Exercise intolerance in pulmonary hypertension: mechanism, evaluation and clinical implications

References

• Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34–D41.
   PubMed Web of Science ®Google Scholar
• Mocumbi AO, Thienemann F, Sliwa K. A global perspective on the epidemiology of pulmonary hypertension. Can J Cardiol. 2015;31:375–381.
   PubMed Web of Science ®Google Scholar
• Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016 Jan 1;37(1):67–119.
   PubMed Web of Science ®Google Scholar
• Arena R, Myers J, Guazzi M. The future of aerobic exercise testing in clinical practice: is it the ultimate vital sign? Future Cardiol. 2010;6:325–342.
   PubMedGoogle Scholar
• Arena R, Lavie CJ, Milani RV, et al. Cardiopulmonary exercise testing in patients with pulmonary arterial hypertension: an evidence-based review. J Heart Lung Transplant. 2010;29:159–173.
   PubMed Web of Science ®Google Scholar
• Arena R, Guazzi M, Myers J, et al. Cardiopulmonary exercise testing in the assessment of pulmonary hypertension. Expert Rev Respir Med. 2011;5:281–293.
   PubMed Web of Science ®Google Scholar
• Arena R, Myers J, Williams MA, et al. Assessment of functional capacity in clinical and research settings: a scientific statement from the American Heart Association Committee on Exercise, rehabilitation, and prevention of the council on clinical cardiology and the council on cardiovascular nursing. Circulation. 2007;116:329–343.
   PubMed Web of Science ®Google Scholar
• Waxman AB. Exercise physiology and pulmonary arterial hypertension. Prog Cardiovasc Dis. 2012;55:172–179.
   PubMed Web of Science ®Google Scholar
• Naeije R, Chesler N. Pulmonary circulation at exercise. Compr Physiol. 2012;2:711–741.
   PubMed Web of Science ®Google Scholar
• Arena R, Cahalin LP, Borghi-Silva A, et al. The effect of exercise training on the pulmonary arterial system in patients with pulmonary hypertension. Progress Cardiovasc Dis. 2015;57:480–488.
   PubMed Web of Science ®Google Scholar
• Naeije R, Vanderpool R, Dhakal BP, et al. Exercise-induced pulmonary hypertension: physiological basis and methodological concerns. Am J Respir Crit Care Med. 2013 Mar 15;187(6):576–583.
   PubMed Web of Science ®Google Scholar
• Herve P, Lau EM, Sitbon O, et al. Criteria for diagnosis of exercise pulmonary hypertension. Eur Respir J. 2015 Sep;46(3):728–737.
   PubMed Web of Science ®Google Scholar
• Tolle JJ, Waxman AB, Van Horn TL, et al. Exercise-induced pulmonary arterial hypertension. Circulation. 2008 Nov 18;118(21):2183–2189.
   PubMed Web of Science ®Google Scholar
• Dell’Italia LJ. Anatomy and physiology of the right ventricle. Cardiol Clin. 2012;30:167–187.
   PubMed Web of Science ®Google Scholar
• Mehra MR, Park MH, Landzberg MJ, et al. Right heart failure: toward a common language. J Heart Lung Transplant. 2014;33:123–126.
   PubMed Web of Science ®Google Scholar
• Haddad F, Hunt SA, Rosenthal DN, et al. Right ventricular function in cardiovascular disease, part I: anatomy, physiology, aging, and functional assessment of the right ventricle. Circulation. 2008 Mar 18;117(11):1436–1448.
   PubMed Web of Science ®Google Scholar
• Haddad F, Doyle R, Murphy DJ, et al. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation. 2008 Apr 1;117(13):1717–1731.
   PubMed Web of Science ®Google Scholar
• Naeije R, Brimioulle S, Dewachter L. Biomechanics of the right ventricle in health and disease (2013 Grover Conference series). Pulm Circ. 2014;4:395–406.
   PubMed Web of Science ®Google Scholar
• Roberts JD, Forfia PR. Diagnosis and assessment of pulmonary vascular disease by Doppler echocardiography. Pulm Circ. 2011;1:160–181.
   PubMedGoogle Scholar
• Spruijt OA, de Man FS, Groepenhoff H, et al. The effects of exercise on right ventricular contractility and right ventricular-arterial coupling in pulmonary hypertension. Am J Respir Crit Care Med. 2015;191(9):1050–1057.
