Pulmonary arterial hypertension (PAH) is a debilitating chronic and progressive condition, characterized by elevated pulmonary pressures due to the loss of small pulmonary vessels, endothelial cell dysfunction, and proliferation that contributes to the stiffening and narrowing of small arterial vessels. These pathologic responses may arise as a result of idiopathic etiologies, heritable pulmonary conditions, pharmacologic interventions, exposure to various toxins, connective tissue disease, human immunodeficiency virus, and/or schistosomiasis.1 Epidemiologic studies have reported prevalence rates of PAH ranging from 11 to 26 cases per million adults, with a large portion of patients between the ages of 362 and 523 yr and a greater prevalence in women.4 To date, limited data exist, characterizing the racial distribution. The available literature suggests that 79% of diagnosed PAH patients are non-Hispanic white, 11% African American, and 10% Hispanic.5 Roughly half of all PAH cases emerge from either idiopathic or genetic origins; the use of appetite suppressing drugs have also been identified to contribute to the development of PAH.3,6,7 Because of pulmonary vascular impairments, patients diagnosed with PAH commonly report symptoms of dyspnea, exertional fatigue, and reduced quality of life, and are left with burdensome health care costs.8
In addition to impaired pulmonary vascular function and structure, chronic right ventricular exposure to elevated pulmonary pressures is particularly concerning as right ventricular failure is an eventual cause of death in a large portion of patients with PAH.9 The significant pressure challenge imposed on the right ventricle leads to concentric remodeling that impairs diastolic and systolic function, while right ventricular morphologic alterations cause a leftward shift of the septum, compressing the left ventricle and compromising its function. Further progression of right ventricular dysfunction can greatly impair its contractile ability, especially during exercise, thus reducing stroke volume and relying on an increase in heart rate to augment cardiac output (CO) to meet the oxygen demands of activity. Consequently, exertional fatigue and limited performance are commonly experienced even at low levels of oxygen uptake. Given the profound clinical consequences of elevated pulmonary pressures on right ventricle function, many pharmacologic interventions aim to restore vasodilatory function, reduce proliferation of vascular smooth muscle cells, improve hemodynamics to reduce pulmonary pressures, and increase functional class and exercise capacity. These clinical advancements have also noticeably improved 1-yr survival expectancy from 65% to 86%-90%, while enhancing 5-yr survival rate from approximately 34% to 60%.10
Medical advancements over recent years have also contributed to reversing long held beliefs that PAH patients should refrain from activities that require physical exertion due to expectations of a rapid deterioration of health. Since the original promotion of regular exercise,11 numerous preclinical and clinical studies have sought to understand the responses to exercise training in PAH patients in order to optimize clinical guidelines. A culmination of evidence from preliminary findings has established the efficacy of exercise training to improve exercise capacity and quality of life and reduce symptom severity. Consequently, a paradigm shift in the clinical management of PAH has occurred to include a strong endorsement for exercise training. Because of the paucity of exercise training trials in PAH compared with other chronic conditions, there have been many knowledge gaps that limit recommendations for optimal training regimens for PAH patients. Therefore, this review aims to provide a summary of exercise interventions, with specific emphasis on randomized controlled trials and outline evidence-based recommendations for exercise programing in patients with PAH not secondary to left heart disease or chronic lung disease.
ACUTE RESPONSES TO EXERCISE
The increase in systemic oxygen demands associated with exercise must be matched by the synergistic increase of both right- and left-sided CO to sustain activity. In healthy individuals, the pulmonary arterial system is able to accommodate the increased blood flow through vasodilation and recruitment of the expansive vascular network to maintain low pulmonary vascular resistance that the right ventricle works against, allowing for the needed increase in right-sided CO during exercise. However, in patients with PAH, pulmonary arterial stiffness and vasodilatory dysfunction significantly increase vascular resistance during exercise, consequently impairing right ventricular stroke volume and CO as well as impairing left-sided CO downstream. In a large proportion of older (>50 yr) PAH patients, chronotropic incompetence12,13 (an attenuated maximal heart rate response to exercise) further limits CO (Figure) and accordingly exercise capacity. In addition, in those with advanced disease severity, ventilation-perfusion mismatching, as a consequence of low CO and ventilation abnormalities, can decrease arterial oxygen saturation and further compound inadequate delivery of oxygen to the periphery. These physiologic consequences of PAH collectively contribute to dyspnea on exertion, fatigue, and reduced exercise capacity.
