# Symptomatic bradyarrhythmias in the athlete-Underlying mechanisms and treatments

Sami Al-Othman, Mark R Boyett, Gwilym M Morris, Aneil Malhotra, Pietro

Mesirca, Matteo E Mangoni, Alicia D'souza

► To cite this version:

Sami Al-Othman, Mark R Boyett, Gwilym M Morris, Aneil Malhotra, Pietro Mesirca, et al.. Symp- tomatic bradyarrhythmias in the athlete-Underlying mechanisms and treatments. Heart Rhythm, 2024, 21 (8), pp.1415-1427. 10.1016/j.hrthm.2024.02.050. hal-04730152

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## Contemporary Review

# Symptomatic bradyarrhythmias in the athlete—Underlying mechanisms and treatments

<figure><img src="image_3.png" /></figure>

Sami Al-Othman, MBChB, MRes,¹,⁸ Mark R. Boyett, BSc, PhD, FSB, FRCP,²,⁸

Gwilym M. Morris, BmBCh, MRCP, PhD,³ Aneil Malhotra, BmBCh, MRCP, PhD,⁴

Pietro Mesirca, BSc, PhD,⁵,⁶ Matteo E. Mangoni, BSc, PhD,⁵,⁶ Alicia D'Souza, BSc, PhD¹,⁷

## ABSTRACT

Bradyarrhythmias including sinus bradycardia and atrioventricular (AV) block are frequently encountered in endurance athletes especially at night. While these are well tolerated by the young athlete, there is evidence that generally from the fifth decade of life onward, such arrhythmias can degenerate into pathological symptomatic bradycardia requiring pacemaker therapy. For many years, athletic bradycardia and AV block have been attributed to high vagal tone, but work from our group has questioned this widely held assumption and demonstrated a role for intrinsic electrophysiological remodeling of the sinus node and the AV node. In this article, we argue that bradyarrhythmias in the veteran athlete arise from the cumulative effects of exercise training, the circadian rhythm and aging on the electrical activity of the nodes. We consider contemporary strategies for the treatment of symptomatic bradyarrhythmias in athletes and highlight potential therapies resulting from our evolving mechanistic understanding of this phenomenon.

**KEYWORDS** Endurance exercise; Bradyarrhythmia; Electrophysiology; Vagal tone; Pacemaking

(Heart Rhythm 2024;21:1415–1427) © 2024 Heart Rhythm Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## A. Introduction

Long-term participation in sports, especially endurance-type sports, results in a spectrum of surface electrocardiographic patterns that would be considered abnormal in untrained individuals. Among these patterns, bradyarrhythmias including sinus bradycardia, sinus arrhythmia, and atrioventricular (AV) conduction block are commonly observed.¹ The prevalence of sinus bradycardia and sinus arrhythmia in the athletic population is up to 90% and 20%, respectively, whereas sinus pauses exceeding 2 seconds are present in up to a third of athletes²; both sinus bradycardia and pauses are particularly evident during sleep.³ Profound bradycardia with a heart rate of <35 beats/min is occasionally observed in highly conditioned athletes at rest (Figure 1A).⁴ The cyclist Miguel Induráin has been reported to have had a resting heart rate of just 28

beats/min (source: Wikipedia). Senturk et al⁵ published a systematic review of cardiac pauses in active trained athletes, and these pauses ranged from 1.35 to 30 seconds in duration. Disturbances in AV conduction, including first-degree AV block and Mobitz type I second-degree (Wenckebach) AV block, are also common in athletes, especially during sleep.³ In 24-hour Holter recordings, first-degree AV block is present in up to 27.5%–40% of athletes while type I second-degree block is present in 15%–22%.⁶,⁷ In the absence of symptoms of structural heart disease, current consensus guidelines consider sinus bradycardia > 30 beats/min, PR interval < 400 ms, Mobitz type I second-degree AV block, and junctional escape rhythms as benign physiological adaptations accompanying a long training history.⁸ However, some evidence suggests that these changes may be on a continuum with

From the ¹Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom, ²Faculty of Life Sciences, University of Bradford, Bradford, United Kingdom, ³Cardiology Department, John Hunter Hospital, Newcastle, New South Wales, Australia, ⁴Institute of Sport, Manchester Metropolitan University and Manchester University NHS Foundation Trust, Manchester, United Kingdom, ⁵Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France, ⁶Laboratory of Excellence "Ion Channel Science and Therapeutics" (ICST), Montpellier, France, and ⁷National Heart and Lung Institute, Imperial College London, London, United Kingdom.

⁸Joint first authors.
symptomatic bradyarrhythmia necessitating the implantation of an electronic pacemaker. For example, Hood and Northcote⁹ studied 19 veteran endurance athletes (mean age 67 years) and reported 2 had implanted pacemakers, a further 6 had significant bradycardia (heart rate < 35 beats/min), and of the 6, 1 had third-degree AV block and asystolic pauses and 1 had second-degree AV block. In a study of 134 Swiss male former professional cyclists (mean age 66 years) and 62 relatively sedentary male age-matched golfers by Baldesberger et al,¹⁰ sinus node disease was more frequent (10% vs 2%) and pacemaker implantation for bradyarrhythmias was more common (3% vs 0%) in former cyclists. Similarly, Zadvorev et al¹¹ reported on a cohort of 36 former athletes (mean age 60 years) and 52 age-matched nonathletes in which pacemaker implantation (14% vs 3%), asystolic pauses (27.3% vs 9.3%), and sinoatrial block (16% vs 3%), including sinus node exit block (first- to third-degree) and arrest, were significantly higher in former athletes. A much larger study of 52,755 long-distance cross-country skiers by Andersen et al¹² demonstrated that a high level of endurance exercise (high number of races completed) and a high intensity of exercise (fast finishing time) conferred a significantly increased risk of hospitalization for sinus node dysfunction and high-degree AV block (Figure 1A). Evidence shows that the likelihood and severity of bradyarrhythmias increase with the degree of training (Online Supplemental Figure S1).¹¹⁻¹³ Table 1 summarizes data from the studies referred to above as well as some other related studies. The studies show that bradyarrhythmias are associated with many types of sports. However, the studies primarily report an association with endurance training rather than power training. The effects of endurance and power training were studied by Bondarev et al,¹⁴ who compared 18 former professional athletes (9 former endurance athletes and 9 former power/mixed athletes) with 20 nonathletes, all of whom required pacemaker implantation and had no history of heart disease. The ages of diagnosis and pacemaker implantation were significantly lower in former endurance athletes (age 64 and 65 years, respectively) than in both former strength/mixed athletes (72 and 73 years of age) and nonathletes (74 and 75 years of age).¹⁴ Furthermore, the former endurance athletes showed a higher prevalence of second- or third-degree AV block (78%) than did the power/mixed athletes (44%).¹⁴

These data indicate that some veteran athletes represent a subpopulation with acquired cardiac conduction system disease, although clinical experience and anecdotal evidence suggest that conduction disturbances in athletes are much more frequent than hitherto described. With media coverage of our work on this topic,¹⁵,¹⁶ we regularly receive correspondence from concerned symptomatic athletes. A common theme has emerged from this correspondence, which is corroborated by clinical practice: symptomatic bradyarrhythmias occur in veteran endurance athletes (frequently but not exclusively male, ~45–80 years of age, marathon runners or cyclists) who have been exercising at a high level for decades, and bradyarrhythmias are most pronounced at night. In these accounts, clinical management of individuals varies substantially:

some athletes already had implanted pacemakers or were considering pacemaker implantation (with trepidation), whereas others had been advised to detrain and 1 athlete was advised to undergo cardioneuroablation. These apparent ambiguities prompted us to review, in the present article, mechanisms underlying athletic bradyarrhythmias and current, upcoming, and potential treatments. We present evidence that symptomatic bradyarrhythmias in the athlete result from the summation of the effects of exercise training, circadian rhythm, and age on the electrical activity of the sinus and AV nodes (Graphical Abstract) and highlight areas of potential therapeutic innovation on the basis of our evolving mechanistic understanding of this commonly encountered condition.