   PubMed Web of Science ®Google Scholar
• Babu AS, Myers J, Arena R, et al. Exercise testing methods in the evaluation of patients with pulmonary artery hypertension. Expert Rev Cardiovasc Ther. 2013;11:729–737.
   PubMedGoogle Scholar
• Sun XG, Hansn JE, Oudiz RJ, et al. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation. 2001;104:429–435.
   PubMed Web of Science ®Google Scholar
• Morgan JM, Griffiths M, du Bois RM, et al. Hypoxic pulmonary vasoconstriction in systemic sclerosis and primary pulmonary hypertension. Chest. 1991;99(3):551–556.
   PubMed Web of Science ®Google Scholar
• Tolle J, Waxman A, Systrom D. Impaired systemic oxygen extraction at maximum exercise in pulmonary hypertension. Med Sci Sports Exerc. 2008;40:3–8.
   PubMed Web of Science ®Google Scholar
• Batt J, Ahmed SS, Correa J, et al. Skeletal muscle dysfunction in idiopathic pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2014 Jan;50(1):74–86.
   PubMed Web of Science ®Google Scholar
• Breda AP, Pereira de Albuquerque AL, Jardim C, et al. Skeletal muscle abnormalities in pulmonary arterial hypertension. PLoS One. 2014 Dec 2;9(12):e114101.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Kabitz HJ, Schwoerer A, Bremer HC, et al. Impairment of respiratory muscle function in pulmonary hypertension. Clin Sci (Lond). 2008;114(2):165–171.
   PubMed Web of Science ®Google Scholar
• de Man FS, van Hees HW, Handoko ML, et al. Diaphragm muscle fiber weakness in pulmonary hypertension. Am J Respir Crit Care Med. 2011;183(10):1411–1418.
   PubMed Web of Science ®Google Scholar
• Fowler RM, Gain KR, Gabbay E. Exercise intolerance in pulmonary arterial hypertension. Pulm Med. 2012;2012:359204. doi:10.1155/2012/359204.
   PubMedGoogle Scholar
• Bauer R, Dehnert C, Schoene P, et al. Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension. Respir Med. 2007;101:2366–2369.
   PubMed Web of Science ®Google Scholar
• Meyer FJ, Lossnitzer D, Kristen AV, et al. Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension. Eur Respir J. 2005;25:125–130.
   PubMed Web of Science ®Google Scholar
• Ramos RP, Arakaki JS, Barbosa P, et al. Heart rate recovery in pulmonary arterial hypertension: relationship with exercise capacity and prognosis. Am Heart J. 2012;163:580–588.
   PubMed Web of Science ®Google Scholar
• Minai OA, Gudavalli R, Mummadi S, et al. Heart rate recovery predicts clinical worsening in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185:400–408.
   PubMed Web of Science ®Google Scholar
• Wang S, Aurora AB, Johnson BA, et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15:261–271.
   PubMed Web of Science ®Google Scholar
• Potus F, Malenfant S, Graydon C, et al. Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014;190:318–328.
   PubMed Web of Science ®Google Scholar
• Bertero T, Lu Y, Annis S, et al. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest. 2014 Aug 1;124:3514–3528.
   PubMed Web of Science ®Google Scholar
• Kitzman DW, Groban L. Exercise intolerance. Cardiol Clin. 2011;29:461–477.
   PubMed Web of Science ®Google Scholar
• Downing J, Balady GJ. The role of exercise training in heart failure. J Am Coll Cardiol. 2011;58:561–569.
   PubMed Web of Science ®Google Scholar
• Conraads VM, Van Craenenbroeck EM, De Maeyer C, et al. Unraveling new mechanisms of exercise intolerance in chronic heart failure: role of exercise training. Heart Fail Rev. 2013;18:65–77.
   PubMed Web of Science ®Google Scholar
• Guazzi M, Arena R. Pulmonary hypertension with left-sided heart disease. Nat Rev Cardiol. 2010;7:648–659.
   PubMed Web of Science ®Google Scholar
• Vachiéry JL, Adir Y, Barberà JA, et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol. 2013;62(25 Suppl):D100–D108.
   PubMed Web of Science ®Google Scholar
• Meyer P, Filippatos GS, Ahmed MI, et al. Effects of right ventricular ejection fraction on outcomes in chronic systolic heart failure. Circulation. 2010;121:252–258.
