J Neurol DOI 10.1007/s00415-017-8497-9
ORIGINAL COMMUNICATION
High-intensity interval training in facioscapulohumeral muscular dystrophy type 1: a randomized clinical trial Grete Andersen1
•
Karen Heje1 • Astrid Emile Buch1 • John Vissing1
Received: 21 February 2017 / Revised: 20 April 2017 / Accepted: 21 April 2017 Ó Springer-Verlag Berlin Heidelberg 2017
Abstract Increasing evidence suggests that high-intensity training (HIT) is a time-efficient exercise strategy to improve fitness. HIT has never been explored in neuromuscular diseases, likely because it may seem counterintuitive. A single session of high-intensity exercise has been studied without signs of muscle damage in facioscapulohumeral muscular dystrophy type 1 (FSHD1). We aimed to determine whether HIT is safe and effective in FSHD1 in a randomized, controlled parallel study. Untrained adults with genetically verified FSHD1 (n = 13) able to perform cycle-ergometer exercise were randomized to 8 weeks of supervised HIT (n = 6) (3 9 10-min cycle-ergometerHIT/week) or 8 weeks of usual care (n = 7). Following this, all participants performed 8 weeks of unsupervised HIT (3 9 10-min cycle-ergometer-HIT/week). Primary outcome was fitness, maximal oxygen uptake/min/kg body weight. Furthermore, workload, 6-min walk distance, 5-time sit-to-stand time, muscle strength, and daily activity levels were measured. Pain, fatigue, and plasma-CK were
monitored. Twelve patients completed the randomized part of the study. Plasma-CK levels and pain scores were unaffected by HIT. Supervised HIT improved fitness (3.3 ml O2/min/kg, CI 1.2–5.5, P \ 0.01, n = 6, NNT = 1.4). Unsupervised HIT also improved fitness (2.0 ml O2/min/kg, CI 0.1–3.9, P = 0.04, n = 4). There was no training effect on other outcomes. Patients preferred HIT over strength and moderate-intensity aerobic training. It may seem counterintuitive to perform HIT in muscular dystrophies, but this RCT shows that regular HIT is safe, efficacious, and well liked by moderately affected patients with FSHD1, which suggests that HIT is a feasible method for rehabilitating patients with FSHD1. Keywords Facioscapulohumeral muscular dystrophy type 1 (FSHD1) Clinical randomized controlled trial (RCT) High-intensity interval training (HIT) 10–20–30 concept
Introduction Statistical analyses were conducted by Grete Andersen, MD with advice from the Section of Biostatistics, Department of Public Health, University of Copenhagen. & Grete Andersen
[email protected] Karen Heje
[email protected] Astrid Emile Buch
[email protected] John Vissing
[email protected] 1
Department of Neurology, Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark
Patients with facioscapulohumeral muscular dystrophy type 1 (FSHD1) are affected by a slow asymmetric progression of muscle weakness often associated with pain, falls, and fatigue [1–3]. No effective treatment that improves muscle strength or slows the progression of muscle weakness in FSHD1 exists. Physical activity is essential for all humans, but exercise training has traditionally been cautioned in patients with muscular dystrophy due to concerns of accelerating the disease process by exerting strain on the muscles. Such notion has been spurred by older studies showing muscle damage in the MDX mice performing eccentric exercise [4]. However, cycle training at moderate intensity has been shown to be safe in patients with FSHD [5]. This has opened up for
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development of potential exercise therapies to improve health in physical, mental, and social aspects in patients with FSHD1 [6–12], but also for problems with compliance [6, 8]. Lack of time is often coined as the cause of low compliance to training in healthy subjects [13, 14]. Many of our FSHD patients have full-time jobs and families in addition to the FSHD fatigue and disabilities, and in our experience, FSHD patients are as different as healthy individuals in their attitude to training. We, therefore, assume that patients with FSHD1 will appreciate saving time on training. High-intensity training (HIT) is exercise at or above an intensity corresponding to the maximal oxygen uptake. Increasing evidence suggests that HIT is a time-efficient exercise strategy to improve cardiorespiratory health in healthy persons [13]. HIT has never been explored in neuromuscular diseases, likely because it may seem counterintuitive to perform maximal muscular work in a diseased muscle. However, a single session of highintensity exercise of 95% of maximal oxygen uptake in 5 9 4 min has been studied without signs of muscle damage in FSHD1 [15]. In this study, we explored whether HIT could be performed without signs of muscle damages, could effectively improve fitness, and whether the training program was feasible to perform by patients affected by FSHD1.
