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

Abstract

Introduction

Pulmonary hypertension (PH) is a broad pathophysiological disorder primarily characterized by increased pulmonary vascular resistance due to multiple possible etiologies. Patients typically present with multiple complaints that worsen as disease severity increases. Although initially discouraged due to safety concerns, exercise interventions for patients with PH have gained wide interest and multiple investigations have established the effective role of exercise training in improving the clinical profile, exercise tolerance, and overall quality of life.

Areas Covered

In this review we discuss the pathophysiology of PH during rest and exercise, the role of cardiopulmonary exercise testing (CPX) in the diagnosis and prognosis of PAH, the role of exercise interventions in this patient population, and the expected physiological adaptations to exercise training.

Expert Opinion

Exercise testing, in particular CPX, provides a wealth of clinically valuable information in the PH population. Moreover, the available evidence strongly supports the safety and efficacy of exercise training as a clinical tool in improving exercise tolerance and quality of life. Although clinical trials investigating the role of exercise in this PH population are relatively few compared to other chronic conditions, current available evidence supports the clinical implementation of exercise training as a safe and effective treatment modality.

1. Introduction

Pulmonary hypertension (PH) is a broad pathophysiological disorder defined by a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest, measured by right heart catheterization (RHC) [1,2]. PH can be isolated within the pulmonary vasculature (pulmonary arterial hypertension [PAH]), or present as a complication to another established pathology (e.g., chronic obstructive lung disease, left heart failure, thromboembolism). As such, five main PH classifications have been established according to the underlying cause (Table 1) [1]. When considering PAH (group 1) specifically, multiple etiological factors and subgroups have been identified and described. These include; hereditary conditions, connective tissue disease, infections such as human immunodeficiency virus and schistosomiasis, drug- and toxin-induced PAH, portal hypertension, and idiopathic PAH. Consequently, these etiologies contribute to endothelial dysfunction, loss of small pulmonary vessels, vascular remodeling, and stiffening of the vascular walls. Based on multiple hemodynamic variables, PH can also be grouped based on distinct hemodynamic variables into precapillary PH if the underlying cause arises from pulmonary vascular remodeling leading to increased pulmonary vascular resistance (PVR), postcapillary PH if resulting from increased pulmonary venous pressure due to left-sided heart disease, or a combination of postcapillary and precapillary PH [3].

Table 1.

Generalized clinical classification of pulmonary hypertension [1].

Group 1	Pulmonary arterial hypertension
Group 2	Pulmonary hypertension due to left heart disease
Group 3	Pulmonary hypertension due to lung disease and/or hypoxia
Group 4	Chronic thromboembolic pulmonary hypertension and/ other pulmonary artery obstructions
Group 5	Pulmonary hypertension with unclear and/or multifactorial mechanisms

Epidemiological studies have revealed a mean age of diagnosis between 50–53 years, with females having greater prevalence rates [4,5]. Within the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Registry conducted in the United States, the female-to-male ratio was reported to range from 3.8:1 to 4.1:1 according to disease etiology [5]. However, the French registry [4] reported a 1.9:1 ratio. Although the exact reason for this discrepancy is not clear, both registries demonstrated that female sex was positively associated with survival rates [5,6]. Although data on racial discrepancies are limited, recent reports have shown that 79% of patients with PAH are non-Hispanic whites, 11% were African-American, and 10% were Hispanic [7]. African-American and Hispanic patients also appear to be younger and have higher female prevalence rates [7].

Patients with PH present with a myriad of signs and symptoms usually starting with dyspnea on exertion, fatigue, coughing, dizziness, and syncope. Symptoms will initially present during exertion and later present during rest in more advanced stages. Due to the lack of specificity regarding these symptoms, they are likely to be dismissed at first under the assumption of a general lack of aerobic conditioning and reduced cardiorespiratory fitness (CRF). As a result, the mean time from symptom onset to diagnosis is approximately 3 years [5], resulting in significant treatment delays.

In this review we will discuss the pathophysiological changes in PAH that can be detected by cardiopulmonary exercise testing (CPX), the role of CPX in the diagnosis and prognosis of PAH, the role of exercise interventions as an add-on to medical therapy, and the expected adaptations to exercise training in this patient population.

2. The Pathophysiology of PAH During Rest and Exercise

As in the systemic circulation, blood flow in the pulmonary circulation is determined by the physical relationship between pressure and resistance [8]. Pulmonary blood flow is directly proportional to the pressure gradient between the pulmonary artery and the pulmonary capillary and inversely proportional to pulmonary vascular resistance (PVR). Pulmonary artery pressure (PAP) can be determined clinically via RHC while pulmonary capillary pressure can be determined clinically via pulmonary artery wedge pressure (PAWP) [3]. By rearranging the relationship, PAP is the product of cardiac output (CO) and PVR.

