The effects of upper and lower limb exercise on the microvascular reactivity in limited cutaneous systemic sclerosis patients

The effects of upper and lower limb exercise on the microvascular reactivity in limited cutaneous... Background: Aerobic exercise in general and high-intensity interval training (HIIT) specifically is known to improve vascular function in a range of clinical conditions. HIIT in particular has demonstrated improvements in clinical outcomes, in conditions that have a strong macroangiopathic component. Nevertheless, the effect of HIIT on microcirculation in systemic sclerosis (SSc) patients is yet to be investigated. Therefore, the purpose of the study was to compare the effects of two HIIT protocols (cycle and arm cranking) on the microcirculation of the digital area in SSc patients. Methods: Thirty-four limited cutaneous SSc patients (65.3 ± 11.6 years old) were randomly allocated in three groups (cycling, arm cranking and control group). The exercise groups underwent a 12- week exercise program twice per week. All patients performed the baseline and post-exercise intervention measurements where physical fitness, functional ability, transcutaneous oxygen tension (ΔTcpO ), body composition and quality of life were assessed. Endothelial-dependent as well as -independent vasodilation were assessed in the middle and index fingers using LDF and incremental doses of acetylcholine (ACh) and sodium nitroprusside (SNP). Cutaneous flux data were expressed as cutaneous vascular conductance (CVC). Results: Peak oxygen uptake increased in both exercise groups (p < 0.01, d = 1.36). ΔTcpO demonstrated an increase in the arm-cranking group only, with a large effect, but not found statistically significant,(p = 0.59, d = 0.93). Endothelial-dependent vasodilation improvement was greater in the arm-cranking (p < 0.05, d = 1.07) in comparison to other groups. Both exercise groups improved life satisfaction (p < 0.001) as well as reduced discomfort and pain due to Raynaud’s phenomenon (p < 0.05). Arm cranking seems to be the preferred mode of exercise for study participants as compared to cycling (p < 0.05). No changes were observed in the body composition or the functional ability in both exercise groups. Conclusions: Our results suggest that arm cranking has the potential to improve the microvascular endothelial function in SSc patients. Also notably, our recommended training dose (e.g., a 12-week HIIT program, twice per week), appeared to be sufficient and tolerable for this population. Future research should focus on exploring the feasibility of a combined exercise such as aerobic and resistance training by assessing individual’s experience and the quality of life in SSc patients. Trial registration: ClinicalTrials.gov (NCT number): NCT03058887, February 23, 2017. Keywords: High-intensity interval training, Vascular function, Quality of life * Correspondence: m.klonizakis@shu.ac.uk Centre for Sport and Exercise Science, Collegiate Campus, Sheffield Hallam University, Collegiate Crescent, Sheffield S10 2BP, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 2 of 11 Background populations. For example, a HIIT protocol with short in- Systemic sclerosis (SSc) is an idiopathic systemic auto- tervals (30 s exercise/30 s passive recovery) may elicit immune disease characterized by an ongoing cutaneous more favourable patient-reported satisfaction/enjoyment and visceral fibrosis, fibroproliferative vasculopathy and levels compared to other longer duration exercise proto- immunologic abnormalities [1–4]. The vascular element cols [13]. In chronic heart failure patients, a short dur- has an important role in the SSc pathophysiology from ation HIIT protocol (30 s exercise/30 s passive recovery) early onset to late complications (e.g., pulmonary arterial has demonstrated to be a well-tolerated, preferred proto- hypertension and kidney disease). SSc can be distin- col with a low perception of effort, patient comfort and guished in either limited cutaneous scleroderma (lcSSc) with a longer time spent at higher percentage of peak with skin involvement mainly limited to the hands oxygen uptake (VO ) than a longer duration HIIT 2peak and face; or diffuse cutaneous scleroderma (dcSSc) protocol with active recovery phases [13]. Recent evi- with skin involvement proximal to the elbows and dence supports this notion; when enjoyment levels in an knees [5]. Blood vessels are directly affected by SSc, overweight/obese cohort were examined after a short as manifested by the diverse clinical complications HIIT protocol and demonstrated that performing a HIIT that take place from the initiation to the propagation protocol on a cycle ergometer present on an average 4.5 of the disease, and have important ramifications on rating on a 7-point scale [14]. the quality of life (QoL) of patients. Although we know the potential of HIIT in improving Raynaud’s phenomenon (RP) precedes other clinical both the micro-and the macro- vascular function in sev- manifestations and is observed in over 95% of SSc pa- eral clinical populations such as heart failure [15] and tients [6]. Evidently, RP is triggered by endothelial injur- cardiometabolic disease [16] by using the treadmill and ies in association with dysregulations in the vascular cycle ergometer as modes of exercise, no evidence exists tone [7]. In addition to the imbalance of vascular tone, about the mode of exercise that would be more effective RP is also associated with structural vascular alterations on digital microcirculation where the RP attacks are in small- and medium-sized arteries leading to luminal present, such as in SSc patients. Assumptions could be narrowing. As a result, the blood vessels are unable to made that utilising an upper-body exercise would poten- compensate for the impairment of blood flow during se- tially be more beneficial for the digital microcirculation vere RP attacks and this leads to the so-called rather than lower-body exercise where the working mus- ischaemia-reperfusion reactions. These vascular compli- cles promote the blood flow in the lower limbs. Hence, cations may progress to gangrene and digital amputation the effects that may occur by the upper- and lower-limb [8]. Notably, SSc has the highest case-specific mortality exercise on digital microcirculation in SSc patients of any rheumatic disease being also associated with sub- should be examined. stantial morbidity [9]. We will attempt to bridge the knowledge gap by asses- Pharmacological agents (e.g., nifedipine) are com- sing the effects of a supervised and individually-tailored monly used as first-line approach. Although it can be exercise programme based on arm cranking (ACE) and effective and provide pain-relief to patients, the short- cycle ergometry (CE) on microvascular reactivity, aer- term (e.g., oedema, headaches, heart palpitations, obic capacity, exercise tolerance and enjoyment levels, as dizziness and constipation) and long-term (e.g., heart well as on QoL in SSc patients. dysfunction, increased cardiovascular risk) side effects of the medical treatment should also be considered as well Methods as the financial cost of treatment. Therefore, alternative Patients approaches with less side effects and cost implications We recruited 34 patients (31 women, 3 men) with lcSSc, are warranted [10, 11], with a view to reducing depend- defined as per the American College of Rheumatology ency on medication. and European League Against Rheumatism criteria [17], Exercise in general and high-intensity interval training with disease duration between 1 to 10 years. All partici- (HIIT) specifically could be a useful adjunct therapy for pants were able to undertake exercise. Patients with pul- this population. HIIT has come to prominence over the monary arterial hypertension, interstitial lung disease, last few years for its effectiveness in inducing greater im- those diagnosed with another inflammatory condition provements in vascular function than moderate-intensity and/ or presenting myositis with proximal muscle weak- continuous training in a number of clinical populations ness were excluded. Moreover, patients with New York (e.g., heart failure, metabolic syndrome, obesity) [12]. Heart Association class 3 or 4, smokers or people who Nevertheless, due to the variation in HIIT protocols, stopped smoking within 4 weeks of screening and limited evidence exists to support which protocol would women who were pregnant were also not permitted to be the most effective in SSc patients, although the op- participate. Eligible patients were recruited from the tions are many, based on evidence from other patient Rheumatology Department of the Royal Hallamshire Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 3 of 11 Hospital in Sheffield. All patients provided written con- mass (kg) segmented in upper and lower limbs were sent to participate. The regional health research ethics assessed by using bio-electrical impedance analysis (In committee for clinical studies approved the protocol. Body 720, Seoul, Korea). Patients’ demographic charac- Patients were randomly allocated between the ACE (n = teristics are illustrated in Table 1. 