胶原分子靶向MR成像评价糖尿病心肌病及TGF-β1模拟肽抗纤维化疗效研究

In recent years, diabetes mellitus has become an epidemic and now represents one of the most prevalent disorders. Diabetic cardiomyopathy (DCM) is an important but less well-recognized complication of longstanding diabetes that is associated with significant mortality at the end stage. The clinical features of DCM include insidious onset, quick progress and poor prognosis, and the precisely diagnosis still depends on biopsy. The pathological basis of DCM is the excessive deposition of extracellular collagen I, which results in diffuse progressive cardiac fibrosis. Therefore, there is a major unmet medical need to quantify fibrosis noninvasively to facilitate early diagnosis of cardiac fibrosis and provide a means to monitor disease progression. In the current design, we intend to use the GKWHCTTKFPHHYCLY-Gd-GOTA, which could bound reversibly and non-saturably to type I collagen, as the magnetic resonance (MR) contrast agent. Using cardiac T1 mapping, myocardial extracellular volume fraction (ECV) will be measured to assess the severity of fibrosis in the molecular level. We also use the P144 to interfere with TGF-β1 binding to its cellular receptors and block the biological activity of this cytokine, which is the most important pathway involved in synthesis of collagen I. The imaging indexes will be verified by histopathology. So we can non-invasively and dynamically monitor the progress of fibrosis and the intervene effects in vivo. Therefore, the study program may be helpful to provide the theory and method to diagnose DCM at the early stage and the effect of intervention in time.

糖尿病心肌病（DCM）是晚期糖尿病患者死亡的重要原因，DCM起病隐匿、进展快、预后差，准确诊断仍依赖活检证实。DCM病理基础为细胞外基质内I型胶原蛋白过度蓄积，导致弥漫性进行性心肌纤维化。若能精确测定I型胶原蛋白含量，进而确定纤维化严重程度，就能进行DCM分期、预后判断及疗效监测。目前临床上尚缺乏一种活体、无创精确检测心肌胶原的方法。因此，本研究拟采用GKWHCTTKFPHHYCLY-Gd-GOTA-MR-T1Mapping成像技术测定I型胶原含量、从分子水平定量DCM纤维化严重程度，并利用TGF-β1模拟肽/P144阻断I型胶原合成的共同分子通路，干预前后的影像学检测指标与组织学活检做相关分析来验证其准确性，从而实现在体、无创、动态监测DCM纤维化进程并验证多功能分子靶向干预效果，为DCM的早期诊断和及时干预提供理论及方法学依据。

本研究已完成对T2DM病人心脏结构、功能和组织特征改变的研究。在结构研究中发现，T2DM病人存在左室同心圆型重构，心内膜下复杂程度增加；在功能研究中发现，T2DM病人存在左室亚临床舒张功能减低，左房功能减低；在组织特征学上发现，T2DM病人存在左室心肌弥漫性纤维化。上述结构、功能和㢟特征学的改变均有可能成为T2DM病人的影像学标记，达到了预期的研究目标。