Question: The absence of a standardized definition of exercise-induced pulmonary hypertension has been a source of controversy in the field for quite some time. Your data take a novel approach to this issue by suggesting that the combination of different hemodynamic variables discriminates normal from abnormal cardiopulmonary hemodynamic responses to exercise. What was the rationale for addressing this problem using this approach?

Response: The previous exercise definition of pulmonary hypertension (PH) using the sole criterion of mean pulmonary artery pressure (mPAP) > 30 mmHg during exercise had stood for a long time until the 4th World Symposium on PH in 2008.¹ During the 4th World Symposium, it was decided that the old exercise criterion was not supported by evidence, and many healthy individuals can actually exceed this threshold. The main problem with the old criterion is that mPAP is not only influenced by pulmonary vascular resistance (PVR) and left atrial pressure (LAP) but is a flow-dependent variable.² Cardio-respiratory physiologists are well aware that athletes can easily exceed a mPAP of 30mmHg during exercise as a result of large augmentation in cardiac output.

Exercise stress testing of the pulmonary circulation is not a new concept. Most experts would agree that an abnormal pulmonary hemodynamic response during exercise can lead to symptoms of effort intolerance.³ What remains elusive is the natural history of exercise PH, and longitudinal follow-up studies are urgently needed. Thus, a standardized working definition that is physiologically rational and clinically robust would facilitate further research in this area, particularly for future therapeutic trials.

Given the mPAP is a flow-dependent variable, we hypothesized that using the mPAP/cardiac output (CO) ratio during exercise would enhance the diagnostic accuracy of the old definition of exercise PH. Incorporating the mPAP/CO ratio or total pulmonary resistance (TPR) should theoretically improve the specificity of the definition by reducing the number of false positive cases (i.e. controls who exceed mPAP of 30 mmHg due to high pulmonary flow). Indeed, this was exactly what we found in our study involving 169 consecutive patients with resting mPAP ≤20 mmHg who underwent invasive exercise hemodynamic testing. These patients were classified into control, pulmonary vascular disease (PVD), and left heart disease (LHD) groups accordingly to a priori clinical definitions. The old definition of mPAP > 30 mmHg had excellent sensitivity but lacked specificity, as evidenced by 18/68 of the control population reaching this threshold. In contrast, when we combined mPAP > 30 mmHg and TPR > 3 Wood units, this new criteria retained sensitivity at 93% but improved specificity to 100%. The high specificity of the new 'combined criteria' effectively solved the previous problem of the large number of false positives resulting from the old definition.

Interestingly, our combined criteria of mPAP > 30 mmHg and TPR >3 WU performed similarly well for exercise pulmonary hypertension due PVD (n=49) or LHD (n=52). Correspondingly, an abnormal hemodynamic response can be due to a high incremental PVR or a brisk increase in LAP during exercise.⁴ This was initially somewhat of a surprise to us given the distinct pathophysiology of PVD and LHD. However, what is relevant here is that regardless of whether PVR or LAP is the main driver of exercise PH, the common consequence is a steep mPAP-CO relationship during exercise. In our cardiac laboratory, if a patient fulfills the combined criteria for exercise PH, it is important to then assess whether the predominant problem is PVD (related to elevated PVR) or LHD (related to elevated LAP).

Question: A number of prior reports have suggested that exercise-induced pulmonary hypertension may be due to a failure for pulmonary vascular resistance to drop during physical activity. How do data from your study compliment or differ from these earlier findings?

Response: As mentioned above, exercise PH can be the result of two main mechanisms - excessive rise in LAP or elevated incremental PVR. Therefore, the concept that exercise PH is due to a failure of PVR to fall during exercise is flawed. In fact, with the epidemic of diastolic dysfunction, LHD is probably the most common cause of exercise PH. In this situation, exercise induces a very rapid rise in LAP due to increased diastolic stiffness of the left ventricle.⁵ This excessive rise in LAP is then transmitted upstream as mPAP, leading to exercise PH. In some instances, PVR can actually fall with exercise since the rise in LAP can result in pulmonary vascular recruitment. Therefore, exercise PVR will not adequately identify patients with exercise PH due to LHD. In contrast, exercise PVR has good accuracy for identifying exercise PH due to PVD, as was shown by our study.

References

1. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S55-66
2. Lau EM, Humbert M, Celermajer DS. Early detection of pulmonary arterial hypertension. Nat Rev Cardiol. 2015;12(3):143-55.
3. Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom DM. Exercise-induced pulmonary arterial hypertension. Circulation. 2008 Nov 18;118(21):2183-9
4. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3(5):588-95
5. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32(6):670-9
6. Herve P, Lau EM, Sitbon O et al. Criteria for diagnosis of exercise pulmonary hypertension. Eur Respir J. 2015 May 28. pii: ERJ-00219-2015. doi: 10.1183/09031936.00021915. [Epub ahead of print]

Keywords: Athletes, Atrial Pressure, Cardiac Output, Exercise Test, Follow-Up Studies, Heart Diseases, Heart Ventricles, Hypertension, Pulmonary, Motor Activity, Pulmonary Artery, Pulmonary Circulation, Vascular Diseases, Vascular Resistance

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