11), CE (n = 11) and control (n = 12) groups. All the pre- and post-intervention tests were performed at the same Peak oxygen uptake test time of the day to minimize intra-day variability. During the cardiopulmonary tests gas exchange was collected and analysed by an online breath-by-breath analysis system Procedures (Ultima™, Medical Graphics, Gloucester, UK). Heart rate Baseline assessments, undertaken at first visit, included (HR) was continuously monitored using a Polar heart rate VO ,anthropometry,functionalability,microvascularre- monitor (Polar FS1, Polar Electro, Kemple, Finland) and 2peak activity and QoL. VO test was performed either on an blood pressure was assessed by the researcher using a manual 2peak arm crank ergometer (ACE group) or on a cycle ergometer sphygmomanometer (DuraShock DS54, Welch Allyn, Bea- (CE and control group). Thereafter, patients were randomly verton, OR, USA) and a stethoscope (Littman Classic II, 3 M, allocated to three groups (ACE, CE and control group). The Maplewood, MI, USA). Rating of perceived exertion (RPE) exercise groups (ACE and CE) performed a 12-week exer- wasrecordedduringthe last 10 sofevery minute during the cise programme and the control group did not perform any exercise test until volitional exhaustion using Borg’s scale [18] type of physical activity. All groups were followed up after a 6–20 point. Peak power output (PPO) and test duration was 12-week period performing the same measurements as in measured in both tests. VO defined as the average oxy- 2peak the baseline. Figure 1 depicts the study’sprocedures. gen consumption was recorded from expiratory samples dur- ing the final 30 s of exercise. Anthropometry The participant’s stature was measured using a Hite-Rite Arm crank test Precision Mechanical Stadiometer. Body weight (kg), The arm crank ergometer (Lode BV, Groningen, body mass index (BMI), fat mass (kg) and lean body Netherlands) was adjusted to ensure alignment between Fig. 1 CONSORT flow diagram. ACE arm crank ergometer, CE cycle ergometer Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 4 of 11 Table 1 Demographic data (means ± SD) Baseline ACE Baseline CE Baseline Control Age (years) 69.1 ± 9.7 65.1 ± 10 62.2 ± 14.3 Body weight (kg) 69 ± 15.8 66 ± 9.7 73.2 ± 14.8 2) Body mass index (kg/m 25.6 ± 4.8 24.5 ± 3.6 27.3 ± 4.0 Stature (cm) 163.7 ± 9.1 164.4 ± 7.9 163.4 ± 6.7 Disease duration (yrs) 7.8 ± 2.3 7.7 ± 2.1 6.3 ± 2.0 Digital ulcers (treatment iloprost infusion) 0/10 0/10 4/11 Raynaud’s treatment 6/10 5/10 8/10 Nifedipine 4/10 4/10 4/10 Sildenafil 2/10 1/10 4/10 Blood pressure treatment 6/10 4/10 4/10 Candesartan 4/10 0/10 1/10 Ramipril 2/10 4/10 3/10 ACE arm crank ergometer, CE cycle ergometer the ergometer’s crankshaft and the centre of the patient’s Exercise program glenohumeral joint. Patients’ sitting position was set up Patients undertook twice-weekly supervised exercise ses- to ensure that the elbows were slightly bent when the sions at the Centre of Sport and Exercise Science at arm was outstretched. Patients were instructed to main- Sheffield Hallam University. Each session started with a tain their feet flat on the floor at all times. Due to differ- 5 min warm-up on an arm crank or cycle ergometer de- ences in gender power capabilities, two separate pending on the group (involving light aerobic exercise protocols were instructed for men and women. Men and gentle range of motion exercises). This was followed commenced at a workload of 30 W and women at by HIIT for 30 s at 100% of PPO interspersed by 30 s 20 W. In both protocols the crank rate was maintained passive recovery for a total of 30 min (Fig. 2). At the end − 1 at 70 rev min [19, 20] and power requirements of the session patients undertook a 5 min cool-down increased as a linear ramp at a rate of 10 W/min and period, involving lower- and upper-limb light intensity 6 W/min for men and women, respectively [20]. The aerobic exercise and light stretching. Patients were wear- test commenced with 3 min resting and then 3 min of ing heart rate monitors throughout the exercise sessions. warm-up (unloaded cranking). RPE ≥ 18 and/or inability Heart rate and RPE and effect (see below) were assessed − 1 to maintain a crank rate above 60 rev min resulted in at regular intervals throughout the supervised exercise the termination of the test. After the exercise session. termination an unloaded bout of 2–3 min exercise at a − 1 crank rate below 50 rev min followed allowing for an Functional ability test active recovery period. The functional ability was assessed through a six-minute walking test (6MWT). Although the 6MWT lacks organ specificity in SSc, it can provide a valuable outcome par- Cycle ergometer test ameter and thus, is suggested as a regular assessment in The cycle ergometer test was performed on an elec- this clinical condition [22]. Patients were instructed to tromagnetic cycle ergometer (Lode Excalibur, Gro- walk as far as possible back and forth on a 10 m corridor ningen, Netherlands). The test commenced with a for 6 min. They were also instructed to slow down, stop 3 min resting period followed by 3 min of unloaded and/or rest as necessary if they got out of breath or be- pedalling. Participants were requested to maintain a came exhausted, but to resume walking as soon as they − 1 cycle rate of 60 rev min during the exercise test. felt able to. The laps and the total walking distance were The starting load and the concomitant increments recorded on a worksheet. were individually calculated according to participants’ estimated physical fitness and Wasserman’seqs.[21]. Microvascular reactivity RPE ≥ 18 and/or inability to maintain a crank rate Microvascular function was assessed by laser Doppler − 1 above 40–45 rev min resulted in the termination of Fluximtery and Iontophoresis technique in a the test. Following the exercise test 2–3minof temperature-controlled room (22–24 °C). Laser Doppler unloaded pedalling was performed to allow for an fluximetry (LDF) electrodes were attached to the dorsal active recovery period. aspect of the reference fingers for acetylcholine (ACh) Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 5 of 11 Fig. 2 Schematic training protocol and sodium nitroprusside (SNP) administration. These below the right scapula on the back away from any were used as indicators of the changes occurring in the bone. endothelial-dependent and -independent vasodilatory Fixation rings were used to hold the probe attached to function. Heart rate (Sports Tester, Polar, Finland) and the skin and this was filled with two small drops of con- blood pressure of the brachial artery (left arm; Dinamap tact fluid before attachment to the sensor. The fluid was Dash 2500, GE Healthcare, Chicago, IL, USA) were then heated causing the subsequent dilatation of the monitored at 5-min intervals throughout the protocol. skin. The raw values of the patient’soxygenperfu- The two drug delivery electrodes (PF383; Perimed AB, Jar- sion, obtained directly from TcpO2 device were de- falla, Sweden) were positioned over healthy-looking skin, fined (Table 2) as previously described in Wasilewski approximately 4 cm apart with one containing 100 μLof et al. [25]. 1% ACh (Miochol-E, Novartis, Stein, Switzerland.) and the other 80 μL of 1% SNP (Nitroprussiat, Rottapharm, Quality of life Monza, Italy). ACh was placed over the middle finger be- The EQ-5D-5 L was the main outcome used to assess tween the distal and proximal interphalangeal joints and the patients’ quality of life pre- and post-exercise inter- SNP was placed over the index finger between the meta- vention. The EQ-5D-5 L is a generic measure of health carpophalangeal and carpometacarpal joints. The incre- state by considering five key dimensions of daily living mental iontophoresis protocol for ACh and SNP delivery (mobility, self-care, ability to undertake usual activities, is described in Klonizakis et al., [23, 24]. pain, anxiety/depression) [26]. Participants were asked to describe their level of health on each dimension using Transcutaneous oxygen pressure (TcpO ) one of five levels: no problems, slight problems, moder- TcpO measurements were performed during the cardio- ate problems, severe problems, extreme problems. Pa- respiratory tests using sensors that were non-invasively tients were also asked about to rate their life satisfaction attached onto the skin and allowed to heat. The sen- on a scale of zero to ten as well as to rate the RP pain sors induce skin blood capillaries dilatation through during the last couple of weeks on one to five ascending heat, which increases the blood flow and results in grading: not at all, slightly, moderately, severely, oxygen diffusion through the skin to the sensor. The Table 2 Definitions of TcpO2 quantities sensor measures TcpO values inwardly through an TcpO2 quantity Definition electrochemical process. Baseline The arithmetic mean of maximum Measurements were performed using the TINA TcpO2 at rest. TCM400 TcpO device (Radiometer, Copenhagen, TcpO2 The highest TcpO2 value recorded max Denmark). The temperature of the probe was set to 44. every minute of exercise or at rest. 5 °C to allow maximal skin vasodilation, thereby de- Maximum change from baseline The outcome of the subtraction of creasing the arterial to skin surface oxygen pressure gra- (ΔTcpO2 ) baseline from TcpO2 : e.g. max max dient. Before the exercise test 15–20 min were allowed TcpO2 - baseline max with the probe attached on the skin for stabilisation of Changes in transcutaneous The average sum of the change from TcpO2 value. After the test the TcpO2 values were auto- oxygen pressure (ΔTcpO2) baseline at rest and exercise period: e.g. (Σ)ΔY1…n) / n) = ΔTcpO2 matically corrected according to a temperature of 37 °C by the TINA device. The electrode was placed slightly ΔTcpO transcutaneous oxygen tension 2 Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 6 of 11 extremely. Digital ulcers and hospitalization for iloprost calculated wherever the results were statistically signifi- infusion and amputations were also recorded. cant with 0.2, 0.5, and 0.8 representing small, medium, and large effects respectively [28]. To compare the be- Exercise tolerance tween group differences using a one-way ANOVA we The exercise tolerance of HIIT was assessed through adjusted the ACE values according to the physiological measures that were interpreted participants’ perception and anthropometrical responses of CE [29]. Statistical regarding the exercise intensity, the effect (Additional significance was set at p ≤ 0.05. file 1), the exercise task self-efficacy (Additional file 2), the intentions (Additional file 3) and the enjoyment Results (Additional file 4). The above data was collected at the Compliance and exercise intensity first and last exercise session each month in order to Compliance to the12-week exercise programme twice examine several time points during the exercise inter- weekly was 92% and 88% for the ACE and CE group re- vention. Specifically, the questionnaires were repeated at spectively, with one drop-out for each exercise group. the 1st, 8th, 16th, and 24th exercise sessions. The indi- No exercise-related complications were reported. The vidual questionnaires and the time points that were in- average percentage peak HR (%HR ) for each exercise peak corporated during the exercise session are described in session was 92.1% ± 6.0 for the ACE group and 90.8% ± Jung et al. [27]. 