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

• 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
• 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

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)已在发达国家流行，约有650万患者 仅在美国。虽然使用β-肾上腺素能阻滞剂、血管紧张素转换酶抑制剂和血管紧张素II受体 在那里，阻滞剂在减缓疾病进展和降低死亡率方面非常有效。 在被诊断为CHF的患者中，死亡率和发病率仍然非常高。在大约一半的患者中 在充血性心力衰竭时，会出现复杂的室性心律失常，包括非持续性室性心动过速。 心脏性猝死(SCD)很常见。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有关。目前化学处理废水的方法 交感神经介导的心律失常只提供短期(即，持续几个小时到一天)的影响 用局麻药暂时阻断星状神经节(SG)神经元的活动(即阻断星状神经节)。 复发的抗药性心律失常患者可接受星状神经节切除术 永久拆卸SG的一部分。虽然这种手术能有效地消除心律失常，但却不能。 这是心脏病专家推荐的首选治疗方法，因为这种手术具有侵入性。 在这里，我们提出了一种创新的策略，通过阻断其周围环境来化学消融SG功能 血管供应，从而诱导交感神经元的凋亡和细胞死亡。在我们的初步研究中，我们 开发了一种基于FDA批准的生物聚合物包埋的可注射水凝胶给药系统 舒尼替尼(SU)微球。SU是FDA批准的小分子，具有抗血管内皮生长因子受体和 神经内分泌肿瘤患者的其他酪氨酸激酶活性。我们证明了苏可以成为 从我们的递送系统中持续释放的SU和释放的SU可以破坏体外血管生成和 体内血管床注射后注入大鼠脑脊液。因此，我们假设持续释放的SU使 血管紧张素转换酶通过破坏其血管供应而发挥功能，并随后逆转CHF相关心脏 心律失常(目标1)和调节心脏重构(目标2)。这个应用程序将使用高度集成的 评价SU载药系统治疗效果的技术，包括新型玫瑰番茄 FLOX/FLOX：：TIE2 Cre报告小鼠模型、组织清除技术、分子生物学技术和 全动物实验(在体清醒心电遥测记录、心电标测、 压力-体积回路分析)。我们相信，这项拟议的研究将奠定坚实的科学和 为充血性心力衰竭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。