小鼠糖尿病心肌纤维化磁共振特征及Nrf2心肌保护的研究

Diabetic cardiomyopathy (DCM) as one of diabetic complications is an important cause of mortality for diabetic patients. Myocardial fibrosis (MF) is a major pathological feature of DCM. We previously confirmed that cardiac magnetic resonance (CMR) can qualitatively and quantitatively assess cardiac morphology, function, and MF in DCM animal models. It is also confirmed that sulforaphane (SFN) prevents diabetes-induced cardiac oxidative damage by up-regulated NFE2-related factor 2 (Nrf2) expression and function, leading to the prevention of DCM; however, due to the lack of a sensitive diagnostic approach to detect the early fibrotic effects in the heart, it remains impossible for us to explore when we can treat these diabetic mice with SFN to revise or stop the MF process. Therefore, three objectives of this study are: (1) To establish criterial database of the earliest diagnosis for MF, based on CMR’s morphologically and functionally quantitative measurements of MF in diabetic and age-matched healthy mice by dynamically performing CMR imaging (monthly) and directly comparing these CMR data with the results, in parallel, collected dynamically from the molecular, histopathological and functional examinations during the 6-month period; (2) To validate the accuracy and sensitivity of the CMR criterial database established in study (1) by comparing CMR data with cellular, histopathological and functional measurements using Nrf2-KO and Nrf2-cTG transgenic mice that are capable of accelerating or slowing-down DM-MF progression relative to their WT diabetic mice. (3) To establish the CMR criteria of diabetic MF when SFN treatment provides the best therapeutic effect on diabetic MF process, by treating diabetic mice with SFN starting at different times from the 1st to the 5th months of diabetes along with CMR imaging collections. This study will reveal the best therapeutic effect at certain time intervals between treatment and the end of study (6th month of diabetes), and at this time-point, the CMR comprehensive criteria will be used as the guide to treat diabetic mice with SFN, and will be potentially extrapolated to diabetic patients for their DCM prevention and/or therapy in the future.

糖尿病心肌病（DCM）是导致糖尿病（DM）患者死亡重要原因之一，其主要病理特征是心肌纤维化（MF）。我们前期研究证实心脏磁共振（CMR）可检测DM动物心脏形态、功能和MF。有研究提示萝卜硫素（SFN）通过上调心肌Nrf2表达，抑制氧化应激反应进而保护心肌。但由于缺乏MF早期检测手段，SFN在减缓或终止DM-MF进程中的作用尚不清楚。本研究（1）对DM小鼠行CMR评价心脏形态、功能和MF变化，与病理和超声等结果对照，建立CMR对模型早期定量检测标准；（2）利用Nrf2-KO （DCM易感）和Nrf2-cTG（DCM抵抗）小鼠获得影像和病理信息，验证CMR早期定量检测标准的准确性和敏感性；（3）基于CMR早期定性和定量标准，明确SFN干预延缓或终止DM-MF进程最佳时间窗及MF不可逆时间窗。为未来利用CMR选择最佳SFN治疗时机、预防 DCM发生、改善DM预后和新药研究提供技术支撑。

糖尿病心肌病(Diabetic Cardiomyopathy, DCM)是糖尿病微血管病变独立并发症，也是导致糖尿病患者心脏衰竭甚至死亡的主要原因之一。心肌纤维化是导致 DCM 舒张功能不全或心力衰竭的主要病理生理基础。研究表明ECV是弥漫性心肌纤维化敏感的影像标志物，更高的ECV预示着更严重的心肌收缩和舒张功能障碍。 .本研究应用CMRI T1 mapping和CMR-FT技术，定量分析1型糖尿病（T1DM）和2型糖尿病（T2DM）模型心脏早期弥漫性心肌纤维化（DMF）和早期心功能改变，揭示糖尿病心肌病（DCM）心肌纤维化的影像学特征，为早期预防及治疗提供影像学依据。研究结果表明随着糖尿病病程的进展，T1DM和T2DM组ECV值逐渐升高，并于12周时较对照组出现统计学差异（ECV T1DM 32.5±1.6 VS control 28.1%±1.8%,P=0.002；T2DM 31.1%±1.2% VS control 28.1%±1.8%, P=0.044），早于心功能出现改变，且ECV值和CVF值呈高度相关（T1DM r=0.861；T2DM r=0.849）。同时，T2DM 组小鼠LV-GCS呈下降趋势，差异有统计学意义；与对照组相比，T2DM 组小鼠LV-GCS于第20th组间出现差异，早于EF差异时间（第24 W）。此外，与对照组比较，随糖尿病病程进展，T1DM和T2DM组E/E’逐渐升高，E/A 和E’/A’逐渐减低。此外，GRS、GCS、Radial strain rate和Circus strain rate逐渐减低，其中T1DM较T2DM更早出现GCS、Circus strain rate减低（T1DM 12W，T2DM 16W）。ECV与GCS、Circus strain rate强负相关，ECV与E/E’强正相关。.本研究证实CMRI T1mapping可在DCM早期准确检测弥漫性心肌纤维化，ECV值是定量心肌纤维化程度影像学敏感标志物，可动态检测DCM小鼠心肌组织学特征。同时，T2DM小鼠早期即出现心肌间质纤维化和心肌力学改变，其左心室整体周向应变较EF更早反应DCM心功能改变.同时，前期研究结果为正在进行CMR选择最佳SFN治疗时机、预防DCM发生、改善DM预后和新药研究奠定坚实基础。