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Heart, Lung and Circulation

Exercise Rehabilitation Training in Patients With Pulmonary Hypertension: A Review

  • Chang Dong
    Affiliations
    Pulmonary and Critical Care Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
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  • Yanxia Li
    Correspondence
    Corresponding author at: Pulmonary and Critical Care Medicine, First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, Liaoning Province, 116011, China.
    Affiliations
    Pulmonary and Critical Care Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
    Search for articles by this author
Open AccessPublished:July 13, 2022DOI:https://doi.org/10.1016/j.hlc.2022.06.660

      Background

      Pulmonary hypertension (PH) has a high morbidity and mortality. Despite the existing disease-targeted therapy, most patients with PH continue to suffer from difficulty in breathing, exercise intolerance, and reduced quality of life. Recently, a large body of research results has suggested that exercise rehabilitation training (ERT) seems to be a beneficial, safe, and cost-effective treatment for patients with PH. However, knowledge gaps still exist for a uniformly accepted ERT protocol, the modality, duration, intensity, and frequency of ERT in PH.

      Aim

      The purpose of this review is to summarise the existing research evidence and knowledge, aiming to strengthen clinicians' awareness of the application of ERT in patients with PH.

      Methods and Results

      PubMed databases were systematically searched for eligible studies. Twelve (12) randomised controlled trials and other important studies documenting effectiveness, safety, and adverse events of ERT are summarised. Additionally, the modality, duration, intensity, and frequency of various types of ERT and future research directions are discussed.

      Conclusions

      In summary, ERT is generally effective and safe for PH patients as an adjuvant treatment to disease-specific therapy. It can improve the exercise capacity and tolerance, skeletal and respiratory muscle performance, cardiopulmonary function, and quality of life of PH patients.

      Recommendations

      In view of the occurrence of a small number of adverse events, we currently recommend a combination of in-hospital and home-based ERT under close supervision. In the future, more multi-centre randomised controlled studies are needed to evaluate the effectiveness and feasibility of long-term, community, or home-based ERT, as well as to explore the molecular mechanism behind it.

      Keywords

      Introduction

      Pulmonary hypertension (PH) is defined as the mean pulmonary arterial pressure (mPAP) ≥25 mmHg measured by right heart catheterisation (RHC) at rest [
      • Galiè N.
      • Humbert M.
      • Vachiery J.L.
      • Gibbs S.
      • Lang I.
      • Torbicki A.
      • et al.
      ESC Scientific Document Group. 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).
      ] with five major groups: group 1 is pulmonary arterial hypertension (PAH), group 2 is PH due to left heart disease (LHD), group 3 is PH due to lung diseases/hypoxia, group 4 is PH due to pulmonary artery obstruction, and group 5 is PH with unclear/multifactorial mechanisms [
      • Simonneau G.
      • Montani D.
      • Celermajer D.S.
      • Denton C.P.
      • Gatzoulis M.A.
      • Krowka M.
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      ]. Due to the progressive pathophysiological process of PH accompanied by the deterioration of right ventricular function, PH has a high morbidity and mortality. Despite the existing disease-targeted therapy, most patients continue to suffer from difficulty in breathing, fatigue, fear, activity intolerance, and reduced quality of life [
      • Chia K.S.W.
      • Brown K.
      • Kotlyar E.
      • Wong P.K.K.
      • Faux S.G.
      • Shiner C.T.
      'Tired, afraid, breathless … .' An international survey of the exercise experience for people living with pulmonary hypertension.
      ,
      • Hoeper M.M.
      • Huscher D.
      • Ghofrani H.A.
      • Delcroix M.
      • Distler O.
      • Schweiger C.
      • et al.
      Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry.
      ]. In the past, it was not recommended for PH patients to exercise in case it would result in disease deterioration or sudden death. Recently, more and more research results suggest that exercise rehabilitation training (ERT) seems to be a beneficial, safe, and cost-effective treatment for patients with PH [
      • 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.
      ,
      • An Q.Y.
      • Wang L.
      • Yuan P.
      • Zhao Q.H.
      • Gong S.G.
      • Zhang R.
      • et al.
      Effectiveness and safety of exercise training and rehabilitation in chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis.
      ,
      • Buys R.
      • Avila A.
      • Cornelissen V.A.
      Exercise training improves physical fitness in patients with pulmonary arterial hypertension: a systematic review and meta-analysis of controlled trials.
      ,
      • Morris N.R.
      • Kermeen F.D.
      • Holland A.E.
      Exercise-based rehabilitation programmes for pulmonary hypertension.
      ]. However, there are still discrepancies in the outcomes of various studies. Moreover, no uniform protocol exists for the modality, duration, intensity, and frequency of ERT. Therefore, we provide a review of the existing research evidence and knowledge, aiming to strengthen clinicians' awareness of the application of ERT in patients with PH.

