尿酸对心房重塑的影响及其机制的研究

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmias leading to public health crisis all over the world. It was found that elevated uric acid (UA) was a risk factor of new onset AF. However, what was the mechanism of UA affecting AF was not elucidated. It was well known that atrial remodeling played a pivotal role in the onset and maintenance of AF. Oxidative stress was one of the most important pathways in atrial remodeling. According to the fact that UA had the ability of pro-oxidative stress and proinflammation, we had the hypothesis that atrial remodeling induced by UA was the main mechanism of UA associated with AF. In this study, atrial effective refractory period, atrial voltage, AF induction, atrial fibrosis, distribution of connexins were analyzed in an experimental hyperuricemia rats in order to identify if UA mediated the process of atrial remodeling. The active oxygen radials were arrayed and the impact of tempol was observed in order to explore if oxidative stress played an important role in the UA mediated AF. Allopurinol and benzbromarone were used to low UA. Atrial remodeling parameters were also arrayed in order to find if atrial remodeling could be relieved by UA modification. It will provide theoretical evidence of UA modification to influence of AF risk after investigating the mechanism of UA associated AF. Lowering UA might be a new target in up-stream therapy in AF.

心房颤动（房颤）是严重危害人群健康的最常见的持续性心律失常。新近的研究发现高尿酸血症是新发房颤的危险因素，但是尿酸参与房颤发病的机制尚不清楚。目前认为心房重构对房颤的发生和维持均起到关键作用，氧化应激是心房重构的重要机制。尿酸具有促进氧化应激的作用，我们提出假设：尿酸通过氧化应激途径引起心房重构是尿酸导致房颤的重要机制。本研究拟建立高尿酸血症的大鼠模型，分析高尿酸血症大鼠左右心房不应期、心房电压、房颤诱发率等电生理特点以及心房纤维化、连接蛋白分布等组织学特征，以明确尿酸对心房重塑的影响。测定左右心房活性氧自由基的水平，观察抗氧化剂进行干预的效果，探讨尿酸引起心房重塑的氧化应激机制。应用别嘌呤醇、苯溴马隆等药物抑制氧化应激、降低尿酸水平，评价降低尿酸对心房重塑的影响。探讨尿酸引起房颤的发病机制，为采取针对性的干预方法降低房颤发病率提供了重要的理论依据，有望为房颤的上游治疗增加新的干预靶点。

背景与目的：高尿酸血症是新发房颤的危险因素，但是尿酸参与房颤发病的机制尚不明确。本研究目的在于探讨尿酸致房颤的机制，包括对心房的电生理特性的影响，致炎症机制。. 方法： 36只Wistar大鼠随机分为对照组、高尿酸组和高尿酸＋别嘌呤组，通过氧嗪酸灌胃建立高尿酸血症大鼠模型。经颈静脉插管，置入标测电极导管，S1S2刺激测定心房不应期、房室结不应期。S1S2、Burst刺激诱发房颤，比较各组间房颤诱发率。测定各组血清高敏C反应蛋白。. 主要成果：（1）建立大鼠高尿酸血症动物模型，通过氧嗪酸灌胃，高尿酸组血清尿酸水平显著高于对照组，证明高尿酸血症模型成功；（2）颈静脉插管进行大鼠心内电生理检查，颈静脉插管进行大鼠心内电生理检查是本研究的技术难点，应用国产导管成功进行颈静脉插管，为以后进行电生理检查创造了条件；（3）高尿酸血症组心房不应期显著短于对照组，高尿酸血症房颤诱发率显著高于对照组，但是别嘌呤未显著降低房颤诱发率；（4）对照组、高尿酸组和高尿酸＋别嘌呤组三组间房室结不应期、校正窦房结恢复时间无显著性差异；（5）对照组、高尿酸组和高尿酸＋别嘌呤组炎症标记物无显著性差异。.意义：本研究通过动物实验证实高尿酸可引起心房不应期缩短等心房电生理重构，高尿酸使房颤易诱发。为揭示高尿酸致房颤的机制提供了重要的依据。