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.

项目总结 众所周知，非糖尿病患者老化心脏中的胰岛素抵抗(IR)是由体内脂肪堆积促进的 在没有肥胖或缺乏运动的情况下衰老的心肌。重要的是，这些变化使得 老年心肌更容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堆积(脂肪瘤 化生，LM)。然而，LM是否影响心肌IR尚不清楚。最近的研究使用的是 非糖尿病大鼠模型显示慢性心肌梗死伴心脏损害时选择性心肌缺血再灌注的直接证据 失败了。然而，目前尚不清楚这些心肌梗死是否也有LM。 心肌梗死后心脏炎症是一种慢性低度无菌炎症状态，在心肌梗死后心脏炎症中起关键作用。 心力衰竭的发生和发展。这是一个肥大细胞(MC)和巨噬细胞(MΦ)驱动的过程，其特征是 通过在促炎和抗炎反应之间进行复杂的平衡。同样重要的是， 脂肪组织(AT)中的MC和促炎性M1 MΦ现在被认为是肥胖的标志。 相关的低级别炎症导致脂肪细胞葡萄糖转运体(GLUT4)表达减少 和系统性IR。急性心肌梗死后非糖尿病患者常可观察到全身性IR 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。 炎症过程中代谢状态与MC和M-Φ的表型密切相关。 而活化的MC和M1 MΦ高度依赖于葡萄糖作为能量底物，抗炎M2 M-Φ优先由脂肪酸β氧化提供燃料。脂质过载和胰岛素(高)刺激各有其作用 已证实可促进MC激活、M1极化和MΦ泡沫细胞的形成，从而启动 动脉粥样硬化的形成过程。此外，MCs的促动脉粥样硬化作用被证明是成功的。 通过MC膜稳定消除。值得注意的是，MC和富含脂质的M1 MΦ都已被证明 在心肌梗塞亚急性期以外的梗死区。然而，他们的长期命运，他们之间的互动 两种，它们在LM和/或IR中的作用尚不清楚。 而18F-氟代脱氧葡萄糖(18FDG)正电子发射计算机断层扫描(18FDG)已成为一种可供选择的无创成像方法 心肌免疫代谢状态和诊断心肌特异性IR，定量心脏磁共振(QCMR)是 现在被广泛接受为定量估计梗塞范围和组织成分的金标准。 在此，我们建议使用18FDG-PET/qCMR联合成像来评估MC稳定化对 在猪模型中，心肌梗塞的代谢表型和重塑。