Cardiopulmonary Exercise Testing in Pulmonary Hypertension

The cardiopulmonary exercise test (CPET) is a complementary test that provides important data about the patient’s actual functional capacity, metabolic and ventilatory responses, and gas exchange. Thus, it enables a classification of the cardiorespiratory fitness of an individual and identification of disorders that limit exercise continuity by analyzing several variables drawn from this diagnostic and prognostic propaedeutic method. In this regard, situations that are relatively common in clinical practice but are not often identified, such as pulmonary hypertension (PH), can be better addressed, assessed, and measured. Thus, the analysis of exhaled gases using CPET may provide better PH management by enabling a classification of the aerobic capacity, ventilatory response and gas exchange in patients with this pulmonary vascular disorder.


Introduction
Cardiopulmonary exercise testing (CPET) is a complementary test increasingly used in clinical practice as an important tool to investigate cardiovascular diseases.CPET has several well-established indications, including the assessment of cardiorespiratory fitness, support in the investigation and follow-up of patients with myocardial ischemia, objective prescription of training zones (in healthy individuals and patients with cardiac diseases) and differential diagnosis of dyspnea, [1][2][3] among others.The foundations of the CPET are based on a ventilatory analysis of the exhaled gases, with the purpose of quantifying the consumption of oxygen (VO 2 ), the production of carbon dioxide (VCO 2 ), and minute ventilation (VE) at rest and during exercise and recovery.
Valuable information provided about pathophysiologic responses in the rest-exercise transition and the identification of the functional capacity include: (1) a precise assessment of the aerobic power, (2) evaluation of cardiometabolic variables at levels of submaximal and maximal effort (e.g.: ventilatory threshold), and (3) evaluation of ventilatory efficiency. 46][7] PH can be associated with several other pathologies, such as those affecting the left cardiac chambers, the arterial circulation, and the interstitium and pulmonary parenchyma.Rarely, this pathology may be primary and not associated with any other causal factor. 8atients with PH have a reduced functional capacity, caused by a decreased ventilatory efficiency, cardiac output (CaO), and oxygen supply to peripheral tissues.Many of these aspects can be assessed and measured by CPET, making it a graphical method displaying ventilation and cardiac and peripheral metabolism with excellent application in such circumstances. 9espite the limited number of studies of CPET in PH, Wensel et   The aim of this article is to highlight the important aspects of CPET in patients with increased pulmonary systolic arterial pressure (PSAP), defining the most frequent standards and characteristic findings of this test.

Pathophysiology
The pathological changes found in PH are multifactorial and complex.Variables such as genetic predisposition, risk factors (use of anorexigenic agents, HIV), and cardiovascular and pulmonary diseases increase the venous and/or arterial pulmonary pressure and cause vascular dysfunction that results in vasoconstriction and remodeling of the pulmonary circulation. 8 the primary pathophysiological process leading to an inadequate increase in pulmonary arterial pressure, there is disproportion between pulmonary ventilation and perfusion (normal ventilation / decreased perfusion), which results in an increased physiological dead space and a decreased ventilatory efficiency.This process translated into a greater ratio between increased VE and VCO 2 production, as well as a change in this ratio's slope (VE/VCO 2 slope).In addition, there is a reduction in the end-tidal carbon dioxide pressure (PETCO 2 ), which characterizes a pattern of hyperventilation.
Patients with PH may also have decreased CaO due to a reduction in the left ventricular preload, causing the interventricular septum to bulge, affecting the function of this ventricle.Such effects lead to a decreased peak VO 2 and VO 2 at the anaerobic (AT) or ventilatory threshold (LV1), which are variables extracted and measured during the CPET.In addition to these described metabolic changes, a decrease in oxyhemoglobin saturation may occur, induced by stress, as a consequence of difficulties in gas diffusion in the pulmonary circulation, contributing to exercise intolerance in these patients.
In short, the decrease in oxygen supply to the skeletal muscle has a negative impact on the aerobic metabolism (reduced VO 2 in LV1 and early lactic acidosis) and on the ventilatory efficiency, with an elevation of the VE/VCO 2 slope 9 (Figure 1).

