Impact of Atrial Fibrillation and Surgical Ablation on Atrial Function

描述（由申请人提供）：房颤（AF）是所有心律失常中最常见的，困扰着全球近550万人。Cox-Maze（CM）手术目前是治疗AF的外科金标准，在过去的六到七年中，每年进行的手术数量大大增加。射频（RF）消融使手术更安全、更快速，新指南已将手术命名为AF导管治疗方法的补充方式。然而，CM手术的生理效应方面的信息很少。此外，认为心房尺寸增大和结构重塑引起的广泛纤维化增加了该手术的失败率，但目前没有方法 能够预测个体患者的结果。该提案的第一部分旨在精确描述持续性AF对心房血流动力学和结构重构的影响。将采用持续性AF的Hanford小型猪模型，其中将以400 bpm对动物进行心房起搏，心室反应率维持在3：1至5：1。这些动物将在开始快速起搏前进行心脏MRI（cMRI）扫描，并在模拟AF两个月后再次进行扫描。将两个时间点的数据与电导导管的压力-容积数据相关联，并与对照组进行比较。在终末研究中，将对心脏的所有四个腔室和两个心房附件进行采样，并进行组织学分析，以评价核变化、纤维化、糖原积累、肌溶解和细胞凋亡的程度。免疫组织化学和蛋白质印迹也将用于定位和定量促凋亡蛋白和抗凋亡蛋白。此外，所有动物将在基线和两个月后接受延迟增强（DE）-MRI扫描，心房增强将与组织学相关，以验证DE-MRI作为能够检测心房纤维化程度的方法。本提案的第二部分将在持续性AF的同一猪模型中测试每个单独CM IV损伤组对心房功能的影响。动物将被随机分为六组，并接受改良的CM程序。动物将接受肺静脉隔离，以及右心房和左心房（LA）病变，这些病变包括6个组中每个组中不同顺序的CM IV手术。将在每个病变集之前和之后采集压力-容积数据。第一次阅读将为我们提供持续性AF两个月后的基线功能，最终阅读将为我们提供完整CM IV病变集完成后的功能，从而使我们能够量化每个病变对整个手术和AF本身血流动力学变化的影响。最后，我们计划测试左心耳（LAA）切除或消融对LA功能的影响。在10只小型猪中，左心耳将在基部进行双极射频消融，并允许保持电静默或与左心房的其余部分同步起搏。功能将 在基线、上述两种情况下和夹闭后，使用电导导管记录。 公共卫生相关性：该提案将确定持续性房颤对心脏功能的影响，将血流动力学变化与结构重塑联系起来，并尝试验证一种新型MRI方法，该方法用于评估心房纤维化，并有可能帮助外科医生预测哪些个体患者会或不会对Cox-Maze手术做出反应。此外，将依次检查包括考克斯-迷宫IV手术的单独病变组的影响，以了解在持续性房颤的情况下手术对心脏功能的损害。知识来自于 本研究将告知在当前临床实践中看到的Cox-Maze程序的扩展使用，指导心律失常的未来手术方法，并阐明心房颤动的重要动物模型中的病理生理学。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common of all cardiac arrhythmias, afflicting nearly 5.5 million people worldwide. The Cox-Maze (CM) procedure is currently the surgical gold standard for the treatment of AF, and the number of operations performed annually has increased greatly in the last six to seven years. Radiofrequency (RF) ablation has made the operation safer and faster to perform, and new guidelines have named surgery as a complimentary modality to catheter based approaches to AF. However, only a paucity of information exists on the physiologic effects of the CM procedure. Moreover, it is thought that enlargement in atrial size and extensive fibrosis from structural remodeling increase the failure rate of this operation, but there is currently no method capable of predicting outcomes in individual patients. The first part of this proposal aims to precisely describe the effects that persistent AF has on atrial hemodynamics and structural remodeling. A Hanford mini-swine model of persistent AF will be employed whereby the animals will be atrially paced at 400 bpm with the ventricular response rate maintained at 3:1 to 5:1. These animals will undergo a cardiac MRI (cMRI) scan prior to initiation of rapid pacing and again after two months in simulated AF. Data from both time points will be correlated with pressure-volume data from conductance catheters and compared to controls. At the terminal study, all four chambers of the heart and both atrial appendages will be sampled and undergo histological analysis to evaluate the degree of nuclear changes, fibrosis, glycogen accumulation, myolysis and apoptosis. Immunohistochemistry and Western blotting will also be used to localize and quantitate pro- and anti-apoptotic proteins. Additionally, all animals will undergo a delayed-enhancement (DE)-MRI scan at baseline and after two months, and atrial enhancement will be correlated with histology in an attempt to validate DE-MRI as a method able to detect the degree of atrial fibrosis. The second part of this proposal will test the effect of each of the individual CM IV lesion sets on atrial function in the same swine model of persistent AF. The animals will be randomized to six groups and undergo a modified CM procedure. Animals will undergo pulmonary vein isolation, as well as the right and left atrial (LA) lesions that comprise the CM IV procedure in a different sequence in each of the six groups. Pressure-volume data will be taken before and after each lesion set. The first reading will give us baseline function after two months of persistent AF and the final reading will give us function after the full CM IV lesion set has been completed, thereby allowing us to quantify the effects of each lesion in relation to both the entire operation and hemodynamic changes from AF itself. Finally, we plan to test the effect that removal or ablation of the left atrial appendage (LAA) has on LA function. The LAA will undergo bipolar RF ablation at the base and either be allowed to remain electrically silent or paced synchronously with the rest of the LA in ten mini-swine. Function will be recorded using conductance catheters at baseline, in the above two scenarios and following clamping. PUBLIC HEALTH RELEVANCE: This proposal will determine the effects of persistent atrial fibrillation on cardiac function, correlate the hemodynamic changes with structural remodeling, and attempt to validate a novel MRI method that is used to assess atrial fibrosis and has the potential to aid a surgeon in predicting which individual patients will or will not respond to the Cox-Maze procedure. Moreover, the effects of the separate lesion sets that comprise the Cox- Maze IV operation will be examined sequentially in order to learn what detriment the operation has on cardiac function in the setting of persistent atrial fibrillation. The knowledge gained from this study will inform the expanded use of the Cox-Maze procedure that is seen in current clinical practice, direct future surgical approaches to the arrhythmia and elucidate the pathophysiology in an important animal model of atrial fibrillation.