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Heart, Lung and Circulation

Effects of Exercise Training on Exercise Capacity in Pulmonary Arterial Hypertension: A Systematic Review of Clinical Trials

Published:November 17, 2015DOI:https://doi.org/10.1016/j.hlc.2015.10.015

      Background

      Pulmonary arterial hypertension (PAH) causes profound functional limitations and poor quality of life. Yet, there is only a limited literature available on the role of exercise training. This paper systematically reviews the effects of exercise training on exercise capacity in PAH.

      Methods

      A systematic search of databases (PubMed, CINAHL, CENTRAL, Web of Science and PEDRo) was undertaken for English language articles published between 1st January 1980 and 31st March 2015. Quality rating for all articles was done using the Downs and Black scoring system.

      Results

      Fifteen articles of good (n=4), moderate (n=6) and poor (n=5) quality were included in the review. Exercise interventions included aerobic, resistance, inspiratory muscle training or a combination, for 6-18 weeks. Improvements were seen in exercise capacity (six minute walk distance (6MWD) and peak VO2) by 17-96m and 1.1-2.1 ml/Kg/min, functional class by one class and quality of life, with minimal adverse events.

      Conclusions

      There is evidence to recommend the use of exercise training as an adjunct to medical treatment in PAH. More clinical trials and research are required to assess the effects of different types of exercise programs in patients with PAH, while focussing on strong exercise endpoints to quantify the improvements seen with exercise training.

      Keywords

      Introduction

      Pulmonary arterial hypertension (PAH) is a disease with high morbidity and mortality [
      • McGoon M.D.
      • Benza R.L.
      • Escribano-Subias P.
      • Jiang X.
      • Miller D.P.
      • Peacock A.J.
      • et al.
      Pulmonary arterial hypertension: epidemiology and registries.
      ]. Intolerance to exercise in PAH is a main finding and is the result of dysfunctions in the cardiovascular (viz., reduced cardiac output due to high pulmonary pressures and septal deviations), pulmonary (viz., ventilation-perfusion abnormalities) and musculoskeletal systems (viz., altered muscle fibre properties, peripheral oxygen extraction dysfunction and respiratory muscle dysfunctions) [
      • Arena R.
      • Lavie C.J.
      • Milani R.V.
      • Myers J.
      • Guazzi M.
      Cardiopulmonary exercise testing in patients with pulmonary arterial hypertension: an evidence-based review.
      ,
      • Arena R.
      • Guazzi M.
      • Myers J.
      • Grinnen D.
      • Forman D.E.
      • Lavie C.J.
      Cardiopulmonary exercise testing in the assessment of pulmonary hypertension.
      ,
      • Babu A.S.
      • Myers J.
      • Arena R.
      • Maiya A.G.
      • Padmakumar R.
      Evaluating exercise capacity in patients with pulmonary arterial hypertension.
      ,
      • Arena R.
      Exercise testing and training in chronic lung disease and pulmonary arterial hypertension.
      ,
      • Sun X.G.
      • Hansen J.E.
      • Oudiz R.J.
      • Wasserman K.
      Exercise pathophysiology in patients with primary pulmonary hypertension.
      ,
      • Tolle J.
      • Waxman A.
      • Systrom D.
      Impaired systemic oxygen extraction at maximum exercise in pulmonary hypertension.
      ,
      • Meyer F.J.
      • Lossnitzer D.
      • Kristen A.V.
      • Schoene A.M.
      • Kubler W.
      • Katus H.A.
      • et al.
      Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension.
      ]. Thus, it can be inferred that exercise training targeting the cardiopulmonary and musculoskeletal systems may prove to be beneficial for patients with PAH.
      Over the last few years, there has been a growth in literature on exercise training in PAH – both in terms of published literature [
      • Desai S.A.
      • Channick R.N.
      Exercise in patients with pulmonary arterial hypertension.
      ,
      • Hassan A.
      • Alison J.
      • Redfern J.
      Exercise in pulmonary hypertension.
      ,
      • Zafrir B.
      Exercise training and rehabilitation in pulmonary arterial hypertension: rationale and current data evaluation.
      ,
      • Arena R.
      • Cahalin L.P.
      • Borghi-Silva A.
      • Myers J.
      The Effect of Exercise Training on the Pulmonary Arterial System in Patients with Pulmonary Hypertension.
      ,
      • Yuan P.
      • Yuan X.T.
      • Sun X.Y.
      • Pudasaini B.
      • Liu J.M.
      • Hu Q.H.
      Exercise training for pulmonary hypertension: a systematic review and meta-analysis.
      ] and on-going studies [
      • Babu A.S.
      • Padmakumar R.
      • Maiya A.G.
      On-going trials in exercise based rehabilitation for pulmonary artery hypertension.
      ] registered in various clinical trial registries around the world. However, there is a lack of systematic reviews in this area specifically assessing the effects of exercise training on exercise capacity in PAH. Therefore, the aim of this review is to update the available evidence by systematically reviewing the current literature available in the area of exercise training for adults with PH and to summarise the changes that occur with exercise training on exercise capacity and other functional outcomes.

      Material and Methods

      Search Strategy

      A systematic search from 1st January 1980 to 31st March 2015, of PubMed, CENTRAL (Cochrane database for randomised controlled trials), CINAHL (Cumulative Index to Nursing and Allied Health), Web of Science and PEDRo was carried out using various search terms. Medical subject headings (MeSH) terms for pulmonary hypertension, exercise training, resistance training and breathing exercise, along with various terms like rehabilitation, respiratory muscle training, physiotherapy and functional training with Boolean terms like OR and AND. Search strategies were modified for each database to achieve the broadest search. Details of the search strategy are available in the online supplement. The review protocol was registered in the PROSPERO (PROSPERO 2011:CRD42011001238).