7.5 for the CE group. The average rate of perceived exertion (RPE) and effect were 13 ± 1 and + 3 (good) ± 1, Statistical analysis respectively, for both exercise groups. Data analysis was performed using SPSS software (ver- sion 23, IBM SPSS, Armonk, NY, USA) and is presented Oxygen uptake and pressure − 1 as mean ± SD. Normal distribution of the data and Both ACE (0.86 L min d = 0.68) and CE (1.22 ± 0. − 1 homogeneity of variances were tested using the Shapiro- 33 L min d = 0.76) VO were significantly greater 2peak Wilk and Levene’s test, respectively. The comparison in post-exercise intervention compared to baseline (p <0. − 1 − 1 the anthropometric, physiological and vascular charac- 01). ACE VO (21.9 ± 7.1 ml kg min d = 1.09) 2peak teristics among the three groups was done through a improved significantly in comparison to control but not one-way ANOVA test. Independent t-tests and chi- compared to CE group (Table 3). squared tests were also used to identify the differences A tendency to improve was also observed in both between two groups. Effect sizes (Cohen’s d) were ΔTcpO2 (p = 0.59, d = 0.93) and transcutaneous oxygen Table 3 Physiological and quality of life outcomes ACE (n = 10) CE (n = 10) Control (n = 11) Pre Post Pre Post Pre Post ACh CVC 0.14 ± 0.06 0.19 ± 0.08 0.20 ± 0.11 0.26 ± 0.1 0.20 ± 0.08 0.15 ± 0.08 ACh CVC 1.28 ± 0.78 1.56 ± 0.88* 1.49 ± 0.99 1.26 ± 0.52 1.40 ± 0.78 0.82 ± 0.47 max ACh T (sec) 159.4 ± 83 104.1 ± 71.8 172 ± 57.9 119.4 ± 82.9 127.9 ± 51.1 149.9 ± 70.3 max SNP CVC 0.15 ± 0.08 0.24 ± 0.14 0.21 ± 0.11 0.25 ± 0.08 0.20 ± 0.09 0.20 ± 0.1 SNP CVC 1.73 ± 2.01 1.88 ± 1.52 1.61 ± 1.21 2.38 ± 1.8 1.70 ± 1.3 1.40 ± 0.56 max SNP T (sec) 161.2 ± 88.5 131.3 ± 77.5 167.4 ± 66.3 138.8 ± 80.5 165.5 ± 56.5 166.9 ± 76.4 max ΔTcpO2 2.5 ± 4.0 9.2 ± 12.1 1.56 ± 4.8 1.56 ± 9.5 1.39 ± 3.4 0.89 ± 2.6 ΔTcpO2 11.5 ± 3.9 18.4 ± 16.5 11.7 ± 3.6 13.6 ± 9.6 9.44 ± 7.7 8.0 ± 7.0 max − 1 − 1 VO (ml kg min ) 17.7 ± 4.7 21.9 ± 7.1* 14.6 ± 2.9 18.5 ± 2.8* 14.3 ± 6.9 14.7 ± 6.2 2peak Life satisfaction 6.5 ± 1.6 8.1 ± 1.7*** 8.4 ± 1.4* 8.8 ± 1.1*** 7.5 ± 1.6 4.9 ± 1.5 Mobility 2.4 ± 1.0 2.3 ± 0.8 1.9 ± 0.9 1.7 ± 1.0 1.9 ± 0.9 2.3 ± 1.2 Self-care 1.1 ± 0.3 1.1 ± 0.3 1.2 ± 0.4 1.0 ± 0.0 1.4 ± 0.9 1.7 ± 1.4 Usual activity 2.3 ± 1.3 1.9 ± 1.1 1.9 ± 1.0 1.6 ± 0.7 1.8 ± 1.0 2.4 ± 1.2 Pain/ discomfort 2.4 ± 1.0 2.3 ± 1.1 2.8 ± 1.1 1.8 ± 0.9 2.4 ± 0.7 2.8 ± 1.2 Anxiety/ depression 1.7 ± 0.8 1.5 ± 0.7 1.6 ± 0.7 1.2 ± 0.4 1.6 ± 0.7 1.9 ± 1.4 Raynaud’s pain 2.4 ± 1.4 1.8 ± 0.6* 2.6 ± 1.5 1.9 ± 1.2* 2.4 ± 0.9 3.1 ± 1.1 Endothelial function presented as cutaneous vascular conductance (CVC). T is the time taken to reach peak perfusion. *p < 0.05 and ***p < 0.000 compared to max the other groups ACE arm crank ergometer, SNP sodium nitroprusside, ΔTcpO transcutaneous oxygen tension VO peak oxygen uptake 2 2peak Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 7 of 11 tension (ΔTcpO2 )(p = 0.71, d = 0.80) in ACE group. Raynaud’s phenomenon. Cycling indicated that it might max Although this improvement is not statistically significant have the potential to decelerate the disease progression the Cohen’s d reveals that the effect size of the change is in the vasculature (ACh) as the endothelial-dependent large (> 0.8) both at rest and during provocation (exer- vasodilation was slightly decreased. On the other hand, cise test). the control group showed a decrease in endothelial- dependent function, which might indicate a disease Cutaneous vascular conductance (CVC) worsening (Table 3). Pearson’s correlation coefficient No statistically significant differences were observed at (Table 4) indicated that the endothelial improvement in baseline between the exercise and control groups (p >0. ACE has a trend to correlate with the soft lean and fat- 05). Post-exercise intervention improvements were ob- free mass as well as with skeletal muscle mass. Interest- served in the ACE group, especially over the control ingly, ACh showed that is not correlated with ACE group, while values in CE group were slightly decreased VO , which does not confirm to previous findings 2peak (Table 3). that have shown association of endothelial-dependent function with the improvement in aerobic capacity in Feasibility and tolerance of exercise patients with rheumatoid arthritis [30]. The correlation ACE showed to be the mode of exercise that will more between the endothelial-dependent function and the likely (p < 0.05) engage SSc patients to physical activity lean muscle is a vital evidence for future exercise pre- twice per week (6.9 ± 0.3, d = 1.17) compared to the CE scription for this population. Resistance training is cap- group (6.2 ± 0.79). Moreover, ACE demonstrated to be able to increase muscle mass and to improve better (p < 0.05) regarding participant’s confidence to microcirculation in obese adults [31]. Thus a combin- perform two bouts per week (95 ± 7%, d = 0.82) than CE ation of the current HIIT protocol with resistance train- (83 ± 19.5%) but not statistically significant. Both exer- ing might increase the chances for further improvement cise modes aggregated a high score of enjoyment levels in the endothelial function. > 94 out of 119 with an average effect before, during and after the exercise session of + 3 equals to “good”. Endothelial-dependent function Our results indicate that exercise training may improve Quality of life and clinical outcomes the microvascular function in SSc patients. This could The EQ-5D-5 L questionnaire did not demonstrate any be largely attributed to a shear-stress-related mechan- significant difference between the groups neither at ism. Shear stress is a mechanical reaction of the blood baseline nor after the completion of the exercise vessel to accommodate the increased blood flow, which intervention, in any of its five elements. However, both activates the potassium channels and facilitates the cal- exercise groups reported improved life satisfaction (p < cium influx into the endothelial cells. Endothelial nitric 0.000) as well as reduced discomfort and pain of oxide synthase (eNOS) activation and expression are Raynaud’s phenomenon (p < 0.05) after the exercise triggered by an increase in intracellular calcium [32], intervention compared to the control group (Table 3). promoting nitric oxide (NO) production and thus vaso- We also reported digital ulcers and hospitalization for dilation [33]. It is possible that the recurring induction iloprost infusion for four out of eleven patients (36.3%) of NOS activity with exercise training decelerates the in the control group. One of them proceeded to amputa- degradation of NO by free radicals in these conditions tion of the distal phalange of the middle finger in one [34] or by reducing directly free radical production [35]. hand. A recent systematic review on exercise training and vas- cular function [12] supports our findings indicating that Discussion the antioxidant status is enhanced after HIIT in patients Overall, this study is the first to demonstrate that upper- with cardiometabolic disorders [36–38] and thus, the limb aerobic exercise may be able to improve micro- NO bioavailability is improved. Mitranun et al. [38] vascular endothelial-dependent function in the digital assessed the effects of interval aerobic exercise training area in patients with systemic sclerosis experiencing (three times/week for 12 weeks) on endothelial- Table 4 Endothelial-dependent correlations in arm cranking ̇ ̇ Soft lean mass (kg) Fat-free mass (kg) Skeletal muscle mass (kg) VO VO 2peak 2peak −1 − 1 − 1 (L min ) (ml kg min ) ACh CVC Pearson’s r 0.529 0.520 0.530 0.120 0.220 max sig (2-tailed) 0.116 0.123 0.115 0.740 0.569 n = 10 10 10 10 10 10 Ach acetylcholine, CVC cutaneous vascular conductance Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 8 of 11 dependent vasodilation in patients with type 2 diabetes persistent digital ulcers developing irreversible tissue loss mellitus. The vascular outcomes demonstrated reduc- in 30% of patients [48]. In our study four out of eleven tions in erythrocyte malondialdehyde and serum von patients in the control group developed digital ulcers Willebrand factor and increases in plasma glutathione and required hospitalization for iloprost infusion [49, 50] peroxidase and nitric oxide (all p < 0.05). Therefore, HIIT for a period of 1 to 3 weeks and one patient proceeded seems to improve the microvascular function by reducing to digital amputation of the distal phalange in the mid- oxidative stress markers and enhance the antioxidants as dle finger in one hand. Hospitalization is a psychologic- well as the vasodilators in cardiometabolic conditions and ally-stressful procedure for the patient, which directly potentially in connective tissue diseases such as SSc. affects QoL. The most common side effects of iloprost infusion could be headache, flushing of the skin, nausea, Vascular remodelling, shear stress and exercise training vomiting and sweating. Amputation has been reported Evidence for the time course of functional or structural to occur in one or more digits due to ischaemia in 20.4% arterial adaptations to exercise training in humans is of patients with SSc, 9.2% of which have multiple digit limited: Short-term effects of exercise improves NO bio- loss [51]. QoL in patients with SSc is adversely affected availability, whereas long-term effects induce changes in due to digital ischaemia. Consequently, our protocol has vascular remodelling [39], an endothelium and NO- demonstrated that is capable of improving digital ischae- dependent outcome [40]. mia and preventing disease progression and digital ul- Prior to this study, we hypothesised that upper limb cers and thus, improving QoL. exercise would be more effective to improve microcircu- lation in the local regions compared to lower limb exer- Transcutaneous oxygen pressure cise; however, the existing evidence supported systemic Although the improvement in oxygen pressure at rest effects occur after exercise training in the lower limbs and under provocation (exercise test) was not significant [12]. Therefore, we proceeded to a comparison between in our study, the effect size of this change was large. the upper and lower limbs. Interestingly, this systemic This indicates that ACE is able to induce systemic effect was not proved with our study, where the micro- changes in oxygen pressure and vascular function in SSc vascular reactivity in the digital area was improved with patients, while the control group showed a slight de- arm cranking but not with cycling. Similar to our find- crease. It is probable that a higher training load or a lar- ings, Klonizakis et al., [41] reported that arm exercise ger cohort would have revealed a statistically significant did not have any impact on lower limbs microcirculation difference between ACE and control group. Evidently, in post-surgical varicose-vein patients. It seems that further research is needed to substantiate our findings systemic effects of exercise training can only affect the and explore other training protocols, which will reveal vascular function in the large arteries (e.g. brachial ar- the effects of exercise on skin oxygen pressure, when tery) but not the conduit and resistance arteries. More- oxygen demand is higher. over, the mass of muscle engaged in exercise training could play an important role in the systemic effects as Quality of life studies that utilized