Physical exercise for pulmonary arterial hypertension diagnosis and therapy

1. Introduction

The pulmonary circulation in normal subjects is a low-pressure, high flow circuit. This predisposes to the retention of fluid in pulmonary vessels minimizing both pulmonary alveolar fluid extravasation by lower hydrostatic forces as well as the energy expenditure of the right ventricle (RV). During exercise, there is a marked increase in oxygen uptake and carbon dioxide output, as well as an up to 6-fold increase in cardiac output required to meet the metabolic demands of exercising muscles. This increased cardiac output leads to increased pulmonary blood flow and raises both pulmonary artery pressure and left and right atrial pressures. Under such stress, the pulmonary vascular bed remains remarkably compliant and distends passively during its increasing recruitment with exercise. This helps to maintain a lower pulmonary vascular resistance (PVR) and compensated state between RV and pulmonary circulation (RV-PA coupling) [1].

In pulmonary hypertension (PH), the pulmonary vasculature is less compliant, and PVR is increased. This leads to increased pulmonary pressures both at rest and on exercise causing an excessive rise in RV afterload with uncoupling of the RV-PA unit. The RV contractile reserve and ability to mount an increased stroke volume on exercise become compromised, leading to reduced forward flow, reduced left ventricular (LV) filling and inadequate cardiac output [2,3]. This manifests as symptoms of exercise intolerance and breathlessness. Exercise testing may therefore be used in the timely diagnosis of PH through its ability to unmask abnormal pulmonary vascular physiology at an earlier stage of pathological adaptation. This has led to the adoption of exercise assessments in particular in those with risk factors for the development of PH, who have yet to develop abnormal resting pulmonary haemodynamics [4].

As a diagnostic tool, exercise assessments also provide further insight into the extent of RV dysfunction in PH which in turn helps to determine prognosis [5]. In recent years, the therapeutic potential of exercise training in PH has also been realized with an expanding evidence base for the role of exercise training modalities which, applied under appropriate supervision, offer clinical benefit. In the main, the diagnostic and prognostic benefit of exercise assessments apply to a subgroup of PH, pulmonary arterial hypertension (PAH) which forms Group 1 of the updated PH diagnostic classification. This review focuses initially on the diagnostic application of exercise assessments relating to PAH and includes the 6-min walk test (6MWT), cardiopulmonary exercise testing (CPET), exercise echocardiography and cardiac MRI, and exercise right heart catheterisation. In the second half of this review, exercise is explored as a therapeutic entity, including a summary of evidence in support of its complementary role within contemporary PH management.

2. Exercise as a diagnostic tool in PAH

2.1. Six minute walk test

The 6 min walk test (6MWT) is a submaximal exercise test which measures the distance a person can walk in 6 min (6MWD). It is a cheap and simple test to perform, requiring a 30-m hallway space and an overseeing staff member. Its role in the diagnosis per se of PH is limited as it lacks sensitivity and specificity, however it is quick to perform at clinic visits and gives valuable information on functional capacity in PH patients. Importantly, it has a strong independent association with mortality and resting cardiac output in this population [6]. Thus, it has been used as a common primary end point in clinical trials of pulmonary vasodilator drug therapies for PAH and is a core component in PAH risk assessment [7].

One of the shortcomings of the 6MWT is the difficulty in deciding whether a change in value represents a truly clinically meaningful change. The 6MWD can vary significantly depending on a person's intrinsic effort and their physical condition e.g. coexistence of pain [8], and studies have shown that there is intra-individual variability in the 6MWD achieved by stable participants who are able to walk >400m, termed the ‘ceiling effect’ [9]. Recent evidence has demonstrated that incorporating heart rate (HR) monitoring during the 6MWT can help improve reproducibility and interpretation of results by giving some indication of intrinsic effort as well as RV contractile reserve. In one study, authors measured a change in HR before and after the 6MWT (ΔHR) and found that in PAH patients, 6MWD increased by 53.3m for every 60 % increase in ΔHR/HR_{at rest} after adjusting for other confounding variables. Comparing this to healthy controls, PAH patients had significantly reduced 6MWD and ΔHR/HR_{at rest}. PAH patients in WHO functional class III also had significantly shorter 6MWD and reduced ΔHR/HR_{at rest} when compared with PAH patients in WHO functional class I/II [10]. A new measure, termed “Cardiac effort”, has been suggested to improve the reproducibility of the 6MWT which gives results that are less effort dependent [11]. Cardiac effort is defined as the total number of heart beats during the 6MWT divided by the 6MWD, and is obtained by the patient wearing a wireless ECG patch during the 6MWT. The increased reproducibility of cardiac effort means that it is more sensitive to change (worsening or improvement) and allows clinicians to be more confident in the significance of a change in 6MWD. In addition, cardiac effort has been shown to strongly correlate with LV indexed stroke volume on cardiac MRI, indicating its potential use as a prognostic marker of cardiac function in PH [12]. Moving forward, continuous heart rate monitoring may be useful to include routinely in the 6MWT performed as part of patient diagnosis and monitoring.

