药物对病毒性心肌炎小鼠模型的影响
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摘要
目的探讨阿托伐他汀对病毒性心肌炎的心肌保护作用及机制。
方法以柯萨奇病毒B3m(CVB3m)诱导的病毒性心肌炎Balb/c小鼠模型为研究对象。143只小鼠随机分为正常组(n=18),病毒组(n=60),阿托伐他汀对照组(n=15),阿托伐他汀治疗组(n=50)。正常组组和阿托伐他汀对照组腹腔无菌注射不含病毒的Eagel's培养液0.3ml。病毒组与阿托伐他汀治疗组腹腔单次接种0.3ml X 3×103 PFU/mL CVB3m。阿托伐他汀治疗组给予阿托伐他汀每天10mg/kg/d,病毒组给予等体积饮用水,分别以灌胃器给药,连续用药2周。用药后3、7、10、14、21、30天,检测超声心动图、苏木素-伊红染色(H&E, hematoxylin-eosine)观察心肌组织炎症浸润程度,电镜观察心肌心肌细胞及各种细胞器的变化。western blot及逆转录酶PCR (reverse transcriptase-Polymerase Chain Reaction, RT-PCR)方法检测心肌Fas蛋白及mRNA表达水平,TUNEL法(terminal-deoxynucleotidyl transferase mediated dUTP nick end labeling,脱氧核苷酸末端转移酶介导的dUTP末端缺口标记法)检测心肌细胞凋亡情况,酶联免疫吸附测定(ELISA, enzyme linked immunosorbent assay)方法检测血清心肌肌钙蛋白I (cardiac troponinl,cTnI)水平。
结果发现病毒性心肌炎小鼠攻毒后第3天开始出现症状,饮水进食减少,体重减轻。随后症状逐渐加重,第4天出现死亡；7-14天为死亡高峰。病毒组小鼠心脏超声提示射血分数在第7天开始出现异常下降,光镜与电镜可以观察到明显的病理改变。TUNEL法检测发现凋亡细胞增多,心肌炎小鼠血清cTnI增高。阿托伐他汀干预后显著提高病毒性心肌炎小鼠生存率(病毒组：治疗组为59.2%：87%,P=0.008)。阿托伐他汀治疗组可以改善小鼠心脏射血分数(病毒组比治疗组：第7天：69.82%：78.99%P<0.01；第14天：74.85%：83.50%P<0.01；第21天：70.78%：82.32%P<0.01；第30天：76.47%：82.69% P<0.01)。阿托伐他汀治疗组较病毒组可以明显减轻心肌组织炎症浸润,心肌病理组织学积分在第10,14,21,30天阿托伐他汀治疗组较病毒组减少。阿托伐他汀治疗组较病毒组显著降低各个时间点血清cTnI水平(病毒组：阿托伐他汀治疗组第7天：3.62：1.65 P=0.042；第10天7.03：2.83 P<0.01；第14天6.30：2.20 P=0.034；第21天2.73：0.63P=0.007)。在阿托伐他汀治疗组Fas蛋白及mRNA表达减少,细胞凋亡率也明显减少(病毒组：阿托伐他汀治疗组第14天12.36：4.82 P=0.006；第21天4.33：1.37P=0.019)。
结论：阿托伐他汀能明显降低病毒性心肌炎的死亡率。减少病毒性心肌炎中心肌细胞的损害,减轻组织的病理改变,提高心脏射血功能,促进病情缓解。其机制可能通过下调Fas转录及分子表达抑制心肌细胞凋亡有关。因此,阿托伐他汀对病毒性心肌炎小鼠有明显的心肌保护作用。病毒性心肌炎小鼠可以从阿托伐他汀的治疗中获益。
目的：强的松是广泛用于临床的一种糖皮质激素药物。本研究拟探讨强的松对Balb/c小鼠病毒性心肌炎的保护作用和机制,以及不同用药时间之间的差别。
方法：以柯萨奇病毒B3诱导的病毒性心肌炎Balb/c小鼠模型为研究对象。303只小鼠随机分为正常组(n=18),强的松对照组(n=15),病毒组(n=60),强的松早期治疗组(n=50),强的松晚期治疗组(n=30),维生素C治疗组(n=50),强的松早期+维生素C治疗组(n=50),强的松晚期+维生素C治疗组(n=30)。强的松治疗组给予强的松每天lmg/kg,早期治疗组为攻毒后第三天用药,晚期治疗组为攻毒后第10天给药；未治疗组给予等体积饮用水,分别以灌胃器给药,连续用药2周。未攻毒同周龄Balb/c小鼠为正常对照组,未攻毒给予强的松每天1mg/kg为强的松药物对照组。用药后3、7、10、14、21、30天,检测超声心动图、HE染色观察心肌组织炎症浸润程度,电镜观察心肌胶原纤维、心肌细胞及各种细胞器的变化。western blot及RT-PCR方法检测心肌Fas蛋白及mRNA表达水平,TUNEL法检测心肌细胞凋亡情况,ELISA方法检测血清cTnI水平。
结果：发现病毒性心肌炎小鼠攻毒后第3天开始出现症状,饮水进食减少,体重减轻。随后症状逐渐加重,第4天出现死亡；7-14天为死亡高峰。病毒组小鼠心脏超声提示心脏射血分数在第7天开始出现异常下降,光镜与电镜可以观察到明显的病理改变。TUNEL法检测发现凋亡细胞增多,心肌炎小鼠血清cTnI增高。强的松干预后显著提高病毒性心肌炎小鼠生存率(病毒组59.2%；强的松早期+维生素C治疗组81.8% P=0.028),维生素C治疗组生存率为71.9%,未见显著性差异。病毒组小鼠心脏射血分数第7天时早期强的松+维生素C组EF显著升高(P=0.038),第21天时与病毒组比较,早期强的松治疗组,早期强的松+维生素C组心脏射血分数显著升高(P=0.005；0.008),第30天时与病毒组比较,早期强的松治疗组射血分数显著升高(P=0.048)。收缩末期直径及容积第21天时与病毒组比较,早期强的松治疗组,早期强的松+维生素C组,晚期强的松+维生素C组的收缩末期直径明显减少(P=0.036；0.003；0.029)。强的松各治疗组较病毒组可以减轻心肌组织炎症浸润。与病毒性组比较,在第10天强的松早期治疗组、维生素治疗组与早期强的松+维生素C组cTnI明显减低(P<0.01；P=0.48；P<0.01),第14天时间点上强的松早期治疗组与早期强的松+维生素C组cTnI明显减低(P=0.015；0.013),第21天时间点上强的松早期治疗组与早期强的松+维生素C组cTnI明显减低(P=0.043；0.032)。与维生素C治疗组比较,在第10天强的松早期治疗组与早期强的松+维生素C组cTnI明显减低(P=0.009；0.005)。细胞凋亡率与病毒性组比较在第7天强的松早期治疗组与早期强的松+维生素C组凋亡指数分明显减低(P<0.01；P<0.01),第21天时间点上强的松早期治疗组与早期强的松+维生素C组,强的松晚期治疗组与晚期强的松+维生素C组的凋亡指数明显减低(P=0.029；P=0.022；P<0.01；P<0.01),第30天时间点上强的松早期治疗组与早期强的松+维生素C组,强的松晚期治疗组与晚期强的松+维生素C组的凋亡指数明显减低(P<0.01；0.0111；0.0161；0.0117)。在强的松+维生素C治疗组Fas蛋白及mRNA表达减少。
结论：强的松与维生素C联用可改善病毒性心肌炎小鼠生存率,提高心功能及改善组织病理学表现,其机制可能通过下调Fas转录及分子表达抑制心肌细胞凋亡有关。表明强的松与维生素C联用对病毒性心肌炎小鼠有明显的心肌保护作用。在病毒性心肌炎小鼠可以从强的松的治疗中获益,第三天应用效果较第十天应用效果好。
Objective:The goal of this study was to investigate the therapeutic benefits of atorvastatin on Coxsackie virus B3-induced myocarditis in Balb/c mice.
Method:143 male 4-week-old Balb/c mice were divided into four groups randomly, including nomal control group (mice were administered Eagle's minimal essential medium 18 mice), virus group (virus solution intraperitoneally,3×103 PFU/mL,60 mice), atorvastatin control group (atorvastatin 10mg/kg/day,15 mice) and atorvastatin treatment group (virus plus atorvastatin 10mg/kg/day,50 mice). Atorvastatin was given 3 days after viral challenge and treatment lasted for 14 days in the atorvastatin control group and atorvastatin treatment group. Echocardiograms were examined on days 3,7, 10,14,21, and 30 after virus inoculation (same days for the atorvastatin control group). Blood samples were collected for cardiac troponin I detection at the same time. Myocardial inflammation, cell apoptosis and Fas expression were detected by histology and western blot, RT-PCR.
Results:The myocardial histopathological score of mice in each infected group on day 7-10 after infection were significantly higher than that in normal control group, H&E staining and transmission electron microscopy revealed significant improvement of quantitative pathological features in the atorvastatin treatment group. Immunohistochemical microscopy also showed a marked decrease in the level of cardiac cell apoptosis in the atorvastatin treatment group compared to virus group that did not receive treatment (virus group:atorvastatin treatment group:12.36:4.82 P=0.006 at 14 days; 4.33:1.37 P=0.019 at 21days). The differences in cTnI values between the virus group and atorvastatin treatment group achieve statistical significance, there was decrease in cTnI in the atorvastatin treatment group(virus group:atorvastatin treatment group:3.62:1.65 P=0.042 at 7 days; 7.03:2.83 P<0.01 at 10 days; 6.30:2.20 P=0.034 at 14 days; 2.73:0.63 P=0.007 at 14 days 21 days). RT-PCR and western blotting revealed that the virus induced marked increases in Fas mRNA and protein expression, which could be prevented by treatment with atorvastatin.
