Pulmonary arterial hypertension (PAH) is a rare disease associated with exercise intolerance due to right ventricular dysfunction. Risk stratification in PAH is essential in defining the prognosis, and cardiopulmonary exercise testing (CPET) provides valuable information about the severity of the disease, with direct implications for clinical management.
 
OVERVIEW
 
A 33-year-old woman, diagnosed with PAH 11 years prior, currently using triple combination therapy, and on the waiting list for lung transplantation, underwent CPET at the time of diagnosis (Figure 1—Panel I) and again at one year before lung transplantation (Figure 1—Panel II). Although both examinations revealed reduced aerobic capacity, signs of cardiocirculatory limitation, and excessive ventilatory responses with gas exchange disturbance, the latter also showed indirect signs of a right-to-left shunt. In patients with PAH, CPET is a valuable tool in assessing prognosis.(1) The primary variable is the peak V•  O2 (V•  O2peak), which is related to oxygen delivery and consumption. If the oxygen delivery is low, the first response of the muscle is to increase the oxygen consumption. However, in PAH, this mechanism could fail with a high dependence on non-oxidative pathways, low energy production, and increased exercise intolerance. In addition, patients with PAH have low type I muscle fiber density, which impairs peripheral oxygen use and limits muscle strength. During high metabolic demand, patients with PAH have a lower V•  O2peak, early anaerobic threshold (AT), and low aerobic efficiency with a low V•   O2-work rate (∆V•   O2/∆WR) or a plateau response. (2) Ultimately, PAH leads to a reduction in stroke volume that requires a compensatory increase in HR to maintain cardiac output, which leads to a steeper ∆HR/∆V•  O2 response, a reduced V•  O2peak, and O2 pulse (V•  O2/HR) with a curve plateau before or after the AT.(3) In the PAH lungs, low perfusion with adequate alveolar ventilation results in ventilation-perfusion mismatch and gas exchange disturbance during exercise, increasing ventilatory demand. This augmented response is also related to lactic acid accumulation, signaling peripheral chemoreceptors and increasing the feedback for ventilation. In this context, a high minute ventilation to carbon dioxide production ratio (V•  E/V•  CO2) and lower end-tidal carbon dioxide partial pressure (PETCO2) values have been reported, suggesting signs of ventilatory inefficiency in PAH.(3) In addition, PAH patients usually experience decreased SpO2 from rest to peak exercise, also related to exercise-induced shunt (EIS).(2) Right-to-left shunting during exercise is attributable to an abnormally high pulmonary vascular resistance to right atrial pressure exceeding left atrial pressure, forcing systemic venous blood through a patent foramen ovale directly into the systemic arterial circulation.(4) An abrupt and sustained decrease in PETCO2 associated with a simultaneous and sustained increase in PETO2, in the ventilatory equivalents of oxygen and carbon dioxide (V•  E/V•  O2 and V•  E/V•  CO2), and in the respiratory exchange ratio (RER), together with a decline in SpO2, are findings present in patients with EIS.(5) The persistence or development of an EIS strongly predicts death or transplantation regardless of the hemodynamics and all other CPET variables. (4)

In the European Respiratory Society guideline, the peak V•  O2peak and the V•  E/V•  CO2 slope have established cutoff values for prognosis assessment. However, other analyses are not considered in the guideline but have provided pathophysiological evidence of an impact on disease severity, such analyses including the assessment of a right-to-left shunt.(5)
 
CLINICAL MESSAGE
 
In PAH risk stratification, CPET can play an important role, having the advantage of being noninvasive. This tool might facilitate the decision-making process and clinical management in patients with PAH.
 
AUTHOR CONTRIBUTIONS
 
EVMF: Participated in the conception; writing; and revision. JSL: Participated in the conception; and writing. RKFO: Participated in the revision. All authors approved the final version to be published.
 
CONFLICTS OF INTEREST
 
None declared.
 
REFERENCES
 
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2.           Farina S, Correale M, Bruno N, Paolillo S, Salvioni E, Badagliacca R, et al. The role of cardiopulmonary exercise tests in pulmonary arterial hypertension. Eur Respir Rev. 2018;27(148):170134. https://doi.org/10.1183/16000617.0134-2017
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4.           Oudiz RJ, Midde R, Hovenesyan A, Sun XG, Roveran G, Hansen JE, et al. Usefulness of right-to-left shunting and poor exercise gas exchange for predicting prognosis in patients with pulmonary arterial hypertension. Am J Cardiol. 2010;105(8):1186-1191. https://doi.org/10.1016/j.amjcard.2009.12.024
5.           Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Gas exchange detection of ex-ercise-induced right-to-left shunt in patients with primary pulmonary hyper-tension. Circulation. 2002;105(1):54-60. https://doi.org/10.1161/hc0102.101509