Bronchial hyperresponsiveness (BHR) and asthma are frequently reported in endurance athletes, in particular swimmers and cross-country skiers (9,15,24,33), but the mechanisms of asthma in athletes have not been fully described.
Parasympathetic cardiac activity, measured by heart rate variability (HRV), is shown to be increased in endurance athletes and to correlate with maximal oxygen uptake (6,14,16,37). Furthermore, Filipe et al. (14) found increased pupil constriction measured by pupillometry, reflecting increased parasympathetic activity, in endurance athletes. The autonomic nervous system mediates the contraction and relaxation of bronchial smooth muscle with parasympathetic cholinergic nerves stimulating bronchoconstriction, whereas sympathetic nerves bronchodilate (8). As BHR denotes an increased bronchoconstrictor response to different stimuli, such as cold air, exercise, or pharmacological substances, increased parasympathetic activity could also theoretically predispose an athlete to increased bronchomotor tone and further susceptibility to bronchospasm (27). Indeed, Pichon et al. (30) demonstrated that subjects with BHR had increased parasympathetic indices of HRV from before to after a methacholine bronchial challenge. Methacholine is a synthetic choline ester that acts as a nonselective muscarinic receptor agonist in the parasympathetic nervous system that is frequently used to assess BHR, which is shown to be a sensitive test in athletes (33,36). An inverse correlation between the bronchodilating effect to inhaled ipratropium bromide, but not inhaled salbutamol, a general bronchodilating agent, and BHR to methacholine was found in elite cross-country skiers (34).
Although increasing evidence suggests that BHR to methacholine is related to increased parasympathetic bronchial activity in athletes, this relationship is not fully established. Langdeau et al. (22) found a weak, although significant, correlation between HRV and PD20 methacholine and concluded that parasympathetic activity did not explain the differences in BHR prevalence found between swimmers and cold-air athletes. In this study, parasympathetic activity was measured by HRV. In a previous study from our group, no agreement between parasympathetic activity measured in the heart, pupil, and lungs were found (35), suggesting that parasympathetic activity measurements depend on the target organ. Yet a strong correlation between the bronchodilating effect of inhaled ipratropium bromide on exercise-induced bronchoconstriction (EIB) blocking efferent cholinergic pathways in the airways, and cardiac vagal activity, measured during a 4-s exercise test, is found in both healthy cross-country runners (20) and asthmatic children (21).
The previously cited studies suggest that increased parasympathetic activity is involved in the pathogenesis of asthma and BHR in athletes. Thus, measuring parasympathetic activity in athletes may be of clinical importance and may improve the understanding of the development of asthma in this group. However, the measurement method of parasympathetic activity seems to be of importance. The primary aim of the present study was to assess the association between BHR to methacholine and parasympathetic activity measured by variation in heart rate and by pupil constriction. Secondarily, we aimed to compare BHR to methacholine and parasympathetic activity between healthy and asthmatic cross-country skiers and swimmers, as well as in nonathletes.
MATERIALS AND METHODS
Subjects and design
We recruited cross-country skiers and swimmers from sport clubs in the southeast part of Norway, as well as through the National Olympic Center in Oslo, Norway. Inclusion criteria were to compete on a high national or international level, to train more than 10 h·wk−1, and to be 16–35 yr old. Simultaneously, healthy nonathletes within the same age range, who trained less than 5 h·wk−1, were recruited as control subjects, mostly students from the Norwegian School of Sport Sciences and the University of Oslo, as well as local high schools.
