Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: The WHOLEi + 12 trial

International Journal of Cardiology 231 (2017) 277–283

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Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: The WHOLEi + 12 trial Laura González-Saiz a,1, Carmen Fiuza-Luces a,b,1, Fabian Sanchis-Gomar c,d,⁎,1, Alejandro Santos-Lozano a,d,e, Carlos A. Quezada-Loaiza f, Angela Flox-Camacho f, Diego Munguía-Izquierdo g, Ignacio Ara h, Alfredo Santalla a,g, María Morán a,b, Paz Sanz-Ayan i, Pilar Escribano-Subías f,2, Alejandro Lucia a,j,2 a

Research Institute Hospital 12 de Octubre (‘i+12’), Madrid, Spain Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, Spain c Department of Physiology, Faculty of Medicine, University of Valencia and Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain d Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, USA e GIDFYS, European University Miguel de Cervantes, Valladolid, Spain f Pulmonary Hypertension Unit, Hospital Universitario 12 de Octubre, Madrid, Spain g Department of Sports and Computer Science, Section of Physical Education and Sports, Universidad Pablo de Olavide, Seville, Spain h GENUD Toledo Research Group, Universidad de Castilla-La Mancha, Toledo, Spain i Pulmonary Hypertension Unit, Department of Rehabilitation, Hospital Universitario 12 de Octubre, Madrid, Spain j European University, Madrid, Spain b

a r t i c l e

i n f o

Article history: Received 16 September 2016 Received in revised form 30 November 2016 Accepted 8 December 2016 Keywords: Resistance exercise Pulmonary disease VO2peak NT-proBNP Cardio-pulmonary exercise testing

a b s t r a c t Background: Pulmonary arterial hypertension is often associated with skeletal-muscle weakness. The purpose of this randomized controlled trial was to determine the effects of an 8-week intervention combining muscle resistance, aerobic and inspiratory pressure-load exercises on upper/lower-body muscle power and other functional variables in patients with this disease. Methods: Participants were allocated to a control (standard care) or intervention (exercise) group (n = 20 each, 45 ± 12 and 46 ± 11 years, 60% women and 10% patients with chronic thromboembolic pulmonary hypertension per group). The intervention included five, three and six supervised (inhospital) sessions/week of aerobic, resistance and inspiratory muscle training, respectively. The primary endpoint was peak muscle power during bench/ leg press; secondary outcomes included N-terminal pro-brain natriuretic peptide levels, 6-min walking distance, five-repetition sit-to-stand test, maximal inspiratory pressure, cardiopulmonary exercise testing variables (e.g., peak oxygen uptake), health-related quality of life, physical activity levels, and safety. Results: Adherence to training sessions averaged 94 ± 0.5% (aerobic), 98 ± 0.3% (resistance) and 91 ± 1% (inspiratory training). Analysis of variance showed a significant interaction (group × time) effect for leg/bench press (P b 0.001/P = 0.002), with both tests showing an improvement in the exercise group (P b 0.001) but not in controls (P N 0.1). We found a significant interaction effect (P b 0.001) for five-repetition sit-to-stand test, maximal inspiratory pressure and peak oxygen uptake (P b 0.001), indicating a training-induced improvement. No major adverse event was noted due to exercise. Conclusions: An 8-week exercise intervention including aerobic, resistance and specific inspiratory muscle training is safe for patients with pulmonary arterial hypertension and yields significant improvements in muscle power and other functional variables. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Patients with pulmonary arterial hypertension (PAH) have limited exercise capacity [1,2]. This is primarily caused by right ventricle (RV) ⁎ Corresponding author at: Leon H Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 805, New York, NY 10016, United States. E-mail address: [email protected] (F. Sanchis-Gomar). 1 Contributed equally. 2 These authors share senior authorship.

http://dx.doi.org/10.1016/j.ijcard.2016.12.026 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.

dysfunction and reflected by low cardiorespiratory fitness, as typically assessed directly by determining the peak oxygen uptake (VO2peak) reached during cardiopulmonary exercise testing (CET) or indirectly, by measuring time to complete the 6-min walking distance (6MWD) test [3–7]. The microcirculatory alterations that characterize this disease can also affect non-lung tissue including skeletal muscle [8], which further impairs oxygen availability in working muscle fibers [9]. Indeed, emerging data suggests that patients with PAH suffer from ‘generalized myopathy’ characterized by muscle atrophy and dysfunction [10–13], including

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also weakness of respiratory muscles [14]. On the other hand, chronic thromboembolic pulmonary hypertension (CTEPH) is a main cause of severe PAH, and is associated with increased morbidity/mortality [15]. Although several drugs/drug combinations are available for the management of PAH [16], a complementary option that is gaining attention is exercise training [17], with non-controlled studies reporting improvements in patients' VO2peak or 6MWD [5,6,18–20]. A meta-analysis [21] of five controlled trials [3,7,22–24] showed that interventions based on aerobic exercise during 3–15 weeks, sometimes combined with additional exercises such as resistance [3,23] or respiratory exercises (e.g., yoga) [7, 22,23], elicited significant improvements in 6MWD or VO2peak. Of these, however, only one study was a randomized controlled trial (RCT) [7]. Subsequent meta-analyses have corroborated the safety and efficacy of exercise intervention to improve the functional capacity (e.g., 6MWD) of PAH patients [25]. A recent RCT showed that 10-week exercise training increased 6MWD and treadmill test duration coupled with decreased fatigue symptoms in women with PAH [26], and another RCT demonstrated improved VO2peak after 15-week exercise training in patients of both genders [27]. However, none of the aforementioned RCTs focused on the training of muscle power/strength. This is an important issue when considering that PAH patients present skeletal muscle weakness. The purpose of this RCT (‘WHOLEi + 12’ trial) with PAH/CTEPH outpatients was to determine the effects of an 8-week intervention combining muscle resistance, aerobic and inspiratory pressure load exercises on the following: (i) upper/lower-body muscle power (primary end point); and (ii) N-terminal pro-brain natriuretic peptide (NT-proBNP), CET-variables, 6MWD, five-repetition sit-to-stand (5-STS) test, maximal inspiratory pressure (PImax), health-related quality of life (HRQoL), objectively assessed levels of physical activity (PA) and safety (secondary end points). 2. Methods 2.1. Trial registration and funding This study was approved by the local ethics committee (approval number: 13/377) and performed in accordance with the Declaration of Helsinki.