2.2. Cardiopulmonary exercise testing

Cardiopulmonary exercise testing (CPET) is a further non-invasive method of assessing exercise limitation, but with more specific indicators for the diagnosis of PH compared with the 6MWT; several abnormalities in exercise physiology and gas exchange during CPET can suggest the presence of PH (Fig. 1). Firstly, there is a reduction in the amount of oxygen uptake by skeletal muscle during exercise (low peak VO₂). This is due to the lack of forward flow from the failing RV against an increased afterload which results in reduced LV filling, reduced cardiac output and lack of oxygenated blood flow to skeletal muscle [13,14]. Reduced oxygen supply to exercising muscles reduces their aerobic metabolic capacity and leads to the premature onset of anaerobic metabolism (lower anaerobic threshold (AT)) and earlier lactic acidosis, which increases carbon dioxide production (increased VCO₂). Pulmonary vascular remodelling in PH results in poorly perfused pulmonary airspaces. This leads to increased physiological dead space that underlies the excessive ventilatory response to exercise, characteristic of PH. Excessive ventilation is defined by an increase in minute ventilation (VE), which is the total volume of air entering the lungs over 1 min. In addition, a reduced end tidal CO₂ and elevated VE/VCO₂ slope are characteristic given both an increase in physiological dead space and increased chemosensitivity to CO₂. Gas exchange abnormalities include the development of arterial hypoxaemia on exercise, attributed to deterioration in V/Q matching on exercise, reduced saturation of mixed venous blood and where present, exercise shunting of right atrial blood through a patent foramen ovale (PFO). Though many of these physiological changes may exist to some extent at rest, CPET may help identify such abnormalities at earlier stages of pathological remodelling in PH, offering important clues as to the onset of clinical deterioration.

Fig. 1.

Summary of echocardiographic variables employed in during rest and exercise with typical representative views. Case represented is of a patient with severe congenital heart disease associated PAH demonstrating compressed LV by pressure and volume loaded RV (upper left panel). Further measurements include FAC: fractional area change, TV S′ Tricuspid valve S prime, TAPSE: tricuspid annual plane systolic excursion, RV FWS: free wall strain, PR Vmax: pulmonary regurgitant maximum velocity, TR Vmax: tricuspid regurgitation maximum velocity, LVEF: LV ejection fraction.

One example where CPET may be used diagnostically is in patients with connective tissue disease (CTD) who harbour an increased risk of developing PAH. Recently, a composite predictive model of three CPET parameters was shown to indicate the presence of PAH in patients with CTD.(15) This study found that the presence of low resting end tidal CO₂ (≤27.2 mmHg), together with low peak VO₂ (≤14.1 ml/kg/min) and a raised VE/VCO₂ slope (>34), predicted patients with a mean pulmonary artery pressure of 25 mmHg or greater in patients with CTD with a sensitivity of 87.5 % and 99.1 % for PAH [15]. CPET may therefore indicate those patients who could be prioritised for invasive haemodynamic testing with right heart catheterisation, thus allowing those with a normal exercise response on CPET to avoid the risks associated with this procedure.

CPET has also been shown to unmask early features of RV dysfunction in PAH including reduced contractile reserve [16], impaired RV lusitropy [17], and RV-PA uncoupling [1]. A high VE/VCO₂ slope is both poorly prognostic in PAH and been shown to correlate with increased RV diastolic stiffness and afterload measured by right heart catheterisation [17,18]. Reduced peak VO₂ in PAH further correlates with a blunted increase in stroke volume index and reflects the presence of RV-PA uncoupling, assessed by RV end-systolic elastance/pulmonary arterial elastance at right heart catheterisation during maximum exercise [1]. This study also showed that in patients with exercise PH, RV contractility appeared to be preserved, although its level was still insufficient to fully compensate for the increased afterload. Overall, reduced peak VO₂ and stroke volume index are present in both PAH and exercise PH and are associated with dynamic RV-PA uncoupling on exercise.

In summary, there are several useful key parameters measured on CPET which can help in the diagnosis of PAH and reflect prognostically important changes in RV contractile reserve and function.

