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

项目总结 拟议项目的总体目标是评估一种新型药理作用的有效性。 应用定量多参数磁共振成像(QMRI)治疗心肌梗死(MI) 心肌梗死是世界范围内死亡和致残的主要原因。闭塞动脉的紧急再通以恢复 心肌血流是急性血栓性心肌梗死(AMI)临床治疗的中心环节。然而， 罪犯动脉的再通也可能导致微血管阻塞，从而造成意外损伤。 急性期出现微静脉阻塞(MVO)、心肌内出血(IMH)和水肿。在慢性心肌梗死的背景下，铁 心肌梗死后可见脂肪沉积和脂肪堆积(脂肪瘤样化生，LM)。 所有这些生物标志物都是主要不良心血管事件(如心力衰竭)的有力预测指标。到目前为止， 然而，目前还没有有效的治疗策略来减轻MVO、IMH、慢性铁 再灌流后沉积，或LM。肥大细胞(MC)来源于血液传播的多能造血细胞。 祖细胞一旦定位在组织中，在局部细胞的影响下分化为最终的表型 微环境。一般说来，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(脱颗粒)。最近的实验研究表明 显示脑缺血后的血肿增长、水肿扩大和整体神经损害- 早期使用MC稳定剂可以减少再灌注，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提供了强有力的 MC参与泡沫细胞形成和斑块形成的证据。基于这些研究，我们 假设MC通过服用非处方药氯雷他定稳定下来 减少急性心肌梗死时的心肌水肿、IMH体积和改善心肌微循环； 减轻慢性期心肌梗死后的心肌肥厚。定量心血管磁共振(QCMR)成像 已被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情况。在本方案中，我们旨在验证MC的有效性 稳定剂氯雷他定对药物治疗后猪心脏结构和功能重构的影响 通过使用成熟的qCMR技术对急性和慢性心肌梗死的成像生物标志物进行时间跟踪。 该项目的成功完成将提供初步证实，早期氯雷他定干预具有 通过我们的定量评估，有可能成为预防心肌梗死后心力衰竭的一种新的治疗策略 多参数磁共振成像方法。

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.