RESPONSES TO CHRONIC EXERCISE TRAINING
Early exercise training studies in patients with PAH sought to establish the safety and feasibility of implementing exercise interventions, given the long-held belief that exercise would exacerbate symptoms and accelerate the clinical deterioration of patients.14 As a result, collective investigative efforts have provided overwhelming evidence supporting the safety and efficacy of exercise training to improve exercise capacity, quality of life, and reduced symptomology in PAH patients (Tables 1 and 2).22–24 However, many of these findings have come from cohort or retrospective study designs that included small numbers of subjects,25,26 with only a few randomized controlled trials comparing the efficacy of an exercise intervention to nonexercise, standard of care control groups. Moreover, there has not been a study to date that compares different exercise interventions (ie, aerobic, resistance, inspiratory muscle training [IMT]), making it difficult to objectively determine the optimal training regimen to improve health outcomes of interest.
Unlike early exercise training interventions that tested the effects of aerobic exercise alone on markers of interest in healthy individuals or patients, the first randomized controlled trial in PAH employed a multimodal approach that integrated aerobic, muscle strength/endurance and respiratory training.17 The seminal investigation by Mereles and colleagues randomized 15 PAH patients categorized under the World Health Organization II-IV classification27 to either a control sedentary group or a 3-wk inpatient and 15-wk home-based training program (Table 1).17 This time-intensive exercise program contributed to a significant improvement in peak oxygen uptake (
O2 peak) mean ± standard deviation values (baseline, 13.2 ± 3.1 mLO2/kg/min; follow-up, 15.4 ± 3.7 mLO2/kg/min, P < .05) and significant reduction in resting pulmonary artery systolic pressure (baseline, 61 ± 18 mm Hg; follow-up, 54 ± 18 mm Hg, P < .05) at 15 wk compared with control. Moreover, 6-min walk test (6MWT) distance significantly increased (96 ± 61 m in the exercise group, P < .001) as well as physical functioning (45 ± 16.5 to 62.8 ± 13.6) and vitality (41.3 ± 11.3 to 60 ± 17.0) scores assessed by the 36-Item Short Form Health Survey. In addition, 6 patients improved from World Health Organization class III to II and 1 improved from IV to III in the exercise group, while patients in the control group did not change functional classification. The compelling outcomes from this preliminary study reinforced use of the training protocol and led to subsequent studies employing the same intervention to elicit reductions in circulating N-terminal fragment of probrain natriuretic peptide (NT pro-BNP, a biomarker of cardiac function and prognosis that is secreted in response to ventricular wall stress),28 increased perfusion of the pulmonary circulation,29 and decreases in both pulmonary vascular resistance and mean pulmonary artery pressure.30 Although this clinical approach provided empirical support for the efficacy of enhancing numerous health markers (Table 2), the time-intensive requirements for the delivery of the intervention may not be feasible for all rehabilitation programs that provide supervised exercise sessions 2 to 3 times per week, 1 hr at a time.
A less time-intensive approach was taken by Fox and colleagues,19 who nonrandomly allocated 22 PAH patients categorized as New York Heart Association functional class II-III to receive 24, 1-hr sessions of moderate to vigorous (60%-80% of maximal heart rate) exercise training, 2 d/wk (n = 11) (Table 1) or serve as a nonexercise control group (n = 11). Despite not being a randomized study, participant characteristics between the 2 groups were similar. Although there was no statistically significant difference, the distribution of patients classified as New York Heart Association class III was greater in the exercise intervention group (n = 7) than in the control group (n = 2). Patients in the intervention group increased 6MWT distance by 32 ± 11 m from 353 ± 18 m and
O2 peak by 1.1 ± 0.3 mLO2/kg/min from a baseline of 8.2 ± 0.56 mLO2/kg/min, with no significant changes in NT-pro-BNP, resting systolic pulmonary artery pressure, or resting CO. Subsequent investigations utilized a similar training model that emphasized aerobic exercise training but made significant contributions by prescribing higher training intensities (70%-80% of heart rate reserve).15,16 These studies demonstrated a greater average increase in 6MWT distance of 56 ± 45 m from 411 ± 73 m16 and a 2.1 ± 0.8 min increase in symptom-limited treadmill exercise test duration from 6.6 ± 1.8 min using the modified Naughton protocol,15 whereas the education control group experienced no changes over the course of the 10-wk intervention.15,16 Of particular note, the participants randomized to the exercise training group did not experience any adverse events, thereby providing preliminary evidence supporting the application of vigorous intensity exercise in patients with PAH undergoing optimal medical therapy.