Unlike other physiologic systems, the lungs are taxed with receiving the total amount of CO. This also means that when CO increases, such as during exercise, PAP would be expected to rise. However, under normal conditions PAP does not rise significantly due to a significant drop in PVR that would offset the effect of increased CO. The significant drop in PVR during exercise in healthy individuals is a result of increased capillary recruitment leading to increased cross-sectional area of the vascular bed, especially in the lung apices. Vasodilation of already recruited capillaries is another important contributor to the drop in PVR. Without this decrease in PVR, an increase in PAP would occur and place significant load on the right ventricle (RV) as well as increase the capillary hydrostatic pressure, forcing fluid out of the vasculature and into the alveoli. This increase of pulmonary capillary filtration into the alveoli would impair optimal oxygen diffusion and lead to arterial hypoxemia. A decrease in oxygen diffusion will also lead to hypoxic vasoconstriction of the pulmonary vessels and thus further increases in PVR [9]. It can therefore be realized that the increased PVR seen in PH can result from vasoconstriction of the pulmonary vasculature, decreased arterial compliance, increased arterial stiffness, and reductions in lumen size due to vascular remodeling or in situ thrombosis. Given the contribution of elevated PVR to the development of PAH, a PVR ≥ 3 Wood units is an important inclusion criterion in the definition of PAH [1], and has been recommended for the definition all precapillary PH [10].

In early disease stages the increase in PVR can be appropriately compensated during rest. However, with the stress of exercise, the body loses the ability to appropriately compensate for the excessive increase in PVR. This leads to reduced pulmonary perfusion and an increase in physiological dead space (V_D), an increase in the dead space to tidal volume ratio (V_D/V_T), and a consistently positive arterial-end tidal PCO₂ difference [P(a-ET)CO₂]. In an attempt to compensate for the ventilation-perfusion mismatch, minute ventilation (VE) is increased leading to reduced ventilatory efficiency demonstrated by increases in minute ventilate/carbon dioxide production (VE/VCO₂) [11]. Furthermore, the arterial hypoxemia that develops leads to stimulation of the carotid bodies and drives further increases in VE and reductions in ventilatory efficiency. As a result of the increased ventilatory drive and reduced ventilatory efficiency, patients with PH may experience dynamic hyperinflation, even in the absence of resting airflow obstruction, which will also contribute to dyspnea on exertion and exercise intolerance (Figure 1) [11–13].

Figure 1. Pathophysiology of PAH during rest and exercise.

Increases in PAP drive increases in pulmonary capillary hydrostatic pressure that will eventually increase pulmonary capillary filtration causing alveolar edema and reduced oxygen diffusing capacity. The resulting hypoxia triggers hypoxic vasoconstriction of the pulmonary vasculature and increases PVR. The increase in PVR leads to physiological shunting and an increased V_D/V_T ratio. In attempts to compensate, VE will increase causing inefficient ventilation that will be evident by an increased VE/VCO₂ ratio. The increased VE will also cause dynamic hyperinflation and eventually DOE and exercise intolerance. LA: left atrium; MV: mitral valve; HF: heart failure; PAP: pulmonary artery pressure; RV: right ventricle; LEDV: left end diastolic volume; CO: cardiac output; P_pc: hydrostatic pressure of the pulmonary capillaries; PVR: pulmonary vascular resistance. V_D/V_T: dead space to tidal volume ratio; VE: minute ventilation; VE/VCO₂: minute ventilation to carbon dioxide production; DOE: dyspnea on exertion.

In patients with PH, the increased mPAP leads to significant increases in afterload imposed on the RV. As a result, blood flow through the pulmonary circulation is reduced leading to a reduction in left end-diastolic volume (LEDV) and CO. The increased afterload can lead to RV enlargement and overload which can lead to a leftward shift in the interventricular septum that would further impair left ventricular function and CO [14]. Furthermore, patients with PH also experience peripheral impairments in 1) skeletal muscle such as a reduction in type 1 fiber density, 2) microcirculatory function, 3) overall oxygen extraction ability, and 4) mitochondrial dysfunction [11,15–20]. Altogether, these pulmonary, cardiac, muscular, and bioenergetic limitations contribute to reduced peak oxygen consumption (VO₂), a primary measure of exercise capacity and CRF.

3. The Role of Cardiopulmonary Exercise Testing in PAH

Considering the multisystemic, pathophysiologic consequences of PAH and the associated exertional symptoms, CPX, combining traditional exercise testing techniques with ventilatory expired gas analysis, serves as an ideal exam to identify abnormalities that may indicate PAH [21]. As outlined earlier, impairments in the pulmonary, cardiac, and skeletal muscle systems, contribute to reductions in peak VO₂, which has been widely documented to be a strong prognosticator [22–24]. In patients with PAH, peak VO₂ values <10.4 ml•kg⁻¹•min⁻¹ are associated with a 50% one-year survival rate [25]. Furthermore, the VO₂ response to an increasing workload has also been shown to be independently associated with prognosis; 82.7% of patients with a change in VO₂ to change in work rate ratio >5.5 ml/min/Watt were free from a negative PAH-related event over a five-year observation period [26]. However, because many health disorders and lifestyle behaviors (i.e., heart failure, cardiovascular disease [CVD], morbid obesity, physical inactivity, high sedentary time) are associated with reduced peak VO₂ values [27–31], additional ventilatory measures are necessary to refine the diagnostic applications of CPX to detect PAH.