handgrip training have not demon- Both modes of exercise have shown improvement in life strated contralateral limb remodelling [42–44]. The ex- satisfaction and reduction in pain or discomfort induced planation probably relies on the magnitude and pattern by RP attacks after the exercise training. However, fur- of shear stress, which in turn triggers the release of NO ther research is required to confirm the improvement in and acts as a main determinant for its bioavailability. It RP by applying more qualitative measures (e.g. case- is possible that the induced-shear stress by lower limbs specific questionnaires and face-to-face interviews). Ex- is not sufficient to improve the microcirculation in the ercise tolerance, cardiorespiratory fitness, walking dis- acral body parts of the upper limbs. Therefore, the tance, muscle strength and function as well as health- volume of blood flow and the magnitude of shear stress related QoL have been demonstrated to be improved in induced by HIIT could account for the local effects of SSc patients after participation in exercise programmes exercise training in the smaller arteries [45, 46]. involving aerobic exercise and aerobic exercise com- bined with resistance training [52]. Therefore, promoting Clinical outcome physical activity for the improvement of QoL in SSc Inadequate blood flow to living tissue is often a painful patients should be deemed as one of the priorities for experience, threatening the life of the tissue involved. future research. Digital tissue loss not only results in disfigurement and functional disability, it is also the clinical manifestation Feasibility of HIIT of an underlying systemic disease process [47]. One of Our findings demonstrate that HIIT (30 s 100% PPO/ 30 the direct consequences of digital ischaemia is the s passive recovery) maintained an average effect of + 3 Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 9 of 11 (“Good”) throughout the exercise training for both until symptomatic limitation of exercise, which might modes of exercise. It is also noteworthy that the patient’s affect the accuracy of TcpO2, however, we need to stress effect was similar before, during and after the exercise that the utilization of TcpO2 measurement in our study session which could be explained by the moderate car- was more of a research interest aiming to evaluate the diorespiratory stress induced by this protocol. Support- improvement in vascular function after an exercise ive to this finding is the RPE for both groups which programme rather than accurately depicting hypoxemia averaged to 13 (“Somewhat hard”), a value which is levels in the arterial wall. strongly correlated to anaerobic threshold and low to Our patients were only of limited cutaneous systemic moderate exercise intensity in a large cohort of adults sclerosis, where the change in skin thickness is little over [53]. Exercise intensity and affective response have pre- time compared to diffuse cutaneous systemic sclerosis sented a negative relationship in inactive and overweight (Khanna et al., 2017). Moreover, it is common practice adults and it has been reported that as incremental exer- in the NHS clinics to assess mRSS only in patients with cise progresses above the ventilatory threshold, the dcSSc. Therefore, we did not include this measurement affective response to exercise becomes more negative in our study; however, we believe that this does not [54, 55]. Therefore, a short protocol of HIIT seems to affect our results, as the categorisation of the patients is not induce great cardiovascular responses in patients clear. Also the autoantibody specificities for SSc patients with SSc and that might explain the effect’s stability are not included in our study as this is not a standard throughout the session. clinical practice in the area of Sheffield. The intentions regarding engagement to exercise and the task self-efficacy questionnaires as well as the enjoy- Conclusions ment levels of the patients could further substantiate whether HIIT is a feasible mode of exercise in SSc pa- Aerobic exercise in general, and HIIT (30 s 100% tients. Both modes of exercise demonstrated a strong pa- PPO/30 s passive recovery) specifically, involving the tient’s confidence to perform two and three bouts of upper limbs may improve the microvascular exercise with arm cranking being slightly higher than reactivity through an enhancement of the cycling. Both modes of exercise were enjoyable for the endothelial-dependent function. Our results corre- patients, however, arm cranking was found to be signifi- lated well with the lean muscle mass, which indi- cantly higher in the intentions for engagement in two cates that resistance training could be a bouts of exercise per week compared to cycling. HIIT is complementary training element in inducing further a feasible protocol to be implemented in patients with improvements in microcirculation. SSc and ACE is considered more acceptable than CE po- Our protocol appears to reduce digital ischaemia tentially, because it is a new mode of exercise for this risk, which can be the leading cause for further population and that might increase their interest to per- systemic complications and a major factor affecting form an alternative type of exercise. the quality of life. Exercise is a non-invasive, adjunct treatment with no adverse effects that is well- Limitations tolerable by patients with SSc. The sample size of the current study could be deemed a There is a need for large multi-centre, randomised- limitation for the current study but we need to stress controlled studies to further establish the effects of that SSc is not a common condition such as cardiometa- exercise on SSc patients. bolic diseases (e.g. hypertension, obesity, diabetes) and we strictly adhered to the pre-defined eligibility criteria Additional files to present a consistent and reproducible outcome. Moreover, the ratio between women and men is uneven, Additional file 1: Feeling scale (SF). (DOCX 38 kb) with SSc women to men ratio being estimated to be 5.2:1 Additional file 2: Exercise task self-efficacy. (DOCX 38 kb) in northeast England [56]. Additional file 3: Intentions for engagement to exercise. (DOCX 35 kb) TcpO2 is a direct value of vascular function as changes Additional file 4: Physical activity enjoyment scale. (DOCX 48 kb) at rest mimic the changes in arterial pO during mild or moderate exercise [57, 58]. However, the time response Abbreviations of these changes is relatively slow (90% time response of 6MWT: Six-minute walking test; ACE: Arm crank ergometer; TcpO2 being approximately 20 s). Carter and Banham Ach: Acetylcholine; BMI: Body mass index; CE: Cycle ergometer; [59] demonstrated that TcpO2 values closely followed CVC: Cutaneous vascular conductance; dcSSc: Diffuse cutaneous scleroderma; eNOS: Endothelial nitric oxide synthase; HIIT: High-intensity interval training; those assessed by direct arterial sampling during cardio- HR: Heart rate; LDF: Laser Doppler fluximetry; lcSSc: Limited cutaneous pulmonary exercise testing with 2 min intervals. We ac- scleroderma; NO: Nitric oxide; PPO: Peak power output; QoL: Quality of life; knowledge that our protocol utilized 1 min intervals RP: Raynaud’s phenomenon; RPE: Rating of perceived exertion; SNP: Sodium Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 10 of 11 ̇ ̇ nitroprusside; SSc: Systemic sclerosis; VE: Minute ventilation; VO : Peak 9. Altman RD, Medsger TA Jr, Bloch DA, Michel BA. Predictors of survival in 2peak oxygen uptake; VT: Tidal volume; ΔTcpO : Transcutaneous oxygen tension systemic sclerosis (scleroderma). Arthritis Rheum. 1991;34:403–13. 10. Pope JE. The diagnosis and treatment of Raynaud's phenomenon: a practical approach. Drugs. 2007;67:517–25. Acknowledgements 11. Prescribing & Medicines Team Health and Social Care Information Centre. The authors would like to thank the study participants and report no Prescription Cost Analysis for England 2015. 2016. https://digital.nhs.uk/ conflicts of interest with this manuscript. The experiments comply with the catalogue/PUB20200. Accessed 07 May 2016. current UK laws. 12. Ramos JS, Dalleck LC, Tjonna AE, Beetham KS, Coombes JS. The impact of high-intensity interval training versus moderate-intensity continuous Funding training on vascular function: a systematic review and meta-analysis. Sports The work was supported by the Centre for Sports and Exercise Science, Med. 2015;45:679–92. Sheffield Hallam University. 13. Meyer P, Normandin E, Gayda M, Billon G, Guiraud T, Bosquet L, et al. High- intensity interval exercise in chronic heart failure: protocol optimization. J Availability of data and materials Card Fail. 2012;18:126–33. Relevant files of this work will be shared on request. 14. Smith-Ryan A. Enjoyment of high-intensity interval training in an overweight/ obese cohort: a short report. Clin Physiol Funct Imaging. 2017;37:89–93. Authors’ contributions 15. Guiraud T, Nigam A, Gremeaux V, Meyer P, Juneau M, Bosquet L. High-intensity AM helped to draft the manuscript, designed the exercise intervention, interval training in cardiac rehabilitation. Sports Med. 2012;42:587–605. contributed to the study design and critically reviewed and revised the 16. Kessler HS, Sisson SB, Short KR. The potential for high-intensity interval training manuscript for important intellectual content. HC developed the qualitative to reduce cardiometabolic disease risk. Sports Med. 2012;42:489–509. aspects of the study, contributed to the study design and critically reviewed 17. Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 and revised the manuscript for important intellectual content. GA provided Classification Criteria for Systemic Sclerosis: An American College of statistical and health economics support, contributed to the study design Rheumatology/European League Against Rheumatism Collaborative and critically reviewed and revised the manuscript for important intellectual Initiative. Arthritis Rheum. 2013;65:2737–47. content. ΜΑ is the study’s clinical lead, contributed to the study design and 18. Borg GA. Perceived exertion: a note on “history” and methods. Med Sci critically reviewed and revised the manuscript for important intellectual Sports. 1973;5:90–3. content. MK is the project leader and helped to draft the manuscript, 19. Smith PM, Price MJ, Doherty M. The influence of crank rate on peak oxygen contributed to the study design and critically reviewed and revised the consumption during arm crank ergometry. J Sports Sci. 2001;19:955–60. manuscript for important intellectual content. All authors read and approved 20. Smith PM, Doherty M, Price MJ. The effect of crank rate strategy on peak the final manuscript for publication. aerobic power and peak physiological responses during arm crank ergometry. J Sports Sci. 2007;25:711–8. Ethics approval and consent to participate 21. Wasserman K. In: Hansen JE, Sue DY, Stringer WW, Sietsema KE, Sun XG, All the patients before their participation to the study were signed informed Whipp BJ, editors. 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The effects of upper and lower limb exercise on the microvascular reactivity in limited cutaneous systemic sclerosis patients