To date, no study has examined the effects of high-intensity interval training that incorporates alternating bouts of maximal or supramaximal intensity exercise with either rest or light intensity recovery periods. This form of training is receiving widespread attention and acceptance in many other chronic conditions (ie, cardiovascular disease,31 heart failure [HF],32,33 chronic obstructive pulmonary disease [COPD]34) due to the potentially superior health effects compared with traditional continuous, moderate intensity exercise. To date, only PAH-induced animal models have been used to study the effects of high-intensity interval training on functional and physiologic parameters. These initial studies indicate that interval training does not induce right ventricular inflammation or cardiomyocyte apoptosis but rather stimulates the upregulation of pulmonary endothelial nitric oxide synthase, reduces fibrosis, and improves metabolic profile in right ventricular myocardium.35 Future studies in patients with PAH will be required to test the efficacy and safety of this form of training.
Although the aforementioned studies15,16 implementing vigorous intensity exercise reported greater functional outcomes compared with those of Fox and colleagues,19 they were comparatively modest to those documented in the study by Mereles et al.17 This variance in findings suggests a potential dose-response relationship in patients with PAH. In addition, the multimodal approach taken by Mereles et al suggests that this form of training may be more efficacious than 1 mode alone. This is corroborated by the findings of Gonzalez-Saiz and colleagues,18 who observed an increase in
O2 peak (baseline values were 15.7 ± 3.3 mLO2/kg/min; follow-up were 18.3 ± 3.2 mLO2/kg/min) over an 8-wk period that included whole body resistance exercise and inspiratory muscle exercise sessions (Table 1). However, the benefit related to resistance training or IMT alone compared with aerobic exercise or a combination is not known due to the limited research in this area.
RESPONSES TO RESISTANCE TRAINING
In addition to altered pulmonary vascular function, patients with PAH show increased systemic endothelial dysfunction36 along with a variety of skeletal muscle abnormalities. These skeletal abnormalities include increased protein degradation, a decrease in the type I/type II fiber ratio, reduced capillarization, decreased oxidative enzyme activity, altered mitochondrial function, and impaired excitation-contraction coupling.37,38 The combination of these changes, along with skeletal muscle atrophy, results in skeletal muscle dysfunction, which if left untreated can lead to impaired physical function, a poor quality of life, and the loss of independence. The etiology of these abnormalities is unclear; however, systemic inflammation and the effect of proinflammatory cytokines are thought to be contributing factors.36
Because of the effects of PAH on skeletal muscle, a number of studies have examined the effects of adding resistance training to an aerobic training regimen.18–20 As recommended by the American Heart Association,39 most of these studies used a low-resistance, high-repetition protocol. Results from these studies show that such training protocols result in increases in
O2 peak, physical function, muscular strength and power and health-related quality of life.17–19,25,29,30,40–43 In addition, 1 study also showed a decrease in the proportion of type II fibers, indicative of a shift to a more oxidative phenotype.25 While the above cited studies have examined the effects of combined aerobic and strength training, we are not aware of studies that have examined responses to resistance/strength only training in patients with PAH. There are, however, a number of trials that have examined the effects of resistance only training in patients with HF and COPD. In both conditions, similar skeletal muscle abnormalities as are seen in patients with PAH have been observed, as is the risk of developing PAH.44 In addition, patients with HF and COPD suffer a loss of physical function and a decrease in health-related quality of life.
In patients with HF and COPD, resistance training has been shown to be effective in ameliorating skeletal muscle abnormalities and improving physical function and health-related quality of life. Studies in patients with HF have shown that moderate-intensity resistance training can improve peripheral vascular function45 and blood flow46 and increase strength,46–49 walk distance,47,48 and aerobic capacity.46,50,51 Patients with COPD, completing 12 wk of resistance training experienced increases in strength, muscle mass, and decreased levels of proinflammatory cytokines.52–54 Given these patients exhibit skeletal muscle abnormalities, impaired physical function, and a reduced health-related quality of life similar to that seen in patients with PAH, it is not unreasonable to hypothesize that resistance training may serve as an effective treatment option for patients with PAH. However, additional research is needed to confirm this hypothesis.
