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Cardiopulmonary Exercise Testing with Echocardiography to Identify Mechanisms of Unexplained Dyspnea


Little data is available about the pathophysiological mechanisms of unexplained dyspnea and their clinical meaning. Consecutive patients with unexplained dyspnea underwent prospective standardized cardiopulmonary exercise testing with echocardiography (CPETecho). Patients were grouped as having normal exercise capacity (peak VO2 > 80% with respiratory exchange [RER] > 1.05), reduced exercise capacity (peak VO2 ≤ 80% with RER > 1.05), or a submaximal exercise test (RER ≤ 1.05). From 307 patients, 144 (47%) had normal and 116 (38%) reduced exercise capacity, and 47 (15%) had a submaximal exercise test. Patients with reduced versus normal exercise capacity had significantly more mechanisms for unexplained dyspnea (2.3±1.0 vs 1.5±1.0, respectively; p<0.001). Exercise PH (42%), low heart rate reserve (51%), low stroke volume reserve (38%), low diastolic reserve (18%), and peripheral muscle limitation (17%) were most common. Patients with more mechanisms for dyspnea displayed poorer peak VO2 and had an increased risk for cardiovascular hospitalization (p=0.002). Patients with unexplained dyspnea display multiple coexisting mechanisms for exercise intolerance, which relate to the severity of exercise limitation and risk of subsequent cardiovascular hospitalizations.

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  1. 1.

    Sarkar, S., & Amelung, P. J. (2006). Evaluation of the dyspneic patient in the office. Primary Care, 33(3), 643–657.

    PubMed  Article  Google Scholar 

  2. 2.

    Shiber, J. R., & Santana, J. (2006). Dyspnea. The Medical Clinics of North America, 90(3), 453–479.

    PubMed  Article  Google Scholar 

  3. 3.

    Martinez, F. J., Stanopoulos, I., Acero, R., Becker, F. S., Pickering, R., & Beamis, J. F. (1994). Graded comprehensive cardiopulmonary exercise testing in the evaluation of dyspnea unexplained by routine evaluation. Chest, 105(1), 168–174.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Gillespie, D. J., & Staats, B. A. (1994). Unexplained dyspnea. Mayo Clinic Proceedings, 69(7), 657–663.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Borlaug BA. (2020). Evaluation and management of heart failure with preserved ejection fraction. Nature Reviews. Cardiology

  6. 6.

    Huang, W., Resch, S., Oliveira, R. K., Cockrill, B. A., Systrom, D. M., & Waxman, A. B. (2017). Invasive cardiopulmonary exercise testing in the evaluation of unexplained dyspnea: Insights from a multidisciplinary dyspnea center. European Journal of Preventive Cardiology, 24(11), 1190–1199.

    PubMed  Article  Google Scholar 

  7. 7.

    Obokata, M., Kane, G. C., Reddy, Y. N., Olson, T. P., Melenovsky, V., & Borlaug, B. A. (2017). Role of diastolic stress testing in the evaluation for heart failure with preserved ejection fraction: A simultaneous invasive-echocardiographic study. Circulation, 135(9), 825–838.

    PubMed  Article  Google Scholar 

  8. 8.

    Borlaug, B. A., Nishimura, R. A., Sorajja, P., Lam, C. S., & Redfield, M. M. (2010). Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circulation. Heart Failure, 3(5), 588–595.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Martens, P., Verbrugge, F. H., Bertrand, P. B., Verhaert, D., Vandervoort, P., Dupont, M., Tang, W. H. W., Janssens, S., & Mullens, W. (2018). Effect of cardiac resynchronization therapy on exercise-induced pulmonary hypertension and right ventricular-arterial coupling. Circulation. Cardiovascular Imaging, 11(9), e007813.

    PubMed  Article  Google Scholar 

  10. 10.

    Guazzi, M., Bandera, F., Ozemek, C., Systrom, D., & Arena, R. (2017). Cardiopulmonary exercise testing: What is its value? Journal of the American College of Cardiology, 70(13), 1618–1636.

    PubMed  Article  Google Scholar 

  11. 11.

    Obokata, M., Reddy, Y. N. V., & Borlaug, B. A. (2020). Diastolic dysfunction and heart failure with preserved ejection fraction: Understanding mechanisms by using noninvasive methods. JACC: Cardiovascular Imaging, 13(1 Pt 2), 245–257.

    PubMed  Google Scholar 

  12. 12.