The assessment of ventilatory inefficiency, quantified either by an increase in VE/VCO₂ or a decrease in the partial pressure of end tidal CO₂ (P_ETCO₂), have emerged as telling markers of elevated pulmonary pressures and have been shown to correlate well with an abnormal V_D/V_T ratio [32]. An elevated VE/VCO₂ slope in response to graded exercise, particularly at the ventilatory threshold, is partly attributed to reduced blood flow and pulmonary vascular perfusion due to impaired RV CO. The inadequate removal of CO₂ from the system thereby triggers a hyperventilatory response. Similarly, the inadequate perfusion of the alveoli contributes to a decrease in P_ETCO₂. VE/VCO₂ slope/ratio and P_ETCO₂ values above 30 and below 36 mm Hg, respectively, increase the likelihood of a PAH diagnosis [32]. Although, VE/VCO₂ at the ventilatory threshold has been found to have the strongest prognostic value, the VE/VCO₂ slope obtained over the course of a CPX also holds prognostic value [33,34]. This is especially useful due to patient specific barriers to providing a maximal effort.

Elevated PAPs as a consequence of PAH are associated with RV structural and functional abnormalities. Right ventricular and right atrial area has been closely associated with reduced right ventricular contractile reserve, represented by reduced cardiac output increase during exercise [35]. This was confirmed through right heart catherization during exercise in patients with early PAH [36]. Incorporating echocardiography during or immediately after a graded exercise test enhances the diagnosis and prognosis of PAH [37]. Under normal conditions, upon initiating exercise, a decrease in PVR and an increase in mPAP as a function of increased RV CO should occur. Under abnormal conditions, a reduced increase in pulmonary arterial systolic pressures (PASP) <30 mm Hg portents a worse prognosis [38]. Furthermore, assessment of RV size changes during an exercise test can help discern between healthy individuals and those with PH. Where healthy individuals experience a decrease in RV end-systolic area, end-diastolic area, and mid-diameter compared to those with PH, which exhibit an increase in these values [39]. Additionally, there are compelling observations that incorporated resting echocardiography and CPX data to evaluate the efficacy of PAH treatment [40]. Patients that have experienced a high change in cardiac index and peak VO₂ after one year of treatment have been found to have 100% event-free survival over a three year period, whereas individuals with low change in cardiac index and peak VO₂ had event-free survival rates of 72% one year after treatment, 54% two years after, and 33% three years after [40]. Due to the added benefits of incorporating CPX in the clinical management of PAH patients, the European Society of Cardiology and European Respiratory Society Guidelines for the diagnosis and treatment of PH [1] recommends performing CPX at baseline and 6–12 months to assess a patient’s response to treatment.

CPX with or without echocardiography are attractive clinical tools that can be used in diagnosing and managing PAH. Their non-invasive nature also allows for them to be widely implemented across clinical settings and reduces the burden on patients. Moreover, as discussed in this review, physical activity and exercise training (both aerobic and strength) are highly recommended to improve fitness and quality of life in patients with PAH. Data acquired during CPX can provide a wealth of information regarding level of effort put forth during the test, peak heart rate, blood pressure, and workload responses that can be utilized to optimize a patient’s exercise training plan [41]. Collectively considering the clinical utility of CPX in this population, we strongly promote its application within the continuum of patient care.

4. Exercise Training as a Treatment for PAH

Patients with PH demonstrate impaired exercise capacity and tolerance due to multiple factors. Historically, exercise training (ET) was discouraged for this patient population due to safety concerns, notably acute elevation in pulmonary artery pressures and potentially right heart failure. However, several clinical trials, in similar fashion to the early ET studies in patients with heart failure [42,43], have challenged this historical view by demonstrating that when dosed appropriately ET may result in improved clinical outcomes with low adverse events in patients with stable PH [44–50]. Additionally, recent systematic reviews with meta-analysis have reported that ET for patients with PH is safe, and is associated with improved exercise capacity, quality of life, and PAP [51–54]. Multiple professional organizations have now also included exercise training as a recommendation for the management of stable PH [1,2,55]. The following section will summarize the available evidence regarding ET for patients with PH.

4.1. Training protocols

Most studies investigating the effects of ET in patients with PH utilized a combined ET (CET) protocol (Table 2). In these CET protocols, aerobic ET (AET) was the primary exercise intervention and patients also performed low intensity resistance ET (RET), stretching exercise, breathing exercises, and respiratory muscle training (RMT). The most often utilized mode of AET in the available clinical studies was stationary cycling at intensities ranging between 60–80% of maximal heart rate (HR_max) measured during CPX. The training duration utilized has ranged between 10–15 weeks at various training frequencies per week. All published clinical trials investigating ET in PH have utilized supervised or semi-supervised programs, the latter of which entails patients being monitored at home with routine follow-ups. Several studies have also utilized a two-phase training protocol based on the first RCT investigating the effects of ET in patients with PH by Mereles et al [47]. Phase 1 involved 3 weeks of hospital-based ET at a high training frequency and volume (5–7 sessions/week for at least 1.5 hrs/day) [44,47–49]. Phase 2 involved 12 weeks of home-based ET at a lower training frequency and volume (5 sessions/week for 15–30 min/day) with follow-ups conducted via phone call every 2 weeks [44,47–49].

