Pulmonary Hypertension: Exercise Intolerance and the Benefits of Respiratory Muscle and Exercise Training

Right ventricular (RV) dysfunction is a major factor that limits exercise in patients with PH. In the early stages of disease, a progressive rise in the pulmonary vasculature load leads to increased RV afterload.²  The RV adapts by becoming hypertrophied to maintain stroke volume at rest. During exercise, the RV may not be able to meet increased metabolic demands, leading to a subsequent decrease in stroke volume¹³  (Figure 1).

As the disease progresses, RV maladaptation occurs in response to the chronic, pressure-overloaded state.¹⁴  This results in RV dilatation, eccentric hypertrophy, and decreased systolic function. Associated cellular changes include a decrease in α-myosin heavy chain filaments and an increase in β-myosin heavy chain filaments.^15,16  Ventriculoarterial uncoupling is the physiologic consequence of RV maladaptation and occurs when the increase in RV contractility is inadequate to meet the demands of high afterload.^17-19  In PAH patients, RV-PA coupling is often preserved at rest, but a deterioration is noted during exercise.

Myocardial ischemia may also contribute; perfusion is dependent on the gradient between aortic root pressure and intramural pressure.²⁰  In PAH, an increase in systolic RV pressure leads to biphasic right coronary flow. This leads to decreased systolic function, which is most pronounced in exercise.²⁰  Furthermore, external compression of the left main coronary artery by dilated main pulmonary arteries has been shown to be a cause of angina and decreased exercise tolerance in PAH patients.²¹ 

Pulmonary vasculopathy is central to the pathophysiology of PH and contributes to exercise limitation. Endothelial dysfunction leads to vascular remodeling via vasoconstriction, cellular hyperplasia, and sclerosis.^2,22-24  During exercise, there is an increase in blood flow to the lungs, and the pulmonary vasculature must distend to accommodate this. These mechanisms are impaired in PAH due to a decrease in pulmonary vasculature distensibility; this causes an increase in mean pulmonary arterial pressure and RV afterload on exertion (Figure 1).²⁵ 

In the absence of concomitant lung disease or obesity, most PAH patients have preserved gas exchange at rest. During exercise, however, arterial desaturation can occur from reduced mixed venous oxygen content from a widening of the systemic arterial-venous oxygen difference from a low cardiac output state.²  Hyperventilation and ventilatory insufficiency also contribute to dyspnea likely secondary to enhanced chemosensitivity and increased physiologic dead space from vascular obliteration.²⁶  Mechanical ventilatory limitations from dynamic hyperinflation and peripheral muscle dysfunction also contribute to dyspnea and exercise intolerance.²⁷ 

Respiratory muscle dysfunction is now increasingly recognized as a key factor contributing to exercise limitation in PAH patients. Approximately 15% of cardiac output is directed to respiratory muscles during maximal exercise and thus may be affected by reduced blood flow in PAH and CTEPH.²⁸  PAH patients have been documented to have a >50% reduction in force-generating capacity and atrophy of the diaphragm.²⁹  This reduction in diaphragmatic strength likely contributes to exercise limitation and dyspnea. Furthermore, an association has been documented between peripheral muscle strength and maximal inspiratory pressure (MIP), suggesting that respiratory muscles may influence exercise intolerance.^30,31 

Weak respiratory muscle may impair the function of the respiratory muscle pump, which helps to increase RV stroke volume. In the setting of increased pulmonary vascular resistance, augmentation of the respiratory muscle pump may help enhance pulmonary blood flow.² 

Skeletal muscle abnormalities are now recognized as important factors contributing to reduced exercise capacity in PH.^5,31  Abnormalities include muscle atrophy, impaired oxygen extraction, reduced angiogenesis, and contractility.^5,31  These findings are similar to those observed in systemic myopathy seen in heart failure patients.^2,5  Unfortunately, while physical inactivity is known to lead to muscle atrophy and a myocyte fiber transition, PH patients often avoid physical activity to avoid precipitating symptoms, leading to an atrophy spiral (Figure 1).² 

Skeletal muscle density correlates with exercise capacity and muscle strength. Diminished amounts of CD31⁺ cells, which promote revascularization, and miR-26, which is proangiogenic, are seen in the skeletal muscle of PAH patients.^32,33  Furthermore, low cardiac output leads to a hypoxic state during increased metabolic demand, which, combined with impaired skeletal oxygen extraction, leads to reduced exercise capacity. In addition, systemic inflammation, seen in chronic diseases, is known to have a catabolic effect on skeletal muscle and is seen in PAH.³⁴ 

