立体定向射波刀放射治疗肥厚型心肌病的基础研究及临床探索

The basic research and clinical exploration on the stereotactic radiotherapy(cyber knife)in hypertrophic cardiomyopathy

目的探索立体定向射波刀放射治疗肥厚型心肌病的可行性、有效性及安全性。方法(1)有效照射剂量探索:原代培养的乳鼠心肌细胞于培养第4天,分别以20、30及40 Gy单次剂量体外射波刀照射,于照射后24、48及72 h光镜下观察细胞收缩活性及细胞死亡率。(2)室间隔放疗区域定位方法及安全性的整体动物研究:普通级成年雄性6月龄新西兰大耳兔26只,异丙肾上腺素0.3 mg·kg^(-1)·d^(-1)静脉注射方法制备心肌肥厚模型,心脏CT增强造影及心超获取心脏影像学数据,导入射波刀工作站中勾画自主动脉瓣下完整左心室结构作为放射靶区,以X-Sight脊柱追踪系统自动对射线进行实时校准,探索室间隔精确定位、追踪方法;随后随机分组按照0、20、30及40 Gy的剂量完成靶区照射。治疗前后超声心动图评估心肌肥厚情况,4周后处死动物获取心脏及其邻近组织开展病理研究、动态检测血清TnI、NT-proBNP改变量进行安全性评价。(3)临床放疗方法的探索:经华山医院伦理委员会批准,选取肥厚型心肌病合并房颤患者3例开展临床研究,根据基础实验数据制定放疗方案并实施射波刀放疗,随访收集临床数据,评估可行性、有效性及安全性,观察不良反应。结果(1)20 Gy以上剂量可抑制心肌细胞搏动,并存在剂量依赖性;20、30、40 Gy单剂量照射可作为合理的后续射波刀放射剂量梯度。(2)射波刀治疗4周后,各辐照组均未出现治疗相关的家兔死亡,且各家兔未有显著的体重、食欲、精神状态及大小便等情况改变。复查超声心动图参数:造模20~40 Gy组室间隔厚度及左室重量/体重比值均呈负增长;与造模0 Gy组相比,造模40 Gy组两者均具有显著性差异(P=0.01),照射野外组织未见明显损伤。(3)3例患者按照试验方案顺利完成室间隔肥厚区域心肌无创射波刀治疗,随访4周无严重不良反应。结论体外无创射波刀放疗减轻肥厚型心肌病室间隔肥厚技术可行性、有效性、安全性良好,可降低兔肥厚型心肌病模型的室间隔厚度及左室重量/体重比值,改善肥厚型心肌病患者的临床症状,均未对动物及临床患者造成严重不良反应,其临床疗效值得进一步探索。

Objective To explore the feasibility,safety and efficacy of stereotactic radiotherapy(cyber knife)for hypertrophic cardiomyopathy(HCM).Methods(1)The exploration of effective radiation dose:Neonatal rat cardiomyocytes were isolated and cultured for 4 days and radiated with 20 Gy,30 Gy and 40 Gy.The contraction ability and death rate were collected 24 h,48 h and 72 h after radiation under light microscope.(2)The animal research of the location of ventricular septum and safety:26 male 6-month-old New Zealand rabbits were applied.0.3 mg·kg-1·d-1 of isoproterenol was intravenously injected to induce HCM model.Imaging data were collected through enhanced CT and echocardiograph.The left ventricular structure under aortic valve was derived as target area.X-Sight spine tracking system was used for radiation calibration.Target area was radiated with randomly 0,20,30 and 40 Gy.Hypertrophic myocardium was evaluated by echocardiograph 4 weeks after radiation therapy.The animals were sacrificed for pathological research of heart and adjacent organs.Serum TnI and NT-proBNP were dynamically monitored for safety exploration.(3)Clinical exploration of cyber knife:Three HCM patients were recruited into the study approved by the Ethics Committee of Huashan Hospital.The protocol was determined based on the basic research.The patients accepted cyber knife therapy and was followed up.The feasibility,safety,efficacy and quality of life(QOL)were collected.Results(1)No less than 20 Gy of radiation could inhibit the contraction of cardiomyocytes with dose-dependency.20,30,40 Gy were reasonable doses for further research.(2)All groups of rabbits received cyber knife therapy.During 4 weeks of observation,there was no treatment-related death in each group.The weight,appetite,spirit state and defecation did not show any change in all groups.The interventricular septal diameter(IVSD)and the ratio of left ventricular mass to total body weight(LVM/BW)decreased in 20 Gy group,30 Gy group and 40 Gy group.Compared to 0 Gy group,40 Gy group was statistically different(P=0.01).No obvious injury was observed in adjacent organs.(3)The cyber knife therapy was managed to carry out on 3 patients.The QOL was increased.Data of echocardiograph were slightly improved.No severely adverse effects was observed during 4-week followup.Conclusion Cyber knife therapy for treating HCM is feasible,effective and safe.The therapy could decrease IVSD,LVM/BW in rabbits and increase the QOL of clinical patients without severe adverse effects.The clinical efficacy is worthy further exploration.