All subjects attended the laboratory on 2 d, separated by >24 h, but no more than 3 wk. Parasympathetic activity was measured in standardized settings in both visits. In addition, measurements of fractional exhaled nitric oxide (FENO) and skin prick test were performed, followed by a methacholine bronchial challenge at the first visit. A modified Allergy Questionnaire for Athletes, developed and validated for screening allergic diseases in athletes (4), was administered to record past or present history of asthma, allergy, and exercise-induced asthmalike symptoms in relation to sport participation. On the second visit, measurements of body composition were conducted. All subjects were to refrain from exercise and caffeine on the same day, as well as to avoid food and drinks >2 h before each visit. The subjects had to be free from any acute respiratory disease, including upper viral infections, for the last 3 wk and to refrain from exercise on the same day before each visit. Inhaled short acting β2-agonists were withheld for 8 h before each visit; inhaled long-acting β2-agonists, theophylline, and leukotriene antagonists were withheld for the last 72 h; antihistamines were withheld for the last 7 d; and orally administered glucocorticosteroids were withheld for the last month. Inhaled corticosteroids were not to be used on the same day. Athletes were grouped on whether they had current asthma or not. Current asthma was defined as a doctor’s diagnosis of asthma, combined with the presence of either current BHR to methacholine (PD20met ≤8 μmol) or the current use of asthma medication. Data collection occurred from September 2013 to September 2014, and subjects with known or suspected allergies were not tested during the pollen season. The study was approved by the Regional Committee for Medical and Health Research Ethics. All subjects gave their written informed consent for participation, and an additional signed consent was acquired by a parent or a guardian when subjects were younger than 18 yr.
Parasympathetic activity was assessed noninvasively in two target organs: 1) the heart and 2) the pupil. 1) A 4-s exercise test (4sET) analyzed the acute cardiac vagal response to exercise (2,3). Subjects were instructed to pedal as fast as possible on a cycle ergometer with no load, from the fourth to the eighth second of a maximal inspiratory apnea. HRV was recorded with a heart rate monitor (Polar Electro®, OY, Kempele, Finland). The ratio between the longest RR interval before exercise and the shortest RR interval during the exercise was identified as the cardiac vagal index (CVI), as defined by Araújo et al. (2). The highest CVI from two consecutive trials was used for analysis. 2) The autonomic regulation of the pupil was assessed by pupillometry, according to Felipe et al. (14). A portable infrared PLR-200™ pupillometer (NeurOptics Inc., Berkeley, CA) stimulated the eye with a light flash (180-nm peak wave light) and measured the initial diameter (mm) of the pupil and just at the peak of the (minimal) constriction. The percent pupil constriction and the average and maximum constriction velocity (mm·s−1) were also recorded. Pupil amplitude was calculated by subtracting the minimal diameter from the initial pupil diameter. The subjects spent 15 min in a semidark room to adjust to low lighting levels before measurement. One pupil light response curve to each eye was recorded for each subject, and mean values were used for further analyses. The parasympathetic activity tests were performed on two separate days, with the mean values used for statistical analyses, to minimize effects from day-to-day variability.
FENO was measured with a single-breath online technique and a chemiluminescence analyzer (EcoMedics AG, Duerten, Switzerland). Subjects inhaled NO-free air to total lung capacity and exhaled for 10 s through a mouthpiece against a target pressure of 20 cm H2O (1). Mean values of three measurements with a <10% difference were used in the analysis.
Lung function was measured by maximal expiratory flow volume curves (MasterScreen Pneumo spirometer; CareFusion, Höchberg, Germany) according to current guidelines (26) and recorded as forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flow in 25%–75% of FVC. Predicted spirometry values were defined according to Quanjer et al. (31).
Allergy skin prick test was performed using extracts of 10 common allergens (ALK-Abelló as, Hørsholm, Denmark): dog, cat and horse dander, birch, timothy and mugwort pollens, mold (Cladosporium herbarum), house dust mite (Dermatophagoides pteronyssinus), cow’s milk, and hen’s egg white. A test was considered positive if at least one allergen caused a weal of ≥3 mm greater than the negative saline control in diameter, in the presence of a positive histamine control (6).
Methacholine bronchial challenge was performed during controlled tidal breathing with an inspiration-triggered Aerosol Provocation System (Jäger, Würzburg, Germany) (12). After inhalation of 0.9% isotonic saline, spirometry was performed to establish baseline FEV1. Then subjects inhaled doubling doses of methacholine chloride (32 mg·mL−1) starting with 0.25 μmol. Spirometry was repeated 1 min after every delivered dose until FEV1 decreased 20% from baseline (PD20met), or the maximal dose of methacholine (24.48 μmol) was reached. A positive response was defined as a 20% reduction in FEV1 at a cumulative dose of ≤2 μmol (0.4 mg) of methacholine, calculated by linear interpolation on the dose–response curve. Clinical significant BHR was defined as PD20met ≤8 μmol (1.6 mg). We are aware that other groups have used a stricter cutoff of 4 or 2 μmol, and therefore we also analyzed our data using these criteria (10). After the methacholine provocation, all subjects received salbutamol inhalation (0.1 mg·mL−1 × 10 kg body mass) to reverse bronchial obstruction.
