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.

项目概要慢性心力衰竭 (CHF) 在发达国家已成为流行病，约有 650 万名患者在美国虽然单独使用β-肾上腺素能阻断剂、ACE抑制剂和血管紧张素II受体。阻滞剂在减缓疾病进展和降低死亡率方面非常有效，诊断为 CHF 的患者中约有一半的患者死亡率和发病率仍然极高。患有 CHF 时，会出现复杂的室性心律失常，包括非持续性室性心动过速，并且心源性猝死 (SCD) 是常见的心脏交感神经控制的异常和改变。与危及生命的心律失常、CHF 和 SCD 的现有化学治疗方法有关。交感神经介导的心律失常仅提供短期（即持续几小时到一天）的影响使用局部麻醉剂暂时阻断星状神经节 (SG) 神经活动（即 SG 阻断）。复发性耐药心律失常患者可以接受星状神经节切除术永久切除部分 SG 虽然这种手术对于消除心律失常有效，但效果并不理想。由于该手术具有侵入性，因此是心脏病专家推荐的首选治疗方法。在这里，我们提出了一种创新策略，通过阻断周围的 SG 功能来化学消除 SG 功能。血管供应，从而诱导交感神经元凋亡和细胞死亡。开发了一种基于 FDA 批准的生物聚合物的可注射水凝胶输送系统舒尼替尼 (SU) 负载微球是 FDA 批准的小分子，具有抗 VEGF 受体和我们证明了 SU 可能对神经内分泌肿瘤患者具有其他酪氨酸激酶活性。从我们的递送系统中持续释放，释放的 SU 可能会破坏体外血管生成，并在注射到大鼠 SG 后的体内血管床因此我们追求持续释放的 SU 禁用。 SG 通过破坏其血管供应发挥功能，随后逆转 CHF 相关的心脏功能心律失常（目标 1）和调节心脏重塑（目标 2）该应用程序将使用高度集成。评估 SU 负载递送系统（包括新型 Rosa-tdTomato）治疗效果的技术 flox/flox::Tie2 Cre 报告小鼠模型、组织清除技术、分子生物学技术和整体动物实验（体内有意识心电图遥测记录、心电图绘制、我们相信这项研究将奠定坚实的科学和基础。为CHF和其他心肌病患者开发新疗法奠定了技术基础改善这些患者的生活质量。