心率管理对延缓病毒性心肌炎向扩张型心肌病演变的作用及机制研究

It is well established that increased heart rate is a risk factor for the development of cardiovascular events. Heart rate-controlling treatments exert several beneficial effects. We have found that increased heart rate is associated with systemic inflammation, leads to severe inflammatory injury and increases mortality in acute myocarditis, and both β-blockade and pure bradycardic agent significantly reduced the myocardial inflammation in murine acute viral myocarditis. However, the effects of heart rate reduction on the prevention of progression from viral myocarditis to dilated cardiomyopathy are unknown. Our previous studies have demonstrated that heart rate-lowering treatments significantly downregulated the expression of proinflammatory cytokines in acute myocarditis, which were associated with myocardial fibrosis and remolding. Hence, we postulate that heart-rate-reducing drugs might prevent progression from viral myocarditis to dilated cardiomyopathy by inhibiting myocardial inflammation and fibrosis and remolding. In the present study, we will investigate whether heart-rate-reducing drugs attenuates inflammation and prevents progression from viral myocarditis to dilated cardiomyopathy in mice with chronic viral myocarditis induced by coxsackievirus B3. Cardiac size and function, inflammatory cytokines, myocardial fibrosis, MAPK protein expression within the myocardium will be determined using quantitative PCR. The most novel insight of the study is that heart rate might be associated with the progression from viral myocarditis to dilated cardiomyopathy. The study will help elucidate the novel mechanism involved in the progression from viral myocarditis to dilated cardiomyopathy, and open new possibilities in the therapeutic management of viral myocarditis.

心率是心血管疾病的晴雨表。心率的管理显著改善心血管疾病的预后。我们前期研究发现，心率在急性病毒性心肌炎（VMC）中介导促炎作用，心率增快，炎症反应增强，死亡率增加，无论采用β受体阻断剂还是单纯减慢心率药物均可以降低急性VMC小鼠心肌炎症反应。然而，心率的管理能否延缓VMC向扩张型心肌病（DCM）的演变尚未见报道。申请者发现，心率降低后可抑制多种促炎因子的表达，而这些炎症因子与VMC心肌纤维化相关，这些启示我们心率降低后很可能通过调控炎症因子的表达改善心肌纤维化，从而阻止VMC演变成DCM。本项目以慢性VMC小鼠为研究对象，从降低/增加小鼠心率着手，观察心率降低或增加后对VMC向DCM转化的作用，解析其抗心肌纤维化的下游信号转导机制。本项目最大特色是将VMC演变成DCM的机制与心率相联系。开展此项研究，不仅对VMC演变成DCM的发生发展机制提供新认识，而且还可能对VMC的治疗提供崭新的思路。

心率是心血管疾病的晴雨表。心率的管理显著改善心血管疾病的预后。我们前期研究发现，心率在急性病毒性心肌炎（VMC）中介导促炎作用，心率增快，炎症反应增强，死亡率增加，无论采用β受体阻断剂还是单纯减慢心率药物均可以降低急性VMC小鼠心肌炎症反应。然而，心率的管理能否延缓VMC向扩张型心肌病（DCM）的演变尚未见报道。伊伐布雷定（Ivabradine，IVA）是一种特异性作用于窦房结P细胞的If通道的抑制剂，只单纯发挥减慢心率作用。本项目旨在通过柯萨奇病毒B3（coxsackie virus B3, CVB3）反复刺激Balb/c小鼠来建立CVMC模型，经IVA治疗后来进一步探讨其对CVMC演变成DCM的作用，明确减慢心率对小鼠生存率、心功能、炎症因子的表达、心肌细胞凋亡、心肌组织纤维化及逆转心室重塑的作用，初步探讨p38MAPK通路是否参与IVA抑制慢性病毒性心肌炎小鼠心肌重塑及其作用。慢性病毒性心肌炎组小鼠厌食精神状态欠佳，体重减轻，毛发粗糙无光泽，死亡率明显高于正常空白对照组。慢性病毒性心肌炎小鼠心肌间质纤维化明显加重, TNF-α、IL-1β及IL-6的表达均明显上调,心腔扩大，心室壁明显变薄，LVEF和LVFS明显下降，差异均有统计学意义（P<0.05）。30天后，经IVA治疗的慢性心肌炎小鼠的生存率80%（16/20），显著高于未处理组小鼠的生存率48.57% (17/35)。IVA能显著降低心肌组织胶原蛋白水平，减少心肌组织纤维化程度，减慢心室率，逆转心室重塑，抑制并逆转心腔扩大，心室壁及室间隔厚度明显增加，LVEF及FS升高，差异均有统计学意义（P<0.05）。经IVA治疗后CVMC小鼠凋亡的心肌细胞明显减少，Bax及Caspase-3蛋白表达降低，Bcl-2表达量升高，炎症因子水平明显下降，p38 MAPK通路蛋白表达水平明显下调，差异均有统计学意义（P<0.05）。本项目最大特色是将VMC演变成DCM的机制与心率相联系。开展此项研究，不仅对VMC演变成DCM的发生发展机制提供新认识，而且还可能为VMC的治疗提供崭新的思路。