INSPIRATORY MUSCLE TRAINING
A hallmark consequence of PAH is a significant attenuation of inspiratory muscle strength and endurance,55,56 which provokes fatigue and dyspnea during activity,55,56 and has high prognostic utility.57 Inspiratory muscle training, performed using a small handheld device with adjustable inspiratory pressure threshold loads that prohibit inhalation until exceeding a set negative pressure, has been established to effectively improve respiratory muscle strength and endurance. Even when performed on its own, IMT promotes increases in functional capacity in patients with heart disease.58 The first study to examine the efficacy of IMT in improving functional status in patients with PAH was reported in 2015 by Saglam et al.21 Patients randomized to IMT, utilized the inspiratory device for 30 min/d, 7 d/wk, for 6 wk at 30% of maximal inspiratory pressure. At the end of the trial, 6MWT distance increased from 427 ± 98 m to 476 ± 90 m (P = .001) along with improvements in severity of fatigue and dyspnea, as well as maximal inspiratory and expiratory pressure, whereas the control group on optimized clinical management experienced no changes. The modulatory effects of IMT that contribute to these improvements are not well understood in patients with PAH. However, previous studies in patients with HF indicate that IMT can reduce the accumulation of inspiratory muscle metabolites that are partly responsible for an exaggerated sympathetic response that causes vasoconstriction and reduced peripheral blood flow,58,59 thus improving skeletal muscle perfusion and submaximal exercise capacity.60 Although studies are needed to identify if these mechanisms are responsible for the improvements seen in the study by Saglam et al, the findings support the rationale for the clinical adoption of IMT in patients with PAH.
APPLICATION TO PRACTICE
Patients with isolated PAH are commonly referred to pulmonary rehabilitation (PR) programs to undergo exercise therapy to improve physical function, increase walking distance and/or intensity while maintaining normal oxygen saturation, reduce symptoms, and receive education on safe exercise practices. The clinical rationale supporting referral to PR over cardiac rehabilitation relates to the patient experiencing oxygen desaturation with activity and/or needing supplemental oxygen during activity. Although evidence supports the efficacy of PR in enhancing physical function and improving quality of life in PAH, cardiac remodeling associated with chronic PAH places patients at an increased risk of experiencing serious arrhythmias (ie, high-density ventricular ectopy, inappropriate bradyarrhythmias, pulseless electrical activity),61 thereby justifying electrocardiographic monitoring that is not available in traditional PR. Furthermore, advanced right ventricular remodeling in PAH patients increases the risk for right ventricular failure and requires pharmacologic interventions guided by cardiac specialists to enhance right ventricular contractility and treat venous congestion.10 Cardiac rehabilitation programs may, therefore, be more appropriate settings that facilitate the clinical management of PAH patients by providing exercise electrocardiographic monitoring and an open line of communication with cardiologists responsible for titrating medications. This is a topic that certainly requires greater attention by the clinical and investigative communities.
Regardless of whether cardiac rehabilitation or PR is more appropriate for patients with PAH, the global aim of an exercise rehabilitation program is to implement individualized exercise training regimens to favorably modify the clinical profile of participating patients by reducing common symptoms and morbidity, while increasing functional capacity and physical function to preserve independence. As evident from the investigations reviewed previously, this can be accomplished through different modes of therapy in patients with PAH. Thus, a number of training options (highlighted in Table 1) that cater to the strengths, limitations, and interests of patients can be considered to improve clinical status.
Among exercise intervention studies in PAH and previous PR guidelines for COPD,62 there is clear agreement that aerobic exercise should be a significant portion of the training regimen. Although aerobic exercise performed 2 to 3 d/wk is sufficient to promote increases in 6MWT distance as well as modest increases in
O2 peak,19 aerobic exercise performed on 5 or more d/wk promotes greater increases in physical fitness17,18,30 and can be accomplished by encouraging home-based exercise. Because of the deconditioned state of most PAH patients, the initial exercise sessions of a training intervention can utilize alternating, time equivalent bouts of moderate-intensity exercise, followed by passive rest. This training style provides an opportunity for patients to avoid prolonged periods of dyspnea. As a patient's exercise tolerance increases, longer duration exercise should be promoted, eventually increasing to at least 30 to 45 min of continuous activity. Furthermore, Weinstein et al15 and Chan et al16 provided support for high-intensity exercise at 70% to 80% of heart rate reserve in patients who were on stable PAH medical regimens for at least 3 mo. It is worth noting that prior to these studies, an exercise precaution applied in the early work of Mereles et al17 limited exercise intensity to a heart rate of 120 beats/min. In contrast, Chan et al16 demonstrated that 8 out of 10 participants had heart rates that exceeded 120 beats/min during a training session without any reported adverse events. Given the dramatic variations in maximal heart rate within populations,63–66 determination of an individual's peak heart rate through maximal exercise testing is highly recommended to optimize a training program and ensure that patients exercise at an objectively determined intensity associated with improved health outcomes. Although cardiopulmonary exercise testing is highly encouraged for developing an exercise prescription, programs that do not have this capability should utilize submaximal protocols (ie, 6MWT) to document heart rate responses to exercise and prescribe a target heart rate range accordingly.