IMT is a feasible and well-tolerated physical therapy that aims to induce adaptive changes in respiratory muscle structures, thereby increasing inspiratory muscle strength and in turn reducing exercise intolerance.^35,36  Prior studies have objectively documented that MIP and maximal expiratory pressure are significantly lower in PAH patients, independent of ventilation efficiency or reduced pulmonary hemodynamics.^6,7  Respiratory muscle weakness has also been documented in the CTEPH population, with reduced diaphragmatic contractility noted within slow-contracting muscle fibers and reduced calcium sensitivity of fast-contracting fibers.³⁴  It is postulated that IMT may improve exercise capacity by increasing the strength, fatigue resistance, and endurance of diaphragm-based inspiratory muscles, thereby allowing patients to maintain higher ventilation volumes, increase gas exchange, and have a lesser sensation of dyspnoea.^15,35,37 

Broadly speaking, IMT is performed using a handheld device that applies resistance to inspiration.³⁸  Patients can participate in training at home or in a supervised setting. Training protocols include cycles of resistive breathing (either a certain number of repetitions or a certain amount of time) multiple times a week over a 6- to 10-week period. The feasibility and effectiveness of this training has been well established in chronic obstructive pulmonary disorder and heart failure populations, but the utility in PAH and CTEPH populations remains less clear.^10-12 

The literature on IMT in the PAH and CTEPH populations is limited to 6 small, randomized control trials (n = 10-31).^{15,35,37,39-41}  Table 1 summarizes these 6 studies; the interventional groups undertook IMT of varying resistance 3 to 7 times per week over a 6- to 10-week period. At baseline, respiratory muscle strength was reduced, with pooled data from a recent meta-analysis showing a mean MIP of 61 cmH₂O in included studies (normal MIP is ≥80 cmH₂O).^15,36,37  The MIP increased significantly in the intervention group of all studies, with pooled results showing a mean increase of 19 cmH₂O (P < .001) compared with control groups.^15,36,37,39  After intervention, the mean MIP reached normal thresholds, highlighting that IMT can potentially help PAH patients reach normal levels of resting respiratory muscle function.³⁶  Several studies reported a concomitant improvement in maximal expiratory pressure, suggesting that expiratory muscles also become retrained through forced ventilation.¹⁵  However, this was not a consistent finding across studies.^35,37 

Prior studies have sought to determine whether these improvements in respiratory muscle strength translate into improved functional capacity and outcomes. Six-minute walking distance (6MWD) is generally accepted as a surrogate endpoint for long-term clinical outcomes in PAH patients.⁴²  Another recent meta-analysis reported the pooled data from 4 studies and reported a mean increase in 6MWD of 39 m compared with control groups.⁴³  This improvement, while likely clinically significant,^44,45  does not quite meet the reported threshold of 42 m, which has been associated with reduced incidence of clinical events.⁴⁶  Furthermore, meta-analytic studies show that the lower limit of the 95% confidence interval is less than 33 m, which is generally considered to be the lower limit of clinical significance for 6MWD.⁴³  These modest improvements in 6MWD suggest that IMT is an adjunct form of exercise training rather than a replacement for exercise training.

The attenuation of the inspiratory muscle metaboreflex through IMT is likely to explain functional improvement.³⁵  During exercise, sympathoexcitation leads to vasoconstriction and decreased vascular conductance. Blood is redirected from exercising muscles toward respiratory muscles to sustain ventilation and is further accentuated when the diaphragm fatigues.^28,47-49  Increased work of breathing therefore increases the cardiac output required to maintain ventilation. In PAH, this is particularly significant as cardiac output is often limited; thus, the redirection of blood flow comes at the expense of premature exercise muscle fatigue.³⁵  Increased ventilatory load and weak respiratory muscle capacity augment neural respiratory drive, while the recruitment of accessory respiratory muscles to facilitate ventilation during diaphragmatic fatigue provides further sensory feedback to the central nervous system.^48,50  These further compound the sensation of breathlessness. Increasing inspiratory muscle strength through IMT increases the ventilatory load needed for the onset of the metaboreflex and may thus improve exercise capacity.³⁵ 

Interestingly, despite objective improvements in respiratory muscle strength and functional capacity, only Saglam et al¹⁵  reported significant improvements in forced expiratory volume in the first second, with no other studies reporting significant improvements in lung function as measured by spirometry.^{15,35,37,39-41}  This was reflected in the pooled data reported in both recent ­meta-analyses.^36,43  The sensation of dyspnea during daily activities was only reported in 2 studies (modifiec medical research council scale). Pooled analysis showed a small but significant decrease of 0.5 points in the IMT group compared with the control group.^15,40  QoL scores were assessed in 4 studies; pooled analysis of 3 studies showed no significant difference in emotional or physical measures of QOL.^15,37,40  One of the remaining studies showed that the IMT group had significant improvements in physical QoL measures (P = .002) and some subcomponents of emotional QoL but had no significant differences between intervention and control groups.³⁹  Safety of IMT has been reported in 2 studies, with Aslan et al reporting no adverse outcomes and Saglam et al having 1 patient self-report wrist pain.^15,37  Compliance to IMT training programs was reported as ≥98% in the 3 studies that reported on completion rates.^15,35,37 

Exercise training has been shown to be a feasible, safe, and efficacious treatment for PH patients.⁵¹  It has been reported to improve skeletal muscle function by increasing capillarization and changing muscle fiber type.²⁹  Exercise training also influences the pulmonary vasculature through regulating pulmonary vascular remodeling and has recently been shown to improve pulmonary hemodynamics, with reductions in mean pulmonary arterial pressure noted on right heart catheterization following exercise-based rehabilitation.^52-54  It is important to note, however, that to achieve hemodynamic improvements, high volumes of exercise per patient (>220 hours) was needed, with a recent study unable to replicate this at lower levels.⁵⁵ 

Exercise training in this setting refers to a combination of aerobic and low-load resistance exercise training. Aerobic exercise involves activation of large skeletal muscle groups through walking or cycling for 20 to 40 minutes. Resistance training may also be used with upper and/or lower body muscle groups targeted through repetitions of set exercises. However, evidence on the safety and efficacy of isolated resistance training in PH remains limited. Exercise training is often supervised and can occur in an inpatient, outpatient, or remote setting. Sessions are generally 2 to 3 times per week over a minimum of 4 weeks.⁵¹ 

A recent Cochrane review analyzed data from 14 parallel grouped randomized control trials (n = 10-129) that looked at the impact of exercise rehabilitation on outcomes in patients with PH.⁵¹  Included studies enrolled 571 patients with PAH or CTEPH who were stable on medical therapy. All exercise training programs were similar to standardized recommended cardiac and pulmonary rehabilitation programs. ­Programs were primarily aerobic, although some included additional resistance training components. Table 2 summarizes the studies and their ­outcomes.^53,54,56-67 

Exercise capacity was the key outcome assessed across studies. A pooled analysis of 11 studies showed a mean difference in 6MWD of 49 m following exercise training when comparing the intervention and control groups,^53,54,57-65  which exceeds both the minimal threshold for clinical significance and the threshold for reduced clinical events. Cardiopulmonary exercise testing was also assessed in 7 studies and showed a significant increase in peak oxygen uptake (VO₂ max), the gold standard measure of cardiopulmonary fitness, following intervention when comparing the exercise groups with the control groups (mean difference of 2.1 mL/kg/min, 95% confidence interval of 1.57-2.57).^{53,54,58,60-62,64}  A significant increase in peak power between groups was also noted. There was a large amount of heterogeneity between studies, and it remains unclear if these variations were due to disease severity, location of program (inpatient versus outpatient), or study population.⁵¹ 

Aerobic exercise training in athletes has been shown to lead to an increase in skeletal muscle capillarization with elevated capillary density and capillary-to-fiber ratio.^68,69  This leads to enhanced transport and extraction of oxygen from skeletal muscles causing increased aerobic activity. In chronic heart failure patients, exercise training has been shown to reverse skeletal muscle atrophy, improve ventilatory efficacy, and attenuate endothelial dysfunction.^70-72  These mechanisms are also likely to play a role in increasing exercise capacity in PH patients.⁵¹  Further research is needed to determine if there are PH-specific mechanisms.

No increased risk of serious adverse events were seen in a recent metanalysis when comparing exercise programs to usual care.⁵¹  Only 5 serious adverse events were reported across 11 studies (439 patients).⁵¹  Grünig et al reported 3 events in the exercise group (stroke, generalized edema, and decompensated diabetes), whereas Ganderton et al reported that 1 patient experienced presyncope during 1 training session.^54,60 

Exercise training programs have also been shown to significantly improve physical and emotional indicators of QoL in PH patients undergoing ­training compared with controls using both general and PH-specific QoL scores.^56-58,65-67  This emphasizes the holistic approach adopted in such rehabilitation programs, which enables patients to not only improve in objective measures of functional capacity but also extend their individual spectrum of daily activity.⁵¹  Future studies should investigate the optimal type, intensity, and volume of exercise required to improve physiological measures and clinical outcomes. Major PH treatment centers are often located within major cities; thus, access to face-to-face exercise programs may be limited for patients who face geographic or socioeconomic barriers. More recently, entirely remote exercise programs have been evaluated and have been shown to be effective, suggesting that this may be suitable for stable patients as a more scalable intervention.⁷³ 

Exercise intolerance is a predominant symptom in patients with both PAH and CTEPH, with complex pathophysiology. IMT and exercise training target different pathophysiologic pathways and can feasibly be used as an adjunct to standard medical therapy. Both exercise training programs and IMT have been shown to lead to significant objective improvements in functional capacity, although increases with the former are more marked. Exercise training also consistently improves QoL indicators and should be incorporated into standard care models for stable patients.

SR has received a PhD Scholarship from the National Heart Foundation (106796). DT was supported by the Medical Research Future Fund, Cardiovascular Health Mission, ­Congenital Heart Disease Grant (ARGCHDG000016) and by an Additional Ventures Tools & Technology Expansion Award (1048066).