Effects of interventions Constant WR testing Assessment of the tolerance of constant WR exercise pre- and post-interventions, usually accompanied by non-invasive evaluation of lung mechanics (serial IC measurements) and dyspnoea, has been more widely used in patients with COPD (the role of exercise testing in defining the response to COPD interventions is discussed in a chapter by O’DONNELL et al. [16] later in this Monograph). There has also been renewed interest (albeit to a lesser extent) in the same testing modality for assessing the effects of interventions in patients with ILD, PAH and cystic fibrosis (as reviewed in [15]). Incremental exercise testing Changes in the submaximal responses to incremental exercise, particularly those reflecting improved O2 delivery and lower ventilatory demands, have been more frequently used to demonstrate the beneficial effects of selected interventions in pulmonary vascular disease, e.g. sildenafil in PAH [69] and heart failure with reduced ejection fraction [70], calcium channel blockers in selected patients with idiopathic PAH [71], and vasodilators and thromboendarterectomy in chronic thromboembolic pulmonary hypertension [72, 73]. The incremental protocol has also been used to detect the effects of cardiovascular medications in heart failure with reduced and preserved ejection fraction, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, different types of β-blockers and sildenafil (as reviewed in [58]). What are the current challenges facing clinical CPET interpretation? Investigation of exercise intolerance The patient with multiple potential causes of exercise intolerance As previously mentioned, the patient with isolated respiratory or cardiovascular causes of exercise intolerance is an uncommon client of modern clinical CPET laboratories. It is more common for patients to have multiple comorbidities whose individual contribution to exertional symptoms is difficult to ascertain, particularly against a background of polypharmacy. This complex combination of abnormalities was less prevalent (and complex) some decades ago when CPET was initially used to uncover the “main” mechanism of exercise intolerance in subjects with unexplained dyspnoea [74–77]. The emergence of “novel” causes of exercise intolerance The burden of obesity [78] and extreme sedentarism [79] has markedly increased in the past few decades worldwide. It follows that the boundaries between heart–lung disease and the physiological consequences of these contemporary changes have become difficult to discriminate in individual patients. It is worth noting that nowadays, many patients are referred to CPET with pre-existing abnormalities whose individual contribution to exertional symptoms remains largely unknown, e.g. metabolic syndrome [80], exercise-induced diastolic dysfunction [81], atrial fibrillation [82], left atrial abnormalities [83, 84], isolated respiratory muscle weakness [85] and chronotropic incompetence [86]. https://doi.org/10.1183/2312508X.10015318 xv