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