session. If SpO2 decreased below 80%, BP (systolic or diastolic) dropped by 20+ mmHg or below baseline, BP rose above 220 mmHg (systolic) or 110 mmHg (diastolic), or previously non-reported ECG abnormalities occurred, exercise was stopped until these variables returned to baseline levels or ECG abnormalities disappeared. Resistance training sessions followed the aerobic sessions, and heart rate, SpO2, and BP were recorded. The program included three sessions/week (Monday, Wednesday and Friday, total number of planned sessions, 24). Make-up sessions (on a Tuesday/Thursday) were allowed if an originally planned session was missed. Each session included a threetime circuit of exercises involving large muscle groups and performed with specific weight training equipment (Gervasport, Pleven, Bulgaria) in the following order: leg and bench press, leg extension, lateral pulldown and abdominal crunches (Supplemental file 1). The inspiratory muscle training included two daily sessions (one in the morning, inhospital, and the other in the evening, at the patient's home), 6 days/week (Monday–Saturday). Each session consisted of 30 inspirations performed through a specific pressure-load device (Powerbreathe® Classic Medium Resistance, Powerbreathe International Ltd., Southam, UK) against 40% of PImax (total session duration ~5 min) [29]. Paticipants' PImax were reassessed at the beginning of each week to adjust the weekly load accordingly. For the determination of adherence to training, we considered a session completed when ≥90% of the prescribed exercises were successfully performed [30]. 2.4. End point assessment Outcome assessment was consistently performed in the following order: (i) blood sampling for NT-proBNP determination, PImax, 6MWD, muscle power, 5-STS, and distribution of HRQoL questionnaires (1st day); (ii) after 2–3 days (to allow recovery from power testing), CET; and (iii) accelerometry recording for objective PA determination. 2.4.1. Primary end point After participants' familiarization with the equipment, we assessed their upper/lowerbody muscle power with bench/leg press tests and the same equipment used for training, connected to a linear encoder (Power Encoder, Smartcoach Europe). Patients performed one set of three repetitions for each exercise at the maximum possible speed; each set was followed by a recovery period of 60–90 s. Heart rate, SpO2 and BP were monitored at the end of each set. The load (or ‘resistance’) was increased by 5 or 10 kg (leg press) and 1 or 2 kg (bench press) in each successive set. Because power is the product of force × velocity, it initially increases with resistance and then decreases when the resistance causes a substantial decrease in velocity. Thus, the test is stopped when the decrease in velocity is so pronounced that it also causes a decrease in average muscle concentric power. An advantage of this test is that it ends with a submaximal load, thereby avoiding major/hemodynamic problems and attenuating the need for performing a full Valsalva maneuver. For statistical analyses, we recorded the highest value of average power (watts) and load (kg) in the concentric-propulsive phase, which typically coincides with the start of a decline in this variable together with the occurrence of the highest value of average force (newtons) [31].

2.2. Participants and general design The RCT (ClinicalTrials.gov ID: NCT02288442) was conducted from January 2015 to June 2016 at the Hospital 12 de Octubre (Madrid, Spain) following the Consolidated Standards of Reporting Trials (CONSORT) guidelines [28]. Inclusion criteria were as follows: outpatient (male/female) aged 18–65 years; hemodynamically diagnosed with PAH or inoperable CTEPH and under treatment in the aforementioned hospital; living in the Madrid area; functional New York Heart Association (NYHA) class I–III; clinically/hemodynamically stable (with no syncope or heart failure requiring hospitalization); no treatment modification within the previous 6 months and not starting treatment with prostanoids; and having no comorbidity associated with life expectancy b6 months and no acute/ chronic condition contraindicating exercise. Following an informative session, those willing to participate signed an informed consent form prior to baseline end point assessment, after which they were assigned to a standard care (control) or intervention group (exercise) with a block on sex using a computergenerated list of random numbers (Fig. 1). End points were also assessed after the intervention period. The researchers responsible for assessing participants' eligibility and study outcomes (but not the study participants or the researchers supervising the exercise sessions) were blinded to group allocation. Assessment/training sessions were performed in the PAH unit of the Hospital's cardiac rehabilitation department. Participants in the control group attended regularly scheduled visits with their clinicians, whereas those allocated to the exercise group performed the exercise intervention. 2.3. Exercise intervention The intervention lasted 8 weeks and included three main components: aerobic, muscle resistance and specific inspiratory muscle training. All sessions were supervised by experienced fitness instructors (one/participant) and were performed before noon. The program included five aerobic sessions/week (Monday–Friday; total number of planned sessions, 40; session duration, 20–40 min) on a cycle-ergometer (Ergoselect 100P, Ergoline, Bitz, Germany). The duration/intensity of each session was gradually increased according to each individual's characteristics; that is, starting with exercise-rest intervals at a 1:1 ratio and at 50% of the power output eliciting the anaerobic (also termed ‘ventilatory’) threshold (AT) during baseline assessment, and aiming to reach 40 min (with ~15 min at the AT) during the second half of the program (weeks 4–8). Three-lead ECG, peripheral oxygen saturation (SpO2) using an ear pulse oximeter sensor (TrusatTM, General Electric Oy, Helsinki, Finland) and blood pressure (BP) were recorded during each