   PubMed Web of Science ®Google Scholar
• Guazzi M. Pulmonary hypertension in heart failure preserved ejection fraction: prevalence, pathophysiology, and clinical perspectives. Circ Heart Fail. 2014;7:367–377.
   PubMed Web of Science ®Google Scholar
• Borlaug BA. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction. Circ J. 2014;78:20–32.
   PubMed Web of Science ®Google Scholar
• Magne J, Pibarot P, Sengupta PP, et al. Pulmonary hypertension in valvular disease: a comprehensive review on pathophysiology to therapy from the HAVEC group. JACC Cardiovasc Imaging. 2015;8:83–99.
   PubMed Web of Science ®Google Scholar
• Nellessen U, Inselmann G, Ludwig J, et al. Rest and exercise hemodynamics before and after valve replacement–a combined Doppler/catheter study. Clin Cardiol. 2000;23:32–38.
   PubMed Web of Science ®Google Scholar
• Guazzi M, Adams V, Conraads V, et al. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation. 2012;126:2261–2274.
   PubMed Web of Science ®Google Scholar
• Ferrazza AM, Martolini D, Valli G, et al. Cardiopulmonary exercise testing in the functional and prognostic evaluation of patients with pulmonary diseases. Respiration. 2009;77:3–17.
   PubMedGoogle Scholar
• Weitzenblum E, Chaouat A, Kessler R. Pulmonary hypertension in chronic obstructive pulmonary disease. Pneumonol Alergol Pol. 2013;81:390–398.
   PubMedGoogle Scholar
• Man WD, Kemp P, Moxham J, et al. Exercise and muscle dysfunction in COPD: implications for pulmonary rehabilitation. Clin Sci (Lond). 2009;117:281–291.
   PubMed Web of Science ®Google Scholar
• Maltais F, Decramer M, Casaburi R, et al. ATS/ERS Ad Hoc Committee on limb muscle dysfunction in COPD. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189:e15–e62.
   PubMed Web of Science ®Google Scholar
• Oliveira MF, Zelt JT, Jones JH, et al. Does impaired O2 delivery during exercise accentuate central and peripheral fatigue in patients with coexistent COPD-CHF? Front Physiol. 2015 Jan;7(5):514. doi:10.3389/fphys.2014.00514.
   Web of Science ®Google Scholar
• Mathur S, Brooks D, Carvalho CR. Structural alterations of skeletal muscle in COPD. Front Physiol. 2014 Mar 19; 5:104. doi:10.3389/fphys.2014.00104.
   PubMed Web of Science ®Google Scholar
• Arena R. Exercise testing and training in chronic lung disease and pulmonary arterial hypertension. Prog Cardiovasc Dis. 2011;53:454–463.
   PubMed Web of Science ®Google Scholar
• Boutou AK, Pitsiou GG, Siakka P, et al. Phenotyping exercise limitation in systemic sclerosis: the use of cardiopulmonary exercise testing. Respiration. 2016;91(2):115–123.
   PubMed Web of Science ®Google Scholar
• Dumitrescu D, Oudiz RJ, Karpouzas G, et al. Developing pulmonary vasculopathy in systemic sclerosis, detected with non-invasive cardiopulmonary exercise testing. PLoS One. 2010;5(12):e14293.
   PubMed Web of Science ®Google Scholar
• Boutou AK, Pitsiou GG, Trigonis I, et al. Exercise capacity in idiopathic pulmonary fibrosis: the effect of pulmonary hypertension. Respirology. 2011;16(3):451–458.
   PubMed Web of Science ®Google Scholar
• Hellebrandová L, Chlumský J, Vostatek P, et al. Airflow limitation is accompanied by diaphragm dysfunction. Physiol Res. 2016 Apr 12. [Epub ahead of print].
   PubMed Web of Science ®Google Scholar
• Holland AE. Exercise limitation in interstitial lung disease - mechanisms, significance and therapeutic options. Chron Respir Dis. 2010;7(2):101–111.
   PubMedGoogle Scholar
• Faisal A, Alghamdi BJ, Ciavaglia CE, et al. Common mechanisms of dyspnea in chronic interstitial and obstructive lung disorders. Am J Respir Crit Care Med. 2016 Feb 1;193(3):299–309.
