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: 10420091
• 负责人: Frederick H Epstein
• 金额: $ 64.9万
• 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/10420091
• 关键词: Acceleration; Accounting; Address; Adenosine; Adipose tissue; Anti-Inflammatory Agents; Cardiac; Cardiovascular Diseases; Cells; Coronary; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Dictionary; Diet; Endothelium; Engineering; Evaluation; Event; Exhibits; Fatty Acids; Fatty acid glycerol esters; Female; Gender; Human; Image; Impairment; Inflammatory; Investigation; Knock-out; Lead; Least-Squares Analysis; Link; Lipids; Magnetic Resonance Imaging; Mediator of activation protein; 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; Pharmacology; Play; Positron-Emission Tomography; Protocols documentation; Protons; Reference Standards; Resolution; Rest; Role; Saturated Fatty Acids; Signal Transduction; Sucrose; System; Testing; Tissues; Transgenic Organisms; Triglycerides; base; cardiac magnetic resonance imaging; clinical effect; high risk; human subject; imaging modality; improved; in vivo; inhibitor; macrophage; mortality; mouse model; novel marker; 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 该提案旨在促进我们对冠状动脉微血管疾病（CMD）的理解和治疗 通过开发新的成像方法及其应用， 疾病机制（在小鼠模型中）和药理学治疗的评价（在小鼠和 人类）。CMD定义为内皮非依赖性冠状动脉微血管反应性受损， 通过静息和腺苷定量心肌灌注储备（MPR）成像进行无创评估 PET或MRI。虽然越来越多的认识，导致CMD的机制是不完全理解 并且没有既定的治疗方法。使用临床前MRI，我们已经表明，高脂饮食的小鼠， 蔗糖饮食（HFHSD）发展CMD，也发展增加心外膜脂肪组织（EAT），一个储存器 脂质和炎症细胞以及与心肌共享微循环的介质。我们 初步数据显示，iNOS-/-小鼠完全免受HFHSD-induced CMD.由于iNOS与M1极化巨噬细胞密切相关，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 SFAs触发M1巨噬细胞 极化，增加促炎介质和iNOS，并导致冠状动脉微血管氧化 应力和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）和脂肪组织体积和脂肪酸组成。后者 方法（脂肪酸组成的MRI）尚未应用于EAT或加速在心脏中的有效使用。 MRI方案。最后，已知对心血管疾病具有有益临床作用的SGLT 2抑制剂， 在CMD的临床前研究中显示出前景;然而，SGLT 2抑制剂对CMD和其他 参数和作用机制在小鼠和人类患者中仍然未知。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组成（FAC）MRI 组织.具体目标2是使用基因修饰的小鼠来测试以下假设：（a）抗炎药， 脂肪酸组合物减少CMD，并且（B）巨噬细胞表达的iNOS在CMD中起中心作用， 到HFHSD。并且，具体目的3是在小鼠和人类中检验SGLT 2抑制降低 CMD，并将该机制与EAT和iNOS联系起来。成功实现这些目标将：（a） 用于EAT的FAC成像的广泛适用的MRI方法，（B）使用成像来促进我们对EAT的FAC成像的理解。 CMD的细胞和分子机制，和（c）证明疗效和机制， 用于治疗CMD的SGLT 2抑制。