## B. Mechanisms underlying sinus bradycardia and AV block in athletes

Sinus bradycardia and AV block in athletes have been commonly attributed to high vagal tone; we have previously addressed the role of vagal tone,¹⁷ and we briefly summarize the arguments for and against this hypothesis in the Online Supplement. Here, we address new mechanisms proposed to explain sinus bradycardia and AV block in athletes. Electrical activity is ultimately the result of the activity of ion channels, and our work over the last 2 decades has demonstrated that plasticity in the expression profile of pacemaking ion channels is an important mechanism by which heart rate and AV node conduction are regulated in response to chronic physiological and pathological stimuli.¹⁸ Endurance exercise is one such stimulus for change.

We and others have shown in the human and rodent models, after exercise training, there is a decrease of the intrinsic heart/pacemaker rate in the absence of autonomic tone measured after complete autonomic blockade, in the isolated denervated sinus node, or isolated denervated sinus node myocyte (Figures 2A and 2B). Similarly, we have shown in the human, horse, and mouse that after exercise training, there is an alteration of intrinsic AV node electrophysiology (prolongation of the Wenckebach cycle length, a related prolongation of the AV node effective refractory period, prolongation of the PR interval, or decrease in the pacemaker rate) in the absence of autonomic tone (Figures 2C and 2D). In rodent models, we have shown that swim- or treadmill running-training results in a diffuse transcriptional remodeling (downregulation) of key ion channels in both the sinus and AV nodes.¹⁹⁻²² According to work on the rat, mouse, and horse, there is an exercise training-dependent downregulation of the hyperpolarization-activated cyclic nucleotide-gated (HCN) and L- and T-type Ca²⁺ channels at the protein and/or messenger RNA (mRNA) levels in both nodes (eg, Figure 3A).¹⁹⁻²² There is also a downregulation of the corresponding ionic currents, funny current (I<sub>f</sub>), L-type Ca²⁺ current (I<sub>Ca,L</sub>), and T-type Ca²⁺ current I<sub>Ca,T</sub>), in sinus and AV node myocytes from swim-trained mice (eg, Figure 3A).¹⁹⁻²² I<sub>Ca,L</sub> and I<sub>Ca,T</sub> are well known to play an important role in both sinus node pacemaking and AV node
<figure><img src="image_4.png" /><figcaption>**Figure 1**</figcaption></figure>

Effect of endurance exercise (panel A), circadian rhythm (panel B), and aging (panel C) on functional properties of sinus and atrioventricular nodes. A (left panel): Distribution of resting heart rates in elite athletes and a normal population. The red bars correspond to histogram of the resting heart rate of 142 elite cyclists and rowers. The gray bars correspond to histogram of the resting heart rate of 3061 20- to 39-year-old female subjects. From D'Souza et al.⁷⁹ A (right panel): Risk of any arrhythmia, atrial fibrillation, and bradyarrhythmias for cross-country skiers either completing the highest number of races or with fastest finishing times as compared with cross-country skiers completing just 1 race or with slowest finishing times. Drawn from Andersen et al.¹² B (left panel): Mean heart rate of 8 male subjects plotted against time of day. Mean ± SEM shown for the first 28 hours; for next 24 hours, only mean shown for clarity. Modified from Vandewalle et al.⁸⁰ B (right panel): Mean (± SEM) hourly PR interval of 50 subjects plotted against time of day. The shaded area corresponds to the fitted curve. Modified from Dilaveris et al.²⁸ C (top left panel): Relationship between the intrinsic heart rate measured after complete autonomic blockade and age in 56 human subjects. The dashed lines correspond to ±1SD. Modified from Kuga et al.³⁶ The shaded area corresponds to the 95% confidence limit for the intrinsic heart rate from Jose and Collison.³⁵ C (top right panel): 2nd, 50th, and 98th percentiles for the PR interval of 486,014 male (blue curves) and female (red curves) subjects plotted against age. Modified from Palhares et al.⁸¹ C (bottom left panel): Relationship between the incidence of sick sinus syndrome (as measured by the number of new pacemaker implants in Sweden in 2019) and age in male and female subjects. Based on Härtel and Talvensaari⁸² and Benditt et al.³³ C (bottom right panel): In 224 patients with complete heart block, the relationship between the percentage of patients and age of patients. Drawn from Penton et al.³⁴

conduction.²³ Although the role of $I_f$ in pacemaking is well known, its role in AV node conduction is only now emerging: reduction in $I_f$ slows not only pacemaking but also AV node conduction as seen in studies of $I_f$ blockers,²⁴ HCN4 loss-of-function mutations,²⁵ and HCN4 knockout²⁶; genome-wide association studies have also shown that polymorphisms at

the HCN4 locus associate not only with the risk of sinus node dysfunction but also with first-degree and complete AV block and pacemaker implantation.²⁷

