PLoS ONE (Jan 2017)

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.

  • Alice C O'Farrell,
  • Rhys Evans,
  • Johanna M U Silvola,
  • Ian S Miller,
  • Emer Conroy,
  • Suzanne Hector,
  • Maurice Cary,
  • David W Murray,
  • Monika A Jarzabek,
  • Ashwini Maratha,
  • Marina Alamanou,
  • Girish Mallya Udupi,
  • Liam Shiels,
  • Celine Pallaud,
  • Antti Saraste,
  • Heidi Liljenbäck,
  • Matti Jauhiainen,
  • Vesa Oikonen,
  • Axel Ducret,
  • Paul Cutler,
  • Fionnuala M McAuliffe,
  • Jacques A Rousseau,
  • Roger Lecomte,
  • Suzanne Gascon,
  • Zoltan Arany,
  • Bonnie Ky,
  • Thomas Force,
  • Juhani Knuuti,
  • William M Gallagher,
  • Anne Roivainen,
  • Annette T Byrne

DOI
https://doi.org/10.1371/journal.pone.0169964
Journal volume & issue
Vol. 12, no. 1
p. e0169964

Abstract

Read online

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.