleC/ETreadmill running for 12 wkIn vivo; 4 pro +5 atr359 ± 6331 ± 4*28.2401.4 ± 5.32382.5 ± 6.34*5056.4%4Rossi et al. (17)Rat; male; n = 14/groupC/ETreadmill running for 10 wkIn vivo; 4 pro +5 atr366 ± 8333 ± 5*33389 ± 8359 ± 4*3090%5Souza et al. (25)Rat; male; n = 14/groupC/ESwimming for 8 wkIn vivo; 5 pro +4 atr346 ± 5314 ± 6*32392 ± 6332 ± 4*60187.50%6Negrao et al. (15)Rat; male; n = 12/15C/ETreadmill running for 13 wkIn vivo; 4 pro +3 atr308 ± 3299 ± 3*9369 ± 5329 ± 4*40444%7Lin and Horvath (13)Rat; male; n = 6/groupC/ESwimming for 6 wkIn vivo; 8 pro +1 atr382 ± 12344 ± 10.5*38426 ± 25372 ± 9*54142%8Schaeffer et al. (20)Rat; male; n = 9 control, 7 trainedC/ETreadmill running for 10 wkEx vivo; isolated right atrium and 10−6 M pro +10−6 M atr320 ± 6301 ± 8*19264 ± 14.21243 ± 8.4*21110%9Bolter and Atkinson (3)Rat; male; n = 9 control, 7 trainedC/ETreadmill running for 16 wkEx vivo; isolated right atrium373 ± 4353 ± 7*20299 ± 22231 ± 22*68340%Values are means ± SE. HRab is a measure of the intrinsic heart rate, if autonomic blockade is complete. See Table 1 legend for meaning of abbreviations.Problem with heart rate variability as a measure of vagal tone.The ideas here are a further development of the original idea of Zaza and colleagues (16, 29) concerning heart rate variability). Al-Ani et al. (1) described an individual who prior to training had a heart rate of 62 beats/min and a standard deviation of the normal beat-to-normal beat interval (SDNN; measure of heart rate variability) of 169 ms. After training (cycling) for 6 wk, the subject's heart rate was 50 beats/min and the SDNN was 247 ms (1). The increase in heart rate variability (increase in SDNN) was interpreted as evidence of an increase in vagal tone (1). When the heart rate was 62 beats/min (value in untrained individual) and assuming the sinoatrial node action potential duration was 160 ms (typical value), then the diastolic interval was 808 ms. If the membrane potential covers 20 mV from the maximum diastolic potential (approximately −60 mV) to the threshold potential (approximately −40 mV), then the rate of change of membrane potential during diastole in the sinoatrial node cell, dVm/dt, was 0.025 V/s or 25 mV/s. Now consider a perturbation (perhaps a change in autonomic nerve activity) that results in an ionic current, Iper, flowing across the cell membrane of a sinoatrial node cell with a membrane capacitance, Cm. This will change dVm/dt. Because the cell membrane behaves as a capacitor, the change in dVm/dt, i.e., Δ dVm/dt, is given by: ΔdVmdt=−IperCm.Iper is a fluctuating current giving rise to heart rate variability. It will be assumed that during one diastolic period Iper = 0.2 pA, and this is the perturbing current necessary to give rise to a 1 SD change in the cycle length. Cm is typically 50 pF. Therefore, dVmdt=0.2×10−1250×10−12=0.004V/s or 4 mV/s. Therefore, during diastole dVm/dt = 25 −4 = 21 mV/s. Consequently, the diastolic interval will be 977 ms and the cycle length will be 1,137 ms. Therefore, there will be a change in cycle length of 169 ms. This is the SDNN (measure of heart rate variability) and it is the same as in the untrained individual in the study of Al-Ani et al. (1).After training, when the subject's heart rate was 50 beats/min in the study of Al-Ani et al. (1), the diastolic interval was 1,040 ms and dVm/dt was 19 mV/s. Assume that Iper is the same, i.e., 0.2 pA. The change in dVm/dt it gives rise to will be the same, i.e., 4 mV/s. During diastole dVm/dt = 19 − 4 = 15 mV/s and consequently the diastolic interval will be 1,338 ms and the cycle length will be 1,498 ms. Therefore, there will be a change in cycle length of 298 ms. This will be the SDNN of cycle length (measure of heart rate variability) after training. In summary, simply a decrease in the heart rate from 62 to 50 beats/min, with no change in the underlying perturbing current, is predicted to increase the heart rate variability, i.e., SDNN, from 169 to 298 ms. This is more than sufficient to explain the observed increase in heart rate variability (SDNN) from 169 to 247 ms in the study of Al-Ani et al. (1). There is no need to invoke any change in vagal tone. Analysis shows that the increases in heart rate variability with training reported in other studies (7, 18, 21) can similarly be accounted for by the reported decreases in heart rate. In conclusion, studies of heart rate variability