Exercise-Induced Pulmonary Hypertension: How to Define, Diagnose, and Treat At-Risk Patients
Introduction Pulmonary hypertension is a devastating disease with a rapid progression of symptoms leading to high patient mortality. It is characterized by high blood pressure in the pulmonary vasculature and poor pulmonary perfusion, resulting in patient fatigue, dyspnea, and syncope, especially upon physical exertion. A sub-clinical form of pulmonary hypertension also exists which is referred to as exercise induced pulmonary hypertension, where patients display normal resting hemodynamic properties but abnormal pulmonary responses to exercise.
Discussion Recent evidence suggests early intervention and treatment of pulmonary hypertension can improve patient outcomes. However, there is a lack of clinical evidence supporting effective treatments for exercise induced pulmonary hypertension (EIPH), arguably the earliest stage of pulmonary hypertension. This is due in part to the removal of EIPH from official guidelines such as the European Respiratory Society in 2008. EIPH was removed from clinical guidelines due to a lack of consensus on the definition and standardized testing procedures for diagnosing EIPH. Emerging evidence suggests that exercise testing following a standardized protocol of stress echocardiography or right heart catheterization of patients may allow for the classification of EIPH as a mean pulmonary artery pressure/cardiac output slope > 3 mmHg/L/min, and/or mean pulmonary artery pressure > 30 mmHg with a pulmonary vascular resistance > 3 Wood Units.
Conclusion Providing evidence for a consensus definition of EIPH, along with a validated, standardized testing procedure, will hopefully foster the progression of research on EIPH and further the development of treatments and improve patient outcomes for people with pulmonary hypertension.
- Hoeper MM, Humbert M, Souza R, Idrees M, Kawut SM, Sliwa-Hahnle K, et al. A global view of pulmonary hypertension. Lancet Respir Med. 2016;4(4):306-22. DOI:10.1016/S2213-2600(15)00543-3
- Fowler RM, Maiorana AJ, Jenkins SC, Gain KR, O'Driscoll G, Gabbay E. Implications of exercise-induced pulmonary arterial hypertension. Medicine and Science in Sports and Exercise. 2011;43(6):983-9. DOI:10.1249/MSS.0b013e318204cdac
- Steen V, Chou M, Shanmugam V, Mathias M, Kuru T, Morrissey R. Exercise-induced pulmonary arterial hypertension in patients with systemic sclerosis. Chest. 2008;134(1):146-51. DOI:10.1378/chest.07-2324
- Yamada H, Saijo Y, Hotchi J, Hayashi S, Bando M, Nishio S, et al. Right Ventricular Dysfunction in Patients With Exercise-Induced Pulmonary Hypertension Associated With Connective Tissue Disease. Journal of the American College of Cardiology. 2014;63(12):A1499-A. DOI:10.1016/S0735-1097(14)61500-X
- Wijeratne DT, Lajkosz K, Brogly SB, Lougheed MD, Jiang L, Housin A, et al. Increasing Incidence and Prevalence of World Health Organization Groups 1 to 4 Pulmonary Hypertension. Circulation: Cardiovascular Quality and Outcomes. 2018;11(2):e003973. DOI:10.1161/circoutcomes.117.003973
- Galiè N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. The Lancet. 2008;371(9630):2093-100. DOI:10.1016/S0140-6736(08)60919-8
- Proudman SM, Stevens WM, Sahhar J, Celermajer D. Pulmonary arterial hypertension in systemic sclerosis: The need for early detection and treatment. Internal Medicine Journal. 2007;37(7):485-94. DOI:10.1111/j.1445-5994.2007.01370.x
- Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. European Respiratory Journal. 2009;34(6):1219-63. DOI:10.1183/09031936.00139009
- Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. European Respiratory Journal. 2019;53(1):1801913. DOI:10.1183/13993003.01913-2018
- Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JSR, Vrapi F, et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. American Journal of Respiratory and Critical Care Medicine. 2009;179(2):151-7. DOI:10.1164/rccm.200806-953OC
- Denton CP, Cailes JB, Phillips GD, Wells AU, Black CM, Du Bois RM. Comparison of Doppler Echocardiography and Right Heart Catheterization To Assess Pulmonary Hypertension in Systemic Sclerosis. British Journal of Rheumatology. 1997;36:239-43. DOI:10.1093/rheumatology/36.2.239
- Obokata M, Nagata Y, Kado Y, Kurabayashi M, Otsuji Y, Takeuchi M. Ventricular-Arterial Coupling and Exercise-Induced Pulmonary Hypertension During Low-Level Exercise in Heart Failure With Preserved or Reduced Ejection Fraction. Journal of Cardiac Failure. 2017;23(3):216-20. DOI:10.1016/j.cardfail.2016.10.001