2.3. Use of exercise imaging for PAH diagnosis

2.3.1. Echocardiography

Exercise echocardiography provides an non-invasive method of assessing pulmonary artery pressure responses to exercise in those with risk factors for pulmonary vascular disease, for example those with underlying connective tissue disease or mutation carriers of known genetic mutations associated with the development of PAH [19,20]. This has the clinical use as both a diagnostic and prognostic tool especially given potential for earlier identification of pulmonary haemodynamic abnormalities [21].

Current methods of resting haemodynamic assessment rely on pulmonary vascular resistance (PVR) as the principle descriptor of RV afterload. As described earlier, more detailed evaluation of RV function may be obtained through calculation of RV coupling which may be approached using either invasive or non-invasive methods [22,23]. At present however, neither approach is validated on exercise which limits limiting its current clinical deployment as a measure of exercise RV performance.

Despite established correlations between resting echocardiographic variables and peak VO₂, the increased use of exercise echocardiography may offer further insight beyond changes in systolic pulmonary artery pressure (sPAP) given incorporation of functional capacity, RV contractile reserve and left ventricular diastolic function in totality (Fig. 1). In PAH, an increase in echocardiographic-derived sPAP has demonstrated close association with improvement in 6MWD, peak VO₂, NYHA functional class and reduction in serum BNP [24]. However, agreement between invasively derived exercise pulmonary artery pressure measurements and those derived from exercise echocardiogram suggests a potential future role for echocardiographic surrogates of RV reserve which includes the estimation of RV coupling during exercise [25].

Concerns over validation of the use of exercise echocardiography include lack of reliability of the use of IVC collapsibility to estimate right atrial pressure during exercise, given changes in venous capacitance and respiratory pleural pressure swings. Secondly, the contribution of pulmonary capillary wedge pressure (PCWP) elevation and left ventricular filling to the rise in sPAP during exercise requires further investigation, given its potential increase in the setting of LV diastolic dysfunction [26,27]. Finally, the contribution of cardiac output to pulmonary artery pressure needs also to be considered which reflects the exercise response in PVR, a key metric in the accurate diagnosis of pulmonary vasculopathy.

2.3.2. Cardiac magnetic resonance

Cardiac MRI is frequently less available than echocardiography and comes at higher cost. Nevertheless, exercise CMR can also interrogate for abnormal pulmonary vascular reserve. On exercise, cardiac output and pulmonary artery pulse wave velocity increase both in healthy and patients with PH, while pulmonary artery relative area change decreases with an inverse linear relationship to PVR [28]. In PAH, exercise RV stroke volume responses assessed by CMR also differ according to WHO functional class potentially adding to current PAH risk stratification parameters [29]. Exercise CMR may also disclose abnormal pulmonary vascular function not evident at rest as shown in asymptomatic individuals with bone morphogenetic protein receptor type 2 mutations [30].

In patients with PAH and preserved resting RV function (RVEF >45 %), real time exercise CMR may expose several abnormalities in RV function such as reduced RV contractile reserve and an inability to increase stroke volume index [16]. PAH patients also increased their cardiac index 1.8-fold, significantly less than in normal subjects (2.5-fold), probably due to LV underfilling secondary to RV dysfunction. The ability to unmask RV dysfunction on exercise CMR before the development of resting RV dilatation and dysfunction could help to risk stratify patients non-invasively, for example in populations at increased risk of PAH progression such as those with connective tissue disease-associated PAH [31].

2.4. Exercise right heart catheterisation

Exercise PH is defined as a mean PAP/CO slope > 3 mmHg/L/min and is associated with worse functional capacity, abnormal RV contractile reserve and worse cardiovascular event-free survival [32]. The diagnostic cut-off for exercise PH has recently been further validated in a large multicentre exercise haemodynamic registry [33]. This study demonstrated the presence of exercise PH to be a robust and independent predictor of prognosis in patients with normal or mildly elevated resting pulmonary arterial pressure that provides prognostic information beyond well-accepted prognostic resting hemodynamic variables. This suggests that in patients with chronic dypsnoea in the setting of normal resting pulmonary haemodynamics, exercise is an important factor in unmasking abnormal pulmonary vascular responses that contribute to patients’ symptoms and survival. However, the treatment of exercise PH remains largely unexplored with no randomized studies of pulmonary vasodilators undertaken to date.

A further advantage of exercise RHC is its ability to detect not only the presence of PH in those with normal resting parameters, but provide clarification of the influences of pulmonary vascular and left heart disease in the pathophysiology of PH. This can lead to the re-classification of PH group in some cases. In one study, exercise RHC unmasked the presence of PH in 59 % of patients who did not have PH at rest [34]. Exercise also re-classified the PH diagnosis from PAH to PH-LHD in almost half of patients. Whilst the study was not powered to identify an association between a change in PH diagnosis or group and patient outcome, it did however show that quality of life was improved following exercise RHC and subsequent initiation of PAH therapy. Further studies evaluating the use of exercise during RHC have demonstrated its capacity to inform both the presence of exercise PH before and after pulmonary endarterectomy [35], as well as more detailed evaluation of RV performance informed by RV pressure volume loop physiology including evaluation of predisposing factors to RV failure [36], responses to endurance exercise [37], and effects of heart rate modulation (Fig. 2) [38].

