Exercise Capacity Recovery After Myocardial Infarction: Response to Novel Therapy

心肌梗塞后的运动能力恢复：对新疗法的反应

• 批准号: 9052058
• 负责人: RUPAK MUKHERJEE
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052058
• 关键词: Acute myocardial infarction; Adhesions; Area; Attenuated; Biological Assay; Biological Preservation; Blood; Cardiac Output; Cardiovascular Diseases; Cause of Death; Characteristics; Cicatrix; Clinical; Coronary Arteriosclerosis; Deterioration; Development; Devices; Diet; Disadvantaged; EFRAC; Echocardiography; Exercise; Exercise Tolerance; Exercise stress test; Extracellular Matrix; Family suidae; Fibrillar Collagen; Fibroblasts; Frequencies; Functional disorder; General Population; Geometry; Healed; Heart; Heart Rate; Heart failure; In Vitro; Incidence; Infarction; Inflammation; Institutes; Lead; Left; Left Ventricular Ejection Fraction; Left Ventricular Function; Left Ventricular Remodeling; Left ventricular structure; Measurement; Measures; Mechanics; Mediating; Modeling; Myocardial; Myocardial Infarction; Myocardium; Obesity; Outcome; Oxygen; Patients; Phenotype; Physical Exercise; Physical activity; Physiologic pulse; Population; Prevention; Pump; Recovery; Reperfusion Therapy; Risk Factors; Signs and Symptoms; Smoking; Stress; Techniques; Testing; Time; Translating; United States; Venous; Ventricular; Veterans; attenuation; base; blood pump; cell type; exercise capacity; functional improvement; healing; improved; innovation; migration; novel; novel therapeutics; outcome forecast; prevent; programs; public health relevance; response; treadmill

 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.

 描述（由申请人提供）： 在美国，每年有超过一百万人患有心肌梗塞 (MI)。心肌梗死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群体中往往会加剧。尽管心肌梗死时有充分的再灌注，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，其中包括左心室泵功能下降，以及缓慢进展为心力衰竭，这可能会损害身体活动。细胞含量随时间变化，成纤维细胞成为 MI 区域内的主要细胞类型，导致 MI 区域扩张和逐渐变薄。与此同时，心肌梗死后，左心室扩张，左心室泵功能恶化。最近的一项研究提供的证据表明，在“治愈”的 MI 区域内使用低振幅电脉冲的局部高频刺激 (LHFS) 的新范例可减轻左心室壁变薄（梗塞扩张）和心梗后左心室扩张，并与左心室射血分数的相对保留相关。然而，左心室泵功能的这种功能性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然未知。鉴于过去左心室泵功能的改善与体育锻炼能力的提高之间存在关联，该项目的假设是，LHFS 对心肌梗死后左心室重塑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征的根本影响。在猪 MI 模型中，LHFS 将在明确的时间窗口内在 MI 区域内启动，在该时间窗口内，MI 后愈合反应从炎症转变为 ECM 积累。体外研究将确定 LHFS 作用的基本细胞基础是 MI 区域成纤维细胞的表型变化。因此，通过综合方法，该项目将利用 新颖的 LHFS 技术可中断 MI 扩张并保留 LV 泵功能，从而提供一种进一步开发/表征这种基于设备的技术（并且可能临床适用）的方法，以改善心肌梗塞后运动能力方面的预后。