CPET findings
Changes in the ratio or relation between pulmonary ventilation and perfusion increase the dead space and reduce the ventilatory efficiency, which can be easily observed by increased VE/VCO 2 values and a steeper slope in the relation VE X VCO 2 (Figure 2b).Monitoring of the changes in VE/VCO 2 at rest and during the entire exercise should be the focus of special attention in PH since it helps to identify objectively the development of rightleft shunt during exercise.The changes in the analysis of the VE/VCO 2 slope are comparable to changes found in patients with HF. 9 However, individuals with advanced PH tend to show proportionately higher values (Figure 2).The ventilatory inefficiency is also evidenced in the PETCO 2 at rest, its curve during effort, and its values obtained at the peak, characteristics of patients with PH, who require greater ventilation to release the same amount of CO 2 when compared with normal patients.Therefore, a reduction in PETCO 2 values is observed in such condition. 9,11e ratio between the dead space (Vd) and the tidal volume (Vt) decreases at the beginning of the exercise due to a more evident and expressive increase in Vt than Vd.Due to a greater increase in dead space, patients with PH do not display the expected behavior for this ratio (Vd/Vt), which then shows much higher values during exercise. 11e VO 2 is directly proportional to the CaO, demonstrated by Fick's equation: VO 2 = CaO x C(a-v) 2 ; therefore, the CaO reduction in patients with PH is evidenced by a reduction in the peak VO 2 and in the ratio between VO 2 and heart rate, named O 2 pulse (the latter represents a behavior of the stroke volume during effort).The VO 2 at the AT is also decreased, and the hypoxemia caused by PH associated with a reduction in the CaO causes lower availability of O 2 for aerobic metabolism, resulting in earlier lactic acidosis and first threshold.To better analyze the aerobic power measurement, the peak VO 2 must be correlated with the body weight and predicted value for the patient's age. 11 addition to the ventilation, gas diffusion also seems to be impaired in patients with PH, since recent studies have shown a reduction in the oxygen uptake efficiency slope (OUES) associated with an elevation in PSAP, in addition to a correlation between the O 2 uptake efficiency with the VE/VCO 2 and the PETCO 2 . 9,11t is important to emphasize that PH must be regarded as the main pathophysiological mechanism in patients with unexplained dyspnea and with (1) no echocardiographic left ventricular abnormalities, (2) a normal pulmonary function test, (3) changes in CPET, including low aerobic capacity, elevation in the VE/ VCO 2 slope, and decrease in PETCO 2 , and (4) a possible desaturation during exercise.
It should also be noted that patients with HF, hypertrophic cardiomyopathy, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis may also develop PH as a result of the primary pathophysiological condition.If PH coexists with these primary cardiac or pulmonary conditions, the ventilatory changes in the exhaled gases (peak VO 2 , VE/VCO 2 slope, and PETCO 2 ) will be typically more severe and reflect the degree of the PSAP elevation. 9,11us, as in HF, the peak VO 2 and the VE/VCO 2 are prognostic variables and some articles have demonstrated a superiority of the latter, since it does not rely on maximum exercise and has better discrimination in identifying patients with worse prognosis.These CPET variables (peak VO 2 , respiratory exchange ratio [RER], VE/VCO 2 slope, and PETCO 2 ) have high reliability in the diagnostic and prognostic evaluation of patients with PH and should, therefore, be included in the assessment of these patients. 9,11e improvements in peak VO 2 , VE/VCO 2 slope, RER, and PETCO 2 may be evident in assessments conducted before and after treatment (both medical and intervention treatments), in particular in treatments improving pulmonary hemodynamics (e.g., correction of congenital heart diseases). 9,11th regard to safety, data in the literature indicate that CPET is a safe test to be carried out in patients with PH.Episodes of syncope, complex cardiac arrhythmias, and/or acute right ventricular failure are some examples of adverse events and are considered contraindications for a maximal exercise test.An analysis of the VE/ VCO 2 slope and the PETCO 2 at rest and at submaximal exercise may provide valuable clinical information when the performance at maximal exercise test raises safety concerns.

Use of CPET in the prescription of exercise
The reduction in the peak VO 2 and VO 2 at the AT in patients with PH represents a decreased ability to perform daily activities.[14] The CPET analysis, particularly VO 2 in the LV1, if detectable, serves to recommend aerobic activities that the patient can perform safely. 15ided physical training improves symptoms and functional capacity in patients with PH. 9,16 The current evidence indicates that CPET also provides a precise and objective description of the PH severity and may offer prognostic information related to the ventilatory efficiency, 17 (Figure 3) including after therapeutic interventions.In addition, the exercise protocols used in the tests and the key variables analyzed in the exhaled gases (peak VO 2 , VE/VCO 2 , and PETCO 2 ) are very similar among patients diagnosed with HF and PH. 9

Final comments
CPET has an important role in evaluating patients with PH, evidencing the pathophysiological mechanisms of exercise intolerance and contributing to therapeutic assessment, monitoring, and prognosis in this group of patients.However, additional studies are needed for a better understanding of these mechanisms during the diagnostic and prognostic evaluation of patients with clinical suspicion of this disease entity.

Figure 2
Figure 2To the left (2a), a VE/VCO 2 curve in a patient without comorbidities and to the right (2b), in a patient with PH with a clear tendency toward verticalization of the line, in which the slope (S) corresponds to 60, i.e., to eliminate 1 liter of CO 2 , the patient had to ventilate 60 liters of air.Adapted from J Alberto Neder et al.11 Annals ATS Volume 12 Number 4 / April-2015.
10. demonstrated in 2002 its value in the prognostic evaluation of patients with PH.10