Cystic fibrosis (CF) is an autosomal recessive disease caused by the mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located in the chromosome 7 (Wainwright et al., 1985). The defect of the chlorine channel affects all epithelial cells, altering ionic transport in several tissues and causing obstruction of the secretory glands (Savant and McColley, 2019). Although CF is a multisystemic disease, pulmonary impairment is the most frequent symptom, as a result of small airway obstruction that triggers a chronic inflammatory process (Savant and McColley, 2019). However, the effects of the CFTR malfunction on the autonomic nervous system (ANS), as well as its physiological consequences, still remain to be better understood.

CFTR dysfunction may lead to abnormalities in the ANS (Davis and Kaliner, 1983), as it facilitates neuronal activity, as well as plays an important role in the regulation of energy homeostasis, motor function and autonomic control of visceral organs, such as the heart (Kahle et al., 2008). Several studies suggest that ANS could be altered in CF (Davis and Kaliner, 1983). A simple and non-invasive method to analyze the function of ANS is to record the sympathetic-parasympathetic balance measured through heart rate variability (HRV). This method allows a non-invasive overview of the nervous system. HRV is highly sensitive as its negative variations may anticipate autonomic neuropathy clinical symptoms, gaining importance as an useful tool for diagnosis (Malik et al., 1996). In recent years, HRV complexes, as time-domain and frequency-domain values, have generated interest on health science studies and applications based on ANS changes have been used on training programs (Grant et al., 2011). Evidence shows an excellent reproducibility of HRV in healthy children, indicating that this may be an useful tool to evaluate the effectiveness of interventions in this population, as well as a prognostic tool in children with CF (McNarry and Mackintosh, 2016). Early dysfunction of the ANS, measured through HRV, has been described for children with CF (Florêncio et al., 2013; McNarry and Mackintosh, 2016). In addition, in adults with CF, a significant association between HRV, lung impairment and clinical symptoms, such as pulmonary exacerbations, gastrointestinal motility or cough have been reported (Reznikov, 2017).

Exercise in healthy children can positively modulate the ANS (Winsley, 2002). Although there are no studies assessing the effect of exercise on HRV in individuals with CF, there is evidence that exercise may positively influence HRV in obese (Prado et al., 2010) and asthmatic (McNarry et al., 2019) children. Children with CF are characterized by exercise intolerance and higher perceived fatigue, resulting in higher sedentary habits that may negatively impact the evolution and prognosis of the disease. In individuals with CF, the CFTR protein is not expressed in the muscles (Divangahi et al., 2009), leading to cellular alterations that include the oxidative metabolism (Antigny et al., 2009), and reduction of contractile excitability (Clay, 2013), translating into exercise intolerance and decreased muscle strength (Gruet et al., 2017), which contributes to a decreased level of activities, causing a worst response of the ANS. Although there is evidence on the use of aerobic exercise in CF (Radtke et al., 2017), the relative benefits of resistance training for children with CF has been poorly investigated to date (Kriemler et al., 2013; Santana-Sosa et al., 2014).

Thus, the aim of the present study is to determine the effects of a short-term resistance-training program on HRV in children and adolescents with CF. We hypothesize that a resistance exercise-training program would improve the sympatho-vagal balance in individuals with CF.

A total of 30 individuals were assessed for eligibility, between March and September 2020, and 6 refused to participate. Therefore, 24 were randomized (CON = 12 and EX = 12), but one subject in the control group and four in the exercise group were lost to follow-up. Figure 1 shows the flow diagram of the study.

The final sample presented differences regarding genotyping (p = 0.032), as the percent of F508del heterozygous was higher in the CON group. Apart from that, no statistically significant differences between groups were found at baseline regarding demographic, clinical, lung function and microbiological variables. As for anthropometric measurements, although significant differences were found for absolute values of body weight and BMI, when variables were normalized in z-scores, no differences were found (Table 1).

