CPET findings indicative of combined metabolic–cardiovascular (e.g. low ΔV′CO 2 /ΔWR, an O2 pulse plateau, early θL) and ventilatory gas exchange abnormalities (high V′E–V′CO 2 indices, low PETCO 2 ) suggest pulmonary vascular disease in patients with a high pre-test likelihood of disease [36, 37] pulmonary vascular diseases are considered further later in this Monograph [39]. Atypically high V′E–V′CO 2 indices in a COPD patient in whom there is no anatomic cause for increased wasted ventilation (e.g., extensive emphysema) [40] and/ or a low PaCO2 set-point (e.g. selected patients with associated heart failure) [41] might also prompt further investigation to rule out PH [42, 43]. Conversely, a test showing a normal V′E–V′CO 2 indices and PETCO 2 (values and trajectory) can reassure that “significant” PH is Somatosensory cortex Motor commands Respiratory muscles PaO2 PaCO2 pH Respiratory afferents Thorax Limbic cortex Corollary discharges Motor cortex Medulla Motoneurone relay Lungs Bronchi Pleura Vessels Figure 2. Integrative mechanisms at the origin of dyspnoea. Respiratory command derives from the input of both the motor cortex and the medulla. These commands are integrated at the spinal level and transmitted to the muscular effectors of the respiratory system. The subsequent activation of the respiratory muscles will generate afferent inputs that are fed back to the respiratory command centres and the somatosensory cortex. The comparison of the corollary discharge and the ensuing afferent feedback may present a mismatch, and dyspnoea will occur when a negative effect is attributed to this mismatch by the limbic cortex, which will also be influenced and modulated by memory and the prevailing environment. Reproduced and modified from [6] with permission. https://doi.org/10.1183/2312508X.10015318 xiii