Table 2.

Characteristics of Exercise Testing Studies in Patients with PH. ET, exercise training; AET, aerobic exercise training; CET, combined exercise training; IMT, inspiratory muscle training; RET, resistance exercise training; HRR, heart rate reserve; CPX, cardiopulmonary exercise test; 6MWD, 6-minute walk distance; MSE, muscle strength exercise; MEE, muscle endurance exercise.

Study	N	PH Cause	Functional Classification	Design	Groups	Training Type	Training Protocol	Minimal Total Weekly ET Volume (min/week)	Modes Used	Serious Adverse Events	Compliance Rate
Weinstein A et al 2013	24	PAH	WHO: I n = 1; II n = 12; III n = 10; IV n = 1	RCT	ET (n= 11) vs Control (n=13)	AET	ET: 10 weeks, 3 sessions/week, 30–40 minutes of supervised AET at 70–80% HRR, and 20 1hr Education Sessions; Control: 1hr Education sessions, 2/week for 10 weeks	90	Treadmill	None Reported	Patients completed 26.8/30 visits
Fox B et al 2011	22	PAH or CTEPH	NYHA: II n = 13; III n = 9	RCT	ET (n= 11) vs Control (n=11)	AET and CET	ET: Part 1, 6 weeks, 2 sessions/week, 1hr of supervised AET at 60–80% of Max HR determined during CPX. Part 2: 6 weeks, 2 sessions/week, 1hr of supervised combined training, at 60–80% HRMax determined during CPX. Control: Normal Daily Physical Activity	Part 1: 120 Part 2: 120	Cycling, Treadmill, Step Climbing, Weight Training, Body Weight Exercises	None Reported in ET and 3 in Control	95%
Nagel C et al 2012	35	CTEPH	WHO: II n = 7; III n = 26; IV n = 2	Non-Randomized, Single Group, Prospective Clinical Trial	ET (n = 35)	CET	Same as Mereles D et al (except Part 1, 3 weeks, 5 sessions/week, 1.5hrs of supervised CET. Part 2: 12 weeks, 5 sessions/week for at least 30 minutes)	Part 1: 450/week Part 2: 150	Stationary Cycling, Step Climbing, Dumbbell Weight Training, RMT	None Reported	Not Provided
Mereles D et al 2006	30	PAH or CTEPH	WHO: II n = 6; III n = 22; IV n = 2	RCT	ET (n = 15) vs Control (n = 15)	CET	ET: Part 1, 3 weeks, 7 sessions/week, 10–25min/session of supervised low intensity AET at 60–80% of Max HR determined during CPX, 30 min of low intensity RET, 30 min of RMT, Breathing Exercises and Yoga, and 5 sessions/week 60 min of low intensity over ground walking Part 2: 12 weeks, 5 sessions/week home-based CET for 15–30 minutes, and 15 to 30 min of RET and RMT every other day. Control: Normal Daily Physical Activity	Part 1: 630 Part 2: ~120	Stationary Cycling, Step Climbing, Dumbbell Weight Training, RMT	None Reported	92%
Grünig E et al 2011	58	PAH or CTEPH	WHO: II n = 10; III n = 44; IV n = 4	Non-Randomized, Single Group, Prospective Clinical Trial	ET (n = 58)	CET	Same as Mereles D et al	Part 1: 630 Part 2: ~120	Stationary Cycling, Step Climbing, Dumbbell Weight Training, RMT	No Serious Events, 2 episodes of dizziness	Not Provided
Ehlken N et al 2016	87	PAH or CTEPH	WHO: II n = 14; III n = 66; IV n = 4	RCT	ET (n = 46) vs Control (n = 41)	CET	Same as Mereles D et al (except ET during Part 2 was 12 weeks of 5 sessions/week of least 15min )	Part 1: 630 Part 2: 75	Stationary Cycling, Step Climbing, Dumbbell Weight Training, RMT	None Reported	Not Provided
Grünig E et al 2012	183	PAH, CTEPH and Secondary PH	WHO: I n = 2; II n = 26; III n = 137; IV n = 18	Non-Randomized, Single Group, Prospective Clinical Trial	ET (n =183)	CET	Same as Mereles D et al (except ET during Part 2 was 12 weeks of 5 sessions/week of least 30 min CET)	Part 1: 630 Part 2: 150	Stationary Cycling, Step Climbing, Dumbbell Weight Training, RMT	25 total during Part 1 (only 3 related to exercise), None during Part 2	Not Provided
deMan FS et al 2009	19	PAH	NYA: II n = 3; III n = 16	Non-Randomized, Single Group, Prospective Clinical Trial	ET (n = 19)	CET	ET: 12 weeks, 3 sessions/week, supervised, CET (20–25 min Interval Cycling at 50–70% VO2Max, and MSE 50–75% 1RM, MEE 30–40% 1RM)	~90	Stationary Cycling, Quadriceps Muscle Training	No Serious Events, 2 episodes of dizziness	91 ± 2%
Chan L et al 2013	23	PAH	WHO: I n = 1; II n = 12; III n = 9; IV n = 1	RCT	ET (n = 10) vs Control (n = 13)	AET	ET: 10 weeks, 24–30 total sessions, 30–45 minutes of supervised AET at 70–80% HRR, and 1/week, 1hr Education Sessions; Control: 10 weeks, 1/week, 1hr Education sessions	~90	Treadmill	None Reported	Patients completed 27.8/30 visits
Ley S et al 2013	20	PAH or CTEPH	WHO: II n = 4; III n = 16	RCT	ET (n= 10) vs Control (n=10)	CET	ET: Part 1 of Mereles D et al protocol	630	Stationary Cycling, Step Climbing, Dumbbell Weight Training, RMT		Not Provided
Gonzalez-Saiz L 2017	40	PAH or CTEPH	NYHA?????	RCT	ET (n=20) vs Control (n=20)	CET	ET: 8 weeks, 5 sessions of AET for 20–40min/session at 50% of AT, 3 sessions of whole body RET for ~30min, and 12 sessions (6 sessions 2/day) of RMT for 5 min at 40% MIP	150	Stationary Cycling, Dumbbell Weight Training, RMT	No Serious Events, 1 episode of dizziness and 1 episode of AVNRT	90%

