Multiparametric MRI for the investigation of coronary microvascular disease

项目总结 这项建议旨在促进我们对冠状动脉微血管疾病(CMD)的认识和治疗 通过开发新的成像方法及其应用来研究潜在的细胞和分子 疾病机制(在小鼠模型中)，以及药物治疗的评价(在小鼠和 人类)。CMD被定义为内皮非依赖性冠状动脉微血管反应性受损， 静息和腺苷定量心肌灌注储备(MPR)显像无创性评价 宠物或核磁共振。虽然越来越多的人认识到引起CMD的机制，但尚不完全清楚 而且目前还没有既定的疗法。使用临床前核磁共振，我们已经表明，高脂肪高饮食的小鼠 蔗糖饮食(HFHSD)会发展成CMD，也会导致心外膜脂肪组织(EAT)增加，这是一种蓄水池 与心肌共享微循环的脂类、炎性细胞和介质。我们的 初步数据显示，iNOS-/-小鼠完全免受HFHSD诱导的保护 CMD。因为iNOS与M1极化的巨噬细胞密切相关，而饱和脂肪酸(SFA)是 M1巨噬细胞极化的关键触发因素，我们假设食用SFA会触发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 应激和CMD。MRI非常适合研究这一系统，因为MRI可以定量腺苷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(脂肪酸组成的磁共振成像)尚未应用于EAT或加速在心脏中的有效使用 核磁共振成像方案。最后，SGLT2抑制剂，已知对心血管疾病有有益的临床效果， 在CMD的临床前研究中显示出希望；然而，SGLT2抑制剂对CMD和其他 在小鼠和人类患者中，参数和作用机制仍不清楚。在我们的项目中， 具体目的1是建立和验证心外膜脂肪的加速脂肪酸组成(FAC)磁共振成像 组织。具体目标2是使用转基因小鼠来测试以下假设：(A)一种抗炎药物 脂肪酸组成减少CMD和(B)巨噬细胞表达iNOS在CMD中起核心作用 向HFHSD致敬。而且，具体目标3是在小鼠和人类身上测试SGLT2抑制减少 Cmd，并将EAT和iNOS的机制联系起来。这些目标的成功实现将(A)发展 广泛应用的磁共振成像方法用于EAT的FAC成像，(B)使用成像来促进我们对 CMD的细胞和分子机制，以及(C)证明了黄连的疗效和机制。 SGLT2抑制对CMD的治疗作用。

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.