Fig. 2.

Use of cardiopulmonary exercise testing and exercise right heart catheterisation in the diagnosis of PH. Upper panels: shown here are typical responses derived from non-invasive cardiopulmonary exercise test (CPET) for changes in ventilatory and cardiovascular parameters associated with resting PAH disclosed on upright exercise cycle ergometer (photo). Normal responses represented by dotted arrow with solid line reflecting expected changes in PAH. VO₂: oxygen uptake, VCO₂: carbon dioxide production, VE: minute ventilation, HR: heart rate, O₂ pulse: oxygen pulse, etCO₂: end tidal CO₂. Lower panels: changes in mean pulmonary artery pressure (mPAP), and cardiac output (CO) disclosed from supine exercise right heart catheterisation (photo), associated with normal exercise haemodynamic response (dotted arrow), and those associated with exercise PH (solid arrow). Exercise PH response also demonstrated (Ex PH). Lower right panel shows pressure volume (PV) loop representation of increased right ventricular contractile response between resting (green loop) and exercise (red PV loop) states. Ees: end systolic elastance of the right ventricle. Further abbreviations: PvO₂: mixed venous partial pressure of oxygen, Vd/Vt: physiological dead space to tidal volume ratio.

3. Exercise as a therapeutic intervention in PAH

Advances in PAH-specific therapies have extended patient survival and slowed disease progression, yet patients still contend with a high symptom burden and reduced quality of life (QoL). Underlying these are a complex interplay of factors such as RV dysfunction and pulmonary vascular remodelling, RV-PA uncoupling, reduced stroke volume, chronotropic incompetence, ventilatory abnormalities and skeletal muscle dysfunction. All of these factors reduce the transportation or uptake of oxygen during exercise. Exercise training is thought to improve patients’ exercise capacity and symptoms by modulating several of these underlying pathophysiological mechanisms, including oxidative stress, inflammation, vasoconstriction, vascular remodelling and thrombosis. However, exercise recommendations have historically been conservative due to concerns regarding increased pulmonary blood flow and subsequent shear effect on the pulmonary vasculature, risk of RV decompensation, arrhythmia and sudden cardiac death associated with more advanced disease.

Over the last 10 years, there has been a growing body of evidence supporting the safety and efficacy of supervised, low-intensity exercise specifically tailored for PH patients [[39], [40], [41], [42], [43], [44], [45], [46], [47]], and the European Respiratory Society (ERS) and European Society of Cardiology guidelines now recommend exercise training (Class 1; Level A evidence) as a means of helping improve exercise capacity, QoL and potentially RV function [48,49]. Yet, significant knowledge gaps remain concerning optimal training approaches, supervision characteristics, adaptive mechanisms, and long-term survival impacts. Here, we consider the existing evidence, as well as knowledge gaps, relating to the clinical impacts of exercise training and various training modalities in PH patients in order to enhance clinician awareness and its clinical application. The authors include a summary of key studies involving the use of exercise training in PH in Table 1.

Table 1.

Summary of exercise training interventional studies in PAH including population of interest, key methodologies, principle findings and conclusions.