      Effectiveness of ERT

      Exercise has always been considered to have a host of physiologic advantages for not only healthy individuals [
      • Fiatarone M.A.
      • O'Neill E.F.
      • Ryan N.D.
      • Clements K.M.
      • Solares G.R.
      • Nelson M.E.
      • et al.
      Exercise training and nutritional supplementation for physical frailty in very elderly people.
      ,
      • Liu-Ambrose T.
      • Davis J.C.
      • Best J.R.
      • Dian L.
      • Madden K.
      • Cook W.
      • et al.
      Effect of a home-based exercise program on subsequent falls among community-dwelling high-risk older adults after a fall: a randomized clinical trial.
      ] but also in patients with a variety of serious cardiopulmonary diseases [
      • Spruit M.A.
      • Pitta F.
      • McAuley E.
      • ZuWallack R.L.
      • Nici L.
      Pulmonary rehabilitation and physical activity in patients with chronic obstructive pulmonary disease.
      ,
      • Villareal D.T.
      • Aguirre L.
      • Gurney A.B.
      • Waters D.L.
      • Sinacore D.R.
      • Colombo E.
      • et al.
      Aerobic or resistance exercise, or both, in dieting obese older adults.
      ,
      • Piepoli M.F.
      • Conraads V.
      • Corrà U.
      • Dickstein K.
      • Francis D.P.
      • Jaarsma T.
      • et al.
      Exercise training in heart failure: from theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation.
      ]. Due to impaired pulmonary and cardiac haemodynamics in PH patients, symptoms of dyspnoea, fatigue, and syncope often occur after physical activity, which seriously affects the patient’s quality of life (QoL). A PH patients’ exercise capacity, World Health Organization (WHO) functional class (FC), oxygen therapy, right heart failure symptoms, right atrial pressure, and mental disorders are closely related to the QoL of patients [
      • Halank M.
      • Einsle F.
      • Lehman S.
      • Bremer H.
      • Ewert R.
      • Wilkens H.
      • et al.
      Exercise capacity affects quality of life in patients with pulmonary hypertension.
      ]. In 2006, the first randomised controlled trial (RCT) on ERT for patients with severe chronic PH was published. This study pointed out that through 15 weeks (3 weeks in the hospital, 12 weeks at home) exercise training at low workloads, including bicycle ergometer, dumbbell, walking, and respiratory training, the 6-minute walking distance (6MWD) of the training group significantly increased by 111 minutes (95% CI 65–139, p<0.001) compared with the control group. In addition, other parameters in cardiopulmonary exercise testing (eg, the peak oxygen consumption [VO2], VO2 at the anaerobic threshold [AT], achieved workload, mean WHO-FC, physical and mental questionnaire scores, and the QoL in the exercise group) were also significantly improved [
      • 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.
      ]. This study provided high-quality evidence-based evidence for the application of ERT to PH patients as an adjunct to optimal medical therapy. On this basis, the 2009 PH guidelines recommended supervised exercise to be considered for PAH patients within symptom limits [
      • Galiè N.
      • Hoeper M.M.
      • Humbert M.
      • Torbicki A.
      • Vachiery J.L.
      • Barbera J.A.
      • et al.
      ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the 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 the International Society of Heart and Lung Transplantation (ISHLT).
      ]. After that, more and more other high-quality RCTs have been published. The 5th PAH World Symposium consensus statement [
      • Galiè N.
      • Corris P.A.
      • Frost A.
      • Girgis R.E.
      • Granton J.
      • Jing Z.C.
      • et al.
      Updated treatment algorithm of pulmonary arterial hypertension.
      ] upgraded ERT as an add-on treatment for patients affected by PAH (class I, level of evidence: A). Current guidelines recommended that supervised exercise training should be applied to PAH patients who are physically deconditioned and clinically stable as an add-on to medical therapy (Class IIa recommendation, Level of Evidence B) [
      • Galiè N.
      • Humbert M.
      • Vachiery J.L.
      • Gibbs S.
      • Lang I.
      • Torbicki A.
      • et al.
      ESC Scientific Document Group. 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).
      ,
      • Grünig E.
      • Eichstaedt C.
      • Barberà J.A.
      • Benjamin N.
      • Blanco I.
      • Bossone E.
      • et al.
      ERS statement on exercise training and rehabilitation in patients with severe chronic pulmonary hypertension.
      ,
      • Klinger J.R.
      • Elliott C.G.
      • Levine D.J.
      • Bossone E.
      • Duvall L.
      • Fagan K.
      • et al.
      Therapy for pulmonary arterial hypertension in adults: update of the CHEST Guideline and Expert Panel Report.
      ].

      The Effect of ERT on Different Groups of PH

      We used “hypertension, pulmonary” Medical Subject Headings (MESH) terms as the keyword in the electronic PubMed database, combined with “exercise” (MESH) OR “rehabilitation” (MESH) OR “exercise training,” respectively. Twelve (12) RCTs [
      • 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.
      ,
      • Wojciuk M.
      • Ciolkiewicz M.
      • Kuryliszyn-Moskal A.
      • Chwiesko-Minarowska S.
      • Sawicka E.
      • Ptaszynska-Kopczynska K.
      • et al.
      Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study.
      ,
      • Ehlken N.
      • Lichtblau M.
      • Klose H.
      • Weidenhammer J.
      • Fischer C.
      • Nechwatal R.
      • 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.
      ,
      • Gerhardt F.
      • Dumitrescu D.
      • Gärtner C.
      • Beccard R.
      • Viethen T.
      • Kramer T.
      • et al.
      Oscillatory whole-body vibration improves exercise capacity and physical performance in pulmonary arterial hypertension: a randomised clinical study.
      ,
      • 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.K.
      • 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.
      ,
      • Kagioglou O.
      • Mouratoglou S.A.
      • Giannakoulas G.
      • Kapoukranidou D.
      • Anifanti M.
      • Deligiannis A.
      • et al.
      Long-term effect of an exercise training program on physical functioning and quality of life in pulmonary hypertension: a randomized controlled trial.
      ,
      • 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.
      ,
      • González-Saiz L.
      • Fiuza-Luces C.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Quezada-Loaiza C.A.
      • Flox-Camacho A.
      • et al.
      Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial.
      ,
      • Saglam M.
      • Arikan H.
      • Vardar-Yagli N.
      • Calik-Kutukcu E.
      • Inal-Ince D.
      • Savci S.
      • et al.
      Inspiratory muscle training in pulmonary arterial hypertension.
      ,
      • Aslan G.K.
      • Akıncı B.
      • Yeldan I.
      • Okumus G.
      A randomized controlled trial on inspiratory muscle training in pulmonary hypertension: effects on respiratory functions, functional exercise capacity, physical activity, and quality of life.
      ,
      • Tran D.
      • Munoz P.
      • Lau E.M.T.
      • Alison J.A.
      • Brown M.
      • Zheng Y.
      • et al.
      Inspiratory muscle training improves inspiratory muscle strength and functional exercise capacity in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a pilot randomised controlled study.
      ] were found, and the main contents were summarised in Table 1. All patients enrolled in the current studies have received optimised medical therapy and are in the clinically stable phase of PH. Studies suggest that ERT seems to be somewhat independent of the aetiology of PH and has an effect on various types of PH [
      • Arena R.
      • Lavie C.J.
      • Borghi-Silva A.
      • Daugherty J.
      • Bond S.
      • Phillips S.A.
      • et al.
      Exercise training in group 2 pulmonary hypertension: which intensity and what modality.
      ,
      • Grünig 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.
      ].
      Table 1A summary of published RCT studies on exercise training in PH.
      Author (yr)AetiologyNo. of participantsMean age (yr)WHO-FCmPAP (mmHg)Exercise Rehabilitation Training InterventionControlImproved factors (compared with Control)
      DurationTypeIntensityFrequency
      Mereles et al. [
      • 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.
      ], 2006
      PAH

