Schilling, Joel D

AbstractMacitentan is a dual endothelin receptor antagonist (ERA) approved for treating pulmonary arterial hypertension (PAH). SOPRANO evaluated the efficacy and safety of macitentan versus placebo in pulmonary hypertension (PH) patients after left ventricular assist device (LVAD) implantation. SOPRANO was a phase 2, multicenter, double‐blind, randomized, placebo‐controlled, parallel‐group study. Patients with an LVAD implanted within the prior 90 days who had persistent PH (i.e., mean pulmonary arterial pressure ≥25 mmHg, pulmonary artery wedge pressure [PAWP] ≤18 mmHg, and pulmonary vascular resistance [PVR] >3 Wood units [WU]) were randomized (1:1) to macitentan 10 mg or placebo once daily for 12 weeks. The primary endpoint was change in PVR. Secondary endpoints included change in right‐heart catheterization hemodynamic variables, N‐terminal prohormone of brain natriuretic peptide levels, World Health Organization functional class, and safety/tolerability. Fifty‐seven patients were randomized to macitentan (n = 28) or placebo (n = 29). A statistically significant reduction in PVR from baseline to Week 12 was observed with macitentan versus placebo (placebo‐corrected geometric mean ratio, 0.74; 95% confidence interval, 0.58–0.94; p = .0158). No statistically significant differences were observed in secondary endpoints. In a post‐hoc analysis, 66.7% of patients receiving macitentan achieved PVR <3 WU versus 40.0% receiving placebo (p = .0383). Macitentan was generally well tolerated; adverse events were consistent with those in previous PAH studies with macitentan. In conclusion, macitentan showed promising tolerability and significantly reduced PVR in PH patients with persistently elevated PVR after LVAD implantation. ClinicalTrials. gov identifier: NCT02554903.

Abstract Ligation of the Fc γ R on NK cells by Ab-coated target cells initiates a mode of killing referred to as antibody-dependent cell-mediated cytotoxicity (ADCC). There is clear evidence that the release from NK cells of granules containing pore-forming proteins and serine proteases can result in the rapid (within minutes) cell death of Ab-coated targets. However, little information is available as to whether NK cells can initiate subsequent killing through granule-independent mechanisms and as to the mechanisms that down-regulate NK cell-mediated responses. We demonstrate in this study that FcR stimulation of activated human NK cells not only induces granule exocytosis, but also subsequently results in the transcriptional up-regulation of Fas ligand. These FcR-stimulated NK cells can then kill targets that bear Fas (CD95/APO-1), as this cytotoxicity can be inhibited by blocking Abs to the Fas receptor. In addition, as resting NK cells become activated, their Fas receptors become competent to deliver autocrine suicide signals. We demonstrate in this work that the interaction of Fas ligand on the FcR-stimulated NK cells with their Fas receptors can result in apoptosis of the NK cells. These results suggest that the FcR-induced expression of Fas ligand on activated NK cells can critically influence the capacity of these cells to mediate paracrine and autocrine cell death.