Mechanisms of Myocardial Radiofrequency Scar Expansion

经导管射频消融是控制儿童难治性心律失常的重要手段。虽然射频消融有效地终止了儿童心律失常，但射频损伤后发生的心肌重构仍然知之甚少。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，射频疤痕已被证明以时间依赖的方式增加。因此，射频消融后，儿童患者的心肌可能会发生显著的射频疤痕扩张。因此，这项研究的总体目标是确定导致儿科动物模型中RF瘢痕扩张的心肌重构的决定因素，并确定这一事件的生理后果。此外，一个潜在的分子机制，有助于扩大射频消融疤痕将被定义。射频消融瘢痕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，在射频消融性病变产生后，基质金属蛋白酶活性增加，并沿射频瘢痕的边缘区域保持升高，直接导致瘢痕扩张。在射频损伤形成期间和之后，直接阻断基质金属蛋白酶的激活将导致射频瘢痕扩张的减弱和这一过程的生理后果。为了验证这一假设，我们将测量射频瘢痕边缘的基质金属蛋白酶的表达和活性程度，并将其与射频瘢痕大小的时间变化相关联。此外，为了更准确地确定基质金属蛋白酶活性在射频瘢痕扩张中的作用，将进行两组实验。首先，在建立射频损伤时，将在一组动物身上建立对基质金属蛋白酶的抑制，并持续到随访期。其次，将在缺乏负责基质金属蛋白酶表达或内源性控制基质金属蛋白酶活性的基因的转基因小鼠中检测RF瘢痕扩张特征。因此，这项研究的结果将确定射频损伤扩张在儿科模型中的生理后果，确定射频瘢痕扩张的分子基础，以及确定一种潜在的治疗方式来减轻这一过程。

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.