title: Tyrosine kinase inhibitor BIBF1000 does not hamper right ventricular pressure adaptation in rats.
abstract: BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment of idiopathic pulmonary fibrosis (IPF). A safety concern pertaining to VEGFR, FGFR, and PDGFR inhibition is the possible interference with right ventricular (RV) responses to an increased afterload, which could adversely affect clinical outcome in patients with IPF who developed pulmonary hypertension. We tested the effect of BIBF1000 on the adaptation of the RV in rats subjected to mechanical pressure overload. BIBF1000 was administered for 35 days in pulmonary artery-banded (PAB) rats. RV adaptation was assessed by echocardiography, pressure volume loop analysis, histology, and determination of atrial natriuretic peptide (ANP) expression. BIBF1000 treatment resulted in growth attenuation but had no effects on RV function after PAB, given absence of changes in cardiac index, end-systolic elastance, connective tissue disposition, and capillary density. We conclude that, in this experimental model of increased afterload, combined VEGFR, FGFR, and PDGFR inhibition does not hamper RV adaptation to pressure overload.
authors.affiliation: Department of Pulmonology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands; INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Université Paris-Sud and Université Paris-Saclay, School of Medicine, Kremlin-Bicêtre, France; Department of Physiology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands;
authors.forename: Michiel Alexander
authors.initials: MA
authors.lastname: de Raaf
authors.affiliation: Boehringer Ingelheim Pharma, Dept. Respiratory Diseases Research, Biberach, Germany.
authors.forename: Franziska Elena
authors.initials: FE
authors.lastname: Herrmann
authors.affiliation: Department of Pulmonology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands;
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schalij
authors.affiliation: Department of Pulmonology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands; Department of Physiology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands;
authors.forename: Frances S
authors.initials: FS
authors.lastname: de Man
authors.affiliation: Department of Pulmonology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands;
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk-Noordegraaf
authors.affiliation: INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Université Paris-Sud and Université Paris-Saclay, School of Medicine, Kremlin-Bicêtre, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.affiliation: Boehringer Ingelheim Pharma, Dept. Respiratory Diseases Research, Biberach, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Wollin
authors.affiliation: Department of Pulmonology, VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands; HJ.Bogaard@vumc.nl.
authors.forename: Harm Jan
authors.initials: HJ
authors.lastname: Bogaard
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D004452:Echocardiography; D065627:Familial Primary Pulmonary Hypertension / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D011312:Pressure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016278:Ventricular Function, Right / Q000187:drug effects*
chemical_list: C509119:BIBF 1000; D007211:Indoles; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D009320:Atrial Natriuretic Factor; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: BIBF1000; cardiac remodeling; experimental pulmonary hypertension; pulmonary artery banding; tyrosine kinase inhibitor