透析相关线粒体能量代谢障碍在血透诱导心肌顿抑中的功能机制研究

The prevalence and mortality of cardiovascular disease in hemodialysis patients are significantly higher than those in the general population. Our previous studies found that over 60% of hemodialysis patients had hemodialysis induced myocardial stunning (HIMS), which was significantly related to the decrease of blood volume during dialysis sessions. However, there is little research on the mechanisms of HIMS. Further experiments showed that there are many abnormal expressions of mitochondrial energy metabolism related proteins in uremic models. Besides, the reduced circulating volume lead to abnormal mitochondrial ultrastructure in stunned myocardium, suggesting that mitochondrial energy metabolism disturbance may be the key pathogenesis of HIMS. At the same time, the concentrations of K+ and Ca2+ changes significantly in hemodialysis. What effects are the changes of these metabolic related ions on the mitochondrion? Do they interfere with mitochondrial energy metabolism? It's not yet clear. On the basis of preliminary studies, this study aims to investigate the decreased circulatory volume and changes of ion concentrations on the impact of mitochondrial energy metabolism and myocardial stunning. And also to explore the cardio-protective mitoKATP channel opener on the protective effect of HIMS. So as to elucidate the pathogenesis of HIMS and to seek effective intervention measures, which has important significance to reduce cardiovascular complications in hemodialysis patients.

血透患者心血管疾病发病率和死亡率极高，我们前期研究发现60%以上血透患者存在血透诱导的心肌顿抑（HIMS），但目前对HIMS发生机制鲜有研究。我们进一步实验发现尿毒症模型大鼠存在多种线粒体能量代谢相关蛋白表达异常，与血透相当的循环血量下降可引起顿抑心肌线粒体超微结构异常，但不出现缺血性心肌损伤经典的微丝破坏，提示线粒体能量代谢障碍可能是HIMS的关键和特有发病机制。同时，血透时生命重要离子浓度的显著变化（K+快速下降和Ca2+快速升高）对线粒体能量代谢产生何种影响？尚不清楚。本项目拟在前期研究基础上，借助小动物透析和离体心脏灌流技术，研究并揭示容量下降和生命重要离子浓度变化对线粒体能量代谢和心肌顿抑的影响及其关键机制，探索心脏保护性通道mitoKATP开放剂对HIMS的保护作用，阐明HIMS的发病机制，寻求有效干预措施。本项目如获资助并取得预期成果将对防治血透患者心血管并发症具有重要意义。

心血管疾病在血透患者中广泛存在，且是血透患者主要死亡原因之一。我们前期研究发现约60%以上血透患者存在血透诱导的心肌顿抑（HIMS），但HIMS发生机制尚不明确。本研究使用5/6肾切除大鼠搭建小动物血液透析平台，比较使用不同离子浓度透析液情况下心肌线粒体能量代谢指标和心肌顿抑发生情况。结果显示，当使用低钾、低钙透析液和血钾、血钙降低显著时，线粒体H-ATP酶活性、线粒体膜电位、线粒体内钙超载显著异常，同时实时超声心动图显示心肌纵向应变和径向应变显著下降。使用特异性 mitoKATP开放剂二氮嗪和钙通道阻滞剂Adalat 有助于减轻透析峰值压力时心肌收缩功能的减退和线粒体代谢异常。反之，使用特异性 mitoKATP阻断剂5-HD可加重前述异常，同时线粒体形态出现肿胀、大小不一，部分线粒体嵴断裂。临床研究同样证实血液透析中患者心肌收缩功能可逆性受损（环向和纵向应变均减小），透析结束后可逐渐恢复。超滤量、透析后血钾、血钙下降幅度与心肌顿抑发生呈正相关。该研究提示使用心脏保护性通道mitoKATP开放剂对血液透析中离子浓度改变诱发的HIMS具有潜在保护作用，有望成为透析患者心肌保护的新的干预靶点。