      Inclusion and Exclusion Criteria

      All clinical trials utilising exercise training (aerobic, resistance, inspiratory muscle training or combinations of these) as an intervention for patients with PAH delivered through any setting (i.e., hospital, home, community or a combination of them), in the English language were included. Pulmonary arterial hypertension secondary to lung disease and studies assessing only single response to exercise, exercise testing studies and reviews were excluded from this study. A summary of the selection of articles has been reported as per the PRISMA guidelines (Figure 1) [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

      Quality Assessment

      The quality of studies was assessed using the Downs and Black Quality Index (QI) which is rated among the top 14 tools to assess the quality of studies for both randomised and non-randomised trials.[
      • Downs S.H.
      • Black N.
      The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.
      ,
      • Deeks J.J.
      • Dinnes J.
      • D’Amico R.
      • Sowden A.J.
      • Sakarovitch C.
      • Song F.
      • et al.
      Evaluating non-randomised intervention studies.
      ] The scale has five sub-domains which include reporting, external validity, bias, confounding and power being scored out of 11, 3, 7, 6 and 5 respectively. The total score obtained is scored out of 32. The studies were rated as excellent, good, moderate and poor based on the percentage of the total score achieved viz., >95% (>30), 75-95% (24-29), 55-74% (18-23) and <55% (<18).

      Data Extraction

      Data was extracted from the included articles using a data extraction form that included information on the publication (i.e., journal, country, type of article). Details on training interventions were then collected with respect to the FITT principle (frequency, intensity, type and time). Effects of the training on outcomes like exercise capacity (i.e., six minute walk distance (6MWD), peak oxygen consumption (peakVO2)), quality of life scores, functional class, survival, safety and cost-effectiveness were collected. All the included articles had data extracted by the primary author (ASB), with further assistance from AGM and RP as required. Authors of the included articles were contacted if further information was required. In the case of discrepancy during the data extraction, AKM/RLK acted as arbitrators. Data was collected and the number of patients were pooled together. No meta-analysis was performed due to heterogeneity in data and has been discussed under the limitations of this paper.

      Results

      The literature search resulted in a total of 4402 studies from which a total of 15 articles were finally included in the review [
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • Ghofrani S.
      • Hoeper M.M.
      • Halank M.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      ,
      • Shoemaker M.J.
      • Wilt J.L.
      • Dasgupta R.
      • Oudiz R.J.
      Exercise training in patients with pulmonary arterial hypertension: a case report.
      ,
      • de Man F.S.
      • Handoko M.L.
      • Groepenhoff H.
      • van’t Hul A.J.
      • Abbink J.
      • Koppers R.J.
      • et al.
      Effects of exercise training in patients with idiopathic pulmonary arterial hypertension.
      ,
      • Martinez-Quintana E.
      • Miranda-Calderin G.
      • Ugarte-Lopetegui A.
      • Rodriguez-Gonzalez F.
      Rehabilitation program in adult congenital heart disease patients with pulmonary hypertension.
      ,
      • Mainguy V.
      • Maltais F.
      • Saey D.
      • Gagnon P.
      • Martel S.
      • Simon M.
      • et al.
      Effects of a rehabilitation program on skeletal muscle function in idiopathic pulmonary arterial hypertension.
      ,
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ,
      • Fox B.D.
      • Kassirer M.
      • Weiss I.
      • Raviv Y.
      • Peled N.
      • Shitrit D.
      • et al.
      Ambulatory rehabilitation improves exercise capacity in patients with pulmonary hypertension.
      ,
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ,
      • Grunig E.
      • Lichtblau M.
      • Ehlken N.
      • Ghofrani H.A.
      • Reichenberger F.
      • Staehler G.
      • et al.
      Safety and efficacy of exercise training in various forms of pulmonary hypertension.
      ,
      • Nagel C.
      • Prange F.
      • Guth S.
      • Herb J.
      • Ehlken N.
      • Fischer C.
      • et al.
      Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension.
      ,
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ,
      • Weinstein A.A.
      • Chin L.M.
      • Keyser R.E.
      • Kennedy M.
      • Nathan S.D.
      • Woolstenhulme J.G.
      • et al.
      Effect of aerobic exercise training on fatigue and physical activity in patients with pulmonary arterial hypertension.
      ,
      • Chan L.
      • Chin L.M.
      • Kennedy M.
      • Woolstenhulme J.G.
      • Nathan S.D.
      • Weinstein A.A.
      • et al.
      Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension.
      ,
      • Ley S.
      • Fink C.
      • Risse F.
      • Ehlken N.
      • Fischer C.
      • Ley-Zaporozhan J.
      • et al.
      Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension.
      ,
      • Kabitz H.J.
      • Bremer H.C.
      • Schwoerer A.
      • Sonntag F.
      • Walterspacher S.
      • Walker D.J.
      • et al.
      The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension.
      ]. Of these 15, four were randomised controlled trials, eight were non-randomised clinical trials (i.e., single group pre-post design) and three were case reports or case series. A summary of the included studies has been summarised in Table 1. The quality of 15 studies included was of moderate (n=6) to good (n=4) quality (Table 2). Most studies (7/15) lacked in components related to external validity, despite the majority (13/15) scoring > 8/11 for reporting – irrespective of study design.
      Table 1Summary of articles included in the review (n=15)
      Author

      (year)
      NumberDesignNYHA grade at enrolmentPH cause (n)Intervention (Intensity)DurationOutcome measuresResults
      Mereles et al. (2006)30RCTII – IVCTEPH (6),

