Mouse heart toxicity - A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate

Background Sunitinib is a small molecule tyrosine kinase inhibitor approved for the treatment of diverse cancers. Despite widespread clinical approval the associated cardiovascular toxicity sequelae are of concern; high grade toxicities may lead to dose reduction, interruption or discontinuation. Thus, an effective strategy for the early detection of cardiac damage in the context of sunitinib treatment is warranted. Although yet to be fully elucidated, molecular pathways and kinases implicate include those related to cardiac energy metabolism. We hypothesised that plasticity in cardiac metabolism could represent a novel early marker of cardiotoxicity. Methods and Results Female Balb/CJ mice (n = 36) or Sprague-Dawley rat (n = 12) models were treated with sunitinib. Physiological parameters were measured. An hypothesis driven cardiac positron emission tomography (PET) approach was implemented to investigate alterations in myocardial glucose, fatty acid and oxidative metabolism. Following treatment, blood pressure increased, whilst left ventricular ejection fraction decreased in both models. Increased myocardial glucose uptake after 48 hours indicated early perturbations in glucose metabolism. Myocardial fatty acid metabolism appeared increased as a result of sunitinib treatment indicated by PET but electron microscopy revealed significantly increased storage of lipids in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top cardiac signalling pathways perturbed by sunitinib treatment. [11C]Acetate-PET data suggested a decrease in myocardial perfusion following 5 days of treatment. Conclusions Data implicates sunitinib as a mediator of compromised myocardial energy metabolism. Increased reliance on glycolysis, increases in myocardial lipid deposition and perturbed mitochondrial function may ultimately result in a fundamental energy crisis manifesting as compromised cardiac function, the long term effects of which are unknown. Our data support the utility of an hypothesis driven PET approach to monitor cardiac metabolic pathway remodelling in response to sunitinib, which may ultimately have clinical utility as a novel safety imaging biomarker strategy.

背景 舒尼替尼（Sunitinib）是一种获批用于多种癌症治疗的小分子酪氨酸激酶抑制剂。尽管该药已在临床广泛获批使用，但其相关的心血管毒性后遗症仍备受关注；严重不良反应可导致剂量减量、给药中断甚至停药。因此，亟需开发舒尼替尼治疗背景下心脏损伤的早期检测有效策略。尽管相关分子机制尚未完全阐明，但已明确的分子通路与激酶靶点多与心脏能量代谢相关。本研究假设，心脏代谢可塑性可作为心脏毒性的新型早期生物标志物。
方法与结果 本研究采用36只雌性Balb/CJ小鼠及12只Sprague-Dawley大鼠作为模型，给予舒尼替尼干预。检测相关生理参数，并采用基于研究假设驱动的心脏正电子发射断层显像（PET）技术，探究心肌葡萄糖、脂肪酸及氧化代谢的变化情况。干预后，两种模型动物的血压均升高，左心室射血分数则出现下降。给药48小时后，心肌葡萄糖摄取量增加，提示葡萄糖代谢已出现早期紊乱。PET结果显示舒尼替尼干预后心肌脂肪酸代谢水平升高，但电子显微镜观察发现心肌内脂质沉积显著增加。蛋白质组学分析表明，氧化代谢、脂肪酸β-氧化及线粒体功能障碍是舒尼替尼干预后紊乱程度最高的心脏信号通路之一。碳-11标记乙酸盐PET（[11C]Acetate-PET）数据显示，给药5天后心肌灌注水平出现下降。
结论 本研究数据表明，舒尼替尼可损害心肌能量代谢。心肌对糖酵解的依赖增强、脂质沉积增加及线粒体功能紊乱，最终可能引发根本性的能量危机，表现为心脏功能受损，其长期影响尚不清楚。本研究数据证实，基于假设驱动的PET技术可用于监测舒尼替尼干预后心脏代谢通路的重塑，该策略有望作为新型安全性影像学生物标志物方案应用于临床。