Conclusion:These results demonstrate that atorvastatin reduces the histological and functional severity of CVB3m-induced myocarditis, and inhibits apoptosis and Fas expression in the myocardium of CVB3m-infected mice. The therapeutic benefits of atorvastatin on myocarditis may be explained, at least in part, by inhibition of Fas expression and inhibition of cell apoptosis.
Objective:The goal of this study was to investigate the therapeutic benefits of prednisone on Coxsackie virus B3m-induced myocarditis in Balb/c mice. Discussion the difference between different time of prednisone on viral myocarditis in mice at the medication.
Method:303 male 4-week-old Balb/c mice were divided into eight groups randomly, including nomal control group(Mice were administered Eagle's minimal essential medium, n=18), prednisone group(Mice were administered prednisone(1mg/kg/day) at 3 days, n=15), infected control group(virus solution intraperitoneally,3×103 PFU/mL n=60), group of infected mice with prednisone treatment at early stage(Mice were administered prednisone(1mg/kg/day) at 3 days post-inoculation, n=50), group of infected mice with prednisone treatment at late stage(Mice were administered prednisone(1mg/kg/day) at 10 days post-inoculation, n=30), group of infected mice with prednisone treatment at early stage and Vit C(Mice were administered prednisone at 3 days post-inoculation and Vit C, n=50), group of infected mice with prednisone treatment at late stage and Vit C(Mice were administered prednisone at 10 days post-inoculation and VitC, n=30), group of infected mice with Vit C(Mice were administered VitC n=50). Prednisone was given 3 or 10days after viral challenge and treatment lasted for 14 days. The Echocardiograms were examined on days 3,7,10,14,21, and 30 after virus inoculation. Blood samples were collected for cardiac troponinⅠdetection at the same time. Myocardial inflammation, cell apoptosis and Fas expression were detected by histology and western blot, RT-PCR.
Results:The myocardial histopathological score of mice in each infected group on day 7-10 after infection were significantly higher than that in normal control group, but no significant difference in each infected group. On day 14 after infecteion, the myocardial histopathologic socre of mice with Prednisone treatment at early stage were significantly lower than that in other infected groups, H&E staining and transmission electron microscopy revealed significant improvement of quantitative pathological features in the prednisone treatement at early stage. Immunohistochemical microscopy also showed a marked decrease in the level of cardiac cell Apoptosis in the Prednisone-treated group compared to infected animals that did not receive treatment. The differences in cTnI values between the virus-challenged animals and prednisone -treated virus-challenged mice achieve statistical significance, there was a trend toward a decrease in cTnl in the Prednisone-treated mice.RT-PCR and western blotting revealed that the virus induced marked increases in Fas mRNA and protein expression, which could be prevented by treatment with Prednisone.
Conclusion:Prednisone and vit c therapy at early stage ameliorated the severity of myocardial lesions in viral myocarditis, especially used in early stage of the disease. Prednisone and vit c therapy reduced the inflammatory infiltration in myocardium, inhibited autoimmune response. Prednisone therapy reduced the lever of serum cardiac troponin I in viral myocarditis. These results demonstrate that Prednisone and vit c reduces the histological and functional severity of CVB3m-induced myocarditis, and inhibits apoptosis and Fas expression in the myocardium of CVB3m-infected mice. The therapeutic benefits of prednisone on myocarditis may be explained, at least in part, by inhibition of Fas expression and inhibition of cell apoptosis.
方法以柯萨奇病毒B3m(CVB3m)诱导的病毒性心肌炎Balb/c小鼠模型为研究对象。143只小鼠随机分为正常组(n=18),病毒组(n=60),阿托伐他汀对照组(n=15),阿托伐他汀治疗组(n=50)。正常组组和阿托伐他汀对照组腹腔无菌注射不含病毒的Eagel's培养液0.3ml。病毒组与阿托伐他汀治疗组腹腔单次接种0.3ml X 3×103 PFU/mL CVB3m。阿托伐他汀治疗组给予阿托伐他汀每天10mg/kg/d,病毒组给予等体积饮用水,分别以灌胃器给药,连续用药2周。用药后3、7、10、14、21、30天,检测超声心动图、苏木素-伊红染色(H&E, hematoxylin-eosine)观察心肌组织炎症浸润程度,电镜观察心肌心肌细胞及各种细胞器的变化。western blot及逆转录酶PCR (reverse transcriptase-Polymerase Chain Reaction, RT-PCR)方法检测心肌Fas蛋白及mRNA表达水平,TUNEL法(terminal-deoxynucleotidyl transferase mediated dUTP nick end labeling,脱氧核苷酸末端转移酶介导的dUTP末端缺口标记法)检测心肌细胞凋亡情况,酶联免疫吸附测定(ELISA, enzyme linked immunosorbent assay)方法检测血清心肌肌钙蛋白I (cardiac troponinl,cTnI)水平。
结果发现病毒性心肌炎小鼠攻毒后第3天开始出现症状,饮水进食减少,体重减轻。随后症状逐渐加重,第4天出现死亡；7-14天为死亡高峰。病毒组小鼠心脏超声提示射血分数在第7天开始出现异常下降,光镜与电镜可以观察到明显的病理改变。TUNEL法检测发现凋亡细胞增多,心肌炎小鼠血清cTnI增高。阿托伐他汀干预后显著提高病毒性心肌炎小鼠生存率(病毒组：治疗组为59.2%：87%,P=0.008)。阿托伐他汀治疗组可以改善小鼠心脏射血分数(病毒组比治疗组：第7天：69.82%：78.99%P<0.01；第14天：74.85%：83.50%P<0.01；第21天：70.78%：82.32%P<0.01；第30天：76.47%：82.69% P<0.01)。阿托伐他汀治疗组较病毒组可以明显减轻心肌组织炎症浸润,心肌病理组织学积分在第10,14,21,30天阿托伐他汀治疗组较病毒组减少。阿托伐他汀治疗组较病毒组显著降低各个时间点血清cTnI水平(病毒组：阿托伐他汀治疗组第7天：3.62：1.65 P=0.042；第10天7.03：2.83 P<0.01；第14天6.30：2.20 P=0.034；第21天2.73：0.63P=0.007)。在阿托伐他汀治疗组Fas蛋白及mRNA表达减少,细胞凋亡率也明显减少(病毒组：阿托伐他汀治疗组第14天12.36：4.82 P=0.006；第21天4.33：1.37P=0.019)。
结论：阿托伐他汀能明显降低病毒性心肌炎的死亡率。减少病毒性心肌炎中心肌细胞的损害,减轻组织的病理改变,提高心脏射血功能,促进病情缓解。其机制可能通过下调Fas转录及分子表达抑制心肌细胞凋亡有关。因此,阿托伐他汀对病毒性心肌炎小鼠有明显的心肌保护作用。病毒性心肌炎小鼠可以从阿托伐他汀的治疗中获益。
目的：强的松是广泛用于临床的一种糖皮质激素药物。本研究拟探讨强的松对Balb/c小鼠病毒性心肌炎的保护作用和机制,以及不同用药时间之间的差别。
方法：以柯萨奇病毒B3诱导的病毒性心肌炎Balb/c小鼠模型为研究对象。303只小鼠随机分为正常组(n=18),强的松对照组(n=15),病毒组(n=60),强的松早期治疗组(n=50),强的松晚期治疗组(n=30),维生素C治疗组(n=50),强的松早期+维生素C治疗组(n=50),强的松晚期+维生素C治疗组(n=30)。强的松治疗组给予强的松每天lmg/kg,早期治疗组为攻毒后第三天用药,晚期治疗组为攻毒后第10天给药；未治疗组给予等体积饮用水,分别以灌胃器给药,连续用药2周。未攻毒同周龄Balb/c小鼠为正常对照组,未攻毒给予强的松每天1mg/kg为强的松药物对照组。用药后3、7、10、14、21、30天,检测超声心动图、HE染色观察心肌组织炎症浸润程度,电镜观察心肌胶原纤维、心肌细胞及各种细胞器的变化。western blot及RT-PCR方法检测心肌Fas蛋白及mRNA表达水平,TUNEL法检测心肌细胞凋亡情况,ELISA方法检测血清cTnI水平。
结果：发现病毒性心肌炎小鼠攻毒后第3天开始出现症状,饮水进食减少,体重减轻。随后症状逐渐加重,第4天出现死亡；7-14天为死亡高峰。病毒组小鼠心脏超声提示心脏射血分数在第7天开始出现异常下降,光镜与电镜可以观察到明显的病理改变。TUNEL法检测发现凋亡细胞增多,心肌炎小鼠血清cTnI增高。强的松干预后显著提高病毒性心肌炎小鼠生存率(病毒组59.2%；强的松早期+维生素C治疗组81.8% P=0.028),维生素C治疗组生存率为71.9%,未见显著性差异。病毒组小鼠心脏射血分数第7天时早期强的松+维生素C组EF显著升高(P=0.038),第21天时与病毒组比较,早期强的松治疗组,早期强的松+维生素C组心脏射血分数显著升高(P=0.005；0.008),第30天时与病毒组比较,早期强的松治疗组射血分数显著升高(P=0.048)。收缩末期直径及容积第21天时与病毒组比较,早期强的松治疗组,早期强的松+维生素C组,晚期强的松+维生素C组的收缩末期直径明显减少(P=0.036；0.003；0.029)。强的松各治疗组较病毒组可以减轻心肌组织炎症浸润。与病毒性组比较,在第10天强的松早期治疗组、维生素治疗组与早期强的松+维生素C组cTnI明显减低(P<0.01；P=0.48；P<0.01),第14天时间点上强的松早期治疗组与早期强的松+维生素C组cTnI明显减低(P=0.015；0.013),第21天时间点上强的松早期治疗组与早期强的松+维生素C组cTnI明显减低(P=0.043；0.032)。与维生素C治疗组比较,在第10天强的松早期治疗组与早期强的松+维生素C组cTnI明显减低(P=0.009；0.005)。细胞凋亡率与病毒性组比较在第7天强的松早期治疗组与早期强的松+维生素C组凋亡指数分明显减低(P<0.01；P<0.01),第21天时间点上强的松早期治疗组与早期强的松+维生素C组,强的松晚期治疗组与晚期强的松+维生素C组的凋亡指数明显减低(P=0.029；P=0.022；P<0.01；P<0.01),第30天时间点上强的松早期治疗组与早期强的松+维生素C组,强的松晚期治疗组与晚期强的松+维生素C组的凋亡指数明显减低(P<0.01；0.0111；0.0161；0.0117)。在强的松+维生素C治疗组Fas蛋白及mRNA表达减少。
结论：强的松与维生素C联用可改善病毒性心肌炎小鼠生存率,提高心功能及改善组织病理学表现,其机制可能通过下调Fas转录及分子表达抑制心肌细胞凋亡有关。表明强的松与维生素C联用对病毒性心肌炎小鼠有明显的心肌保护作用。在病毒性心肌炎小鼠可以从强的松的治疗中获益,第三天应用效果较第十天应用效果好。
Objective:The goal of this study was to investigate the therapeutic benefits of atorvastatin on Coxsackie virus B3-induced myocarditis in Balb/c mice.