2.4.2. Secondary end points Blood samples were obtained for NT-proBNP determination using an electrochemiluminescence immunoassay (Roche Diagnostics GmbH, Mannheim, Germany). The CET was performed on the same cycle-ergometer used for training, following a ramp-like protocol; that is, workload increases of 5 W/30 s (for those in NYHA class I) or 5 W/45 s (II–III) starting from an initial load of 10 W, while pedal cadence was maintained at 50–70 rpm throughout the tests. Gas-exchange variables were collected breath-bybreath with an automated metabolic cart (Metalyzer 3B, Cortex, Leipzig, Germany). VO2peak was computed as the highest value of VO2 obtained for any 20-s period during the tests. AT was detected using the criteria of an increase in the ventilatory equivalent for oxygen (VE/ VO2) and end-tidal pressure of O2 (PETO2), with no concomitant increase in the ventilatory equivalent for carbon dioxide (VE/VCO2) [32]. Participants' 12-lead ECG, BP and SpO2 were continuously monitored, and the following criteria were used for test termination: voluntary cessation by the patient; inability to maintain a pedaling cadence ≥50 rpm; chest pain; ECG signs of ischemia; severe dyspnea disproportionate to the effort; tachyarrhythmias; drop in BP of 20+ mmHg or below baseline, or reaching a peak systolic/diastolic BP N220/ 110 mmHg; pre-syncope; asthma; central nervous symptoms (ataxia, tremors); SpO2 b 80% or signs of poor peripheral perfusion. The 6MWD was evaluated on a straight, 30-m-long corridor in accordance with established standards [33]. The 5-STS test was used as a proxy for the intervention effect on lower-body muscle power at the practical level (i.e., during common activities of daily living [ADLs]) [34]. The test measures the time taken to stand 5 times from a sitting position (using a 48-cm-high seat) as rapidly as possible [34]. We measured participants' PImax at the residual volume using a mouth pressure meter (Micro Medical Inc., Chatham, Kent, UK) under standard conditions [35,36]. The best result from three attempts was taken. We used the Spanish version [37,38] of the Short Form 36-Item Health Survey (SF-36) questionnaire (version 2) to assess patients' HRQoL [39]. The SF-36 includes 36 questions on eight physical/mental health domains and physical/mental component summary scores (on a 0–100 scale). All subjects wore a triaxial accelerometer (GT3X, Actigraph, Pensacola, FL, USA) for objective PA determination during 5–10 consecutive days (including two weekend days) as detailed elsewhere [40]. Outcome variables were expressed as counts/min, and counts were transformed into time (average min/week) engaged in inactivity or moderate-vigorous PA using cut-offs previously described [41]. Safety assessment included evaluation of adverse episodes such as syncopal/ pre-syncopal episodes, severe dyspnea, arrhythmias, asthma, signs of poor

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Fig. 1. Flow diagram of study participants. Abbreviations: PAH, pulmonary arterial hypertension; CTEPH, chronic thromboembolic pulmonary hypertension. peripheral perfusion, or central nervous symptoms (ataxia, tremors). These were reported directly by the study researchers in charge of training sessions (in the exercise group) and by a telephone interview every 2 weeks in all participants. For those subjects who volunteered for this additional assessment, muscle mass was determined (after CET) with dual-energy X-ray absorptiometry (DXA, Hologic Serie Discovery QDR, Software Physician's Viewer, APEX System Software Version 3.1.2. Bedford, MA, USA) [31] at the University of Castilla-La Mancha.

for multiple comparisons with the stringent Bonferroni's method, in which the threshold P-value is obtained by dividing 0.05 by the number of comparisons. For each end point, we reported the P-value for the main group (between-subjects), time (within-subjects) and interaction (group × time) effect. To further minimize risk of type I error, we performed post hoc analysis by group (with the Bonferroni test) only when a significant interaction (group × time) effect was present. All analyses were performed using the Statistical Package for Social Sciences (SPSS) program, version 22.0 for MAC.

2.5. Statistical approach

3. Results

Analyses adhered to the intention-to-treat principle. When post-test data were missing, baseline values were used. We applied a two-factor (group, time) repeated-measures analysis of variance (ANOVA) and repeated the analyses with disease etiology and NYHA class as covariates. To minimize the risk of statistical error type I, analyses were corrected

Twenty participants in each group started the study (Fig. 1). Their main characteristics at baseline are shown in Table 1. Adherence to the intervention averaged 94 ± 0.5%, 98 ± 0.3% and 91 ± 1% for aerobic,

