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.

Cardiac Metabolic Deregulation Induced by the Tyrosine Kinase Receptor Inhibitor Sunitinib is rescued by Endothelin Receptor Antagonism

“…O'Farrel et al . also showed increased FDG uptake as early 2-3 days after introduction of sunitinib in mice and 5 days in rats 30 . Overall, the sunitinib-treated heart tends to switch towards an anaerobic glycolysis metabolism with accumulation of lactate, similar to the one found in hypoxic muscles and during heart failure 43 .…”

“…Sunitinib treatment is limited by its cardiovascular side effects. A recent study reported that sunitinib induces an early switch of cardiac metabolism to anaerobic glycolysis and impairs heart function 30 . Here, we show that in addition to this metabolic switch, myocardial remodeling by sunitinib also induces a reduced glucose uptake resembling the one found during insulin resistance, and show that sunitinib cardiotoxicity is a combination of several complex mechanisms occurring over a sequential time course.…”

“…Borde et al described a higher uptake of 2'-deoxy-2'-[ 18 F]fluoro-D-glucose (FDG) in the myocardium of patients treated with adriamycin, highlighting the capacity of positron emission tomography (PET) to detect a deregulation of myocardial metabolism induced by a cancer treatment 29 . Recently, O'Farrell et al described an early increase of the metabolic rate of glucose in sunitinib-treated rodents 30 . This is particularly interesting from a clinical perspective as PET can simultaneously stage cancer and explore cardiac metabolism.…”

Evaluation of cardiac function by nuclear imaging in preclinical studies

“…1 Nuclear imaging in small animal models of ischemic heart disease is appealing, because it enables accurate measurement of MI size, 5-9 evaluation of myocardial perfusion, 10,11 and molecular imaging of metabolism such as oxygen consumption combined with substrate metabolism. 12,13 However, previous studies evaluating nuclear imaging for the assessment of cardiac volumes and function have been mainly focused on other conditions than MI. [14][15][16][17] Therefore, the study of Hess et al provides valuable information by validating nuclear imaging with anatomical imaging modalities in mice after MI.…”

Production of highly polarized [1‐13C]acetate by rapid decarboxylation of [2‐13C]pyruvate – application to hyperpolarized cardiac spectroscopy and imaging

“…In combination with [ 11 C]acetate as a validated tracer, cardiac oxidative metabolism has been assessed. Numerous clinical applications using [ 11 C]acetate as cancer imaging agent are documented …”