Body composition was measured by bioelectrical impedance analysis using Inbody 720 (Biospace Co. Ltd., Soul, Korea). The standardization of procedures included 5 min of resting and a minimum of 2-h fasting before measurement. To increase the reliability, the measurements were conducted twice (19), and the mean values were used in the analyses.
Continuous data are presented using standard summary statistics (mean and SD). Categorical variables are presented as counts (N) with percentages. Results are presented as mean values and β coefficients with 95% confidence intervals (CI), unless otherwise stated. Subjects with a PD20met of >24.48 μmol were assigned a PD20met value of 25 μmol, and subjects with a PD20met of <0.1 μmol were assigned a PD20met value of 0.1 μmol. Associations of BHR and parasympathetic activity were assessed by robust regression models with PD20met as the dependent variable. For all parasympathetic variables, robust regression analyses were used, as the residuals were clearly nonnormal. We performed Hosmer’s step-down procedure (18) retaining significant background variables only. We had the following basic set of background variables: age, sport type, and gender. Group means were compared using Student’s t-test for two independent samples and ANOVA for three or more groups after tests for normality. Post hoc tests (Tukey’s multiple comparisons technique) were applied to determine within-group differences. Chi-square tests (χ2) were used to assess group differences of categorical variables. Correlations were calculated by Spearman’s rank order correlation (ρ), or Pearson’s correlation coefficient (rp) where applicable. All P values less than 0.05 (5%) were considered significant. Analyses were conducted in IBM SPSS Statistics version 21.0 (SPSS Inc., Chicago, IL) and SAS version 9.4 (SAS Institute Inc., Cary, NC). Power calculations are based on variations in the mean values (represented by SD) from a study previously performed at our lab (35). A total sample of 90 subjects (30 in each group) achieves 80% power to detect a difference in percent pupil constriction and CVI between controls and the two athletes groups of 0.18 and 0.14, respectively, and the difference between two athlete groups of at least 0.06 for both variables.
Twenty-eight cross-country skiers (♂18/♀10), 29 swimmers (♂17/♀12), and 30 healthy nonathletes (♂14/♀16) completed both visits. Fourteen swimmers (48%) and 16 cross-country skiers (57%) met the criteria set for current asthma. Of these, seven athletes (five swimmers and two cross-country skiers) were not aware of asthma when entering the study. Demographic and clinical characteristics of the subjects are presented in Table 1. The occurrence of BHR (defined as PD20met ≤2, ≤4, or ≤8 μmol) did not differ significantly between the asthmatic athletes, healthy athletes, and controls.
Parasympathetic activity and BHR
CVI was significantly associated with PD20met, with the model explaining 18.2% (r2) of the variation in PD20met after adjusting for age, sex, and type of sport (Table 2). When adjusted for the type of sport, a stronger association between CVI and PD20met was observed in swimmers as compared with the reference group (controls), but the association for cross-country skiers was not statistically significant. Neither of the pupillometry variables were associated with PD20met in the crude analysis. However, when adjusting for age, sex, and type of sport, all parasympathetic pupillometry variables were significantly associated with PD20met in swimmers (Table 2). Furthermore, the associations between PD20met and any parasympathetic variables were not significantly different when only including the asthmatic athletes, or subjects with severe or clinically relevant BHR (PD20met ≤2, 4, or 8 μmol), respectively (data not presented). No correlations (ρ) were observed between CVI and any of the pupillometry variables (data not presented).