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resistance, and inspiratory muscle training sessions, respectively. The main reasons for missing 1+ sessions were upper respiratory tract infections (30 sessions in total), medical visits (20 sessions) and inability to travel to the hospital (11 sessions). There were 57 make-up sessions in a total of 456 resistance training sessions. Six subjects in the exercise group used oxygen supplementation (with nasal cannulas). 3.1. Primary end points We found a significant interaction (group × time) effect for lower (P b 0.001) and upper-body muscle power (P = 0.002), specifically, peak wattage attained during the contraction propulsive phase in the leg and bench press tests, respectively (Table 2). In post hoc analyses, both tests showed a significant improvement in the exercise group (P b 0.001) but not in controls (P N 0.1). The results remained essentially unchanged when entering disease etiology and NYHA class as covariates. Of note, we also found a significant interaction effect, indicating a training-induced improvement, for the load (kg) eliciting the peak wattage in the leg (P b 0.001) and bench press tests (P = 0.008), specifically, mean values of leg press of 57 ± 27 kg (baseline) and 76 ± 29 kg (post) in the exercise group vs. 62 ± 18 kg (baseline) and 63 ± 19 kg (post) in controls, and mean values of bench press of 18 ± 7 kg (baseline) and 21 ± 7 kg (post) in the exercise group vs. 22 ± 9 kg (baseline) and 23 ± 9 kg (post) in controls. Six patients (all in the exercise group, two men, four women) volunteered to undergo DXA assessment. Their muscle mass did not change with training: upper-body, baseline 26,356 ± 6893 g; posttraining 26,169 ± 6727 g (Wilcoxon's test P = 0.917); lower-body, baseline 13,336 ± 3239 g; post-training 13,340 ± 3332 g (P = 0.917). Importantly, however, peak power attained in both bench and leg press relative to upper and lower-body muscle mass (in kg), respectively, improved with training in all subjets (Fig. 2A and B), yielding the following mean values: bench press 4 ± 2 W/kg (baseline) and 12 ± 6 W/kg (post-training, Wilcoxon's test P = 0.028); leg press 20 ± 10 W/kg (baseline) and 34 ± 11 W/kg (post-training, P = 0.028).

Table 1 Characteristics of study participants.

Female, n (%) Age (years) BMI (kg/m2) NYHA class I I–II II II–III III Hemodynamic variables at rest Mean pulmonary arterial pressure (mmHg) Pulmonary vascular resistance (Woods Units) Cardiac output (mL/min) Right atrial pressure (mmHg) Disease type/etiology PAH Idiopathic Hereditary Toxic oil syndrome HIV Connective tissue disorders Congenital cardiopathy Inoperable CTEPH Main treatment characteristics Oral monotherapy Combined oral therapy Combined oral therapy + prostanoids Monotherapy + prostanoids

Exercise (n = 20)

Control (n = 20)

P-value for the comparison between groups

12 (60%) 46 ± 11 24 ± 4

12 (60%) 45 ± 12 25 ± 5

3 (15%) 2 (10%) 11 (55%) 4 (20%) 0 (%)

6 (30%) 2 (10%) 10 (50%) 0 (0%) 2 (10%)

47 ± 15

47 ± 14

0.955

11 ± 6

9±5

0.183

4414 ± 91 8±4

4827 ± 135 7±3

0.296 0.350 0.518

5 (25%) 2 (10%) 2 (10%) 2 (10%) 5 (25%) 2 (10%) 2 (10%)

10 (50%) 1 (5%) 3 (15%) 2 (10%) 1 (5%) 1 (5%) 2 (10%)

7 (35%) 7 (35%) 4 (20%)

9 (45%) 8 (40%) 3 (15%)

2 (10%)

0 (0%)

0.856 0.462 0.133

0.483

Data are mean ± SD or n (%). Comparisons between groups were performed with the unpaired Student's t (for data presented as mean ± SD) or χ2 test (for data presented as frequencies). Abbreviations: BMI, body mass index; CTEPH, chronic thromboembolic pulmonary hypertension; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension.

3.2. Secondary end points A significant interaction effect was found for three secondary end points: VO2peak, 5-STS and PImax (all P b 0.001). In post hoc analyses, participants in the intervention group showed a significant improvement (all P b 0.001), whereas no change was observed in the control group. A trend towards a training-induced improvement was found for 6MWD (P = 0.015 for the interaction effect). The results remained essentially unchanged when entering disease etiology and NYHA class as covariates. All the subjects undergoing DXA scans showed a posttraining increase in VO2peak relative to lower-body muscle mass (Fig. 2C). 3.3. Safety No major adverse event or health-related issue attributable to exercise was noted. Only an episode of atrioventricular nodal reentrant tachycardia during post-intervention CET in one participant and dizziness (without syncope) during an aerobic training session in another patient (which was attributed to hypoglycemia) were noted. 4. Discussion The main finding of our study is that relatively short-duration (8week) exercise intervention including aerobic and specific inspiratory muscle training (all week days) combined with large muscle mass resistance training (3 days per week) for patients with PAH or inoperable CTEPH induces significant improvements in muscle power/strength (both absolute and per unit of muscle mass), ability to cope with ADLs (5-STS), as well as in PImax and in a common indicator of aerobic capacity

with potential predictive value of PAH progression/outcome and also of health status in all population groups, VO2peak. Importantly, the intervention proved safe, as shown by the absence of major adverse effects with exercise and further supported by the finding that changes in mean NTproBNP values over the intervention period did not differ among the two groups (i.e., P = 0.428 for the interaction (group × time) effect). The finding that only one patient in the exercise group (vs. also one subject among controls) showed an increase in NT-proBNP at postintervention above the threshold-values predictive of non-survival at 2 (915 pg/mL) or 4 years (917 pg/mL) in Spanish PAH patients [42] provides further support for the safety of the intervention in terms of eventual cardiac damage (see also Supplemental file 2). Determining the benefits of an exercise intervention on the muscle power of patients with PAH is clinically relevant because the limited exercise capacity of these patients is not only explained by their altered pulmonary hemodynamics but also by peripheral muscle weakness, resulting in lower values of muscle strength than in healthy controls [11]. To the best of our knowledge, this is the first RCT applying a relatively demanding resistance training program involving large muscle groups and using specific weight-training equipment in PAH/CTEPH patients. Previous valuable controlled studies used much lighter resistance exercises for example, lifting 1–2 kg weights [22], dumbbell training of single muscle groups with 0.5–1 kg weights [3,7,23,27] or supporting body weight over a chair [3]. Only Mainguy et al., using a noncontrolled design, applied a resistance training program with exercises at 70% of 1-repetition maximum (1RM) [19]. Resistance exercise programs like the one applied in the present study should be an integral component of any exercise training program [43], including in patients [44]. Indeed, increased muscle power/strength induced by resistance

