Assessment of Mast Cell Degranulation in Infarcted Myocardium Using Quantitative Multiparametric MRI

使用定量多参数 MRI 评估梗死心肌中肥大细胞脱颗粒

• 批准号: 10643915
• 负责人: Ivan Cokic
• 金额: $ 82.69万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643915
• 关键词: Acute; Acute myocardial infarction; Adipose tissue; Aftercare; Aging; Animal Model; Anti-Allergic Agents; Arteries; Atherosclerosis; Attenuated; Biological Markers; Blood Vessels; Blood flow; Cardiac; Cardiovascular system; Cause of Death; Cell Degranulation; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Chronic; Chronic Phase; Cicatrix; Clinical; Clinical Management; Coculture Techniques; Collagen; Compensation; Cytoplasmic Granules; Deposition; Development; Early treatment; Edema; Event; Fatty acid glycerol esters; Foam Cells; Gadolinium; Goals; Growth; Heart Injuries; Heart failure; Hematoma; Hematopoietic stem cells; Hemorrhage; Histamine; Hypersensitivity; Infarction; Inflammation; Injury; Intervention; Iron; Longitudinal Studies; Loratadine; Low-Density Lipoproteins; Macrophage; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Mast Cell Stabilizer; Mediator; Metaplasia; Microcirculation; Muscle; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial tissue; Myocardium; Nervous System Trauma; Obstruction; Outcome; Pathologic; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Phenotype; Physiological; Pilot Projects; Prevention strategy; Proteoglycan; Reperfusion Therapy; Reporting; Reproducibility; Research; Role; Techniques; Tissues; Validation; Ventricular Remodeling; artery occlusion; blood-brain barrier permeabilization; disability; effective therapy; effectiveness evaluation; effectiveness validation; experimental study; imaging biomarker; imaging modality; improved; in vivo; injured; mast cell; myocardial injury; non-invasive imaging; novel; novel therapeutic intervention; pharmacologic; porcine model; prevent; response; therapeutically effective; thrombotic; uptake

PROJECT SUMMARY The overall objective of the proposed project is to evaluate the effectiveness of a novel pharmacological treatment of myocardial infarction (MI) using quantitative multiparametric magnetic resonance imaging (qMRI). MI is a major cause of death and disability worldwide. Urgent reperfusion of the occluded artery to restore myocardial blood flow is central to the clinical management of acute thrombotic MI (AMI). However, recanalization of the culprit artery may also result in unintended injury by causing microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and edema during the acute phase. In the setting of chronic MI, iron deposition and fat accumulation (lipomatous metaplasia, LM) are frequently observed in infarcted myocardium. All these biomarkers are strong predictors of major adverse cardiovascular events such as heart failure. To date, however, there have been no effective therapeutic strategies for attenuating either MVO, IMH, chronic iron deposition, or LM post-reperfusion. Mast cells (MC) are derived from blood-borne, multipotent hematopoietic progenitor cells that, once located in tissue, differentiate to a final phenotype under the influence of the local microenvironment. In general, MC exert their physiological and pathological functions by releasing cytoplasmic granules (degranulation) containing a variety of biologically active mediators. Recent experimental studies have shown that hematoma growth, edema expansion and overall neurological damage after cerebral ischemia- reperfusion can be reduced by early treatment with MC stabilizers, which are known to suppress MC degranulation. Equally important, atherosclerosis research over the last two decades has provided strong evidence for MC involvement in foam cell formation and plaque development. Based on these studies, we hypothesized that MC stabilization via the administration of over-the-counter anti-allergy medication loratadine reduces myocardial edema, IMH volume and improves myocardial microcirculation in the acute MI setting; and attenuates LM of infarcted myocardium in the chronic phase. Quantitative cardiovascular MR (qCMR) imaging has been widely used to characterize myocardial ischemia, hemorrhage, edema, inflammation, iron deposition, fat accumulation and other pathological conditions. In this proposal, we aim to validate the effectiveness of MC stabilizer loratadine on structural and functional cardiac remodeling post-pharmacotherapy in a porcine model of MI by temporally following imaging biomarkers of acute and chronic MI using well-established qCMR techniques. Successful completion of the project will provide initial validation that early loratadine intervention has the potential to be a novel therapeutic strategy for prevention of heart failure post-MI as evaluated by our quantitative multiparametric MRI approach.

项目概要 该项目的总体目标是评估一种新型药理学的有效性 使用定量多参数磁共振成像 (qMRI) 治疗心肌梗死 (MI)。 心肌梗死是全世界死亡和残疾的主要原因。闭塞动脉紧急再灌注以恢复 心肌血流对于急性血栓性心肌梗死（AMI）的临床治疗至关重要。然而， 罪魁祸首动脉的再通也可能通过引起微血管阻塞而导致意外伤害 （MVO）、心肌内出血（IMH）和急性期水肿。在慢性心梗的情况下，铁 梗塞心肌中经常观察到沉积和脂肪堆积（脂肪瘤化生，LM）。 所有这些生物标志物都是心力衰竭等主要不良心血管事件的有力预测因子。迄今为止， 然而，目前还没有有效的治疗策略来减轻 MVO、IMH、慢性铁 沉积，或 LM 再灌注后。肥大细胞 (MC) 来源于血源性多能造血细胞 祖细胞一旦定位在组织中，就会在局部细胞的影响下分化为最终表型 微环境。一般来说，MC通过释放细胞质发挥其生理和病理功能。 含有多种生物活性介质的颗粒（脱粒）。最近的实验研究 研究表明，脑缺血后血肿增长、水肿扩大和整体神经损伤 通过早期使用 MC 稳定剂治疗可以减少再灌注，众所周知，MC 稳定剂可以抑制 MC 脱颗粒。同样重要的是，过去二十年的动脉粥样硬化研究为我们提供了强有力的证据。 MC 参与泡沫细胞形成和斑块发展的证据。基于这些研究，我们 假设通过服用非处方抗过敏药物氯雷他定来稳定 MC 在急性 MI 情况下减少心肌水肿、IMH 体积并改善心肌微循环；和 减弱慢性期梗塞心肌的 LM。定量心血管 MR (qCMR) 成像 已广泛用于表征心肌缺血、出血、水肿、炎症、铁沉积、 脂肪堆积和其他病理状况。在本提案中，我们旨在验证 MC 的有效性 稳定剂氯雷他定对猪模型药物治疗后结构和功能性心脏重塑的影响 使用成熟的 qCMR 技术暂时跟踪急性和慢性 MI 的成像生物标志物来进行 MI。 该项目的成功完成将初步验证早期氯雷他定干预具有 根据我们的定量评估，有可能成为预防 MI 后心力衰竭的新治疗策略 多参数 MRI 方法。