Method:143 male 4-week-old Balb/c mice were divided into four groups randomly, including nomal control group (mice were administered Eagle's minimal essential medium 18 mice), virus group (virus solution intraperitoneally,3×103 PFU/mL,60 mice), atorvastatin control group (atorvastatin 10mg/kg/day,15 mice) and atorvastatin treatment group (virus plus atorvastatin 10mg/kg/day,50 mice). Atorvastatin was given 3 days after viral challenge and treatment lasted for 14 days in the atorvastatin control group and atorvastatin treatment group. Echocardiograms were examined on days 3,7, 10,14,21, and 30 after virus inoculation (same days for the atorvastatin control group). Blood samples were collected for cardiac troponin I detection at the same time. Myocardial inflammation, cell apoptosis and Fas expression were detected by histology and western blot, RT-PCR.
Results:The myocardial histopathological score of mice in each infected group on day 7-10 after infection were significantly higher than that in normal control group, H&E staining and transmission electron microscopy revealed significant improvement of quantitative pathological features in the atorvastatin treatment group. Immunohistochemical microscopy also showed a marked decrease in the level of cardiac cell apoptosis in the atorvastatin treatment group compared to virus group that did not receive treatment (virus group:atorvastatin treatment group:12.36:4.82 P=0.006 at 14 days; 4.33:1.37 P=0.019 at 21days). The differences in cTnI values between the virus group and atorvastatin treatment group achieve statistical significance, there was decrease in cTnI in the atorvastatin treatment group(virus group:atorvastatin treatment group:3.62:1.65 P=0.042 at 7 days; 7.03:2.83 P<0.01 at 10 days; 6.30:2.20 P=0.034 at 14 days; 2.73:0.63 P=0.007 at 14 days 21 days). RT-PCR and western blotting revealed that the virus induced marked increases in Fas mRNA and protein expression, which could be prevented by treatment with atorvastatin.
Conclusion:These results demonstrate that atorvastatin reduces the histological and functional severity of CVB3m-induced myocarditis, and inhibits apoptosis and Fas expression in the myocardium of CVB3m-infected mice. The therapeutic benefits of atorvastatin on myocarditis may be explained, at least in part, by inhibition of Fas expression and inhibition of cell apoptosis.
Objective:The goal of this study was to investigate the therapeutic benefits of prednisone on Coxsackie virus B3m-induced myocarditis in Balb/c mice. Discussion the difference between different time of prednisone on viral myocarditis in mice at the medication.
Method:303 male 4-week-old Balb/c mice were divided into eight groups randomly, including nomal control group(Mice were administered Eagle's minimal essential medium, n=18), prednisone group(Mice were administered prednisone(1mg/kg/day) at 3 days, n=15), infected control group(virus solution intraperitoneally,3×103 PFU/mL n=60), group of infected mice with prednisone treatment at early stage(Mice were administered prednisone(1mg/kg/day) at 3 days post-inoculation, n=50), group of infected mice with prednisone treatment at late stage(Mice were administered prednisone(1mg/kg/day) at 10 days post-inoculation, n=30), group of infected mice with prednisone treatment at early stage and Vit C(Mice were administered prednisone at 3 days post-inoculation and Vit C, n=50), group of infected mice with prednisone treatment at late stage and Vit C(Mice were administered prednisone at 10 days post-inoculation and VitC, n=30), group of infected mice with Vit C(Mice were administered VitC n=50). Prednisone was given 3 or 10days after viral challenge and treatment lasted for 14 days. The Echocardiograms were examined on days 3,7,10,14,21, and 30 after virus inoculation. Blood samples were collected for cardiac troponinⅠdetection at the same time. Myocardial inflammation, cell apoptosis and Fas expression were detected by histology and western blot, RT-PCR.
Results:The myocardial histopathological score of mice in each infected group on day 7-10 after infection were significantly higher than that in normal control group, but no significant difference in each infected group. On day 14 after infecteion, the myocardial histopathologic socre of mice with Prednisone treatment at early stage were significantly lower than that in other infected groups, H&E staining and transmission electron microscopy revealed significant improvement of quantitative pathological features in the prednisone treatement at early stage. Immunohistochemical microscopy also showed a marked decrease in the level of cardiac cell Apoptosis in the Prednisone-treated group compared to infected animals that did not receive treatment. The differences in cTnI values between the virus-challenged animals and prednisone -treated virus-challenged mice achieve statistical significance, there was a trend toward a decrease in cTnl in the Prednisone-treated mice.RT-PCR and western blotting revealed that the virus induced marked increases in Fas mRNA and protein expression, which could be prevented by treatment with Prednisone.
Conclusion:Prednisone and vit c therapy at early stage ameliorated the severity of myocardial lesions in viral myocarditis, especially used in early stage of the disease. Prednisone and vit c therapy reduced the inflammatory infiltration in myocardium, inhibited autoimmune response. Prednisone therapy reduced the lever of serum cardiac troponin I in viral myocarditis. These results demonstrate that Prednisone and vit c reduces the histological and functional severity of CVB3m-induced myocarditis, and inhibits apoptosis and Fas expression in the myocardium of CVB3m-infected mice. The therapeutic benefits of prednisone on myocarditis may be explained, at least in part, by inhibition of Fas expression and inhibition of cell apoptosis.
引文
1. Haas GJ. Etiology, evaluation, and management of acute myocarditis. Cardiology in Review 2001;9(2):88-95.
2. Feldman AM, McNamara D. Myocarditis. The New England Journal of Medicine 2000;343(19):1388-98.
3. Drory Y, Turetz Y, Hiss Y, Lev B, Fisman EZ, Pines A, et al.Sudden unexpected death in persons less than 40 years of age. American Journal of Cardiology 1991;68(13):1388-92.
4. Ellis CR, Di Salvo T. Myocarditis:basic and clinical aspects. Cardiol Rev.2007 Jul-Aug; 15(4):170-7.
5. Brunetti L, DeSantis ER. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
6. Dec GW Jr, Waldman H, Southern J, Fallon JT, Hutter AM Jr, Palacios I. Viral myocarditis mimicking acute myocardial infarction. Journal of the American College of Cardiology 1992;20:85-9.
7. Parrillo JE. Inflammatory cardiomyopathy (myocarditis):which patients should be treated with anti-inflammatory therapy?. Circulation 2001;104(1):4
8. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, et al.Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy:two-year follow-up results. Circulation 2001;104(1):39-45
9. Brunetti L, DeSantis ER.Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
10. Staudt A, Schaper F, Stangl V, Plagemann A, Bohm M, Merkel K, et al.Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation 2001;103:2681-6
11. Miric M, Miskovic A, Vasiljevic JD, Keserovic N, Pesic M. Interferon and thymic hormones in the therapy of human myocarditis and idiopathic dilated cardiomyopathy. European Heart Journal 1995;Suppl 0:150-2.
12. Grinda JM, Chevalier P, et al. Fulminant myocarditis in adults and children: bi-ventricular assist device for recovery. Eur J Cardiothorac Surg.2004 Dec;26(6):1169-73.
13. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis a histopathologic definition and classification. Am. J. Cardiovasc. Pathol.1987 Jan;1(1):3-14.
14. Chen H, Liu J, Yang M. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev.2006 Oct 18;(4):CD004471.
15. Kitabayashi H, Isobe M, et al. FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes. J Cardiovasc Pharmacol.2000 Mar;35(3):410-6.