      CTEPH
      Intervention: 15

      Control: 15
      50IIIVIntervention: 49.5

      Control: 49.6
      3 wk inhospital+12 wk homebicycle ergometer

      dumbbell

      respiratory training

      walking
      1030 min/d

      30 min/d

      1530 min/d

      60 min/d
      5–7 d/wk

      5–7 d/wk

      5–7 d/wk

      2–5 d/wk
      Usual care6MWD, QoL

      WHO-FC peak VO2 VO2 at AT workload
      Chan et al. [
      • Chan L.
      • Chin L.M.K.
      • 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.
      ], 2013
      PAHIntervention: 13

      Control: 13
      54.3IIVIntervention: 40.3

      Control: 43.8
      10 wksupervised treadmill walking30–45 min per session3 sessions/wkEducation only6MWD, QoL time to exercise intolerance

      peak work rate
      Ley et al. [
      • 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.
      ], 2013
      PAH

      CTEPH
      Intervention: 10

      Control: 10
      50.5II–IIIIntervention: 48

      Control: 50
      3 wk in-hospitalbicycle ergometer

      dumbbell

      respiratory training

      walking
      10–25 min/d

      30 min/d

      15–30 min/d

      60 min/d
      7 d/wk

      5 d/wk

      5 d/wk

      5 d/wk
      Usual care6MWD

      MR pulmonary flow

      MR pulmonary perfusion
      Weinstein et al. [
      • 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.
      ], 2013
      PAHIntervention: 11

      Control: 13
      54.4I–IVNA10 wksupervised treadmill walking30–45 min per session24–30 sessionsEducation only6MWD treadmill duration

      peak power output

      Adjusted Activity Score, MAS, FSS
      Saglam et al. [
      • Saglam M.
      • Arikan H.
      • Vardar-Yagli N.
      • Calik-Kutukcu E.
      • Inal-Ince D.
      • Savci S.
      • et al.
      Inspiratory muscle training in pulmonary arterial hypertension.
      ], 2015
      PAHIntervention:14

      Control: 15
      49.7II–IIIIntervention: 77.1

      Control: 59.5
      6 wkIMT30 min/d7 d/wkShame IMT6MWD, QoL

      MIP, MEP

      FEV1, % predicted

      FSS, MMRC
      Ehlken et al. [
      • Ehlken N.
      • Lichtblau M.
      • Klose H.
      • Weidenhammer J.
      • Fischer C.
      • Nechwatal R.
      • 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.
      ], 20156
      PAH

      CTEPH
      Intervention:46

      Control: 41
      56II–IVIntervention: 41

      Control: 37.6
      3 wk in-hospital +12 wk homebicycle ergometer

      dumbbell

      respiratory training

      walking
      1.5 h/d (inpatient) 15 min/d (home)7 d/wk

      5 d/wk

      5 d/wk

      5 d/wk
      Usual care6MWD, QoL peak VO2

      CI

      mPAP

      PVR
      Gerhardt et al. [
      • Gerhardt F.
      • Dumitrescu D.
      • Gärtner C.
      • Beccard R.
      • Viethen T.
      • Kramer T.
      • et al.
      Oscillatory whole-body vibration improves exercise capacity and physical performance in pulmonary arterial hypertension: a randomised clinical study.
      ], 2017
      PAHIntervention: 11

      Control: 11
      55.6II–IVIntervention: 35.5

      Control: 41.9
      4 wkoscillatory whole-body vibration1 h per session16 sessionsUsual care6MWD, QoL peak VO2

      oxygen uptake at the AT muscle power, force, and contraction velocity
      González-Sai et al. [
      • González-Saiz L.
      • Fiuza-Luces C.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Quezada-Loaiza C.A.
      • Flox-Camacho A.
      • et al.
      Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial.
      ], 2017
      PAH

      CTEPH
      Intervention:19

      Control: 16
      45.5I–IIIIntervention: 47

      Control: 47
      8 wkaerobic resistance

      IMT
      20–40 min/d

      ∼5 min/d
      5 d/wk

      3 d/wk

      6 d/wk
      Usual careBody muscle power

      peak VO2

      5-STS and MIP
      Aslan et al. [
      • Aslan G.K.
      • Akıncı B.
      • Yeldan I.
      • Okumus G.
      A randomized controlled trial on inspiratory muscle training in pulmonary hypertension: effects on respiratory functions, functional exercise capacity, physical activity, and quality of life.
      ], 2020
      PAH

      CTEPH
      Intervention:15

      Control: 12
      48.9I–IIIIntervention: 54.1

      Control: 46.1
      8 wkHome-based IMT30 min/d5 d/wkShame IMTMIP

      6MWD
      Tran et al. [
      • Tran D.
      • Munoz P.
      • Lau E.M.T.
      • Alison J.A.
      • Brown M.
      • Zheng Y.
      • et al.
      Inspiratory muscle training improves inspiratory muscle strength and functional exercise capacity in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a pilot randomised controlled study.
      ], 20201
      PAH

      CTEPH
      Intervention:6

      Control: 6
      60II–IIIIntervention: 37.9

      Control: 38.3
      8 wkIMT2 cycles of 30 breaths/d5 d/wkUsual care6MWD

      MIP
      Wojciuk et al. [
      • Wojciuk M.
      • Ciolkiewicz M.
      • Kuryliszyn-Moskal A.
      • Chwiesko-Minarowska S.
      • Sawicka E.
      • Ptaszynska-Kopczynska K.
      • et al.
      Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study.
      ], 2021
      PAHIntervention:16

