Multiparametric MRI for the investigation of coronary microvascular disease

多参数 MRI 用于研究冠状动脉微血管疾病

• 批准号: 10621313
• 负责人: Frederick H Epstein
• 金额: $ 78.34万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-12 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621313
• 关键词: Acceleration; Accounting; Address; Adenosine; Adipose tissue; Anti-Inflammatory Agents; Blood Vessels; Cardiac; Cardiovascular Diseases; Cells; Coronary; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Dictionary; Diet; Endothelium; Engineering; Evaluation; Event; Exhibits; FAT gene; Fatty Acids; Fatty acid glycerol esters; Female; Gender; Human; Image; Impairment; Inflammation Mediators; Inflammatory; Investigation; Knock-out; Least-Squares Analysis; Link; Lipids; Macrophage; Magnetic Resonance Imaging; Maps; Mediator; Metabolic syndrome; Methods; Microcirculation; Microvascular Dysfunction; Modeling; Molecular; Molecular Disease; Mus; Myocardial; Myocardial Ischemia; Myocardial perfusion; Myocardium; N-3 polyunsaturated fatty acid; NMR Spectroscopy; Obesity; Oxidative Stress; Patients; Play; Positron-Emission Tomography; Protocols documentation; Protons; Reference Standards; Resolution; Rest; Role; Saturated Fatty Acids; Signal Transduction; Sucrose; System; Testing; Tissues; Transgenic Organisms; Triglycerides; cardiac magnetic resonance imaging; clinical effect; high risk; human subject; imaging Segmentation; imaging modality; improved; in vivo; inhibitor; mortality; mouse model; novel marker; pharmacologic; pre-clinical; preclinical study; preservation; primary endpoint

Project summary This proposal seeks to advance our understanding and treatment of coronary microvascular disease (CMD) through the development of new imaging methods and their use investigating underlying cellular and molecular disease mechanisms (in mouse models), and in the evaluation of pharmacological therapy (in mice and humans). CMD is defined as impaired endothelial-independent coronary microvascular reactivity and is assessed noninvasively by quantitative myocardial perfusion reserve (MPR) imaging using rest and adenosine PET or MRI. While increasingly recognized, the mechanisms that cause CMD are incompletely understood and there are no established therapies. Using preclinical MRI, we have shown that mice fed a high fat high sucrose diet (HFHSD) develop CMD, and also develop increased epicardial adipose tissue (EAT), a reservoir of lipids and inflammatory cells and mediators that shares a microcirculation with the myocardium. Our preliminary data show the remarkable finding that iNOS-/- mice are completely protected from HFHSD-induced CMD. As iNOS is strongly associated with M1-polarized macrophages, and saturated fatty acids (SFAs) are key triggers of M1 macrophage polarization, we hypothesize that EAT SFAs trigger M1 macrophage polarization, increase proinflammatory mediators and iNOS, and lead to coronary microvascular oxidative stress and CMD. MRI is well suited to investigate this system, as MRI can quantify adenosine MPR, myocardial oxidative stress (preclinical), and adipose tissue volume and fatty acid composition. The latter method (MRI of fatty acid composition) has yet to be applied to EAT or accelerated for efficient use in a cardiac MRI protocol. Lastly, SGLT2 inhibitors, known to have beneficial clinical effects on cardiovascular disease, have shown promise in a preclinical study of CMD; however, the effects of SGLT2 inhibitors on CMD and other parameters and the mechanisms of action remain unknown in both mice and human patients. In our project, specific aim 1 is to develop and validate accelerated fatty acid composition (FAC) MRI of epicardial adipose tissue. Specific aim 2 is to use genetically-modified mice to test the hypotheses that (a) an anti-inflammatory fatty acid composition reduces CMD and (b) iNOS expressed by macrophages plays a central role in CMD due to HFHSD. And, specific aim 3 is to test the hypothesis, in mice and humans, that SGLT2 inhibition reduces CMD, and to link the mechanism to EAT and iNOS. The successful completion of these aims will (a) develop broadly applicable MRI methods for FAC imaging of EAT, (b) use imaging to advance our understanding of the cellular and molecular mechanisms underlying CMD, and (c) demonstrate the efficacy and mechanisms of SGLT2 inhibition for the treatment of CMD.

项目概要 该提案旨在增进我们对冠状动脉微血管疾病（CMD）的理解和治疗 通过新成像方法的开发及其使用来研究潜在的细胞和分子 疾病机制（在小鼠模型中），以及药物治疗的评估（在小鼠和 人类）。 CMD 被定义为内皮依赖性冠状动脉微血管反应性受损， 使用休息和腺苷通过定量心肌灌注储备 (MPR) 成像进行无创评估 PET 或 MRI。尽管人们越来越认识到导致 CMD 的机制尚不完全清楚 并且没有既定的治疗方法。使用临床前 MRI，我们发现小鼠喂食高脂肪 蔗糖饮食 (HFHSD) 会导致 CMD，并且还会导致心外膜脂肪组织 (EAT) 增加，这是一个储存库 脂质和炎症细胞以及与心肌共享微循环的介质。我们的 初步数据显示，iNOS-/- 小鼠完全免受 HFHSD 诱导的显着发现 命令。由于 iNOS 与 M1 极化巨噬细胞密切相关，而饱和脂肪酸 (SFA) M1 巨噬细胞极化的关键触发因素，我们假设 EAT SFA 触发 M1 巨噬细胞 极化，增加促炎介质和 iNOS，导致冠状动脉微血管氧化 压力和CMD。 MRI 非常适合研究该系统，因为 MRI 可以量化腺苷 MPR， 心肌氧化应激（临床前）、脂肪组织体积和脂肪酸组成。后者 方法（脂肪酸成分的 MRI）尚未应用于 EAT 或加速在心脏疾病中有效使用 MRI 协议。最后，已知对心血管疾病具有有益的临床效果的 SGLT2 抑制剂， 在 CMD 的临床前研究中显示出前景；然而，SGLT2 抑制剂对 CMD 和其他疾病的影响 在小鼠和人类患者中的参数和作用机制仍然未知。在我们的项目中， 具体目标 1 是开发和验证心外膜脂肪的加速脂肪酸成分 (FAC) MRI 组织。具体目标 2 是使用转基因小鼠来测试以下假设：(a) 抗炎药 脂肪酸组成可降低 CMD，并且 (b) 巨噬细胞表达的 iNOS 在 CMD 中发挥核心作用，因为 至 HFHSD。并且，具体目标 3 是在小鼠和人类中测试这一假设，即 SGLT2 抑制会降低 CMD，并将该机制与 EAT 和 iNOS 联系起来。成功完成这些目标将 (a) 发展 广泛适用于 EAT FAC 成像的 MRI 方法，(b) 使用成像来加深我们对 EAT 的理解 CMD 的细胞和分子机制，以及 (c) 证明了 CMD 的功效和机制 SGLT2 抑制用于治疗 CMD。