经导管去肾交感神经支配术对急性心肌梗死后左室重塑的影响及相关机制

The chronic overactivity of thesympathetic nervous system is the main mechanism of post-MI myocardial remodeling which often resulting in heart failure. By disrupting the afferent and the efferent neuro-traffic, the Catheter-based Renal Sympathetic Denervation (CRSD) significantly reduced the activation of renal and systemic sympathetic system, and has been shown to be a viable therapeutic approach for resistant hypertension and a series of illnesses related to chronic sympathetic activation. However, the?the validity of this novel therapeutic strategy has not been tested on post-MI myocardial remodeling. Accordingly, we developed a STEMI mini-pig model by balloon occlusion method and performed echocardiography, post-mortem morphological and histological analysis to evaluated the effects of CRSD on post-MI myocardial remodeling. The activity of systemic, renal and cardiac sympathetic nerve would be determined by measuring plasma and tissue NE, respectively. In parallel, RAS activation would be determined by measuring plasma RAS and the expression of RAS receptors in corresponding tissues. Molecluar changes, such as apoptotic, inflammatory, and fibrotic markers are also investigated. Furthermore, we would explore novel parameters to accurately reflect the clinical outcome of CRSD treatment as well as in combination with ACEI and b-Blocker. In summary, we aim to provide primary experimental data to evaluate the clinical applicability of CRSD on preventing post-MI myocardial remodeling.

急性心肌梗死后左室重塑是一个多神经体液因素参与的进展性过程，是心衰发生发展的基本机制，其中交感神经慢性过度激活在整个病理过程中发挥了重要作用。近年来新兴的经导管去肾交感神经支配术（CRSD）通过降低肾脏及全身交感神经活性，在多种交感神经过度激活性疾病中展现了显著的改善效果，但目前尚无临床及动物实验证实其对梗死后左室重塑的作用。本研究拟采用球囊封堵法建立小型猪ST段抬高心肌梗死模型，并行CRSD。通过肾动脉病理切片、肾动脉血流状态及尿钠尿量改变验证CRSD有效性并探寻手术成功的临床指标；通过形态学、病理组织学以及分子生物学指标评价心室重构情况,研究CRSD对全身和心、肾交感神经和RAS活性，以及心脏局部重构相关的凋亡、炎症、纤维化细胞分子影响,以明确CRSD改善心梗后左室重塑作用机制；进一步研究CRSD的药物优化方案，为CRSD日后在临床上用于心梗后心室重构的防治提供实验依据及理论支持。

本研究拟在动物模型中讨论经导管肾脏去交感神经支配术(Renal denervation,RDN)对急性心肌梗死后左室重塑的影响及机制:第一部分采用球囊封堵再灌注法建立小型猪心肌梗死模型，通过形态学、功能学、病理组织学以及血清学指标验证心肌梗死后左室重塑的发生、发展情况，证实模型成功建立；第二部分在心梗造模后行RDN，通过病理染色从组织水平观察证实肾脏交感神经的成功消除，通过形态学、功能学、病理组织学以及血清学指标验证RDN对急性心肌梗死后左室重塑的影响；第三部分初探机制，通过比较基线状态、心梗后、RDN后和8周后外周静脉、肾静脉血及肾脏皮质和心脏组织去甲肾上腺素、肾上腺素浓度，及肾素活性、血管紧张素II、醛固酮浓度，讨论RDN对急性心肌梗死动物模型循环、肾脏和心脏交感神经系统及肾素血管紧张醛固酮系统活性的影响。.研究结果表明球囊封堵前降支建立急性心肌缺血再灌注模型安全有效，存活率80%(28/35)。实验证实RDN能够改善急性心梗再灌注8周后的心功能状态，超声检查显示RDN能够显著增加实验模型8周后的心脏舒张末期容量EDV，提示其能够改善急性心梗再灌注后由于高交感活性引起的心室纤维化及顺应性降低，病理检查也显示RDN能够明显降低实验组心脏质量指数及心脏重构指数，masson及天狼星染色提示其可以改善梗死远端心肌的反应性纤维化，都证实RDN能够改善心梗再灌注后的心脏重构。通过进一步检测交感神经系统（去甲肾上腺素NE）及RAAS系统（肾素、血管紧张素II、醛固酮）的生物标志物显示RDN能够显著降低肾脏皮质的去甲肾上腺素水平，提示消融方式有效；静脉血检测结果显示RDN能够降低全身的交感神经活性及RAAS系统活性，提示肾动脉交感神经消融能够降低全身的交感神经活性；最后通过检测梗死远端部位的去甲肾上腺素水平证实RDN能够改善由于心梗后交感神经高活性状态导致的“心肌去甲肾上腺素储存耗竭”，实验组NE显著高于对照组，提示心脏高交感兴奋受到有效抑制。.综上，我们认为RDN能够有效降低急性心梗再灌注后全身及心脏的交感神经活性，从而改善心功能及心脏重构。