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.
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