The most common modes of aerobic exercise performed in the reviewed studies were treadmill, cycle ergometer, or both. Although there was no study that tested the effects of other popular modes of exercise for deconditioned patients, such as a recumbent step machine or arm ergometer, it stands to reason that activity performed at moderate to vigorous intensities, regardless of the mode should elicit improvements in physical function.62 An effort should still be made to advance patients to incorporate bouts of walking during exercise sessions so that day-to-day ambulation can be less burdensome. In addition to aerobic exercise, the incorporation of resistance exercise and IMT within the rehabilitation setting has been associated with significant improvements in symptomology, cardiorespiratory fitness, and skeletal muscle profile. However, due to the lack of studies comparing outcomes between aerobic exercise alone and a multimodal approach in patients with PAH, we cannot say with certainty that the latter leads to greater improvements. Yet, previous studies in patients with COPD have demonstrated greater improvements in timed walk distance, muscle strength, and muscle size when resistance exercise was added to traditional aerobic exercise interventions.67 Based on the available literature in patients with PAH, resistance exercise that utilizes body weight and light dumbbells is sufficient to complement aerobic exercise training. Facilities that are equipped with leg and chest press, leg extension, lateral pull-down, and abdominal crunch machines should encourage patients to complete a 1-hr exercise session with 1 to 2 sets of 10 to 15 repetitions on these machines, as performed in the study by Gonzalez-Saiz and colleagues.18 In addition, given the outlined benefits of performing IMT on physical performance, if IMT devises are available, completing each session with 30 inspirations at 40% of inspiratory maximum is recommended. A more rigorous IMT program can be performed at home by breathing against 30% of inspiratory maximum for 30 min, 6 d/wk.21
Finally, adoption of home exercise should be a major emphasis for all PAH patients to achieve the optimal 5 to 6 d of structured exercise, particularly in rural areas where distance to rehabilitation facilities and/or transportation barriers commonly limit adherence and participation. Brown and colleagues68 demonstrated the efficacy of either a hybrid approach that incorporated infrequent facility-based training sessions for patients living within 10 mi of the hospital or a completely home-based exercise program for patients living outside of proximity. Initial consultations should be used to educate patients on signs and symptoms associated with exertion, safety considerations, oxygen saturation monitoring, recommended exercise intensities using rating of perceived exertion, and/or heart rate monitoring with exercise equipment, heart rate monitors, or palpation. Brown and colleagues encouraged home walking 6 d/wk, initially for 25 min and gradually increased to 45 min by the end of week 2, but the authors did not outline session-by-session progression strategies. Lessons taken from previous in-facility studies can be applied to home exercise recommendations to endorse intermittent exercise during the early weeks of the exercise program and then utilize progression models provided in Table 1.
The adoption of exercise training in patients with PAH has been accepted as a safe and effective method of significantly enhancing a patient's clinical status. Among the available literature, it is evident that aerobic exercise, resistance exercise, and IMT, alone or together, impart significant functional and physiologic improvements. Although a study has not tested health and functional responses to different volumes of exercise, it appears as though a dose-response relationship exists; therefore, patients should be encouraged to perform exercise on most, if not all days of the week. While future studies are still required to identify optimal training methods, the available evidence is more than sufficient for practitioners to provide strong endorsement for patients with PAH to participate in rehabilitation programs.
1. Simonneau G, Gatzoulis MA, Adatia I, et al Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 suppl):D34–D41.
2. Rich S, Dantzker DR, Ayres SM, et al Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107(2):216–223.
3. Humbert M, Sitbon O, Chaouat A, et al Pulmonary arterial hypertension
in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023–1030.
