Exploration of glucose metabolism dysregulation and vascular dysfunction of anti-angiogenic related cardiotoxicity by dynamic FDG PET scanner. Sourdon J., Viel T., Balvay D., Lager F., Renault G., & Tavitian B. 2016.
abstract   bibtex   
Since neovascularization through angiogenesis is a major event during tumor development, antiangiogenic chemotherapy has been proposed as cancer treatment intended to prevent tumor development. However, drugs targeting angiogenesis may induce severe systemic side effects such as hypertension (Gupta R, Curr Hypertens Rep 2011). During a PET imaging study with the multi-targeted receptor tyrosine kinase inhibitor, sunitinib, we observed an increase in 2-deoxy-2[18F]fluoro-D-glucose (18FDG) uptake in the myocardium of nude mice (Figure 1). Here, we aim to explore further with PET the effect of sunitinib on the myocardium and subsequently develop a protocol to study pathophysiology of chemo-therapy induced cardiotoxicity. Four groups of mice (aged 17-20 weeks) were compared: (1) nude mice treated with sunitinib 50 mg.kg-1 (n=9), (2) nude mice treated with placebo (DMSO + PBS) (n=6), (3) C57Bl6 mice treated with sunitinib 50 mg.kg-1 (n=6), (4) C57Bl6 mice treated with placebo (n=6). Mice were fasted and a baseline PET dataset was acquired in a nanoScan PET-CT camera (Mediso, Hungary) during 60 min after IV injection of 10 MBq 18FDG. Mice were then treated by gavage with sunitinib or placebo during 5 days, followed by a post-treatment PET-CT at day 7. Heart FDG images were analyzed using PMOD software. C57Bl6 mice were also explored by echocardiography at baseline and post-treatment using a Vevo 2100 (VisualSonics, Canada). Heart samples were collected and rapidly frozen for histology and molecular investigations. Compared to baseline, SUV was increased by 50+/-13 percent in nude mice treated with sunitinib (p=0.0003) while it increased only by 17+/-26 percent in the placebo-treated group (n.s). In the sunitinib group, compartmental modeling demonstrated a significant increase of 57+/-11 percent of the metabolic rate of glucose (p=0.002); However, this was associated with a significant decrease of glucose Influx Rate Constant (ml/ccm/min) compared to baseline (p=0.001), while these parameters remained unchanged in the placebo group (Figure 2). In C57Bl6 mice, PET results were similar and moreover, sunitinib-treatment induced a dramatic reduction of cardiac output down by 59+/-36 percent (p=0.01), while in placebo-treated mice there was a slight increase of 13+/-22 percent (n.s). Lectine immunostaining were performed and showed no difference in the number of capillaries between groups. Proteomics and western blotting revealed metabolic pathways alterations with principally a switch for anaerobic carbohydrate utilization. In conclusion, molecular imaging revealed sunitinib-induced cardiotoxicity. This study showed myocardium vascular dysfunction which led to metabolic dysregulation with a shift for glycolytic phenotype. Work is in progress in our laboratory to follow pathophysiology using our new imaging device PET Registered Ultrafast Sonography in a long term treatment study and for validation with molecular mechanisms. We believe this study could be easily use as follow-up for pharmacological and clinical protocols since we know that metabolic dysregulation is responsible for contractile dysfunction (Kundu BK, Cardiology 2015). [IMAGE PRESENTED].
@misc{sourdon_j._exploration_2016,
	title = {Exploration of glucose metabolism dysregulation and vascular dysfunction of anti-angiogenic related cardiotoxicity by dynamic {FDG} {PET} scanner},
	abstract = {Since neovascularization through angiogenesis is a major event during tumor development, antiangiogenic chemotherapy has been proposed as cancer treatment intended to prevent tumor development. However, drugs targeting angiogenesis may induce severe systemic side effects such as hypertension (Gupta R, Curr Hypertens Rep 2011). During a PET imaging study with the multi-targeted receptor tyrosine kinase inhibitor, sunitinib, we observed an increase in 2-deoxy-2[18F]fluoro-D-glucose (18FDG) uptake in the myocardium of nude mice (Figure 1). Here, we aim to explore further with PET the effect of sunitinib on the myocardium and subsequently develop a protocol to study pathophysiology of chemo-therapy induced cardiotoxicity. Four groups of mice (aged 17-20 weeks) were compared: (1) nude mice treated with sunitinib 50 mg.kg-1 (n=9), (2) nude mice treated with placebo (DMSO + PBS) (n=6), (3) C57Bl6 mice treated with sunitinib 50 mg.kg-1 (n=6), (4) C57Bl6 mice treated with placebo (n=6). Mice were fasted and a baseline PET dataset was acquired in a nanoScan PET-CT camera (Mediso, Hungary) during 60 min after IV injection of 10 MBq 18FDG. Mice were then treated by gavage with sunitinib or placebo during 5 days, followed by a post-treatment PET-CT at day 7. Heart FDG images were analyzed using PMOD software. C57Bl6 mice were also explored by echocardiography at baseline and post-treatment using a Vevo 2100 (VisualSonics, Canada). Heart samples were collected and rapidly frozen for histology and molecular investigations. Compared to baseline, SUV was increased by 50+/-13 percent in nude mice treated with sunitinib (p=0.0003) while it increased only by 17+/-26 percent in the placebo-treated group (n.s). In the sunitinib group, compartmental modeling demonstrated a significant increase of 57+/-11 percent of the metabolic rate of glucose (p=0.002); However, this was associated with a significant decrease of glucose Influx Rate Constant (ml/ccm/min) compared to baseline (p=0.001), while these parameters remained unchanged in the placebo group (Figure 2). In C57Bl6 mice, PET results were similar and moreover, sunitinib-treatment induced a dramatic reduction of cardiac output down by 59+/-36 percent (p=0.01), while in placebo-treated mice there was a slight increase of 13+/-22 percent (n.s). Lectine immunostaining were performed and showed no difference in the number of capillaries between groups. Proteomics and western blotting revealed metabolic pathways alterations with principally a switch for anaerobic carbohydrate utilization. In conclusion, molecular imaging revealed sunitinib-induced cardiotoxicity. This study showed myocardium vascular dysfunction which led to metabolic dysregulation with a shift for glycolytic phenotype. Work is in progress in our laboratory to follow pathophysiology using our new imaging device PET Registered Ultrafast Sonography in a long term treatment study and for validation with molecular mechanisms. We believe this study could be easily use as follow-up for pharmacological and clinical protocols since we know that metabolic dysregulation is responsible for contractile dysfunction (Kundu BK, Cardiology 2015). [IMAGE PRESENTED].},
	journal = {Molecular Imaging and Biology},
	author = {{Sourdon J.} and {Viel T.} and {Balvay D.} and {Lager F.} and {Renault G.} and {Tavitian B.}},
	year = {2016},
	keywords = {*PET scanner, *cardiotoxicity, *glucose metabolism, C57BL 6 mouse, Canada, Hungary, Software, Western blotting, adolescent, animal experiment, animal model, animal tissue, capillary, carbohydrate absorption, cardiology, chemotherapy, clinical protocol, compartment model, controlled study, drug therapy, drug toxicity, echocardiography, endogenous compound, enteric feeding, follow up, glucose, glucose transport, heart output, immunohistochemistry, influx rate constant, intravenous drug administration, metabolic rate, molecular imaging, mouse, nonhuman, phenotype, placebo, positron emission tomography-computed tomography, proteomics, side effect, sunitinib, tyrosine kinase receptor, validation process}
}

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