Exercise Capacity Recovery After Myocardial Infarction: Response to Novel Therapy

 描述(由申请人提供)： 在美国，每年有100多万人患有心肌梗塞。MI的危险因素包括肥胖、吸烟、压力增加、饮食等，这些因素在退伍军人中往往会加剧。尽管在心肌梗死时进行了充分的再灌注，但疤痕形成和随之而来的左心室(LV)重塑仍然是导致不良预后的后遗症，包括左心室泵功能降低-以及缓慢进展为心力衰竭，这可能会损害体力活动。随着细胞含量的时间变化，成纤维细胞成为MI区域内的主要细胞类型，导致MI区域的扩张和渐进性变薄。随之而来的是，在MI后的设置中，LV扩张，LV泵功能恶化。最近的一项研究提供了证据表明，一种新的局部高频刺激(LHFS)模式，使用“愈合”的MI区域内的低幅度电脉冲，可以减弱MI后的室壁变薄(梗塞扩大)和LV扩张，并与相对保留LV射血分数有关。然而，这种对左心室泵功能的功能益处是否以及在多大程度上转化为运动能力的切实变化仍是未知的。鉴于过去左心室泵功能的改善与运动能力的增加之间的关系，该项目的假设是，LHFS对心肌梗死后左室重构的影响将直接转化为运动能力的切实改善。此外，LHFS在运动耐量方面的这些MI后益处将伴随着对MI区域成纤维细胞功能特性的基本影响。在猪心肌梗死模型中，LHFS将在MI区域内启动，在这个明确的时间窗口，MI后愈合反应从炎症过渡到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，通过综合方法，本项目将利用 新的LHFS技术可以阻断心肌梗死的扩大并保留左心室泵功能，从而提供了一种手段，进一步开发/表征这种基于设备的-可能的，临床适用的-技术，以改善心肌梗死后运动能力的预后。

 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.