4. Taichman DB, Mandel J. Epidemiology of pulmonary arterial hypertension
. Clin Chest Med. 2013;34(4):619–637.
5. Al-Naamani N, Paulus JK, Roberts KE, et al Racial and ethnic differences in pulmonary arterial hypertension
. Pulm Circ. 2017;7(4):793–796.
6. Badesch DB, Raskob GE, Elliott CG, et al Pulmonary arterial hypertension
: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376–387.
7. Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension
. Eur Respir J. 2007;30(1):104–109.
8. Zhai Z, Zhou X, Zhang S, et al The impact and financial burden of pulmonary arterial hypertension
on patients and caregivers: results from a national survey. Medicine (Baltimore). 2017;96(39):e6783.
9. Schrier RW, Bansal S. Pulmonary hypertension, right ventricular failure, and kidney: different from left ventricular failure? Clin J Am Soc Nephrol. 2008;3(5):1232–1237.
10. Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension
: pathogenesis and clinical management. BMJ. 2018;360:j5492.
11. Galie N, Hoeper MM, Humbert M, et al Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493–2537.
12. Oliveira RKF, Faria-Urbina M, Maron BA, Santos M, Waxman AB, Systrom DM. Functional impact of exercise
pulmonary hypertension in patients with borderline resting pulmonary arterial pressure. Pulm Circ. 2017;7(3):654–665.
13. Wu C, Guo J, Liu H, et al The correlation of decreased heart rate recovery and chronotropic incompetence with exercise
capacity in idiopathic pulmonary arterial hypertension
patients. Biomed Res Int. 2017;2017:3415401.
14. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet. 1998;352(9129):719–725.
15. Weinstein AA, Chin LM, Keyser RE, et al Effect of aerobic exercise
training on fatigue and physical activity in patients with pulmonary arterial hypertension
. Respir Med. 2013;107(5):778–784.
16. Chan L, Chin LMK, Kennedy M, et al Benefits of intensive treadmill exercise
training on cardiorespiratory function and quality of life in patients with pulmonary hypertension. Chest. 2013;143(2):333–343.
17. Mereles D, Ehlken N, Kreuscher S, et al Exercise
and respiratory training improve exercise
capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation. 2006;114(14):1482–1489.
18. Gonzalez-Saiz L, Fiuza-Luces C, Sanchis-Gomar F, et al Benefits of skeletal-muscle exercise
training in pulmonary arterial hypertension
: the WHOLEi+12 trial. Int J Cardiol. 2017;231:277–283.
19. Fox BD, Kassirer M, Weiss I, et al Ambulatory rehabilitation
capacity in patients with pulmonary hypertension. J Card Fail. 2011;17(3):196–200.
20. de Man FS, Handoko ML, Groepenhoff H, et al Effects of exercise
training in patients with idiopathic pulmonary arterial hypertension
. Eur Respir J. 2009;34(3):669–675.
21. Saglam M, Arikan H, Vardar-Yagli N, et al Inspiratory muscle training in pulmonary arterial hypertension
. J Cardiopulm Rehabil Prev. 2015;35(3):198–206.
22. Arena R, Cahalin LP, Borghi-Silva A, Myers J. The effect of exercise
training on the pulmonary arterial system in patients with pulmonary hypertension. Prog Cardiovasc Dis. 2015;57(5):480–488.
23. Buys R, Avila A, Cornelissen VA. Exercise
training improves physical fitness in patients with pulmonary arterial hypertension
: a systematic review and meta-analysis of controlled trials. BMC Pulm Med. 2015;15:40.
24. Nogueira-Ferreira R, Moreira-Goncalves D, Santos M, Trindade F, Ferreira R, Henriques-Coelho T. Mechanisms underlying the impact of exercise
training in pulmonary arterial hypertension
. Respir Med. 2018;134:70–78.
25. Mainguy V, Maltais F, Saey D, et al Effects of a rehabilitation
program on skeletal muscle function in idiopathic pulmonary arterial hypertension
. J Cardiopulm Rehabil Prev. 2010;30(5):319–323.
26. Martinez-Quintana E, Miranda-Calderin G, Ugarte-Lopetegui A, Rodriguez-Gonzalez F. Rehabilitation
program in adult congenital heart disease patients with pulmonary hypertension. Congenit Heart Dis. 2010;5(1):44–50.
