Role of Exercise in Pulmonary Hypertension: Evidence from Bench to Bedside

Abstract

Background

Pulmonary hypertension (PH) is a debilitating condition characterized by elevated pulmonary arterial pressure and progressive vascular remodelling, leading to exercise intolerance. The progression of PAH is regulated at a cellular and molecular level which influences various physiological processes. Exercise plays an important role in improving function in PH. Although the signalling pathways that regulate cardio-protection through exercise have not been fully understood, the positive impact of exercise on the various physiological systems is well established.

Summary

Exercise has emerged as a potential adjunctive therapy for PH, with growing evidence supporting its beneficial effects on various aspects of the disease pathophysiology. This review highlights the contributions of cellular and molecular pathways and physiological processes to exercise intolerance. Preclinical studies have provided insight into the mechanisms underlying exercise-induced improvements in PH which are modulated through improvements in endothelial function, inflammation, oxidative stress, and mitochondrial function. Along with preclinical studies, various clinical studies have demonstrated that exercise training can lead to significant improvements in exercise capacity, haemodynamics, quality of life, and functional status. Moreover, exercise interventions have been shown to improve skeletal muscle function and enhance pulmonary vascular remodelling, contributing to overall disease management. Further research efforts aimed at better understanding the role of exercise in PH pathophysiology, and refining exercise interventions are warranted to realize its full potential in the management of this complex disease.

Key Messages

Despite the promising benefits of exercise in PH, several challenges remain, including the optimal intensity, duration, and type of exercise training, as well as patient selection criteria and long-term adherence. Additionally, the mechanisms underlying the observed improvements require further elucidation to optimize exercise protocols and personalize treatment strategies. Nonetheless, exercise represents a promising therapeutic approach that can complement existing pharmacological therapies and improve outcomes in PH patients.

Introduction

Pulmonary arterial hypertension (PAH) is a complex and debilitating condition characterized by elevated blood pressure in the pulmonary arteries (PAs) [1]. In 10% of cases, PAH is hereditary, and the great majority of individuals with hereditary PAH have heterozygous mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) [2]. Exercise intolerance is a hallmark of PAH. The contributors to exercise intolerance have been described to be due to a complex interplay of physiological systems which eventually cause exercise intolerance [3].

These physiological systems are regulated by an even more complex interaction of cellular systems. The pathology of the disease is known to affect not just the above-mentioned systems but also different cellular processes. Inflammation and endothelial function are two of the key pathways responsible for vascular remodelling. However, the source of these dysfunctions could potentially stem from altered mitochondrial function.

Even though medical therapy targets various pulmonary hypertension (PH) disease pathways, there is a key role for non-pharmacological approaches. The recent guidelines have now recommended the role of exercise training in those with PH. These findings are further supported by two recent high-quality reviews: one, a Cochrane review [4] and meta-analysis and another a meta-analysis and meta-regression of all exercise interventions [5]. Therefore, the evidence to support exercise is available. This review will therefore further elucidate the literature from laboratory-based exercise studies (to highlight the cellular contributors) to clinical trials (to highlight the physiological contributors) on factors contributing to exercise intolerance and thereby demonstrating the rationale for exercise interventions in PH.

Exercise Intolerance in PH: Cellular and Vascular Contributors

Contributions to exercise intolerance arise from various factors starting from the cell to the physiological systems.

Endothelial Function

Pulmonary vascular remodelling, a key finding in PH, is mediated by the progression of endothelial dysfunction due to an abnormal expression of reactive oxygen species (ROS), which is common in PH [6]. Endothelial cells (ECs) play a critical part in this structural shift by generating and releasing mediators (such as nitric oxide [NO], prostaglandin I2, endothelin-1, thromboxane A2, C-X3-C motif chemokine ligand 1, and C-C motif chemokine ligand 2) that influence platelet and smooth muscle cell (SMC) behaviour [7, 8]. It is also known that SMCs may “shift” from a contractile to a synthetic, proliferative phenotype during vascular injury to aid vascular healing. Important to highlight here is that this “shift” through an improvement in vascular SMC function may be improved through exercise training for many chronic diseases (e.g., heart failure, diabetes, hypertension, obesity, hypercholesterolemia, and rheumatoid arthritis) [9]. Even though these findings have not been specifically observed in PH, it could be hypothesized that a similar improvement could occur. This improvement could be mediated through endothelial NO synthase, which in turn would improve NO production [10] (Fig. 1).

Fig. 1.