    Pugliese, N. R., De, B. N., Conte, L., Gargani, L., Mazzola, M., Fabiani, I., Natali, A., Dini, F. L., Frumento, P., Rosada, J., Taddei, S., Borlaug, B. A., & Masi, S. (2021). Cardiac reserve and exercise capacity: Insights from combined cardiopulmonary and exercise echocardiography stress testing. Journal of the American Society of Echocardiography, 34(1), 38–50.

    PubMed  Article  Google Scholar 

  13. 13.

    Pugliese, N. R., Mazzola, M., Fabiani, I., Gargani, L., De, B. N., Pedrinelli, R., Natali, A., & Dini, F. L. (2020). Haemodynamic and metabolic phenotyping of hypertensive patients with and without heart failure by combining cardiopulmonary and echocardiographic stress test. European Journal of Heart Failure, 22(3), 458–468.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Elliott, P. M., Anastasakis, A., Borger, M. A., Borggrefe, M., Cecchi, F., Charron, P., Hagege, A. A., Lafont, A., Limongelli, G., Mahrholdt, H., McKenna, W. J., Mogensen, J., Nihoyannopoulos, P., Nistri, S., Pieper, P. G., Pieske, B., Rapezzi, C., Rutten, F. H., Tillmanns, C., & Watkins, H. (2014). 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). European Heart Journal, 35(39), 2733–2779.

    PubMed  Article  Google Scholar 

  15. 15.

    von EE Altman, D. G., Egger, M., Pocock, S. J., Gotzsche, P. C., & Vandenbroucke, J. P. (2007). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Lancet, 370(9596), 1453–1457.

    Article  Google Scholar 

  16. 16.

    Chemla, D., Castelain, V., Humbert, M., Hebert, J. L., Simonneau, G., Lecarpentier, Y., & Herve, P. (2004). New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest, 126(4), 1313–1317.

    PubMed  Article  Google Scholar 

  17. 17.

    Obokata M, Kane GC, Sorimachi H, Reddy YNV, Olson TP, Egbe AC, Melenovsky V, Borlaug BA. (2020) Noninvasive evaluation of pulmonary artery pressure during exercise: The importance of right atrial hypertension. The European Respiratory Journal 55(2)

  18. 18.

    Ross, R. M. (2003). ATS/ACCP statement on cardiopulmonary exercise testing. American Journal of Respiratory and Critical Care Medicine, 167(10), 1451.

    PubMed  Article  Google Scholar 

  19. 19.

    Brubaker, P. H., & Kitzman, D. W. (2011). Chronotropic incompetence: Causes, consequences, and management. Circulation, 123(9), 1010–1020.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Higginbotham, M. B., Morris, K. G., Williams, R. S., McHale, P. A., Coleman, R. E., & Cobb, F. R. (1986). Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circulation Research, 58(2), 281–291.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Lancellotti, P., Pellikka, P. A., Budts, W., Chaudhry, F. A., Donal, E., Dulgheru, R., Edvardsen, T., Garbi, M., Ha, J. W., Kane, G. C., Kreeger, J., Mertens, L., Pibarot, P., Picano, E., Ryan, T., Tsutsui, J. M., & Varga, A. (2017). The clinical use of stress echocardiography in non-ischaemic heart disease: Recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Journal of the American Society of Echocardiography, 30(2), 101–138.

    PubMed  Article  Google Scholar 

  22. 22.

    Kovacs G, Herve P, Barbera JA, Chaouat A, Chemla D, Condliffe R, Garcia G, Grunig E, Howard L, Humbert M, Lau E, Laveneziana P, Lewis GD, Naeije R, Peacock A, Rosenkranz S, Saggar R, Ulrich S, Vizza D, Vonk NA, Olschewski H. (2017) An official European Respiratory Society statement: Pulmonary haemodynamics during exercise. The European Respiratory Journal ;50(5).

  23. 23.

    Guazzi, M., Adams, V., Conraads, V., Halle, M., Mezzani, A., Vanhees, L., Arena, R., Fletcher, G. F., Forman, D. E., Kitzman, D. W., Lavie, C. J., & Myers, J. (2012). EACPR/AHA Joint Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. European Heart Journal, 33(23), 2917–2927.

    PubMed  Article  Google Scholar 

  24. 24.

    Knuuti, J., Wijns, W., Saraste, A., Capodanno, D., Barbato, E., Funck-Brentano, C., Prescott, E., Storey, R. F., Deaton, C., Cuisset, T., Agewall, S., Dickstein, K., Edvardsen, T., Escaned, J., Gersh, B. J., Svitil, P., Gilard, M., Hasdai, D., Hatala, R., Mahfoud, F., Masip, J., Muneretto, C., Valgimigli, M., Achenbach, S., & Bax, J. J. (2020). 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. European Heart Journal, 41(3), 407–477.

