A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate
Byrne AT; Conroy E; Cutler P; Liljenback H; AliceO'Farrell AC; Miller IS; Alamanou M; Jauhiainen M; Oikonen V; Gascon S; Murray DW; Roivainen A; Evans R; Pallaud C; Jarzabek MA; Maratha A; Gallagher WM; Lecomte R; Hector S; Knuuti J; Ducret A; Cary M; Force T; Arany Z; Saraste A; Rousseau JA; Udupi GM; Shiels L; McAuliffe FM; Silvola JMU; Ky B
A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate
Byrne AT
Conroy E
Cutler P
Liljenback H
AliceO'Farrell AC
Miller IS
Alamanou M
Jauhiainen M
Oikonen V
Gascon S
Murray DW
Roivainen A
Evans R
Pallaud C
Jarzabek MA
Maratha A
Gallagher WM
Lecomte R
Hector S
Knuuti J
Ducret A
Cary M
Force T
Arany Z
Saraste A
Rousseau JA
Udupi GM
Shiels L
McAuliffe FM
Silvola JMU
Ky B
PUBLIC LIBRARY SCIENCE
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042716733
https://urn.fi/URN:NBN:fi-fe2021042716733
Tiivistelmä
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 [F-18]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [C-11] 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 beta-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.
Kokoelmat
- Rinnakkaistallenteet [19207]