Interaction of ECs, SMCs, inflammation cells, platelets, and fibroblasts in PAH. Brown arrows signify interactions between ECs, platelets, and SMCs, involving NO and PGI2, inducing vasodilation, anti-proliferation, and anti-platelet aggregation effects. Blue arrows indicate interactions mediated by various cellular and vascular contributors leading to vasoconstriction, proliferation, migration, and platelet aggregation (created with BioRender.com). PGI2, prostaglandin I2.

Inflammation

Inflammatory processes have long been recognized as key contributors to pulmonary vascular remodelling [11]. Inflammatory indicators such as interleukin (IL)-1b, IL-6, IL-8, monocyte chemoattractant protein-1, fractalkine, CCL5/RANTES, and tumour necrosis factor-a have been found to link with PAH progression and worse clinical outcomes in cytokine profiling studies [12] (Fig. 1). In addition, mast cells may stimulate vascular remodelling, contributing to PAH [13] (Fig. 1). Vascular cells (ECs and SMCs) can release mediators such as cytokines and chemokines (soluble cytokines with chemoattractant function) in response to inflammatory/injury events, which are responsible for the recruitment of inflammatory cells (T cells, B cells, macrophages, dendritic cells, mast cells). As a result, these inflammatory cells can continue to secrete chemokines, cytokines, and growth factors like vascular endothelial growth factor, which enhance EC proliferation and migration as well as resistance to apoptosis, resulting in vascular remodelling [14]. At the muscular level, pro-inflammatory cytokines have detrimental effects on the muscle’s secondary to destruction of contractile proteins and stimulation of proteolysis [15, 16].

Cellular Metabolism

Altered cellular metabolism is a major factor affecting exercise performance in PAH. Main pathways involved in PAH are related to fatty acid, glucose, and lactate metabolism [17].

Fatty acid metabolism is the primary source of energy, followed by contributions from glucose metabolism. Abnormalities in fatty acid metabolism are observed in PAH, affecting blood, right ventricle (RV), and pulmonary vascular cells [18, 19]. Triglyceride, diacylglycerol, and ceramide accumulation occurs in the RV [19, 20], while severe PAH may impair fatty acid uptake in the RV [21]. Elevated fatty acid absorption does not correlate with upregulated fatty acid oxidation (FAO) [22], as incomplete mitochondrial FAO is indicated by elevated lipid metabolites [22]. Hypoxia-inducible factor-1α activation in PAH leads to glycolytic gene upregulation, reducing FAO, contributing to lipid accumulation and RV dysfunction [23, 24]. Similarly, reduced FAO is observed in pulmonary arterial ECs [25]. Targeting FAO with inhibitors improves RV function [26].

Glucose metabolism is altered in PAH through the Warburg effect, or aerobic glycolysis is a key feature in the progression of PAH. This is thought to occur due to the mitochondrial failure of glucose metabolism and oxygen sensing [17]. Abnormal glucose metabolism is observed in individuals with PAH, even in those without diabetes [26, 27]. This metabolic dysregulation in PAH appears different from the insulin resistance commonly associated with obesity and early type 2 diabetes.

Lactate metabolism is an important system contributing to exercise intolerance in PAH. The pathophysiology of PAH is influenced by changes in lactate generation, utilization, and clearance, all of which are important aspects of lactate metabolism. Increased glycolysis in PAH is caused by metabolic reprogramming in pulmonary vascular cells, which raises lactate production [28]. The characteristic features of PAH, namely, decreased oxidative phosphorylation, hypoxia-inducible factor-1α activation, and mitochondrial dysfunction [29], lead to this shift towards glycolysis and lactate generation. Increased lactate levels have the potential to worsen inflammation, endothelial dysfunction, and pulmonary vascular remodelling, which will continue to advance PAH [30]. In general, dysregulated lactate metabolism plays a significant role in the pathophysiology of PAH.

Mitochondrial Dysfunction

Much of the above-mentioned altered pathways of cellular metabolism are mediated through alterations in mitochondrial function [31]. Mitochondria are an important source of ROS, and their dysfunction secondary to hypoxia results in an increased amount of ROS. In a study conducted by Afolayan et al. [32], using a sheep model of persistent PAH has elucidated the role of inhaled NO in reducing mitochondrial ETC subunits, mitochondrial DNA copy number, and ATP levels to advance mitochondrial dysfunction and harm their biogenesis. This may result in the reduced oxidative capacity and weakened exercise capacity [33].