Authors, year	Aims	Study type	Study size	Inpatient or outpatient exercise program	Results	Conclusions
Mereles D et al. (2006) (26)	To evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH.	Prospective randomised study	n = 30 patients with PH on stable disease-targeted medication were randomised to a control (n = 15) and a primary training (n = 15) group. Medication remained unchanged during the study period.	3 week in-hospital programme followed by continued exercises at home, supervised by phone every 2 weeks.	Patients in the training groups had improved 6MWD (mean difference between controls and the primary training group was 111 m (95 % confidence interval, 65–139 m; P < 0.001)), scores of QoL, WH-FC, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training (from 61 ± 18 to 54 ± 18 mm Hg) within the training group.	Respiratory and physical training could be a promising adjunct to medical treatment in severe PH.
Becker-Grünig et al. (2013) (27)	To assess the efficacy of ET as add-on to medical therapy in patients with CHD associated PAH	Prospective study	n = 20 consecutive patients were included.	In-hospital ET for 3 weeks and continued at home	In the ET group, there was significant improvement in 6MWD after 3 weeks (p < 0.001) and after 15 weeks (p = 0.001), QoL-score (p = 0.05), peak oxygen consumption (p = 0.002) and maximal workload (p = 0.003) after 15 weeks.	ET as add-on to medical therapy may be effective in patients with CHD associated PAH and improved work capacity, QoL and further prognostic relevant parameters.
Nagel C et al. (2012) (28)	To evaluate the effects of ET in patients with inoperable or residual CTEPH.	Single centre prospective study	n = 35 consecutive patients with invasively confirmed inoperable or residual CTEPH on stable disease-targeted medication.	In-hospital ET for 3 weeks, continued at home for 15 weeks. Medication remained unchanged during the study period.	All patients tolerated ET without severe adverse events. Patients significantly improved the mean distance walked in 6 min compared to baseline by 61 ± 54 m after 3 weeks (p < 0.001) and by 71 ± 70 m after 15 weeks (p = 0.001), as well as scores of QoL questionnaire, peak oxygen consumption and maximal workload. NT-proBNP improved significantly after 3 weeks of ET (p = 0.046).	Training as add-on to medical therapy may be effective in patients with CTEPH to improve work capacity, QoL and further prognostic relevant parameters
Grünig et al. (2012) (29)	To assess short- and long-term efficacy of ET as add-on to medical therapy in patients with CTD-associated PAH	Prospective study	n = 21 consecutive patients with CTD-associated PAH between 18 and 80 years and classified as WHO-FC II to IV. Patients had to be under optimized medical therapy for PAH and for the underlying rheumatologic disease for at least 2 months before entering the study.	In-hospital ET for 3 weeks and continued at home for 12 weeks	Patients significantly improved 6MWD compared to baseline by 67 ± 52 m after 3 weeks (p < 0.001) and by 71 ± 35 m after 15 weeks (p = 0.003), scores of QoL (p < 0.05), heart rate at rest, peak oxygen consumption, oxygen saturation and maximal workload. Systolic pulmonary artery pressure and diastolic systemic blood pressure improved significantly after 3 weeks of ET.	ET as add-on to medical therapy is highly effective in patients with CTD-associated PAH to improve work capacity, QoL and further prognostic relevant parameters
Ehlken et al. (2016) (37)	To investigate the effects of ET on peak VO2/kg, haemodynamics, and further clinically relevant parameters in PH patients.	Prospective randomised controlled study	n = 87 with PAH and inoperable CTEPH on stable disease-targeted medication, randomly assigned to a control (n = 41) and training group (n = 46). Medication remained unchanged during the study period.	3-week in-hospital exercise and respiratory training programme (at least 1.5 h/day ET 7 days a week, respiratory training 5 days/week). The training was continued at home; at least 15 min/day 5 days/week for the following 12 weeks.	In the ET group, there was significant improvement in peak VO2/kg (difference from baseline to 15 weeks: training +3.1 ± 2.7 mL/min/kg equals +24.3 % vs. control −0.2 ± 2.3 mL/min/kg equals +0.9 %, P < 0.001), cardiac index at rest and during exercise, mean pulmonary arterial pressure, pulmonary vascular resistance, 6MWD, QoL, and exercise capacity.	Low-dose ET at 4–7 days/week significantly improved peak VO2/kg, haemodynamics, and further clinically relevant parameters. The improvements of CI at rest and during exercise indicate that ET may improve the right ventricular function.
