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Background: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH., Methods: In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints., Results: At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05)., Conclusions: Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Background: Exhaled nitric oxide (FeNO), a marker of airway inflammation, is often elevated in lung transplant recipients (LTxRs) with acute rejection or infection. Isolated measurements in the setting of bronchiolitis obliterans syndrome have been variable. We sought to assess the utility of serial FeNO in predicting chronic allograft dysfunction or the presence of acute rejection or infection., Methods: Eighty-six LTxRs underwent 325 serial FeNO measurements at an expiratory flow rate of 50 ml/s. The change in FeNO (ΔFeNO) between two measurements obtained during a stable state (ΔFeNO-SS) was compared with ΔFeNO, where the first measurement was taken during a stable state and the second during an unstable state (defined as a subsequent decline in FEV1 > 10% over 3 months [ΔFeNO-SU]) or an acute complication (acute rejection, lymphocytic bronchiolitis or acute infection [ΔFeNO-SAC]). The median follow-up time after the baseline FeNO was 10 (range 3 to 25) months., Results: ΔFeNO-SS in 117 FeNO pairs was similar to ΔFeNO-SU in 26 pairs (2.1 ± 3 ppb vs 2.3 ± 4 ppb; p = 0.2). ΔFeNO-SAC in 17 pairs was markedly increased (27 ± 20 ppb; p < 0.001 vs ΔFeNO-SS). The area under the receiver-operating characteristic curve for ΔFeNO in detecting an acute complication was 0.93 (p < 0.001). By applying a cut-off of >10 ppb, the sensitivity and specificity was 82% and 100%, respectively, with positive and negative predictive values of 100% and 97.5%., Conclusions: Changes in FeNO may serve as a useful adjunct in the detection of acute complications after lung transplantation. In this limited analysis, ΔFeNO was not predictive of a subsequent decline in allograft function., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is one of the leading causes of death in systemic sclerosis (SSc). Despite advances in treatment options for PAH, long-term prognosis remains poor for scleroderma-associated PAH (SSc-PAH). Although prompt diagnosis and treatment of PAH may have significant impact on survival rates, early detection of the syndrome continues to be challenging in SSc due to several factors ranging from limitations of the current screening tools and the complexities of the disease. In comparison with other PAH subgroups, SSc-PAH patients respond poorly to conventional forms of PAH therapy. Recent findings indicate that factors such as autoimmune and inflammatory responses, more severe vasculature remodeling, and intrinsic cardiac involvement may account for these differences., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)