Vascular Remodelling

The capacity to effectively perfuse the pulmonary circulation and meet the oxygen requirements of exercise is constrained by pathological pulmonary vascular remodelling, impaired vasodilation, increased physiological dead space, and disrupted pulmonary haemodynamics [34]. The pulmonary arterioles’ abnormal vascular remodelling is a defining characteristic of PAH. EC proliferation and pulmonary vascular SMC hypertrophy and hyperplasia are two aspects of this remodelling [35]. These modifications cause the pulmonary arterioles to constrict and stiffen, increasing pulmonary vascular resistance and increasing RV afterload [36]. As a result, RV-PA coupling becomes affected and RV cardiac output can become compromised, particularly during exercise leading to a loss of exercise capacity [37].

Various types of growth factors, such as insulin-like growth factor 1, platelet-derived growth factor (PDGF), and vascular endothelial growth factor, have been reported to be stimulated following exercise training and released into the circulatory system [38]. PDGF, which is produced and secreted by a variety of cell types, is another factor that promotes cell proliferation (SMCs, ECs, macrophages, and platelets). In the PAs of PAH patients, the expression of PDGF and its receptors was shown to be higher [39]. SMCs and fibroblasts proliferate at a faster pace because of this. Platelets also play a role in vascular remodelling by releasing factors such as PDGF, thromboxane A2, and 5-hydroxytryptamine, which cause vasoconstriction, proliferation, and migration in fibroblasts and SMCs. In PAH, cellular migration has been observed and is linked to vascular wall thickness. Myofibroblasts can migrate from the adventitia to the media and intima, leading to the thickening of these structures [40, 41].

Exercise Intolerance in PH: Physiological Contributions

Cardiopulmonary exercise test (CPET) represents the gold standard measurement of exercise capacity and factors that contribute to exercise intolerance [42] in clinical populations. Parameters derived from the cardiopulmonary gas exchange measured during the CPET such as peak oxygen uptake, end-tidal carbon dioxide tension, and the minute ventilation/carbon dioxide production relationship have been shown to be related to disease severity in PAH patients [43]. Moreover, CPET provides a comprehensive pathophysiological evaluation of factors contributing to patients’ exercise intolerance and dyspnoea, which are the main and early symptoms of the disease [43]. The invasive CPET, which includes simultaneous right heart catheterization and measurement of pulmonary gas exchange, is extremely valuable in the identification of exercise-induced PH and the evaluation of unexplained dyspnoea [44, 45]. The CPET represents an integrated response of the respiratory, muscular, and cardiovascular systems and with interpretation during exercise enables the identification sites of limitation in the oxygen cascade and hence factors that contribute to exercise intolerance in a clinical population. The description of CPET and how it identifies exercise intolerance is beyond the scope of this paper. However, the readers are directed to these seminal publications for a description of CPET variables in PH [46], role of CPET in PH [47–49], and the interpretation of CPET variables to exercise intolerance [3].

Haemodynamics within the pulmonary circulation is changed because of many of the above-mentioned changes to the pulmonary circulation. During exercise, these adaptations lead to a decreased cardiac output and stroke volume (SV) leading to a reduction in convective oxygen delivery and thereby causing a reduction in exercise capacity [50]. Because of poor alveolar bed recruitment seen in PAH, a high ventilation-perfusion (V′/Q′) mismatch is formed which results in a high ventilatory response to exercise (V′E/V′CO2 slope) that is partly related to pulmonary vascular remodelling [51].

The impact of these changes cannot be taken in isolation but needs to include the RV, considering the connection of the pulmonary circulation to the RV in series. According to Bellofiore and Chesler [52], ventricular adaptation to pressure overload is the process of maintaining SV without increasing RV filling pressures. According to Laplace’s rule, the RV first adjusts to the increased pulmonary arterial load by improving muscular contractility and thickening its walls (i.e., RV hypertrophy) to reduce wall stress [36]. The ventricle responds with an increase in myocardial inotropy, and SV is restored without changing chamber geometry. This first inotropic reaction is a process known as homeometric adaptation [52]. When this process fails, heterometric adaptation (i.e., an increase in RV end-diastolic volume which produces an equal increase in SV to restore SV and secure cardiac output) remains the only effective response to an increased afterload output [36, 53]. This results in uncoupling of the RV systolic function and PA pressures.

The contributions from the respiratory, cardiovascular, pulmonary vascular, and skeletal muscles vary based on the aetiology of PH (Table 1). Irrespective of the aetiology causing PAH, the impact on the skeletal muscle cannot be highlighted enough [54]. It is these abnormalities that form the basis for exercise training in PAH.