There is a growing number of studies exploring RMT as a treatment option in patients with PH [56–58]. Respiratory muscle training may be particularly useful in patients with PH since impaired respiratory muscle performance is often observed which may contribute to increased perceptions of dyspnea in this population [59,60]. Respiratory muscle training is also performed while seated and in shorter time periods which may help improve adherence to training. However, the available evidence investigating the isolated treatment effects of RMT or potential additive effects when combined with CET is limited, yet promising. An RCT by Saglam et al [56] reported that 6 weeks of RMT at 30% of maximal inspiratory pressure (MIP) performed for 30 minutes 7 days/week resulted in statistically significant improvements, both within group and compared to control, in 6MWD (50m), MIP (26.14 +/− 12.15 cmH₂O), dyspnea, and perceptions of fatigue [56].

Due to the frequent use of CET protocols in the available clinical trials, the specific type of training (AET, RET, RMT) which provides the greatest benefit to patients with PH remains uncertain. However, this also indicates that a CET protocol in patients with PH is an effective modality of ET for patients with PH. This uncertainty regarding type of exercise has valuable clinical implications considering that in practice a CET protocol is typically utilized, and rarely would a single type of ET be used or recommended to patients for a home exercise program.

4.2. Monitoring Considerations

In all available studies, the supervision and monitoring of ET was performed by a physician specialized in physical rehabilitation or pulmonology or other qualified health professional (e.g., physiotherapist, exercise physiologist, etc.). Most ET sessions either took place onsite at experienced PH clinics or at home with close monitoring by experienced clinicians. Patients were continuously monitored for HR, blood pressure (BP), and oxygen saturation throughout the duration of exercise training. If oxygen saturation decreased below 90% during ET, patients received supplemental oxygen (3–10 L/min) throughout ET [47]. If oxygen saturation dropped below 85%, or HR exceeded 120 bpm, the training session was paused or terminated early [47]. If systolic BP decreased greater than 20 mmHg or below baseline, increased above 220 mmHg, or if diastolic BP increased above 110 mmHg exercise was stopped until these variables returned to baseline levels [58]. If electrocardiography (ECG) monitoring was utilized and previously non-reported ECG abnormalities occurred, exercise was stopped until they disappeared [58].

4.3. Safety and Adverse events

When appropriately prescribed, and with adequate supervision and monitoring, ET for patients with PH is safe [51]. The available clinical trials investigating the role of ET in patients with PH have reported no serious adverse events related to ET. Four different studies have reported a total of 9 adverse events related to exercise, which were primarily minor dizziness or a cardiac abnormality that occurred either during training or immediately afterward [48,58,61,62]. Interestingly, a study by Fox et al, reported that participants in the ET group experienced no serious adverse events while those in the control group experienced three events[50].

It is also important to acknowledge that the available clinical trials utilized protocols at relatively low exercise intensities [44,46–50,58,61,62] and patients were monitored closely. This indicates that the therapeutic range of intensity for effective and safe exercise training in patients with PH is perhaps small. Patients in these studies were also clinically stable and pharmacologically controlled for at least 3 months prior to initiation of ET. Additionally, most patients enrolled in these studies had a functional status of either NYHA/WHO class II and III and few were class IV. However, there is evidence that patients with PH of lower functional classification may potentially demonstrate greater improvements following ET than those of a higher functional classification [61].