Pharmacological block of $I_f$ abolishes the difference in heart rate between swim-trained and sedentary mice in vivo and in the isolated sinus node.²¹ In an attempt to extend these
<table><caption>**Table 1** Studies reporting bradyarrhythmias in athletes</caption><thead><tr><th>Study</th><th>No. of subjects studied</th><th>Age of athletes</th><th>Gender of athletes</th><th>Sport</th><th>Sports level</th><th>Extent of exercise training</th><th>Duration of exercise training</th><th>Main findings in athletes</th></tr></thead><tbody><tr><td>Meytes et al<sup>59</sup></td><td>126 Athletes</td><td>Not stated</td><td>Not stated</td><td>Swimming, athletics, volleyball, gymnastics</td><td>Professional</td><td>Israeli national team athletes</td><td>Not stated</td><td>9% First-degree AV block and 2% second-degree (Wenckebach) AV block</td></tr><tr><td>Beswick and Jordan<sup>13</sup></td><td>60 Athletes and 47 normal control subjects</td><td>Not stated</td><td>Male</td><td>Short distance (sprint, field events, ring events, etc) and long distance (≥1 mile)</td><td>Professional</td><td>Participants in 1958 Sixth British Empire and Commonwealth Games</td><td>Not stated</td><td>Lower heart rate (heart rate of long-distance athletes lower than that of short-distance athletes)</td></tr><tr><td>Cohen et al<sup>84</sup></td><td>30 Ballet dancers and 15 sedentary control subjects</td><td>18–32 y</td><td>~50% Male; ~50% female</td><td>Ballet</td><td>Professional</td><td>Not stated</td><td>Mean: 14 y</td><td>Higher prevalence of sinus bradycardia and sinus arrhythmia</td></tr><tr><td>Murayama and Kuroda<sup>58</sup></td><td>356 athletes</td><td>17–50 y</td><td>82% Male; 18% female</td><td>Various</td><td>Professional</td><td>Japanese athletes from 1964 Olympic games</td><td>Not stated</td><td>Higher prevalence of sinus bradycardia and first- or second-degree AV block</td></tr><tr><td>Talan et al<sup>6</sup></td><td>20 runners and 50 age-matched sedentary control subjects</td><td>19–28 y</td><td>Male</td><td>Running</td><td>Nonprofessional; university track and team club members</td><td>≥50 miles/wk for 250–365 d/y</td><td>≥3 y</td><td>Lower heart rate; prolonged sinus pauses; higher prevalence of AV block</td></tr><tr><td>Palatini et al<sup>7</sup></td><td>40 Athletes (20 runners and 20 cyclists) and 40 age- and sex-matched sedentary control subjects</td><td>20.3 ± 7 y</td><td>Male</td><td>Running or cycling</td><td>Nonprofessional; members of sports clubs and schools</td><td>Runners: ~75 km/wk; cyclists: ~16,500 km/y</td><td>>3 y</td><td>Lower heart rate; higher prevalence of first- and second-degree (Wenckebach) AV block</td></tr><tr><td>Northcote et al<sup>3</sup></td><td>20 Runners and 20 age- and sex-matched sedentary control subjects</td><td>56 ± 7 y</td><td>Male</td><td>Running</td><td>Nonprofessional</td><td>47 ± 23 miles/wk</td><td>>25 y</td><td>Lower heart rate; higher prevalence of sinus bradycardia, asystolic pauses, and first-, second-, and third-degree AV block; prolonged PR interval</td></tr></tbody></table>
<table><tr><td>Hood and Northcote<sup>9</sup></td><td>19 Runners (12-y follow-up study of athletes from Northcote et al<sup>3</sup>)</td><td>56–83 y</td><td>Male</td><td>Running</td><td>Nonprofessional</td><td>34 ± 21 miles/wk</td><td>26–60 y</td><td></td></tr><tr><td>Bjørnstad et al<sup>85</sup></td><td>1299 Athletes and 151 age- and sex-matched sedentary control subjects</td><td>24.2 ± 4.3 y</td><td>58% Male; 42% female</td><td>Various</td><td>Nonprofessional; students of the Norwegian College of Physical Education and Sport</td><td>Males: ran 3 km in 12 min; females: ran 1.5 km in 7 min</td><td>Not stated</td><td>• Low heart rate; bradycardia; AV block; asystolic pauses<br/>• 11% of veteran athletes now required pacemaker implantation<br/>Lower heart rate; higher prevalence of sinus bradycardia; 0.9% had rhythms other than sinus rhythm; prolonged PQ interval</td></tr><tr><td>Bjørnstad et al<sup>86</sup></td><td>30 Top athletes, 30 age- and sex-matched athletic students, and 30 age- and sex-matched sedentary control subjects</td><td>Mean: 24</td><td>50% Male; 50% female</td><td>Cross-country skiing, biathlon, long-distance running, orienteering, running</td><td>Professional</td><td>International/ national level athletes</td><td>Not stated</td><td>Lower heart rate and paroxysmal bradycardia; higher prevalence of second-degree AV block</td></tr><tr><td>Sharma et al<sup>87</sup></td><td>1000 Athletes and 300 age- and sex-matched sedentary control subjects</td><td>14–18 y</td><td>73% Male; 27% female</td><td>Soccer, tennis, rugby, cycling, swimming, athletics, boxing, rowing, and modern triathlon</td><td>Nonprofessional; junior elite athletes</td><td>9.7 ± 3.3 h/wk of intensive training</td><td>1–10 y at the county level</td><td>Higher prevalence of sinus bradycardia, sinus arrhythmia, and first-degree AV block; small number of rhythms other than sinus rhythm; prolonged PR interval</td></tr><tr><td>Baldesberger et al<sup>10</sup></td><td>62 Former professional cyclists and 62 age-matched sedentary control subjects</td><td>66 ± 7 y</td><td>Male</td><td>Cycling</td><td>Former professional cyclists but retired for 38 ± 7 y at the time of study</td><td>25,200 ± 9700 km/y when professional</td><td>11 ± 4 y as professionals</td><td>Lower heart rate; higher prevalence of sinus node disease and pacemaker implantation</td></tr></table>

(continued)
<table><caption>**Table 1** Continued</caption><thead><tr><th>Study</th><th>No. of subjects studied</th><th>Age of athletes</th><th>Gender of athletes</th><th>Sport</th><th>Sports level</th><th>Extent of exercise training</th><th>Duration of exercise training</th><th>Main findings in athletes</th></tr></thead><tbody><tr><td>Andersen et al<sup>12</sup></td><td>52,755 Cross-country skiers</td><td>15–65+ y</td><td>90% Male; 10% female</td><td>Cross-country skiing</td><td>Mixture of professional and nonprofessional</td><td>All Swedish finishers of a 90-km cross-country skiing event during 1989–1998</td><td>Not stated</td><td><ul><li>Higher risk of bradyarrhythmias for those who completed the highest number of races or those with the fastest finishing time</li><li>Higher risk of hospitalization for bradyarrhythmias in skiers who completed more races</li></ul></td></tr><tr><td>Zadvorev et al<sup>11</sup></td><td>36 Former athletes and 52 age-matched sedentary control subjects admitted to a cardiology ward</td><td>60.1 ± 10.6 y</td><td>83% Male; 17% female</td><td>Various</td><td>Former athletes</td><td>Various—ranked by sporting rank or title</td><td>Mixed</td><td><ul><li>Higher prevalence of asystolic pauses, sinoatrial exit block, AV block, and pacemaker implantation</li><li>Prevalence of AV block increased with higher sporting rank/title</li></ul></td></tr></tbody></table>

Studies are listed chronologically with the exception of 2 related studies from Northcote and others.

AV = atrioventricular.
findings to humans, we have assessed the role of $I_f$ remodeling in human endurance athletes using the $I_f$ blocker ivabradine. We observed a significant correlation between the heart rate-lowering effect of oral ivabradine and the intrinsic heart rate (measured after complete autonomic blockade) of athletes and nonathletes: subjects with a lower intrinsic heart rate (generally athletes) had a blunted response to ivabradine.²⁰ This suggests that in both the human athlete and the exercise-trained rodent, the downregulation of HCN channels and $I_f$ (Figure 3A) is at least contributing to sinus bradycardia.²⁰ In the case of the AV node, biophysically detailed modeling suggests that the downregulation of $I_f$ and $I_{Ca,L}$ is contributing to the slowing of AV node conduction after exercise training.¹⁹ Furthermore, in the swim-trained mouse, the role of $I_f$ is confirmed by the finding that a period of detraining restores HCN4 expression and AV conduction to pretraining levels.¹⁹

**C. Role of circadian rhythm in ion channel expression**

Bradyarrhythmias in human athletes primarily occur at night.³
In humans and laboratory animals, there is a circadian rhythm

in both the heart rate and the PR interval (Figure 1B).³,²⁸ The heart rate is higher during the awake period, presumably to anticipate the increase in demand for cardiac output during the awake period, and the PR interval is shorter (ie, AV conduction is faster) at the same time, presumably because there is less time during the shorter cardiac cycle for all events (the QRS duration and QT interval are also shorter). Once again, the circadian rhythm in heart rate and PR interval is commonly attributed to high vagal tone during sleep (see arguments for and against in the Online Supplement), but once again we address new proposed mechanisms here.