Morris et al. (2023) (44)	To evaluate the benefits and harms of exercise-based rehabilitation for people with PH compared with usual care or no exercise-based rehabilitation.	Systematic review including 14 RCTs. Most participants were women and classified as Group I PAH. Study durations ranged from 3 to 25 weeks.	n = 462 participants in meta-analyses comparing exercise-based rehabilitation to control groups.	Included both inpatient- and outpatient-based rehabilitation incorporating upper and lower limb exercise.	Following exercise-based rehabilitation, mean 6MWD was 48.52 m higher than control, mean peak oxygen uptake was 2.07 ml/kg/min higher than control and SF-36 questionnaire measures of QoL improved.	Supervised exercise-based rehabilitation may result in increased exercise capacity and improved QoL in patients with PH, and is probably not associated with an increased risk of serious adverse events.
Grünig et al. (2021) (46)	To evaluate efficacy and safety of ET in patients with PAH and CTEPH.	Prospective, randomised, controlled, multicentre study implemented in 11 centers across 10 European countries.	n = 116 on disease-targeted medication were randomised into training (n = 58) vs. usual care (n = 58).	In-hospital rehabilitation programme with mean duration 25 days, continued at home	Significant improvements in the training group vs. control group were seen in: 6MWD (increased by 34.1 ± 8.3 m) (95 % CI, 18–51 m; P < 0.0001), QoL (SF-36 mental health 7.3 ± 2.5, P = 0.004), WHO-FC (training vs. control: improvement 9:1, worsening 4:3; χ2P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048). ET was feasible, safe, and well-tolerated.	ET as an add-on to medical therapy in PAH and CTEPH patients is feasible, safe and well-tolerated.
Kahraman et al. (2023) (49)	The study aimed to examine the effects of IMT in patients with PH	Randomised controlled evaluator-blind study.	n = 24 patients with PH (treatment = 12, control = 12)	Outpatient IMT was performed at 40 %–60 % of the maximal inspiratory pressure for 30 min/d, 7 d/week (1 day supervised) for 8 weeks.	Brachial and central blood pressure, dyspnoea, respiratory muscle strength, diaphragm thickness in total lung capacity, knee extension muscle strength, functional exercise capacity, upper extremity functional exercise capacity, physical activity, ADL, fatigue, anxiety, and QoL improved in favour of the IMT group (p < 0.05)	IMT improved brachial and central blood pressure, dyspnoea, respiratory muscle strength, diaphragm thickness in total lung capacity, knee extension muscle strength, functional exercise capacity, upper extremity functional exercise capacity, physical activity, ADL, fatigue, anxiety, and QoL compared with the control group.
Zhao et al. (2021) (51)	To evaluate the effectiveness and safety of ET in CTEPH after PEA.	Meta-analysis and systematic review.	n = 208 exercise-training participants across 4 studies.	All studies used a supervised ET programme combined with aerobic exercise (treadmill or bicycle Ergometer) and resistance training. One study was performed at an outpatient rehabilitation centre, while three studies were performed in-hospital for the first few weeks followed by home-based ET.	There was a significant increase in the peak VO2/kg or peak VO2 after ET. 3 months of ET increased the right ventricular ejection fraction by 3.53 % (95 % CI: 6.31–11.94, P < 0.00001, I2 = 0) independently of PEA surgery. NT-proBNP significantly improved with ET after PEA [weighted mean difference (WMD): −524.79 ng/L, 95 % CI: 705.16 to −344.42, P < 0.0001, I2 = 0]. The partial pressure of oxygen and pH improved progressively over 12 weeks of ET (WMD: 4 mmHg, 95 % CI: 1.01–8.33, P = 0.01; WMD: 0.03, 95 % CI: 0.02–0.04, P < 0.0001, respectively). Subscales of the QoL measured by the SF-36 questionnaire also improved.	ET may be associated with a significant improvement in the exercise capacity and QoL among CTEPH patients after PEA and was proven to be safe.
Bussotti M et al. (2017) (54)	To evaluate the impact of a training program on functional outcomes in patients with PAH.	Observational study.	n = 15 patients with PAH in WHO-FC II or III and in a stable condition were included.	4-week ET programme conducted in the outpatient service.	Significant improvements were recorded in QoL (HADS-Anxiety mean change 3.5 ± 3.3 and HADS-Depression mean change 1.6 ± 2.0, all p < 0.01), functional capacity (6MWD increased from 455 ± 115 to 487 ± 120 (+8 %, p < 0.01), workload during CPET (increased by 22 %, p < 0.001), peak $\dot{\mathrm{V}}$ O2 (increased from 17.3 ± 4.2 to 19.9 ± 4.5 mL/kg/min (p < 0.001)) and pulse O2 (increased from 7.8 ± 1.8 to 8.8 ± 2.4 mL/beat (p < 0.01)). No adverse events or deterioration in clinical status were observed.	Cardiorespiratory training in a outpatient service is a suitable option for patients with PAH in WHO-FC II/III thanks to improved exercise capacity and QoL, which may allow them to achieve better outcomes.