Copenhagen (H-4-2014-035) and registered at ClinicalTrials.gov (NCT02159963). Part 1 Patients were randomized to either 8 weeks of usual care or supervised HIT. According to the zip-code, patients living close to our clinic were randomized to supervised HIT. Healthy participants also performed 8 weeks of supervised HIT. Part 2 All participants were offered an optional 8 weeks of unsupervised HIT, following part 1 (Fig. 2a). In supervised HIT, one weekly session was performed in our clinic. Advice was provided and plasma creatine kinase (CK) was measured for safety reasons. All participants received live training instructions and a recorded training guide for home use. Participants trained three times weekly on an upright stationary bike at home or in fitness center, provided by the investigators. Participants wore pulse watches (POLAR ELECTRO S610i, Finland) to evaluate training intensity (Fig. 2d). Compliance and training-related pain were noted in a diary, and physical activity, fatigue, and muscle pain were recorded daily by participants on a visual analog scale (VAS 0–100 mm).
Method HIT The study was performed at the Copenhagen Neuromuscular Center from August 2014 to September 2015 as an 8-week randomized, controlled parallel study (part 1) with an extension of 8 weeks of unsupervised HIT (part 2). Participants Of 124 patients with genetically verified FSHD1 followed at our Center, 27 patients did not meet the inclusion criterion of age. Thus, 97 patients were invited (Fig. 1). Inclusion criteria were: age 18–70 years and genetically verified FSHD1. Exclusion criteria were: inability to cycle, regular cardio-exercise ([1 h/week), or factors that potentially could confound the results (pregnancy, breastfeeding, disabilities other than FSHD1, participation in other studies). Disease severity was evaluated by the validated FSHD score [16] and MRC score. Healthy controls, invited through posters in the local area, were matched for age, gender, BMI, and activity level [International Physical Activity Questionnaire (IPAQ)] [17]. Participants were not allowed to change diets or activity level during the study. All participants gave informed written consent to participate. The study is approved by the Ethics Committee of
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After reviewing the literature on HIT, we chose the 10–20– 30 concept, originally designed for running [14]. Since many patients are unable to run, we redesigned the program for cycle exercise. Training sessions lasted 21 min including an 8-min standardized warm-up and two sets of 5-min HIT separated by a 3-min break at very low intensity (Fig. 2b, c). Each minute of HIT was performed at three different work intensities: 30 s of easy pedaling (low intensity), 20 s of hard work (middle high intensity), and 10 s of all-out, maximal intensity (Fig. 2b–d). Outcomes The primary outcome was change in fitness [maximal oxygen uptake (VO2max)]. Secondary outcomes were changes in maximal workload (Wmax), 6-min walk test (6MWT), 5-time sit-to-stand-test (5STS), muscle strength, self-assessed functions, and daily activity levels. Outcomes were assessed at baseline and after 8 and 16 weeks of intervention, 2–3 days after the last training session (Fig. 2a). Fitness and workload were assessed by an exhaustion test on a cycle ergometer (Sport Excalibur, Lode,
J Neurol Fig. 1 Flow diagram of participants. Part 1 is a randomized, parallel controlled study of HIT in patients with FSHD1 and matched healthy subjects. BMI body mass index, DAL daily activity level. Part 2 is an extension of the study in which all participants performed unsupervised HIT. Six participants did not complete the entire study due to: a abdominal surgery, bnew work, c lack of motivation, ddisliked intervention, and epregnancy. Participants were tested by three care providers: usual care (GA: n = 7), supervised patients (GA: n = 6, KH: n = 3, AB: n = 2), and supervised healthy subjects (GA: n = 2, KH: n = 3, AB: n = 2). Participants were supervised by GA and either KH or AB