      PAH (24)
      Exercise + respiratory muscle training3 weeks – institution-based and 12 weeks – home-based6MWD



      SF36
      85m increase after 3 weeks and 96m after 15 weeks (p<0.001)



      Improved QoL in physical function and vitality (p<0.005)
      Shoemaker et al. (2009)2Case reportiPH and PAH due to sclerodermaCycle ergometry (50% peak workload)6 weeks – institution-based, 3 days/weekpeak VO2



      CAMPHOR

      SF36
      4% and 14% increase



      Improved
      deMan et al. (2009)19Pre-postII – IIIiPHCycling and quadriceps muscle training while maintaining SpO2>85% and HR <120 bpm12 weeks – institution-based6MWD



      Workload at AT



      Quadriceps endurance and strength
      4% increase (p=0.13)



      Increase in workload of AT from 32 to 46 Watt; (p=0.003)



      13% and 34% increase (p<0.05)
      Martinez-Quintana et al. (2010)8Non-randomised controlled trialII – IIICongenital heart diseaseInterval training on bicycle and resistance training2 days a week for 12 weeks – institution-based6MWD

      SF12
      No significant change in 6MWD and QoL
      Mainguy et al. (2010)5Case seriesII – IIIiPHAerobic and resisted exercises

      (60% max workload and 70% MVC)
      12 weeks – institution based6MWD58m improvement (p=0.01)

      Fox et al. (2011)22Non-randomised controlled trialII – IIIiPH and CTEPHAerobic and resisted exercises + stair climbing

      (60-80% HRmax)
      12 weeks – institution- and home-based6MWD

      peak VO2
      32m and 1.1ml/Kg/min improvement (p<0.05)
      Grunig et al. (2011)58Pre-post

      II – IViPHAerobic and resistance training + respiratory muscle training3 weeks – institution-based and 12 weeks – home-based6MWD

      peak VO2



      SF36
      87m and 2.1ml/Kg/min improvement (p<0.001)



      Improvement in all domains of SF36 (p<0.05)
      Grunig et al.

      (2012)
      183Pre-postII – IVPAH, CTEPH, PH due to lung and heart diseaseExercise + respiratory muscle training3 weeks – institution-based and 12 weeks – home-based6MWD



      SF36
      68m increase after 3 weeks and 78m after 15 weeks (p<0.001)



      Improved QoL (p<0.05)
      Grunig et al. (2012)21Pre-postII – IVPAH due to CTDExercise + respiratory muscle training3 weeks – institution-based and 12 weeks – home-based6MWD



      SF36
      67m increase after 3 weeks and by 71m after 15 weeks (p<0.05)



      Improved QoL (p<0.05)
      Nagel et al. (2012)35Pre-postII – IVCTEPHExercise + respiratory muscle training3 weeks – institution-based and 12 weeks – home-based6MWD



      peak VO2



      SF36



      NT-proBNP



      Survival
      61m increase after 3 weeks and 71m after 15 weeks



      1.9ml/Kg/min after 15 weeks



      Improved QoL (p<0.05)



      >20% reduction at 3 weeks



      1,2 and 3year survival rates of 97%, 94% and 86%
      Chan et al. (2013)23RCTI-IVPAHEducation versus exercise training10 weeks6MWD



      SF36

      CAMPHOR
      56m increase with exercise training (p=0.002)



      Improvements in both QoL measurements (p<0.05)
      Becker-Grunig et al. (2013)20Pre-postII – IVPAH due to CHDExercise + respiratory muscle training3 weeks – institution-based and 12 weeks – home-based6MWD



      peakVO2



      SF36



      Survival
      63m increase after 3 weeks and 67m increase after 15 weeks (p<0.001)

      Increased from 8.3L/min to 9.02 and 9.25L/min at 3 and 15 weeks respectively



      Significant improvement only in bodily pain



      100% survival at years 1 and 2. Transplantation free survival 100% and 93% at years 1 and 2
      Ley et al.

      (2013)
      20RCTII-IIIPAH, CTD, CTEPH, Portal hypertensionExercise + respiratory muscle training3 weeks6MWD

      91m improvement in the experimental group (p=0.008)
      Weinsten et al. (2013)24RCTI-IVPAH, CTDEducation versus exercise training10 weeks6MWD



      Fatigue
      53m increase (p=0.003) with exercise training



      Improved
      Kabitz et al. (2014)7Case seriesIII-IVPAH3 weeks – institution-based and 12 weeks – home-based6MWD



      Respiratory muscle strength



      92m increase after 3 weeks and 81m increase after 15 weeks (p<0.001)



      Improved PImax by 1 kPa (p=0.086), PEmax by 2.3 kPa (p=0.021), SnPna by 1.3 kPa (p=0.025) at 15 weeks
      6MWD – Six minute walk distance, 6MWT – Six minute walk test, CHD – Congenital heart disease, CTD – connective tissue disorder, CTEPH – Chronic thromboembolic pulmonary hypertension, HR – Heart rate, HRmax – Maximum heart rate, iPH – Idiopathic pulmonary hypertension, MVC – maximal voluntary contraction, NR – Not reported, PAH – Pulmonary artery hypertension, PEmax – Peak expiratory pressure, PImax – Peak inspiratory pressure, QoL – Quality of life, SF36 – Medical outcomes survey short form 36, SF12 – Medical outcomes survey short form 12, SnPna – Sniff nasal pressure, SpO2 – Oxygen saturation, peak VO2 – Peak oxygen consumption.
      Table 2Summary of quality of studies included in the review
      Author

      (year)
      Reporting (11)External validity (3)Bias

      (7)
      Confounding (6)Power

      (5)
      TOTAL

      (32)
      Quality as per cut-off described
      >34: Excellent, 24-34: Good, 18-23: Moderate, <18: Poor.
      Randomised controlled trials
      Mereles D et al., (2006)10055529Good
      Chan et al. (2013)10155526Good
      Ley et al.

