Background:Coxsackie-B-viruses (CVB) are frequent causes of acute myocarditis and dilated cardiomyopathy, but an effective antiviral therapy is still not available. Previously, we and others have demonstrated that treatment with an engineered sCAR-Fc (soluble coxsackievirus-adenovirus receptor fused to the carboxyl-terminus of human IgG) efficiently neutralizes CVB3 and inhibits the development of cardiac dysfunction in mice with acute CVB3-induced myocarditis. In this study, we analyzed the potential of sCAR-Fc for treatment of chronic CVB3-induced myocarditis in an outbred NMRI mouse model.Methods:NMRI mice were infected with the CVB3 strain 31-1-93 and treated with a sCAR-Fc expressing adeno-associated virus 9 vector 1, 3, and 7 days after CVB3 infection. Chronic myocarditis was analyzed on day 28 after infection.Results:Initial investigations showed that NMRI mice develop pronounced chronic myocarditis between day 18 and day 28 after infection with the CVB3 strain 31-1-93. Chronic cardiac infection was characterized by inflammation and fibrosis as well as persistence of viral genomes in the heart tissue and by cardiac dysfunction. Treatment of NMRI mice resulted in a distinct reduction of cardiac inflammation and fibrosis and almost complete elimination of virus RNA from the heart by day 28 after infection. Moreover, hemodynamic measurement revealed improved cardiac contractility and diastolic relaxation in treated mice compared with mice treated with a control vector (mean±SD; maximal pressure, 81.9±9.2 versus 69.4±8.6 mm Hg, P=0.02; left ventricular ejection fraction, 68.9±8.5 versus 54.2±11.5%, P=0.02; dP/dt_max, 7275.2±1674 versus 4432.6±1107 mm Hg/s, P=0.004; dP/dt_min, −4046.9±776 versus −3146.3±642 mm Hg/s, P=0.046). The therapeutic potential of sCAR-Fc is limited, however, since postponed start of sCAR-Fc treatment either 3 or 7 days after infection could not attenuate myocardial injury.Conclusions:Early therapeutic employment of sCAR-Fc, initiated at the beginning of the primary viremia, inhibits the development of chronic CVB3-induced myocarditis and improves the cardiac function to a level equivalent to that of uninfected animals.

中文翻译：

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可溶性柯萨奇病毒-腺病毒受体对柯萨奇病毒B3感染的动物的早期治疗抑制了慢性柯萨奇病毒B3心肌病的发展。

背景：柯萨奇B病毒（CVB）是急性心肌炎和扩张型心肌病的常见病因，但仍然没有有效的抗病毒治疗方法。以前，我们和其他人证明用工程sCAR-Fc（与人IgG羧基末端融合的可溶性柯萨奇病毒-腺病毒受体）治疗可以有效中和CVB3，并抑制患有急性CVB3诱导的心肌炎的小鼠心脏功能障碍的发展。在这项研究中，我们分析了sCAR-Fc在异种NMRI小鼠模型中治疗慢性CVB3诱发的心肌炎的潜力。方法：NMRI小鼠感染CVB3株31-1-93并用表达sCAR-Fc的药物治疗CVB3感染后第1天，第3天和第7天感染了腺相关病毒9载体。感染后第28天对慢性心肌炎进行了分析。结果：初步研究表明，NMRI小鼠在感染CVB3株31-1-93之后的第18天到28天之间出现明显的慢性心肌炎。慢性心脏感染的特征是炎症和纤维化以及心脏组织中病毒基因组的持久性和心脏功能障碍。感染后第28天，对NMRI小鼠的治疗可明显减少心脏炎症和纤维化，并从心脏中几乎完全清除病毒RNA。此外，血流动力学测量显示，与使用对照载体治疗的小鼠相比，治疗小鼠的心脏收缩力和舒张舒张性有所改善（平均值±SD；最大压力分别为81.9±9.2和69.4±8.6 mm Hg，慢性心脏感染的特征是炎症和纤维化以及心脏组织中病毒基因组的持久性和心脏功能障碍。感染后第28天，对NMRI小鼠的治疗可明显减少心脏炎症和纤维化，并从心脏中几乎完全清除病毒RNA。此外，血流动力学测量显示，与使用对照载体治疗的小鼠相比，治疗小鼠的心脏收缩力和舒张舒张性有所改善（平均值±SD；最大压力分别为81.9±9.2和69.4±8.6 mm Hg，慢性心脏感染的特征是炎症和纤维化以及心脏组织中病毒基因组的持久性和心脏功能障碍。感染后第28天，对NMRI小鼠的治疗可明显减少心脏炎症和纤维化，并从心脏中几乎完全清除病毒RNA。此外，血流动力学测量显示，与使用对照载体治疗的小鼠相比，治疗小鼠的心脏收缩力和舒张舒张性有所改善（平均值±SD；最大压力分别为81.9±9.2和69.4±8.6 mm Hg，感染后第28天，对NMRI小鼠的治疗可明显减少心脏炎症和纤维化，并从心脏中几乎完全清除病毒RNA。此外，血流动力学测量显示，与使用对照载体治疗的小鼠相比，治疗小鼠的心脏收缩力和舒张舒张性有所改善（平均值±SD；最大压力分别为81.9±9.2和69.4±8.6 mm Hg，感染后第28天，对NMRI小鼠的治疗可明显减少心脏炎症和纤维化，并从心脏中几乎完全清除病毒RNA。此外，血流动力学测量显示，与使用对照载体治疗的小鼠相比，治疗小鼠的心脏收缩力和舒张舒张性有所改善（平均值±SD；最大压力分别为81.9±9.2和69.4±8.6 mm Hg，P = 0.02；左心室射血分数，68.9±8.5对54.2±11.5％，P = 0.02; dP / dt _max，为7275.2±1674，而4432.6±1107 mm Hg / s，P = 0.004；dP / dt _min，-4046.9±776与-3146.3±642 mm Hg / s，P = 0.046）。sCAR-Fc的治疗潜力有限，但是，由于感染后3或7天推迟开始sCAR-Fc治疗不能减轻心肌损伤。病毒血症抑制慢性CVB3诱导的心肌炎的发展，并将心脏功能提高到与未感染动物相同的水平。