IntroductionSarcoidosis-associated pulmonary hypertension (SAPH) is associated with reduced survival in single-centre studies. The international Registry for SAPH (ReSAPH) with long-term follow-up was established to enrich our knowledge of this complication of sarcoidosis. This analysis aims to elucidate factors associated with reduced transplant-free survival in SAPH patients.MethodsReSAPH contains prospectively collected outcomes of SAPH patients since the time of registry enrolment. Information analysed includes right heart catheterisation data, pulmonary function testing, chest radiography, Scadding stage and 6-min walk distance (6MWD), among others. Cox regression models were used to identify independent predictors of transplant-free survival.ResultsData from 215 patients followed for a mean±sd 2.5±1.9 years were available for analysis. In the 159 precapillary patients, the Kaplan–Meier-adjusted 1-, 3- and 5-year transplant-free survival was 89.2%, 71.7% and 62.0%, respectively. Kaplan–Meier-adjusted 1-, 3- and 5-year transplant-free survival in the incident group was 83.5%, 70.3% and 58.3%, respectively, and in the prevalent group was 94.7%, 72.2% and 66.3%, respectively. Patients with reduced diffusing capacity of the lung for carbon monoxide (DLCO) (<35% predicted) and 6MWD <300 m in the precapillary cohort had significantly worse transplant-free survival. Reduced 6MWD and preserved forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio were identified as independent risk factors for reduced transplant-free survival in the precapillary cohort.ConclusionReduced DLCO (<35% pred) and 6MWD (<300 m) at the time of registry enrolment were associated with reduced transplant-free survival in the overall precapillary cohort. Preserved FEV1/FVC ratio was identified as an independent risk factor for worsened outcomes.

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs63), c.1996C>T (p.Arg666), c.2632G>T (p.Glu878), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.

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Experimental evidence indicates that the potent vasoconstrictor peptide endothelin-1 (ET-1) has a pivotal role in the pathogenesis of both primary (1) and secondary (2) forms of human pulmonary hypertension. Despite this little is known about the control and sites of ET-1 production during these disease processes. In patients with primary pulmonary hypertension (PPH) urinary excretion of prostacyclin metabolites is lowered (3). In the same patient group, prostacyclin (epoprostenol) administered as a continuous intravenous infusion improves pulmonary vascular resistance (4) and mortality (5). The mechanism of this beneficial effect remains unclear. We aimed to compare the ability of human pulmonary artery smooth muscle cells (HPASM) to produce ET-1 under inflammatory conditions with human pulmonary microvascular endothelial cells (HPMVE) under the same conditions. In addition, we assessed a possible interaction between prostacyclin and endogenously pro-duced ET-1 by HPASM in order to identify a potential control mechanism. MATERIALS AND METHODS Cell cultureSpecimens of human pulmonary artery were obtained from patients undergoing pulmonary resection at the Royal Brompton Hospital (London, U.K.). Vessels were cleaned of adventitia, the endothelium removed and cut into 3-4 mm sections. Dulbecco's modified Eagle medium was added to the tissue, supplemented with 15% fetal calf serum (FCS), glutamine, streptomycin, penicillin and non-essential amino acids. HPASM were identified by staining with fluorescein isothiocyanate-(FITC) labelled anti-smooth muscle actin antibody and were used at passage 2-9 (6). HPMVE cells were purchased from Clonetics (San Diego, CA, U.S.A.).Journal of Cardiovascular Pharmacology™ 36 (Suppl. 1):S410-S413