超声斑点追踪显像甄别蒽环类化疗药物早期心脏毒性的实验和临床研究

Anthracycline remains the most effective cytotoxic agent for the treatment of lymphoma, advanced breast cancer and other malignant tumors. But it has inevitable cardiac toxicities. It has been reported more than 50% patients treated with anthracycline had subclinical left ventricular dysfunction during the first year. So the detection of early cardiac damage plays an important role. There are no widely accepted noninvasive standards available for the identification of subclinical cardiac damage related with anthracycline yet. As new emerging echocardiographic techniques, two-dimensional(2D) and three-dimensional(3D) speckle tracking imaging(STI) allow for the assessment of left ventricular function in the longitudinal，radial and circumferential planes. Strain and strain rate derived from STI has been widely applied in the evaluation of heart function. Compared with conventional measurements, we have demonstrated 2D-STI could inspect subtle segmental systolic dysfunction and dyssynchrony of left ventricle in microembolism swine models whose LVEF showed no obvious change. Our hypothesis is that early cardiac injury caused by anthracycline maybe be investigated by STI since it is mild myocardial variation too. Firstly, we have conducted a pilot study. After intraperitoneal injection of adriamycin 2mg/w for 4 weeks, the rat's radial strain reduced from 46.7% to 34.6% while its LVEF remained almost stable. Secondly, since lymphoma is a common immune system malignancy which is usually treated using anthracycline, we have enrolled 40 adult patients with lymphoma. In 25 cases who have completed the whole chemotherapy, the analysis of 2D-STI revealed their left ventricular longitudinal strain deteriorated (-17.85±2.96% vs -16.56±1.71%, P=0.05) as well as circumferential strain (-20.68±2.05% vs -17.83±2.14%, P<0.05) while their LVEF remained unchanged (P>0.05) 1 week after the therapy. Based on the data above, our aim is: ① To build cardiac toxicity rat models using different dosage of anthracycline, analyze the correlation between 2D-STI parameters and serum levels of myocardial damage biomarkers- - high sensitive cardiac troponin T(hs-cTnT) and amin-n-terminal brain natriuretic peptide(NT-proBNP), compared with pathological examination. ② To continue the follow-up of patients with lymphoma who received anthracycline, investigate the correlation between 2D- and 3D-STI systolic and diastolic parameters and serum concentration of hs-cTnT and NT-proBNP. Meanwhile, to calculate the cut-off values of 2D- and 3D-STI parameters detecting early cardiac toxicity events which diagnosed according to the current clinical diagnosis standards. We are going to commit ourselves to reveal the STI index which can sensitively estimate early myocardial damage associated with anthracycline, for the clinical consideration to adjust the treatment, and it will be useful if these noninvasive echocardiographic standards could be extended to other chemotherapy drugs.

蒽环类化疗药物应用广泛，但其诱发的心肌损伤难以逆转。目前临床缺乏检测蒽环类早期心脏毒性的有效手段。我们前期发现，二维斑点追踪显像（2D-STI）可先于LVEF识别心肌微栓塞导致的左室功能异常。动物预实验及对淋巴瘤患者的初步随访结果显示，使用蒽环类后，2D-STI早期可检测到左室径向、纵向和环向应变降低。本研究拟建立不同剂量蒽环类大鼠心脏毒性模型，分析2D-STI参数与血清心肌损伤指标hs-cTnT、NT-proBNP以及心脏组织病理学的相关性。继续随访淋巴瘤蒽环类化疗患者，分析其2D-STI和三维斑点追踪显像（3D-STI）收缩及舒张功能参数的变化与hs-cTnT、NT-proBNP的相关性。并参照现行临床诊断标准，筛选出蒽环类早期心脏毒性临床事件，分析2D-和3D-STI参数鉴别早期心脏毒性临床事件的阈值。旨在为采用蒽环类治疗的患者提供无创、早期心脏毒性监测指标。

蒽环类药物显著提高了恶性肿瘤患者的生存率，但其不可逆的剂量累积性的心脏毒性不容忽视。左心室射血分数（LVEF）是监测药物所致心脏毒性最为常用的一项参数，但由于LVEF评价心功能敏感性差，且一旦出现LVEF降低，心肌病变已经难以逆转，因而不宜作为早期检测蒽环类药物心脏毒性的诊断指标。本课题研究结果发现：（1）经蒽环类药物化疗后20±9个月的患者，即使LVEF正常，仍存在舒张功能及收缩功能异常，表现为减速时间（DT）、等容舒张时间（IVRT）延长，左室整体及节段长轴应变及圆周应变下降。（2）在应用STI结合心脏生物学标志物的研究中发现，左室长轴应变（LS）降低率【（化疗后应变值-化疗前应变值）/化疗前应变值】与超敏肌钙蛋白（hs-cTnT）（化疗后hs-cTnT值-化疗前hs-cTnT值）之间相关性良好。并且，左室LS下降率是心脏毒性发生的独立预测因素。（3）在阿霉素诱导心脏毒性的Wistar大鼠模型中我们发现，基于2DSTI分析的径向应变与蒽环类药物所致心脏损害的病理表现和血清肌钙蛋白水平一致，提示左心室径向应变可以作为早期监测蒽环类药物所致的心脏损害的可靠指标。（4）蒽环类药物化疗后左心室扭转及同步性亦有显著变化：与化疗前相比，淋巴瘤患者蒽环类化疗2、4周期后左心室心尖段旋转、心底段旋转、整体旋转（Twist）及扭转（Torsion）进行性下降，心尖段与心底段旋转达峰时间延迟指数明显延长。其中，Torsion 与左心室射血分数相关性最显著。（5）蒽环类对右心系统亦有损害：蒽环类药物化疗后患者右心房舒张末面积（RAEDA）、收缩末面积（RAESA）、右心室舒张末面积（RVEDA）、收缩末面积（RVESA）在化疗6周期后显著增大。与此同时，右心室舒张末容积（RVEDV）、收缩末容积（RVESV）明显增大，右心室射血分数（RVEF）显著下降，但仍维持在正常范围内。（6）与2DSTE相比，3DSTE能在早期更敏感的评估心室功能减退：蒽环类化疗2周期后，3D 左心室长轴应变（LVLS）、圆周应变（LVCS）、右心室长轴应变（RVLS）均显著下降。相比之下，2D LVLS、LVCS、RVLS 在化疗2周期后差异无统计学意义。蒽环类化疗4周期后，2D LVLS、LVCS亦明显减低，但RVLS仍无明显差异。