Imaging Incipient Heart Failure by PET

通过 PET 对早期心力衰竭进行成像

• 批准号: 10680080
• 负责人: Juan Arturo Azcona
• 金额: $ 6.95万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-09-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680080
• 关键词: Accounting; Acetate-CoA Ligase; Acetyl Coenzyme A; Acids; Animal Model; Behavior; Biochemical Pathway; Biological Assay; Biological Markers; Bypass; Cancer Detection; Cardiac; Cardiac Myocytes; Cardiomyopathies; Catabolism; Cells; Clinic; Coenzyme A; Coenzyme A Ligases; Detection; Diagnosis; Disease; Early Diagnosis; Echocardiography; Effectiveness; Enzymes; Event; Family; Family member; Fellowship; Fluorine; Foundations; Goals; Health; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Image; Impairment; In Vitro; Incubated; Intervention; Isoproterenol; Isotopes; Kinetics; Knock-out; Knowledge; Label; Malignant neoplasm of prostate; Medical; Membrane; Metabolic; Metabolism; Methods; Mitochondria; Modality; Modeling; Mus; Myocardium; Organelles; Pathologic; Pathway interactions; Patients; Phase; Positron; Positron-Emission Tomography; Preventive care; Propionic Acids; Reporting; Research; Risk; Rodent; Role; Safety; Severity of illness; Surveys; System; Testing; Therapeutic Intervention; Tracer; Training; Translations; United States; Validation; Volatile Fatty Acids; aorta constriction; cancer imaging; cardiometabolism; cardiovascular health; career; clinical translation; dosimetry; experience; fatty acid metabolism; fatty acid oxidation; heart damage; heart imaging; heart metabolism; imaging probe; improved; liquid chromatography mass spectrometry; long chain fatty acid; metabolic imaging; molecular imaging; mortality; patient prognosis; prevent; response; tool; uptake

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.

项目摘要 心力衰竭是美国疾病和死亡率的主要原因。先发制人和预防性 护理是缓解这种疾病严重程度的最有效方法。因此，早期发现心脏 失败对患者预后和整体心血管健康至关重要。诊断的常规方法 仅限于检测明显的心脏损伤和病理重塑。我们建议使用2- [18F]氟丙酸（[18F] FPA）成像脂肪酸代谢的代谢改变 心脏损伤。 [18F] FPA-PET非常适合成像这些事件并将其转换为诊所，例如：1） [18F] FPA-PET已用于成像人类的肿瘤并在心脏中积聚，从而确认 它的安全性和有利的剂量法，2）短链脂肪酸（例如[18F] FPA）优先用 对长链脂肪酸氧化的损害响应受伤的心脏，3）丙酸代谢是 仅限于单个线粒体途径，该途径将[18F] FPA靶向该细胞器，并限制其潜力 降解。我们预测心力衰竭期间发生的代谢改变会有效增加摄取 并将[18F] FPA固定到心肌。 [18F] FPA的代谢诱捕由乙酰辅酶A驱动 合成酶短链家族1（ACSS1），将这些短链脂肪酸转换为代谢活性 和膜不渗透的COA中间体。患者的ACSS1表达和活性上调 经历心力衰竭和许多心力衰竭的动物模型。因此，我们假设[18F] FPA 有效地积聚在受伤的心脏中，可以应用于心脏的早期表现 在不可逆的心脏损伤和重塑之前的疾病。该团契项目的目标是1） 确定[18F] FPA是否可以用于图像心力衰竭，以及2）研究ACSS1在会计中的作用 [18F] FPA的心脏积累。大多数成像探针的成功应用取决于 对这些探针报告的生化途径的全面理解。在建造我们的 理解，我们可以为这些示踪剂开发精确的应用程序，以形象心力衰竭以及其他 疾病状态。该项目的长期目标将成为申请人独立的基础 研究职业。这些技术，概念和实践知识将促进这些知识 在奖学金培训的过程中。