Mechanisms of Myocardial Radiofrequency Scar Expansion

经导管射频消融是控制儿科患者药理学难治性心律失常的一种重要方式。虽然射频消融术能有效地终止儿童心律失常，但对射频损伤后发生的心肌重构仍知之甚少。临床病例报告提供的证据表明，瘢痕扩大发生在射频消融后的婴儿。此外，在儿童动物模型中，射频疤痕已被证明以时间依赖的方式增加。因此，射频消融术后儿科患者心肌中可能出现明显的射频瘢痕扩张。因此，本研究的总体目标是确定在儿童动物模型中导致RF疤痕扩大的心肌重塑的决定因素，并确定这一事件的生理后果。此外，一个潜在的分子机制，有助于扩大射频烧蚀疤痕将被定义。射频消融瘢痕的扩张必须伴有心肌重构。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，这个项目的总体假设是，MMP活性升高发生在射频消融损伤形成之后，并且沿着射频疤痕的边界区保持升高，直接导致疤痕扩张。在射频损伤形成期间和之后，直接中断MMP的激活将导致射频疤痕扩张的衰减和这一过程的生理后果。为了验证这一假设，将测量射频疤痕边缘的MMP表达和活性程度，并将其与射频疤痕大小的时间变化联系起来。此外，为了更精确地定义MMP活性在射频疤痕扩展中的作用，将进行两组实验。首先，在一组动物RF病变形成时对其进行MMP抑制，并在随访期间继续进行。其次，将在缺乏负责MMP表达或内源性控制MMP活性的基因的转基因小鼠中检测RF疤痕扩展特性。因此，本研究的结果将定义儿童模型中射频病变扩张的生理后果，确定射频瘢痕扩张的分子基础，并确定一种潜在的治疗方式来减弱这一过程。

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.