- Voilliot D, Magne J, Dulgheru R, Kou S, Henri C, Laaraibi S, et al. Determinants of exercise-induced pulmonary arterial hypertension in systemic sclerosis. International Journal of Cardiology. 2014;173(3):373-9. DOI:10.1016/j.ijcard.2014.02.042
- McGoon M, Gutterman D, Steen V, Barst RJ, McCorry D, Fortin T, et al. Screening, Early Detection, and Diagnosis of Pulmonary Arterial Hypertension. Chest. 2004;126(1 Suppl):78S-92S. DOI:10.1378/chest.126.1
- Misra D, Kendes A, Sulica R, Carabello B. Exercise-induced pulmonary hypertension by stress echocardiography: Prevalence and correlation with right heart hemodynamics. International Journal of Cardiology. 2017;228:518-22. DOI:10.1016/j.ijcard.2016.11.191
- Oudiz RJ, Rubin LJ. Exercise-induced pulmonary arterial hypertension: A new addition to the spectrum of pulmonary vascular diseases. Circulation. 2008;118(21):2120-1. DOI:10.1161/CIRCULATIONAHA.108.819573
- Raeside Da, Chalmers G, Clelland J, Madhok R, Peacock aJ. Pulmonary artery pressure variation in patients with connective tissue disease: 24 hour ambulatory pulmonary artery pressure monitoring. Thorax. 1998;53(10):857-62. DOI:10.1136/thx.53.10.857
- Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom DM. Exercise-induced pulmonary arterial hypertension. Circulation. 2008;118(21):2183-9. DOI:10.1161/CIRCULATIONAHA.108.787101
- Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: A systematic review. European Respiratory Journal. 2009;34(4):888-94. DOI:10.1183/09031936.00145608
- Naeije R, Mélot C, Niset G, Delcroix M, Wagner PD. Mechanisms of improved arterial oxygenation after peripheral chemoreceptor stimulation during hypoxic exercise. Journal of Applied Physiology. 1993;74(4):1666-71.
- Herve P, Lau EM, Sitbon O, Savale L, Montani D, Godinas L, et al. Criteria for diagnosis of exercise pulmonary hypertension. European Respiratory Journal. 2015;46(3):728-37. DOI:10.1183/09031936.00021915
- Guseh JS. The Evolving Landscape of Exercise-Induced Pulmonary Hypertension. Current Treatment Options in Cardiovascular Medicine. 2016;18(6). DOI:10.1007/s11936-016-0459-5
- Hirani N, Brunner NW, Kapasi A, Chandy G, Rudski L, Paterson I, et al. Canadian Cardiovascular Society/Canadian Thoracic Society Position Statement on Pulmonary Hypertension. Canadian Journal of Cardiology. 2020;36(7):977-92. DOI:10.1016/j.cjca.2019.11.041
- Lewis GD, Bossone E, Naeije R, Grünig E, Saggar R, Lancellotti P, et al. Pulmonary vascular hemodynamic response to exercise in cardiopulmonary diseases. Circulation. 2013;128(13):1470-9. DOI:10.1161/CIRCULATIONAHA.112.000667
- Naeije R, Vanderpool R, Dhakal BP, Saggar R, Saggar R, Vachiery JL, et al. Exercise-induced pulmonary hypertension: Physiological basis and methodological concerns. American Journal of Respiratory and Critical Care Medicine. 2013;187(6):576-83. DOI:10.1164/rccm.201211-2090CI
- MacIver DH, Adeniran I, MacIver IR, Revell A, Zhang H. Physiological mechanisms of pulmonary hypertension. American Heart Journal. 2016;180:1-11. DOI:10.1016/j.ahj.2016.07.003
- McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association Developed in Collaboration With the American College o. Journal of the American College of Cardiology. 2009;53(17):1573-619. DOI:10.1016/j.jacc.2009.01.004
- Sumner MJ, Cannon TR, Mundin JW, White DG, Watts IS. Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction. British Journal of Pharmacology. 1992;107(3):858-60. DOI:10.1111/j.1476-5381.1992.tb14537.x
- Giaid A, Yanagisawa M, Langleben D, Michel R, Levy R, Shennib H, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. New England Journal of Medicine. 1993;328:1732-9.
- Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased Plasma Endothelin-1 in Pulmonary-Hypertension - Marker or Mediator of Disease. Annals of Internal Medicine. 1991;114(6):464-9. DOI:10.7326/0003-4819-114-6-464
- Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. Journal of Clinical Investigation. 1989;83(5):1774-7. DOI:10.1172/JCI114081
- Ignarro LJ, Buga GM, Wei LH, Bauer PM, Wu G, del Soldato P. Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. Proc Natl Acad Sci U S A. 2001;98(7):4202-8. DOI:10.1073/pnas.071054698
- Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. American Journal of Respiratory & Critical Care Medicine. 1999;159(6):1925-32.