      (2013)
      10144524Good
      Weinsten et al. (2013)10144524Good
      Non-randomised controlled trials
      deMan et al. (2009)10254527Good
      Shoemaker et al. (2009)
      Case series/ case reports.
      8230013Poor
      Mainguy et al. (2010)
      Case series/ case reports.
      8222014Poor
      Martinez-Quintana E et al. (2010)612009Poor
      Fox BD et al. (2011)9231520Moderate
      Grunig E et al.

      (2011)
      9043521Moderate
      Grunig E et al.

      (2012)
      9043521Moderate
      Nagel et al.

      (2012)
      9043521Moderate
      Grunig et al.

      (2012)
      9043521Moderate
      Becker-Grunig et al. (2013)9043521Moderate
      Kabitz et al. (2014)
      Case series/ case reports.
      9022013Poor
      * >34: Excellent, 24-34: Good, 18-23: Moderate, <18: Poor.
      ** Case series/ case reports.
      Most studies utilised a combination of aerobic and resistance training protocols. Eight [
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • Ghofrani S.
      • Hoeper M.M.
      • Halank M.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ,
      • Grunig E.
      • Lichtblau M.
      • Ehlken N.
      • Ghofrani H.A.
      • Reichenberger F.
      • Staehler G.
      • et al.
      Safety and efficacy of exercise training in various forms of pulmonary hypertension.
      ,
      • Nagel C.
      • Prange F.
      • Guth S.
      • Herb J.
      • Ehlken N.
      • Fischer C.
      • et al.
      Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension.
      ,
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ,
      • Ley S.
      • Fink C.
      • Risse F.
      • Ehlken N.
      • Fischer C.
      • Ley-Zaporozhan J.
      • et al.
      Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension.
      ,
      • Kabitz H.J.
      • Bremer H.C.
      • Schwoerer A.
      • Sonntag F.
      • Walterspacher S.
      • Walker D.J.
      • et al.
      The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension.
      ] of the 15 studies used a combination of supervised (three weeks) and home-based (12 weeks) training programs which included Interval bicycle ergometry (60-80% VO2peak; 5 days/week), Walking (level ground and uphill), Strength training (0.5-1.0Kg; 5 days/week), Respiratory muscle training and yoga during the first three weeks followed by Bicycle training (close to target heart rate;30 minutes), Strength training (15-30 minutes; alternate days) and Respiratory training for the remaining 12 weeks. Other studies that made use of cycle ergometry guided the intensity either by percentage of peak/maximal workload [
      • Shoemaker M.J.
      • Wilt J.L.
      • Dasgupta R.
      • Oudiz R.J.
      Exercise training in patients with pulmonary arterial hypertension: a case report.
      ,
      • Mainguy V.
      • Maltais F.
      • Saey D.
      • Gagnon P.
      • Martel S.
      • Simon M.
      • et al.
      Effects of a rehabilitation program on skeletal muscle function in idiopathic pulmonary arterial hypertension.
      ], percentage of VO2max [
      • de Man F.S.
      • Handoko M.L.
      • Groepenhoff H.
      • van’t Hul A.J.
      • Abbink J.
      • Koppers R.J.
      • et al.
      Effects of exercise training in patients with idiopathic pulmonary arterial hypertension.
      ] or HRmax [
      • Fox B.D.
      • Kassirer M.
      • Weiss I.
      • Raviv Y.
      • Peled N.
      • Shitrit D.
      • et al.
      Ambulatory rehabilitation improves exercise capacity in patients with pulmonary hypertension.
      ]. Strength and endurance training to improve lower limb strength was exclusively used in only one study [
      • de Man F.S.
      • Handoko M.L.
      • Groepenhoff H.
      • van’t Hul A.J.
      • Abbink J.
      • Koppers R.J.
      • et al.
      Effects of exercise training in patients with idiopathic pulmonary arterial hypertension.
      ]. Exercise prescription followed the principle of percentages of one repetition maximum (RM) ranging from 50-75% for strength and 30-40% for endurance. All these programs, whether delivered in-hospital during admission or in an out-patient department, were supervised.