Measurement of the transcriptome of the mouse sinus node using RNA sequencing over 24 hours has shown that ~44% (7134 transcripts) of the measured sinus node transcriptome exhibits a circadian rhythm.²⁹ In the mouse sinus node, the rhythmic transcripts include the components of a functioning molecular circadian clock in the sinus node and this is presumably playing a role in the circadian rhythm in the sinus node.²⁹,³⁰ Transcripts for many ion channels, including HCN channels, in the mouse sinus node exhibit a circadian rhythm,²⁹,³⁰ and consistent with this, there is a circadian rhythm in $I_f$ (Figure 3B).³⁰ In the mouse, pharmacological

<figure><img src="image_5.png" /><figcaption>**Figure 2**</figcaption></figure>

Endurance exercise induces intrinsic sinus bradycardia and atrioventricular (AV) conduction slowing. A (left panel): Intrinsic heart rate (measured by electrocardiogram recording under complete pharmacological blockade of the autonomic nervous system) in human competitive endurance athletes and sedentary subjects. From D'Souza et al.²⁰ A (right panels): Intrinsic heart rate (measured in the isolated sinus node) in treadmill running-trained and sedentary rats and swim-trained and sedentary mice. From D'Souza et al.²¹ B: Spontaneous action potentials recorded from myocytes isolated from the sinus node of swim-trained and sedentary mice. From Bidaud et al.²² C (left panel): Wenckebach cycle length (WCL) and AV node effective refractory period (AVERP) recorded under complete pharmacological autonomic blockade in human endurance athletes and sedentary subjects. Digitized from Stein et al.⁸³ C (middle panel): PR interval recorded under complete pharmacological autonomic blockade from trained and sedentary racehorses. C (right panel): Atrio-His (A-H) interval recorded from isolated denervated AV node preparations from swim-trained and sedentary mice. From Mesirca et al.¹⁹ D: Spontaneous action potentials recorded from myocytes isolated from the AV node of swim-trained and sedentary mice. From Mesirca et al.¹⁹ Mean ± SEM shown. *Significantly different.
block of HCN channels and $I_f$ both in vivo and in vitro (in the isolated sinus node) abolishes the circadian rhythm in heart rate and this suggests that the channels play an important role in the circadian rhythm in heart rate.³⁰ Many other transcripts in the mouse sinus node exhibit a circadian rhythm, and it is interesting that transcripts from genes identified by genome-wide association studies as determinants of the resting heart rate and transcripts from genes responsible for familial and acquired sick sinus syndrome all exhibit a circadian rhythm.²⁹ As in the case of the sinus node, we have shown that there is a circadian rhythm in the expression of circadian clock and ion channel (including HCN4) transcripts in the mouse AV node.¹⁸ Although it is likely that the local circadian clocks in the 2 nodes are involved in the circadian rhythms of ion channel transcripts and so on and ultimately

pacemaker activity and AV node conduction, we have shown that circadian rhythms in the sympathetic nervous system and plasma glucocorticoids are also involved.³¹,³²

### D. Effect of aging on ion channel expression

Reports of symptomatic bradyarrhythmias in human athletes primarily concern the veteran athlete who has been exercising at a high level for decades rather than the young athlete.³,¹⁰,¹⁴ This shows that age as well as exercise and time of day are important when considering symptomatic bradyarrhythmias in athletes. Age is important, because with age the functioning of both the sinus and AV nodes in the human declines; the prevalence of both sinus and AV node dysfunction increases in an exponential-like manner with age (Figure 1C).³³⁻³⁶ The

<figure><img src="image_6.png" /><figcaption>**Figure 3**</figcaption></figure>

Downregulation of HCN channels and $I_f$ in mice with exercise training during the sleep period (day in the case of mouse) and during aging. A (left panel): Mean (+SEM) expression of the 3 functionally important HCN transcripts in the sinus node of sedentary and treadmill running-trained rats. A (right panel): Families of $I_f$ recordings from isolated sinus node myocytes from sedentary and swim-trained mice. Data in panel A from D'Souza et al.²¹ B (left panel): Mean (± SEM) expression of the HCN4 transcripts in the sinus node of mice at 4 time points over 24 hours. Time given as Zeitgeber time (ZT): 0 h, start of the 12-hour light period; 12 h, start of the 12-hour dark period. B (right panel): Families of $I_f$ recordings from isolated sinus node myocytes from mice at ZT12 and ZT6. Data in panel B from D'Souza et al.³⁰ C (left panel): HCN transient expression in the sinus node of ~24-month-old mice as a percentage of that in ~2-month-old mice. Data from D'Souza et al as published by Boyett et al.¹⁸ C (right panel): Families of $I_f$ recordings from isolated sinus node myocytes from 2 to 3 and 32+-month-old mice. Data from Larson et al.⁵² *Significantly different. HCN, hyperpolarization-activated cyclic nucleotide-gated; $I_f$, funny current; mRNA, messenger RNA.
age-dependent decline in nodal function is also seen in animal
studies.<sup>37,38</sup> The age-dependent sinus node dysfunction has
been attributed to fibrosis (proliferation of the extracellular ma-
trix),<sup>39-42</sup> although no evidence of this has been reported in the
aged human, cat, and rat.<sup>43,44</sup> However, there is widespread
evidence of an age-dependent downregulation of various ion
channels and ionic currents in the sinus node of various animal
species.<sup>18,38,40,44-51</sup> For example, in the mouse, there is an
age-dependent downregulation of HCN channels<sup>18</sup> as well as
$I_f$<sup>52</sup> (Figure 3C). Computer modeling has suggested that this
electrical remodeling in the aged sinus node contributes to si-
nus node dysfunction.<sup>53</sup> Consistent with this, the decline in the
intrinsic heart rate of the rat (measured in vivo after autonomic
blockade)<sup>51</sup> as well as the beating rate of the isolated sinus
node of the mouse from the adult to the senescent animal is
reduced after pharmacological block of HCN channels and $I_f$ (unpublished observations). It is likely that age-dependent
downregulation of other ion channels (eg, Ca<sup>2+</sup> channels)
also contribute to age-dependent sinus node dysfunction.<sup>49,52</sup>
Compared to the sinus node, less is known about the effect of
age on the AV node. However, in the rat, once again there is
evidence of electrical remodeling of the AV node (as well as
fibrosis and apoptosis).<sup>37</sup>

E. The whole is greater than the part<sup>54</sup>

In summary, exercise training results in electrical remodeling
of the sinus and AV nodes and consequently a slowing of
intrinsic sinus node pacemaking and AV conduction. Because
of the circadian rhythm in the 2 nodes, this will be more
marked at night (during sleep). For the young human athlete
(eg, <50 years of age), this is well tolerated and not symptom-
atic. However, for the older veteran athlete with compromised
nodal function as a result of aging, this is not necessarily the
case. For the sinus node, this can be put in another way
focusing on the HCN channels and $I_f$ (although this does not
mean that other factors are not involved): exercise training,
nighttime (in the case of the human), and aging all result in
a diminution of HCN channels and $I_f$ (Figure 3), whereas any
1 of these or even 2 of these are unlikely to result in symptoms
requiring medical intervention; symptomatic bradyarrhyth-
mias may arise from the summation of all 3 physiological phe-
nomena.

