Cardiopulmonary exercise testing (CPET) is a diagnostic tool used to investigate functional capacity and characterize exercise limitations related to circulatory impairment and ventilatory inefficiency (1, 2). It is a durable and versatile test that provides invaluable information on a patient's cardiovascular and pulmonary disease. Traditionally the 6 min walk distance is routinely used to assess the functional capacity of patients with PH for risk stratification, but can lack cardiopulmonary specificity. Therefore current ESC/ERS guidelines (3) recommend CPET for further evaluation in symptomatic patients with intermediate echocardiographic findings of pulmonary hypertension (PH), therefore we will try to provide key parameters to understand and interpret those findings. CPET allows the analysis of gas exchange at rest as well as during exercise and recovery, using breath-by-breath analysis of oxygen uptake (V_O2), carbon dioxide output (V_CO2), and ventilation (V_E). This data is integrated with measurements of symptoms, heart rate, blood pressure, work rate, and electrocardiographic findings.

The definition of PH was recently updated to emphasize early disease detection in the guidelines from the World Health Organization (WHO) -European Society of Cardiology (3). Currently, PH is defined as a mean pulmonary artery pressure (mPAP) of greater than 20 mmHg and pulmonary vascular resistance (PVR) of greater than 2 Wood Units. There are 5 clinical categories based on the etiology of PH, and we will focus on pulmonary arterial hypertension (PAH)- WHO Group 1, and chronic thromboembolic pulmonary hypertension (CTEPH)- WHO Group 4.

PAH is precapillary PH characterized by endothelial dysfunction leading to increased pulmonary vascular resistance (3). It can be idiopathic, hereditary, or associated with predisposing diseases. CTEPH is an uncommon complication of pulmonary embolism (PE) defined by the presence of precapillary PH with angiographic evidence (i.e., computed tomography of the chest, magnetic resonance imaging of the pulmonary arteries, catheter-based pulmonary angiography) of organized thrombotic residua within the pulmonary arteries that are present in spite of at least 3 months of anticoagulation therapy. For those with imaging evidence of chronic PE in the absence of rest-hemodynamic evidence of PH, the diagnosis of chronic thromboembolic disease (CTED), or most recently the proposed designation, chronic thromboembolic pulmonary disease (CTEPD), is suggested.

In both PAH and CTEPH, there are multiple variables affecting cardiac function and pulmonary gas exchange leading to exercise intolerance and exertional dyspnea. These changes reflect the underlying exercise pathophysiology and can be evaluated via CPET. This review summarizes the developments and evidence on the application of CPET in PH.

The usefulness of the CPET depends on an individual's capacity to perform physical exercise, evaluating the ability of the pulmonary system's ability to clear CO₂ and the cardiovascular system's ability to supply oxygen to the muscles. There is a close evaluation of the delivery and removal systems (i.e., ventilation, diffusion, transport of O₂ and CO₂ in the blood, and capillary gas exchange). The increase in oxygen uptake by the peripheral muscles is a response to an increase in cardiac output (CO = heart rate × stroke volume), which increases 6 times with exercise. The cardiac output is distributed to skeletal muscles and shunted away from the non-active tissues (e.g., splanchnic circulation). There is an increase in blood flow to the lung in addition to vasodilation of the pulmonary vessel, with increased extraction of O₂ from the blood to the muscles, resulting in an increased arteriovenous oxygen difference. Ventilation (V_E) increases proportionally with the work rate. When inhalation takes place, the air in the alveoli, known as the tidal volume (Vt), accounts for the gas exchange. The air not participating in this exchange, is known as the dead space (Vd). During exercise, both dilation of the respiratory passages and the effective areas of gas exchange (tidal volume) increase, therefore gas exchange remains intact. The increase in V_E should be matched with an increase in blood flow, hence an appropriate cardiac output is important to maintain gas exchange. The point at which oxygen uptake is unable to increase adequately for peripheral oxygen demand marks the aerobic-anaerobic transition at which lactic acidosis will begin to occur. This is called the anaerobic threshold. If at any point there is a mismatch in this supply-demand chain there will be a clinical symptom.