3.1. Clinical effects of exercise training in PAH

Several randomised control trials (RCTs) have investigated the effectiveness of exercise training on exercise capacity, with the commonest primary end point being 6MWD and peak VO₂ on CPET [39,46,47,[50], [51], [52], [53], [54], [55], [56]]. A recent Cochrane review including 14 RCTs reviewed the benefits of exercise-based rehabilitation, predominantly in Group 1 PAH patients [57]. Study duration ranged from 3 to 25 weeks and included both inpatient and outpatient-based rehabilitation that incorporated upper and lower limb exercise. They found an improvement of 48.52m in 6MWD, a 2.07 mL/kg/min higher mean peak VO₂, and 9.6Watt higher peak power in the exercise training group. A randomised trial by Ehlken et al. included 87 patients with PAH and inoperable CTEPH and compared exercise and rest RHC data in those who had undergone a 15 week exercise training program vs. controls [50]. They found a significant increase in cardiac index (CI), decrease in mean pulmonary arterial pressure and PVR during maximal exercise in the training group vs. controls. Cardiac index during exercise has been reported to be an independent predictor of survival in PAH and these data suggest prognostic benefit from exercise training [58].

QoL tends to be poor in PH patients and a recent multicentre RCT showed improvements in QoL (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004) and WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; v2 p = 0.027) as secondary outcomes in the exercise training group [59].

PH patients often develop disease-related sarcopenia leading to skeletal and inspiratory muscle dysfunction negatively impacting the force-generating capacity of the diaphragm. These changes manifest as leg fatigue and breathlessness during exercise and are independently associated with reduced exercise capacity [60,61]. Exercise training in PAH has been associated with a switch to use of type 1 (oxidative) muscle fibres [43], and quadriceps muscle training and endurance training (cycling) have been shown to improve endurance capacity [52]. Though several studies have reported an improved QoL and exercise capacity, and reduced breathlessness symptoms in PH patients after inspiratory muscle training (IMT), the evidence was less clear in a more recent systematic review, indicating that larger RCTs are required to better understand the benefits of IMT [62]. A summary of effects of exercise training on organ systems in PH is displayed in Fig. 3.

Fig. 3.

Summary of potential associated effects of exercise training in PH summarized by organ system. TAPSE: tricuspid annular plane systolic excursion, RV: right ventricular, BP: blood pressure, QoL: Quality of Life. Diagram of exercise modalities made available via Bioreader, with source material based on Ref 48.

3.2. Effect of exercise training in different PH groups

Exercise training has been reported to benefit patients regardless of the aetiology and type of PH [43,63]. However the majority of evidence to date has been observed in those with Group 1 PAH or CTEPH [64]. Exercise training in addition to medical therapy may be highly effective in patients with CTD-associated PAH with respect to improvements in exercise capacity, QoL and possibly prognosis [42]. Exercise physiology in congenital heart disease associated-PAH is significantly more complex due to the anatomical and pathophysiological heterogeneity in this population and very few studies have investigated the role of exercise training in this group [42,65]. Some non-randomised studies found that exercise training improved 6MWD, QoL and peak VO₂, indicating that exercise training may be an effective adjuvant therapy for patients with this form of PAH. It is however accepted that carefully considered personalised exercise prescriptions, with input from a clinical expert in adult congenital heart disease, may be beneficial in this PH subgroup.

3.3. Adverse events and safety

A recent large multicentre study in Europe revealed that the total number of adverse events was similar between patient undergoing exercise training and those in the non-training group [59]. However, patients in the training group exhibited a greater dropout rate during the study. Importantly, none of the serious adverse events in the study were attributed to the training intervention. Reported side effects include excessive fatigue, muscle aches, back pain, decompensated diabetes, generalized oedema, stroke, and severe light-headedness necessitating exercise termination.

Adverse events are more likely to occur within the initial few weeks of training, but as patients become more aware of their limitations, the occurrence of adverse events diminishes. Overall, the net benefit of exercise training appears to be most pronounced in stable, optimized patients without high-risk clinical features, particularly when they are prescribed a low-intensity exercise regimen within a closely supervised and monitored environment.

3.4. Exercise training modalities and settings

Currently, there is no standardised protocol for exercise training that is recommended in the management of PH. Studies have employed various settings for exercise, including a 3-week inpatient stay followed by outpatient (OP) ambulatory exercise (akin to the Heidelberg model) [[39], [40], [41]], outpatient-based exercise programs supervised by specialist PH centers, or home-based programs [45,47,52,66,67]. Inpatient-based training programs offer close clinical supervision and allow for titration of exercise regimes and training intensity based on clinical parameters. However, they are resource-intensive and may not be universally applicable in many healthcare settings. Outpatient-based programs typically entail 2 to 3 sessions per week for up to 12 weeks, employing a variety of training frequencies and total training durations. Home-based training with virtual monitoring represents a promising future direction, as the convenience of training at home can enhance patient compliance and is economically attractive.

In terms of exercise modality, various combinations of aerobic and strength training have been used, including treadmills, ergometers, cross trainers, resistance training with dumbbells targeting specific muscle groups, and inspiratory muscle training via various breathing techniques. Exercises are typically conducted at low intensities (60–80 % of peak exercise heart rate), monitored subjectively using parameters including the Borg scale, and objectively through oxygen saturations and heart rate, which help guide adjustments in training intensity in each individual.

Effective delivery of an exercise program in PH patients requires a multidisciplinary team involving physiologists, physiotherapists, psychologists and clinicians and nurse specialists with PH expertise, as well as an individualised exercise prescription which describes the type, workload, intensity, duration and frequency of the exercise activity recommended. Practical advice on day-to-day activities, psychological support, relaxation techniques, and good patient education are also very important in maintaining patient engagement in the program. Future studies are required to directly compare different exercise training settings and modalities in order to identify the most effective exercise activities in PH patients.