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Table 2 Results of the primary and secondary end points by group. End points

Group

N with initial data

Baseline

Post-intervention

Mean (95%CI) change post minus baseline

P for group effect

P for time effect

P for (group × time) effect

Power, effect size (η2p)a

Exercise Control Exercise Control

20 19 20 19

332 385 125 160

498 382 177 166

278 191 105 125

166 (132, 200) −3 (−38, 32) 53 (34, 72) 6 (−14, 27)

0.671

b0.001

b0.001

1.00, 0.60

0.726

b0.001

0.002

0.90, 0.26

Exercise Control

20 16

292 ± 238 212 ± 234

305 ± 291 280 ± 432

14 (−80, 107) 69 (−35, 173)

0.588

0.239

0.428

Exercise Control Exercise Control Exercise Control Exercise Control Exercise Control

20 19 20 18 20 18 20 18 20 18

15.7 ± 3.3 19.8 ± 6.5 29 ± 5 31 ± 6 107 ± 6 105 ± 7 38 ± 7 38 ± 8 36 ± 8 34 ± 8

18.3 ± 3.2 19.4 ± 6.8 31 ± 6 32 ± 5 105 ± 7 104 ± 6 37 ± 8 37 ± 6 34 ± 9 32 ± 5

2.6 (1.8, 3.4) −0.3 (−1.2, 0.5) 1 (0, 2) 1 (0, 2) −2 (−3, −1) −1 (−3, 0) −1 (−3, 1) −1 (−3, 1) −2 (−4, 0.2) −2 (−4, 0.1)

0.120

b0.001

b0.001

0.370

0.022

0.679

0.522

0.004

0.514

0.968

0.102

0.892

0.472

0.012

0.802

Other physical capacity variables PImax (cmH2O) Exercise Control 6MWD (meters) Exercise Control 5-STS (performance time, sb) Exercise Control

20 19 20 20 19 20

76 ± 36 74 ± 31 500 ± 70 546 ± 99 7.5 ± 1.4 7.0 ± 1.6

111 ± 31 77 ± 31 528 ± 68 551 ± 99 6.0 ± 1.1 6.9 ± 1.4

35 (27, 43) 3 (−5, 12) 27 (14, 40) 4 (−9, 17) −1.5 (−2.0, −1.0) −0.1 (−0.6, 0.4)

0.083

b0.001

b0.001

1.00, 0.53

0.204

0.001

0.015

0.70, 0.15

0.668

b0.001

b0.001

0.97, 0.29

Exercise Control Exercise Control

15 13 15 12

556 ± 100 593 ± 84 44 ± 20 47 ± 25

563 ± 97 584 ± 81 33 ± 16 32 ± 18

7 (−52, 66) −9 (−72, 54) −11 (−24, 2) −15 (−24, −3)

0.309

0.964

0.708

0.899

0.010

0.641

Exercise Control Exercise Control

19 13 19 14

50 51 37 42

53 52 41 44

3 (0, 6) 1 (−3, 5) 4 (2, 6) 2 (−1, 5)

0.971

0.081

0.378

0.135

0.002

0.335

Primary Leg press (peak watts) Bench press (peak watts)

Secondary Blood variables NT-proBNP (pg/mL)

CET VO2peak (mL/kg/min) PETCO2@AT (mmHg) PETO2@AT (mmHg) VE/VCO2@AT VE/VO2@AT

PA levels Inactivity time (min/day) MVPA (min/day)

HRQoL (SF-36) Mental component Physical component

± ± ± ±

± ± ± ±

224 223 88 120

10 10 8 6

± ± ± ±

± ± ± ±

10 8 8 7

1.00, 0.43

Data are mean ± SD. Significant P-values are in bold. Threshold P-value was set at 0.025 (=0.05/2) for primary end points and 0.004 (=0.05/13) for secondary end points. Abbreviations: 6MWD, 6-min walking distance; 5-STS, 5-repetition sit-to-stand; CET, cardiopulmonary exercise testing: HRQoL, health-related quality of life; MVPA, moderate-vigorous physical activity; NT-proBNP (pg/mL), N-terminal pro-B-type-natriuretic peptide; PETCO2@AT, end-tidal pressure of carbon dioxide at the anaerobic threshold; PETO2@AT, end-tidal pressure of oxygen at the anaerobic threshold; PImax, maximal inspiratory pressure; SF-36, Short Form-36 Item Health Survey; VE/VCO2@AT, ventilatory equivalent for carbon dioxide at the anaerobic threshold; VE/VO2@AT, ventilatory equivalent for oxygen at the anaerobic threshold; VO2peak, peak oxygen uptake. a Only reported for those significant interactions (group × time) effects. b A decrease in 5-STS performance time reflects an improvement performance.

training results in an attenuated cardiovascular stress response to any given load because the load now represents a lower percentage of the maximal voluntary contraction [45]. Further, we used a novel, practical approach to measure muscle power by studying the force–velocity curve which, besides avoiding performing maximal efforts and the Valsalva maneuver (as opposed to ‘classical’ 1RM weight lifting exercises), allows the measurement of muscle power. The latter variable is of practical applicability in patients' ADLs (e.g., standing from a chair, stair climbing vs. 1RM tests). This was indeed reflected by the significant training-induced improvement we found (P b 0.001 for the interaction effect) in the functional 5-STS test that evaluates the ability to stand from a chair. Our exercise intervention induced significant improvements in patients' VO2peak. While keeping in mind the limitation that baseline values of this variable were considerably higher in the control group versus the exercise group (~20 vs. ~16 mL O2/kg/min, respectively), aside from one recent RCT (reporting a main improvement of 3.3 mL O2/kg/min) [27], the main improvement we found in VO2peak (~ 3 mL O2/kg/min) after only 8 weeks of exercise is higher than that reported in previous controlled studies in PAH/CTEPH patients after longer training periods of

