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  • In patients with CTEPH ET levels are raised and


    In patients with CTEPH, ET-1 levels are raised and have been shown to fall after PEA surgery [24]. After an acute pulmonary embolism there is obstruction of the pulmonary UNC1999 by acute thrombus and elevated levels of ET-1 [28], [30]. Elevated levels of ET-1 have also been observed in air embolus in animal models [25], [26] and pretreatment with an ET antagonist ameliorated the haemodynamic change after acute pulmonary embolism [25]. In addition ET-1 is increased most in the muscularised pulmonary arteries [16]. Intriguingly in human coronary arteries we have previously shown that recanalisation of thrombus is characterised by formation of new vessels which show intense endothelial ET-like immunoreactivity with ETA but not ETB receptors on the smooth muscle of recanalised vessels [2]. Crucially, ET antagonists have been shown to block proliferation of smooth muscle in the intimal layer of vessels growing in organ culture [19]. The pathogenesis of CTEPH is complex but one question that arises is how much of the disease progression is driven by changes within the unresolved thrombus in parallel to the vasculopathy in the distal arterial bed. Despite many centres offering off-label use of ET receptor antagonist in the treatment of CTEPH, little is understood concerning the presence and underlying pattern distribution of ET receptors within PEA material. Here we identify ET receptors in PEA material and provide a rationale for the ET receptor antagonists for treatment of CTEPH.
    Material and methods
    Results Pulmonary endarterectomy specimens from 19 patients were collected; 14 male, 5 female. The mean age was 63±9.7years. One patient died in hospital and another patient did not return for post-operative follow-up. Table 1 shows the severity of the pulmonary hypertension and includes the surgical disease type (from the classification by [12]), haemodynamics at the time of initial diagnosis and any pre-operative drug treatment. The haemodynamic variables demonstrate reasonably severe pulmonary hypertension (pulmonary vascular resistance 763±377dyn·s·cm). Ten patients had received pre-operative drug treatment with a phosphodiesterase V inhibitor, sildenafil, prior to PEA surgery. Mean pulmonary artery pressure (mPAP) was higher (p=0.024) in the sildenafil treated group (50.90±9.92mmHg) compared to patients not on therapy (39.33±10.36mmHg). PVR was similar between both groups. Pre-operative drug treatment did not appear to have any significant effect on ET receptor expression (data not shown). The majority of cases were Jaimeson classification type 1 or type 2. A typical example of a PEA specimen is included in Fig. 1A. §=died following PEA surgery. #=did not return for follow-up.
    Discussion CTEPH is caused by chronic thromboembolic obstruction of the pulmonary vasculature and the more distal portions of this residual material can completely occlude the lumen and have been shown to contain frequent newly formed vascular channels [1], [31]. Our results show that ET receptors are present within the luminal obstructions removed from pulmonary artery branches during PEA surgery for patients with CTEPH. To our knowledge this is the first time this has been shown using autoradiography. A crucial advantage of using autoradiography to identify ET receptors is that the receptor must be expressed on the cell surface and functionally viable for the radiolabelled ET ligand to bind. This provides UNC1999 mechanistic evidence for circulating ET to play a role in the organised thrombus present in the larger pulmonary vessels. This novel observation implies that ET receptor antagonists could act on the pulmonary circulation in CTEPH at the level of the organising thrombus as well as in the small-vessel arteriopathy. Analysis of the distribution of the ET receptors in the specimens shows that the larger less occluded pulmonary arteries (>14mm diameter) had fewer recanalised channels present and a lower expression of ET receptors, in contrast to the smaller specimens.