Exercise Capacity Recovery After Myocardial Infarction: Response to Novel Therapy

 描述（由申请人提供）： 在美国，每年有超过一百万人发生心肌梗死（MI）。心肌梗死的风险因素包括肥胖、吸烟、压力增加、饮食等，这些因素在退伍军人人群中往往会加剧。尽管在MI时有充分的再灌注，但瘢痕形成和伴随的左心室（LV）重塑仍然是导致不良预后的后遗症，包括LV泵功能降低-以及缓慢进展为心力衰竭，这可能会损害体力活动。细胞内容物的时间依赖性变化，其中成纤维细胞成为MI区域内的主要细胞类型，导致MI区域的扩张和进行性变薄。同时，MI后左心室扩张，左心室泵功能恶化。最近的一项研究提供了证据表明，在“愈合”的MI区域内使用低振幅电脉冲的局部高频刺激（LHFS）的新范例减弱了MI后的LV壁变薄（梗死扩张）和LV扩张，并与LV射血分数的相对保留相关。然而，这种对左心室泵功能的功能性益处是否以及在多大程度上转化为运动能力的有形变化仍然未知。鉴于LV泵功能改善与进行体育锻炼的能力增加之间的既往相关性，本项目的假设是LHFS对MI后LV重塑的影响将直接转化为运动能力的明显改善。此外，LHFS在运动耐量方面的这些MI后益处将伴随着对MI区域中成纤维细胞的功能特征的基本影响。在猪MI模型中，LHFS将在明确定义的时间窗期间在MI区域内启动，在该时间窗处，MI后愈合反应从炎症转变为ECM积聚。体外研究将确定LHFS作用的基本细胞基础是MI区成纤维细胞的表型变化。因此，通过综合办法，本项目将利用 新型LHFS技术中断MI扩张并保留LV泵功能，从而提供了一种方法来进一步开发/表征这种基于器械的技术（可能具有临床适用性），以改善心肌梗死后运动能力方面的障碍。

 DESCRIPTION (provided by applicant): Myocardial infarction (MI) occurs in more than a million people in the United States annually. Risk factors for MI include obesity, smoking, increased stress, diet, etc. which tend to be exacerbated in the Veteran population. Despite adequate reperfusion at the time of a MI, scar formation and the attendant left ventricular (LV) remodeling remain sequelae that contribute to poor prognoses, which include reduced LV pump function - and a slow progression to heart failure, which could impair physical activity. Time-dependent changes with respect to the cellular content, where fibroblasts become the predominant cell type within the MI region, lead to expansion and progressive thinning of the MI region. Concomitantly, the LV dilates and there is a deterioration of LV pump function in the post-MI setting. A recent study has provided evidence that a novel paradigm of localized high frequency stimulation (LHFS) using low amplitude electrical pulses within the "healed" MI region attenuated LV wall thinning (infarct expansion) and LV dilation post-MI and was associated with a relative preservation of LV ejection fraction. However, whether and to what degree this functional benefit on LV pump function translates to tangible changes in exercise capacity remains unknown. Given the past association between improved LV pump function and an increase in the capacity to perform physical exercise, the hypothesis of this project is that the effects of LHFS with respect to effects LV remodeling post-MI will directly translate to tangible improvements in exercise capacity. Furthermore, these post- MI benefits of LHFS with respect to exercise tolerance will be accompanied by fundamental effects on functional characteristics of fibroblasts in the MI region. In a porcine MI model, LHFS will be initiated within the MI region during a well-defined temporal window at which the post-MI healing response transitions from inflammation to ECM accumulation. In vitro studies will establish that the fundamental cellular basis for the effects of LHFS is phenotypic changes in fibroblasts from the MI region. Thus, through an integrated approach, this project will utilize the novel LHFS technique to interrupt MI expansion and preserve LV pump function, thus providing a means to further develop/characterize this device-based - and likely, clinically applicable - technique to improve prognoses with respect to exercise capacity after myocardial infarction.