    PubMed  Article  Google Scholar 

  25. 25.

    Pieske, B., Tschope, C., de Boer, R. A., Fraser, A. G., Anker, S. D., Donal, E., Edelmann, F., Fu, M., Guazzi, M., CSP, L., Lancellotti, P., Melenovsky, V., Morris, D. A., Nagel, E., Pieske-Kraigher, E., Ponikowski, P., Solomon, S. D., Vasan, R. S., Rutten, F. H., Voors, A. A., Ruschitzka, F., Paulus, W. J., Seferovic, P., & Filippatos, G. (2019). How to diagnose heart failure with preserved ejection fraction: The HFA-PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). European Heart Journal, 40(40), 3297–3317.

    PubMed  Article  Google Scholar 

  26. 26.

    Reddy, Y. N. V., Carter, R. E., Obokata, M., Redfield, M. M., & Borlaug, B. A. (2018). A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation, 138(9), 861–870.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Hicks, K. A., Mahaffey, K. W., Mehran, R., Nissen, S. E., Wiviott, S. D., Dunn, B., Solomon, S. D., Marler, J. R., Teerlink, J. R., Farb, A., Morrow, D. A., Targum, S. L., Sila, C. A., MTT, H., Jaff, M. R., Joffe, H. V., Cutlip, D. E., Desai, A. S., Lewis, E. F., Gibson, C. M., Landray, M. J., Lincoff, A. M., White, C. J., Brooks, S. S., Rosenfield, K., Domanski, M. J., Lansky, A. J., JJV, M. M., Tcheng, J. E., Steinhubl, S. R., Burton, P., Mauri, L., O’Connor, C. M., Pfeffer, M. A., HMJ, H., Stockbridge, N. L., Chaitman, B. R., & Temple, R. J. (2017). Cardiovascular and stroke endpoint definitions for clinical trials. Circulation 2018, 137(9), 961–972.

    Google Scholar 

  28. 28.

    Houstis, N. E., Eisman, A. S., Pappagianopoulos, P. P., Wooster, L., Bailey, C. S., Wagner, P. D., & Lewis, G. D. (2018). Exercise intolerance in heart failure with preserved ejection fraction: Diagnosing and ranking its causes using personalized O2 pathway analysis. Circulation, 137(2), 148–161.

    PubMed  Article  Google Scholar 

  29. 29.

    Reddy, Y. N. V., Olson, T. P., Obokata, M., Melenovsky, V., & Borlaug, B. A. (2018). Hemodynamic correlates and diagnostic role of cardiopulmonary exercise testing in heart failure with preserved ejection fraction. JACC Heart Fail, 6(8), 665–675.

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Tramarin, R., Torbicki, A., Marchandise, B., Laaban, J. P., & Morpurgo, M. (1991). Doppler echocardiographic evaluation of pulmonary artery pressure in chronic obstructive pulmonary disease. A European multicentre study. Working Group on Noninvasive Evaluation of Pulmonary Artery Pressure. European Office of the World Health Organization, Copenhagen. European Heart Journal, 12(2), 103–111.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Borlaug, B. A., Olson, T. P., Lam, C. S., Flood, K. S., Lerman, A., Johnson, B. D., & Redfield, M. M. (2010). Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. Journal of the American College of Cardiology, 56(11), 845–854.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Oldham, W. M., Oliveira, R. K. F., Wang, R. S., Opotowsky, A. R., Rubins, D. M., Hainer, J., Wertheim, B. M., Alba, G. A., Choudhary, G., Tornyos, A., MacRae, C. A., Loscalzo, J., Leopold, J. A., Waxman, A. B., Olschewski, H., Kovacs, G., Systrom, D. M., & Maron, B. A. (2018). Network analysis to risk stratify patients with exercise intolerance. Circulation Research, 122(6), 864–876.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Lewis, G. D., Murphy, R. M., Shah, R. V., Pappagianopoulos, P. P., Malhotra, R., Bloch, K. D., Systrom, D. M., & Semigran, M. J. (2011). Pulmonary vascular response patterns during exercise in left ventricular systolic dysfunction predict exercise capacity and outcomes. Circulation. Heart Failure, 4(3), 276–285.