The resistance exercise-training program induced a significant increase on muscle strength (bench press, pectoral, and dorsal) when compared to the CON group, demonstrating the effectiveness of the program (Table 2). As for cardiorespiratory fitness (CPET), a significant difference between groups (p = 0.019) was found only for the HR at 2 min of recovery. Although VO₂ at the anaerobic threshold (AT) and VCO₂ at AT presented moderate effect-size differences in percent change between groups (d = −0.49 and d = −0.58, respectively), these differences were not statistically significant (Table 2).

When HRV data were normalized, according to reference values (Gasior et al., 2018), 57.9% of subjects presented at least one HRV variable classified as altered. No differences in baseline respiratory rate was found between groups (Pre: CON = 25.2 ± 7.4; EX = 27.5 ± 8.6, and Post: CON = 23.6 ± 5.0; EX = 25.5 ± 7.8; p = 0.801). Figure 2 presents mean and standard deviation for main HRV data. While no statistically significant pre-to-post differences in HRV were determined for the control group, the exercise group presented large effect sizes and statistically significant differences in frequency-domain metrics (LF power, HF power and LF/HF ratio). Moderate and small effect sizes were also observed in time-domain and non-linear measurements for the exercise group (Table 3). Accordingly, differences between control and exercise groups in percent change were found to be statistically significant in LF power (p = 0.006, d = 1.20), HF power (p = 0.025, d = −1.01) and LF/HF ratio (p = 0.007, d = 1.17). Although SDNN and RMSSD also presented large effect-size differences in percent change between groups (d = −0.81 and d = −0.84, respectively), these differences were not statistically significant.

The results of the present study confirmed our hypothesis that an 8-week resistance exercise program is able to modulate HRV in children with CF. To the best of our knowledge, this is the first study to investigate the influence of an exercise program on HVR in children and adolescents with CF.

HRV has been commonly applied to high-performance athletes in order to control working load doses during training periods (Manzi et al., 2009). In addition, other areas, such as nutrition, have also studied the influence of ergogenic supplements and its association with HRV (Zimmermann-Viehoff et al., 2016). Psychological factors as stress or anxiety have been related to sympatho-vagal balance (Goessl et al., 2017). On the other hand, HRV may also play an important role in clinical settings, as a complementary tool to extract information on the diagnosis and evolution of several diseases, including Diabetes (Gutin et al., 1997), Asthma (McNarry et al., 2019), and CF (McNarry and Mackintosh, 2016). Although HRV is well-reported in several studies with adults (Nunan et al., 2010), there is considerably less evidence available in children. The evaluation of the sympatho-vagal balance in children with CF, measured through HRV, was associated with a good to excellent reproducibility and a useful prognostic tool (McNarry and Mackintosh, 2016). On the other hand, we believe it is important to note that the use of LF/HF to evaluate sympatho-vagal balance is still a matter of debate, as the utility of LF HRV as an index of sympathetic cardiac tone has been questioned (Billman, 2013; Reyes del Paso et al., 2013). Considering that autonomic function is altered in people with CF (Davis and Kaliner, 1983) and that exercise may be a regulator of its function (Caruso et al., 2015), the present study focused on the effects of an exercise program and have used HRV to provide an indirect assessment of cardiac autonomic activity, rather than a direct measure of cardiac parasympathetic or sympathetic nerve activity. In spite of that, normal values for HRV have been described for the healthy children population. CF children exhibit a sympathetic dominance at rest compared to healthy children, which persisted after a 6-min walk test (Florêncio et al., 2013). Resting values described by Florêncio et al. (2013) were comparable to the ones found in the present study. Although differences regarding the recording tool and protocol exists between studies, our results have shown that the majority (57.9%) of individuals with CF presented at least one altered HRV variable when data was normalized using reference values for healthy children (Gasior et al., 2018).

