Multiparametric PET/MRI Assessment of Mast Cell Stabilization Effects on Inflammaging and Glucose Utilization in Infarcted Myocardium

多参数 PET/MRI 评估肥大细胞稳定对梗塞心肌炎症和葡萄糖利用的影响

• 批准号: 10650676
• 负责人: MARILYN ADER
• 金额: $ 83.49万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650676
• 关键词: Adipocytes; Adipose tissue; Aftercare; Aging; Animal Model; Anti-Allergic Agents; Anti-Inflammatory Agents; Attenuated; Cardiac; Cardiomyopathies; Cell Degranulation; Cell membrane; Cholesterol; Chronic; Cicatrix; Coculture Techniques; Complex; Defect; Deposition; Diagnosis; Equilibrium; Event; Exhibits; Family suidae; Fatty Acids; Fatty acid glycerol esters; Foam Cells; Glucose; Glucose Clamp; Glucose Transporter; Goals; Heart; Heart Injuries; Heart failure; High Prevalence; Hyperinsulinism; Impairment; Infarction; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Ischemia; Link; Lipids; Loratadine; Macrophage; Magnetic Resonance Imaging; Measurement; Metabolic; Metaplasia; Methods; Modeling; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Obesity; Pathologic; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Positron-Emission Tomography; Predisposition; Process; Rattus; Reproducibility; Role; Sterility; Stress; Sudden Death; Tissues; Ventricular Remodeling; aged; atherogenesis; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose disposal; glucose uptake; imaging approach; imaging modality; improved; injured; insulin sensitivity; mast cell; metabolic phenotype; non-diabetic; non-invasive imaging; novel; novel therapeutic intervention; oxidation; physical inactivity; porcine model; senescence; uptake

PROJECT SUMMARY Insulin resistance (IR) in aging hearts of nondiabetics is known to be promoted by fat accumulation within senescent myocardium in the absence of obesity or physical inactivity. Importantly, these changes make the aged myocardium more susceptible to heart failure and sudden death. Similarly, aging of infarcted myocardium in nondiabetic subjects is commonly accompanied by fat accumulation in myocardial scar tissue (lipomatous metaplasia, LM). However, whether LM influences myocardial IR, remains unknown. Recent studies using a nondiabetic rat model have demonstrated direct evidence of selective myocardial IR in chronic MIs with heart failure. However, it remains unknown whether these MIs also had LM. Cardiac inflammaging post-MI is a state of chronic low-grade sterile inflammation that plays a key role in the onset and progression of heart failure. It is a mast cell (MC)- and macrophage (MΦ)-driven process characterized by a complex balance between pro- and anti-inflammatory responses. Equally important, the preponderance of MC and proinflammatory M1 MΦ within adipose tissue (AT) is now recognized as a hallmark of obesity- associated low-grade inflammaging which leads to reduced expression of adipocyte glucose transporter (GLUT4) and systemic IR. Systemic IR has been commonly observed in nondiabetic patients with ischemic post-MI cardiomyopathy. However, whether these subjects also exhibit myocardial IR and/or LM, is unknown. Metabolic state and the phenotype of MC and MΦ throughout the inflammatory process are tightly linked. While activated MC and M1 MΦ are highly dependent on glucose as an energy substrate, anti-inflammatory M2 MΦ are preferentially fueled by fatty acid β-oxidation. Lipid-overloading and insulin (hyper) stimulation have each been demonstrated to promote MC activation, M1 polarization, and MΦ foam cell formation, thus initiating the process of atherogenesis. Moreover, the pro-atherogenic effects of MCs were shown to be successfully abolished via MC membrane stabilization. Notably, MC and lipid-laden M1 MΦ have each been demonstrated in infarcted territory beyond subacute phase of MI. However, their long-term fate, the interaction between the two, and their respective roles in LM and/or IR remain unknown. While 18F-fluorodeoxyglucose (18FDG) PET has emerged as a non-invasive imaging of choice to assess myocardial immunometabolic state and to diagnose myocardium-specific IR, quantitative cardiac MR (qCMR) is now widely accepted as the gold standard for the quantitative estimation of infarct size and tissue composition. Herein, we propose to use a combined 18FDG-PET/qCMR imaging to evaluate the effects of MC stabilization on metabolic phenotype and remodeling of MI, in a porcine model.

项目概要 众所周知，非糖尿病患者衰老心脏中的胰岛素抵抗 (IR) 是由体内脂肪堆积所促进的。 重要的是，在没有肥胖或缺乏身体活动的情况下，这些变化会导致心肌衰老。 老化的心肌更容易发生心力衰竭和猝死，同样，梗死的心肌也会老化。 在非糖尿病受试者中，通常伴有心肌疤痕组织中的脂肪堆积（脂肪瘤） 化生 (LM) 然而，LM 是否影响心肌 IR，目前尚不清楚。 非糖尿病大鼠模型已证明慢性心梗中选择性心肌 IR 的直接证据 然而，目前尚不清楚这些 MI 是否也有 LM。 心肌梗死后心脏炎症是一种慢性低度无菌炎症状态，在心肌梗死后的心脏炎症中发挥着关键作用。 心力衰竭的发生和进展是肥大细胞（MC）和巨噬细胞（MΦ）驱动的过程。 同样重要的是，促炎反应和抗炎反应之间存在复杂的平衡。 脂肪组织 (AT) 内的 MC 和促炎性 M1 MΦ 现在被认为是肥胖的标志 - 相关的低度炎症，导致脂肪细胞葡萄糖转运蛋白（GLUT4）表达减少 全身性 IR 常见于患有心肌梗死后缺血性的非糖尿病患者。 然而，这些受试者是否也表现出心肌 IR 和/或 LM 尚不清楚。 整个炎症过程中MC和MΦ的代谢状态与表型紧密相连。 虽然激活的 MC 和 M1 MΦ 高度依赖葡萄糖作为能量底物，但抗炎 M2 MΦ 优先由脂肪酸 β-氧化和胰岛素（过度）刺激提供能量。 已被证明可以促进 MC 活化、M1 极化和 MΦ 泡沫细胞形成，从而启动 此外，MCs 的促动脉粥样硬化作用被证明是成功的。 通过 MC 膜稳定化消除 值得注意的是，MC 和载脂 M1 MΦ 均已被证明。 然而，在 MI 亚急性期之后的梗塞区域中，它们之间的相互作用是长期的。 两个，它们各自在 LM 和/或 IR 中的作用仍然未知。 虽然 18F-氟脱氧葡萄糖 (18FDG) PET 已成为一种非侵入性成像评估的选择 心肌免疫代谢状态和诊断心肌特异性 IR，心脏 MR (qCMR) 是定量的 现在被广泛接受为定量估计梗死面积和组织成分的金标准。 在此，我们建议使用 18FDG-PET/qCMR 组合成像来评估 MC 稳定对 猪模型中 MI 的代谢表型和重塑。