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Effects of multikinase inhibitors on pressure overload-induced right ventricular remodeling.
MedLine Citation:
PMID:  22854298     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Little is known about the effects of current PAH therapies and receptor tyrosine kinase inhibitors on heart remodeling. We sought to investigate the effects of the multikinase inhibitors sunitinib (PDGFR-, VEGFR- and KIT-inhibitor) and sorafenib (raf1/b-, VEGFR-, PDGFR-inhibitor) on pressure overload induced right ventricular (RV) remodeling. METHODS: We investigated the effects of the kinase inhibitors on hemodynamics and remodeling in rats subjected either to monocrotaline (MCT)-induced PH or to surgical pulmonary artery banding (PAB). MCT rats were treated from days 21 to 35 with either vehicle, sunitinib (1mg/kg, 5mg/kg and 10mg/kg/day) or sorafenib (10mg/kg/day). PAB rats were treated with vehicle, sunitinib (10mg/kg/day) or sorafenib (10mg/kg/day) from days 7 to 21. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurement and histomorphometry. RESULTS: Treatment with both sorafenib and sunitinib decreased right ventricular systolic pressure, pulmonary vascular remodeling, RV hypertrophy and fibrosis in MCT rats. This was associated with an improvement of RV function. Importantly, after PAB, both compounds reversed RV chamber and cellular hypertrophy, reduced RV interstitial and perivascular fibrosis, and improved RV function. CONCLUSION: We demonstrated that sunitinib and sorafenib reversed RV remodeling and significantly improved RV function measured via a range of invasive and non-invasive cardiopulmonary endpoints in experimental models of RV hypertrophy.
Authors:
Baktybek Kojonazarov; Akylbek Sydykov; Soni Savai Pullamsetti; Himal Luitel; Bhola K Dahal; Djuro Kosanovic; Xia Tian; Matthaeus Majewski; Christin Baumann; Steve Evans; Peter Phillips; David Fairman; Neil Davie; Chris Wayman; Iain Kilty; Norbert Weissmann; Friedrich Grimminger; Werner Seeger; Hossein Ardeschir Ghofrani; Ralph Theo Schermuly
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-30
Journal Detail:
Title:  International journal of cardiology     Volume:  -     ISSN:  1874-1754     ISO Abbreviation:  Int. J. Cardiol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-8-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8200291     Medline TA:  Int J Cardiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Affiliation:
Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Germany.
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