F. Existing, new, and potential treatments

F.1. Detraining

The most straightforward treatment of exercise training-
induced bradyarrhythmias may be detraining. There is
evidence from both human athletes and animal models of
exercise training that detraining can reverse exercise
training-induced bradyarrhythmias as well as exercise
training-induced atrial tachyarrhythmia.<sup>55-59</sup> There is
evidence that detraining is effective in young as well as
veteran athletes: Giada et al<sup>56</sup> reported that after 2 months
of detraining, exercise training-induced bradycardia was
reversed by 15% in young (~24 years of age) and 50% in vet-
eran (~55 years of age) cyclists. From clinical experience, we

know that the drawback of detraining is that the athlete may
be reluctant or even refuse to detrain. Detraining can have
adverse psychological effects<sup>60</sup>; individuals with a strong "ath-
letic identity" are prone to high levels of psychological distress
on detraining.<sup>61</sup> Studies suggest that individuals who are "ad-
dicted" to exercise will continue exercising regardless of phys-
ical injury, personal inconvenience, or disruption in other areas
of life and addicted exercisers experience disturbing depriva-
tion sensations when unable to exercise.<sup>62,63</sup>

F.2. Pacemaker implantation

Adequately powered prospective studies assessing the prev-
alence of pacemaker implantation in athletes and conse-
quences for sports practice have yet to be performed.
However, as discussed above, athletes are more likely to
need pacemaker implantation than nonathletes and the
limited available evidence base indicates that this is a safe
and effective strategy for bradyarrhythmia management in
this population that does not impinge on the ability to
perform endurance exercise of high intensity or duration.<sup>64</sup>

F.3. Cardioneuroablation

Cardiac neuroablation (cardioneuroablation) is a new tech-
nique involving radiofrequency ablation of the vagal ganglia
located on the outside of the atria or great vessels. Cardio-
neuroablation has been shown to relieve sinus node dysfunc-
tion and high-grade AV block (as well as neurally mediated
reflex syncope) in carefully selected patients for at least 9-
24 months with a low incidence of complications.<sup>65-69</sup> This
is a promising new treatment of symptomatic
bradyarrhythmias. However, currently, there are no
recommendations for this method for the treatment of
athletes with sinus node dysfunction.<sup>70</sup> Why is cardioneuroa-
blation effective? The vagal nerves innervating the sinus and
AV nodes are tonically active and act as a constant brake on
both the heart rate and AV conduction; removal of this brake
is expected to quicken the heart rate and reduce or eliminate
AV block (by strengthening and quickening AV conduction).
This mechanism will operate regardless of whether vagal
tone is heightened in the athlete.

F.4. Molecular targeting of ion channel remodeling as a
potential therapeutic approach

Insight into the molecular processes by which ion channels are
remodeled in response to exercise-training presents possibil-
ities for therapeutic innovation. The data reviewed above sug-
gests that a downregulation of HCN4 and, therefore, $I_f$ is
playing an important role in exercise training-induced nodal
dysfunction. What is responsible for the downregulation of
HCN4? Currently there are 3 clues:

1. micro-RNAs (miRs). miRs are endogenous small noncoding RNAs that have emerged as central regulators of gene expression, exerting posttranscriptional repressive effects on virtually all classes of protein-coding genes by degradation or translational inhibition of target mRNAs. The notion
<figure><img src="image_7.png" /><figcaption>Figure 4</figcaption></figure>

In vivo suppression of hyperpolarization-activated cyclic nucleotide-gated channel 4-targeting micro-RNAs (miRs) using anti-miRs restores sinus node automaticity and atrioventricular (AV) conduction in swim-trained mice. A: Summary of miR-mediated sinus and AV node dysfunction in endurance training and its alleviation using anti-miRs. Blue correspond to messenger RNA; green, miR; red, anti-miR. B–E: Anti-miR treatment in mice suppresses the swim training-induced upregulation of miR-423-5p in the sinus node (panel B), downregulation of the HCN4 protein in the sinus node (panel C), reduction in funny current density in sinus node myocytes (panel D; mean current-voltage relationships shown), and decrease in heart rate measured in vivo (panel E). From D’Souza et al.²⁰ F and G: Combined administration of anti-miRs targeting miR-432 and miR-211-5p suppresses the swim training-induced upregulation of these miRs in the AV node (panel F) and downregulation of the HCN4 protein in the AV node (panel G) in mice. From Mesirca et al.¹⁹ H and I: Restoration of PR prolongation in mice in vivo at a fixed pacing cycle length of 130 ms (panel H; electrocardiogram recordings shown; example P and R waves labeled) and in sinus rhythm (panel I). From Mesirca et al.¹⁹ Mean ± SEM shown. *Significantly different.

<figure><img src="image_8.png" /><figcaption>Figure 5</figcaption></figure>

Schematic diagram showing prevention of endurance exercise-induced sinus bradycardia by ACh (acetylcholine)-activated K⁺ current (I<sub>K,ACh</sub>) targeting. Left: Summary of changes in inward ionic currents (shown in the green box) and outward I<sub>K,ACh</sub> (shown in the red box) in isolated sinus node myocytes from sedentary mice, swim-trained mice, and swim-trained mice lacking I<sub>K,ACh</sub>. Middle: Corresponding action potentials recorded from isolated sinus node myocytes showing changes in intrinsic pacemaker activity. Right: Corresponding electrocardiogram (ECG) recordings showing changes in heart rate in vivo. Data from Bidaud et al.²² Endurance exercise induces the downregulation (shown by a red arrow) of key inward ionic currents underlying diastolic depolarization, thereby creating an imbalance between inward currents and outward I<sub>K,ACh</sub>; consequently, I<sub>K,ACh</sub> acts as a brake, slowing pacemaker activity and thereby heart rate. I<sub>K,ACh</sub> targeting (genetic ablation) both removes the brake and prevents downregulation of inward ionic currents, thereby preventing the slowing. I<sub>Ca,L</sub>, L-type Ca²⁺ current; I<sub>Ca,T</sub>, T-type Ca²⁺ current; I<sub>f</sub>, funny current.
that miRs play fundamental roles in arrhythmia pathophysiology has gained progressive ground over the last decade.⁷¹ We hypothesized that miRs that repress HCN4 and Ca<sub>v</sub>1.2 mRNAs are upregulated in the sinus node after exercise training and might constitute novel targets for pacemaker-selective therapeutic intervention using specific inhibitors—anti-miRs: a screen of 750 miRs in the mouse sinus node identified significant increases in 25 miRs after swim training, and based on extensive in vitro investigations, miR-423-5p was determined as a key HCN4 regulator (Figures 4A and 4B).²⁰ Strikingly, pharmacological inhibition of miR-423-5p with an anti-miR reversed training-induced bradycardia both in vivo and in the isolated sinus node via restoration of HCN4 and I<sub>f</sub> (Figures 4B–4E).²⁰ In recent work, we have determined the therapeutic efficacy of miR targeting in the treatment of swim training-induced AV node dysfunction.¹⁹ In mice, intraperitoneal injection of a combination of 2 anti-miRs designed to restore expression levels of HCN4 and Ca<sub>v</sub>1.2 by suppression of miR-432 and miR-211-5p (upregulated by exercise training in both horse and mouse AV nodes) restored the PR interval to pretraining levels (Figures 4F–4I).¹⁹ These studies are the first proof of concept of miR targeting as a therapeutic approach to restore nodal function. miRs have recently emerged as druggable targets for cardiovascular disease,⁷² and the first-in-human study repressing miR-132 with antisense oligonucleotides (anti-miRs) in patients with heart failure has been reported.⁷³