Table 1.

Potential contributors to exercise intolerance based on aetiology of PH (from Babu et al. [50])

WHO aetiological group of PH	Respiratory system	Respiratory muscles	Pulmonary vascular system	RV	Left ventricle	Peripheral muscles
Group 1	+++	++	+++	++	+	+++
Group 2	+	++	++	++	+++	+++
Group 3	+++	+++	++	++	+	++
Group 4	+++	++	+++	+++	+	++
Group 5	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear

+++, strong contribution; ++, moderate contribution; +, weak contribution.

Rationale for Exercise Training in PH

Exercise training has been found to have numerous benefits on the cardiovascular system [55] and skeletal muscle systems. Considering the above-mentioned contributors to exercise intolerance, we need to understand the potential impact of exercise on its ability to control and even mitigate some of these processes. Contributions from central factors, vascular function, respiratory system, and peripheral muscles [3] are common in PAH (Fig. 2).

Fig. 2.

Impact of exercise training on various processes and systems in PAH. PA, pulmonary artery; RV, right ventricle; SMC, smooth muscle cell; mPAP, mean pulmonary artery pressure.

At the cellular level, exercise is known to improve endothelial function. Improvement in endothelial NO synthase expression may prevent PAH resulting from NO signal transduction, and suppression of their degradation may restore mitochondrial function, thus preventing the emergence and progression of PAH [56]. Improvements in endothelial function in PAH have been seen in human participants completing exercise training. Recently, it was shown that aerobic exercise training improved progenitor cells and the progenitor cell to endothelial microvesicle ratio (an important marker of endothelial damage and repair capacity) [57].

Improvements in inflammatory markers following exercise training are well established. It was in fact the antioxidant effects and improved vascular function with exercise in HF that drove the hypothesis for the first study on exercise training in PH [58]. Since then, numerous studies have continued to demonstrate significant benefits with exercise training on functional capacity (6-min walk distance [6MWD]), cardiorespiratory fitness (peak $\dot{\mathrm{V}}$O₂), peripheral and respiratory muscle function, and quality of life in individuals with PH. In the first review on this topic, Desai and Channick [59] highlighted the rationale for exercise training in 2008. These authors also hypothesized the benefits of exercise in chronic obstructive pulmonary disease and their mechanisms as potential reasons to advocate exercise training. Since then, the recent systematic reviews of the existing literature have supported the benefits of exercise training on various functional outcomes [50, 60, 61]. Thus, it appears that exercise training through various mechanisms (Fig. 2), which still need to be elucidated, has an impact on clinical and functional outcomes in PH.

Status of Exercise Training: Animal Studies

A search in PubMed on February 20, 2024, was performed using the search strategy developed for a recent systematic review [5] and was conducted for studies related to exercise training in PH. This resulted in 1,489 hits. After application of filters restricted to “animal species,” a total of 120 articles were identified, of which (n = 22) were directly related to the effects of exercise training. Numerous studies have investigated the effects of exercise on PH pathophysiology and its potential therapeutic benefits using various animal models, including monocrotaline-induced PAH and hypoxia-induced PAH. These studies typically involve subjecting animals to exercise regimens like treadmill running, followed by assessing various physiological parameters and disease markers. The findings from these animal studies have provided valuable insights into the potential benefits of exercise training in PAH. Some studies have reported improvements in exercise capacity, haemodynamics, right ventricular function, and pulmonary vascular remodelling following exercise interventions. Additionally, exercise training has been associated with reduced inflammation, oxidative stress, and endothelial dysfunction in PAH animal models. However, the specific effects of exercise training may vary depending on factors such as the duration, intensity, and type of exercise, as well as the stage of PAH progression and the animal model used. We have recently shown that moderate intensity treadmill training significantly alters cellular functioning in PAH [62]. Furthermore, some studies have reported conflicting results or highlighted potential limitations and challenges associated with exercise interventions in PAH animal models. Overall, while animal studies (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000539537) have provided valuable preclinical evidence supporting the potential benefits of exercise training in PAH, further research is needed to elucidate the underlying mechanisms, optimize exercise protocols, and effectively translate these findings into clinical practice.