      Control: 23
      48.9II–IIIIntervention: 47.2

      Control: 45.8
      6 mohome-based interval march training

      IMT
      45–60 min/d

      5 cycles
      5-7 d/wkUsual care6MWD respiratory muscle strength

      SF-36
      Kagioglou et al. [
      • Kagioglou O.
      • Mouratoglou S.A.
      • Giannakoulas G.
      • Kapoukranidou D.
      • Anifanti M.
      • Deligiannis A.
      • et al.
      Long-term effect of an exercise training program on physical functioning and quality of life in pulmonary hypertension: a randomized controlled trial.
      ], 2021
      PAH

      CTEPH
      Intervention:12

      Control: 10
      53.9II–IIIIntervention: 42.3

      Control: 45.1
      6 moaerobic strength45–60 min/d3 d/wkUsual care6MWD physical aspects

      psychological aspects
      Abbreviations: 6MWD, 6-minute walk test distance; 5-STS, five-repetition sit-to-stand test; AT, anaerobic threshold; CI, cardiac index; CTEPH, chronic thromboembolic pulmonary hypertension; FEV1, forced expiratory volume in 1 second; FSS, fatigue severity scale; IMT, inspiratory muscle training; mPAP, mean pulmonary arterial pressure; MR, magnetic resonance imaging; MAS, the maximum activity score; MMRC, modified Medical Research Council; MIP, maximum inspiratory pressure; MEP, maximum expiratory pressure; PH, pulmonary hypertension; PAH, pulmonary artery hypertension; PVR, pulmonary vascular resistance; QoL, quality of life; RCT, random control trails; SF-36, 36-Item short form health survey; VO2, oxygen consumption; WHO-FC, World Health Organization-functional class.
      The connective tissue disease-associated PAH (CTD-APAH) in group 1 is the second most common cause of PAH after idiopathic PAH (IPAH) [
      • Humbert M.
      • Sitbon O.
      • Chaouat A.
      • Bertocchi M.
      • Habib G.
      • Gressin V.
      • et al.
      Pulmonary arterial hypertension in France: results from a national registry.
      ]. These patients may also be combined with CTD-related interstitial lung diseases and require immunosuppressive therapy, which further complicates the condition. Since patients with CTD-APAH were also included in most of the RCTs, the treatment strategy of CTD-APAH is the same as IPAH. However, it was reported that PAH-targeted drugs were less effective for CTD-APAH compared with IPAH [
      • Rubin L.J.
      • Badesch D.B.
      • Barst R.J.
      • Galie N.
      • Black C.M.
      • Keogh A.
      • et al.
      Bosentan therapy for pulmonary arterial hypertension.
      ], so other adjuvant treatments for this subgroup of PAH are particularly important. One self-control study [
      • Grünig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ] enrolled 21 patients with invasively confirmed CTD-APAH, 95% of which were women, with an average age of 52±18 years and mPAP being 49±13 mmHg. After 15 weeks of ERT, the patients’ 6MWD increased by 71±35 minutes from the baseline, accompanied by improvements in the cardiopulmonary exercise test (CPET) and QoL. The survival rate in the first 2 years was 100%, and 73% in the third year, much better than previously reported [
      • Condliffe R.
      • Kiely D.G.
      • Peacock A.J.
      • Corris P.A.
      • Gibbs J.S.
      • Vrapi F.
      • et al.
      Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era.
      ].
      Congenital heart disease associated PAH (CHD-APAH) in group 2 has a heterogeneous patient population, for whom the first choice of treatment should include consideration of the feasibility to perform shunt closure surgery. Those patients who developed Eisenmenger Syndrome are usually severely restricted in physical activities. There are relatively few studies on ERT as an add-on to medical therapy in patients with CHD-APAH. One self-controlled study [
      • Becker-Grünig 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.
      ] prospectively studied 20 CHD-APAH patients, 80% of which were women, with an average age of 48±11-years-old. Most of the patients had combined cardiac anomaly with mPAP of 60±23 mmHg, 50% of the patients had Eisenmenger syndrome, and nine patients had undergone surgery. The study found that 15-week ERT improved the patients’ 6MWD, QoL, peak VO2, and maximum workload without transplantation needed in the long-term follow-up. The 1-year and 2-year survival rates were excellent, 100% and 92%, respectively. Another small sample sized non-RCT [
      • Martínez-Quintana E.
      • Miranda-Calderín G.
      • Ugarte-Lopetegui A.
      • Rodríguez-González F.
      Rehabilitation program in adult congenital heart disease patients with pulmonary hypertension.
      ] also found that the 6MWD and WHO-FC of the training group were significantly improved compared with the control group after 3-month ERT. These findings suggest that ERT can be used as an effective adjuvant therapy in addition to specific PAH drug therapy for patients with CHD-APAH.
      As to the management of chronic thromboembolic PH (CTEPH) in group 4, pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) can be considered in addition to the currently recommended oral drug, riociguat. A large number of clinical studies have suggested that ERT is beneficial for inoperable CTEPH patients with respect to the 6MWD, performance in CPET, QoL, WHO-FC, pulmonary flow and perfusion, mPAP, pulmonary vascular resistance (PVR), muscle strength, respiratory muscle function, and five-repetition sit-stand test [
      • 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.
      ,
      • Ehlken N.
      • Lichtblau M.
      • Klose H.
      • Weidenhammer J.
      • Fischer C.
      • Nechwatal R.
      • 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.
      ,
      • Kagioglou O.
      • Mouratoglou S.A.
      • Giannakoulas G.
      • Kapoukranidou D.
      • Anifanti M.
      • Deligiannis A.
      • et al.
      Long-term effect of an exercise training program on physical functioning and quality of life in pulmonary hypertension: a randomized controlled trial.
      ,
      • 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.
      ,
      • González-Saiz L.
      • Fiuza-Luces C.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Quezada-Loaiza C.A.
      • Flox-Camacho A.
      • et al.
      Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial.
      ,
      • Aslan G.K.
      • Akıncı B.
      • Yeldan I.
      • Okumus G.
      A randomized controlled trial on inspiratory muscle training in pulmonary hypertension: effects on respiratory functions, functional exercise capacity, physical activity, and quality of life.
      ,
      • Tran D.
      • Munoz P.
      • Lau E.M.T.
      • Alison J.A.
      • Brown M.
      • Zheng Y.
      • et al.
      Inspiratory muscle training improves inspiratory muscle strength and functional exercise capacity in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a pilot randomised controlled study.
      ]. Recently published studies have shown that ERT is also beneficial to patients who have just received PEA and BPA, and is an effective means of follow-up treatment after surgery. In 2020, Nagel et al. [
      • Tran D.
      • Munoz P.
      • Lau E.M.T.
      • Alison J.A.
      • Brown M.
      • Zheng Y.
      • et al.
      Inspiratory muscle training improves inspiratory muscle strength and functional exercise capacity in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a pilot randomised controlled study.
      ] reported the first results of supervised ERT as an early follow-up treatment for CTEPH patients after PEA. The study enrolled 45 CTEPH patients who had undergone PEA surgery at an average of 3.3 weeks before. After 19 weeks of ERT (3 weeks in hospital, 16 weeks at home), the results showed that the cardiac output (CO), mPAP, PVR, and other haemodynamic indicators measured by RHC were all significantly improved, accompanied by an increased 6MWD, QoL, oxygen saturation, and decreased size of the right ventricle as assessed by echocardiography. A recently published systematic review and meta-analysis [
      • Zhao Y.L.
      • Yuan P.
      • Zhao Q.H.
      • Gong S.G.
      • Zhang R.
      • He J.
      • et al.
      Comparative effectiveness of exercise training for patients with chronic thromboembolic pulmonary hypertension after pulmonary endarterectomy: a systematic review and meta-analysis.
      ] analysed four studies [
      • Nagel C.
      • Nasereddin M.
      • Benjamin N.
      • Egenlauf B.
      • Harutyunova S.
      • Eichstaedt C.A.
      • et al.
      Supervised exercise training in patients with chronic thromboembolic pulmonary hypertension as early follow-up treatment after pulmonary endarterectomy: a prospective cohort study.
      ,
      • 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.
      ,
      • 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.
      ,
      • La Rovere M.T.
      • Pinna G.D.
      • Pin M.
      • Bruschi C.
      • Callegari G.
      • Zanotti E.
      • et al.
      Exercise training after pulmonary endarterectomy for patients with chronic thromboembolic pulmonary hypertension.
      ] with a total of 208 CTEPH patients after PEA. The results suggested that short-term ERT can significantly improve the patients’ 6MWD, peak VO2, maximal workload, and O2 pulse. Three (3) months of ERT further improved right ventricular ejection fraction, QoL scores and reduced N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma level. For patients with inoperable CTEPH, BPA can also be considered. A non-RCT [
      • Fukui S.
      • Ogo T.
      • Takaki H.
      • Ueda J.
      • Tsuji A.
      • Morita Y.
      • et al.
      Efficacy of cardiac rehabilitation after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.
      ] divided 41 CTEPH patients after BPA into an early (6.8 days) ERT group or no training group. The results found that compared with the control group, most of the exercise capacity indices in the CPET, such as peak workload and peak VO2, were significantly improved in the ERT group. The quadriceps isometric strength and WHO-FC were also significantly improved. The above studies suggest that ERT as a follow-up therapy after PEA and BPA may be effective as an add-on to routine medical therapy.

