Fasudil Prevents Pulmonary Vascular Remodeling in a Rat Model of Pulmonary Hypertension with Left Heart

Abstracts S359 73% of pts and included functional complications related to the device (54%), cutaneous complications at catheter site (15%) and local and systemic infections (each 22%). 10 pts prematurely discontinued: lung-transplant (6), sudden death (1), RVF requiring venous-arterial extracorporeal support (1), thrombocytopenia (1) and pt/investigator decision (1). Conclusion: The safety profile of long-term epo-AS in PAH pts appeared consistent with the known safety profile of IV epo and symptoms associated with the underlying disease and its progression. No new safety concerns were identified. 1( 000) Fasudil Prevents Pulmonary Vascular Remodeling in a Rat Model of Pulmonary Hypertension with Left Heart X. Zhou ,1 J. Wu,2 F. Lin,1 Q. Meng,1 J. Liu,1 H. Fan,1 Z. Liu.1  1Tongji University School of Medicine, Shanghai East Hospital, Shanghai, China; 2Zhengzhou University, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Purpose: Pulmonary hypertension (PH), characterized by a progressive increase in pulmonary vascular resistance, leads to elevation of pulmonary arterial pressure and ultimately heart failure and death. Inhibition of ROCK signaling can effectively reverse the elevation in pulmonary vascular resistance. Fasudil, a specific ROCK inhibitor, has been reported to ameliorate PH in animal models, including PH induced by monocrotaline (MCT), Sugen5416/hypoxia and bleomycin. However, little information is available concerning the possible impact of fasudil on PH with left heart disease (PH-LHD). Methods: Rat models with PH-LHD were induced by supracoronary aortic banding for 63 day. Hemodynamics measurements were done by cardiac catheterization. Left lung tissues were fixed for H&E staining and the thickness of pulmonary artery walls were measured. QPCR were used to detect the mRNA levels and Elisa and Western Blot to evaluate the protein expressions. Results: Supracoronary aortic banding for 63 days induced a great elevation of mean pulmonary pressure and right vitricular systolic pressure in rats, and treatment with fasudil (30mg/Kg/day, i.p.)for 4 weeks reversed the elevation. Ration of RV/(LV+S) down-regulated while (LV+S)/RV up-regulated in rat at day 63 after opration, compared to sham group, indicating that this operation induced PH models due to left heart disease in rats. Fasudil treatment attenuated the left ventricular hypertrophy and prevents pulmonary vascular remodeling in rat PH-LHD models. The expression of NO and ET1 in serum were detected by Elisa. ET1 expression enhanced while NO levels reduced in PH group, compared to sham rats. Fasudil treatment reversed ET-1 expression and NO content in comparison with PH group. Moreover, mRNA levels of ROCK1, Rho and ETA increased greatly in lungs of rat with PH-LHD, compared to that in sham rats, while decreased in Fasudil treated PH-LHD group. Supracoronary aortic banding for 63 days induced MYPT-1 phosphorylation in lungs and Fasudil treatment inhibited this process. Conclusion: The efficacy of treatment with fasudil suggests that blockade of RhoA/ROCK signaling pathway may be a promising therapy for patients with PH-LHD

efficacy of riociguat on oxygenation state during exercise in patients with CTEPH. Methods: Consecutive 10 patients with CTEPH (age 60.0±7.1 year-old, male: female =  4: 6) treated with riociguat and received cardiopulmonary exercise test (CPET) before and after treatment with riociguat were enrolled to the study. CPET was performed with symptom limited manner using a cycle ergometer (a 5 or 10 Watt/min ramp protocol). Oxygen saturation of peripheral artery (SpO2) was monitored during exercise and the changes in SpO2 between before and after treatment with riociguat were compared. Results: Maintenance dose of riociguat was 2.4±0.2 t.i.d and mean treatment period was 6.7±8.7 months. Maximum load increased form 66 watt to 70 watt without statistical significance (p= 0.11). Borg scale, peak VO2 and anaerobic threshold did not change before and after treatment with riociguat (16.7±1.6 vs 16.6±1.4, 15.7±2.6 mL/kg/min vs 15.1±2.3 mL/kg/min, 11.8±2.1 mL/ kg/min vs 11.4±1.6 mL/kg/min, respectively). SpO2 at rest improved from 93.4±1.9% to 94.0±1.3% without statistical significance and SpO2 during exercise were significantly improved after treatment with riociguat (p= 0.009 by 2-way ANOVA) (Figure). Conclusion: Riociguat significantly improved SpO2 during exercise in patients with CTEPH.

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Riociguat Significantly Improved SpO2 during Exercise in Patients with CTEPH M. Hatano , H. Maki, T. Inaba, S. Minatsuki, I. Komuro.  Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan.

Multi-Disciplinary Care Impacts Mortality in Children with Idiopathic Pulmonary Arterial Hypertension - Results from a Bi-National Population Based Study P.M. Alexander ,1 M. Rose,2 C. O’Donnell,3 S. Vidmar,4 R. Justo,5 M. Richardson,6 J. Ramsay,7 S. Hope,8 G. Sholler,9 D.J. Penny,10 I. King,11 R.J. Weintraub.2  1Cardiology, Boston Children’s Hospital, Boston, MA; 2Cardiology, The Royal Children’s Hospital, Melbourne, Australia; 3Cardiology, Starship Children’s Hospital, Auckland, New Zealand; 4Clinical Epidemiology and Biostatistics Unit, Murdoch Children’s Research Institute, Melbourne, Australia; 5Cardiology, Lady Client Children’s Hospital, Brisbane, Australia; 6Cardiology, Women’s and Children’s Hospital, Adelaide, Australia; 7Cardiology, Princess Margaret Hospital for Children, Perth, Australia; 8Cardiology, Monash Medical Centre, Melbourne, Australia; 9Cardiology, The Children’s Hospital at Westmead, Sydney, Australia; 10Cardiology, Texas Children’s Hospital, Houston, TX; 11Cardiology, Murdoch Children’s Research Institute, Melbourne, Australia.

Purpose: Hypoxia during exercise constitutes a limiting factor of physical activity in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Although preceding pulmonary vasodilators such as bosentan and sildenafil were demonstrated to improve hemodynamics in patients with CTEPH, they did not show the efficacy on exercise capacity. Riociguat seems to exert a favorable effect on oxygenation state during exercise in patients with CTEPH because it was the only agent which was proved to improve not only hemodynamics but also exercise capacity in patients with CTEPH. The purpose of this study is to elucidate the

Purpose: Childhood idiopathic pulmonary arterial hypertension (IPAH) is characterized by elevated pulmonary vascular resistance. Care in specialized centers may result in better outcomes for these patients than standard care. Methods: The Pediatric Pulmonary Hypertension Registry (PPHR) is a collaboration between 9 Australian and New Zealand hospitals from 1/1/2002 to 12/31/2013, enrolling patients 3 months to 18 years old at diagnosis. Children diagnosed before 2002 were included as historic controls. Expert center care was multidisciplinary, with

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