Netherlands) following a standardized protocol. The test was started at 20–50 W (40–60 W in healthy participants), with subsequent increases of half the start load (10–30 W), after 2, and 4 min, and then every minute until exhaustion. Gas exchanges and ventilation were measured continuously (Cosmed, quark CPET, Italy). VO2max and Wmax are presented as 30-s average at peak exercise. 6MWT and 5STS were performed as described earlier [8]. Static muscle strength was assessed by hand-held dynamometer (CITEC, C.I.T. Technics, Netherlands) [18]. Hip flexion, knee extension and flexion, and elbow flexion were assessed with participants in supine position and joint angle at 90°. Questionnaires were filled out before other tests were performed. Questionnaires of self-assessed function and preferences of training forms were graded, using VAS (0–100 mm). Daily activity was assessed by a pedometer (Omron Walking Style Pro Pedometer HJ-720IT-E2), which was worn for 4–7 consecutive days (Fig. 2a).
Statistics HIT has never been performed in patients with neuromuscular disorders; therefore, sample size was predicted using the SD of changes in fitness after moderate-intensity cycle-ergometer training in patients with FSHD1 [5]. The sample size was calculated to include eight patients in each arm, based on an effect size of 10%, SD = 8.5 [5], b = 0.8, and a = 0.05. Dropouts were given pessimistic outcomes in the calculation of number needed to treat (NNT). We tested data with Shapiro–Wilk-normality test, compared before and after intervention by Wilcoxonsigned-rank test or paired two-tailed t test, and tested the effect size between groups by equal variance test and twotailed t test or Mann–Whitney rank-sum test (Sigmaplot 11.2 Systate Software Inc. US). Descriptive data are expressed as mean ± SD, effect sizes with 95% CI, and P \ 0.05 was considered significant.
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Fig. 2 Study design. a The 2 9 8-week study program included two arms of intervention: (1) usual care and unsupervised HIT (total three visits), which only included FSHD1 patients and (2) supervised HIT with weekly visits following by unsupervised HIT (total ten visits), which included both FSHD1 and healthy matched participants. Evaluations were planned 2–3 days after the last training session. Pedometers were worn a week prior to visits. Diaries were filled in for 2 weeks before HIT started and during the 8 weeks of HIT. b A training session included 8 min of standardized warm-up with
increasing cadence and workload, two sets of 5-min interval training (see part label c), and 3 min of very low intensity exercise in between. c Each interval of 1 min of HIT was performed at three different work intensities; 30 s of easy pedaling (low intensity), 20 s of hard work (middle high intensity), and 10 s of all-out, maximal intensity. d Heart rate during one unsupervised training session, downloaded from a pulse-watch (FSHD1 male, 46 years old). Percent of maximal heart rate: red zone (90–100%), yellow zone (75–90%), and green zone (60–75%)
Results
No episodes of muscle damage occurred according to patient reports and plasma-CK levels, which range 67–600 U/l before training and 71–700 U/l during HIT. Self-rated levels of muscle pain before training (mean score 1–21, max scores 2–51; n = 6) did not change during HIT. Max scores of activity and fatigue increased, but the mean scores were unchanged. Supervised HIT improved fitness (16 ± 4%, Fig. 3) and performed workload (17 ± 5%, P = 0.03) in patients. In healthy participants, only workload increased (8 ± 7%, P = 0.03). Similar HRmax (146–195 beat/min) was obtained in all tests in each participant. The 5STS, 6MWT, and muscle strength measures were unchanged by the training intervention. Self-assessed functions improved or
Part 1 Twelve patients (age = 26–67 years, BMI = 20–36 kg/ m2, FSHD score = 1–11) completed the study (Fig. 1). Baseline demography was similar in the groups (Table 1). Supervised HIT was completed by six patients with a frequency of 2.8 ± 0.1 21-min sessions/week. Healthy participants trained with a frequency of 2.5 ± 0.3 sessions/ week. The intensity was high for the whole exercise session of 21 min (patients: 80 ± 7% of HRmax, healthy: 78 ± 4% of HRmax) with peaks close to HRmax (patients: 96 ± 4%, healthy: 94 ± 5%) (Fig. 2d).
