title: A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.
abstract: Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Alice C
authors.identifier: http://orcid.org/0000-0002-6732-2966
authors.initials: AC
authors.lastname: O'Farrell
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Rhys
authors.initials: R
authors.lastname: Evans
authors.affiliation: Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.
authors.forename: Johanna M U
authors.initials: JM
authors.lastname: Silvola
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Miller
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Emer
authors.initials: E
authors.lastname: Conroy
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Hector
authors.affiliation: Pathology Experts GmbH, Basel, Switzerland.
authors.forename: Maurice
authors.initials: M
authors.lastname: Cary
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Oncomark Ltd, Dublin, Ireland.
authors.forename: David W
authors.initials: DW
authors.lastname: Murray
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Jarzabek
authors.affiliation: Oncomark Ltd, Dublin, Ireland.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Maratha
authors.affiliation: Oncomark Ltd, Dublin, Ireland.
authors.forename: Marina
authors.initials: M
authors.lastname: Alamanou
authors.affiliation: Oncomark Ltd, Dublin, Ireland.
authors.forename: Girish Mallya
authors.initials: GM
authors.lastname: Udupi
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Liam
authors.initials: L
authors.lastname: Shiels
authors.affiliation: Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Pallaud
authors.affiliation: Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.|Heart Center, Turku University Hospital and Åbo Akademi University, Turku, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Saraste
authors.affiliation: Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Liljenbäck
authors.affiliation: Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.
authors.forename: Vesa
authors.initials: V
authors.lastname: Oikonen
authors.affiliation: Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland.
authors.forename: Axel
authors.initials: A
authors.lastname: Ducret
authors.affiliation: Roche Innovation Center Basel, F Hoffman La Roche, Basel, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Cutler
authors.affiliation: UCD Obstetrics & Gynaecology, School of Medicine, University College, Dublin, National Maternity Hospital, Dublin, Ireland.
authors.forename: Fionnuala M
authors.initials: FM
authors.lastname: McAuliffe
authors.affiliation: Université de Sherbrooke, Québec, Canada.
authors.forename: Jacques A
authors.initials: JA
authors.lastname: Rousseau
authors.affiliation: Université de Sherbrooke, Québec, Canada.
authors.forename: Roger
authors.initials: R
authors.lastname: Lecomte
authors.affiliation: Université de Sherbrooke, Québec, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Gascon
authors.affiliation: Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, United States of America.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Arany
authors.affiliation: Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, United States of America.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Ky
authors.affiliation: Vanderbilt University School of Medicine, Nashville, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
authors.affiliation: Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.
authors.forename: Juhani
authors.initials: J
authors.lastname: Knuuti
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.|Oncomark Ltd, Dublin, Ireland.
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.affiliation: Turku PET Centre, Turku University Hospital and Åbo Akademi University, Turku, Finland.|Turku Center for Disease Modeling, University of Turku, Turku, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Roivainen
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Byrne
mesh_terms: D000818:Animals; D019788:Fluorodeoxyglucose F18 / Q000627:therapeutic use; D006321:Heart / Q000000981:diagnostic imaging* / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D040901:Proteomics; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077210:Sunitinib; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D007211:Indoles; D011758:Pyrroles; D019788:Fluorodeoxyglucose F18; D000077210:Sunitinib