   PubMed Web of Science ®Google Scholar
• Menzel T, Wagner S, Kramm T, et al. Pathophysiology of impaired right and left ventricular function in chronic embolic pulmonary hypertension: changes after pulmonary thromboendarterectomy. Chest. 2000;118:897–903.
   PubMed Web of Science ®Google Scholar
• Lang IM, Simonneau G, Pepke-Zaba JW, et al. Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. A case-control study. Thromb Haemost. 2013 Jul;110(1):83–91.
   PubMed Web of Science ®Google Scholar
• Iwase T, Nagaya N, Ando M, et al. Acute and chronic effects of surgical thromboendarterectomy on exercise capacity and ventilatory efficiency in patients with chronic thromboembolic pulmonary hypertension. Heart. 2001;86:188–192.
   PubMed Web of Science ®Google Scholar
• Bonderman D, Martischnig AM, Vonbank K, et al. Right ventricular load at exercise is a cause of persistent exercise limitation in patients with normal resting pulmonary vascular resistance after pulmonary endarterectomy. Chest. 2011 Jan;139(1):122–127.
   PubMed Web of Science ®Google Scholar
• Claessen G, La Gerche A, Dymarkowski S, et al. Pulmonary vascular and right ventricular reserve in patients with normalized resting hemodynamics after pulmonary endarterectomy. J Am Heart Assoc. 2015 Mar 23;4(3):e001602.
   PubMed Web of Science ®Google Scholar
• Fonseca GH, Souza R, Salemi VM, et al. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J. 2012;39:112–118.
   PubMed Web of Science ®Google Scholar
• Potoka KP, Gladwin MT. Vasculopathy and pulmonary hypertension in sickle cell disease. Am J Physiol Lung Cell Mol Physiol. 2014 Nov 14. [Epub ahead of print]. doi:10.1152/ajplung.00252.2014.
   PubMed Web of Science ®Google Scholar
• Machado RF, Farber HW. Pulmonary hypertension associated with chronic hemolytic anemia and other blood disorders. Clin Chest Med. 2013;34:739–752.
   PubMed Web of Science ®Google Scholar
• Anthi A, Machado RF, Jison ML, et al. Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med. 2007;175:1272–1279.
   PubMed Web of Science ®Google Scholar
• Balady GJ, Arena R, Sietsema K, et al. Clinician’s guide to cardiopulmonary exercise testing in adults. A scientific statement from the American Heart Association. Circulation. 2010;122:191–225.
   PubMed Web of Science ®Google Scholar
• Fletcher GF, Ades PA, Kligfield P, et al. Exercise standards for testing and training: a scientific statement from the American Heart Association. Circulation. 2013;128:873–934.
   PubMed Web of Science ®Google Scholar
• Skalski J, Allison TG, Miller TD. The safety of cardiopulmonary exercise testing in a population with high-risk cardiovascular diseases. Circulation. 2012;126:2465–2472.
   PubMed Web of Science ®Google Scholar
• Abumehdi MR, Wardle AJ, Nazzal R, et al. Feasibility and safety of cardiopulmonary exercise testing in children with pulmonary hypertension. Cardiol Young. 2015 Sep;16:1–7.
   Web of Science ®Google Scholar
• Pinkstaff SO, Burger CD, Daugherty J, et al. Cardiopulmonary exercise testing in patients with pulmonary hypertension: clinical recommendations based on a review of the evidence. Exp Rev Resp Med. 2016;10(3):279–295.
   PubMed Web of Science ®Google Scholar
• Held M, Grün M, Holl R, et al. Cardiopulmonary exercise testing to detect chronic thromboembolic pulmonary hypertension in patients with normal echocardiography. Respiration. 2014;87:379–387.
   PubMed Web of Science ®Google Scholar
• ATS Statement. Guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111–117.
   PubMed Web of Science ®Google Scholar
• Holland AE, Spruit MA, Troosters T, et al. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014;44:1428–1446.
   PubMed Web of Science ®Google Scholar
• Mathai SC, Puhan MA, Lam D, et al. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:428–433.
   PubMed Web of Science ®Google Scholar
• Bellet RN, Adams L, Morris NR. The 6-minute walk test in outpatient cardiac rehabilitation: validity, reliability and responsiveness – a systematic review. Physiotherapy. 2012;98:277–286.
   PubMed Web of Science ®Google Scholar
• Du H, Newton PJ, Salamonson Y, et al. A review of the six-minute walk test: its implications as a self-administered assessment tool. Eur J Cardiovasc Nurs. 2009;8:2–8.