      Effects of Exercise Training on Exercise Capacity

      A total number of 482 patients (male and female) belonging to the various groups of PH were included from the various studies. Patients were enrolled into an exercise program ranging from 6-15 weeks. Exercise programs included aerobic training, respiratory muscle training, resistance training and combinations of them through either a direct program or combined institutional and home based delivery models.[
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • Ghofrani S.
      • Hoeper M.M.
      • Halank M.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      ,
      • Shoemaker M.J.
      • Wilt J.L.
      • Dasgupta R.
      • Oudiz R.J.
      Exercise training in patients with pulmonary arterial hypertension: a case report.
      ,
      • de Man F.S.
      • Handoko M.L.
      • Groepenhoff H.
      • van’t Hul A.J.
      • Abbink J.
      • Koppers R.J.
      • et al.
      Effects of exercise training in patients with idiopathic pulmonary arterial hypertension.
      ,
      • Martinez-Quintana E.
      • Miranda-Calderin G.
      • Ugarte-Lopetegui A.
      • Rodriguez-Gonzalez F.
      Rehabilitation program in adult congenital heart disease patients with pulmonary hypertension.
      ,
      • Mainguy V.
      • Maltais F.
      • Saey D.
      • Gagnon P.
      • Martel S.
      • Simon M.
      • et al.
      Effects of a rehabilitation program on skeletal muscle function in idiopathic pulmonary arterial hypertension.
      ,
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ,
      • Fox B.D.
      • Kassirer M.
      • Weiss I.
      • Raviv Y.
      • Peled N.
      • Shitrit D.
      • et al.
      Ambulatory rehabilitation improves exercise capacity in patients with pulmonary hypertension.
      ,
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ,
      • Grunig E.
      • Lichtblau M.
      • Ehlken N.
      • Ghofrani H.A.
      • Reichenberger F.
      • Staehler G.
      • et al.
      Safety and efficacy of exercise training in various forms of pulmonary hypertension.
      ,
      • Nagel C.
      • Prange F.
      • Guth S.
      • Herb J.
      • Ehlken N.
      • Fischer C.
      • et al.
      Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension.
      ,
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ,
      • Weinstein A.A.
      • Chin L.M.
      • Keyser R.E.
      • Kennedy M.
      • Nathan S.D.
      • Woolstenhulme J.G.
      • et al.
      Effect of aerobic exercise training on fatigue and physical activity in patients with pulmonary arterial hypertension.
      ,
      • Chan L.
      • Chin L.M.
      • Kennedy M.
      • Woolstenhulme J.G.
      • Nathan S.D.
      • Weinstein A.A.
      • et al.
      Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension.
      ,
      • Ley S.
      • Fink C.
      • Risse F.
      • Ehlken N.
      • Fischer C.
      • Ley-Zaporozhan J.
      • et al.
      Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension.
      ,
      • Kabitz H.J.
      • Bremer H.C.
      • Schwoerer A.
      • Sonntag F.
      • Walterspacher S.
      • Walker D.J.
      • et al.
      The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension.
      ] The intensity of exercises given, ranged from 50-80% VO2max.
      The improvements seen in 6MWD ranged from 17m to 96m. These changes were also reflected by improvements in peak VO2 (1.1 ml/Kg/min to 2.1 ml/Kg/min). In addition, improvements were also seen in other exercise testing variables like ventilatory efficiency, PETCO2 and VO2 at VT following exercise training.

      Effects of Exercise Training on Functional Class, QoL, Survival, Safety and Cost-effectiveness

      Patients with WHO-FC II-IV were part of the patient profile. Following exercise training, there was an average improvement by one functional class in a few studies [
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • Ghofrani S.
      • Hoeper M.M.
      • Halank M.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Lichtblau M.
      • Ehlken N.
      • Ghofrani H.A.
      • Reichenberger F.
      • Staehler G.
      • et al.
      Safety and efficacy of exercise training in various forms of pulmonary hypertension.
      ]. However, other studies did observe similar changes, though they were statistically not significant [
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ,
      • Nagel C.
      • Prange F.
      • Guth S.
      • Herb J.
      • Ehlken N.
      • Fischer C.
      • et al.
      Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension.
      ,
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ].
      Three separate measures to evaluate QoL were seen viz., Medical Outcomes Survey short form (SF36) in seven studies [
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • Ghofrani S.
      • Hoeper M.M.
      • Halank M.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ,
      • Grunig E.
      • Lichtblau M.
      • Ehlken N.
      • Ghofrani H.A.
      • Reichenberger F.
      • Staehler G.
      • et al.
      Safety and efficacy of exercise training in various forms of pulmonary hypertension.
      ,
      • Nagel C.
      • Prange F.
      • Guth S.
      • Herb J.
      • Ehlken N.
      • Fischer C.
      • et al.
      Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension.
      ,
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ,
      • Weinstein A.A.
      • Chin L.M.
      • Keyser R.E.
      • Kennedy M.
      • Nathan S.D.
      • Woolstenhulme J.G.
      • et al.
      Effect of aerobic exercise training on fatigue and physical activity in patients with pulmonary arterial hypertension.
      ,
      • Chan L.
      • Chin L.M.
      • Kennedy M.
      • Woolstenhulme J.G.
      • Nathan S.D.
      • Weinstein A.A.
      • et al.
      Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension.
      ,
      • Ley S.
      • Fink C.
      • Risse F.
      • Ehlken N.
      • Fischer C.
      • Ley-Zaporozhan J.
      • et al.
      Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension.
      ,
      • Kabitz H.J.
      • Bremer H.C.
      • Schwoerer A.
      • Sonntag F.
      • Walterspacher S.
      • Walker D.J.
      • et al.
      The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension.
      ] and SF12 [
      • Martinez-Quintana E.
      • Miranda-Calderin G.
      • Ugarte-Lopetegui A.
      • Rodriguez-Gonzalez F.
      Rehabilitation program in adult congenital heart disease patients with pulmonary hypertension.
      ] and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) [
      • Shoemaker M.J.
      • Wilt J.L.
      • Dasgupta R.
      • Oudiz R.J.
      Exercise training in patients with pulmonary arterial hypertension: a case report.
      ,
      • Chan L.
      • Chin L.M.
      • Kennedy M.
      • Woolstenhulme J.G.
      • Nathan S.D.
      • Weinstein A.A.
      • et al.
      Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension.
      ] in one and two studies respectively. Irrespective of the tool used, all the studies demonstrated statistically significant improvements in QoL (Table 1). Physical domains showed greater improvements when compared to the other sub-domains for the SF36 [
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • Ghofrani S.
      • Hoeper M.M.
      • Halank M.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ,
      • Grunig E.
      • Lichtblau M.
      • Ehlken N.
      • Ghofrani H.A.
      • Reichenberger F.
      • Staehler G.
      • et al.
      Safety and efficacy of exercise training in various forms of pulmonary hypertension.
      ,
      • Nagel C.
      • Prange F.
      • Guth S.
      • Herb J.
      • Ehlken N.
      • Fischer C.
      • et al.
      Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension.
      ,
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ,
      • Chan L.
      • Chin L.M.
      • Kennedy M.
      • Woolstenhulme J.G.
      • Nathan S.D.
      • Weinstein A.A.
      • et al.
      Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension.
      ,
      • Ley S.
      • Fink C.
      • Risse F.
      • Ehlken N.
      • Fischer C.
      • Ley-Zaporozhan J.
      • et al.
      Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension.
      ,
      • Kabitz H.J.
      • Bremer H.C.
      • Schwoerer A.
      • Sonntag F.
      • Walterspacher S.
      • Walker D.J.
      • et al.
      The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension.
      ]. Exercise training was also found to have improvements in the pulmonary arterial system as demonstrated by changes in PASP determined by echocardiography and also through magnetic resonance imaging of the pulmonary arterial system [
      • Ley S.
      • Fink C.
      • Risse F.
      • Ehlken N.
      • Fischer C.
      • Ley-Zaporozhan J.
      • et al.
      Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension.
      ]. These results have been recently summarised by Arena and colleagues in a detailed review and have not been described here [
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • Ghofrani S.
      • Hoeper M.M.
      • Halank M.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      ].
      Survival rates among those participating in exercise programs in addition to medical therapy have reported good survival rates (between 100% and 73%) at one, two and three years [
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ]. One study further reported a 100% transplantation-free survival rate after one year and 93% after two years [
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ]. Adverse events were reported in a few studies – though they have not been thought to be the direct effects of exercises. A summary of the adverse events are given in Table 3.
      Table 3Exercise and non-exercise related adverse events reported in various studies (n=15)
      Author

