CTEPH and pulmonary embolism CTEPH is classified within group 4 PH [1], and is characterised pathologically by organised thromboembolic material and by altered vascular remodelling initiated or potentiated by a combination of defective angiogenesis, impaired fibrinolysis and endothelial dysfunction [2–4]. These changes lead to PH and ultimately right ventricular failure [5, 6]. The precise pathogenesis of CTEPH remains unclear, but appears to be incited by acute pulmonary embolism [7]. However, classic risk factors for venous thromboembolism do not appear to increase the risk of CTEPH [8] and there are clear geographic differences in CTEPH epidemiology. An international CTEPH registry (Europe and Canada) indicated that 75% of patients with CTEPH had a documented antecedent history of acute pulmonary embolism [9], while in Japan, the rates of acute pulmonary embolism preceding CTEPH range from only 15% to 33% [10, 11]. There is an 80% female preponderance of CTEPH in Japan; these statistics differ significantly from the USA and Europe [9]. A number of abnormal autoimmune, inflammatory and thrombophilia markers have been found in CTEPH patients [2]; it is feasible that variability in this underlying pathological milieu contributes to the variability in the worldwide CTEPH epidemiology. Furthermore, variable gene expression has been demonstrated in pulmonary artery endothelial cells from patients with CTEPH compared with normal controls [12]. In published prospective studies with the diagnosis confirmed by right heart catheterisation (RHC) the incidence of CTEPH after symptomatic acute pulmonary embolism is reported to range from 0.4% to 6.2% [13–25], giving a pooled incidence of 3.4% (95% CI 2.1−4.4%) [7]. Since that analysis, a new report from Switzerland screened 508 patients after acute pulmonary embolism over 2 years and found a cumulative incidence of CTEPH confirmed with RHC of just 0.79% [26]. Determining the precise CTEPH incidence is complex. CTEPH is likely both underdiagnosed and the incidence of CTEPH after acute pulmonary embolism prone to overestimation, making the actual incidence difficult to quantify. Non-specific symptoms, variable rates of antecedent acute pulmonary embolism and the expertise required to read computed tomography pulmonary angiography (CTPA) contribute to underdiagnosis [27, 28]. Underdiagnosis is further compounded by the infrequent use of lung ventilation/perfusion scintigraphy (V/Q scan) despite guideline recommendations [29, 30]. Approximately 30 000 acute pulmonary embolism cases are diagnosed annually in France, with the CTEPH incidence estimated at 3.4% [31]. GUÉRIN et al. [22] suggested a CTEPH incidence of 4.8%. Neither of these estimates is consistent with the current frequency of newly diagnosed CTEPH. A limitation of the numerous CTEPH incidence reports after acute pulmonary embolism may be attributed to an unrecognised amalgam of incident and prevalent cases [22]. In terms of reducing the risk of CTEPH following acute pulmonary embolism, no prospective randomised acute pulmonary embolism trials have examined systemic or catheter-based thrombolysis or clot extraction with RHC as an outcome measure in patients with persistent symptoms. Claims have been made that the incidence of CTEPH in patients receiving thrombolytic therapy is reduced, but end-points such as an echocardiogram-derived systolic pulmonary arterial pressure (sPAP) of 40 mmHg do not define PH or CTEPH [32]. Systemic thrombolysis failed to reduce the risk of CTEPH in intermediate/high-risk (submassive) pulmonary embolism patients in the 3-year follow-up of the PEITHO trial (average sPAP at follow-up was around 31 mmHg in each group) [33]. To date, there is no proof that aggressive treatment of acute pulmonary embolism can prevent CTEPH.