Mending a Broken Heart with Vagal Nerve Stimulation and Stem Cell Therapy

通过迷走神经刺激和干细胞疗法修复破碎的心脏

• 批准号: 9119529
• 负责人: Steven W Lee
• 金额: $ 2.89万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119529
• 关键词: Address; Animals; Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Anti-inflammatory; Arrhythmia; Blood Pressure; Canis familiaris; Cardiac; Cell Differentiation process; Cell Survival; Cell Transplants; Cells; Chronic; Clinical; Combined Modality Therapy; Development; Devices; Diagnosis; Echocardiography; Electrocardiogram; Electrophysiology (science); Engraftment; Environment; Enzyme-Linked Immunosorbent Assay; Face; Goals; Healed; Health; Heart; Heart Diseases; Heart failure; Hour; Image; Immune; Immune response; Immunohistochemistry; Inflammation; Inflammatory Response; Injury; Innovative Therapy; Ischemia; Lead; Longitudinal Studies; Maps; Measurement; Mechanics; Modeling; Morbidity - disease rate; Myocardial Infarction; Myocardium; Necrosis; Nerve; Optics; Outcome; Patients; Pharmacotherapy; Play; Property; Quality of life; Rattus; Reperfusion Therapy; Reporting; Research; Risk; Role; Stem cell transplant; Stem cells; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translations; Transplantation; United States; Ventricular Fibrillation; Woman; Work; clinical practice; healing; improved; in vivo; injured; interest; men; mortality; novel; prevent; repaired; research study; stem cell therapy; sudden cardiac death; time use

 DESCRIPTION (provided by applicant): Annually 785,000 people in the United States suffer from myocardial infarction (MI). MI often results in decreased contractility, electrical instabilit, and tissue necrosis in the heart leading to lethal cardiac arrhythmias and 22% of men and 46% of women are diagnosed with heart failure (HF) within six years. Stem cell therapy has gained relevance as a technique to repair the damaged myocardium. However, while this treatment shows great promise, there are limitations. One such limitation is after transplantation, only a very low percentage of the injected cells remain in the injured myocardium, known as low cell engraftment rate. This critical issue needs to be addressed before stem cell therapies can be applied in clinical settings. This research aims at addressing this limitation and improving cardiac stem cell therapies for the treatment of MI and MI-induced HF. Vagal nerve stimulation (VNS) is a contemporaneous emerging potential therapy for the treatment of injured hearts. VNS has been shown to 1) greatly reduce inflammation and 2) markedly suppress arrhythmias in animals with MI. Our major hypothesis is that the anti-inflammatory mechanism of VNS will result in an increase in stem cell engraftment while the anti-arrhythmic effects of VNS will reduce the likelihood of arrhythmias associated with MI injury and/or stem cell transplantation. We propose to implement three specific aims in order to test our hypothesis. First, we aim to determine the optimal time for the onset of VNS to obtain maximal anti- inflammatory effects. Specifically, we will investigate four different timings of VNS, i.e. 1) 30 minutes prior to ischema, 2) at the onset of ischemia, 3) 15 minutes at ischemia, or 4) at the onset of reperfusion, and precisely determine which will provide the optimal benefits. After determining this optimal time, we will use this time to complete our remaining two aims. Second, we aim to study the long term anti-inflammatory effects of VNS and stem cell engraftment rate to test our hypothesis that VNS therapy is able to create an intramyocardial microenvironment more receptive to stem cell transplantation and differentiation due to its anti-inflammatory effects, and thus, increase engraftment rate. Third, we aim to perform telemetric ECG and blood pressure measurements, echocardiography, in vivo ventricular fibrillation induction, and optical mapping experiments to assess the electrophysiological and functional effects of the combined VNS and stem cell therapy to test our hypothesis that stem cell transplantation in combination with active VNS will result in higher levels of stem cell engraftment, and thus, an enhanced healing of the damaged heart. We anticipate that the outcome of this work will be pivotal in the development of a novel combination therapy to treat MI patients.

 描述（由适用提供）：美国每年有785,000人患有心肌梗塞（MI）。 MI通常会导致心脏中的收缩力，电稳定性和组织坏死导致致命性心律失常，男性22％和46％的女性在六年内被诊断出患有心力衰竭（HF）。干细胞疗法已成为修复受损心肌的一种技术。但是，尽管这种疗法显示出巨大的希望，但仍存在局限性。这样的局限性是在移植后，只有很低的注射细胞保留在受伤的心肌中，称为低细胞植入率。在将干细胞疗法应用于临床环境之前，需要解决这个关键问题。这项研究旨在解决这种局限性并改善心脏干细胞疗法以治疗MI和MI诱导的HF。迷走神经刺激（VNS）是一种现代的新兴疗法，用于治疗受伤的心脏。 VNS已显示为1）大大降低感染，2）显着抑制了具有MI的动物的心律不齐。我们的主要假设是，VNS的抗炎机制将导致干细胞植入术的增加，而VNS的抗心律失常作用将降低与MI损伤和/或干细胞移植相关的心律不齐的可能性。我们建议实施三个特定目标，以检验我们的假设。首先，我们旨在确定VN的最佳时间获得最大的抗炎作用。具体而言，我们将研究VN的四个不同时机，即1）在缺血前30分钟，2）在缺血开始时，3）15分钟在缺血或4）重新灌注时，并精确确定哪个将提供最佳益处。在确定了这一最佳时间之后，我们将利用这段时间来完成其余的两个目标。其次，我们的目的是研究VNS和干细胞植入率的长期抗炎作用，以测试我们的假设，即VNS治疗能够创造出由于其抗炎作用而引起的干细胞移植和分化，从而产生了心脏内的微环境，从而增加了染色率。第三，我们旨在进行远程记录的心电图和血压测量，超声心动图，体内心室纤维化诱导以及光学映射实验，以评估组合VNS和干细胞疗法的电生理和功能效应，以测试我们的较高的干细胞和干细胞的损害，从而恢复活跃的细胞，从而恢复活跃的细胞损伤，并恢复活性。 心。我们预计这项工作的结果将在开发新型组合疗法以治疗MI患者方面至关重要。