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Abstract

Background: Aerobic exercise in general and high-intensity interval training (HIIT) specifically is known to improve vascular function in a range of clinical conditions. HIIT in particular has demonstrated improvements in clinical outcomes, in conditions that have a strong macroangiopathic component. Nevertheless, the effect of HIIT on microcirculation in systemic sclerosis (SSc) patients is yet to be investigated. Therefore, the purpose of the study was to compare the effects of two HIIT protocols (cycle and arm cranking) on the microcirculation of the digital area in SSc patients. Methods: Thirty-four limited cutaneous SSc patients (65.3 ± 11.6 years old) were randomly allocated in three groups (cycling, arm cranking and control group). The exercise groups underwent a 12- week exercise program twice per week. All patients performed the baseline and post-exercise intervention measurements where physical fitness, functional ability, transcutaneous oxygen tension (ΔTcpO ), body composition and quality of life were assessed. Endothelial-dependent as well as -independent vasodilation were assessed in the middle and index fingers using LDF and incremental doses of acetylcholine (ACh) and sodium nitroprusside (SNP). Cutaneous flux data were expressed as cutaneous vascular conductance (CVC). Results: Peak oxygen uptake increased in both exercise groups (p < 0.01, d = 1.36). ΔTcpO demonstrated an increase in the arm-cranking group only, with a large effect, but not found statistically significant,(p = 0.59, d = 0.93). Endothelial-dependent vasodilation improvement was greater in the arm-cranking (p < 0.05, d = 1.07) in comparison to other groups. Both exercise groups improved life satisfaction (p < 0.001) as well as reduced discomfort and pain due to Raynaud’s phenomenon (p < 0.05). Arm cranking seems to be the preferred mode of exercise for study participants as compared to cycling (p < 0.05). No changes were observed in the body composition or the functional ability in both exercise groups. Conclusions: Our results suggest that arm cranking has the potential to improve the microvascular endothelial function in SSc patients. Also notably, our recommended training dose (e.g., a 12-week HIIT program, twice per week), appeared to be sufficient and tolerable for this population. Future research should focus on exploring the feasibility of a combined exercise such as aerobic and resistance training by assessing individual’s experience and the quality of life in SSc patients. Trial registration: ClinicalTrials.gov (NCT number): NCT03058887, February 23, 2017. Keywords: High-intensity interval training, Vascular function, Quality of life * Correspondence: m.klonizakis@shu.ac.uk Centre for Sport and Exercise Science, Collegiate Campus, Sheffield Hallam University, Collegiate Crescent, Sheffield S10 2BP, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 2 of 11 Background populations. For example, a HIIT protocol with short in- Systemic sclerosis (SSc) is an idiopathic systemic auto- tervals (30 s exercise/30 s passive recovery) may elicit immune disease characterized by an ongoing cutaneous more favourable patient-reported satisfaction/enjoyment and visceral fibrosis, fibroproliferative vasculopathy and levels compared to other longer duration exercise proto- immunologic abnormalities [1–4]. The vascular element cols [13]. In chronic heart failure patients, a short dur- has an important role in the SSc pathophysiology from ation HIIT protocol (30 s exercise/30 s passive recovery) early onset to late complications (e.g., pulmonary arterial has demonstrated to be a well-tolerated, preferred proto- hypertension and kidney disease). SSc can be distin- col with a low perception of effort, patient comfort and guished in either limited cutaneous scleroderma (lcSSc) with a longer time spent at higher percentage of peak with skin involvement mainly limited to the hands oxygen uptake (VO ) than a longer duration HIIT 2peak and face; or diffuse cutaneous scleroderma (dcSSc) protocol with active recovery phases [13]. Recent evi- with skin involvement proximal to the elbows and dence supports this notion; when enjoyment levels in an knees [5]. Blood vessels are directly affected by SSc, overweight/obese cohort were examined after a short as manifested by the diverse clinical complications HIIT protocol and demonstrated that performing a HIIT that take place from the initiation to the propagation protocol on a cycle ergometer present on an average 4.5 of the disease, and have important ramifications on rating on a 7-point scale [14]. the quality of life (QoL) of patients. Although we know the potential of HIIT in improving Raynaud’s phenomenon (RP) precedes other clinical both the micro-and the macro- vascular function in sev- manifestations and is observed in over 95% of SSc pa- eral clinical populations such as heart failure [15] and tients [6]. Evidently, RP is triggered by endothelial injur- cardiometabolic disease [16] by using the treadmill and ies in association with dysregulations in the vascular cycle ergometer as modes of exercise, no evidence exists tone [7]. In addition to the imbalance of vascular tone, about the mode of exercise that would be more effective RP is also associated with structural vascular alterations on digital microcirculation where the RP attacks are in small- and medium-sized arteries leading to luminal present, such as in SSc patients. Assumptions could be narrowing. As a result, the blood vessels are unable to made that utilising an upper-body exercise would poten- compensate for the impairment of blood flow during se- tially be more beneficial for the digital microcirculation vere RP attacks and this leads to the so-called rather than lower-body exercise where the working mus- ischaemia-reperfusion reactions. These vascular compli- cles promote the blood flow in the lower limbs. Hence, cations may progress to gangrene and digital amputation the effects that may occur by the upper- and lower-limb [8]. Notably, SSc has the highest case-specific mortality exercise on digital microcirculation in SSc patients of any rheumatic disease being also associated with sub- should be examined. stantial morbidity [9]. We will attempt to bridge the knowledge gap by asses- Pharmacological agents (e.g., nifedipine) are com- sing the effects of a supervised and individually-tailored monly used as first-line approach. Although it can be exercise programme based on arm cranking (ACE) and effective and provide pain-relief to patients, the short- cycle ergometry (CE) on microvascular reactivity, aer- term (e.g., oedema, headaches, heart palpitations, obic capacity, exercise tolerance and enjoyment levels, as dizziness and constipation) and long-term (e.g., heart well as on QoL in SSc patients. dysfunction, increased cardiovascular risk) side effects of the medical treatment should also be considered as well Methods as the financial cost of treatment. Therefore, alternative Patients approaches with less side effects and cost implications We recruited 34 patients (31 women, 3 men) with lcSSc, are warranted [10, 11], with a view to reducing depend- defined as per the American College of Rheumatology ency on medication. and European League Against Rheumatism criteria [17], Exercise in general and high-intensity interval training with disease duration between 1 to 10 years. All partici- (HIIT) specifically could be a useful adjunct therapy for pants were able to undertake exercise. Patients with pul- this population. HIIT has come to prominence over the monary arterial hypertension, interstitial lung disease, last few years for its effectiveness in inducing greater im- those diagnosed with another inflammatory condition provements in vascular function than moderate-intensity and/ or presenting myositis with proximal muscle weak- continuous training in a number of clinical populations ness were excluded. Moreover, patients with New York (e.g., heart failure, metabolic syndrome, obesity) [12]. Heart Association class 3 or 4, smokers or people who Nevertheless, due to the variation in HIIT protocols, stopped smoking within 4 weeks of screening and limited evidence exists to support which protocol would women who were pregnant were also not permitted to be the most effective in SSc patients, although the op- participate. Eligible patients were recruited from the tions are many, based on evidence from other patient Rheumatology Department of the Royal Hallamshire Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 3 of 11 Hospital in Sheffield. All patients provided written con- mass (kg) segmented in upper and lower limbs were sent to participate. The regional health research ethics assessed by using bio-electrical impedance analysis (In committee for clinical studies approved the protocol. Body 720, Seoul, Korea). Patients’ demographic charac- Patients were randomly allocated between the ACE (n = teristics are illustrated in Table 1. 