   PubMed Web of Science ®Google Scholar
• Deboeck G, Niset G, Vachiery JL, et al. Physiological response to the six-minute walk test in pulmonary arterial hypertension. Eur Respir J. 2005;26:667–672.
   PubMed Web of Science ®Google Scholar
• Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med. 1998;158:1384–1387.
   PubMed Web of Science ®Google Scholar
• Srikanth AM, D’souza GA, Devaraj V, et al. Reference equations for the six-minute walk distance in the Indian population [abstract]. Chest. 2006;130(suppl):119S.
   PubMed Web of Science ®Google Scholar
• Poh H, Eastewood PR, Cecins NM, et al. Six-minute walk distance in healthy Singaporean adults cannot be predicted using reference equations derived from Caucasian populations. Respirology. 2006;11:211–216.
   PubMed Web of Science ®Google Scholar
• Neal JE, Lee AS, Burger CD. Submaximal exercise testing may be superior to the 6-min walk test in assessing pulmonary arterial hypertension disease severity. Clin Respir J. 2014;8:404–409.
   PubMed Web of Science ®Google Scholar
• Sicari R, Nihoyannopoulos P, Evangelista A, et al. Stress echocardiography xpert consensus statement: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J Echocardiogr. 2008;9:415–437.
   PubMed Web of Science ®Google Scholar
• Douglas PS, Khandheria B, Stainback RF, et al. ACCF/ASE/ACEP/AHA/ASNC/SCAI/SCCT/SCMR 2008 appropriateness criteria for stress echocardiography: a report of the American College of Cardiology Foundation Appropriateness Criteria Task Force, American Society of Echocardiography, American College of Emergency Physicians, American Heart Association, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance endorsed by the Heart Rhythm Society and the Society of Critical Care Medicine. J Am Coll Cardiol. 2008;51:1127–1147.
   PubMed Web of Science ®Google Scholar
• Grünig E, Tiede H, Enyimayew EO, et al. Assessment and prognostic relevance of right ventricular contractile reserve in patients with severe pulmonary hypertension. Circulation. 2013;128:2005–2015.
   PubMed Web of Science ®Google Scholar
• Argiento P, Chesler N, Mule M, et al. Exercise stress echocardiography for the study of the pulmonary circulation. Eur Respir J. 2010;35:1273–1278.
   PubMed Web of Science ®Google Scholar
• Maron BA, Cockrill BA, Waxman AB, et al. The invasive cardiopulmonary exercise test. Circulation. 2013;127:1157–1164.
   PubMed Web of Science ®Google Scholar
• Berry NC, Manyoo A, Oldham WM, et al. Protocol for exercise hemodynamic assessment: performing an invasive cardiopulmonary exercise test in clinical practice. Pulm Circ. 2015 Dec;5(4):610–618.
   PubMed Web of Science ®Google Scholar
• American Thoracic Society/European Respiratory Society. ATS/ERS statement on respiratory muscle testing. Am J Respir Crit Care Med. 2002;166(4):518–624.
   PubMed Web of Science ®Google Scholar
• Yuan P, Yuan XT, Sun XY, et al. Exercise training for pulmonary hypertension: a systematic review and meta-analysis. Int J Cardiol. 2014;178C:142–146.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Pandey A, Garg S, Khunger M, et al. Efficacy and safety of exercise training in chronic pulmonary hypertension: systematic review and meta-analysis. Circ Heart Fail. 2015 Nov;8(6):1032–1043.
   PubMed Web of Science ®Google Scholar
• Babu AS, Padmakumar R, Maiya AG, et al. Effects of exercise training on exercise capacity in pulmonary arterial hypertension: a systematic review of clinical trials. Heart Lung Circ. 2016;25(4):333–341.
   Web of Science ®Google Scholar
• 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 Jan 1;37(1):35–44.
   PubMed Web of Science ®Google Scholar
• Ehlken N, Verduyn C, Tiede H, et al. Economic evaluation of exercise training in patients with pulmonary hypertension. Lung. 2014;192:359–366.
   PubMed Web of Science ®Google Scholar
• Arena R, Myers J, Forman DE, et al. Should high-intensity-aerobic interval training become the clinical standard in heart failure? Heart Fail Rev. 2013;18:95–105.
   PubMed Web of Science ®Google Scholar