10 [24], 12 [3] or 15 weeks [7]. Further, the improvement in VO2peak found in the present study occurred in spite of the fact that the mean VO2peak of the exercise group at baseline was relatively high when compared with most previous studies in the field (where mean baseline VO2peak ≤ 13–14 mL O2/kg/min [3,7,23]). Thus, VO2peak can be effectively increased with supervised, appropriate training in PAH/CTPEH patients, including the less affected, fitter ones. Our findings on VO2peak are clinically relevant because this variable is an integrative variable that reflects (and is largely limited by) both central (cardiorespiratory) factors, specifically, maximal O2 supply to muscles (maximal cardiac pump/lung diffusing capacity as well as maximal ventilatory rate), and peripheral (skeletal muscle) factors, that is, maximal rate of O2 utilization, which in turn depends on muscle fiber capillarization and oxidative capacity [46]. Further, VO2peak is linearly associated with RV function [47,48], with both variables severely reduced in PAH patients, and RV dysfunction is a crucial factor in the exercise limitation and mortality associated with PAH [27]. Exercise-induced improvements in the VO2peak of these patients are partly attributable to an increase in both the capillary density and oxidative enzyme activity of skeletal muscle fibers [18]. Indeed, all the subjects undergoing DXA scans showed a post-training increase in VO2peak obtained

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Fig. 2. Peak value of average power attained during the concentric-propulsive phase in the bench press (Panel A) and leg press (Panel B) test relative to upper and lower-body muscle mass, respectively, in those subjects of the exercise group who underwent dual-energy Xray absorptiometry (DXA) scans. Panel C. Individual values of VO2peak (peak oxygen uptake) divided by lower-body muscle mass in those subjects of the exercise group who underwent dual-energy X-ray absorptiometry (DXA) scans.

during CET on a bicycle-ergometer as a function of lower-body muscle mass, suggesting an increased capacity to extract oxygen in recruited muscles (Fig. 2C). The limited exercise capacity of PAH patients is also partly attributable to weakness of respiratory muscles [49], independent from hemodynamic alterations [14] and reflects the ‘generalized myopathy’ associated with this disease [49]. Aside from one previous RCT focusing only on this type of training (with no inclusion of aerobic/resistance exercises) [50], ours is the first exercise RCT to use a threshold-loading device to apply specific inspiratory muscle training. This type of training was successful in improving PImax. Finally, although our program failed to induce a significant improvement in several secondary end points such as HRQoL, we found a trend towards a training-induced improvement in the SF-36 subscale ‘physical role’ (P = 0.049 for the interaction effect) and especially ‘vitality’ (P = 0.014), with the latter finding being in agreement with previous research [27]. The fact that the baseline values of our exercise group for those SF-36 subscales related to physical components were overall higher than those of previous controlled studies showing improvements in the HRQoL of PAH patients after an exercise intervention [7,24] might also explain, at least in part, a certain ‘ceiling effect’ for further improvements to occur in those patients with comparatively high functional capacity, as was the case for our subjects (mostly belonging to NYHA classes I/II). Some methodological limitations of our study should be noted, such as the fact that we did not assess exercise effects on hemodynamics. Also, the program failed to induce a significant improvement in several secondary end points including 6MWD. Nonetheless, we found a trend towards a training-induced improvement in 6MWD (P-value of 0.015 for the interaction effect) despite the fact that the aforementioned ‘ceiling effect’ may mask intervention efficacy in patients who, like ours, show good baseline scores in this test, that is, mean of ~500 m in the exercise group. This would explain why we found a smaller magnitude of improvement in 6MWD (mean difference between the two groups in post-intervention minus baseline values (‘Δ6MWD’) ~23 m) compared with previous exercise RCTs performed with patients with lower (by ~50–100 m) baseline 6MWD scores, in which Δ6MWD ranged between ~40 and 70 m [7,26, 27]. Importantly, however, the mean Δ6MWD value we obtained after only 8 weeks of exercise training is almost identical to the average value, 22.4 m, reported after a longer time period (12 weeks) for drug RCTs in PAH patients [51]. While the Δ6MWD for our trial is clearly below the Δ6MWD treshold for clinical events (=41.8 m), it should be considered that 6MWD per se is likely not adequate for use as a surrogate end point in PAH RCTs because Δ6MWD only explains a modest proportion of the actual treatment effect [51]. Strengths and novelties of our design are the integrative approach we used to assess the effects of the training program (including measurement of physiological, functional and biochemical outcomes, together with HRQoL), the use of specific inspiratory training together with the successful muscle resistance program, the novel, practical approach to measure peak muscle power, and the minimization of statistical error type I using stringent threshold Pvalues. In summary, a relatively short-duration (8-week) exercise intervention including aerobic and specific inspiratory muscle training combined with large muscle mass resistance training is safe for patients with PAH or inoperable CTEPH and induces significant improvements in muscle power (including during ADLs), as well as in PImax and VO2peak. The use of a ‘complete’ practical training approach (combinining aerobic, inspiratory muscle and resistance exercises) might explain why we obtained physiological gains after only 8 weeks that are overall in the range of those reported for longer interventions (N10 weeks) in patients with a poorer functional status [3,7,24,27]. Besides contributing to the current body of knowledge supporting the feasibility, safety and overall effectiveness of supervised exercise interventions in PAH/CTEPH patients, we believe a novel addition of our study with practical applicability is that weight lifting (‘power’) exercises performed against relatively high resistances could also be included in the training scheme of these patients, as well as in their overall medical management, similar to what has been