2. G-protein-gated inwardly rectifying K⁺ channel 4 (GIRK4). The vagus nerve acts on the nodes via the release of the neurotransmitter acetylcholine (ACh), which activates the muscarinic M2 receptor, leading to direct activation of GIRK channels underlying the ACh-activated K⁺ current (I<sub>K,ACh</sub>). The channel underlying I<sub>K,ACh</sub> is made of 2 sub-units: GIRK1 and GIRK4 (also known as K<sub>ir</sub>3.1 and K<sub>ir</sub>3.4). We have shown that I<sub>K,ACh</sub> suppression, either by GIRK4 knockout or by pharmacological block of I<sub>K,ACh</sub> by tertiapin-Q, rescues bradyarrhythmias in mouse models of congenital channelopathies caused by loss of function of HCN4, Ca<sub>v</sub>1.3, and Ca<sub>v</sub>3.1 channels.⁷⁴⁻⁷⁶ Of relevance here, we have shown that I<sub>K,ACh</sub> suppression also rescues swim training-induced sinus bradycardia (in the case of GIRK4 knockout or pharmacological block of I<sub>K,ACh</sub> by tertiapin-Q) and prolongation of the PR interval (in the case of GIRK4 knockout; tertiapin-Q not tested) in the mouse.²² The rescue is presumably, in part, the result of the removal of the tonic “brake” on the nodes by I<sub>K,ACh</sub> as in the case of cardioneuroablation (Figure 5). However, there is another factor contributing to the rescue: GIRK4 knockout prevents the swim training-induced downregulation of I<sub>f</sub> (as well as of I<sub>Ca,T</sub> and I<sub>Ca,L</sub>) (Figure 5)²²; GIRK4 appears to be involved in the transcriptional regulation of pacemaker ion channels and thus the long-term regulation of pacemaker activity. GIRK4 inhibition by tertiapine-Q or a related drug is therefore a potential therapeutic strategy for exercise training-induced bradyarrhythmias. GIRK4

knockout blocks the swim training-induced upregulation of a set of miRs, including the HCN4-downregulating miR-423-5p,²² and this is consistent with the hypothesis that GIRK4 is acting via miRs.

3. AMP-activated protein kinase (AMPK). AMPK is a fuelsensing enzyme, and it is activated by an increase in the adenosine monophosphate/adenosine triphosphate (AMP/ATP) ratio; once activated, AMPK will restore the AMP/ATP ratio by stimulating energy-generating processes and decreasing energy-consuming processes.⁷⁷ A decrease in heart rate is one means of reducing energy consumption, and activation of AMPK (as a result of a gain-of-function mutation in AMPK) results in bradycardia in the human, and in the mouse the same mutation results in a downregulation of HCN4 and I<sub>f</sub>, potentially a downregulation of the Ca²⁺ clock pacemaker mechanism (as a result of an upregulation of phospholamban), and a slowing of pacemaking and the intrinsic heart rate.⁷⁸ Yavari et al⁷⁸ showed that in the mouse, exercise training as a result of 10 weeks of voluntary wheel running results not only in a downregulation of I<sub>f</sub> and a slowing of pacemaking and the intrinsic heart rate but also in activation of AMPK and knockout of the γ2 subunit of AMPK prevents the downregulation of I<sub>f</sub> and slowing of pacemaking. This suggests that AMPK is responsible (in part at least) for the exercise training-induced bradycardia and therefore AMPK is a potential therapeutic target. However, although Yavari et al⁷⁸ did not comment on the effect of knockout of the γ2 subunit of AMPK on the exercise training-induced prolongation of the PR interval, they did report that activation of AMPK (as a result of a gain-of-function mutation in AMPK) did not affect the PR interval. If and how AMPK works with GIRK4 and miRs is not known.

## Conclusion

With increasing popularity of recreational exercise and competitive athletics, the clinician caring for athletes may be confronted with an increasing number who exhibit exercise training-induced symptomatic bradyarrhythmias. Appreciation of the fundamental biology underlying this phenomenon may help dispel uncertainties in the management of these patients, provide novel insights into the pathophysiology of cardiac conduction system disease that may extend to management of bradyarrhythmias in the general population, and help in the development of novel therapies.

## Appendix

### Supplementary data

Supplementary data associated with this article can be found in the online version at https://doi.org/10.1016/j.hrthm.2024.02.050.

**Funding Sources:** This work was supported by a British Heart Foundation Intermediate Basic Science Research Fellowship (FS/19/1/34035, to Dr D'Souza), a British Heart Foundation project grant (PG/22/10919, to Dr D'Souza), and British Heart
Foundation grants (PG/14/24/30626, RG/11/18/29257, and PG/13/99/30233, to Drs Boyett and D'Souza). Work within the Institut de Génomique Fonctionnelle research group was funded by the Laboratory of Excellence "Ion Channel Science and Therapeutics," supported by grants from the Agence Nationale de Recherche (ANR-11-LABX-0015; ANR-15-CE14-0004-01 to M.E. Mangoni), the Fondation pour la Recherche Medicale Physiopathologie Cardiovasculaire (DPC20171138970 to M.E. Mangoni), and the Fondation Leducq TNE FANTASY (19CV03 to M.E. Mangoni, M.R. Boyett and A. D'Souza).

**Disclosures:** The authors have no conflicts to disclose.

**Address reprint requests and correspondence:** Dr Mark R. Boyett, Faculty of Life Sciences, University of Bradford, Richmond Rd, Bradford BD7 1DP, United Kingdom. E-mail address: mark.richard.boyett@gmail.com

## References

1. McEnteggart S, Bhonsale A, Link MS, Mark Estes NA. Arrhythmias in the athlete. In: Yan G-X, Kowey PR, Antzelevitch C, eds. Management of Cardiac Arrhythmias. Switzerland: Springer International Publishing; 2020. p. 623-643.

2. Brugada J, Benito B. Electrocardiographic findings in athletes. E J Cardiol Pract 2006;4.

3. Northcote RJ, Canning GP, Ballantyne D. Electrocardiographic findings in male veteran endurance athletes. Br Heart J 1989;61:155-160.

4. Zipes DP, Link MS, Ackerman MJ, Kovacs RJ, Myerburg RJ, Mark Estes NA III. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 9: Arrhythmias and conduction defects: a scientific statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015;66:2412-2423.

5. Senturk T, Xu H, Puppala K, et al. Cardiac pauses in competitive athletes: a systematic review examining the basis of current practice recommendations. Euroace 2016;18:1873-1879.

6. Talan DA, Bauernfeind RA, Ashley WW, Kanakis C Jr, Rosen KM. Twenty-four hour continuous ECG recordings in long-distance runners. Chest 1982;82:19-24.

7. Palatini P, Maraglino G, Sperti G, et al. Prevalence and possible mechanisms of ventricular arrhythmias in athletes. Am Heart J 1985;110:560-567.

8. Sharma S, Drezner JA, Baggish A, et al. International recommendations for electrocardiographic interpretation in athletes. J Am Coll Cardiol 2017; 69:1057-1075.

