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.

项目概要 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，及早发现心脏 失败对于患者预后和整体心血管健康至关重要。常规诊断方法 仅限于检测显着的心脏损伤和病理重塑。我们建议使用 2- [18F]氟丙酸 ([18F]FPA) 可对脂肪酸代谢中的代谢变化进行成像 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 已用于对人类肿瘤进行成像并在心脏中积聚，从而证实 其安全性和有利的剂量测定，2）短链脂肪酸，例如[18F]FPA，优先被 因长链脂肪酸氧化受损而受伤的心脏，3) 丙酸代谢是 仅限于单一线粒体途径，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可有效增加摄取 以及 [18F]FPA 与心肌的隔离。 [18F]FPA 的代谢捕获由乙酰辅酶 A 驱动 合成酶短链家族 1 (ACSS1)，可将这些短链脂肪酸转化为具有代谢活性的脂肪酸 和膜不可渗透的 CoA 中间体。患者中 ACSS1 表达和活性上调 经历心力衰竭，以及许多心力衰竭的动物模型。因此，我们假设 [18F]FPA 有效地积聚在受伤的心脏中，可用于心脏疾病早期表现的成像 在不可逆的心脏损伤和重塑之前发生的疾病。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，2) 研究 ACSS1 在解释心力衰竭中的作用 [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。在建设我们的 了解后，我们可以开发这些示踪剂的精确应用，以对心力衰竭以及其他疾病进行成像 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。他将获得的技术、概念和实践知识将促进这些工作 在奖学金培训过程中。