4.4. Feasibility and Compliance

The compliance rate for ET studies in patients with PH is excellent. The available clinical trials which have provided data on compliance all report rates over ~90% [45,47,58,60]. These high compliance rates to ET may be due to the close monitoring implemented in these studies [45,47,58,62], which occurred even if a study involved a home-based phase of the training protocol [47]. These excellent compliance rates strengthen the validity of the observed training effects in these studies. However, a referral, attendance, and exercise compliance rate of 90% over 8–15 weeks of care may not be readily achievable in ambulatory or home-based clinical settings, a phenomenon frequently observed in cardiac rehabilitation [63]. Therefore, similar to cardiac rehabilitation, ongoing efforts are needed to monitor and optimize referral, participation, and compliance to ET in the PH population in order to ensure translation of promising research findings into standard clinical practice.

4.5. Adaptations to Exercise in Patients with PH

The following section describes the evidence regarding treatment effects of ET in patients with PH on key clinical markers for this population. A tabulation description of these effects has been provided in (Table 3).

Table 3.

Reported clinical and physiological adaptations to exercise training in patients with PH. RV, right ventricular; QOL, quality of life; PA, physical activity

Study	6MWD	Peak VO2	%Predicted Peak VO2	Peak Workload	Muscle Strength	Muscle Endurance	RV Function	Pulmonary Vasculature Function	Ventilatory Efficiency	Survival	QOL	Spontaneous PA
Weinstein A et al 2013	↑	N/A	N/A	↑	N/A	N/A	N/A	N/A	N/A	N/A	↑	N/A
Fox B et al 2011	↑	↑	N/A	-	N/A	N/A	-	-	-	N/A	N/A	N/A
Nagel C et al 2012	↑	↑	N/A	↑	N/A	N/A	-	-	-	↑	↑	↑
Mereles D et al 2006	↑	↑	↑	↑	N/A	N/A	-	-	↑	N/A	↑	N/A
Grünig E et al 2011	↑	↑	↑	↑	N/A	N/A	N/A	N/A	-	N/A	↑	N/A
Ehlken N et al 2016	↑	↑	N/A	↑	N/A	N/A	↑	↑	N/A	N/A	↑	N/A
Grünig E et al 2012	↑	↑	N/A	↑	N/A	N/A	N/A	↑	N/A	↑	↑	N/A
deMan FS et al 2009	↑	↑	N/A	↑	↑	↑	-	N/A	N/A	N/A	N/A	N/A
Chan L et al 2013	↑	-	N/A	↑	N/A	N/A	N/A	N/A	↑	N/A	↑	↑
Ley S et al 2013	↑	N/A	N/A	N/A	N/A	N/A	N/A	↑	N/A	N/A	N/A	N/A
Gonzalez-Saiz L 2017	↑	↑	N/A	N/A	↑	N/A	-	N/A	↑	N/A	↑	-

4.5.1. 6-minute walk distance (6MWD)

The 6-min walk test (6MWT) has been used as a primary outcome for determining the efficacy of interventions in patients with PH due to its association with mortality and key clinical markers such as peak VO₂, the VE/VCO₂ slope, and oxygen (O₂) pulse [64]. Most clinical trials investigating the role of ET in patients with PH report significant within group improvements in 6MWT distance [44–50], and when compared to controls [44–47,50]. It is important to acknowledge that in most of these studies the reported mean improvements in 6MWT distance also exceeded the established minimally clinically important difference (MCID) for this submaximal functional assessment (i.e., 33m) [65] in patients with PH [44–49]. Recent systematic reviews with metanalysis have demonstrated that ET improvements on 6MWT distance may range between 53.3m (95% CI, 39.5–67) [51] to 72.2m (95% CI, 45.7 to 98.6) [53], and that similar effects may be observed in shorter high volume ET protocols compared to longer protocols using a lower training volume[52]. Grüning et al identified that in patients with PH, a baseline 6MWT distance greater than 550m may be less responsive to ET as such a score would be close to normal 6MWT response [61].

4.5.2. Peak VO₂

A peak VO₂ greater than 15 ml•kg⁻¹•min⁻¹ or above 65% of age/sex predicted is associated with a lower risk of mortality and improved clinical status in patients with PH [1,66]. The absolute improvement in peak VO₂ following ET in patients with PH is modest (i.e., 1–3 ml•kg⁻¹•min⁻¹) [45,47–50,61,62]. Recent systematic reviews with metanalysis have reported a mean improvement in peak VO₂ following ET in patients with PH of 1.8 ml•kg⁻¹•min⁻¹ (95% CI, 1.4–2.3) [51]. Similar to the effects of ET on 6MWT distance, comparable effects may be observed in shorter high volume ET protocols compared to longer protocols using a lower training volume [52].

While the reported absolute improvement in peak VO₂ following ET in patients with PH is modest, the baseline values for peak VO₂in these patients are low (i.e., 8.2–17.1 ml•kg⁻¹•min⁻¹). Therefore, the relative increase in peak VO₂ following ET for many patients with PH would be approximately 15–25%, which is a considerable improvement. Additionally, the two available studies which measured percent-predicted peak VO₂, reported improvements from approximately 51% at baseline to 60% upon completion of the ET protocol [47,48].

