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.

项目摘要 该建议旨在提高我们对冠状动脉微血管疾病（CMD）的理解和治疗 通过开发新成像方法及其使用，研究了潜在的细胞和分子 疾病机制（在小鼠模型中）和药理学疗法的评估（在小鼠和 人类）。 CMD被定义为受损内皮依赖性冠状动脉微血管反应性，IS 通过使用REST和腺苷的定量心肌灌注储备（MPR）成像进行非侵入性评估 宠物或MRI。虽然越来越认识，但引起CMD的机制不完全理解 而且没有既定的疗法。使用临床前MRI，我们已经表明小鼠喂高脂肪高 蔗糖饮食（HFHSD）开发CMD，并且还会发展出心外膜脂肪组织（EAT），一种储层 与心肌具有微循环的脂质和炎症细胞和介体的膜片。我们的 初步数据表明，iNOS - / - 小鼠完全保护了HFHSD诱导的显着发现 CMD。因为iNOS与M1极化巨噬细胞密切相关，饱和脂肪酸（SFA）为 M1巨噬细胞极化的关键触发器，我们假设吃SFAS触发M1巨噬细胞 极化，增加促炎性介体和iNOS，并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）以及脂肪组织体积和脂肪酸组成。后者 方法（脂肪酸成分的MRI）尚未应用于饮食或加速以有效地用于心脏 MRI协议。最后，SGLT2抑制剂，已知对心血管疾病具有有益的临床作用， 在CMD的临床前研究中表现出了希望；但是，SGLT2抑制剂对CMD和其他的影响 在小鼠和人类患者中，参数和作用机制均尚不清楚。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组成（FAC）MRI 组织。具体目的2是使用遗传改性小鼠测试（a）抗炎的假设 脂肪酸组成减少了CMD和（B）巨噬细胞表达的Inos在CMD中起着核心作用 到HFHSD。并且，具体目的3是在小鼠和人类中检验假设，即SGLT2抑制减少了 CMD，并将其饮食和iNos链接起来。这些目标的成功完成将（a）发展 广泛适用的MRI方法用于FAC的饮食成像，（b）使用成像来促进我们对 CMD的细胞和分子机制，（c）证明了功效和机制 SGLT2抑制CMD的治疗。