Imaging Incipient Heart Failure by PET

项目摘要 心力衰竭是美国疾病和死亡的主要原因。先发制人和预防性 护理是减轻这种疾病严重程度的最有效方法。因此，心脏的早期检测 失败对于患者预后和总体心血管健康是至关重要的。常规诊断方法 仅限于检测显著的心脏损伤和病理性重塑。我们建议使用2- [18 F]氟丙酸（[18 F]FPA）成像脂肪酸代谢的代谢改变， 心脏损伤[18F]FPA-PET非常适合对这些事件进行成像并转化为临床：1） [18F]FPA-PET已用于人体肿瘤成像，并在心脏中积累，从而证实了 由于其安全性和良好的剂量测定，2）短链脂肪酸，如[18 F]FPA，优先被 长链脂肪酸氧化损伤引起的心脏损伤，3）丙酸代谢， 仅限于单一线粒体途径，其将[18 F]FPA靶向该细胞器并限制其潜在的 降解我们预测，心力衰竭期间发生的代谢改变有效地增加了摄取 和[18F]FPA对心肌的隔离。[18 F]FPA的代谢捕获由乙酰辅酶A驱动 合成酶短链家族1（ACSS 1），其将这些短链脂肪酸转化为代谢活性的脂肪酸。 和膜不可渗透的CoA中间体。ACSS 1表达和活性在患者中上调 以及许多心力衰竭的动物模型。因此，我们假设[18F]FPA 有效地积累在受伤的心脏，并可用于成像心脏病的早期表现， 不可逆心脏损伤和重塑之前的疾病。该奖学金项目的目标是1） 确定[18F]FPA是否可用于心力衰竭成像，以及2）研究ACSS 1在解释 [18F]FPA的心脏蓄积。大多数成像探头的成功应用取决于 全面了解这些探针报告的生化途径。在建立我们的 理解，我们可以开发这些示踪剂的精确应用，以成像心力衰竭，以及其他 疾病状态。该项目的长期目标将作为申请人独立的基础 研究生涯。这些将通过他将获得的技术、概念和实践知识来促进 在奖学金培训的过程中。

PROJECT SUMMARY Heart failure represents a major cause of illness and mortality in the United States. Preemptive and preventative care are the most effective methods for mitigating the severity of this disease. Thus, the early detection of heart failure is critical to patient prognosis and overall cardiovascular health. The conventional methods for diagnosis are limited to detection of significant cardiac damage and pathological remodeling. We propose using 2- [18F]fluoropropionic acid ([18F]FPA) to image the metabolic alterations in fatty acid metabolism which precede cardiac injury. [18F]FPA-PET is favorably suited for imaging these events and translation to the clinic as: 1) [18F]FPA-PET has been used for imaging tumors in humans and accumulates in the heart, thereby confirming its safety and favorable dosimetry, 2) short chain fatty acids, such as [18F]FPA, are preferentially taken up by the injured heart in response to the impairment in long chain fatty acid oxidation, 3) propionic acid metabolism is restricted to a single mitochondrial pathway which targets [18F]FPA to this organelle and limits its potential for degradation. We predict the metabolic alterations that occur during heart failure effectively increase the uptake and sequestration of [18F]FPA to the myocardium. The metabolic trapping of [18F]FPA is driven by acetyl-CoA synthetase short chain family 1 (ACSS1), which converts these short chain fatty acids to metabolically active and membrane impermeable CoA intermediates. ACSS1 expression and activity are upregulated in patients experiencing heart failure, and many animal models of heart failure. Thus, we hypothesize that [18F]FPA effectively accumulates in the injured heart and can be applied to image the early manifestations of cardiac disease which precede irreversible cardiac injury and remodeling. The goals of this fellowship project are to 1) determine if [18F]FPA can be used to image heart failure, and 2) investigate the role of ACSS1 in accounting for the cardiac accumulation of [18F]FPA. The successful application of most imaging probes depends on a comprehensive understanding of the biochemical pathways that these probes report on. In building our understanding, we can develop precise applications for these tracers to image heart failure, as well as other disease states. The long-term goals of this project will serve as a foundation for the applicant's independent research career. These will be facilitated by the technical, conceptual, and practical knowledge that he will gain over the course of the fellowship training.