16. Knowlton KU. Unsolved medical issues and new targets for further research in viral myocarditis and dilated cardiomyopathy. Ernst Schering Res Found Workshop. 2006;(55):19-35.
17. Wu JL, Matsui S, et al. Amelioration of myocarditis by statin through inhibiting cross-talk between antigen presenting cells and lymphocytes in rats. Mol Cell Cardiol.2008 Jun;44(6):1023-31. Epub 2008 Apr 1.
18. Szalay G, Meiner S, Voigt A, et al. Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial. immunoproteasomes[J]. Am J Pathol,2006.168(5):1542-1552
19.吴辉,唐其柱等,阿托伐他汀对自身免疫性心肌炎小鼠心肌细胞外基质重构的影响.武汉大学学报(医学版),2007,28(2)：172-176
20. Saraste A, Kyto" V, Saraste M, Vuorinen T, Hartiala J, Saukko P. Coronary flow reserve and heart failure in experimental coxsackievirus myocarditis. A transthoracic Doppler echocardiography study. Am J Physiol Heart Circ Physiol 2006;291:H871-5.
21. Broberg CS, Pantely GA, Barber BJ, Mack GK, Lee K, Thigpen T et al. Validation of the myocardial performance index by echocardiography in mice:a noninvasive measure of left ventricular function. J Am Soc Echocardiogr 2003;16:814-23.
22. Rezkalla S, Kloner RA, Khatib G, Khatib R. Effect of delayed captopril therapy on left ventricular mass and myonecrosis during acute coxsackievirus murine myocarditis. Am Heart J.1990 Dec; 120(6 Pt 1):1377-81.
23. Kyto" V, Lapatto R, et al. Glutathione depletion and cardiomyocyte apoptosis in viral myocarditis. Eur J Clin Invest 2004;34:167-75.
24. Zaidi SH, Hui CC, et al. Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis.J Clin Invest.1999 Apr;103(8):1211-9.
25.崔小岱马连华.柯萨奇B3病毒心肌株与非亲心肌株感染小鼠心肌细胞的实验比较.中华实验和临床病毒学杂志.1997(11)3：274-276
26.崔小岱 孙国贤.VitC保护病毒感染小鼠心肌细胞的机理探讨.中华实验和临床病毒学杂志.1993.7：401-404
27.崔小岱 马连华.制造病毒性心肌炎动物模型毒株的比较.中华儿科杂.2000,(38),2：83-85
28. Hufnagel G, Chapman N, Tracy S. A non-cardiovirulent strain of coxsackievirus B3 causes myocarditis in mice with severe combined immunodeficiency syndrome. Eur Heart J.1995 Dec; 16 Suppl 0:18-9.
29. Gauntt CJ, Pallansch MA.Coxsackievirus B3 clinical isolates and murine myocarditis. Virus Res.1996 Mar;41(1):89-99.
30. Szalay G, Meiner S, Voigt A, et al. Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial immunoproteasomes. Am J Pathol,2006.168(5):1542-1552.
31. Lim BK, Shin jo, Choe SC, et al. Myocardial injury occur earlier than myocardial inflammation in acute experimental viral myocarditis.Exp Mol Med,2005,37(1): 51-57.
32. Latva-Hirvela J, Kyto V, et al. Development of troponin autoantibodies in experimental coxsackievirus B3 myocarditis. Eur J Clin Invest.2009 Apr 8.
33. Zhang ZC, Li SJ, Yang YZ, Chen RZ, Ge JB, Chen HZ. Effect of astragaloside on cardiomyocyte apoptosis in murine coxsackievirus B3 myocarditis.J Asian Nat Prod Res.2007 Mar;9(2):145-51.
34. Ellis CR, Di Salvo T.Myocarditis:basic and clinical aspects.Cardiol Rev.2007 Jul-Aug; 15(4):170-7.
35. Seko Y, Yagita H, Okumura K, et al. Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3. Cardiovasc Res.2007 Jul 1;75(1):158-67.
36. Ishiyama S, Hiroe M, Nishikawa T, et al. The Fas/Fas ligand system is involved in the pathogenesis of autoimmune myocarditis in rats. J Immunol.1998 Nov 1;161(9):4695-701.
37. Shovman O, Levy Y, Gilburd B, Shoenfeld Y. Antiinflammatory and immunomodulatory properties of statins.Immunol Res.2002;25(3):271-85.
38. Liu W, Li WM, Gao C, Sun NL. Effects of atorvastatin on the Thl/Th2 polarization of ongoing experimental autoimmune myocarditis in Lewis rats. J Autoimmun.2005 Dec;25(4):258-63.
39. Syka J, Ouda L, Nachtigal P, Solichova D, Semecky V. Atorvastatin slows down the deterioration of inner ear function with age in mice. Neurosci Lett.2007 Jan 10；411(2):112-6.
40. Ghule BV, Ghante MH, Saoji AN, Yeole PGAntihyperlipidemic Effect of the Methanolic Extract from Lagenaria siceraria Stand. Fruit in Hyperlipidemic Rats.J Ethnopharmacol.2009 Apr 24.
41. Seko Y, Kayagaki N, Seino K, Yagita H, Okumura K, Nagai R. Role of Fas/FasL pathway in the activation of infiltrating cells in murine acute myocarditis caused by Coxsackievirus B3. J Am Coll Cardiol.2002 Apr 17;39(8):1399-403.
42. Seko Y. Effect of the angiotensin Ⅱ receptor blocker olmesartan on the development of murine acute myocarditis caused by coxsackievirus B3. Clin Sci (Lond).2006 Mar;110(3):379-86.
43. Seko Y, Yagita H, Okumura K, Azuma M, Nagai R. Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3. Cardiovasc Res.2007 Jul 1;75(1):158-67. Epub 2007 Mar 16.
44. Kawano H, Okada R, Kawano Y, Sueyoshi N, Shirai T. Apoptosis in acute and chronic myocarditis. Jpn Heart J.1994 Nov;35(6):745-50.
45. DeBiasi RL, Robinson BA, et al. Caspase inhibition protects against reovirus-induced myocardial injury in vitro and in vivo. J Virol.2004 Oct;78(20):11040-50.
46. DeBiasi RL, Clarke P, et al. Reovirus-induced alteration in expression of apoptosis and DNA repair genes with potential roles in viral pathogenesis. J Virol.2003 Aug;77(16):8934-47.
47. Huber S, Shi C, Budd RC. Gammadelta T cells promote a Th1 response during coxsackievirus B3 infection in vivo:role of Fas and Fas ligand. J Virol.2002 Jul;76(13):6487-94.
1. Haas GJ. Etiology, evaluation, and management of acute myocarditis. Cardiology in Review 2001;9(2):88-95.
2. Feldman AM, McNamara D. Myocarditis. The New England Journal of Medicine 2000;343(19):1388-98.
3. Drory Y, Turetz Y, Hiss Y, Lev B, Fisman EZ, Pines A, et al.Sudden unexpected death in persons less than 40 years of age. American Journal of Cardiology 1991;68(13):1388-92.
4. Ellis CR, Di Salvo T. Myocarditis:basic and clinical aspects. Cardiol Rev.2007 Jul-Aug;15(4):170-7.
5. Brunetti L, DeSantis ER. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
6. Dec GW Jr, Waldman H, Southern J, Fallon JT, Hutter AM Jr, Palacios I. Viral myocarditis mimicking acute myocardial infarction. Journal of the American College of Cardiology 1992;20:85-9.
7. Parrillo JE. Inflammatory cardiomyopathy (myocarditis):which patients should be treated with anti-inflammatory therapy?. Circulation 2001;104(1):4
8. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, et al.Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy:two-year follow-up results. Circulation 2001;104(1):39-45
9. Brunetti L, DeSantis ER.Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
10. Staudt A, Schaper F, Stangl V, Plagemann A, Bohm M, Merkel K, et al.Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation 2001;103:2681-6
11. Miric M, Miskovic A, Vasiljevic JD, Keserovic N, Pesic M. Interferon and thymic hormones in the therapy of human myocarditis and idiopathic dilated cardiomyopathy. European Heart Journal 1995;Suppl 0:150-2.
12. Grinda JM, Chevalier P, et al. Fulminant myocarditis in adults and children: bi-ventricular assist device for recovery. Eur J Cardiothorac Surg.2004 Dec;26(6):1169-73.
13. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis a histopathologic definition and classification. Am. J. Cardiovasc. Pathol.1987 Jan;1(1):3-14.
14. Chen H, Liu J, Yang M. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev.2006 Oct 18;(4):CD004471.
15. Kitabayashi H, Isobe M, et al. FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes. J Cardiovasc Pharmacol.2000 Mar;35(3):410-6.
16. Knowlton KU. Unsolved medical issues and new targets for further research in viral myocarditis and dilated cardiomyopathy. Ernst Schering Res Found Workshop. 2006;(55):19-35.
17. Maisch B, Schonian U, et al.Immunosuppressive treatment in autoreactive myocarditis results from a controlled trial. Postgrad Med J.1994;70 Suppl 1:S29-34.
18. Doroshenko BH, Nazar PS. Corticosteroid therapy of acute viral myocarditis in patients with severe clinical course of disease. Lik Sprava,2002,74:76.
19. Tomioka N, Kishimoto C, Matsumori A, Kawai C. Effects of prednisolone on acute viral myocarditis in mice. J Am Coll Cardiol.1986 Apr;7(4):868-72.