      (year)
      Sample sizeAdverse eventsTotal

      n, (%)
      Exercise related (n)Non-exercise related (n)
      Mereles et al. (2006)30Dizziness without fainting after training on cycle ergometer (2)

      Desaturation (1)
      None reported3 (10%)
      Shoemaker et al. (2009)2None reportedNone reported0 (0)
      deMan et al. (2009)19None reportedNone reported0 (0)
      Martinez-Quintana et al. (2010)8None reportedNone reported0 (0)
      Mainguy et al. (2010)5Progressive fatigue towards the end of 12 weeks of training (1)Recurrent light dizziness (1)2 (40%)
      Fox et al. (2011)22None reportedWorsening PAH (1)

      New diagnosis of lung cancer (1)

      Re-admission for community acquired pneumonia (1)

      Re-admitted for correction of anaemia (1)
      4 (18.2%)
      Grunig et al. (2011)58Dizziness without fainting after training on cycle ergometer (2)Respiratory infection (7)

      Death (2)

      Lung transplantation (1)
      12 (20.6%)
      Grunig et al.

      (2012)
      183Pre-syncope (5)

      Syncope (1)

      Supraventricular tachycardia (2)

      Syncope (1)

      Acute respiratory infection (14)

      Haemoptysis (1)
      24 (13.1%)
      Grunig et al. (2012)21None reportedGastrointestinal infection with diarrhoea (1)

      Respiratory infection (2)
      3 (14.2%)
      Nagel et al. (2012)35Syncope (1)

      Herpes zoster (1)
      Respiratory infections (3)5 (14.3%)
      Chang et al. (2013)26None reportedNone reported0 (0)
      Becker-Grunig et al. (2013)20None reportedRespiratory infection (4)4 (20%)
      Ley et al. (2013)22None reportedNone reported0 (0)
      Weinsten et al. (2013)24None reportedNone reported0 (0)
      Kabitz et al. (2014)7None reportedNone reported0 (0)
      Total48216 (3.3%)41 (8.5%)57 (11.8%)
      *Not related to exercise training.
      6MWT – Six minute walk test, HR – Heart rate, HRmax – Maximum heart rate, RM – repetition maximum, RPE – Rating of perceived exertion, VO2max – Maximal oxygen consumption, VO2peak – Peak oxygen consumption.

