Mechanisms of Myocardial Radiofrequency Scar Expansion

心肌射频疤痕扩张的机制

• 批准号: 6537910
• 负责人: RUPAK MUKHERJEE
• 金额: $ 25.03万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537910
• 关键词: arrhythmia; electrocardiography; electrophysiology; enzyme activity; genetically modified animals; heart catheterization; heart conduction system; heart electrical activity; heart function; iatrogenic disease; infant animal; laboratory mouse; metalloendopeptidases; molecular pathology; myocardium disorder; myogenesis; nonhuman therapy evaluation; radiation therapy; radiobiology; radiowave radiation; scars; swine; western blottings

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.

经导管射频（RF）消融是控制儿科患者药物难治性心律失常的重要方式。虽然射频消融可以有效终止儿童心律失常，但射频损伤产生后发生的心肌重塑仍然知之甚少。临床病例报告提供的证据表明，婴儿射频消融后会发生疤痕扩张。此外，在儿科动物模型中，射频疤痕已被证明会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明显的射频疤痕扩张。因此，本研究的总体目标是确定导致儿科动物模型中射频疤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，还将确定有助于射频消融疤痕扩张的潜在分子机制。射频消融疤痕的扩张必须伴随着心肌重塑。负责细胞外胶原蛋白降解和重塑的内源酶系统是基质金属蛋白酶（MMP）。因此，该项目的总体假设是，射频消融性病变形成后，MMP 活性增强，并且沿射频疤痕的边缘区域保持升高状态，直接导致疤痕扩张。在射频损伤产生期间和之后直接中断 MMP 激活将导致射频疤痕扩张和该过程的生理后果减弱。为了检验这一假设，将测量 RF 疤痕边缘 MMP 表达和活性的程度，并将其与 RF 疤痕大小的时间变化相关联。此外，为了更精确地定义MMP活性在RF疤痕扩张中的作用，将进行两组实验。首先，MMP 抑制将在 RF 损伤产生时在一组动物中开始，并持续到后续阶段。其次，将在缺乏负责 MMP 表达或 MMP 活性内源控制的基因的转基因小鼠中检查 RF 疤痕扩张特征。因此，这项研究的结果将定义儿科模型中射频病变扩张的生理后果，确定射频疤痕扩张的分子基础，并确定减弱这一过程的潜在治疗方式。