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J Neurol Table 1 Baseline characteristics of participants
Participants
FSHD1
Healthy
Intervention
Usual care (n = 6)
Supervised HIT(n = 6)
Supervised HIT(n = 6)
Mean ± SD
Range
Mean ± SD
Range
Mean ± SD
Range
Age (years)
46 ± 9
32–59
53 ± 15
26–67
52 ± 14
27–64
BMI (kg/m2)
27 ± 6
20–36
26 ± 4
22–31
26 ± 3
24–32
FSH clinical score
7.5 ± 2.1
5–11
6.3 ± 4.3
1–11
–
–
Creatine kinase (U/l)
266 ± 105
171–447
227 ± 133
61–412
162 ± 75
85–276
IPAQ (MET h/week)
25 ± 19
7–49
14 ± 6
9–25
27 ± 7*
18–36
Sedentary (h/day)
7.7 ± 4.3
5–15
10.8 ± 3.8
4–13
9.4 ± 3.3
5–14
Steps (km/day) MRC score (0–5)
2.9 ± 1.0 3.9 ± 0.6
1.6–4.2 3.1–4.6
2.5 ± 1.1 4.2 ± 0.5
1.0–3.8 3.8–4.9
4.9 ± 1.7* 4.9 ± 0.1*
3.0–7.3 4.8–5
M. strength leg (N)
103 ± 40*
11–182
80 ± 60
4–295
163 ± 76*
52–329
M. strength arm (N)
108 ± 52
18–162
123 ± 50
56–196
202 ± 40*
151–257
6MWT (m)
468 ± 112
312–642
460 ± 92
323–642
660 ± 93*
550–780
11–34
21 ± 12
11–39
8±2
6–11
5STS (s)
18 ± 9
Gender w/m (#)
1/5
2/4
2/4
Assistant walk (#)
2
4
0
Disease/medication (#)
3/2
3/2
3/1
Work hours full/part/no
1/4/1
2/3/1
4/2/0
Smokers (#)
1
0
1
FSH clinical score range from asymptomatic (0) to severely affected (15). IPAQ: International Physical Activity Questionnaire. Sedentary hours/day is assessed by IPAQ. Steps were assessed by a pedometer. Muscle strength was assessed by a hand-held dynamometer in Newton (N). 6MWT: distance walked in 6 min. 5STS (sit-to-stand): time to rise from a chair 5 times in a row. Assistant walk devices included: walking stick, mini crosser, and drop foot brace. Diseases included: osteoporosis, depression, atrial fibrillation, hypertension, and psoriasis. Work hours are described as full time, part time, or retired/reported sick/unemployed BMI body mass index * Significantly different compared with the supervised HIT FSHD1 participants
were unchanged (Fig. 4a). Patients preferred HIT over moderate-intensity aerobic training (Fig. 4b). Fitness and performed workload did not change with usual care (Fig. 3), but the 6-min walk distance increased slightly by 21 ± 16 m (CI 4-38, P \ 0.03, n = 6). Daily activity levels (step/day) were unchanged in all groups. The treatment effect, comparing supervised HIT and usual care, was significant for fitness (3.3 ml/min/kg; CI 1.2–5.5, P \ 0.01, n = 12) and workload (19 W; CI 4–33, P \ 0.02). Fitness increased ([10%) in five of six patients performing supervised HIT, but in none of the patients following usual care. NNT was 1.4 (n = 13). The difference in effect of supervised HIT was significantly higher percentage-wise (10%, CI 0–21, P \ 0.05) in FSHD vs. healthy participants, but not in absolute values. Part 2 The patients, who had performed usual care in part 1, had high compliance to the unsupervised training program (2.7 ± 0.5 sessions/week) and were able to increase fitness
(7%, P = 0.04, Fig. 3) and workload (25 W, CI 11–39, P = 0.003, n = 4) with similar results as the supervised patients in part 1. No further improvements occurred in the trained patients from part 1, but fitness and workload remained increased compared to baseline (fitness: 16 ± 13%, P = 0.03, workload: 16 ± 13%, P = 0.02, n = 6; Fig. 3). The frequency of HIT sessions decreased in part 2 (patients: 2.2 ± 1.0 sessions/week; healthy: 1.6 ± 0.5 sessions/week). In healthy, fitness and workload tended to improve compared to baseline (10 ± 9%, P = 0.08 and 14 ± 9%, P = 0.06, respectively) (Fig. 3).