11), CE (n = 11) and control (n = 12) groups. All the pre- and post-intervention tests were performed at the same Peak oxygen uptake test time of the day to minimize intra-day variability. During the cardiopulmonary tests gas exchange was collected and analysed by an online breath-by-breath analysis system Procedures (Ultima™, Medical Graphics, Gloucester, UK). Heart rate Baseline assessments, undertaken at first visit, included (HR) was continuously monitored using a Polar heart rate VO ,anthropometry,functionalability,microvascularre- monitor (Polar FS1, Polar Electro, Kemple, Finland) and 2peak activity and QoL. VO test was performed either on an blood pressure was assessed by the researcher using a manual 2peak arm crank ergometer (ACE group) or on a cycle ergometer sphygmomanometer (DuraShock DS54, Welch Allyn, Bea- (CE and control group). Thereafter, patients were randomly verton, OR, USA) and a stethoscope (Littman Classic II, 3 M, allocated to three groups (ACE, CE and control group). The Maplewood, MI, USA). Rating of perceived exertion (RPE) exercise groups (ACE and CE) performed a 12-week exer- wasrecordedduringthe last 10 sofevery minute during the cise programme and the control group did not perform any exercise test until volitional exhaustion using Borg’s scale [18] type of physical activity. All groups were followed up after a 6–20 point. Peak power output (PPO) and test duration was 12-week period performing the same measurements as in measured in both tests. VO defined as the average oxy- 2peak the baseline. Figure 1 depicts the study’sprocedures. gen consumption was recorded from expiratory samples dur- ing the final 30 s of exercise. Anthropometry The participant’s stature was measured using a Hite-Rite Arm crank test Precision Mechanical Stadiometer. Body weight (kg), The arm crank ergometer (Lode BV, Groningen, body mass index (BMI), fat mass (kg) and lean body Netherlands) was adjusted to ensure alignment between Fig. 1 CONSORT flow diagram. ACE arm crank ergometer, CE cycle ergometer Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 4 of 11 Table 1 Demographic data (means ± SD) Baseline ACE Baseline CE Baseline Control Age (years) 69.1 ± 9.7 65.1 ± 10 62.2 ± 14.3 Body weight (kg) 69 ± 15.8 66 ± 9.7 73.2 ± 14.8 2) Body mass index (kg/m 25.6 ± 4.8 24.5 ± 3.6 27.3 ± 4.0 Stature (cm) 163.7 ± 9.1 164.4 ± 7.9 163.4 ± 6.7 Disease duration (yrs) 7.8 ± 2.3 7.7 ± 2.1 6.3 ± 2.0 Digital ulcers (treatment iloprost infusion) 0/10 0/10 4/11 Raynaud’s treatment 6/10 5/10 8/10 Nifedipine 4/10 4/10 4/10 Sildenafil 2/10 1/10 4/10 Blood pressure treatment 6/10 4/10 4/10 Candesartan 4/10 0/10 1/10 Ramipril 2/10 4/10 3/10 ACE arm crank ergometer, CE cycle ergometer the ergometer’s crankshaft and the centre of the patient’s Exercise program glenohumeral joint. Patients’ sitting position was set up Patients undertook twice-weekly supervised exercise ses- to ensure that the elbows were slightly bent when the sions at the Centre of Sport and Exercise Science at arm was outstretched. Patients were instructed to main- Sheffield Hallam University. Each session started with a tain their feet flat on the floor at all times. Due to differ- 5 min warm-up on an arm crank or cycle ergometer de- ences in gender power capabilities, two separate pending on the group (involving light aerobic exercise protocols were instructed for men and women. Men and gentle range of motion exercises). This was followed commenced at a workload of 30 W and women at by HIIT for 30 s at 100% of PPO interspersed by 30 s 20 W. In both protocols the crank rate was maintained passive recovery for a total of 30 min (Fig. 2). At the end − 1 at 70 rev min [19, 20] and power requirements of the session patients undertook a 5 min cool-down increased as a linear ramp at a rate of 10 W/min and period, involving lower- and upper-limb light intensity 6 W/min for men and women, respectively [20]. The aerobic exercise and light stretching. Patients were wear- test commenced with 3 min resting and then 3 min of ing heart rate monitors throughout the exercise sessions. warm-up (unloaded cranking). RPE ≥ 18 and/or inability Heart rate and RPE and effect (see below) were assessed − 1 to maintain a crank rate above 60 rev min resulted in at regular intervals throughout the supervised exercise the termination of the test. After the exercise session. termination an unloaded bout of 2–3 min exercise at a − 1 crank rate below 50 rev min followed allowing for an Functional ability test active recovery period. The functional ability was assessed through a six-minute walking test (6MWT). Although the 6MWT lacks organ specificity in SSc, it can provide a valuable outcome par- Cycle ergometer test ameter and thus, is suggested as a regular assessment in The cycle ergometer test was performed on an elec- this clinical condition [22]. Patients were instructed to tromagnetic cycle ergometer (Lode Excalibur, Gro- walk as far as possible back and forth on a 10 m corridor ningen, Netherlands). The test commenced with a for 6 min. They were also instructed to slow down, stop 3 min resting period followed by 3 min of unloaded and/or rest as necessary if they got out of breath or be- pedalling. Participants were requested to maintain a came exhausted, but to resume walking as soon as they − 1 cycle rate of 60 rev min during the exercise test. felt able to. The laps and the total walking distance were The starting load and the concomitant increments recorded on a worksheet. were individually calculated according to participants’ estimated physical fitness and Wasserman’seqs.[21]. Microvascular reactivity RPE ≥ 18 and/or inability to maintain a crank rate Microvascular function was assessed by laser Doppler − 1 above 40–45 rev min resulted in the termination of Fluximtery and Iontophoresis technique in a the test. Following the exercise test 2–3minof temperature-controlled room (22–24 °C). Laser Doppler unloaded pedalling was performed to allow for an fluximetry (LDF) electrodes were attached to the dorsal active recovery period. aspect of the reference fingers for acetylcholine (ACh) Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 5 of 11 Fig. 2 Schematic training protocol and sodium nitroprusside (SNP) administration. These below the right scapula on the back away from any were used as indicators of the changes occurring in the bone. endothelial-dependent and -independent vasodilatory Fixation rings were used to hold the probe attached to function. Heart rate (Sports Tester, Polar, Finland) and the skin and this was filled with two small drops of con- blood pressure of the brachial artery (left arm; Dinamap tact fluid before attachment to the sensor. The fluid was Dash 2500, GE Healthcare, Chicago, IL, USA) were then heated causing the subsequent dilatation of the monitored at 5-min intervals throughout the protocol. skin. The raw values of the patient’soxygenperfu- The two drug delivery electrodes (PF383; Perimed AB, Jar- sion, obtained directly from TcpO2 device were de- falla, Sweden) were positioned over healthy-looking skin, fined (Table 2) as previously described in Wasilewski approximately 4 cm apart with one containing 100 μLof et al. [25]. 1% ACh (Miochol-E, Novartis, Stein, Switzerland.) and the other 80 μL of 1% SNP (Nitroprussiat, Rottapharm, Quality of life Monza, Italy). ACh was placed over the middle finger be- The EQ-5D-5 L was the main outcome used to assess tween the distal and proximal interphalangeal joints and the patients’ quality of life pre- and post-exercise inter- SNP was placed over the index finger between the meta- vention. The EQ-5D-5 L is a generic measure of health carpophalangeal and carpometacarpal joints. The incre- state by considering five key dimensions of daily living mental iontophoresis protocol for ACh and SNP delivery (mobility, self-care, ability to undertake usual activities, is described in Klonizakis et al., [23, 24]. pain, anxiety/depression) [26]. Participants were asked to describe their level of health on each dimension using Transcutaneous oxygen pressure (TcpO ) one of five levels: no problems, slight problems, moder- TcpO measurements were performed during the cardio- ate problems, severe problems, extreme problems. Pa- respiratory tests using sensors that were non-invasively tients were also asked about to rate their life satisfaction attached onto the skin and allowed to heat. The sen- on a scale of zero to ten as well as to rate the RP pain sors induce skin blood capillaries dilatation through during the last couple of weeks on one to five ascending heat, which increases the blood flow and results in grading: not at all, slightly, moderately, severely, oxygen diffusion through the skin to the sensor. The Table 2 Definitions of TcpO2 quantities sensor measures TcpO values inwardly through an TcpO2 quantity Definition electrochemical process. Baseline The arithmetic mean of maximum Measurements were performed using the TINA TcpO2 at rest. TCM400 TcpO device (Radiometer, Copenhagen, TcpO2 The highest TcpO2 value recorded max Denmark). The temperature of the probe was set to 44. every minute of exercise or at rest. 5 °C to allow maximal skin vasodilation, thereby de- Maximum change from baseline The outcome of the subtraction of creasing the arterial to skin surface oxygen pressure gra- (ΔTcpO2 ) baseline from TcpO2 : e.g. max max dient. Before the exercise test 15–20 min were allowed TcpO2 - baseline max with the probe attached on the skin for stabilisation of Changes in transcutaneous The average sum of the change from TcpO2 value. After the test the TcpO2 values were auto- oxygen pressure (ΔTcpO2) baseline at rest and exercise period: e.g. (Σ)ΔY1…n) / n) = ΔTcpO2 matically corrected according to a temperature of 37 °C by the TINA device. The electrode was placed slightly ΔTcpO transcutaneous oxygen tension 2 Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 6 of 11 extremely. Digital ulcers and hospitalization for iloprost calculated wherever the results were statistically signifi- infusion and amputations were also recorded. cant with 0.2, 0.5, and 0.8 representing small, medium, and large effects respectively [28]. To compare the be- Exercise tolerance tween group differences using a one-way ANOVA we The exercise tolerance of HIIT was assessed through adjusted the ACE values according to the physiological measures that were interpreted participants’ perception and anthropometrical responses of CE [29]. Statistical regarding the exercise intensity, the effect (Additional significance was set at p ≤ 0.05. file 1), the exercise task self-efficacy (Additional file 2), the intentions (Additional file 3) and the enjoyment Results (Additional file 4). The above data was collected at the Compliance and exercise intensity first and last exercise session each month in order to Compliance to the12-week exercise programme twice examine several time points during the exercise inter- weekly was 92% and 88% for the ACE and CE group re- vention. Specifically, the questionnaires were repeated at spectively, with one drop-out for each exercise group. the 1st, 8th, 16th, and 24th exercise sessions. The indi- No exercise-related complications were reported. The vidual questionnaires and the time points that were in- average percentage peak HR (%HR ) for each exercise peak corporated during the exercise session are described in session was 92.1% ± 6.0 for the ACE group and 90.8% ± Jung et al. [27]. 