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Background: Macitentan, an oral dual endothelin receptor antagonist (ERA), has demonstrated improved morbidity and mortality in patients with pulmonary arterial hypertension (PAH) in a long-term event-driven study. Aims: To provide data on clinical efficacy and safety of switching to macitentan, in adult PAH patients. Methods: PAH patients were included in this single center restrospective study, provided they were switched from another ERA to macitentan. Patients were managed following the currently held guidelines, and other PAH-specific treatment with phosphodiesterase-5 inhibitors and prostanoids were prescribed accordingly. Functional class, 6 minute walk distance, NT-proBNP levels and hemodynamic measurements were assessed. The last available measurements pre and the first available measurements post initiation of macitentan were compared. Safety end-points focused on liver enzymes and hemoglobin levels, as well as peripheral edema. Results: 10 PAH patients (3 males), aged 59±13 years, with a PAH history of 5±2years, were studied. They did not demonstrate any difference in functional class after switching to macitentan. They had an increase in 6 minute walk distance (from 407±81 m to 416±85, p=0.06), and a significant improvement in NT-proBNP levels (1044±878 ng/L to 832±901, p=0.03). A non-significant increase in cardiac output (from 4.9±0.6 L/min to 5±0.6, p=0.7) and decrease in pulmonary vascular resistance (from 5.9±2.5 Wood Units to 5.5±2.6, p=0.08) were observed. No episodes of increased liver enzymes, anemia or peripheral edema were observed. Conclusion: Switching to macitentan was well tolerated and associated with improved natriuretic peptide levels in our patient cohort.

Background: Although CTEPH is a thromboembolic disorder, the effect of the coagulation process in the pathogenesis and progression of the disease has not been fully elucidated. Aims: To assess coagulation in CTEPH and to evaluate differences after the initiation of PH-specific treatment. Methods: We studied 20 CTEPH patients (not on anticoagulation therapy at the time of tests) and 20 controls. CTEPH patients were reevaluated 1 year after therapy initiation. We performed Platelet- Function Analyzer/PFA-100 testing, ADP and epinephrine/EPI induced Light Transmission Aggregometry/LTA, Thrombelastometry/ROTEM (na-TEM) and Endogenous Thrombin Potential/ETP essay. Results: Before treatment and when compared to controls, CTEPH patients presented prolonged PFA-100 closure times (174.8sec±27.3, p=0.003), lower EPI and ADP-LTA (43.9%±11.2, p Conclusions: Our data suggest that the observed coagulation defects in CTEPH persist even after PH treatment initiation. EPI-LTA was the only index displaying significant increase after treatment.

Background: Ghrelin is a peptide mainly produced by cells of the gastric mucosa; Ghrelin’s active form is the main modulator of a variety of biological actions, while both forms are involved in systemic inflammation. Aim: We investigated ghrelin levels at different stages of sepsis in critical illness, as well as associations with proinflammatory mediators and organ dysfunction markers. Methods: All consecutive admissions to our hospital ICU were screened for eligibility. Non-septic patients upon ICU admission who subsequently developed sepsis and septic shock (Crit Care Med 1992, 20(6):864-874) were enrolled (n=25). Clinical data and scores were recorded, and blood samples were obtained at baseline (upon ICU admission), and upon sepsis and septic shock development. Total and active ghrelin, leptin, and cytokine serum concentrations were measured. Results: Total ghrelin and active ghrelin concentrations in serum were significantly elevated in septic shock compared to baseline (mean±SEM: 236.5±66.6 vs 57±12.5pg/ml, and 149.6±64.3 vs 15±7.4pg/ml, respectively). Leptin, TNF-α, and IL-6 levels did not differ significantly. Notably, active ghrelin levels on ICU admission correlated inversely with the length of patient mechanical ventilation (r=-0.487, p=0.016) and active ghrelin levels at sepsis stage correlated inversely with the length of stay in ICU (r=-0.584, p=0.0005). Conclusions: We demonstrated that in a well-defined cohort of ICU patients active and total ghrelin increase at septic shock. In addition, active ghrelin levels might have a protective role during the septic process. This work was supported by an unrestricted research grant by GSK

The mammalian peripheral lung contains at least three aquaporin (Aqp) water channels: Aqp1 in microvascular endothelia, Aqp4 in airway epithelia, and Aqp5 in alveolar epithelia. These aquaporins play a major role in osmotic water movement and participate in edema formation, however, their precise role in lung injury or inflammation is still controversial. Three murine (8-10 week old C57/BL6) models of lung inflammation and corresponding controls (n= 9/group) were used to evaluate the expression of Aqps: I) LPS-induced lung injury; intratracheal instillation (it) of normal saline (NS) or LPS (5mg/kg), II) HCl-induced lung injury; it NS or 0.1N HCl. Animals of groups I & II were sacrificed 24hrs post-treatment. III) Ventilation-induced lung injury (VILI); tidal volumes of 8ml/kg or 25ml/kg; mice were sacrificed after 4hrs of mechanical ventilation. Following sacrifice lung tissues were obtained and snap frozen in liquid nitrogen. Aqp1, 4 and 5 mRNAs were quantified by real-time PCR and protein levels were measured by immunoblotting. All models yielded increased lung vascular permeability and inflammatory cell infiltration in the bronchoalveolar lavage fluid; VILI additionally produced altered lung mechanics. Aqp1 expression remained unaltered; Aqp4 decreased in HCl-induced lung injury and VILI and Aqp5 tended to increase, whereas it decreased in the LPS model. These results show that Aqp4 decreases and Aqp5 tends to increase in the models that target primarily the alveolar epithelium, i.e. acid aspiration and mechanical ventilation, while Aqp5 decreases in the model that targets primarily the capillary endothelium, i.e. LPS, indicating that participation of Aqps in the acute inflammatory process is location and type of lung injury specific.