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Guazzi, M., Naeije, R., Arena, R., Corra, U., Ghio, S., Forfia, P., Rossi, A., Cahalin, L. P., Bandera, F., & Temporelli, P. (2015). Echocardiography of right ventriculoarterial coupling combined with cardiopulmonary exercise testing to predict outcome in heart failure. Chest, 148(1), 226–234.

    Article  Google Scholar 

  35. 35.

    Lewis, G. D., Bossone, E., Naeije, R., Grunig, E., Saggar, R., Lancellotti, P., Ghio, S., Varga, J., Rajagopalan, S., Oudiz, R., & Rubenfire, M. (2013). Pulmonary vascular hemodynamic response to exercise in cardiopulmonary diseases. Circulation, 128(13), 1470–1479.

    PubMed  Article  Google Scholar 

  36. 36.

    Ho, J. E., Zern, E. K., Lau, E. S., Wooster, L., Bailey, C. S., Cunningham, T., Eisman, A. S., Hardin, K. M., Farrell, R., Sbarbaro, J. A., Schoenike, M. W., Houstis, N. E., Baggish, A. L., Shah, R. V., Nayor, M., Malhotra, R., & Lewis, G. D. (2020). Exercise pulmonary hypertension predicts clinical outcomes in patients with dyspnea on effort. Journal of the American College of Cardiology, 75(1), 17–26.

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Fayyaz, A. U., Edwards, W. D., Maleszewski, J. J., Konik, E. A., DuBrock, H. M., Borlaug, B. A., Frantz, R. P., Jenkins, S. M., & Redfield, M. M. (2018). Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circulation, 137(17), 1796–1810.

    PubMed  Article  Google Scholar 

  38. 38.

    Claessen, G., La, G. A., Voigt, J. U., Dymarkowski, S., Schnell, F., Petit, T., Willems, R., Claus, P., Delcroix, M., & Heidbuchel, H. (2016). Accuracy of echocardiography to evaluate pulmonary vascular and RV function during exercise. JACC: Cardiovascular Imaging, 9(5), 532–543.

    PubMed  Google Scholar 

  39. 39.

    Guazzi, M., & Naeije, R. (2017). Pulmonary hypertension in heart failure: Pathophysiology, pathobiology, and emerging clinical perspectives. Journal of the American College of Cardiology, 69(13), 1718–1734.

    PubMed  Article  Google Scholar 

  40. 40.

    Shim, C. Y., Kim, S. A., Choi, D., Yang, W. I., Kim, J. M., Moon, S. H., Lee, H. J., Park, S., Choi, E. Y., Chung, N., & Ha, J. W. (2011). Clinical outcomes of exercise-induced pulmonary hypertension in subjects with preserved left ventricular ejection fraction: Implication of an increase in left ventricular filling pressure during exercise. Heart, 97(17), 1417–1424.

    PubMed  Article  Google Scholar 

  41. 41.

    Borlaug, B. A., Kane, G. C., Melenovsky, V., & Olson, T. P. (2016). Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. European Heart Journal, 37(43), 3293–3302.

    PubMed  Article  Google Scholar 

  42. 42.

    Yoshida, Y., Nakanishi, K., Daimon, M., Ishiwata, J., Sawada, N., Hirokawa, M., Kaneko, H., Nakao, T., Mizuno, Y., Morita, H., Di Tullio, M. R., Homma, S., & Komuro, I. (2019). Alteration of cardiac performance and serum B-type natriuretic peptide level in healthy aging. Journal of the American College of Cardiology, 74(14), 1789–1800.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Reddy, Y. N. V., Obokata, M., Egbe, A., Yang, J. H., Pislaru, S., Lin, G., Carter, R., & Borlaug, B. A. (2019). Left atrial strain and compliance in the diagnostic evaluation of heart failure with preserved ejection fraction. European Journal of Heart Failure, 21(7), 891–900.

    PubMed  Article  Google Scholar 

  44. 44.

    Deferm, S., Martens, P., Verbrugge, F. H., Bertrand, P. B., Dauw, J., Verhaert, D., Dupont, M., Vandervoort, P. M., & Mullens, W. (2020). LA Mechanics in decompensated heart failure: Insights from strain echocardiography with invasive hemodynamics. JACC: Cardiovascular Imaging.

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Martens, P., Herbots, L., Timmermans, P. et al. Cardiopulmonary Exercise Testing with Echocardiography to Identify Mechanisms of Unexplained Dyspnea. J. of Cardiovasc. Trans. Res. (2021).

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  • Dyspnea
  • Heart failure
  • Cardiopulmonary exercise testing
  • Pathophysiology
  • Exercise-induced pulmonary hypertension