Evidence on the influence of exercise upon the ANS in healthy children is limited. In 2009, a study using 7 weeks of high aerobic intensity training (HIIT) was not able to demonstrate influence on the heart rate autonomic regulation (Gamelin et al., 2009). However, 13 weeks of aerobic exercise had a positive effect on HRV global cardiac parameters, although this improvement was seen during nocturnal long-term recordings (Mandigout et al., 2002). Studies have also evaluated the effects of exercise on HRV in children with several diseases (Prado et al., 2010; McNarry et al., 2019). Our results have shown that a resistance exercise-training program was able to modulate the sympatho-vagal balance in children with CF. To the best of our knowledge, no studies have investigated the effects of an exercise program focused on resistance training and its influence on the ANS in children and adolescents with CF. However, evidence in obese children shows that a 12-week resistance training program also improved HRV (Farinatti et al., 2016). In addition, a recent study has shown the effectiveness of a 5-week multimodal program (aerobic and resistance training combined with diet) for obese adolescents on HRV parameters (Huang et al., 2019). On the other hand, the effects of aerobic exercise-training on HRV have been widely explored in obese children (Farah et al., 2014) and most of the studies concluded that training was able to change the cardiac autonomic function by reducing the sympathetic activity (Gutin et al., 1997). Taken together, we believe it is important to highlight that comparisons must be interpreted with caution, as baseline mechanisms leading to altered HRV may differ between obese and CF individuals, and several factors may have influenced results, including the length of exercise programs, the influence of diet, among others. As for chronic respiratory diseases, evidence has shown that a 6-month HIIT in adolescents with asthma produced no effects in both time-domain and non-linear indices (Prado et al., 2010; McNarry et al., 2019). No studies on the effects of exercise training on HRV in individuals with CF were found for comparisons.

Physical activity and exercise programs have been largely used in children with CF as a tool to improve general physical health, morbi-mortality and exercise tolerance (Radtke et al., 2017; Vendrusculo et al., 2019). The majority of studies evaluating the effects of exercise training in children were performed using aerobic exercise programs (Gutin and Owens, 1999; Huang et al., 2019), in contrast to the present study, in which the exercise program was based on resistance training. Evidence evaluating the effects of resistance exercise for individuals with CF have shown positive results in both aerobic and anaerobic performance, health-related quality of life and lung function (Kriemler et al., 2013; Santana-Sosa et al., 2014). Our results have shown that an 8-week resistance-training program was able to improve the sympatho-vagal balance. Considering the well-known compromise of peripheral muscles in individuals with CF, including decreased muscle strength (Gruet et al., 2017), reduction of contractile excitability (Clay, 2013), cellular alterations (Antigny et al., 2009), and loss of muscle mass, it is possible that the resistance-training would improve muscle performance leading to the several benefits already described, including the modulation of the ANS.

The present study also has limitations, including the reduced sample size, which may have prevented time-domain variables from reaching statistical significance, although a moderate effect size was seen. The inclusion of a sample of children with CF and high aerobic fitness (mean VO₂peak of 42.7 mL.Kg^–1.min^–1) may have also decreased the effects of an exercise-based program. In spite of that, significant improvements were seen on the modulation of the ANS. The use of long-term HRV protocols could improve the precision of data collection, although its application decreases clinical practicability in routine CF management and short-term protocols have been validated. Respiratory rate is known to influence HRV, specially the HF band, and although breathing pattern was not controlled, patients remained in a quiet environment, without speaking or performing any important body movements, and no differences between baseline respiratory rate were seen between groups.

Our findings support the effectiveness of a short-term exercise resistance training program to modulate HRV in children and adolescents with CF presenting mild to moderate lung function impairment and a good physical state.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Hospital Universitario Niño Jesús de Madrid and Universidad Europea de Madrid. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

AE-G, MD, and FC-V: literature search. AE-G, FC-V, ÁF-L, TI, and MF-d-V: data collection. MP-R, MD, VS-S, and JV: study design. ID-V, EL-Z, AE-G, and MD: analysis of data. AE-G and MD: manuscript preparation. MP-R, EL-Z, and MD: final critical review. All authors read and approved the final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.