- Skalski J, Allison TG, Miller TD. The safety of cardiopulmonary exercise testing in a population with high-risk cardiovascular diseases. Circulation. 2012;126(21):2465-72. DOI:10.1161/CIRCULATIONAHA.112.110460
- Linehan JH, Haworth ST, Nelin LD, Krenz GS, Dawson CA. A simple distensible vessel model for interpreting pulmonary vascular pressure-flow curves. Journal of applied physiology (Bethesda, Md : 1985). 1992;73(3):987-94.
- Hillis LD, Firth BG, Winniford MD. Analysis of factors affecting the variability of fick versus indicator dilution measurements of cardiac output. The American Journal of Cardiology. 1985;56(12):764-8. DOI:10.1016/0002-9149(85)91132-4
- Hsu S, Brusca SB, Rhodes PS, Kolb TM, Mathai SC, Tedford RJ. Use of thermodilution cardiac output overestimates diagnoses of exercise-induced pulmonary hypertension. Pulmonary Circulation. 2017:690629-. DOI:10.1086/690629
- Raeside Da, Smith a, Brown a, Patel KR, Madhok R, Cleland J, et al. Pulmonary artery pressure measurement during exercise testing in patients with suspected pulmonary hypertension. The European respiratory journal. 2000;16(2):282-7.
- Sheriff DD, Augustyniak RA, O’Leary DS. Muscle chemoreflex-induced increases in right atrial pressure. American Journal of Physiology-Heart and Circulatory Physiology. 1998;275(3):H767-H75. DOI:10.1152/ajpheart.1998.275.3.H767
- Argiento P, Chesler N, Mulè M, D'Alto M, Bossone E, Unger P, et al. Exercise stress echocardiography for the study of the pulmonary circulation. European Respiratory Journal. 2010;35(6):1273-8. DOI:10.1183/09031936.00076009
- Argiento P, Vanderpool RR, Mulè M, Russo MG, D'Alto M, Bossone E, et al. Exercise stress echocardiography of the pulmonary circulation: Limits of normal and sex differences. Chest. 2012;142(5):1158-65. DOI:10.1378/chest.12-0071
- McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation. 2001;104(23):2797-802. DOI:10.1161/hc4801.100076
- Bossone E, Naeije R. Exercise-Induced Pulmonary Hypertension. Heart Failure Clinics. 2012;8(3):485-95. DOI:10.1016/j.hfc.2012.04.007
- Bossone E, Rubenfire M, Bach DS, Ricciardi M, Armstrong WF. Range of tricuspid regurgitation velocity at rest and during exercise in normal adult men: Implications for the diagnosis of pulmonary hypertension. Journal of the American College of Cardiology. 1999;33(6):1662-6. DOI:10.1016/S0735-1097(99)00055-8
- Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. Journal of the American College of Cardiology. 2004;43(12 SUPPL.):40-8. DOI:10.1016/j.jacc.2004.02.032
- Lewis GD, Shah RV, Pappagianopolas PP, Systrom DM, Semigran MJ. Determinants of ventilatory efficiency in heart failure: the role of right ventricular performance and pulmonary vascular tone. Circulation Heart failure. 2008;1(4):227-33. DOI:10.1161/CIRCHEARTFAILURE.108.785501
- Kovacs G, Maier R, Aberer E, Brodmann M, Graninger W, Kqiku X, et al. Pulmonary arterial hypertension therapy may be safe and effective in patients with systemic sclerosis and borderline pulmonary artery pressure. Arthritis and rheumatism. 2012;64(4):1257-62. DOI:10.1002/art.33460
- Saggar R, Khanna D, Furst DE, Shapiro S, Maranian P, Belperio JA, et al. Exercise-induced pulmonary hypertension associated with systemic sclerosis: Four distinct entities. Arthritis and Rheumatism. 2010;62(12):3741-50. DOI:10.1002/art.27695
- Schmeisser A, Schroetter H, Braun-Dulleaus RC. Management of pulmonary hypertension in left heart disease. Therapeutic advances in cardiovascular disease. 2013;7(3):131-51. DOI:10.1177/1753944713477518
- Ho JE, Zern EK, Lau ES, Wooster L, Bailey CS, Cunningham T, et al. Exercise Pulmonary Hypertension Predicts Clinical Outcomes in Patients With Dyspnea on Effort. Journal of the American College of Cardiology. 2020;75(1):17-26. DOI:10.1016/j.jacc.2019.10.048
- Parasuraman S, Walker S, Loudon BL, Gollop ND, Wilson AM, Lowery C, et al. Assessment of pulmonary artery pressure by echocardiography—A comprehensive review. IJC Heart & Vasculature. 2016;12:45-51. DOI:10.1016/j.ijcha.2016.05.011