4.5.3. Ventilatory efficiency

Patients with PH present with elevated VE/VCO₂ slopes and lower P_ETCO₂ at rest and during exercise. These changes may be due to impaired ventilation/perfusion matching in the lung, and potentially increased chemoreflex activity and ventilatory drives [67]. Following ET, significant improvements in VE/VCO₂ at ventilatory threshold (44.4±11.5 to 42.9±10.4) [47] and P_ETCO₂ (1–2mmHg) [45,58] have both been observed.

4.5.4. Skeletal Muscle Performance

Emerging evidence suggests that patients with PH experience generalized muscle atrophy and dysfunction which may be induced by changes in microcirculatory function occurring with this disease [68,69]. Due to these impairments, designing ET protocols to improve strength, endurance, and capillary function in the peripheral muscle of this patient population has received increased attention [45,58,62]. The available evidence investigating the effects of ET on muscle strength and endurance demonstrates that significant improvements can be made following training in patients with PH [58,62]. An RCT by deMan et al reported improvements in quadriceps muscle strength (13%) and endurance (34%) following 10 weeks of weight training in patients with class IV PH [62]. The same study also reported increased muscle capillary density (1.36±0.10 to 1.78±0.13 capillaries per muscle fiber; p < 0.001) and increased oxidative enzyme activity of the type I muscle fibers. However, no changes were observed in muscle cross-sectional area and fiber type distribution. Similar results were demonstrated by Gonzalez-Saiz et al who reported significant improvements in peak power for bench press and leg press in patients with PH following 8 weeks of CET; however, no improvements in muscle mass were observed [58]. Several studies have also reported improvements in peak workload attained during CPX using an upright cycle ergometer following ET [44–49,52,60–62].

4.5.5. Right Ventricle Function

Measures of RV function are key indicators for determining the effectiveness of therapeutic interventions in patients with PH [1]. However, the evidence regarding the effect of ET on RV function is limited and inconclusive. Following 15 weeks of ET, Elkhen et al reported improvements in cardiac index at rest and during exercise [44]. A prospective single group clinical trial by Nagel et al reported significant improvements in N-terminal-pro brain natriuretic peptide (NT-proBNP) following 3 weeks of supervised CET; however, those improvements were not maintained at 15 weeks in the same study [49]. Despite the limited data reporting improvements in RV function, RV function does not appear to worsen with ET as no significant increases in NT-proBNP have been reported in several studies [44,49,50,58]. It is important to note that peak VO₂ is linearly associated with RV function [70]. Therefore, improvements in peak VO₂ following ET in patients with PH may primarily be attributed to improvements in capillary density and oxidative enzyme function in the peripheral muscles [60].

4.5.6. Pulmonary Vasculature Function

The impact of ET on the pulmonary vasculature remains inconclusive [71]. The majority of the available studies investigating the effects of ET on pulmonary vasculature function have utilized rat models which have demonstrated conflicting results with some studies demonstrating improvements, and others demonstrating no improvement or even worsening [71]. Preliminary work by Ley et al demonstrated significant increases in pulmonary perfusion and reductions in peak velocity in the main pulmonary artery following 3 weeks of hospital-based CET in patients with WHO Class II and III PH [72]. Additionally, an RCT by Elkhen et al reported significant reductions in mean pulmonary arterial pressure (−7.3%), and pulmonary vascular resistance (−19.3%) following 15 weeks of supervised CET in patients with WHO Class II-IV PH. Similar findings were reported in a large prospective single group study by Grüning et al of 183 patients with Class I-IV PH following a similar training protocol [61]. A systematic review with meta-analysis by Pandey et al reported that the pooled effect of ET was associated with a significant improvement in resting pulmonary artery systolic pressure from baseline to follow-up (weighted mean difference [WMD] −3.7 mm Hg; 95% CI, −5.4 to −1.9) [51]. However, there are several studies which have demonstrated no significant changes in pulmonary vascular pressure following ET in patients with PH [47,49,50].

4.5.7. Quality of Life, Dyspnea and Fatigue

In addition to improvements in measures of physical performance, ET has also consistently been shown to improve quality of life, and perceptions of fatigue in patients with PH [44,47–49,51]. For quality of life most studies have utilized either the Short Form 36 (SF-36) or Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and have reported improvements, particularly in the domains of physical functioning and energy/vitality [44,45,47–49]. Regarding fatigue specifically, ET has been shown to improve scores on the Fatigue Severity Scale (FSS) [46]. It is important to acknowledge that in many of these ET studies patients also receive structured education on the disease process of PH, medication management, panic control, relaxation technique, yoga, social wellbeing, and energy conservation techniques and many other topics. The combination of structured education and ET used in many of these trials may have contributed to these consistent significant improvements in these psychosocial domains [45–47].

4.5.8. Daily Physical Activity and Long-Term Exercise Participation

In addition to increasing daily physical activity level during training sessions, ET has been shown to increase the amount of spontaneous daily physical activity in patients with PH [45]. These improvements were demonstrated using a validated questionnaire (The International Physical Activity Questionnaire) which may limit the reliability of these findings due to potential self-report bias [45]. However, these improvements were shown both within group and compared to control [45].