7.5 for the CE group. The average rate of perceived exertion (RPE) and effect were 13 ± 1 and + 3 (good) ± 1, Statistical analysis respectively, for both exercise groups. Data analysis was performed using SPSS software (ver- sion 23, IBM SPSS, Armonk, NY, USA) and is presented Oxygen uptake and pressure − 1 as mean ± SD. Normal distribution of the data and Both ACE (0.86 L min d = 0.68) and CE (1.22 ± 0. − 1 homogeneity of variances were tested using the Shapiro- 33 L min d = 0.76) VO were significantly greater 2peak Wilk and Levene’s test, respectively. The comparison in post-exercise intervention compared to baseline (p <0. − 1 − 1 the anthropometric, physiological and vascular charac- 01). ACE VO (21.9 ± 7.1 ml kg min d = 1.09) 2peak teristics among the three groups was done through a improved significantly in comparison to control but not one-way ANOVA test. Independent t-tests and chi- compared to CE group (Table 3). squared tests were also used to identify the differences A tendency to improve was also observed in both between two groups. Effect sizes (Cohen’s d) were ΔTcpO2 (p = 0.59, d = 0.93) and transcutaneous oxygen Table 3 Physiological and quality of life outcomes ACE (n = 10) CE (n = 10) Control (n = 11) Pre Post Pre Post Pre Post ACh CVC 0.14 ± 0.06 0.19 ± 0.08 0.20 ± 0.11 0.26 ± 0.1 0.20 ± 0.08 0.15 ± 0.08 ACh CVC 1.28 ± 0.78 1.56 ± 0.88* 1.49 ± 0.99 1.26 ± 0.52 1.40 ± 0.78 0.82 ± 0.47 max ACh T (sec) 159.4 ± 83 104.1 ± 71.8 172 ± 57.9 119.4 ± 82.9 127.9 ± 51.1 149.9 ± 70.3 max SNP CVC 0.15 ± 0.08 0.24 ± 0.14 0.21 ± 0.11 0.25 ± 0.08 0.20 ± 0.09 0.20 ± 0.1 SNP CVC 1.73 ± 2.01 1.88 ± 1.52 1.61 ± 1.21 2.38 ± 1.8 1.70 ± 1.3 1.40 ± 0.56 max SNP T (sec) 161.2 ± 88.5 131.3 ± 77.5 167.4 ± 66.3 138.8 ± 80.5 165.5 ± 56.5 166.9 ± 76.4 max ΔTcpO2 2.5 ± 4.0 9.2 ± 12.1 1.56 ± 4.8 1.56 ± 9.5 1.39 ± 3.4 0.89 ± 2.6 ΔTcpO2 11.5 ± 3.9 18.4 ± 16.5 11.7 ± 3.6 13.6 ± 9.6 9.44 ± 7.7 8.0 ± 7.0 max − 1 − 1 VO (ml kg min ) 17.7 ± 4.7 21.9 ± 7.1* 14.6 ± 2.9 18.5 ± 2.8* 14.3 ± 6.9 14.7 ± 6.2 2peak Life satisfaction 6.5 ± 1.6 8.1 ± 1.7*** 8.4 ± 1.4* 8.8 ± 1.1*** 7.5 ± 1.6 4.9 ± 1.5 Mobility 2.4 ± 1.0 2.3 ± 0.8 1.9 ± 0.9 1.7 ± 1.0 1.9 ± 0.9 2.3 ± 1.2 Self-care 1.1 ± 0.3 1.1 ± 0.3 1.2 ± 0.4 1.0 ± 0.0 1.4 ± 0.9 1.7 ± 1.4 Usual activity 2.3 ± 1.3 1.9 ± 1.1 1.9 ± 1.0 1.6 ± 0.7 1.8 ± 1.0 2.4 ± 1.2 Pain/ discomfort 2.4 ± 1.0 2.3 ± 1.1 2.8 ± 1.1 1.8 ± 0.9 2.4 ± 0.7 2.8 ± 1.2 Anxiety/ depression 1.7 ± 0.8 1.5 ± 0.7 1.6 ± 0.7 1.2 ± 0.4 1.6 ± 0.7 1.9 ± 1.4 Raynaud’s pain 2.4 ± 1.4 1.8 ± 0.6* 2.6 ± 1.5 1.9 ± 1.2* 2.4 ± 0.9 3.1 ± 1.1 Endothelial function presented as cutaneous vascular conductance (CVC). T is the time taken to reach peak perfusion. *p < 0.05 and ***p < 0.000 compared to max the other groups ACE arm crank ergometer, SNP sodium nitroprusside, ΔTcpO transcutaneous oxygen tension VO peak oxygen uptake 2 2peak Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 7 of 11 tension (ΔTcpO2 )(p = 0.71, d = 0.80) in ACE group. Raynaud’s phenomenon. Cycling indicated that it might max Although this improvement is not statistically significant have the potential to decelerate the disease progression the Cohen’s d reveals that the effect size of the change is in the vasculature (ACh) as the endothelial-dependent large (> 0.8) both at rest and during provocation (exer- vasodilation was slightly decreased. On the other hand, cise test). the control group showed a decrease in endothelial- dependent function, which might indicate a disease Cutaneous vascular conductance (CVC) worsening (Table 3). Pearson’s correlation coefficient No statistically significant differences were observed at (Table 4) indicated that the endothelial improvement in baseline between the exercise and control groups (p >0. ACE has a trend to correlate with the soft lean and fat- 05). Post-exercise intervention improvements were ob- free mass as well as with skeletal muscle mass. Interest- served in the ACE group, especially over the control ingly, ACh showed that is not correlated with ACE group, while values in CE group were slightly decreased VO , which does not confirm to previous findings 2peak (Table 3). that have shown association of endothelial-dependent function with the improvement in aerobic capacity in Feasibility and tolerance of exercise patients with rheumatoid arthritis [30]. The correlation ACE showed to be the mode of exercise that will more between the endothelial-dependent function and the likely (p < 0.05) engage SSc patients to physical activity lean muscle is a vital evidence for future exercise pre- twice per week (6.9 ± 0.3, d = 1.17) compared to the CE scription for this population. Resistance training is cap- group (6.2 ± 0.79). Moreover, ACE demonstrated to be able to increase muscle mass and to improve better (p < 0.05) regarding participant’s confidence to microcirculation in obese adults [31]. Thus a combin- perform two bouts per week (95 ± 7%, d = 0.82) than CE ation of the current HIIT protocol with resistance train- (83 ± 19.5%) but not statistically significant. Both exer- ing might increase the chances for further improvement cise modes aggregated a high score of enjoyment levels in the endothelial function. > 94 out of 119 with an average effect before, during and after the exercise session of + 3 equals to “good”. Endothelial-dependent function Our results indicate that exercise training may improve Quality of life and clinical outcomes the microvascular function in SSc patients. This could The EQ-5D-5 L questionnaire did not demonstrate any be largely attributed to a shear-stress-related mechan- significant difference between the groups neither at ism. Shear stress is a mechanical reaction of the blood baseline nor after the completion of the exercise vessel to accommodate the increased blood flow, which intervention, in any of its five elements. However, both activates the potassium channels and facilitates the cal- exercise groups reported improved life satisfaction (p < cium influx into the endothelial cells. Endothelial nitric 0.000) as well as reduced discomfort and pain of oxide synthase (eNOS) activation and expression are Raynaud’s phenomenon (p < 0.05) after the exercise triggered by an increase in intracellular calcium [32], intervention compared to the control group (Table 3). promoting nitric oxide (NO) production and thus vaso- We also reported digital ulcers and hospitalization for dilation [33]. It is possible that the recurring induction iloprost infusion for four out of eleven patients (36.3%) of NOS activity with exercise training decelerates the in the control group. One of them proceeded to amputa- degradation of NO by free radicals in these conditions tion of the distal phalange of the middle finger in one [34] or by reducing directly free radical production [35]. hand. A recent systematic review on exercise training and vas- cular function [12] supports our findings indicating that Discussion the antioxidant status is enhanced after HIIT in patients Overall, this study is the first to demonstrate that upper- with cardiometabolic disorders [36–38] and thus, the limb aerobic exercise may be able to improve micro- NO bioavailability is improved. Mitranun et al. [38] vascular endothelial-dependent function in the digital assessed the effects of interval aerobic exercise training area in patients with systemic sclerosis experiencing (three times/week for 12 weeks) on endothelial- Table 4 Endothelial-dependent correlations in arm cranking ̇ ̇ Soft lean mass (kg) Fat-free mass (kg) Skeletal muscle mass (kg) VO VO 2peak 2peak −1 − 1 − 1 (L min ) (ml kg min ) ACh CVC Pearson’s r 0.529 0.520 0.530 0.120 0.220 max sig (2-tailed) 0.116 0.123 0.115 0.740 0.569 n = 10 10 10 10 10 10 Ach acetylcholine, CVC cutaneous vascular conductance Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 8 of 11 dependent vasodilation in patients with type 2 diabetes persistent digital ulcers developing irreversible tissue loss mellitus. The vascular outcomes demonstrated reduc- in 30% of patients [48]. In our study four out of eleven tions in erythrocyte malondialdehyde and serum von patients in the control group developed digital ulcers Willebrand factor and increases in plasma glutathione and required hospitalization for iloprost infusion [49, 50] peroxidase and nitric oxide (all p < 0.05). Therefore, HIIT for a period of 1 to 3 weeks and one patient proceeded seems to improve the microvascular function by reducing to digital amputation of the distal phalange in the mid- oxidative stress markers and enhance the antioxidants as dle finger in one hand. Hospitalization is a psychologic- well as the vasodilators in cardiometabolic conditions and ally-stressful procedure for the patient, which directly potentially in connective tissue diseases such as SSc. affects QoL. The most common side effects of iloprost infusion could be headache, flushing of the skin, nausea, Vascular remodelling, shear stress and exercise training vomiting and sweating. Amputation has been reported Evidence for the time course of functional or structural to occur in one or more digits due to ischaemia in 20.4% arterial adaptations to exercise training in humans is of patients with SSc, 9.2% of which have multiple digit limited: Short-term effects of exercise improves NO bio- loss [51]. QoL in patients with SSc is adversely affected availability, whereas long-term effects induce changes in due to digital ischaemia. Consequently, our protocol has vascular remodelling [39], an endothelium and NO- demonstrated that is capable of improving digital ischae- dependent outcome [40]. mia and preventing disease progression and digital ul- Prior to this study, we hypothesised that upper limb cers and thus, improving QoL. exercise would be more effective to improve microcircu- lation in the local regions compared to lower limb exer- Transcutaneous oxygen pressure cise; however, the existing evidence supported systemic Although the improvement in oxygen pressure at rest effects occur after exercise training in the lower limbs and under provocation (exercise test) was not significant [12]. Therefore, we proceeded to a comparison between in our study, the effect size of this change was large. the upper and lower limbs. Interestingly, this systemic This indicates that ACE is able to induce systemic effect was not proved with our study, where the micro- changes in oxygen pressure and vascular function in SSc vascular reactivity in the digital area was improved with patients, while the control group showed a slight de- arm cranking but not with cycling. Similar to our find- crease. It is probable that a higher training load or a lar- ings, Klonizakis et al., [41] reported that arm exercise ger cohort would have revealed a statistically significant did not have any impact on lower limbs microcirculation difference between ACE and control group. Evidently, in post-surgical varicose-vein patients. It seems that further research is needed to substantiate our findings systemic effects of exercise training can only affect the and