9. Hood S, Northcote RJ. Cardiac assessment of veteran endurance athletes: a 12 year follow up study. Br J Sports Med 1999;33:239-243.

10. Baldesberger S, Bauersfeld U, Candinas R, et al. Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists. Eur Heart J 2008; 29:71-78.

11. Zadvore SF, Krysiukc OB, Obrezanc AG, Yakovlev AA. Effect of personal history of athletic activity on the clinical course of cardiovascular diseases in former athletes. Adv Gerontol 2019;9:91-97.

12. Andersen K, Farahmand B, Ahlbom A, et al. Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study. Eur Heart J 2013;34:3624-3631.

13. Beswick FW, Jordan RC. Cardiological observations at the sixth British Empire and Commonwealth games. Br Heart J 1961;23:113-130.

14. Bondarev S, Achkasov E, Zorzi A, Safarian A, Graziano F, Sizov A. Intrinsic sinus node/atrioventricular node dysfunction requiring pacemaker implantation: role of former professional sport activity. J Clin Med 2024;13:203.

15. Endurance exercise 'interferes with heart rhythm' BBC News Web site, https://www.bbc.co.uk/news/health-27389257. Accessed April 9, 2024. Published May 14, 2014.

16. Researchers identify cause of heart block in athletes. The Independent Web site, https://www.independent.co.uk/independentpremium/athletes-heart-block-cause-b1871645.html. Published June 24, 2021. Accessed April 9, 2024.

17. Boyett MR, D'Souza A, Zhang H, Morris GM, Dobrzynski H, Monfredi O. Viewpoint: Is the resting bradycardia in athletes the result of remodelling of the sinoatrial node rather than high vagal tone? J Appl Physiol 2013;114:1351-1355.

18. Boyett MR, Yanni J, Tellez J, et al. Regulation of sinus node pacemaking and atrioventricular node conduction by HCN channels in health and disease. Progr Biophys Mol Biol 2021;166:61-85.

19. Mesirca P, Nakao S, Nissen SD, et al. Intrinsic electrical remodeling underlies atrioventricular block in athletes. Circ Res 2021;129:e1-e20.

20. D'Souza A, Pearman CM, Wang Y, et al. Targeting miR-423-5p reverses exercise training-induced HCN4 channel remodeling and sinus bradycardia. Circ Res 2017;121:1058-1068.

21. D'Souza A, Bucchi A, Johnsen AB, et al. Exercise training reduces resting heart rate via downregulation of the funny channel HCN4. Nat Commun 2014;5:3775.

22. Bidaud I, D'Souza A, Forte G, et al. Genetic ablation of G protein-gated inwardly rectifying K⁺ channels prevents training-induced sinus bradycardia. Front Physiol 2021;11:1798.

23. Mesirca P, Torrente AG, Mangoni ME. Functional role of voltage gated Ca²⁺ channels in heart automaticity. Front Physiol 2015;6:19.

24. Ragueneau I, Laveille C, Jochemsen R, Resplandy G, Funck-Brentano C, Jaillon P. Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers. Clin Pharmacol Ther 1998;64:192-203.

25. Milano A, Vermeer AM, Lodder EM, et al. HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. J Am Coll Cardiol 2014;64:745-756.

26. Baruscotti M, Bucchi A, Viscomi C, et al. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc Natl Acad Sci U S A 2011;108:1705-1710.

27. den Hoed M, Eijgelsheim M, Esko T, et al. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Na Genet 2013; 45:621-631.

28. Dilaveris PE, Färborn P, Batchvarov V, Ghuran A, Malik M. Circadian behavior of P-wave duration, P-wave area, and PR interval in healthy subjects. Ann Noninvasive Electrocardiol 2001;6:92-97.

29. Wang Y, Anderson C, Dobrzynski H, Hart G, D'Souza A, Boyett MR. RNAseq shows an all-pervasive circadian rhythm in the transcriptome of the pacemaker of the heart, the sinus node. Sci Rep 2021;11:3565.

30. D'Souza A, Wang Y, Anderson C, et al. A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate. Heart Rhythm 2021;18:801-810.

31. Anderson C, Forte G, Boyett MR, D'Souza A. Non-canonical role of the sympathetic nervous system in the circadian rhythm in heart rate. Philos Trans R Soc Lond B Biol Sci 2023;378:20220179.

32. Tikhomirov R, Oakley RH, Anderson C, et al. The cardiac glucocorticoid receptor mediates the day-night rhythm in ventricular arrhythmia susceptibility. Circ Res 2024; https://doi.org/10.1161/CIRCRESAHA.123.323464.

33. Benditt DG, Sakaguchi S, Goldstein MA, et al. Sinus node dysfunction: pathophysiology, clinical features, evaluation, and treatment. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside, 2nd ed. Philadelphia: Saunders; 1995. p. 1215-1247.

34. Penton GB, Miller H, Levine SA. Some clinical features of complete heart block. Circulation 1956;13:801-824.

35. Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970;4:160-167.

36. Kuga K, Yamaguchi I, Sugishita Y. Age-related changes of sinus node function and autonomic regulation in subjects without sinus node disease: assessment by pharmacologic autonomic blockade. Jpn Circ J 1993;57:760-768.

37. Saeed Y, Temple IP, Borbas Z, et al. Structural and functional remodeling of the atrioventricular node with aging in rats: the role of hyperpolarization-activated cyclic nucleotide-gated and ryanodine 2 channels. Heart Rhythm 2018; 15:752-760.

38. Jones SA, Lancaster MK, Boyett MR. Ageing-related changes of connexins and conduction within the sinoatrial node. J Physiol 2004;560:429-437.

39. de Melo SR, de Souza RR, Mandarim-de-Lacerda CA. Stereologic study of the sinoatrial node of rats—age related changes. Biogerontology 2002;3:383-390.

40. Hao X, Zhang Y, Zhang X, et al. TGF-β1 mediated fibrosis and ion channel remodeling are key mechanisms producing sinus node dysfunction associated with SCNSA deficiency and aging. Circ Arrhythm Electrophysiol 2011;4:397-406.

41. Moghtadaei M, Jansen HJ, Mackasey M, et al. The impacts of age and frailty on heart rate and sinoatrial node function. J Physiol 2016;594:7105-7126.

42. Csepel TA, Kalyanasundaram A, Hansen BJ, Zhao J, Fedorov VV. Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction. Front Physiol 2015;6:37.

43. Alings AM, Abbas RF, Bouman LN. Age-related changes in structure and relative collagen content of the human and feline sinoatrial node: a comparative study. Eur Heart J 1995;16:1655-1667.

44. Yanni J, Tellez JO, Sutyagin PV, Boyett MR, Dobrzynski H. Structural remodelling of the sinoatrial node in obese old rats. J Mol Cell Cardiol 2010;48:653-662.

45. Alings AMW, Bouman LN. Electrophysiology of the ageing rabbit and cat sinoatrial node—a comparative study. Eur Heart J 1993;14:1278-1288.

46. Huang X, Du Y, Yang P, et al. Age-dependent alterations of voltage-gated Na⁺ channel isoforms in rat sinoatrial node. Mech Ageing Dev 2015;152:80-90.

47. Zhang H, Boyett MR, Holden AV, Honjo H, Kodama I. A hypothesis to explain the decline of sinoatrial node function with age. J Physiol 1998;511:76P-77P.