Nagel et al monitored long-term participation in exercise in 35 patients with PH after completing 15 weeks of CET. Of the 29 patients assessed during the follow-up period, 23 (79%) reported that they continued exercise training following the study, and 19 had more than 3 years after baseline visit of the study [49]. The most popular type of training continued by these respondents was bicycle ergometer training, followed by dumbbell-training, walking, and respiratory training; 17 patients had also initiated new types of training such as gymnastics [49]. Additionally, 9 patients combined two types of training, 5 patients combined three, and 5 patients combined four types [49]. The combined findings of these studies demonstrate that ET may serve as a catalyst to effective behavior change in patients with PH towards long-term participation in exercise and physical activity which may extend beyond the duration of training protocol.

4.5.9. Survival

There have been two studies which have investigated the effects of ET on long term survival in patients with PH. A prospective single group clinical trial by Grünig et al followed a cohort of 58 patients with class II-IV PH after completing 15 weeks of exercise training for 24 ± 12 months [48]. After 1 year, the survival rate was 100% and 95% at 2 years. A total of 15 major events occurred during the follow up period[48]. Similar findings were reported by Nagel et al in a prospective cohort of 35 patients with class II-IV PH following 15 weeks of training [49]. They reported long-term survival rates of 97% after 1 year, 94% after 2 years, and 86% after 3 years [49]. By comparison, in patients with class III-IV PH receiving optimized medical therapy only survival rates at 1, 2 and 3 years have been reported to range between 82–93%, 75–83.1% and 70–79.9% respectively [73–75]. The combination of these findings demonstrates that ET may provide significant effects on long term survival in patients with PH.

5. Expert Opinion

The pathophysiological alternations in patients with PH are multiple, with exercise intolerance and reduced quality of life being major patient complaints. Although symptoms may not be evident during rest in the early disease stages, the physiological stress of exercise can identify and unmask hidden pathology and assist in early identification and treatment of these patients. With increased awareness regarding the clinical importance of measuring CRF in all populations, CPX specifically has gained a special role in the diagnosis and prognosis of PAH. Measuring peak VO₂, the VE/VCO₂ slope, and P_ETCO₂ during CPX have emerged as strong diagnostic and prognostic variables and should be routinely reported.

The use of exercise training to improve exercise capacity (6MWT distance and peak VO₂) in patients with PH is well supported. Several studies have also demonstrated improvements in other important outcomes such as quality of life and peak work rate. These improvements to exercise capacity have been consistently demonstrated despite a variety of training modes, intensities, frequencies, and durations utilized in the available literature. When dosed and monitored appropriately by well-trained rehabilitation professionals, the risk of adverse events from exercise in patients with PH is negligible even in those more severe cases. The long-term effects of exercise training on mortality in patients with PH, and the continued reductions in exercise capacity observed in patients with PH who do not exercise indicate that these negligible risks are also substantially outweighed by the potential benefits. It is imperative to mention however, that many multiple questions yet remained to be answered regarding the role of exercise in patients with PH, both in terms of mechanisms of physiological adaptations to exercise and precise exercise prescription for this unique patient population. Furthermore, appropriate supervision and caution by trained personnel should always be exercised. Patients should always be treated with standard of care pharmacological treatment and in a clinically stable condition before participating in supervised exercise programs[1]. Future research should be directed towards identifying the most effective exercise prescription in terms of mode, intensity, frequency, and duration of exercise training for this clinical population. Strategies and policy changes to improve access to supervised ET, and participation in daily physical activity for patients with PH should also be explored. Despite this lack of specificity, exercise training has consistently proven to provide clinically meaningful outcomes for patients with PH.

As mentioned above, the specific mechanisms involved in improving exercise capacity also require further inquiry. The available evidence demonstrates that RV and pulmonary artery function generally do not further deteriorate with exercise in patients with PH; however, neither have consistently been shown to improve. When considering the association between RV to peak VO₂, it appears that the primary mechanism for improved exercise capacity in patients with PH, and likely other outcomes, are peripherally mediated. Previous research has demonstrated impaired peripheral vascular function in patients with PH which improved following exercise training. Emerging research has also linked mitochondrial dysfunction to the pathogenesis of PH [19,20]. Perhaps then both the clinical manifestations of PH and the effects exercise training in patients with PH are driven by broad changes in peripheral and extrapulmonary rather than central and pulmonary adaptations.

Article Highlights.

• Patients with PH have a mean time of 3 years from initial symptom onset to diagnosis resulting in significant treatment delays and stressing the importance of early detection and intervention.

• Multiple pathophysiological mechanisms contribute to exercise intolerance in PH with increased PVR being a central complication. This increase in PVR eventually leads to reduced pulmonary perfusion and V/Q mismatch which contribute to ventilatory inefficiency and exercise intolerance.

• CPX can provide a wealth of information to assist with the diagnosis and prognosis of PH especially in early stages of disease when symptoms are masked during rest.

• Exercise training for patients with PH is generally safe, been shown to improve exercise capacity, quality of life, and has been recommended as an add-on therapy for clinically stable patients by multiple professional organizations.

• Further research is required to identify the optimum exercise prescription for patients with PH as well as explore the mechanistic adaptations to exercise observed in this patient population.