      The Effect of ERT on the Functional and Physiological Factors

      The 6MWD is one of the most commonly used indicators to evaluate the exercise capacity of patients with PH. All the 11 RCTs listed in Table 1, except for one whose primary endpoint was peak muscle power [
      • González-Saiz L.
      • Fiuza-Luces C.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Quezada-Loaiza C.A.
      • Flox-Camacho A.
      • et al.
      Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial.
      ], evaluated 6WMD and all came to the same conclusion that ERT can effectively improve the patients’ 6WMD. There are also a few non-RCTs that did not find a statistically significant change in the 6MWD [
      • Fukui S.
      • Ogo T.
      • Takaki H.
      • Ueda J.
      • Tsuji A.
      • Morita Y.
      • et al.
      Efficacy of cardiac rehabilitation after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.
      ,
      • 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.
      ].
      Cardiopulmonary exercise test (CPET) is another important examination to evaluate the exercise capacity of patients with PH. CPET can simultaneously monitor the variables changes in exercise capacity, cardiac function, ventilation efficacy, and gas exchange during exercise. Together with the 6MWD, it provides important information for the diagnosis and prognosis of PH [
      • 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.
      ]. The important variables of CPET include work rate, workload, heart rate, ventilation (VE), oxygen consumption, carbon dioxide output (VCO2), VE/VCO2 ratio and AT. Peak VO2 is the most commonly used and effective method to evaluate aerobic capacity and exercise tolerance. High-levels of peak VO2 indicates good aerobic exercise capacity, which corresponds positively with an increasing workload. Besides, high VO2 at the AT also indicates an improved aerobic metabolism during exercise. Patients with PH typically experience high VE/VCO2, low end-tidal partial pressure of carbon dioxide and low peak VO2 compared with normal adults, which may be a result of ventilatory inefficiency and increased ventilatory drives in patients with PH [
      • Sun X.G.
      • Hansen J.E.
      • Oudiz R.J.
      • Wasserman K.
      Exercise pathophysiology in patients with primary pulmonary hypertension.
      ,
      • Sabbahi A.
      • Severin R.
      • Ozemek C.
      • Phillips S.A.
      • Arena R.
      The role of cardiopulmonary exercise testing and training in patients with pulmonary hypertension: making the case for this assessment and intervention to be considered a standard of care.
      ]. In return, continuous ventilatory inefficiency and limited lung neutralisation capacity will also hinder the patient's exercise tolerance and exercise adaptability [
      • Morris Z.V.
      • Chin L.M.K.
      • Chan L.
      • Guccione A.A.
      • Ahmad A.
      • Keyser R.E.
      Cardiopulmonary exercise test indices of respiratory buffering before and after aerobic exercise training in women with pulmonary hypertension: differentiation by magnitudes of change in six-minute walk test performance.
      ]. Ehlken et al. [
      • Ehlken N.
      • Lichtblau M.
      • Klose H.
      • Weidenhammer J.
      • Fischer C.
      • Nechwatal R.
      • 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.
      ] reported their RCT with peak VO2 as the primary endpoint that after 15 weeks of ERT, the 6MWD and peak VO2 of the training group were significantly improved compared with the control group. The results of this study are consistent with most other 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.
      ,
      • Gerhardt F.
      • Dumitrescu D.
      • Gärtner C.
      • Beccard R.
      • Viethen T.
      • Kramer T.
      • et al.
      Oscillatory whole-body vibration improves exercise capacity and physical performance in pulmonary arterial hypertension: a randomised clinical study.
      ,
      • Kagioglou O.
      • Mouratoglou S.A.
      • Giannakoulas G.
      • Kapoukranidou D.
      • Anifanti M.
      • Deligiannis A.
      • et al.
      Long-term effect of an exercise training program on physical functioning and quality of life in pulmonary hypertension: a randomized controlled trial.
      ,
      • González-Saiz L.
      • Fiuza-Luces C.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Quezada-Loaiza C.A.
      • Flox-Camacho A.
      • et al.
      Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial.
      ,
      • Grünig 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.
      ,
      • Grünig E.
      • Maier F.
      • Ehlken N.
      • Fischer C.
      • Lichtblau M.
      • Blank N.
      • et al.
      Exercise training in pulmonary arterial hypertension associated with connective tissue diseases.
      ,
      • Becker-Grünig 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.
      ,
      • Grünig 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.
      ]. In addition, Ehlken et al. also invasively measured the haemodynamic changes of studied patients by RHC. The results showed that both cardiac index and CO at rest and during exercise were significantly improved, with resting mPAP and PVR decreased significantly compared with the control group. The results of this study suggested that ERT may reduce PVR and improve right heart function, which is an important factor related to the prognosis of PH patients [
      • McLaughlin V.V.
      • Presberg K.W.
      • Doyle R.L.
      • Abman S.H.
      • McCrory D.C.
      • Fortin T.
      • et al.
      American College of Chest Physicians. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.
      ,
      • Chaouat A.
      • Sitbon O.
      • Mercy M.
      • Ponçot-Mongars R.
      • Provencher S.
      • Guillaumot A.
      • et al.
      Prognostic value of exercise pulmonary haemodynamics in pulmonary arterial hypertension.
      ,
      • Blumberg F.C.
      • Arzt M.
      • Lange T.
      • Schroll S.
      • Pfeifer M.
      • Wensel R.
      Impact of right ventricular reserve on exercise capacity and survival in patients with pulmonary hypertension.
      ]. A study that assessed estimated PAPs by non-invasive methods of stress Doppler echocardiography has not found any difference [
      • 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.
      ].