27. Barst RJ, McGoon M, Torbicki A, et al Diagnosis and differential assessment of pulmonary arterial hypertension
. J Am Coll Cardiol. 2004;43(12 suppl S):40S–47S.
28. Nagel C, Prange F, Guth S, et al Exercise
training improves exercise
capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension. PLoS One. 2012;7(7):e41603.
29. Ley S, Fink C, Risse F, et al Magnetic resonance imaging to assess the effect of exercise
training on pulmonary perfusion and blood flow in patients with pulmonary hypertension. Eur Radiol. 2013;23(2):324–331.
30. Ehlken N, Lichtblau M, Klose H, et al Exercise
training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension
and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial. Eur Heart J. 2016;37(1):35–44.
31. Liou K, Ho S, Fildes J, Ooi SY. High intensity interval versus moderate intensity continuous training in patients with coronary artery disease: a meta-analysis of physiological and clinical parameters. Heart Lung Circ. 2016;25(2):166–174.
32. Wisloff U, Stoylen A, Loennechen JP, et al Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation. 2007;115(24):3086–3094.
33. Wisloff U, Ellingsen O, Kemi OJ. High-intensity interval training to maximize cardiac benefits of exercise
training? Exerc Sport Sci Rev. 2009;37(3):139–146.
34. Neunhauserer D, Steidle-Kloc E, Weiss G, et al Supplemental oxygen during high-intensity exercise
training in nonhypoxemic chronic obstructive pulmonary disease. Am J Med. 2016;129(11):1185–1193.
35. Brown MB, Neves E, Long G, et al High-intensity interval training, but not continuous training, reverses right ventricular hypertrophy and dysfunction in a rat model of pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol. 2017;312(2):R197–R210.
36. Gabrielli LA, Castro PF, Godoy I, et al Systemic oxidative stress and endothelial dysfunction is associated with an attenuated acute vascular response to inhaled prostanoid in pulmonary artery hypertension patients. J Card Fail. 2011;17(12):1012–1017.
37. Manders E, Ruiter G, Bogaard HJ, et al Quadriceps muscle fibre dysfunction in patients with pulmonary arterial hypertension
. Eur Respir J. 2015;45(6):1737–1740.
38. Batt J, Ahmed SS, Correa J, Bain A, Granton J. Skeletal muscle dysfunction in idiopathic pulmonary arterial hypertension
. Am J Respir Cell Mol Biol. 2014;50(1):74–86.
39. Williams MA, Haskell WL, Ades PA, et al Resistance exercise
in individuals with and without cardiovascular disease: 2007 update: a scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2007;116(5):572–584.
40. Maiorana A, O'Driscoll G, Dembo L, et al Effect of aerobic and resistance exercise
training on vascular function in heart failure. Am J Physiol Heart Circ Physiol. 2000;279(4):H1999–H2005.
41. Kabitz HJ, Bremer HC, Schwoerer A, et al The combination of exercise
and respiratory training improves respiratory muscle function in pulmonary hypertension. Lung. 2014;192(2):321–328.
42. Inagaki T, Terada J, Tanabe N, et al Home-based pulmonary rehabilitation
in patients with inoperable or residual chronic thromboembolic pulmonary hypertension: a preliminary study. Respir Investig. 2014;52(6):357–364.
43. Grunig E, Ehlken N, Ghofrani A, et al Effect of exercise
and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension. Respiration. 2011;81(5):394–401.
44. Sakao S, Voelkel NF, Tatsumi K. The vascular bed in COPD: pulmonary hypertension and pulmonary vascular alterations. Eur Respir Rev. 2014;23(133):350–355.
45. Dean AS, Libonati JR, Madonna D, Ratcliffe SJ, Margulies KB. Resistance training improves vasoreactivity in end-stage heart failure patients on inotropic support. J Cardiovasc Nurs. 2011;26(3):218–223.
46. Selig SE, Carey MF, Menzies DG, et al Moderate-intensity resistance exercise
training in patients with chronic heart failure improves strength, endurance, heart rate variability, and forearm blood flow. J Card Fail. 2004;10(1):21–30.
47. Palevo G, Keteyian SJ, Kang M, Caputo JL. Resistance exercise
training improves heart function and physical fitness in stable patients with heart failure. J Cardiopulm Rehabil Prev. 2009;29(5):294–298.