20. Mason JW, O'Connell JB, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med.1995 Aug 3;333(5):269-75.
21. Szalay G, Meiner S, Voigt A, et al. Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial. immunoproteasomes[J]. Am J Pathol,2006.168(5):1542-1552
22.马沛然,王述昀.皮质激素对病毒性心肌炎疗效及其不良反应预防的实验研究.临床儿科杂志,2004,22(7)：467-469
23. Saraste A, Kyto" V, Saraste M, Vuorinen T, Hartiala J, Saukko P. Coronary flow reserve and heart failure in experimental coxsackievirus myocarditis. A transthoracic Doppler echocardiography study. Am J Physiol Heart Circ Physiol 2006;291:H871-5.
24. Broberg CS, Pantely GA, Barber BJ, Mack GK, Lee K, Thigpen T et al. Validation of the myocardial performance index by echocardiography in mice:a noninvasive measure of left ventricular function. J Am Soc Echocardiogr 2003;16:814-23.
25. Rezkalla S, Kloner RA, Khatib G, Khatib R. Effect of delayed captopril therapy on left ventricular mass and myonecrosis during acute coxsackievirus murine myocarditis. Am Heart J.1990 Dec; 120(6 Pt 1):1377-81.
26. Kyto V, Lapatto R, et al. Glutathione depletion and cardiomyocyte apoptosis in viral myocarditis. Eur J Clin Invest 2004;34:167-75.
27. Lee SS, Singh S, Link K, Petri M. High-sensitivity C-reactive protein as an associate of clinical subsets and organ damage in systemic lupus erythematosus. Semin Arthritis Rheum.2008 Aug;38(1):41-54. Epub 2008 Jan 25.
28. Pearl JM, Nelson DP, et al. Glucocorticoids reduce ischemia-reperfusion-induced myocardial apoptosis in immature hearts. Ann Thorac Surg.2002 Sep;74(3):830-6
29. Granchelli JA, Pollina C, Hudecki MS. Pre-clinical screening of drugs using the mdx mouse. Neuromuscul Disord.2000 Jun;10(4-5):235-9.
30.王述昀,马沛然等,肾上腺皮质激素对病毒性心肌炎小鼠c2Fos基因表达的影响,中华儿科杂志2002年10月Vol 40 No10：614-15
31. Providencia R, Botelho A,et al.Viral myocarditis--new advances. Rev Port Cardiol. 2008 May;27(5):707-22.
32. Brunetti L, DeSantis ER. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
33. Spotnitz MD, Lesch M. Idiopathic dilated cardiomyopathy as a late complication of healed viral (Coxsackie B virus) myocarditis:historical analysis, review of the literature, and a postulated unifying hypothesis.Prog Cardiovasc Dis.2006 Jul-Aug;49(1):42-57.
34.沈茜,汪美先,章同华.原位核酸分子杂交检测柯萨基B3病毒感染小鼠心肌组织中病毒RNA.中华微生物学和免疫学杂志.1991,11(3)：193-196
35. Clarke P, Tyler KL.Apoptosis in animal models of virus-induced disease.Nat Rev Microbiol.2009 Feb;7(2):144-55.
36. Kyto V, Lapatto R, et al. Glutathione depletion and cardiomyocyte apoptosis in viral myocarditis. Eur J Clin Invest.2004 Mar;34(3):167-75.
37. Yamada T, Matsumori A, et al. Apoptosis in congestive heart failure induced by viral myocarditis in mice. Heart Vessels.1999;14(1):29-37.
38. Satoh M, Hiramori K, Tamura G, Satodate R. Apoptosis in the process from viral myocarditis to dilated cardiomyopathy Nippon Rinsho.1996 Jul;54(7):1982-5
39. Kawano H, Okada R, Kawano Y, Sueyoshi N, Shirai T. Apoptosis in acute and chronic myocarditis. Jpn Heart J.1994 Nov;35(6):745-50.
40. DeBiasi RL, Robinson BA, et al. Caspase inhibition protects against reovirus-induced myocardial injury in vitro and in vivo. J Virol.2004 Oct;78(20):11040-50.
41. DeBiasi RL, Clarke P, et al. Reovirus-induced alteration in expression of apoptosis and DNA repair genes with potential roles in viral pathogenesis. J Virol.2003 Aug;77(16):8934-47.
42. Huber S, Shi C, Budd RC. Gammadelta T cells promote a Th1 response during coxsackievirus B3 infection in vivo:role of Fas and Fas ligand. J Virol.2002 Jul;76(13):6487-94.
43. Latham RD, Mulrow JP, Virmani R, Robinowitz M, Moody JM. Recently diagnosed idiopathic dilated cardiomyopathy:incidence of myocarditis and efficacy of prednisone therapy. Am Heart J.1989 Apr; 117(4):876-82.
44. Hosenpud JD, McAnulty JH, Niles NR. Lack of objective improvement in ventricular systolic function in patients with myocarditis treated with azathioprine and prednisone. J Am Coll Cardiol.1985 Oct;6(4):797-801.
45.王述昀,牟道玉,肾上腺皮质激素对柯萨奇B3病毒感染小鼠心肌的保护作用中国动脉硬化杂志.2005年第13卷第3期,313-316
1. Brunetti L, DeSantis ER. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
2. Feldman AM, et al. Myocarditis. N Engl J Med 2000;343:1388-1398.
3. Demmler GJ. In:Long S, et al., eds. Principles and Practice of Pediatric Infectious Diseases.2nd ed.2003:258-261
4. Calabrese F, et al. Molecular diagnosis of myocarditis and dilated cardiomyopathy in children:clinicopathologic features and prognostic implications. Diagn Mol Pathol 2002; 11:212-221
5. JAVETT SN, HEYMANN S, MUNDEL B, Myocarditis in the new newborn infant; a study of an outbreak associated with Coxsackie group B virus infection in a maternity home in Johannesburg. J Pediatr.1956 Jan;48(1):1-22.
6. Hirschman SZ, Hammer GS. Coxsackie virus myopericarditis:a microbiological and clinical review. Am J Cardiol.1974; 34:224-32.
7. Kearney MT, Cotton JM, Richardson PJ et al. Viral myocarditis and dilated cardiomyopathy:mechanisms, manifestations, and management. Postgrad Med J. 2001; 77:4-10.
8. Fujioka S, Kitaura Y. Coxsackie B virus infection in idiopathic dilated cardiomyopathy:clinical and pharmacological implications. BioDrugs.2001; 15:791-9.
9. Cihakova D, Rose NR. Pathogenesis of myocarditis and dilated cardiomyopathy. Adv Immunol.2008;99:95-114.
10. Shimojo T, Hiroe M. Ishiyama S et al. Nitric oxide induces apoptotic death of cardiomyocytes via a cyclic-GMP-dependent pathway. Exp Cell Res.1999; 247:38-17.
11. Spotnitz MD, Lesch M. Idiopathic dilated cardiomyopathy as a late complication of healed viral (Coxsackie B virus) myocarditis:historical analysis, review of the literature, and a postulated unifying hypothesis. Prog Cardiovasc Dis.2006; 49:42-57.
12. Beck MA. Nutritionally induced oxidative stress:effect on viral disease. Am J Clin Nutr.2000; 71
13. Wong CY, Woodruff JJ, Woodruff JF. Generation of cytotoxic T lymphocytes during coxsackievirus tb-3 infection. II. Characterization of effector cells and demonstration cytotoxicity against viral-infected myofibersl. J Immunol.1977 Apr;118(4):1165-9.
14. Hjalmarson A, Fu M, Mobini R. Who are the enemies? Inflammation and autoimmune mechanisms. Eur Heart J Suppl.2002; 4(suppl G):G27-32.
15. Kawai C. From myocarditis to cardiomyopathy:mechanisms of inflammation and cell death:learning from the past for the future. Circulation.1999; 99:1091-100.
16. McManus BM, Chow LH, Wilson JE et al. Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditis. Clin Immunol Immunopathol. 1993; 68:159-69.
17. Huber JT, Silva AG, Campos OF, Mathieu CM. Influence of feeding different amounts of milk on performance, health, and absorption capability of baby calves. J Dairy Sci.1984 Dec;67(12):2957-63.
18. Heim A, Stille-Seigener M, Pring-Akerblom P et al. Recombinant interferons beta and gamma have a higher antiviral activity than interferon-alpha in coxsackie B3-infected carrier state cultures of human myocardial fibroblasts. J Interferon Cytokine Res.1996; 16:283-7.
19. Rotbart HA, Webster AD, for the Pleconaril Treatment Registry Group. Treatment of potentially life-threatening enterovirus infections with pleconaril. Clin Infect Dis. 2001; 32:228-35.
20.宋晓东,刘哲.针对病毒性心肌炎的细胞凋亡研究.中国现代医学杂志,2006,16(23)：3549-3552
21. Yamada T, Matsumori A, et al. Apoptosis in congestive heart failure induced by viral myocarditis in mice. Heart Vessels.1999;14(1):29-37.
22. Satoh M, Hiramori K, Tamura G, Satodate R. Apoptosis in the process from viral myocarditis to dilated cardiomyopathy Nippon Rinsho.1996 Jul;54(7):1982-5
23. Kawano H, Okada R, Kawano Y, Sueyoshi N, Shirai T. Apoptosis in acute and chronic myocarditis. Jpn Heart J.1994 Nov;35(6):745-50.