Status of Exercise Training: Human Trials

Given the potential negative effects of exercise on RV function [63], initial recommendations for clinicians were for exercise to be limited in individuals with PAH [64]. Despite these recommendations [64], studies examining the short-term effects of exercise training started to appear in the literature in the early 2000s [58]. Probably, the first and best recognized of these was published by the group from the University of Heidelburg, led by Ekkehard Grünig, that examined the effect of a 3-week inpatient program followed by a 12-week outpatient-based exercise program. This randomized controlled trial of 30 medically stable and well-controlled PAH participants (mean PA pressure = 50 mm Hg) found remarkable increases in exercise capacity measured using the 6MWD (mean difference of 111 m) and peak oxygen uptake (peak VO₂) (mean difference of 2.7 mL/kg/min). Secondary outcome measures of quality of life and functional class also showed substantial improvement. The increases found in exercise capacity, in particular the 6MWD, were well over the minimal important difference for the 6MWD in PAH [65]. The authors reported that all participants tolerated the exercise training well and that there were no adverse events during the inpatient and outpatient arms of this study.

Following this seminal work, there was a substantial increase in the number of studies examining the role of exercise training in PH. Recent systematic reviews have shown similar improvements in exercise capacity and quality of life in a range of randomized control and observational studies [4, 5]. For example, the most recent Cochrane review of 11 randomized controlled trials of supervised exercise training in over 450 individuals with PH concluded that exercise training may result in large increases in exercise capacity and reduce mean PA pressure based on low-quality evidence. The review also noted that supervised exercise training most likely increases quality of life and does not appear to be associated with an increase in adverse events based on moderate quality of evidence. A search in PubMed for systematic reviews using the previously described search strategy was performed on February 20, 2024. The filter of “systematic review” was used to narrow down the articles from 1,420 to 38. From this, a total of 14 articles related to determining the effects of exercise in PH are summarized in the online supplementary Table 2.

As a result of these studies, leading agencies have now included a recommendation for the inclusion of exercise training in PH for individuals with PH. The recent practice guideline for pulmonary rehabilitation from the American Thoracic Society [66] provided a conditional recommendation for participation in pulmonary rehabilitation, still based on low-quality evidence. Similarly, the 2019 European Respiratory Society (ERS) [67] notes that specialized exercise training in PH appears to be effective, cost efficient, and safe. Even though international societies are increasingly recommending exercise training for PH [66, 67], it must be emphasized that the evidence for exercise training in PH has been limited to group 1 (PAH) and group 4 (chronic thromboembolic PH). Based on recent reviews [4, 5], the model of delivery did vary as did the type of exercise training. However, the mode of delivery (i.e., home, supervised, or hybrid) or the type of exercise intervention (aerobic and resistance or inspiratory muscle training or other forms) or the duration of the program (<10 or >10 weeks) did not influence the overall change in 6MWD [4]. Nevertheless, it is important to realize that some form of exercise is better than no exercise.

Irrespective of the prescription being followed, close monitoring is paramount. Assessment of vital signs and rating of perceived exertion should guide each exercise session. Drop in oxygen saturation below 85% with heart rates above 120 bpm has been used to terminate exercise in the past [58]. Similarly, changes to blood pressure (>20 mm Hg drop in systolic blood pressure or >220 mm Hg systolic blood pressure or diastolic blood pressure >110 mm Hg) should warrant altering intensity or termination of exercise [68]. Monitoring is therefore crucial to a successful exercise program in PH – whether it be delivered on-site or remotely [69]. While the mechanisms of adaptation to exercise training in PH remain unclear, there appears to be a range of physiological pathways that may improve exercise capacity and quality of life that include improved central haemodynamics and RV function, skeletal muscle function, improved pulmonary gas exchange and function, and finally improvements through molecular pathways that affect vascular smooth muscle tone and function.

Future Recommendation

Further studies are needed in both animals and human participants to better elucidate cellular and physiological contributors to exercise intolerance. Responsiveness to different forms of exercise training interventions also requires greater exploration to better understand cellular and physiological adaptations that would provide a stronger rationale for exercise training. Future research should look at dose-response relationships, cellular and physiological mechanisms contributing to adaptations, and the impact of different forms of exercise training through both preclinical and translational approaches.

Conclusions

Exercise has immense potential as an adjunct to medical therapy in individuals with PH and should be recommended to those with stable PH. Translational research projects on exercise are vital to further elucidate the mechanisms responsible for the changes due to exercise. Cellular pathways and physiological system interactions need to be studied in greater depth to further substantiate the rationale for exercise training.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

G.P. and A.S.B. conceptualized and drafted the first version. N.R.M. and M.J. contributed to sections, editing, and revisions of the manuscript. All authors contributed to editing and intellectual input and approved the final submitted version.

Funding Statement

This study was not supported by any sponsor or funder.