48. Jankowska EA, Wegrzynowska K, Superlak M, et al The 12-week progressive quadriceps resistance training improves muscle strength, exercise
capacity and quality of life in patients with stable chronic heart failure. Int J Cardiol. 2008;130(1):36–43.
49. Alves JP, Nunes RB, Stefani GP, Dal Lago P. Resistance training improves hemodynamic function, collagen deposition and inflammatory profiles: experimental model of heart failure. PLoS One. 2014;9(10):e110317.
50. Williams AD, Carey MF, Selig S, et al Circuit resistance training in chronic heart failure improves skeletal muscle mitochondrial ATP production rate—a randomized controlled trial. J Card Fail. 2007;13(2):79–85.
51. Giuliano C, Karahalios A, Neil C, Allen J, Levinger I. The effects of resistance training on muscle strength, quality of life and aerobic capacity in patients with chronic heart failure—a meta-analysis. Int J Cardiol. 2017;227:413–423.
52. Silva BSA, Lira FS, Rossi FE, et al Inflammatory and metabolic responses to different resistance training on chronic obstructive pulmonary disease: a randomized control trial. Front Physiol. 2018;9:262.
53. Abd El-Kader SM, Al-Jiffri OH, Al-Shreef FM. Plasma inflammatory biomarkers response to aerobic versus resisted exercise
training for chronic obstructive pulmonary disease patients. Afr Health Sci. 2016;16(2):507–515.
54. Liao WH, Chen JW, Chen X, et al Impact of resistance training in subjects with COPD: a systematic review and meta-analysis. Respir Care. 2015;60(8):1130–1145.
55. Kabitz HJ, Schwoerer A, Bremer HC, et al Impairment of respiratory muscle function in pulmonary hypertension. Clin Sci (Lond). 2008;114(2):165–171.
56. Meyer FJ, Lossnitzer D, Kristen AV, et al Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension
. Eur Respir J. 2005;25(1):125–130.
57. Meyer FJ, Borst MM, Zugck C, et al Respiratory muscle dysfunction in congestive heart failure: clinical correlation and prognostic significance. Circulation. 2001;103(17):2153–2158.
58. Cahalin LP, Arena R, Guazzi M, et al Inspiratory muscle training in heart disease and heart failure: a review of the literature with a focus on method of training and outcomes. Expert Rev Cardiovasc Ther. 2013;11(2):161–177.
59. Coats AJ. The “muscle hypothesis” of chronic heart failure. J Mol Cell Cardiol. 1996;28(11):2255–2262.
60. Borghi-Silva A, Carrascosa C, Oliveira CC, et al Effects of respiratory muscle unloading on leg muscle oxygenation and blood volume during high-intensity exercise
in chronic heart failure. Am J Physiol Heart Circ Physiol. 2008;294(6):H2465–H2472.
61. Rajdev A, Garan H, Biviano A. Arrhythmias in pulmonary arterial hypertension
. Prog Cardiovasc Dis. 2012;55(2):180–186.
62. Garvey C, Bayles MP, Hamm LF, et al Pulmonary rehabilitation exercise
prescription in chronic obstructive pulmonary disease: review of selected guidelines: an official statement from the American Association of Cardiovascular and Pulmonary Rehabilitation
. J Cardiopulm Rehabil Prev. 2016;36(2):75–83.
63. Brawner CA, Ehrman JK, Schairer JR, Cao JJ, Keteyian SJ. Predicting maximum heart rate among patients with coronary heart disease receiving beta-adrenergic blockade therapy. Am Heart J. 2004;148(5):910–914.
64. Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate revisited. J Am Coll Cardiol. 2001;37(1):153–156.
65. Ozemek C, Whaley MH, Finch WH, Kaminsky LA. High cardiorespiratory fitness levels slow the decline in peak heart rate with age. Med Sci Sports Exerc. 2016;48(1):73–81.
66. Arena R, Myers J, Kaminsky LA. Revisiting age-predicted maximal heart rate: can it be used as a valid measure of effort? Am Heart J. 2016;173:49–56.
67. Panton LB, Golden J, Broeder CE, Browder KD, Cestaro-Seifer DJ, Seifer FD. The effects of resistance training on functional outcomes in patients with chronic obstructive pulmonary disease. Eur J Appl Physiol. 2004;91(4):443–449.
68. Brown MB, Kempf A, Collins CM, et al A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension
: a pilot study. Pulm Circ. 2018;8(1):2045893217743966.