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.

项目摘要 已知非糖尿病患者衰老心脏中的胰岛素抵抗（IR）是由心脏内的脂肪积累促进的。 在没有肥胖或缺乏体力活动的情况下衰老的心肌。重要的是，这些变化使 老年心肌更易发生心力衰竭和猝死。同样，梗死心肌的老化 在非糖尿病受试者中通常伴有心肌瘢痕组织中的脂肪积聚（脂肪瘤性 化生，LM）。然而，LM是否影响心肌IR，仍然未知。最近的研究使用了 非糖尿病大鼠模型已经证明了心脏慢性MI中选择性心肌IR的直接证据 失败然而，目前还不清楚这些MI是否也有LM。 心肌梗死后心脏炎症是一种慢性低度无菌性炎症状态，在心肌梗死后心脏炎症反应中起关键作用。 心力衰竭的发作和进展。这是一个肥大细胞（MC）和巨噬细胞（M Φ）驱动的过程，其特征在于 通过促炎和抗炎反应之间的复杂平衡。同样重要的是， 脂肪组织（AT）内的MC和促炎性M1 M Φ现在被认为是肥胖的标志。 导致脂肪细胞葡萄糖转运蛋白（GLUT4）表达减少的相关低度炎症 全身IR通常在非糖尿病心肌梗死后缺血患者中观察到， 心肌病然而，这些受试者是否也表现出心肌IR和/或LM尚不清楚。 MC和M Φ在整个炎症过程中的代谢状态与其表型密切相关。 虽然活化的MC和M1 M Φ高度依赖于作为能量底物的葡萄糖，但抗炎M2 M Φ在活化的MC和M1 M Φ中的作用是非常重要的。 M Φ优先由脂肪酸β-氧化提供燃料。脂质超载和胰岛素（高）刺激各有 已被证明可促进MC活化、M1极化和M Φ泡沫细胞形成，从而启动 动脉粥样硬化形成的过程。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和脂质负载的M1 M Φ均已被证实 在MI亚急性期以外的梗死区域。然而，他们之间的长期命运，相互作用， 两个，他们各自的作用在LM和/或IR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的选择，以评估 心肌免疫代谢状态和诊断心肌特异性IR，定量心脏MR（qCMR）是 现在被广泛接受为定量估计梗塞大小和组织组成的金标准。 在此，我们建议使用18FDG-PET/qCMR联合成像来评估MC稳定对 猪模型中MI的代谢表型和重塑。