Differences between healthy and asthmatic athletes
Athletes with asthma showed increased parasympathetic activity, in terms of percent pupil constriction (P = 0.002), as compared with healthy athletes (Table 3). However, control subjects also showed increased pupil constriction as compared with healthy athletes (P < 0.001). Healthy athletes had increased initial and minimal pupil diameter as compared with both asthmatic athletes (P < 0.01) and control subjects (P < 0.01). Other parasympathetic variables from pupillometry or CVI did not differ between asthmatic athletes, healthy athletes, or controls. We found no differences in neither of the parasympathetic activity parameters between subjects grouped by PD20met cutoff values of 2, 8, and 16 μmol (data not presented). No differences in BHR occurrence or pupillometry parameters were found between athletes using inhaled corticosteroids and athletes who did not (data not presented). No statistical difference in FENO was found between asthmatic and healthy cross-country skiers (Table 1). Although not significant, increased CVI were observed in athletes as compared with controls.
Differences between swimmers and cross-country skiers
The distribution of PD20met, as shown by the Kaplan–Meier curves (Fig. 1), differed significantly between swimmers, cross-country skiers, and controls (P < 0.05). Fourteen swimmers (48%) had a severe BHR (PD20met ≤2 μmol) as compared with only one cross-country skier (P < 0.001), and 72% swimmers had clinical BHR (PD20met ≤8 μmol) as compared with 44% of the cross-country skiers and 39% controls (P = 0.015) (Table 4). The swimmers showed an increased mean FVC compared with cross-country skiers (P = 0.009). A weak to moderate inverse correlation was found between FVC and PD20met (ρ = −0.22, P = 0.036). The swimmers were younger than the cross-country skiers (P < 0.001) and trained more weekly hours than the cross-country skiers (P < 0.001). PD20met did not correlate with training hours per week (ρ = −0.25, P = 0.08). Furthermore, cross-country skiers had increased FENO as compared with the swimmers (P = 0.009).
Variations in parasympathetic activity
Mean day-to-day variance for pupillometry parasympathetic parameters ranged from 0.3% to 3.2%. Group means of initial pupil diameter (P = 0.002) and minimum pupil diameter (P = 0.02) were increased on day 2. Measurements of CVI did not differ between days (P = 0.233). The mean day-to-day CVI variance was 3.4%. The mean difference between day 1 and day 2 was similar when comparing subjects who tested on the same time of day (morning, midday, or afternoon) on both days with subjects who tested at different time points. The majority of the tests (59.5%) were performed in the morning (6:00–10:00 a.m.). No differences in variation between day 1 and day 2 were found between subjects where measurements were performed at the same time of day both days (64% of all subjects) as compared with subjects where time of day varied from day 1 to day 2.
We found no significant differences between left and right eye for any of the pupillometry variables, and significant correlations (rp = 0.62–0.89) were found between the eyes (P < 0.03). Moderate to strong correlations (rp = 0.58–0.90, P < 0.001) were observed in all pupillometry parameters when comparing day 1 and day 2.
The findings from the present study showed that the association between BHR and parasympathetic activity depends on the measurement procedure or target organ of parasympathetic activity. Furthermore, the type of sport influences these associations. If the same applies to other sports or to indirect measurement procedures of BHR remains to be clarified.
A negative association of CVI to PD20met was found, in particular in swimmers, demonstrating that a higher CVI was related to more severe BHR. This supports the hypothesis that increased parasympathetic activity is related to more severe BHR in these athletes and corroborates to previous results (11,22,23,34). However, the same was not found regarding pupillometry variables. Bronchoconstriction is mediated, such as bradycardia, by afferent nerves in the nervus vagus, allowing a link between the regulation of the heart and the bronchi. This may explain why PD20met was associated with CVI and not with pupillometry, and the model explained 18% of the variation in PD20met. In a previous study from our group (35), we found no associations between CVI, nor pupillometry variables, to the reversibility to inhaled ipratropium bromide, an anticholinergic bronchodilator. Furthermore, Horváth et al. (17) found no agreement between HRV and resting specific airway resistance, which they suggested to represent the vagal activity of the bronchi. These findings may reflect that although the parasympathetic regulation of the heart and the bronchi is mediated through nervus vagus, neurogenic differences exist between these organs, for instance, regarding neural pathways, receptor sensitivity, or regulation of sympathetic–vagal balance. In addition, the parasympathetic bronchial tone as shown by reversibility to inhaled ipratropium bromide, specific airway resistance, or cholinergic sensitivity to inhaled methacholine may reflect different aspects of the parasympathetic regulation of the bronchi. The results from the present study suggest that in regard to parasympathetic activity assessments in athletes, the heart is a more appropriate target organ as compared with the pupil. Uusitalo et al. (37) recommend time domain and frequency domain indices of HRV measurements for the assessment of parasympathetic activity in athletes. The HRV protocol used in the present study, the 4sET, is found to be comparable with these HRV indices in healthy subjects (28).
