Mechanisms of Myocardial Radiofrequency Scar Expansion

经导管射频消融是治疗小儿难治性心律失常的重要手段。虽然射频消融能有效终止儿童心律失常，但对射频损伤后发生的心肌重塑仍知之甚少。临床病例报告提供的证据表明，婴儿射频消融后会发生瘢痕扩张。此外，在儿科动物模型中，已证明RF瘢痕以时间依赖性方式增加。因此，射频消融后儿科患者的心肌可能会出现显著的射频瘢痕扩张。因此，本研究的总体目标是确定导致儿科动物模型中RF瘢痕扩张的心肌重塑的决定因素，并确定该事件的生理后果。此外，一个潜在的分子机制，有助于扩大射频消融疤痕将被定义。射频消融瘢痕的扩大必然伴随着心肌重构。负责细胞外胶原降解和重塑的内源性酶系统是基质金属蛋白酶（MMPs）。因此，本项目的总体假设是，在创建RF消融性损伤后MMP活性升高，并且MMP活性沿RF瘢痕的边界区域保持沿着升高，并直接导致瘢痕扩张。在RF损伤创建期间和之后直接中断MMP激活将导致RF瘢痕扩张的衰减和该过程的生理后果。为了检验这一假设，将测量RF瘢痕边缘处MMP表达和活性的程度，并将其与RF瘢痕大小的时间变化相关。此外，为了更精确地定义MMP活性在RF瘢痕扩张中的作用，将进行两组实验。首先，将在RF损伤形成时在一组动物中开始MMP抑制，并持续至随访期。第二，将在缺乏负责MMP表达或MMP活性的内源性控制的基因的转基因小鼠中检查RF瘢痕扩张特征。因此，本研究的结果将定义儿科模型中射频损伤扩张的生理后果，确定射频瘢痕扩张的分子基础，并确定减弱该过程的潜在治疗方式。

Transcatheter radiofrequency (RF) ablation is an important modality for the control of pharmacologically refractory arrhythmias in pediatric patients. While RF ablation effectively terminates arrhythmias in children, the myocardial remodeling that occurs following the creation of a RF lesion remains poorly understood. Clinical case reports have provided evidence to suggest that scar expansion occurs following RF ablation in infants. Furthermore, in a pediatric animal model, RF scars have been demonstrated to increase in a time dependent manner. Thus, significant RF scar expansion may occur in the myocardium of pediatric patients following RF ablation. Accordingly, the overall goal of this study is to define determinants responsible for myocardial remodeling which results in RF scar expansion in a pediatric animal model and to determine the physiological consequences of this event. Furthermore, a potential molecular mechanism which contributes to expansion of the RF ablative scar will be defined. Expansion of the RF ablative scar must be accompanied by myocardial remodeling. An endogenous enzyme system responsible for extracellular collagen degradation and remodeling is the matrix metalloproteinases (MMPs). Therefore, the overall hypothesis of this project is that heightened MMP activity occurs following the creation of a RF ablative lesion, and which remains elevated along the border zone of the RF scar and directly contributes to scar expansion. Direct interruption of MMP activation during and following RF lesion creation will result in an attenuation of RF scar expansion and the physiological consequences of this process. To test this hypothesis, the degree of MMP expression and activity at the border of the RF scar will be measured and related to temporal changes in RF scar size. Furthermore, in order to more precisely define the role of MMP activity in RF scar expansion, two sets of experiments will be performed. First, MMP inhibition will be instituted in a set of animals at the time of RF lesion creation and continued through the follow up period. Second, the RF scar expansion characteristics will be examined in transgenic mice lacking the genes responsible for MMP expression or endogenous control of MMP activity. Thus, results of this study will define the physiological consequences of RF lesion expansion in a pediatric model, determine the molecular basis for RF scar expansion, as well as identify a potential therapeutic modality to attenuate this process.