48. Tellez JO, Maczewski M, Yanni J, et al. Ageing-dependent remodelling of ion channel and Ca²⁺ clock genes underlying sinoatrial node pacemaking. Exp Physiol 2011;96:1163-1178.

49. Jones SA, Boyett MR, Lancaster MK. Declining into failure: the age-dependent loss of the L-type calcium channel within the sinoatrial node. Circulation 2007; 115:1183-1190.

50. Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca²⁺ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ Res 2010;106:659-673.

51. Huang X, Yang P, Du Y, Zhang J, Ma A. Age-related down-regulation of HCN channels in rat sinoatrial node. Basic Res Cardiol 2007;102:429-435.
52. Larson ED, St Clair JR, Sumner WA, Bannister RA, Proenza C. Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate. Proc Natl Acad Sci U S A 2013;110:18011-18016.

53. Alghamdi AM, Boyett MR, Hancox JC, Zhang H. Cardiac pacemaker dysfunction arising from different studies of ion channel remodeling in the aging rat heart. *Front Physiol* 2020;11:546508.

54. Heath TL, ed. Euclid's Elements, Book I, Common Notion 5. New York: Dover; 1956.

55. Obel OA, Davidson C. Arrhythmias in an athlete: the effect of de-training. Post-grad Med J 2005;81:62.

56. Giada F, Bertaglia E, De Piccoli B, et al. Cardiovascular adaptations to endurance training and detraining in young and older athletes. Int J Cardiol 1998; 65:149-155.

57. Mujika I, Padilla S. Cardiorespiratory and metabolic characteristics of detraining in humans. Med Sci Sports Exerc 2001;33:413-421.

58. Murayama M, Kuroda Y. Cardiovascular future of athletes. Jpn J Phys Fit Sports Med 1980;29:117-123.

59. Meytes I, Kaplinsky E, Yahini JH, Hanne-Paparo N, Neufeld HN. Wenckebach A-V block: a frequent feature following heavy physical training. Am Heart J 1975; 90:426-430.

60. Kizhakkekara JS, Joseph SJ, Gowda GS. Psychological ramifications of detraining effects in sportspersons amidst the COVID-19 pandemic: a consensus compen-dium. Open J Psychiatry Allied Sci 2020;12:3-6.

61. Uroh CC, Adewunmi CM. Psychological impact of the COVID-19 pandemic on athletes. Front Sports Act Living 2021;3:603415.

62. Landolfi E. Exercise addiction. Sports Med 2012;43:111-119.

63. Antunes HKM, Leite GSF, Lee KS, et al. Exercise deprivation increases negative mood in exercise-addicted subjects and modifies their biochemical markers. Physiol Behav 2016;156:182-190.

64. Bennekers JH, van Mechelen R, Meijer A. Pacemaker safety and long-distance running. Neth Heart J 2004;12:450-454.

65. Pachon-M JC, Pachon-M EI, Pachon-M JC, et al. "Cardioneuroablation"—new treatment for neurocardiogenic syncope, functional AV block and sinus dysfunc-tion using catheter RF-ablation. Europace 2005;7:1-13.

66. Pachon-M JC, Pachon-M EI, Pachon CTC, et al. Long-term evaluation of the vagal denervation by cardioneuroablation using Holter and heart rate variability. Circ Arrhythm Electrophysiol 2020;13:e008703.

67. Bulava A, Osório TG, Hanis J, Pachón CTC, Pachón JC, de Asmundis C. Cardio-neuroablation instead of pacemaker implantation in a young patient suffering from permanent 2:1 atrioventricular block after a slow pathway ablation. Heart-Rhythm Case Rep 2020;6:261-264.

68. Aksu T, Güler TE, Bozyel S, Özcan KS, Yalın K, Mutluer FO. Cardioneuroablation in the treatment of neurally mediated reflex syncope: a review of the current liter-ature. Turk Kardiyol Dern Ars 2017;45:33-41.

69. Pachon-M JC. Cardioneuroablation for neurocardiogenic syncope. Heart Rhythm 2019;16:1552-1553.

70. Gajda R, Knechtle B, Gębska-Kuczerowska A, et al. Amateur athlete with sinus ar-rest and severe bradycardia diagnosed through a heart rate monitor: a six-year

observation—the necessity of shared decision-making in heart rhythm therapy management. Int J Environ Res Public Health 2022;19:10367.

71. Luo X, Yang B, Mattel S. MicroRNAs and atrial fibrillation: mechanisms and trans-lational potential. Nat Rev Cardiol 2015;12:80-90.

72. Abplanalp WT, Fischer A, John D, et al. Efficiency and target derepression of anti-miR-92a: results of a first in human study. Nucleic Acid Ther 2020; 30:335-345.

73. Täubel J, Hauke W, Rump S, et al. Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study. Eur Heart J 2021; 42:178-188.

74. Bidaud I, Chong ACY, Carcouet A, et al. Inhibition of G protein-gated K⁺ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia. Sci Rep 2020;10:9835.

75. Mesirca P, Alig J, Torrente AG, et al. Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. Nat Commun 2014;5:4664.

76. Mesirca P, Bidaud I, Briec F, et al. G protein-gated IKACH channels as therapeutic targets for treatment of sick sinus syndrome and heart block. Proc Natl Acad Sci U S A 2016;113:E932-E941.

77. Richter EA, Ruderman NB. AMPK and the biochemistry of exercise: implications for human health and disease. Biochem J 2009;418:261-275.

78. Yavari A, Bellahcene M, Bucchi A, et al. Mammalian γ2 AMPK regulates intrinsic heart rate. Nat Commun 2017;8:1258.

79. D'Souza A, Sharma S, Boyett MR. CrossTalk opposing view: bradycardia in the trained athlete is attributable to a downregulation of a pacemaker channel in the sinus node. J Physiol 2015;593:1749-1751.

80. Vandewalle G, Middleton B, Rajaratnam SM, et al. Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod. J Sleep Res 2007;16:148-155.

81. Palhares DMF, Marcolino MS, Santos TMM, et al. Normal limits of the electrocar-diogram derived from a large database of Brazilian primary care patients. BMC Cardiovasc Disord 2017;17:152.

82. Härtel G, Talvensaari T. Treatment of sinoatrial syndrome with permanent cardiac pacing in 90 patients. Acta Med Scand 1975;198:341-347.

83. Stein R, Medeiros CM, Rosito GA, Zimerman LI, Ribeiro JP. Intrinsic sinus and atrioventricular node electrophysiologic adaptations in endurance athletes. J Am Coll Cardiol 2002;39:1033-1038.

84. Cohen JL, Gupta PK, Lichstein E, Chadda KD. The heart of a dancer: noninva-sive cardiac evaluation of professional ballet dancers. Am J Cardiol 1980; 45:959-965.

85. Bjørnstad H, Storstein L, Meen HD, Hals O. Electrocardiographic findings in ath-letic students and sedentary controls. Cardiology 1991;79:290-305.

86. Bjørnstad H, Storstein L, Dyre Meen H, Hals O. Ambulatory electrocardiographic findings in top athletes, athletic students and control subjects. Cardiology 1994; 84:42-50.

87. Sharma S, Whyte G, Elliott P, et al. Electrocardiographic changes in 1000 highly trained junior elite athletes. Br J Sports Med 1999;33:319-324.