When adjusted for the type of sport, differences in the associations of parasympathetic parameters to PD20met became apparent, with the associations being significant in swimmers and not in cross-country skiers. Similarly, a correlation between BHR to methacholine and parasympathetic parameters of pupillometry is previously reported in swimmers with severe BHR (11). This may be explained by the type of training, training volume, or training environment. The exposure of chlorine derivate from indoor swimming pools may irritate the airways, and the high total volume of chlorine inhaled by competitive swimmers is considered responsible for the high occurrence of asthma and BHR reported in these athletes (5,13). Indeed, in the present study, more swimmers than cross-country skiers had a severe BHR (PD20met <2 μmol). Thus, our results may show that the association between BHR and parasympathetic activity is dependent on BHR severity and may be related to the environmental exposure of the swimmers. This means that the use of inhaled corticosteroids, which may influence BHR severity, may have potentially confounded our results. Thus, the differences observed between the type of sport may be influenced by BHR severity and use of inhaled corticosteroids. Five swimmers and two cross-country skiers were unaware of asthma when entering the study and were thus untreated. However, when adjusted for BHR at different PD20met cutoff points (2, 4, or 8 μmol), no differences in parasympathetic activity were observed, nor a correlation between parasympathetic activity and PD20met as opposed to the results of Couto et al. (11). Furthermore, no differences in parasympathetic activity were found between athletes using inhaled corticosteroids and athletes who did not.
A negative correlation between PD20met and age in cross-country skiers was previously reported (34), suggesting that years of accumulated training will increase the risk of BHR in athletes. Pedersen et al. (29) found a lower BHR prevalence in swimmers age 12–16 yr as compared with a control group of unselected adolescences. Yet despite being younger, the swimmers in the present study had higher occurrence of BHR as compared with the (older) cross-country skiers. The 72% prevalence of clinical BHR among swimmers in our study agrees closely with the results of previous studies (5,22,39). Martin et al. (25) reported the same BHR percentage measured by eucapnic voluntary hyperpnoea tests in pool-based athletes. In line with previous studies (5,25,29), the swimmers of the present study had higher lung volumes compared with control subjects and cross-country skiers. Although a weak but significant correlation between FVC and BHR to methacholine (PD20met) was found, it is uncertain if the increased lung volumes found in swimmers are significantly associated with BHR.
We found that asthmatic athletes had increased pupil constriction compared with healthy athletes, but no differences were found in the other pupillometry parameters. An unexpected finding, which may confuse our interpretations, is that increased pupil constriction was also found in healthy nonathletes. Likewise, Filipe et al. (14) did not observe differences in pupillometry parameters between athletes and nonathletes. However, when stratified by the type of sport, endurance-trained runners showed increased pupil amplitude and percent pupil constriction as compared with soccer players, swimmers, and gymnasts, as well as to sedentary control subjects. As opposed to Couto et al. (11), we did not observe differences in pupillometry parameters between subjects when grouped according to their PD20met. Furthermore, increased initial and minimal pupil diameters were found in healthy athletes, which is proposed to reflect sympathetic–parasympathetic balance (14), and the differences observed in pupil constriction and amplitude in cross-country skiers, or in healthy athletes compared with other groups, must therefore be interpreted with care. Surprisingly, no difference in CVI was observed between controls and athletes in the present study. This is in contrast to previous studies reporting increased cardiac vagal tone in endurance athletes compared with nonathletes as well as the positive relationship to V˙O2max (7,16). As power calculations were performed, and the number of subjects included in the present study was similar or greater than that of previous studies showing significant results (11,14,20), a power problem seems unlikely. The controls did exercise regularly, and many of them reported that they previously had participated in competitive sports. However, it is unsure if the inclusion of more sedentary subjects would obtain significant results. Nevertheless, a trend toward a higher CVI in both swimmers and cross-country skiers compared with controls was seen, and the athletes showed a decreased baseline heart rate as compared with the controls, which is suggestive of a higher vagal cardiac flow. In a study by Araújo et al. (2), no difference in parasympathetic activity between athletes (n = 90) and controls (n = 58) was found using the 4sET. This is in agreement with our results and suggest that the 4sET is not sensitive enough to detect differences between such groups. Unfortunately, no objective tests for physical fitness or performance levels are available in the present study. Therefore, we can only assume that the athletes had higher V˙O2max than the control subjects based on the inclusion and exclusion criteria, and indicated by the increased muscle mass and decreased body fat shown in athletes as compared with controls.