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reported for other cardiopulmonary disease populations. This assumes more importance when considering that these patients usually suffer from generalized muscle weakness. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2016.12.026. Author's contribution Conception and design: LGS, CFL, FSG, AFC, DMI, IA, AS, MM, PSA, AL; Analysis and interpretation: ASL, CQL, AFC, DMI, IA, AS, MM, PSA, AL; Drafting the manuscript for important intellectual content: FSG, PES, AL. Conflict of interest statement None of the authors have any conflict of interest. Acknowledgements We acknowledge POWERbreathe International Ltd., through BIOCORP EUROPA S.L./POWERbreathe Spain, for the kind support with equipment for inspiratory muscle training. This study was funded by a grant from Cátedra Real Madrid-Universidad Europea (Grant number P2015/05RM), and L.G.S. was supported by a research training scholarship from GSK to conduct the study. The Research by AL and MM is funded by the Fondo de Investigaciones Sanitarias and Fondos Feder (grants # PI1500558 and PI14/01085). Carmen Fiuza-Luces holds a postdoctoral Sara Borrell contract (file number CD14/00005). Fabian Sanchis-Gomar is supported by a post-doctoral contract granted by Conselleria de Educación, Investigación, Cultura y Deporte de la Generalitat Valenciana (APOSTD/2016/140). We thank Dr. Kenneth McCreath for editorial support. References [1] A.B. Waxman, R.T. Zamanian, Pulmonary arterial hypertension: new insights into the optimal role of current and emerging prostacyclin therapies, Am. J. Cardiol. 111 (2013) 1A–16A (quiz 17A–19A). [2] L.A. Matura, A. McDonough, D.L. Carroll, Cluster analysis of symptoms in pulmonary arterial hypertension: a pilot study, Eur. J. Cardiovasc. Nurs. 11 (2012) 51–61. [3] B.D. Fox, M. Kassirer, I. Weiss, et al., Ambulatory rehabilitation improves exercise capacity in patients with pulmonary hypertension, J. Card. Fail. 17 (2011) 196–200. [4] E. Grunig, N. Ehlken, A. Ghofrani, et al., Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension, Respiration 81 (2011) 394–401. [5] E. Grunig, M. Lichtblau, N. Ehlken, et al., Safety and efficacy of exercise training in various forms of pulmonary hypertension, Eur. Respir. J. 40 (2012) 84–92. [6] E. Grunig, F. Maier, N. Ehlken, et al., Exercise training in pulmonary arterial hypertension associated with connective tissue diseases, Arthritis Res. Ther. 14 (R148) (2012). [7] D. Mereles, N. Ehlken, S. Kreuscher, et al., Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension, Circulation 114 (2006) 1482–1489. [8] S. Dimopoulos, G. Tzanis, C. Manetos, et al., Peripheral muscle microcirculatory alterations in patients with pulmonary arterial hypertension: a pilot study, Respir. Care 58 (2013) 2134–2141. [9] J. Tolle, A. Waxman, D. Systrom, Impaired systemic oxygen extraction at maximum exercise in pulmonary hypertension, Med. Sci. Sports Exerc. 40 (2008) 3–8. [10] A.M. Marra, M. Arcopinto, E. Bossone, et al., Pulmonary arterial hypertension-related myopathy: an overview of current data and future perspectives, Nutr. Metab. Cardiovasc. Dis. 25 (2015) 131–139. [11] V. Mainguy, F. Maltais, D. Saey, et al., Peripheral muscle dysfunction in idiopathic pulmonary arterial hypertension, Thorax 65 (2010) 113–117. [12] J. Batt, S.S. Ahmed, J. Correa, A. Bain, J. Granton, Skeletal muscle dysfunction in idiopathic pulmonary arterial hypertension, Am. J. Respir. Cell Mol. Biol. 50 (2014) 74–86. [13] A.P. Breda, A.L. Pereira de Albuquerque, C. Jardim, et al., Skeletal muscle abnormalities in pulmonary arterial hypertension, PLoS One 9 (2014), e114101. [14] F.J. Meyer, D. Lossnitzer, A.V. Kristen, et al., Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension, Eur. Respir. J. 25 (2005) 125–130. [15] J. Pepke-Zaba, M. Delcroix, I. Lang, et al., Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry, Circulation 124 (2011) 1973–1981. [16] N. Galie, M. Humbert, J.L. Vachiery, et al., 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT), Eur. Heart J. 37 (2016) 67–119. [17] K.S. Chia, P.K. Wong, S. Faux, C.S. McLachlan, E. Kotlyar, The benefit of exercise training in pulmonary hypertension: a clinical review, Intern. Med. J. (2016), http://dx.doi. org/10.1111/imj.13159.