24. DeBiasi RL, Robinson BA, et al. Caspase inhibition protects against reovirus-induced myocardial injury in vitro and in vivo. J Virol.2004 Oct;78(20):11040-50.
25. DeBiasi RL, Clarke P, et al. Reovirus-induced alteration in expression of apoptosis and DNA repair genes with potential roles in viral pathogenesis. J Virol.2003 Aug;77(16):8934-47.
26. Huber S, Shi C, Budd RC. Gammadelta T cells promote a Th1 response during coxsackievirus B3 infection in vivo:role of Fas and Fas ligand. J Virol.2002 Jul;76(13):6487-94.
27. Yang YZ, Jin PY, Guo Q et al. Effect of Astragalus membranaceus on natural killer cell activity and induction of-and-interferon in patients with Coxsackie B viral myocarditis. Chin Med J.1990; 103:304-7.
28. Sen-Chowdhry S, Syrris P et al. DJ. Left-dominant arrhythmogenic ardiomyopathy: an under-recognized clinical entity. J Am Coll Cardiol.2008 Dec 16;52 (25):2175-87.
29. Calabrese F, Rigo E,.Molecular diagnosis of myocarditis and dilated cardiomyopathy in children:clinicopathologic features and prognostic implications. Diagn Mol Pathol.2002 Dec;11(4):212-21.
30. A, Wang H, Abelmann WH, Crumpacker CS.Treatment of viral myocarditis with ribavirin in an animal preparation.Matsumori Circulation.1985 Apr;71(4):834-9.
31. Chiba K. Nihon Rinsho Meneki Gakkai Kaishi.2009 Apr;32(2):92-101. Japanese. A new therapeutic approach for autoimmune diseases by the sphingosine 1-phosphate receptor modulator, fingolimod (FTY720)
32. Tchorsh-Yutsis D, Hecht G,Pig embryonic pancreatic tissue as a source for transplantation in diabetes:transient treatment with anti-LFA1, anti-CD48 and FTY720 enables long term graft maintenance in mice with only mild ongoing immunosuppression. Diabetes.2009 Apr 28.
33. Rustemeyer J, Krajacic A, Dicke U. Histomorphological and functional impacts of postoperative motor training in rats after allograft sciatic nerve transplantation under low-dose FK 506. Muscle Nerve.2009 Apr;39(4):480-8.
34. Tamaki H, Nakase H, The effect of tacrolimus (FK-506) on Japanese patients with refractory Crohn's disease. J Gastroenterol.2008;43(10):774-9. Epub 2008 Oct 29.
35. Ahdoot J, Galindo A,Use of OKT3 for acute myocarditis in infants and children. J Heart Lung Transplant.2000 Nov;19(11):1118-21.
36. Drucker NA, Colan SD,Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation.1994 Jan;89(1):252-7.
37. Fairweather D, Frisancho-Kiss S, IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart. J Immunol.2005 Jan 1;174(1):261-9.
38. Zhao P, Sharma AC, Ren J. Pathogenesis and therapy of autoimmunity-induced dilated cardiomyopathy. Front Biosci.2009 Jan 1;14:1708-15
39. Xiao J, Shimada M, Liu W, Hu D, Matsumori A. Anti-inflammatory effects of eplerenone on viral myocarditis. Eur J Heart Fail.2009 Apr;11(4):349-53.
40. Mikami S, Kawashima S, Low-dose N omega-nitro-L-arginine methyl ester treatment improves survival rate and decreases myocardial injury in a murine model of viral myocarditis induced by coxsackievirus B3. Circ Res.1997 Oct;81(4):504-11.
41. Seko Y, Takahashi N, Effects of in vivo administration of anti-B7-1/B7-2 monoclonal antibodies on the survival of mice with chronic ongoing myocarditis caused by Coxsackievirus B3. J Pathol.1999 May;188(1):107-12.
2. Feldman AM, McNamara D. Myocarditis. The New England Journal of Medicine 2000;343(19):1388-98.
3. Drory Y, Turetz Y, Hiss Y, Lev B, Fisman EZ, Pines A, et al.Sudden unexpected death in persons less than 40 years of age. American Journal of Cardiology 1991;68(13):1388-92.
4. Ellis CR, Di Salvo T. Myocarditis:basic and clinical aspects. Cardiol Rev.2007 Jul-Aug; 15(4):170-7.
5. Brunetti L, DeSantis ER. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
6. Dec GW Jr, Waldman H, Southern J, Fallon JT, Hutter AM Jr, Palacios I. Viral myocarditis mimicking acute myocardial infarction. Journal of the American College of Cardiology 1992;20:85-9.
7. Parrillo JE. Inflammatory cardiomyopathy (myocarditis):which patients should be treated with anti-inflammatory therapy?. Circulation 2001;104(1):4
8. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, et al.Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy:two-year follow-up results. Circulation 2001;104(1):39-45
9. Brunetti L, DeSantis ER.Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
10. Staudt A, Schaper F, Stangl V, Plagemann A, Bohm M, Merkel K, et al.Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation 2001;103:2681-6
11. Miric M, Miskovic A, Vasiljevic JD, Keserovic N, Pesic M. Interferon and thymic hormones in the therapy of human myocarditis and idiopathic dilated cardiomyopathy. European Heart Journal 1995;Suppl 0:150-2.
12. Grinda JM, Chevalier P, et al. Fulminant myocarditis in adults and children: bi-ventricular assist device for recovery. Eur J Cardiothorac Surg.2004 Dec;26(6):1169-73.
13. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis a histopathologic definition and classification. Am. J. Cardiovasc. Pathol.1987 Jan;1(1):3-14.
14. Chen H, Liu J, Yang M. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev.2006 Oct 18;(4):CD004471.
15. Kitabayashi H, Isobe M, et al. FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes. J Cardiovasc Pharmacol.2000 Mar;35(3):410-6.
16. Knowlton KU. Unsolved medical issues and new targets for further research in viral myocarditis and dilated cardiomyopathy. Ernst Schering Res Found Workshop. 2006;(55):19-35.
17. Wu JL, Matsui S, et al. Amelioration of myocarditis by statin through inhibiting cross-talk between antigen presenting cells and lymphocytes in rats. Mol Cell Cardiol.2008 Jun;44(6):1023-31. Epub 2008 Apr 1.
18. Szalay G, Meiner S, Voigt A, et al. Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial. immunoproteasomes[J]. Am J Pathol,2006.168(5):1542-1552
19.吴辉,唐其柱等,阿托伐他汀对自身免疫性心肌炎小鼠心肌细胞外基质重构的影响.武汉大学学报(医学版),2007,28(2)：172-176
20. Saraste A, Kyto" V, Saraste M, Vuorinen T, Hartiala J, Saukko P. Coronary flow reserve and heart failure in experimental coxsackievirus myocarditis. A transthoracic Doppler echocardiography study. Am J Physiol Heart Circ Physiol 2006;291:H871-5.
21. Broberg CS, Pantely GA, Barber BJ, Mack GK, Lee K, Thigpen T et al. Validation of the myocardial performance index by echocardiography in mice:a noninvasive measure of left ventricular function. J Am Soc Echocardiogr 2003;16:814-23.
22. Rezkalla S, Kloner RA, Khatib G, Khatib R. Effect of delayed captopril therapy on left ventricular mass and myonecrosis during acute coxsackievirus murine myocarditis. Am Heart J.1990 Dec; 120(6 Pt 1):1377-81.
23. Kyto" V, Lapatto R, et al. Glutathione depletion and cardiomyocyte apoptosis in viral myocarditis. Eur J Clin Invest 2004;34:167-75.
24. Zaidi SH, Hui CC, et al. Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis.J Clin Invest.1999 Apr;103(8):1211-9.
25.崔小岱马连华.柯萨奇B3病毒心肌株与非亲心肌株感染小鼠心肌细胞的实验比较.中华实验和临床病毒学杂志.1997(11)3：274-276
26.崔小岱 孙国贤.VitC保护病毒感染小鼠心肌细胞的机理探讨.中华实验和临床病毒学杂志.1993.7：401-404
27.崔小岱 马连华.制造病毒性心肌炎动物模型毒株的比较.中华儿科杂.2000,(38),2：83-85
28. Hufnagel G, Chapman N, Tracy S. A non-cardiovirulent strain of coxsackievirus B3 causes myocarditis in mice with severe combined immunodeficiency syndrome. Eur Heart J.1995 Dec; 16 Suppl 0:18-9.
29. Gauntt CJ, Pallansch MA.Coxsackievirus B3 clinical isolates and murine myocarditis. Virus Res.1996 Mar;41(1):89-99.
30. Szalay G, Meiner S, Voigt A, et al. Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial immunoproteasomes. Am J Pathol,2006.168(5):1542-1552.
31. Lim BK, Shin jo, Choe SC, et al. Myocardial injury occur earlier than myocardial inflammation in acute experimental viral myocarditis.Exp Mol Med,2005,37(1): 51-57.
32. Latva-Hirvela J, Kyto V, et al. Development of troponin autoantibodies in experimental coxsackievirus B3 myocarditis. Eur J Clin Invest.2009 Apr 8.
33. Zhang ZC, Li SJ, Yang YZ, Chen RZ, Ge JB, Chen HZ. Effect of astragaloside on cardiomyocyte apoptosis in murine coxsackievirus B3 myocarditis.J Asian Nat Prod Res.2007 Mar;9(2):145-51.