      Discussion

      This review found that with exercise training, patients with PH showed improvements in functional capacity, exercise capacity, WHO-FC and QoL. The improvements in 6MWD varied with method of exercise training in that, a combination of aerobic-resistance and respiratory muscle training [
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • Ghofrani S.
      • Hoeper M.M.
      • Halank M.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ,
      • Fox B.D.
      • Kassirer M.
      • Weiss I.
      • Raviv Y.
      • Peled N.
      • Shitrit D.
      • et al.
      Ambulatory rehabilitation improves exercise capacity in patients with pulmonary hypertension.
      ,
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ,
      • Grunig E.
      • Lichtblau M.
      • Ehlken N.
      • Ghofrani H.A.
      • Reichenberger F.
      • Staehler G.
      • et al.
      Safety and efficacy of exercise training in various forms of pulmonary hypertension.
      ,
      • Nagel C.
      • Prange F.
      • Guth S.
      • Herb J.
      • Ehlken N.
      • Fischer C.
      • et al.
      Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension.
      ,
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ,
      • Ley S.
      • Fink C.
      • Risse F.
      • Ehlken N.
      • Fischer C.
      • Ley-Zaporozhan J.
      • et al.
      Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension.
      ,
      • Kabitz H.J.
      • Bremer H.C.
      • Schwoerer A.
      • Sonntag F.
      • Walterspacher S.
      • Walker D.J.
      • et al.
      The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension.
      ] demonstrated the greatest improvements in 6MWD when compared to those receiving resistance and endurance training for the lower limbs.[
      • de Man F.S.
      • Handoko M.L.
      • Groepenhoff H.
      • van’t Hul A.J.
      • Abbink J.
      • Koppers R.J.
      • et al.
      Effects of exercise training in patients with idiopathic pulmonary arterial hypertension.
      ] This could be impacted by the duration and the specificity of training methods. Nevertheless, the increases observed in 6MWD also corresponded to improvements in peakVO2, maximum work load achieved, exercise time and ventilatory efficiency. Interesting to note was that even though the improvement in 6MWD was large in most studies, the improvements in peak VO2 was still below 3.5 ml/Kg/min. The wide variation in improvements in 6MWD brings to light the need for establishing the minimal clinically important difference (MCID) for the 6MWT in PAH. This was recently put forward by Mathai and colleagues from the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) trial. [
      • Mathai S.C.
      • Puhan M.A.
      • Lam D.
      • Wise R.A.
      The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension.
      ] They identified a distance of 33m, which is similar to the recently put forward MCID (25-33m) for the 6MWD.[
      • Holland A.E.
      • Spruit M.A.
      • Troosters T.
      • Puhan M.A.
      • Pepin V.
      • Saey D.
      • et al.
      An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease.
      ] Whether this distance is to be utilised for sample size calculations is still uncertain as exercise intervention studies have obtained far greater improvements in 6MWD.
      Improvements in the functional class have been shown to have better prognosis in terms of three-year mortality, as has been shown in the REVEAL registry [
      • Barst R.J.
      • Chung L.
      • Zamanian R.T.
      • Turner M.
      • McGoon M.D.
      Functional class improvement and 3-year survival outcomes in patients with pulmonary arterial hypertension in the REVEAL Registry.
      ]. It was therefore encouraging to see that exercise training improved WHO-FC which in turn resulted in an improved QoL.[18,23,25–18,32] All this information supports the argument on the potential benefits for exercise training as an adjunct to existing medical therapies.[
      • Babu A.S.
      • Padmakumar R.
      • Maiya A.G.
      Letter by Babu et al. Regarding Article, “Advances in Therapeutic Interventions for Patients with Pulmonary Arterial Hypertension”.
      ,
      • Lau E.M.T.
      • Montani D.
      • Jais X.
      • Stibon O.
      • Simonneau G.
      • Humbert M.
      Response to letter regarding Article, “Advances in Therapeutic Interventions for Patients with Pulmonary Arterial Hypertension”.
      ] Though implementation requires higher quality evidence.
      Integrating various delivery models into the care for patients with PAH, which are country specific and tailored to meet the needs is imperative. [
      • Clark R.A.
      • Conway A.
      • Poulsen V.
      • Keech W.
      • Tirimacco R.
      • Tideman P.
      Alternative models of cardiac rehabilitation: a systematic review.
      ] In this regard, home-based training has been widely adopted in patients with CHF and has been shown to be highly cost-effective. [
      • Hwang R.
      • Marwick T.
      Efficacy of home-based exercise programmes for people with chronic heart failure: a meta-analysis.
      ] Grunig and colleagues utilised a mixed mode of delivery for exercise training i.e., beginning with a supervised program and progressing to a home-based program in all their research. [
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • Ghofrani S.
      • Hoeper M.M.
      • Halank M.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ,
      • Grunig E.
      • Lichtblau M.
      • Ehlken N.
      • Ghofrani H.A.
      • Reichenberger F.
      • Staehler G.
      • et al.
      Safety and efficacy of exercise training in various forms of pulmonary hypertension.
      ,
      • Nagel C.
      • Prange F.
      • Guth S.
      • Herb J.
      • Ehlken N.
      • Fischer C.
      • et al.
      Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension.
      ,
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ,
      • Ley S.
      • Fink C.
      • Risse F.
      • Ehlken N.
      • Fischer C.
      • Ley-Zaporozhan J.
      • et al.
      Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension.
      ,
      • Kabitz H.J.
      • Bremer H.C.
      • Schwoerer A.
      • Sonntag F.
      • Walterspacher S.
      • Walker D.J.
      • et al.
      The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension.
      ] However, the feasibility of a supervised program for three weeks in other countries where there is lack of insurance support will need to be evaluated. Up until now, no comparison exists to determine the superiority between institutions or home-based programs for patients with PAH.
      Adherence and loss to follow-up are key issues to be addressed in any form of home-based programs with weekly telephonic follow-up. The study by Weinstein and colleagues demonstrated adherence rates of 80-100% with an average adherence of 26.8±2.2 for 30 exercise sessions.[
      • Weinstein A.A.
      • Chin L.M.
      • Keyser R.E.
      • Kennedy M.
      • Nathan S.D.
      • Woolstenhulme J.G.
      • et al.
      Effect of aerobic exercise training on fatigue and physical activity in patients with pulmonary arterial hypertension.
      ] Becker-Grunig observed that 65% of patients (n=13/20) continued exercise training at least three days a week while 50% of them exercised every day.[
      • Becker-Grunig T.
      • Klose H.
      • Ehlken N.
      • Lichtblau M.
      • Nagel C.
      • Fischer C.
      • et al.
      Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease.
      ] From this study, it would appear that good adherence rates could be achieved and is similar to another small heart failure trial which showed adherence rates of 72% in a 12-week exercise program.[
      • Babu A.S.
      • Maiya A.G.
      • George M.M.
      • Padmakumar R.
      • Guddattu V.
      Effects of Combined Early In-Patient Cardiac Rehabilitation and Structured Home-based Program on Function among Patients with Congestive Heart Failure: A randomized controlled trial.
      ] With respect to loss to follow-up, Grunig et al., reported a loss to follow-up of 43.7% (80/183) and 5.1% (3/58) in their recent studies.[
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ,
      • Grunig E.
      • Lichtblau M.
      • Ehlken N.
      • Ghofrani H.A.
      • Reichenberger F.
      • Staehler G.
      • et al.
      Safety and efficacy of exercise training in various forms of pulmonary hypertension.
      ] Strategies like utilisation of tele-monitoring and technology may help curb these effects.[
      • Franklin N.C.
      • Lavie C.J.
      • Arena R.A.
      Personal health technology: A new era in cardiovascular disease prevention.
      ] However, the costs involved and feasibility of such programs for PAH patients worldwide will need to be evaluated in future trials.
      Data with regard to survival benefits with exercise training in PAH is in its early stages. Grunig et al., observed a 100% and 95% survival benefit at one and two years respectively for patients with PAH undergoing their exercise training program [
      • Grunig E.
      • Ehlken N.
      • Ghofrani A.
      • Staehler G.
      • Meyer F.J.
      • Juenger J.
      • et al.
      Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.
      ]. A recent study found survival benefits with exercise training in patients with connective tissue disorder acquired PAH [
      • Grunig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ]. Overall survival rates of 100% at one and two years with 73% at three years was seen in this group of patients receiving exercise training in addition to optimal drug therapy. This survival was found to be higher than that reported by the REVEAL for those with connective tissue disease acquired PAH (93% at one year) [
      • Chung L.
      • Liu J.
      • Parsons L.
      • Hassoun P.M.
      • McGoon M.
      • Badesch D.B.
      • et al.
      Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype.
      ]. Data from these two studies suggest survival benefits with exercise training as an additional treatment intervention. However, more long-term data will be required to confirm definite survival benefits with exercise training.
      As mentioned in Table 3, most of the adverse events were non-fatal and not the direct consequence of the exercise training. Nevertheless, it should be emphasised that keen monitoring is essential to ensuring a safe exercise program. A case report presented at the Inaugural scientific meeting of the Pulmonary Hypertension Society of Australia and New Zealand, 2011, described a patient developing VT during the 6MWT [
      • Seale H.
      • Harris J.
      • Hall K.
      • Kermeen F.
      The hidden risk of a 6-mintue walk test in pulmonary arterial hypertension.
      ]. A similar case was observed at our centre during which a lady with idiopathic PAH developed symptomatic bradycardia and hypoxia during the 6MWT (Abraham Samuel Babu, MPT, unpublished data, 2011). The dangers of adverse events during the 6MWT were recently reported by Morris et al. among three reported cases [
      • Morris N.R.
      • Seale H.
      • Harris J.
      • Hall K.
      • Hopkins P.
      • Kermeen F.
      Serious adverse events during a 6-min walk test in patients with pulmonary hypertension.
      ]. Therefore, even though exercise training as such did not report many adverse events, there is some evidence to suggest that performing simple tests like the 6MWT requires careful monitoring and is essential to ensure safety in these patients.
      Though none of the studies included in the review assessed the cost-effectiveness of exercise interventions, recently, Ehlken and colleagues published a paper which assessed the cost-effectiveness of exercise programs in PAH patients undergoing exercise training [
      • Ehlken N.
      • Verduyn C.
      • Tiede H.
      • Staehler G.
      • Karger G.
      • Nechwatal R.
      • et al.
      Economic Evaluation of Exercise Training in Patients with Pulmonary Hypertension.
      ]. They found a 657€ lower estimated healthcare cost within a period of two years which was due to the reduction in adverse events and better survival with exercise training.
      The authors acknowledge the publication bias which exists in this review. Heterogeneity in study designs and inclusion of underpowered studies in this review require the results of all the studies to be interpreted with caution. Inability to perform a meta-analysis of all the studies due to the heterogeneity in study designs and the limited number of studies only further strengthens the need for more RCTs in exercise training in PAH. Another limitation to this review was the lack of inclusion of a recent paper by Inagaki et al. on home based training for those with inoperable CTEPH [
      • Inagaki T.
      • Terada J.
      • Tanabe N.
      • Kawata N.
      • Kasai H.
      • Sugiura T.
      • et al.
      Home-based pulmonary rehabilitation in patients with inoperable or residual chronic thromboembolic pulmonary hypertension: a preliminary study.
      ]. This was due to the timeframe of the completion of the search (31st March, 2014) and the arrival of the paper online (4th September, 2014). Nevertheless, due to the limited literature in this area, we briefly discuss it here. A 12-week home based program (including strength training, respiratory training and walking) with one supervised session a week, was implemented for eight patients with CTEPH (WHO-FC II-III). Significant improvements in 6MWD (33.3 ± 25.1 m), QoL on the St. George's Respiratory Questionnaire (-12.1 ± 11.0) and muscle strength (quadriceps muscle force: 3.4 ± 3.8 kgf) were seen among them.

      Future Recommendations

      Large clinical trials, with long-term follow-up are required for strengthening the basis for exercise training through the use of active control groups. There is a need to determine the dose-response relationship and its impact on exercise capacity, cardiac function, QoL and survival. Influence of physical activity promotion interventions in this group of patients will be worth exploring in future studies. Determining the NNT in future large randomised trials will add a stronger basis for recommending exercise training for patients with PAH. Moving ahead and assessing the impact exercise has on vascular function, cellular pathways and inflammatory markers in PAH is indeed noteworthy of future research.

      Conclusion

      Exercise training appears to be a promising intervention as an adjunct to medical therapy though close monitoring is required while evaluating exercise capacity. Considering the lack of methodological rigor and duration, better quality evidence and long-term trials are required, if exercise training is to become a part of the evidence-based recommendations for management of patients with PAH.

      Funding

      None

      Disclosures

      None

      Conflicts of interest

      None

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