Is inflammation a potential therapeutic target in chronic thromboembolic pulmonary hypertension?

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but notoriously underdiagnosed complication of pulmonary embolism, which carries a poor prognosis if left untreated. CTEPH results from the obstruction of the pulmonary vascular bed by fibro-thrombotic material, which may completely occlude the lumen. Although massive or recurrent pulmonary embolism is thought to be the initiating event, a significant proportion of patients have no history of symptomatic pulmonary embolism and only a few patients with acute pulmonary embolism develop CTEPH [1]. As a consequence, the true prevalence and incidence of CTEPH remain unknown [2]. Current data, retrieved from registries, suggest that the incidence of CTEPH averages between three and 30 per million in the general population [3], and that the proportion of patients developing CTEPH after acute pulmonary embolism may vary between 0.1% and 9.1% [4]. The standard and potentially curative treatment for CTEPH is a surgical procedure, known as pulmonary endarterectomy (PEA) [5], which involves removing organised thrombi, neointima and media inner layers obstructing the pulmonary arteries (fig. 1b) [6]. PEA, when performed in experienced centres and on selected patients, shows low perioperative mortality, and provides major improvements in haemodynamics, symptoms and survival [7]. Moreover, CTEPH is a ‘‘dual’’ pulmonary vascular disorder combining major vessel obstruction and small vessel arteriopathy, which is histologically indistinguishable from idiopathic pulmonary arterial hypertension (PAH) in the non-occluded lung areas [8]. As a consequence, PAH-targeted therapy, including prostacyclin analogues, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors, has been largely used in CTEPH [9] and should be considered for inoperable patients or patients with persistent pulmonary hypertension after PEA [10]. More recently, riociguat, a stimulator of soluble guanylate cyclase, has been approved for the treatment of inoperable CTEPH and persistent pulmonary hypertension after PEA, on the basis of demonstrated improvements in haemodynamics and exercise capacity [11].