34. Ellis CR, Di Salvo T.Myocarditis:basic and clinical aspects.Cardiol Rev.2007 Jul-Aug; 15(4):170-7.
35. Seko Y, Yagita H, Okumura K, et al. Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3. Cardiovasc Res.2007 Jul 1;75(1):158-67.
36. Ishiyama S, Hiroe M, Nishikawa T, et al. The Fas/Fas ligand system is involved in the pathogenesis of autoimmune myocarditis in rats. J Immunol.1998 Nov 1;161(9):4695-701.
37. Shovman O, Levy Y, Gilburd B, Shoenfeld Y. Antiinflammatory and immunomodulatory properties of statins.Immunol Res.2002;25(3):271-85.
38. Liu W, Li WM, Gao C, Sun NL. Effects of atorvastatin on the Thl/Th2 polarization of ongoing experimental autoimmune myocarditis in Lewis rats. J Autoimmun.2005 Dec;25(4):258-63.
39. Syka J, Ouda L, Nachtigal P, Solichova D, Semecky V. Atorvastatin slows down the deterioration of inner ear function with age in mice. Neurosci Lett.2007 Jan 10；411(2):112-6.
40. Ghule BV, Ghante MH, Saoji AN, Yeole PGAntihyperlipidemic Effect of the Methanolic Extract from Lagenaria siceraria Stand. Fruit in Hyperlipidemic Rats.J Ethnopharmacol.2009 Apr 24.
41. Seko Y, Kayagaki N, Seino K, Yagita H, Okumura K, Nagai R. Role of Fas/FasL pathway in the activation of infiltrating cells in murine acute myocarditis caused by Coxsackievirus B3. J Am Coll Cardiol.2002 Apr 17;39(8):1399-403.
42. Seko Y. Effect of the angiotensin Ⅱ receptor blocker olmesartan on the development of murine acute myocarditis caused by coxsackievirus B3. Clin Sci (Lond).2006 Mar;110(3):379-86.
43. Seko Y, Yagita H, Okumura K, Azuma M, Nagai R. Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3. Cardiovasc Res.2007 Jul 1;75(1):158-67. Epub 2007 Mar 16.
44. Kawano H, Okada R, Kawano Y, Sueyoshi N, Shirai T. Apoptosis in acute and chronic myocarditis. Jpn Heart J.1994 Nov;35(6):745-50.
45. DeBiasi RL, Robinson BA, et al. Caspase inhibition protects against reovirus-induced myocardial injury in vitro and in vivo. J Virol.2004 Oct;78(20):11040-50.
46. DeBiasi RL, Clarke P, et al. Reovirus-induced alteration in expression of apoptosis and DNA repair genes with potential roles in viral pathogenesis. J Virol.2003 Aug;77(16):8934-47.
47. Huber S, Shi C, Budd RC. Gammadelta T cells promote a Th1 response during coxsackievirus B3 infection in vivo:role of Fas and Fas ligand. J Virol.2002 Jul;76(13):6487-94.
1. Haas GJ. Etiology, evaluation, and management of acute myocarditis. Cardiology in Review 2001;9(2):88-95.
2. Feldman AM, McNamara D. Myocarditis. The New England Journal of Medicine 2000;343(19):1388-98.
3. Drory Y, Turetz Y, Hiss Y, Lev B, Fisman EZ, Pines A, et al.Sudden unexpected death in persons less than 40 years of age. American Journal of Cardiology 1991;68(13):1388-92.
4. Ellis CR, Di Salvo T. Myocarditis:basic and clinical aspects. Cardiol Rev.2007 Jul-Aug;15(4):170-7.
5. Brunetti L, DeSantis ER. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
6. Dec GW Jr, Waldman H, Southern J, Fallon JT, Hutter AM Jr, Palacios I. Viral myocarditis mimicking acute myocardial infarction. Journal of the American College of Cardiology 1992;20:85-9.
7. Parrillo JE. Inflammatory cardiomyopathy (myocarditis):which patients should be treated with anti-inflammatory therapy?. Circulation 2001;104(1):4
8. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, et al.Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy:two-year follow-up results. Circulation 2001;104(1):39-45
9. Brunetti L, DeSantis ER.Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
10. Staudt A, Schaper F, Stangl V, Plagemann A, Bohm M, Merkel K, et al.Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation 2001;103:2681-6
11. Miric M, Miskovic A, Vasiljevic JD, Keserovic N, Pesic M. Interferon and thymic hormones in the therapy of human myocarditis and idiopathic dilated cardiomyopathy. European Heart Journal 1995;Suppl 0:150-2.
12. Grinda JM, Chevalier P, et al. Fulminant myocarditis in adults and children: bi-ventricular assist device for recovery. Eur J Cardiothorac Surg.2004 Dec;26(6):1169-73.
13. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis a histopathologic definition and classification. Am. J. Cardiovasc. Pathol.1987 Jan;1(1):3-14.
14. Chen H, Liu J, Yang M. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev.2006 Oct 18;(4):CD004471.
15. Kitabayashi H, Isobe M, et al. FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes. J Cardiovasc Pharmacol.2000 Mar;35(3):410-6.
16. Knowlton KU. Unsolved medical issues and new targets for further research in viral myocarditis and dilated cardiomyopathy. Ernst Schering Res Found Workshop. 2006;(55):19-35.
17. Maisch B, Schonian U, et al.Immunosuppressive treatment in autoreactive myocarditis results from a controlled trial. Postgrad Med J.1994;70 Suppl 1:S29-34.
18. Doroshenko BH, Nazar PS. Corticosteroid therapy of acute viral myocarditis in patients with severe clinical course of disease. Lik Sprava,2002,74:76.
19. Tomioka N, Kishimoto C, Matsumori A, Kawai C. Effects of prednisolone on acute viral myocarditis in mice. J Am Coll Cardiol.1986 Apr;7(4):868-72.
20. Mason JW, O'Connell JB, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med.1995 Aug 3;333(5):269-75.
21. Szalay G, Meiner S, Voigt A, et al. Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial. immunoproteasomes[J]. Am J Pathol,2006.168(5):1542-1552
22.马沛然,王述昀.皮质激素对病毒性心肌炎疗效及其不良反应预防的实验研究.临床儿科杂志,2004,22(7)：467-469
23. Saraste A, Kyto" V, Saraste M, Vuorinen T, Hartiala J, Saukko P. Coronary flow reserve and heart failure in experimental coxsackievirus myocarditis. A transthoracic Doppler echocardiography study. Am J Physiol Heart Circ Physiol 2006;291:H871-5.
24. Broberg CS, Pantely GA, Barber BJ, Mack GK, Lee K, Thigpen T et al. Validation of the myocardial performance index by echocardiography in mice:a noninvasive measure of left ventricular function. J Am Soc Echocardiogr 2003;16:814-23.
25. Rezkalla S, Kloner RA, Khatib G, Khatib R. Effect of delayed captopril therapy on left ventricular mass and myonecrosis during acute coxsackievirus murine myocarditis. Am Heart J.1990 Dec; 120(6 Pt 1):1377-81.
26. Kyto V, Lapatto R, et al. Glutathione depletion and cardiomyocyte apoptosis in viral myocarditis. Eur J Clin Invest 2004;34:167-75.
27. Lee SS, Singh S, Link K, Petri M. High-sensitivity C-reactive protein as an associate of clinical subsets and organ damage in systemic lupus erythematosus. Semin Arthritis Rheum.2008 Aug;38(1):41-54. Epub 2008 Jan 25.
28. Pearl JM, Nelson DP, et al. Glucocorticoids reduce ischemia-reperfusion-induced myocardial apoptosis in immature hearts. Ann Thorac Surg.2002 Sep;74(3):830-6
29. Granchelli JA, Pollina C, Hudecki MS. Pre-clinical screening of drugs using the mdx mouse. Neuromuscul Disord.2000 Jun;10(4-5):235-9.
30.王述昀,马沛然等,肾上腺皮质激素对病毒性心肌炎小鼠c2Fos基因表达的影响,中华儿科杂志2002年10月Vol 40 No10：614-15
31. Providencia R, Botelho A,et al.Viral myocarditis--new advances. Rev Port Cardiol. 2008 May;27(5):707-22.
32. Brunetti L, DeSantis ER. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
33. Spotnitz MD, Lesch M. Idiopathic dilated cardiomyopathy as a late complication of healed viral (Coxsackie B virus) myocarditis:historical analysis, review of the literature, and a postulated unifying hypothesis.Prog Cardiovasc Dis.2006 Jul-Aug;49(1):42-57.
34.沈茜,汪美先,章同华.原位核酸分子杂交检测柯萨基B3病毒感染小鼠心肌组织中病毒RNA.中华微生物学和免疫学杂志.1991,11(3)：193-196
35. Clarke P, Tyler KL.Apoptosis in animal models of virus-induced disease.Nat Rev Microbiol.2009 Feb;7(2):144-55.
36. Kyto V, Lapatto R, et al. Glutathione depletion and cardiomyocyte apoptosis in viral myocarditis. Eur J Clin Invest.2004 Mar;34(3):167-75.
37. Yamada T, Matsumori A, et al. Apoptosis in congestive heart failure induced by viral myocarditis in mice. Heart Vessels.1999;14(1):29-37.
38. Satoh M, Hiramori K, Tamura G, Satodate R. Apoptosis in the process from viral myocarditis to dilated cardiomyopathy Nippon Rinsho.1996 Jul;54(7):1982-5
39. Kawano H, Okada R, Kawano Y, Sueyoshi N, Shirai T. Apoptosis in acute and chronic myocarditis. Jpn Heart J.1994 Nov;35(6):745-50.
