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

项目摘要 该项目的总体目标是评估一种新型药物的有效性。 使用定量多参数磁共振成像（qMRI）治疗心肌梗死（MI）。 心肌梗死是世界范围内死亡和残疾的主要原因。紧急再灌注闭塞动脉以恢复 心肌血流量是急性血栓性MI（AMI）的临床处理的中心。然而，在这方面， 罪犯动脉的再通也可能通过引起微血管阻塞而导致意外损伤 (MVO)急性期心肌内出血（IMH）和水肿。在慢性心肌梗死的情况下，铁 在梗塞心肌中经常观察到沉积和脂肪积累（脂肪瘤性化生，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）的强预测因子。到目前为止， 然而，目前还没有有效的治疗策略来减轻MVO、IMH、慢性铁缺乏症和慢性铁缺乏症。 沉积或再灌注后LM。肥大细胞（MC）来源于血液，多能造血干细胞， 祖细胞，一旦位于组织中，在局部细胞因子的影响下分化为最终表型。 微环境MC一般通过释放胞质内毒素来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 显示脑缺血后血肿生长、水肿扩大和整体神经损伤- 早期应用MC稳定剂治疗可减少再灌注，已知MC稳定剂可抑制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证据， MC参与泡沫细胞形成和斑块发展的证据。根据这些研究，我们 假设通过服用非处方抗过敏药物氯雷他定稳定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;以及 在慢性期减弱梗塞心肌的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。在这个建议中，我们的目的是验证MC的有效性 稳定剂氯雷他定对药物治疗后心脏结构和功能重塑的影响 使用成熟的qCMR技术，通过对急性和慢性MI的成像生物标志物进行时间随访，确定MI。 该项目的成功完成将提供初步验证，即早期氯雷他定干预具有 潜在的是一种新的治疗策略，预防心肌梗死后心力衰竭，我们的定量评估 多参数MRI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.