**4. Natural history and pathogenesis of CTEPH**

The pathophysiological basis of CTEPH is not yet well known. Despite progress in determining the pathophysiology and treatment of PH, CTEPH pathogenesis is complex and poorly understood [39]. The mechanisms by which acute pulmonary embolism evolves into chronic thromboembolic residues incorporated into the pulmonary vessel wall have been difficult to define [39,40]. The incomplete resolution of pulmonary emboli rather than in situ thrombosis of pulmonary arteries appears to be the main contributing factor [41]. Pulmonary hypertension in patients without preexisting cardiopulmonary disease occurs when at least 30% of the pulmonary vascular bed is obstructed [42]. Development of pulmonary hypertension is not simply related to a simple mechanical obstruction by chronic thromboembolic material, but rather the appearance of a secondary vasculopathy developed in regions injured by shear stresses caused by persistent thromboembolic lesions [43]. Vascular injury and shear stress eventually lead to the proliferation of endothelial cells and smooth muscle cells of the pulmo‐ nary arterial bed [42, 43, and 44]. These results were reported from pathological observations in patients examined for CTEPH who displayed an organization of the clot into fibrous tissue, but also vascular remodeling with disappearance of the intima and infiltration of the media arterial wall [45, 46, 47, 48, and 49]. This hypothesis was initially suggested by Moser and Braunwald in 1971 [4]. Indeed, they observed that the pulmonary arteries of small caliber located in the unobstructed territories had remodeling lesions similar to those described in idiopathic pulmonary arterial hypertension.