3.5. Practicalities of implementing exercise training in PH patients

Success of an exercise program for PH patients hinges on four essential steps: patient selection, compliance, motivation, and integration with the healthcare system. First, selected patients must be clinically stable without recent changes in PH medications, and so it is crucial to engage a PH expert when selecting appropriate patients and to oversee the exercise program.

Secondly, patient compliance and motivation play a pivotal role in exercise training because the benefits are dose-dependent and directly linked to adherence to the training regimen. Educating patients about the disease's natural progression, pathophysiology, and the impact of exercise can positively influence motivation, thereby improving adherence. Common barriers such as fear, frustration, and uncertainty about exercise need to be addressed, along with intrinsic factors like breathlessness and fatigue, and external factors like cost and access to appropriate services [68]. If compliance issues arise, it is important to review environmental, social, and cultural factors affecting beliefs about the role of exercise. Tailoring therapy to each individual, involving family or friends in exercise routines, setting realistic long-term goals at the outset of training, and making adjustments as needed are all crucial for maintaining patient motivation. Finally, raising awareness among healthcare providers about the benefits and role of exercise training in PH is also required. Fig. 4 summarizes elements of the above.

Fig. 4.

Summary flow diagram of methods and interventions aimed at optimization of delivery of exercise training in all forms of PH.

Currently, the optimum time frame from achieving clinical stability to being able to begin an exercise program is still unclear and future research should focus on this as well as identifying optimal strategies for sustaining long-term exercise training in PH patients.

3.6. Limitations and future directions

Despite guidelines recommending supervised exercise training in the management of PH, access to such facilities remains limited in many European countries. Exercise settings and modality may also be highly variable due to differences in healthcare organisation and funding. Health economic studies could play a pivotal role in convincing healthcare providers and stakeholders of the positive impact of exercise training, potentially leading to the establishment of more rehabilitation facilities and improved patient access to this treatment intervention. Future research conducted across different countries with diverse healthcare systems and larger-scale multicentre studies are a necessary step towards achieving this goal.

It is also important to note that studies investigating the benefit of exercise training in PH patients have traditionally used outcomes such as 6MWD and peak VO₂ as indirect measures of disease modification and prognosis [69], and some have adopted additional parameters such as muscle strength, endurance, and physical and mental QoL assessed by the SF-36 questionnaire. However, the impact of exercise rehabilitation on disease progression or modification is not yet demonstrated. To advance our understanding, future studies should focus on investigating hard endpoints beyond the 6MWD and peak VO₂, for example, exercise echocardiography may offer more meaningful information beyond exercise capacity by measuring RV contractile responses during exercise, though further data is required. Greater insight from studies may also be gained by using PH-specific QoL questionnaires (Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), emphasis-10, or the PAH-Symptoms and Impact Questionnaire (PAH-SYMPACT)).

Designing high-quality studies in PH patients presents challenges, including difficulties in blinding studies which can introduce bias, the risk of unsupervised self-training among control group members post-randomization, and referral bias that may disproportionately enroll more active and compliant patients in trials. These issues must be carefully addressed and resolved in future studies to ensure robust findings. Furthermore, assessing the impact of exercise training in PH is complex due to the varying effects of different PH subgroups on natural history, disease progression, and survival. Future studies should stratify and analyze the effects of exercise training in individual PH subgroups, which will likely influence the classification of exercise recommendations by disease classification.

4. Conclusions

Exercise has a pivotal role to play in the diagnosis and management of PH. Importantly, we have seen that several modalities of exercise testing can help to unmask abnormal pulmonary vascular physiology even in those where resting pulmonary haemodynamics are normal, which is of particular benefit in screening for PH in those at risk, and in aiming for an earlier diagnosis to achieve, where indicated, timely initiation of PAH specific therapy. Exercise in the treatment of PH is also a useful adjunct to medical therapy and has been shown to improve 6MWD and peak VO₂, markers of patient prognosis, as well as QoL and exercise capacity, with no significant adverse event profile. However, optimal exercise training programs for PH patients, and the impact of exercise training on specific PH subgroups require further clarification.

CRediT authorship contribution statement

Myo Lwin: Conceptualization, Data curation, Resources, Writing – original draft, Writing – review & editing. Abigail Masding: Data curation, Resources, Writing – original draft, Writing – review & editing. Colm McCabe: Conceptualization, Data curation, Methodology, Resources, Visualization, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The authors have no conflicts of interest to declare in relation to any aspect of this work.