title: Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue.
abstract: BACKGROUND
  Left ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an on-target or off-target mechanism.
  
  
  RESULTS
  We studied concentration-response curves and time courses for nine TKIs in three-dimensional, force generating engineered heart tissue (EHT) from neonatal rat heart cells. We detected a concentration- and time-dependent decline in contractile force for gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib and lestaurtinib and no decline in contractile force for erlotinib and dasatinib after 96 hours of incubation. The decline in contractile force was associated with an impairment of autophagy (LC3 Western blot) and appearance of autophagolysosomes (transmission electron microscopy).
  
  
  CONCLUSIONS
  This study demonstrates the feasibility to study TKI-mediated force effects in EHTs and identifies an association between a decline in contractility and inhibition of autophagic flux.
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Fabian
authors: F
authors: Jacob
authors: Molecular Medicine Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: Amina Y
authors: AY
authors: Yonis
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Friederike
authors: F
authors: Cuello
authors: Molecular Medicine Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: Pradeep
authors: P
authors: Luther
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Thomas
authors: T
authors: Schulze
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Alexandra
authors: A
authors: Eder
authors: Department of Clinical Chemistry/Central Laboratories, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Thomas
authors: T
authors: Streichert
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Ingra
authors: I
authors: Mannhardt
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Marc N
authors: MN
authors: Hirt
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Sebastian
authors: S
authors: Schaaf
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Justus
authors: J
authors: Stenzig
authors: Center for Translational Medicine, Cardiology Division, Temple University School of Medicine, Philadelphia, Pennsylvania, 19140, United States of America.
authors: Thomas
authors: T
authors: Force
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Thomas
authors: T
authors: Eschenhagen
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Arne
authors: A
authors: Hansen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D054715:Cardiotoxins / Q000494:pharmacology*; D005240:Feasibility Studies; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000000981:diagnostic imaging / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D023822:Tissue Engineering / Q000379:methods; D014463:Ultrasonography
chemical_list: D054715:Cardiotoxins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases