Novel Stellate Ganglia Chemo-ablation Approach to Treat Cardiac Arrhythmia and Cardiac Remodeling in Heart Failure

新型星状神经节化疗消融方法治疗心律失常和心力衰竭心脏重塑

基本信息

批准号：
10727929
负责人：
Bin Duan
金额：
$ 23.03万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-16 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727929
关键词：
Ablation Accounting Adrenergic beta-Antagonists Adult Affect Angiotensin II Receptor Angiotensin-Converting Enzyme Inhibitors Animal Experiments Apoptosis Arrhythmia Bilateral Biological Biopolymers Blood Vessels Cardiac Cardiac Surgery procedures Cardiac ablation Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cell Death Chemicals Clinic Complex Congestive Heart Failure Conscious Data Developed Countries Development Diagnosis Disabled Persons Disease Disease Progression Dose Drug Delivery Systems Drug resistance Echocardiography Electric Countershock Electric Stimulation Electrocardiogram Encapsulated Endothelial Growth Factors Receptor Endothelium Epidemic Event FDA approved Female Foundations Functional disorder Ganglia Ganglionectomy Goals Heart Heart Diseases Heart Hypertrophy Heart failure Hour Hydrogels Implantable Defibrillators In Vitro Injectable Injections Life Link Local Anesthetics LoxP-flanked allele Maps Measures Mediating Medical Methods Microspheres Molecular Morbidity - disease rate Mus Myocardial Infarction Myocardial dysfunction Nature Nerve Neuroendocrine Tumors Neurons Operative Surgical Procedures Patients Peripheral Persons Pharmaceutical Preparations Procedures Protein Tyrosine Kinase Quality of life Rattus Recommendation Recurrence Refractory Reporter Research Rodent Sensory Ganglia Signal Pathway Solid Structure of stellate ganglion Subgroup Sympathectomy Sympathetic Ganglia System Tachycardia Techniques Technology Telemetry Therapeutic Effect Three-Dimensional Imaging Tissues Treatment Efficacy United States Vascular Endothelial Growth Factors Vascular blood supply Ventricular Arrhythmia Ventricular Tachycardia Work angiogenesis coronary fibrosis density heart function high risk improved in vivo innovation male mortality mouse model neuron apoptosis novel novel strategies novel therapeutics pressure prevent response small molecule structural heart disease sudden cardiac death targeted delivery therapeutic target treatment choice vascular bed

项目摘要

Project Summary Chronic heart failure (CHF) has become epidemic in developed nations accounting for about 6.5 million patients in the US alone. Although the use of β-adrenergic blocking agents, ACE inhibitors and Angiotensin II receptor blockers have been highly effective in slowing the progression of the disease and reducing mortality, there remains an extremely high mortality and morbidity rate for patients diagnosed with CHF. In about half of patients with CHF, complex ventricular arrhythmias, including non-sustained ventricular tachycardia, are present and sudden cardiac death (SCD) is common. Abnormalities and alteration in cardiac sympathetic control of the heart are linked to life threatening arrhythmias, CHF and SCD. Current methods for chemical treatment of sympathetically mediated arrhythmias offer only short-term (i.e., lasting a few hours to one day) effect by temporarily blocking stellate ganglion (SG) neuronal activity with local anesthetics (i.e., SG blockade). Recurrent drug-resistant cardiac arrhythmia patients may be offered surgical stellate ganglionectomy to permanently remove part of the SG. Although this surgery is effective for removing cardiac arrhythmias, it is not the first choice of treatment recommended by cardiologists because of the invasive nature of this procedure. Here, we propose an innovative strategy to chemically ablate the SG function by blocking its surrounding vascular supply, thereby inducing sympathetic neuronal apoptosis and cell death. In our preliminary study, we developed an injectable hydrogel delivery system based on FDA approved biopolymers with encapsulating sunitinib (SU) loaded microspheres. SU is an FDA approved small molecule that has anti-VEGF receptor and other tyrosine kinase activities for patients with neuroendocrine tumors. We demonstrated that SU could be sustained released from our delivery system and the released SU could disrupt the in vitro angiogenesis and in vivo vascular bed after injection into the rat SG. We thus hypothesize that sustained released SU disables the SG function by disrupting its vascular supply and subsequently reverses the CHF-associated cardiac arrhythmia (Aim 1) and regulates cardiac remodeling (Aim 2). This application will use highly integrative techniques to evaluate the therapeutic efficacy of SU loaded delivery system, including novel Rosa-tdTomato flox/flox::Tie2 Cre reporter mouse model, tissue clearance technique, molecular biological techniques and whole animal experiments (in vivo conscious electrocardiogram telemetry recording, cardiac electrical mapping, pressure-volume loop analysis). We believe that this proposed research will lay a solid scientific and technological foundation for developing a new therapy for the patients with CHF and other cardiomyopathy and improve the quality of life of these patients.

项目摘要慢性心力衰竭（CHF）已在发达国家中流行，约为650万患者一个人在美国。尽管使用β-肾上腺素阻塞剂，ACE抑制剂和血管紧张素II受体阻滞剂在减慢疾病进展和降低死亡率方面非常有效对于诊断为CHF的患者，仍然是极高的死亡率和发病率。大约一半的患者使用CHF，存在复杂的心室心律不齐，包括非固定心室心动过速，存在猝死（SCD）很常见。心脏心脏交感神经控制的异常和改变与威胁性心律失常，CHF和SCD有关。当前的化学处理方法对称介导的心律失常仅提供短期（即持续几个小时至一天）的影响暂时阻塞星状神经节（SG）神经元活动（即SG阻滞）。反复抗药性心律失常患者可能会提供手术星状神经节切除术永久删除SG的一部分。尽管该手术可有效去除心律不齐，但不是心脏病专家推荐的治疗的首选是由于此程序的侵入性。在这里，我们提出了一种创新的策略，以通过阻止其周围的周围来化学化化学消融SG功能血管供应，从而引起交感神经凋亡和细胞死亡。在我们的初步研究中，我们开发了一种基于FDA批准的生物聚合物的注射水凝胶输送系统，并封装 Sunitinib（SU）加载的微球。 SU是FDA批准的小分子，具有抗VEGF受体和其他针对神经内分泌肿瘤患者的酪氨酸激酶活性。我们证明了苏可能是从我们的输送系统中释放的持续释放，释放的SU可能会破坏体外血管生成和注入大鼠SG后的体内血管床。因此，我们假设持续释放的su可以禁用 SG功能通过破坏其血管供应并随后逆转与CHF相关的心脏心律不齐（AIM 1）并调节心脏重塑（AIM 2）。该应用程序将使用高度集成评估SU加载输送系统的治疗效率的技术，包括新型Rosa-tdtomato flox/flox :: TIE2 CRE记者小鼠模型，组织清除技术，分子生物学技术和全动物实验（体内意识心电图记录记录，心脏电气映射，压力卷循环分析）。我们认为，这项拟议的研究将奠定扎实的科学性，并且为CHF和其他心肌病和其他心肌病患者开发新疗法的技术基础改善这些患者的生活质量。