      The Effect of ERT on the Skeletal Muscle System

      The abnormalities of pulmonary, cardiac, and skeletal muscle systems in PH patients together lead to exercise intolerance. Impaired oxygen supply, reduced CO, chronic hypoxaemia, and mitochondrial dysfunction are associated with peripheral muscle dysfunction and respiratory muscle weakness in PH patients [
      • Riou M.
      • Pizzimenti M.
      • Enache I.
      • Charloux A.
      • Canuet M.
      • Andres E.
      • et al.
      Skeletal and respiratory muscle dysfunctions in pulmonary arterial hypertension.
      ]. On this basis, an RCT included an 8-week resistance training of large muscle groups combined with the inspiratory muscle training (IMT). The results of the study showed a significant interaction (group × time) effect for leg/bench press in the training group but not in the control group. At the same time, five-repetition sit-to-stand test, maximal inspiratory pressure, and peak VO2 are also significantly increased in the training group [
      • González-Saiz L.
      • Fiuza-Luces C.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Quezada-Loaiza C.A.
      • Flox-Camacho A.
      • et al.
      Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial.
      ]. Muscle biopsy had shown that exercise can induce the decrease in proportion of type IIx fibres [
      • 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.
      ], while capillary density of type I fibre and oxidative enzyme activity of skeletal muscle fibres increased [
      • 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.
      ], thereby increasing aerobic capacity. Other RCTs have also found that IMT can significantly increase the respiratory muscle strength of PH patients as indicated by the significantly increased maximum inspiratory pressure [
      • Saglam M.
      • Arikan H.
      • Vardar-Yagli N.
      • Calik-Kutukcu E.
      • Inal-Ince D.
      • Savci S.
      • et al.
      Inspiratory muscle training in pulmonary arterial hypertension.
      ,
      • Aslan G.K.
      • Akıncı B.
      • Yeldan I.
      • Okumus G.
      A randomized controlled trial on inspiratory muscle training in pulmonary hypertension: effects on respiratory functions, functional exercise capacity, physical activity, and quality of life.
      ,
      • Tran D.
      • Munoz P.
      • Lau E.M.T.
      • Alison J.A.
      • Brown M.
      • Zheng Y.
      • et al.
      Inspiratory muscle training improves inspiratory muscle strength and functional exercise capacity in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a pilot randomised controlled study.
      ,
      • 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.
      ], maximum expiratory pressure [
      • Wojciuk M.
      • Ciolkiewicz M.
      • Kuryliszyn-Moskal A.
      • Chwiesko-Minarowska S.
      • Sawicka E.
      • Ptaszynska-Kopczynska K.
      • et al.
      Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study.
      ,
      • Saglam M.
      • Arikan H.
      • Vardar-Yagli N.
      • Calik-Kutukcu E.
      • Inal-Ince D.
      • Savci S.
      • et al.
      Inspiratory muscle training in pulmonary arterial hypertension.
      ], forced expiratory volume in 1 second (% predicted), and dyspnoea and fatigue score [
      • Saglam M.
      • Arikan H.
      • Vardar-Yagli N.
      • Calik-Kutukcu E.
      • Inal-Ince D.
      • Savci S.
      • et al.
      Inspiratory muscle training in pulmonary arterial hypertension.
      ]. The above research results suggested that resistance training and IMT could enhance muscle performance, improve exercise capability, and respiratory function, thereby improving the QoL of patients with PH.