explore other training protocols, which will reveal vascular function in the large arteries (e.g. brachial ar- the effects of exercise on skin oxygen pressure, when tery) but not the conduit and resistance arteries. More- oxygen demand is higher. over, the mass of muscle engaged in exercise training could play an important role in the systemic effects as Quality of life studies that utilized handgrip training have not demon- Both modes of exercise have shown improvement in life strated contralateral limb remodelling [42–44]. The ex- satisfaction and reduction in pain or discomfort induced planation probably relies on the magnitude and pattern by RP attacks after the exercise training. However, fur- of shear stress, which in turn triggers the release of NO ther research is required to confirm the improvement in and acts as a main determinant for its bioavailability. It RP by applying more qualitative measures (e.g. case- is possible that the induced-shear stress by lower limbs specific questionnaires and face-to-face interviews). Ex- is not sufficient to improve the microcirculation in the ercise tolerance, cardiorespiratory fitness, walking dis- acral body parts of the upper limbs. Therefore, the tance, muscle strength and function as well as health- volume of blood flow and the magnitude of shear stress related QoL have been demonstrated to be improved in induced by HIIT could account for the local effects of SSc patients after participation in exercise programmes exercise training in the smaller arteries [45, 46]. involving aerobic exercise and aerobic exercise com- bined with resistance training [52]. Therefore, promoting Clinical outcome physical activity for the improvement of QoL in SSc Inadequate blood flow to living tissue is often a painful patients should be deemed as one of the priorities for experience, threatening the life of the tissue involved. future research. Digital tissue loss not only results in disfigurement and functional disability, it is also the clinical manifestation Feasibility of HIIT of an underlying systemic disease process [47]. One of Our findings demonstrate that HIIT (30 s 100% PPO/ 30 the direct consequences of digital ischaemia is the s passive recovery) maintained an average effect of + 3 Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 9 of 11 (“Good”) throughout the exercise training for both until symptomatic limitation of exercise, which might modes of exercise. It is also noteworthy that the patient’s affect the accuracy of TcpO2, however, we need to stress effect was similar before, during and after the exercise that the utilization of TcpO2 measurement in our study session which could be explained by the moderate car- was more of a research interest aiming to evaluate the diorespiratory stress induced by this protocol. Support- improvement in vascular function after an exercise ive to this finding is the RPE for both groups which programme rather than accurately depicting hypoxemia averaged to 13 (“Somewhat hard”), a value which is levels in the arterial wall. strongly correlated to anaerobic threshold and low to Our patients were only of limited cutaneous systemic moderate exercise intensity in a large cohort of adults sclerosis, where the change in skin thickness is little over [53]. Exercise intensity and affective response have pre- time compared to diffuse cutaneous systemic sclerosis sented a negative relationship in inactive and overweight (Khanna et al., 2017). Moreover, it is common practice adults and it has been reported that as incremental exer- in the NHS clinics to assess mRSS only in patients with cise progresses above the ventilatory threshold, the dcSSc. Therefore, we did not include this measurement affective response to exercise becomes more negative in our study; however, we believe that this does not [54, 55]. Therefore, a short protocol of HIIT seems to affect our results, as the categorisation of the patients is not induce great cardiovascular responses in patients clear. Also the autoantibody specificities for SSc patients with SSc and that might explain the effect’s stability are not included in our study as this is not a standard throughout the session. clinical practice in the area of Sheffield. The intentions regarding engagement to exercise and the task self-efficacy questionnaires as well as the enjoy- Conclusions ment levels of the patients could further substantiate whether HIIT is a feasible mode of exercise in SSc pa- Aerobic exercise in general, and HIIT (30 s 100% tients. Both modes of exercise demonstrated a strong pa- PPO/30 s passive recovery) specifically, involving the tient’s confidence to perform two and three bouts of upper limbs may improve the microvascular exercise with arm cranking being slightly higher than reactivity through an enhancement of the cycling. Both modes of exercise were enjoyable for the endothelial-dependent function. Our results corre- patients, however, arm cranking was found to be signifi- lated well with the lean muscle mass, which indi- cantly higher in the intentions for engagement in two cates that resistance training could be a bouts of exercise per week compared to cycling. HIIT is complementary training element in inducing further a feasible protocol to be implemented in patients with improvements in microcirculation. SSc and ACE is considered more acceptable than CE po- Our protocol appears to reduce digital ischaemia tentially, because it is a new mode of exercise for this risk, which can be the leading cause for further population and that might increase their interest to per- systemic complications and a major factor affecting form an alternative type of exercise. the quality of life. Exercise is a non-invasive, adjunct treatment with no adverse effects that is well- Limitations tolerable by patients with SSc. The sample size of the current study could be deemed a There is a need for large multi-centre, randomised- limitation for the current study but we need to stress controlled studies to further establish the effects of that SSc is not a common condition such as cardiometa- exercise on SSc patients. bolic diseases (e.g. hypertension, obesity, diabetes) and we strictly adhered to the pre-defined eligibility criteria Additional files to present a consistent and reproducible outcome. Moreover, the ratio between women and men is uneven, Additional file 1: Feeling scale (SF). (DOCX 38 kb) with SSc women to men ratio being estimated to be 5.2:1 Additional file 2: Exercise task self-efficacy. (DOCX 38 kb) in northeast England [56]. Additional file 3: Intentions for engagement to exercise. (DOCX 35 kb) TcpO2 is a direct value of vascular function as changes Additional file 4: Physical activity enjoyment scale. (DOCX 48 kb) at rest mimic the changes in arterial pO during mild or moderate exercise [57, 58]. However, the time response Abbreviations of these changes is relatively slow (90% time response of 6MWT: Six-minute walking test; ACE: Arm crank ergometer; TcpO2 being approximately 20 s). Carter and Banham Ach: Acetylcholine; BMI: Body mass index; CE: Cycle ergometer; [59] demonstrated that TcpO2 values closely followed CVC: Cutaneous vascular conductance; dcSSc: Diffuse cutaneous scleroderma; eNOS: Endothelial nitric oxide synthase; HIIT: High-intensity interval training; those assessed by direct arterial sampling during cardio- HR: Heart rate; LDF: Laser Doppler fluximetry; lcSSc: Limited cutaneous pulmonary exercise testing with 2 min intervals. We ac- scleroderma; NO: Nitric oxide; PPO: Peak power output; QoL: Quality of life; knowledge that our protocol utilized 1 min intervals RP: Raynaud’s phenomenon; RPE: Rating of perceived exertion; SNP: Sodium Mitropoulos et al. Arthritis Research & Therapy (2018) 20:112 Page 10 of 11 ̇ ̇ nitroprusside; SSc: Systemic sclerosis; VE: Minute ventilation; VO : Peak 9. Altman RD, Medsger TA Jr, Bloch DA, Michel BA. Predictors of survival in 2peak oxygen uptake; VT: Tidal volume; ΔTcpO : Transcutaneous oxygen tension systemic sclerosis (scleroderma). Arthritis Rheum. 1991;34:403–13. 10. Pope JE. The diagnosis and treatment of Raynaud's phenomenon: a practical approach. Drugs. 2007;67:517–25. Acknowledgements 11. Prescribing & Medicines Team Health and Social Care Information Centre. The authors would like to thank the study participants and report no Prescription Cost Analysis for England 2015. 2016. https://digital.nhs.uk/ conflicts of interest with this manuscript. The experiments comply with the catalogue/PUB20200. Accessed 07 May 2016. current UK laws. 12. Ramos JS, Dalleck LC, Tjonna AE, Beetham KS, Coombes JS. The impact of high-intensity interval training versus moderate-intensity continuous Funding training on vascular function: a systematic review and meta-analysis. Sports The work was supported by the Centre for Sports and Exercise Science, Med. 2015;45:679–92. Sheffield Hallam University. 13. Meyer P, Normandin E, Gayda M, Billon G, Guiraud T, Bosquet L, et al. High- intensity interval exercise in chronic heart failure: protocol optimization. J Availability of data and materials Card Fail. 2012;18:126–33. Relevant files of this work will be shared on request. 14. Smith-Ryan A. Enjoyment of high-intensity interval training in an overweight/ obese cohort: a short report. Clin Physiol Funct Imaging. 2017;37:89–93. Authors’ contributions 15. Guiraud T, Nigam A, Gremeaux V, Meyer P, Juneau M, Bosquet L. High-intensity AM helped to draft the manuscript, designed the exercise intervention, interval training in cardiac rehabilitation. Sports Med. 2012;42:587–605. contributed to the study design and critically reviewed and revised the 16. Kessler HS, Sisson SB, Short KR. The potential for high-intensity interval training manuscript for important intellectual content. HC developed the qualitative to reduce cardiometabolic disease risk. Sports Med. 2012;42:489–509. aspects of the study, contributed to the study design and critically reviewed 17. Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 and revised the manuscript for important intellectual content. GA provided Classification Criteria for Systemic Sclerosis: An American College of statistical and health economics support, contributed to the study design Rheumatology/European League Against Rheumatism Collaborative and critically reviewed and revised the manuscript for important intellectual Initiative. Arthritis Rheum. 2013;65:2737–47. content. ΜΑ is the study’s clinical lead, contributed to the study design and 18. Borg GA. 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Arthritis Research & TherapySpringer Journals

Published: Jun 5, 2018

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