基于蒽环类化疗药物心脏毒性早期分子水平改变的三维斑点追踪显像研究

Anthracycline-containing chemotherapy results in a 57% incidence of cardiac dysfunction. The drug induced myocardial damage is usually irreversible, 98% of which occurred within the first year. It has been demonstrated that echocardiographic three-dimensional speckle tracking imaging (3DSTI) can detect the subtle cardiac insufficiency beyond the traditional methodology. However, up till now, the most valuable parameters of 3DSTI for predicting cardiotoxicity caused by anthracycline remains unclear. In the previous study, we found that the rotation parameters of 3DSTI had changed prior to the other echocardiographic index in newly diagnosed lymphoma patients received anthracycline treatment. Since rotation parameters of 3DSTI can reflect the motion and interaction between epi- and endocardial muscle fibers simultaneously, we hypothesized that rotation parameters of 3DSTI could sensitively detect the early transmural cardiac toxicity effect of anthracycline. Based on the above theory, this research is designed to build an animal model of anthracycline-induced cardiotoxicity, screen and verify the most valuable 3DSTI parameters, identify the early myocardial mitochondrial dysfunction and apoptosis by 99mTc-MIBI SPECT/CT fusion and 18F-Annexin V PET/CT imaging dynamically. We plan to use the ultra-sensitive serum markers of cardiac injury and pathologic examinations for the definitive diagnosis of the myocardial damage. We believe that our proposed model will combine the latest echocardiographic methods with the new advances in molecular biology of nuclear medicine to detect the early and subtle toxicity of the anthracycline administration, and select the optimal 3DSTI parameters for the clinical utilization in the lymphoma patients. The goal is to provide novel and verified approaches to noninvasively monitor and notice the cardiac toxicity in the earliest phase possible.

接受蒽环类药物化疗的患者57%出现心功能受损，98%发生于第一年，且难以逆转。三维斑点追踪显像（3DSTI）可发现传统方法难以检测的细微心功能改变，但有效预测蒽环类药物早期心脏毒性的具体指标尚不确定。申请人前期研究发现，淋巴瘤患者行蒽环类药物化疗后，3DSTI扭转参数率先改变。由此推测，3DSTI扭转参数因可同时反映心内/外膜下肌纤维的运动与相互作用，所以能敏感评估蒽环类药物累及心肌全层的毒性损伤。本项目拟建立蒽环类药物心脏毒性动物模型，采用放射性核素活体99mTc-MIBI SPECT/CT显像及18F-Annexin V PET/CT显像，指示心肌细胞早期线粒体功能改变及凋亡，同时结合血清心肌损伤指标和病理检查，将超声形态功能改变与蒽环类药物心脏毒性的分子生物学进程联系在一起，直接对比、筛选3DSTI最优参数，并在淋巴瘤患者中验证，为建立监测肿瘤治疗相关心脏病变的无创方法提供新的思路。

以阿霉素为代表的蒽环类化疗药物已被广泛运用于治疗多种恶性肿瘤疾病，然而其剂量依赖性的心脏毒性包括心肌损伤造成的心功能受损，引起了肿瘤心脏病学界的关注。三维斑点追踪显像(3DSTI)可发现传统方法难以检测的细微心功能改变，另外血清学标志物也有助于监测蒽环类药物的早期心脏毒性。本项目通过建立比格犬阿霉素心脏毒性模型，利用3维超声影像技术同时结合血清心肌损伤标志物及病理检查，筛选早期心脏毒性的3DSTI敏感指标。同时，通过建立了采用蒽环类药物化疗的淋巴瘤患者临床数据库，并随访心脏超声三维斑点追踪显像，进一步验证3DSTI 敏感参数对蒽环类心脏毒性的预测价值，确定3DSTI的诊断阈值。本课题的研究结果发现包括：（1）成功建立了比格犬阿霉素心脏毒性模型，表现为阿霉素化疗在T5出现的左室射血分数（LVEF）显著下降。（2）比格犬阿霉素心脏毒性模型中，右心室基底段横向直径（RVD1）和 右心室中段横向直径（RVD2）在 T5 显著增加，扩大的右心室容积被诱导。（3）比格犬阿霉素心脏毒性模型中，血清心肌损伤标志物cTnT在T3就有显著性提高，并在T5时升高更显著，提示血清心肌损伤标志物可作为早期监测蒽环类心脏毒性的可靠指标。（4）比格犬阿霉素心脏毒性模型心脏病理结果显示心肌早期多灶性受累并伴有肥大、心肌纤维空泡化和心肌细胞间质纤维化，提示阿霉素造成的心脏损伤多成弥漫性，纤维化改变。（5）通过对82例淋巴瘤患者进行回顾性分析，发现超声多普勒Tei指数(TDI)、二尖瓣环峰值收缩速度(Sm)结合血清高敏心肌肌钙蛋白T(hs-cTnT)水平可以监测蒽环类药物的早期心脏毒性。（6）3DSTI分析左心室有助于了解淋巴瘤患者蒽环类药物化疗后左室壁节段性损害和左心室损害的可能过程。（7）三维超声心动图（3DE）测量的RV应变和容积与随后右室射血分数（RVEF）的变化相关，可用于预测蒽环类药物右心功能的变化。（8）在接受蒽环类药物治疗的淋巴瘤患者中，基于三维回声的%∆RVEF和%∆RVESV的评估是导致心脏不良结局事件的显著相关因素。