      The Effect of ERT on the Molecular Factors

      NT-proBNP is another important indicator for the risk assessment of PH patients. In most studies, it has not been found that ERT as add-on to medicine can result in significant differences in NT-proBNP levels [
      • Ehlken N.
      • Lichtblau M.
      • Klose H.
      • Weidenhammer J.
      • Fischer C.
      • Nechwatal R.
      • 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.
      ,
      • González-Saiz L.
      • Fiuza-Luces C.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Quezada-Loaiza C.A.
      • Flox-Camacho A.
      • et al.
      Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial.
      ,
      • Tran D.
      • Munoz P.
      • Lau E.M.T.
      • Alison J.A.
      • Brown M.
      • Zheng Y.
      • et al.
      Inspiratory muscle training improves inspiratory muscle strength and functional exercise capacity in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a pilot randomised controlled study.
      ,
      • Koudstaal T.
      • Wapenaar M.
      • van Ranst D.
      • Beesems R.
      • van den Toorn L.
      • van den Bosch A.
      • et al.
      The effects of a 10-wk outpatient pulmonary rehabilitation program on exercise performance, muscle strength, soluble biomarkers, and quality of life in patients with 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.
      ], but there are studies that have reported statistically significant improvement [
      • Wojciuk M.
      • Ciolkiewicz M.
      • Kuryliszyn-Moskal A.
      • Chwiesko-Minarowska S.
      • Sawicka E.
      • Ptaszynska-Kopczynska K.
      • et al.
      Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study.
      ] or deterioration [
      • Becker-Grünig 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.
      ]. The discrepancy may be owing to different comorbidities of PH patients before the study, and the significant difference of NT-proBNP levels in baseline [
      • Ehlken N.
      • Lichtblau M.
      • Klose H.
      • Weidenhammer J.
      • Fischer C.
      • Nechwatal R.
      • 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.
      ].

      The Effect of ERT on PH in the Long Term

      Most of the studies were short-term ERT (3 wks to 15 wks). Recently, two ERT studies lasting 6 months were designed aiming to evaluate the long-term effects of ERT on PH. Studies have shown that after 6 months of combined aerobic and strength training, the physical function of the patients as reflected by the 6MWD, lower limb strength, CPET variables, and mental health scores have been significantly improved compared with the control group [
      • Wojciuk M.
      • Ciolkiewicz M.
      • Kuryliszyn-Moskal A.
      • Chwiesko-Minarowska S.
      • Sawicka E.
      • Ptaszynska-Kopczynska K.
      • et al.
      Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study.
      ], and these beneficial results were still maintained 3 months after the termination of the ERT [
      • Kagioglou O.
      • Mouratoglou S.A.
      • Giannakoulas G.
      • Kapoukranidou D.
      • Anifanti M.
      • Deligiannis A.
      • et al.
      Long-term effect of an exercise training program on physical functioning and quality of life in pulmonary hypertension: a randomized controlled trial.
      ]. In follow-up, the survival rate in the first 2 years for these patients with PH was 100% and 95%, respectively [
      • Grünig 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.
      ]. The research suggests that long-term ERT may be beneficial for patients with PH in terms of favourable prognosis.

      Safety and Adverse Events of ERT

      Most clinical research results has suggested that ERT is an effective and safe adjuvant treatment to disease-targeted medical therapy without serious adverse reactions, such as clinical deterioration and death, reported [
      • Gerhardt F.
      • Dumitrescu D.
      • Gärtner C.
      • Beccard R.
      • Viethen T.
      • Kramer T.
      • et al.
      Oscillatory whole-body vibration improves exercise capacity and physical performance in pulmonary arterial hypertension: a randomised clinical study.
      ,
      • Chan L.
      • Chin L.M.K.
      • 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.
      ,
      • Fukui S.
      • Ogo T.
      • Takaki H.
      • Ueda J.
      • Tsuji A.
      • Morita Y.
      • et al.
      Efficacy of cardiac rehabilitation after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.
      ]. However, ERT is not without risk. One study reported that the incidence of adverse reactions was 13.6% [
      • Grünig 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.
      ], which included decreased blood oxygen during exercise [
      • 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.
      ], excessive fatigue [
      • Wojciuk M.
      • Ciolkiewicz M.
      • Kuryliszyn-Moskal A.
      • Chwiesko-Minarowska S.
      • Sawicka E.
      • Ptaszynska-Kopczynska K.
      • et al.
      Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study.
      ], muscle aches and back pain [
      • Gerhardt F.
      • Dumitrescu D.
      • Gärtner C.
      • Beccard R.
      • Viethen T.
      • Kramer T.
      • et al.
      Oscillatory whole-body vibration improves exercise capacity and physical performance in pulmonary arterial hypertension: a randomised clinical study.
      ], tachycardia [
      • Wojciuk M.
      • Ciolkiewicz M.
      • Kuryliszyn-Moskal A.
      • Chwiesko-Minarowska S.
      • Sawicka E.
      • Ptaszynska-Kopczynska K.
      • et al.
      Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study.
      ,
      • González-Saiz L.
      • Fiuza-Luces C.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Quezada-Loaiza C.A.
      • Flox-Camacho A.
      • et al.
      Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial.
      ], transient dizziness [
      • 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.
      ,
      • González-Saiz L.
      • Fiuza-Luces C.
      • Sanchis-Gomar F.
      • Santos-Lozano A.
      • Quezada-Loaiza C.A.
      • Flox-Camacho A.
      • et al.
      Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial.
      ,
      • Grünig 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.
      ], pre-syncope [
      • 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.
      ], and syncope [
      • Grünig 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.
      ]. Some other adverse events judged to be unrelated to training by physicians were also commonly reported, for example, respiratory, urinary tract and gastrointestinal infections, and pericardial effusion [
      • Kagioglou O.
      • Mouratoglou S.A.
      • Giannakoulas G.
      • Kapoukranidou D.
      • Anifanti M.
      • Deligiannis A.
      • et al.
      Long-term effect of an exercise training program on physical functioning and quality of life in pulmonary hypertension: a randomized controlled trial.
      ,
      • Grünig 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.
      • Nasereddin M.
      • Benjamin N.
      • Egenlauf B.
      • Harutyunova S.
      • Eichstaedt C.A.
      • et al.
      Supervised exercise training in patients with chronic thromboembolic pulmonary hypertension as early follow-up treatment after pulmonary endarterectomy: a prospective cohort study.
      ]. Moreover, the most adverse events occurred during the initial 3 weeks of training in the hospital and the incidence decreased during the study period at home after the patients became aware of their limitations. Therefore, supervised ERT under close guidance and monitoring is very important.