283

[18] F.S. de Man, M.L. Handoko, H. Groepenhoff, et al., Effects of exercise training in patients with idiopathic pulmonary arterial hypertension, Eur. Respir. J. 34 (2009) 669–675. [19] V. Mainguy, F. Maltais, D. Saey, et al., Effects of a rehabilitation program on skeletal muscle function in idiopathic pulmonary arterial hypertension, J. Cardiopulm. Rehabil. Prev. 30 (2010) 319–323. [20] T. Becker-Grunig, H. Klose, N. Ehlken, et al., Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease, Int. J. Cardiol. 168 (2013) 375–381. [21] R. Buys, A. Avila, V.A. Cornelissen, Exercise training improves physical fitness in patients with pulmonary arterial hypertension: a systematic review and meta-analysis of controlled trials, BMC Pulm. Med. 15 (40) (2015). [22] E. Martinez-Quintana, G. Miranda-Calderin, A. Ugarte-Lopetegui, F. RodriguezGonzalez, Rehabilitation program in adult congenital heart disease patients with pulmonary hypertension, Congenit. Heart Dis. 5 (2010) 44–50. [23] S. Ley, C. Fink, F. Risse, et al., Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension, Eur. Radiol. 23 (2013) 324–331. [24] L. Chan, L.M. Chin, M. Kennedy, et al., Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension, Chest 143 (2012) 333–343. [25] A. Pandey, S. Garg, M. Khunger, et al., Efficacy and safety of exercise training in chronic pulmonary hypertension: systematic review and meta-analysis, Circ. Heart Fail. 8 (2015) 1032–1043. [26] A.A. Weinstein, L.M. Chin, R.E. Keyser, et al., Effect of aerobic exercise training on fatigue and physical activity in patients with pulmonary arterial hypertension, Respir. Med. 107 (2013) 778–784. [27] N. Ehlken, M. Lichtblau, H. Klose, et al., Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial, Eur. Heart J. 37 (2016) 35–44. [28] D. Moher, S. Hopewell, K.F. Schulz, et al., CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials, Int. J. Surg. 10 (2012) 28–55. [29] J.B.P.R. Ferreira, C. Stein, K.R. Casali, R. Arena, P.D. Lago, Inspiratory muscle training reduces blood pressure and sympathetic activity in hypertensive patients: a randomized controlled tria, Int. J. Cardiol. 166 (2013) 61–67. [30] E. Santana Sosa, I.F. Groeneveld, L. Gonzalez-Saiz, et al., Intrahospital weight and aerobic training in children with cystic fibrosis: a randomized controlled trial, Med. Sci. Sports Exerc. 44 (2012) 2–11. [31] A. Santalla, D. Munguia-Izquierdo, L. Brea-Alejo, et al., Feasibility of resistance training in adult McArdle patients: clinical outcomes and muscle strength and mass benefits, Front. Aging Neurosci. 6 (2015) 334. [32] A. Lucia, J. Hoyos, M. Perez, J.L. Chicharro, Heart rate and performance parameters in elite cyclists: a longitudinal study, Med. Sci. Sports Exerc. 32 (2000) 1777–1782. [33] G.H. Guyatt, S.O. Pugsley, M.J. Sullivan, et al., Effect of encouragement on walking test performance, Thorax 39 (1984) 818–822. [34] S.E. Jones, S.S. Kon, J.L. Canavan, et al., The five-repetition sit-to-stand test as a functional outcome measure in COPD, Thorax 68 (2013) 1015–1020. [35] Standardization of spirometry–1987 update. Official statement of American Thoracic Society. Respir Care 1987;32:1039–1060 [36] L. Nici, C. Donner, E. Wouters, et al., American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation, Am. J. Respir. Crit. Care Med. 173 (2006) 1390–1413. [37] J. Alonso, E. Regidor, G. Barrio, et al., Population reference values of the Spanish version of the health questionnaire SF-36, Med. Clin. (Barc.) 111 (1998) 410–416. [38] G. Vilagut, J.M. Valderas, M. Ferrer, et al., Interpretation of SF-36 and SF-12 questionnaires in Spain: physical and mental components, Med. Clin. (Barc.) 130 (2008) 726–735. [39] J.E. Ware Jr., C.D. Sherbourne, The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection, Med. Care 30 (1992) 473–483. [40] A. Ruiz-Casado, A.S. Verdugo, M.J. Solano, et al., Objectively assessed physical activity levels in Spanish cancer survivors, Oncol. Nurs. Forum 41 (2014) E12–E20. [41] P.S. Freedson, E. Melanson, J. Sirard, Calibration of the Computer Science and Applications, Inc. accelerometer, Med. Sci. Sports Exerc. 30 (1998) 777–781. [42] C.A. Quezada-Loaiza, A. Flox-Camacho, A. Santos-Lozano, et al., Predictive value of NT-proBNP combined with exercise capacity variables in pulmonary artery disease: insights from a Spanish cohort, Int. J. Cardiol. 186 (2015) 32–34. [43] C.E. Garber, B. Blissmer, M.R. Deschenes, et al., American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise, Med. Sci. Sports Exerc. 43 (2011) 1334–1359. [44] C. Foster, K. Cadwell, B. Crenshaw, et al., Physical activity and exercise training prescriptions for patients, Cardiol. Clin. 19 (2001) 447–457. [45] N. McCartney, R.S. McKelvie, J. Martin, D.G. Sale, J.D. MacDougall, Weight-traininginduced attenuation of the circulatory response of older males to weight lifting, J. Appl. Physiol. 74 (1985) (1993) 1056–1060. [46] D.R. Bassett Jr., E.T. Howley, Limiting factors for maximum oxygen uptake and determinants of endurance performance, Med. Sci. Sports Exerc. 32 (2000) 70–84. [47] G.D. Lewis, E. Bossone, R. Naeije, et al., Pulmonary vascular hemodynamic response to exercise in cardiopulmonary diseases, Circulation 128 (2013) 1470–1479. [48] P. Argiento, R.R. Vanderpool, M. Mule, et al., Exercise stress echocardiography of the pulmonary circulation: limits of normal and sex differences, Chest 142 (2012) 1158–1165. [49] R. Bauer, C. Dehnert, P. Schoene, et al., Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension, Respir. Med. 101 (2007) 2366–2369. [50] M. Saglam, H. Arikan, N. Vardar-Yagli, et al., Inspiratory muscle training in pulmonary arterial hypertension, J. Cardiopulm. Rehabil. Prev. 35 (2015) 198–206. [51] N.B. Gabler, B. French, B.L. Strom, et al., Validation of 6-minute walk distance as a surrogate endpoint in pulmonary arterial hypertension trials, Circulation 126 (2012) 349–356.