provide no evidence of high vagal tone in athletes.Calculations like those above show that there is an exponential-like relationship between SDNN and heart rate. Although the calculations above are based on some simplifying assumptions, using biophysically detailed models of the sinoatrial node action potential, we have confirmed this relationship (data not shown).Ion channel remodeling as alternative to high vagal tone.The pacemaker activity of the heart is the result of the consorted action of ion channels and Ca2+-handling proteins in the sinoatrial node (6). There is (or can be) a bradycardia in familial sinoatrial node disease, in the elderly, in heart failure, and with atrial fibrillation, and in each of these conditions the evidence suggests that the bradycardia is the result of a remodeling of ion channels and/or Ca2+-handling proteins (6). For example, the bradycardia associated with ageing can be attributed to a downregulation of RYR2, which is involved in the Ca2+ clock mechanism of pacemaking (28). The review above suggests that there is little evidence of involvement of high vagal tone in the athletic training-induced bradycardia. If ion channels and Ca2+-handling proteins are responsible for bradycardia in the diverse conditions discussed above, it is likely that they are also responsible for the bradycardia associated with athletic training. In 170 elite athletes, Whyte et al. (27) reported a decrease in the maximum heart rate (measured using a standard ramp protocol to volitional exhaustion) by ∼5 beats/min. Although this could be the result of a remodeling of the sinoatrial node (27), it cannot be explained by high vagal tone.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSAuthor contributions: M.R.B., A.D., and O.M. analyzed data; M.R.B. drafted manuscript; M.R.B. edited and revised manuscript; M.R.B., A.D., H.Z., G.M.M., H.D., and O.M. approved final version of manuscript; H.Z. and O.M. performed experiments; O.M. conception and design of research; O.M. interpreted results of experiments.REFERENCES1. al-Ani M , Munir SM , White M , Townend J , Coote JH. Changes in R-R variability before and after endurance training measured by power spectral analysis and by the effect of isometric muscle contraction. Eur J Appl Physiol Occup Physiol 74: 397–403, 1996.Crossref | PubMed | ISI | Google Scholar2. Barnard RJ , Corre K , Cho H. Effect of training on the resting heart rate of rats. 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D'Souza contributed equally to this work.Address for reprint requests and other correspondence: M. R. Boyett, Institute of Cardiovascular Sciences, Univ. of Manchester, Core Technology Facility, 46 Grafton St., Manchester, M13 9NT (e-mail: mark.[email protected]ac.uk).Supplemental datadescriptions.docx (4.95 kb) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited BySupraventricular Arrhythmias in Athletes: Basic Mechanisms and New DirectionsAlicia D’Souza, Tariq Trussell, Gwilym M. Morris, Halina Dobrzynski, and Mark R. 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Billman, Kristen L. Cagnoli, Thomas Csepe, Ning Li, Patrick Wright, Peter J. Mohler, and Vadim V. Fedorov1 June 2015 | Journal of Applied Physiology, Vol. 118, No. 11CrossTalk opposing view: Bradycardia in the trained athlete is attributable to a downregulation of a pacemaker channel in the sinus node14 April 2015 | The Journal of Physiology, Vol. 593, No. 8Exercise training reduces resting heart rate via downregulation of the funny channel HCN413 May 2014 | Nature Communications, Vol. 5, No. 1Considerations in the assessment of heart rate variability in biobehavioral research22 July 2014 | Frontiers in Psychology, Vol. 5Athlete's bradycardia may be a multifactorial mechanismDavid Matelot, Frédéric Schnell, Gaelle Kervio, Nathalie Thillaye du Boullay, and François Carré15 June 2013 | Journal of Applied Physiology, Vol. 114, No. 12Reply to Matelot, Schnell, Kervio, Thillaye du Boullay, and CarreMark R. Boyett, Alicia D'Souza, Henggui Zhang, Gwilym M. Morris, Halina Dobrzynski, and Oliver Monfredi15 June 2013 | Journal of Applied Physiology, Vol. 114, No. 12 More from this issue > Volume 114Issue 9May 2013Pages 1351-1355Supplemental Information Copyright & PermissionsCopyright © 2013 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01126.2012PubMed23288551History Published online 1 May 2013 Published in print 1 May 2013 Metrics