      Various Types of ERT

      The protocol of ERT has not yet been unified. Different types of ERT includes aerobic exercise, strength training, respiratory function training, or a combination thereof. The duration varies from 3 weeks [
      • 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.
      ] to 6 months [
      • Wojciuk M.
      • Ciolkiewicz M.
      • Kuryliszyn-Moskal A.
      • Chwiesko-Minarowska S.
      • Sawicka E.
      • Ptaszynska-Kopczynska K.
      • et al.
      Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study.
      ,
      • Kagioglou O.
      • Mouratoglou S.A.
      • Giannakoulas G.
      • Kapoukranidou D.
      • Anifanti M.
      • Deligiannis A.
      • et al.
      Long-term effect of an exercise training program on physical functioning and quality of life in pulmonary hypertension: a randomized controlled trial.
      ]. First, aerobic exercise typically includes bicycle ergometer, treadmill, or walking. The intensity of aerobic exercise in most studies is low (10 watts–60 watts) and progressively increased during the program. Second, strength training can be composed of dumbbell, leg and bench press, leg extension, lateral pulldown, and abdominal crunches. The strength training is also generally using low weights (500 g–1,000 g). The length of aerobic exercise and strength training is generally 30 to 60 minutes per day, 3 to 7 days per week. Close monitoring of the patients’ peak heart rate (for example, not >120 bpm or 60% to 80% max heart rate) and blood oxygen saturation (for example, >85%) during exercise are necessary. Third, respiratory training includes threshold inspiratory muscle training and breathing technique, such as pursed lip breathing. Besides, Gerhardt et al. [
      • Gerhardt F.
      • Dumitrescu D.
      • Gärtner C.
      • Beccard R.
      • Viethen T.
      • Kramer T.
      • et al.
      Oscillatory whole-body vibration improves exercise capacity and physical performance in pulmonary arterial hypertension: a randomised clinical study.
      ] reported that oscillatory whole-body vibration is a new type of exercise mode. Rapid vibration can make the whole-body muscles contract reflexively, combining static and dynamic exercises. The study found that patients who received 4 weeks of whole-body vibration significantly improved their 6MWD, CPET variables, muscle power, and QoL.
      The appropriate place for ERT is also being studied, from only in-hospital, and combination of hospital and home, to completely home-based or community-based [
      • Koudstaal T.
      • Wapenaar M.
      • van Ranst D.
      • Beesems R.
      • van den Toorn L.
      • van den Bosch A.
      • et al.
      The effects of a 10-wk outpatient pulmonary rehabilitation program on exercise performance, muscle strength, soluble biomarkers, and quality of life in patients with pulmonary hypertension.
      ,
      • Babu A.S.
      • Padmakumar R.
      • Nayak K.
      • Shetty R.
      • Mohapatra A.K.
      • Maiya A.G.
      Effects of home-based exercise training on functional outcomes and quality of life in patients with pulmonary hypertension: a randomized clinical trial.
      ]. Home-based ERT is undoubtedly a better direction to develop, not only because it can potentially improve the patient’s compliance but also is convenient and cost-effective. However, in view of a certain probability of adverse events, the patients should firstly be trained on how to exercise safely at home, and a sound supervision mechanism should be developed.

      Future Directions

      One recently published RCT study focussed on outpatient ERT programs and their feasibility and acceptability to PAH patients [
      • Chia K.S.W.
      • Shiner C.T.
      • Brown K.
      • Holloway C.J.
      • Moreyra C.
      • Bart N.
      • et al.
      The exercise in pulmonary arterial hypertension (ExPAH) study: a randomized controlled pilot of exercise training and multidisciplinary rehabilitation in pulmonary arterial hypertension.
      ]. Similarly, several open label RCTs are running. One is about the safety, economic applicability, feasibility, and patient compliance of home-based ERT for PH patients, which is supervised by telehealth or distance-based programs [
      • McCormack C.
      • Kehoe B.
      • Hardcastle S.J.
      • McCaffrey N.
      • McCarren A.
      • Gaine S.
      • et al.
      Pulmonary hypertension and home-based (PHAHB) exercise intervention: protocol for a feasibility study.
      ]. Another one has included clinical deterioration time as the endpoint to evaluate the effectiveness of long-term ERT for PH patients as a routine treatment outside the hospital [
      • McGregor G.
      • Bruce J.
      • Ennis S.
      • Mason J.
      • Lall R.
      • Ji C.
      • et al.
      Supervised pulmonary hypertension exercise rehabilitation (SPHERe): study protocol for a multi-centre randomised controlled trial.
      ]. A survey composed of 280 physicians, including cardiologists, pulmonologists, rheumatologists, and general practitioners from 22 countries published in 2020, showed that 86% of physicians recommend ERT for patients with PH. It is consistent with the current guidelines, but the main systemic obstacle is the lack of financial support and limited rehabilitation places [
      • Chia K.S.W.
      • Wong P.K.K.
      • Gonzalez S.
      • Kotlyar E.
      • Faux S.G.
      • Shiner C.T.
      Attitudes towards exercise among medical specialists who manage patients with pulmonary hypertension.
      ]. Moreover, the report format of ERT needs to be standardised [
      • McGregor G.
      • Powell R.
      • Finnegan S.
      • Nichols S.
      • Underwood M.
      Exercise rehabilitation programmes for pulmonary hypertension: a systematic review of intervention components and reporting quality.
      ] for professional supervision and future research. Last but not least, the underlying molecular mechanism of ERT in PH still need further studies.

      Conclusion

      Exercise rehabilitation training is generally effective and safe for PH patients as an adjuvant treatment to disease-specific therapy. It can improve the exercise capacity and tolerance, skeletal and respiratory muscle performance, cardiopulmonary function and the QoL of PH patients. In view of the incidence of a small number of adverse events, we currently recommend a combination of in-hospital and home-based ERT under close supervision. More multi-centre RCTs are needed to evaluate the effectiveness and feasibility of long-term, community, or home based ERT, as well as to explore the underlying molecular mechanism.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Conflicts of Interest

      The authors have no conflicts of interest to disclose.

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