40. DeBiasi RL, Robinson BA, et al. Caspase inhibition protects against reovirus-induced myocardial injury in vitro and in vivo. J Virol.2004 Oct;78(20):11040-50.
41. DeBiasi RL, Clarke P, et al. Reovirus-induced alteration in expression of apoptosis and DNA repair genes with potential roles in viral pathogenesis. J Virol.2003 Aug;77(16):8934-47.
42. Huber S, Shi C, Budd RC. Gammadelta T cells promote a Th1 response during coxsackievirus B3 infection in vivo:role of Fas and Fas ligand. J Virol.2002 Jul;76(13):6487-94.
43. Latham RD, Mulrow JP, Virmani R, Robinowitz M, Moody JM. Recently diagnosed idiopathic dilated cardiomyopathy:incidence of myocarditis and efficacy of prednisone therapy. Am Heart J.1989 Apr; 117(4):876-82.
44. Hosenpud JD, McAnulty JH, Niles NR. Lack of objective improvement in ventricular systolic function in patients with myocarditis treated with azathioprine and prednisone. J Am Coll Cardiol.1985 Oct;6(4):797-801.
45.王述昀,牟道玉,肾上腺皮质激素对柯萨奇B3病毒感染小鼠心肌的保护作用中国动脉硬化杂志.2005年第13卷第3期,313-316
1. Brunetti L, DeSantis ER. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
2. Feldman AM, et al. Myocarditis. N Engl J Med 2000;343:1388-1398.
3. Demmler GJ. In:Long S, et al., eds. Principles and Practice of Pediatric Infectious Diseases.2nd ed.2003:258-261
4. Calabrese F, et al. Molecular diagnosis of myocarditis and dilated cardiomyopathy in children:clinicopathologic features and prognostic implications. Diagn Mol Pathol 2002; 11:212-221
5. JAVETT SN, HEYMANN S, MUNDEL B, Myocarditis in the new newborn infant; a study of an outbreak associated with Coxsackie group B virus infection in a maternity home in Johannesburg. J Pediatr.1956 Jan;48(1):1-22.
6. Hirschman SZ, Hammer GS. Coxsackie virus myopericarditis:a microbiological and clinical review. Am J Cardiol.1974; 34:224-32.
7. Kearney MT, Cotton JM, Richardson PJ et al. Viral myocarditis and dilated cardiomyopathy:mechanisms, manifestations, and management. Postgrad Med J. 2001; 77:4-10.
8. Fujioka S, Kitaura Y. Coxsackie B virus infection in idiopathic dilated cardiomyopathy:clinical and pharmacological implications. BioDrugs.2001; 15:791-9.
9. Cihakova D, Rose NR. Pathogenesis of myocarditis and dilated cardiomyopathy. Adv Immunol.2008;99:95-114.
10. Shimojo T, Hiroe M. Ishiyama S et al. Nitric oxide induces apoptotic death of cardiomyocytes via a cyclic-GMP-dependent pathway. Exp Cell Res.1999; 247:38-17.
11. Spotnitz MD, Lesch M. Idiopathic dilated cardiomyopathy as a late complication of healed viral (Coxsackie B virus) myocarditis:historical analysis, review of the literature, and a postulated unifying hypothesis. Prog Cardiovasc Dis.2006; 49:42-57.
12. Beck MA. Nutritionally induced oxidative stress:effect on viral disease. Am J Clin Nutr.2000; 71
13. Wong CY, Woodruff JJ, Woodruff JF. Generation of cytotoxic T lymphocytes during coxsackievirus tb-3 infection. II. Characterization of effector cells and demonstration cytotoxicity against viral-infected myofibersl. J Immunol.1977 Apr;118(4):1165-9.
14. Hjalmarson A, Fu M, Mobini R. Who are the enemies? Inflammation and autoimmune mechanisms. Eur Heart J Suppl.2002; 4(suppl G):G27-32.
15. Kawai C. From myocarditis to cardiomyopathy:mechanisms of inflammation and cell death:learning from the past for the future. Circulation.1999; 99:1091-100.
16. McManus BM, Chow LH, Wilson JE et al. Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditis. Clin Immunol Immunopathol. 1993; 68:159-69.
17. Huber JT, Silva AG, Campos OF, Mathieu CM. Influence of feeding different amounts of milk on performance, health, and absorption capability of baby calves. J Dairy Sci.1984 Dec;67(12):2957-63.
18. Heim A, Stille-Seigener M, Pring-Akerblom P et al. Recombinant interferons beta and gamma have a higher antiviral activity than interferon-alpha in coxsackie B3-infected carrier state cultures of human myocardial fibroblasts. J Interferon Cytokine Res.1996; 16:283-7.
19. Rotbart HA, Webster AD, for the Pleconaril Treatment Registry Group. Treatment of potentially life-threatening enterovirus infections with pleconaril. Clin Infect Dis. 2001; 32:228-35.
20.宋晓东,刘哲.针对病毒性心肌炎的细胞凋亡研究.中国现代医学杂志,2006,16(23)：3549-3552
21. Yamada T, Matsumori A, et al. Apoptosis in congestive heart failure induced by viral myocarditis in mice. Heart Vessels.1999;14(1):29-37.
22. Satoh M, Hiramori K, Tamura G, Satodate R. Apoptosis in the process from viral myocarditis to dilated cardiomyopathy Nippon Rinsho.1996 Jul;54(7):1982-5
23. Kawano H, Okada R, Kawano Y, Sueyoshi N, Shirai T. Apoptosis in acute and chronic myocarditis. Jpn Heart J.1994 Nov;35(6):745-50.
24. DeBiasi RL, Robinson BA, et al. Caspase inhibition protects against reovirus-induced myocardial injury in vitro and in vivo. J Virol.2004 Oct;78(20):11040-50.
25. DeBiasi RL, Clarke P, et al. Reovirus-induced alteration in expression of apoptosis and DNA repair genes with potential roles in viral pathogenesis. J Virol.2003 Aug;77(16):8934-47.
26. Huber S, Shi C, Budd RC. Gammadelta T cells promote a Th1 response during coxsackievirus B3 infection in vivo:role of Fas and Fas ligand. J Virol.2002 Jul;76(13):6487-94.
27. Yang YZ, Jin PY, Guo Q et al. Effect of Astragalus membranaceus on natural killer cell activity and induction of-and-interferon in patients with Coxsackie B viral myocarditis. Chin Med J.1990; 103:304-7.
28. Sen-Chowdhry S, Syrris P et al. DJ. Left-dominant arrhythmogenic ardiomyopathy: an under-recognized clinical entity. J Am Coll Cardiol.2008 Dec 16;52 (25):2175-87.
29. Calabrese F, Rigo E,.Molecular diagnosis of myocarditis and dilated cardiomyopathy in children:clinicopathologic features and prognostic implications. Diagn Mol Pathol.2002 Dec;11(4):212-21.
30. A, Wang H, Abelmann WH, Crumpacker CS.Treatment of viral myocarditis with ribavirin in an animal preparation.Matsumori Circulation.1985 Apr;71(4):834-9.
31. Chiba K. Nihon Rinsho Meneki Gakkai Kaishi.2009 Apr;32(2):92-101. Japanese. A new therapeutic approach for autoimmune diseases by the sphingosine 1-phosphate receptor modulator, fingolimod (FTY720)
32. Tchorsh-Yutsis D, Hecht G,Pig embryonic pancreatic tissue as a source for transplantation in diabetes:transient treatment with anti-LFA1, anti-CD48 and FTY720 enables long term graft maintenance in mice with only mild ongoing immunosuppression. Diabetes.2009 Apr 28.
33. Rustemeyer J, Krajacic A, Dicke U. Histomorphological and functional impacts of postoperative motor training in rats after allograft sciatic nerve transplantation under low-dose FK 506. Muscle Nerve.2009 Apr;39(4):480-8.
34. Tamaki H, Nakase H, The effect of tacrolimus (FK-506) on Japanese patients with refractory Crohn's disease. J Gastroenterol.2008;43(10):774-9. Epub 2008 Oct 29.
35. Ahdoot J, Galindo A,Use of OKT3 for acute myocarditis in infants and children. J Heart Lung Transplant.2000 Nov;19(11):1118-21.
36. Drucker NA, Colan SD,Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation.1994 Jan;89(1):252-7.
37. Fairweather D, Frisancho-Kiss S, IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart. J Immunol.2005 Jan 1;174(1):261-9.
38. Zhao P, Sharma AC, Ren J. Pathogenesis and therapy of autoimmunity-induced dilated cardiomyopathy. Front Biosci.2009 Jan 1;14:1708-15
39. Xiao J, Shimada M, Liu W, Hu D, Matsumori A. Anti-inflammatory effects of eplerenone on viral myocarditis. Eur J Heart Fail.2009 Apr;11(4):349-53.
40. Mikami S, Kawashima S, Low-dose N omega-nitro-L-arginine methyl ester treatment improves survival rate and decreases myocardial injury in a murine model of viral myocarditis induced by coxsackievirus B3. Circ Res.1997 Oct;81(4):504-11.
41. Seko Y, Takahashi N, Effects of in vivo administration of anti-B7-1/B7-2 monoclonal antibodies on the survival of mice with chronic ongoing myocarditis caused by Coxsackievirus B3. J Pathol.1999 May;188(1):107-12.