Discussion This is the first study to assess the effect and safety of regular training at near-maximal oxygen uptake levels in patients with FSHD1. High-intensity exercise can seem counterintuitive in patients with muscular dystrophies; however, we found that HIT is safe, applicable, and tolerated by patients, based on low fluctuations in plasma-CK levels, no complaints of muscle pain or injury, no changes
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Fig. 3 Changes in fitness. Three maximal exhaustion tests (weeks 0, 8, and 16) were performed in FSHD1 and healthy participants. Fitness measured as maximal oxygen uptake (VO2max). In weeks 0–8, patients were allocated to either usual care or supervised HIT. In weeks 9–16, all participants performed unsupervised HIT. The bars indicate the mean delta (±SEM) of the group between 1st and 2nd tests and 2nd and 3rd tests. Supervised HIT increased fitness (FSHD1: 3.5 ± 0.9 ml/min/kg, CI 1.2–5.7, P \ 0.01, n = 6. Healthy: 1.9 ± 2.2 ml/min/kg, CI 0.7–2.6, P = 0.09, n = 6). Unsupervised HIT increased fitness (FSHD1: 2.0 ml VO2/min/kg, CI 0.1–3.9, P = 0.04, n = 4)
in pain scores, no dropouts, and no worsening of selfassessed health (Fig. 4a). A total of 4 h of HIT in 8 weeks was sufficient to improve fitness significantly in both supervised and unsupervised patients. Furthermore, the daily activity level was unaffected by the training, all participants who started HIT completed the intervention, and participants preferred HIT over other forms of training (Fig. 4b). The current findings suggest that regular HIT is a feasible method to improve maximal oxygen uptake in the rehabilitation of patients affected by FSHD1.
