Abstract 13712: Imaging Short-Chain Fatty Acid Metabolism and Transport in the Failing Heart by PET

医学 心脏毒性 阿霉素 体内分布 脂肪酸 脂肪酸代谢 新陈代谢 正电子发射断层摄影术 药理学 心力衰竭 葡萄糖摄取 内科学 内分泌学 核医学 生物化学 毒性 化学 化疗 胰岛素 体外
作者
Juan A. Azcona,Anja Wacker,Chul-Hee Lee,Pradeep K. Singh,Onorina Laura Manzo,Annarita Di Lorenzo,Thomas M. Jeitner,John W. Babich,Alejandro Amor‐Coarasa,James M. Kelly
出处
期刊:Circulation [Lippincott Williams & Wilkins]
卷期号:148 (Suppl_1)
标识
DOI:10.1161/circ.148.suppl_1.13712
摘要

Introduction: Heart failure compromises the transport and oxidation of long chain fatty acids. Cardiomyocytes can compensate by using short-chain fatty acids (SCFA) which rely on other transport mechanisms. Based on this principle, we used 2-[ 18 F]fluoropropionic acid ([ 18 F]FPA), a radiolabeled SCFA analog, to assess these metabolic changes and image them by positron emission tomography (PET) in a doxorubicin-induced mouse model of cardiotoxicity. Hypothesis: We hypothesize that the increased demand for SCFA by the failing heart promotes cardiac accumulation of [ 18 F]FPA which can be imaged by PET. Methods: [ 18 F]FPA was injected intravenously into male C57BL/6J mice 10 weeks following intraperitoneal injections of 8 x 3 mg/kg doxorubicin (DOX). Dynamic PET acquisitions were performed from 60-120 min post injection of 9.25-11 MBq [ 18 F]FPA. These images were acquired in the presence or absence of 5 mg/kg AZD3965, an inhibitor of monocarboxylate transporters. Heart uptake of [ 18 F]FPA was determined by image-based quantitation and confirmed by a biodistribution study. Mechanistic [ 18 F]FPA uptake studies were also conducted in primary human cardiomyocyte (HCM) cultures. Results: Mice experiencing DOX-induced cardiotoxicity exhibited statistically significant increases in cardiac [ 18 F]FPA. AZD3965 did not significantly alter cardiac uptake but reduced uptake in all other tissues except the kidneys, the route of excretion. Additionally, [ 18 F]FPA uptake is lost in HCM for which mitochondrial acyl-CoA synthetase (ACSS) 1, but not cytosolic ACSS2, is inhibited. Conclusions: Our findings present both mechanistic and translational applications for [ 18 F]FPA. AZD3965 effectively reduced [ 18 F]FPA uptake in other tissues except for the heart and can therefore be co-administered to enhance the heart-to-background ratio. Altogether, our results indicate that [ 18 F]FPA may enter cardiac tissues by diffusion and become metabolically trapped in mitochondria.

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