The assessment of exercise capacity can be performed via a treadmill or stationary cycle ergometer. The selection of the exercise modality will depend on the patient and center's availability. Treadmills are preferred. Meanwhile, cycle ergometers are preferred in cases of gait and balance instability, severe obesity, orthopedic limitations, or when simultaneous right heart catheterization or echocardiogram is planned. The Bal and Ware, Naughton, and individualized ramp protocol involve increments in work rate per stage. They are recommended, as they allow to establish relationships between measured V_O2 and work rate. Individuals should be expected to exercise for 8–12 min (4). Table 1 summarizes the CPET variables that are measured and calculated during the study (1, 3). Normal values may be affected in some individuals depending on their age, gender, volitional effort, and comorbidities.

During exercise, peripheral muscles have increased oxygen demand that is achieved by peripheral vasodilation and increased oxygen extraction. When the normal individual exercises, the cardiac output should increase to match this oxygen delivery for the increasing demand of peripheral muscles (10). In the lungs increased tidal volume and pulmonary blood flow (achieved via vasodilation and pulmonary capillary recruitment) allows for a proportional increase in alveolar oxygen uptake. The maximal achievable oxygen uptake is labeled as the peak O₂ (peak V_O2) (5). In the alveoli, the carbon dioxide is cleared by a corresponding increase in minute ventilation (V_E = Vt × respiratory rate). The point at which oxygen uptake is unable to increase adequately for peripheral oxygen demand marks the aerobic-anaerobic transition at which lactic acidosis will begin to occur. This point is called the anaerobic threshold.

The physiological derangements in PH originate from obliteration and obstruction of pulmonary arteries (Figure 1). In PAH, vascular inflammation, remodeling, and endothelial dysfunction precipitate an increase in pulmonary vascular resistance. There is an imbalance in the production of pulmonary vasodilators and vasoconstrictors, abnormal proliferation of cells in the walls of the pulmonary arteries and arterioles, and intraluminal thrombus (11, 12). In CTEPH, residual thrombotic material causes pulmonary arterial obstruction, hindering pulmonary vasodilation and increasing dead space ventilation. In PAH and CTEPH, there is a decrease in the vasodilatory capacity, as well as in the distensibility and patency of the pulmonary vasculature. This hypoperfusion to ventilated lung regions is reflected as low P_ETCO2. In both entities, PAH and CTEPH, there is an increase in afterload, or pulmonary vascular resistance, which limits the increased stroke volume needed for effective circulation at the time of exercise (10, 13, 14). The pulmonary vascular bed of PH patients is unable to be recruited and distended, leading to increased pulmonary artery pressures (10). The sustained increased afterload causes adaptive myocardial hypertrophy, which is initially reflected by RV wall hypertrophy, and later on by RV dilation (15, 16). There can be RV ischemia related to imbalanced oxygen supply and demand associated with hypertrophy, increased RV workload, and metabolic demands, without an increase in blood supply or microcirculation (17). In addition, there is uncoupling between the pulmonary vascular bed and the right ventricle, leading to right heart failure at peak exercise and inability to augment CO. In addition, elevated right ventricular pressure and dilation can cause interventricular septal shifting, which further reduces the pulmonary venous return to the left atrium, thereby decreasing left ventricular diastolic filling, systemic cardiac output, and tissue oxygen delivery (18–20).

The resulting hypoxia leads to vasoconstriction and impaired tissue oxygen delivery to peripheral muscles, causing lactic acidosis, lowered peak V_O2, and a reduction in the anaerobic threshold. This leads to the production of V_CO2 and an excessive increase in ventilation during exercise (increased V_E/V_CO2). This results in the characteristic CPET pattern of PH with low P_ETCO2, high ventilatory equivalent for carbon dioxide (V_E/V_CO2), and low peak O₂ uptake (peak V_O2).

As PAH and CTEPH diagnosis and management continue to improve the evaluation of the exercise capacity of individuals with the use of CPET may be a key tool to understand the true source of their limitations. Abnormal responses to exercise can be better characterized with the use of CPET and allow for physiologically tailored interventions. We can help stratify the disease via this comprehensive and reproducible method.