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J Neurol b Fig. 4 Self-assessed functions and preferences of exercises. a Partic-
ipants (FSHD1 n = 10, healthy n = 6) graded changes in five daily functions expressed on a two-sided VAS (-100 = worsening, 0 = unchanged, 100 = improvement). b Participants (FSHD1 n = 9, healthy n = 5) graded preferences to HIT, moderate-intensity aerobic training, and resistance training on a VAS ranging from dislike to prefer
In accordance with earlier studies of lower intensity exercise in FSHD1 [6–9, 15, 19], our study shows that regular HIT can be performed in FSHD1 without risk of muscle injuries, which provides evidence against earlier theories of training-induced mechanical stress injuries in dystrophic muscles. However, the safety of HIT in other muscular dystrophies associated with defect membrane repair may still be harmful [15]. Future studies should explore the long-term effects and safety of HIT in FSHD1 and other muscular dystrophies. Despite improved fitness, muscle strength and functional tests were unchanged by HIT. In our study, participants walked 21 m longer after the non-intervention usual care period, which was likely due to a learning effect. After HIT, participants walked 32 m longer, which is a borderline effect similar to other findings in exercise intervention studies with FSHD1 patients (28, 32, 34 m) [6, 8, 11, 19]. The 6-min walk test has recently been validated in FSHD [20]. They defined the minimal detectable change to be 34.3 m, so that changes below this represent a learning effect together with daily variations of performance. Improvements in muscle strength with aerobic exercise are minimal or absent in healthy individuals, and have not been observed in earlier aerobic exercise studies in FSHD1 [5–8], or even with strength training in FSHD1 [12]. In contrast, 24-week combined aerobic and strength training improved crosssectional fiber area, muscle strength and functional outcomes [19], indicating that mixing exercise types in the rehabilitation of patients with FSHD1 could be effective. It remains to be seen whether HIT can also improve muscle strength and functional outcomes in FSHD1 in the long term. The effect of HIT in healthy participants was not as impressive as in the FSHD1 participants. Healthy participants had lower compliance for frequency and intensity of training sessions, which could explain some of the differences. The higher baseline fitness in healthy subjects could also play a role, since persons have to add an exercise intensity above their current performance to improve fitness [14, 21]. Our study was randomized and controlled, but unblinded. However, oxygen uptake, workload, and heart rate are interconnected objective measures, which cannot be biased by either the participant or the investigators. Postcode randomization could potentially introduce bias, i.e., those living closer to the capital city, Copenhagen, may have better employment, finances, mobility, motivation, etc. However,
demography and disease severity were similar between groups (Table 1). Furthermore, the usual care group was able to improve their fitness in part 2 of the study at similar level as the supervised HIT group in part 1 of the study (Fig. 3). We, therefore, do not think that randomization was biased in our study. The estimated sample size, based on lower intensity training, was not reached, but still the improvement on fitness was significant and clinically relevant. Twelve of 13 patients (92%) completed the controlled part of the study. The cause of drop-out, lower abdominal surgery, was unrelated to HIT and FSHD1, and the dropout did not affect the effect of the intervention (NNT = 1.4), which is higher than most pharmaceutical trials. Many patients with FSHD1 and other muscular dystrophies are sedentary, as suggested by the lower baseline fitness than in healthy subjects (Fig. 3). The risk of allcourse death is highly associated with low fitness. Probably, it is not the exact type of training, but the compliance to frequent training that is important for the efficiency. Future studies should confirm this and the effect and safety of HIT in FSHD1 in the long term. Thus, the safety and effect on fitness, together with patients’ persistence and preference to HIT, suggest that regular HIT is a feasible method to rehabilitate patients affected by FSHD1. Acknowledgements We thank Søren P. Andersen MSc, Human Physiology University of Copenhagen, for his help with designing the training program. Dr. Andersen contributed to the design of study, analysis, acquisition and interpretation of data, and drafting the manuscript. Dr. Heje contributed to the design of study, analysis, acquisition of data, and critical revision of the manuscript. Buch BSc contributed to the analysis, acquisition of data, and critical revision of the manuscript. Dr. Vissing contributed to the design of study, interpretation of data, and critical revision of the manuscript. We thank Aase and Einar Danielsens Foundation, Augustinus Foundation, and AP Moeller Foundation for financial support. Dr. Andersen reports no disclosure. Dr. Heje reports no disclosure. Buch BSc reports no disclosure. Dr. Vissing has received research and travel support and speaker honoraria from Genzyme/Sanofi and Ultragenyx Pharmaceuticals, and has acted as consultant on advisory boards for Genzyme/Sanofi, Sarepta, Lundbeck, Ultragenyx Pharmaceuticals, NOVO Nordisk and Alexion Pharmaceuticals within the last 3 years. Compliance with ethical standards Conflicts of interest The authors declare that they have no competing interests. Ethical standards The study was conducted in accordance with the Helsinki declaration of 1964, approved by the Ethics Committee of Copenhagen (H-4-2014-035), and all participants gave informed written consent to participate prior inclusion in the study.
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