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（由申请人提供）：美国每年有785，000人患有心肌梗死（MI）。MI通常导致心脏收缩力降低、电不稳定和组织坏死，导致致命的心律失常，22%的男性和46%的女性在6年内被诊断为心力衰竭（HF）。干细胞治疗作为一种修复受损心肌的技术已经获得了相关性。然而，虽然这种治疗显示出很大的希望，但也有局限性。一个这样的限制是在移植后，只有非常低百分比的注射细胞保留在损伤的心肌中，称为低细胞植入率。在干细胞疗法应用于临床之前，需要解决这个关键问题。本研究旨在解决这一局限性，并改善心脏干细胞治疗MI和MI诱导的HF。迷走神经刺激（VNS）是一种新兴的治疗心脏损伤的潜在疗法。VNS已被证明1）大大减少炎症和2）显著抑制心肌梗死动物的心律失常。我们的主要假设是，VNS的抗炎机制将导致干细胞植入的增加，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失常的可能性。我们建议实现三个具体目标，以检验我们的假设。首先，我们的目的是确定最佳的时间为发作的迷走神经刺激，以获得最大的抗炎作用。具体而言，我们将研究VNS的四个不同时间，即1）缺血前30分钟，2）缺血开始时，3）缺血15分钟，或4）再灌注开始时，并精确确定哪一个将提供最佳益处。在确定了这个最佳时间之后，我们将利用这段时间来完成剩下的两个目标。其次，我们的目的是研究VNS的长期抗炎作用和干细胞植入率，以验证我们的假设，即VNS治疗能够创造一个心肌内微环境，更容易接受干细胞移植和分化，由于其抗炎作用，从而提高植入率。第三，我们的目标是进行遥测心电图和血压测量，超声心动图，在体内室颤诱导，和光学映射实验，以评估电生理和功能的影响相结合的VNS和干细胞治疗，以测试我们的假设，即干细胞移植结合主动VNS将导致更高水平的干细胞植入，从而增强受损心脏的愈合。我们预计，这项工作的结果将是一个新的联合治疗MI患者的发展至关重要。