The methacholine provocation challenge is a well-known direct test used for the assessment of BHR in asthmatics (12) and is regarded as a more sensitive test as compared with indirect tests such as exercise tests, or Mannitol challenge (12,36), but similar sensitivity is reported regarding the eucapnic voluntary hyperventilation test (33). However, the PD20met may also reflect parasympathetic bronchial tone by sensitivity to methacholine. Methacholine is an ester of acetylcholine (ACh), a known transmitter substance of the parasympathetic nervous system, with the parasympathetic (vagal) nerves innervating the contractive muscles of the bronchi. Therefore, one can argue that the increased sensitivity to methacholine, defined as PD20met, is reflecting the parasympathetic bronchial tone. This can, at least partly, explain the high BHR prevalence observed in asthmatic endurance athletes. It is also of interest that it has been described how ACh is produced in an inflamed respiratory mucosa (38), suggesting that ACh may have an additional nonneural role in the pathogenesis of asthma. On the basis of a study from our group (34), reversibility tests to the inhaled anticholinergic ipratropium bromide may be of value for the determination of bronchial parasympathetic tone and asthma treatment strategies for athletes.
A limitation of the present study is the cross-sectional design. Thus, we cannot determine causality in the associations of parasympathetic activity, BHR, and endurance training in these athletes. An unexpectedly high occurrence of BHR was observed in the controls, which may be caused by a selection bias. The use of anti-asthmatic drugs could influence BHR and/or parasympathetic activity measurements. However, these drugs were withheld >8 h before the tests. Inhaled corticosteroids were not withheld because of ethical considerations for the competing athletes, which is a limitation of the present study. When comparing the athletes who used inhaled corticosteroids or bronchodilators with nonusers, we found no differences in neither of the parasympathetic activity parameters. However, small sample sizes and lack of power may influence these results and they must therefore be interpreted carefully.
In the present study, we used the Polar® heart rate monitor to assess HRV, which is shown to be comparable with ECG (32). A previous study from our group showed good repeatability for the 4sET and pupillometry (35). A strength of the present study is that parasympathetic activity was measured in two target organs, as well as on two different days. In the present study, we aimed to schedule all visits at the same time of the day to avoid potential circadian variations. However, because of practical reasons, the time of testing could vary, but the day-to-day variability was low, and no effect from diurnal variation seemed to influence our results. All parameters of parasympathetic activity are performed at rest, except CVI, which was assessed during a short (4-s) cycling exercise. Thus, differences of autonomic regulation during exercise may differ from our observations.
The results from the present study show that the association between BHR and parasympathetic activity differ between measurement procedures of parasympathetic activity. Cardiac vagal activity is associated with BHR to methacholine, but not pupillometry parameters, suggesting that the parasympathetic activities of the heart and lungs are more closely related than to the activity of the pupils. However, the associations between parasympathetic activity and PD20met are dependent of the type of sport (swimming or cross-country skiing) and may thus be influenced by training environment or other sport-specific factors such as type of training. More severe BHR is apparent in swimmers as compared with cross-country skiers.
The authors are grateful to all subjects who took part in the study. They acknowledge Sveinung Blikom, Jonas Croff, and Stian Roterud for their efforts during data collection. The authors have no conflicts of interest or financial ties to disclose. Results of the study do not constitute endorsement by the American College of Sports Medicine.
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Keywords:© 2016 American College of Sports Medicine
ASTHMA; ASTHMA MECHANISMS; AUTONOMIC NERVOUS SYSTEM; CROSS-COUNTRY SKIERS; EXERCISE; SWIMMERS