Cardiac Sympathetic Afferent Denervation and Remodeling in Heart Failure

心力衰竭中的心脏交感神经传入去神经和重塑

• 批准号: 9197673
• 负责人: Hanjun Wang
• 金额: $ 49.58万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-18 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197673
• 关键词: Ablation; Address; Adrenergic Agents; Affect; Afferent Neurons; Agonist; Angiotensins; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attenuated; Autonomic Dysfunction; Blood flow; Capsaicin; Cardiac; Cardiac ablation; Cardiovascular system; Chest; Chronic; Clinical; Collagen; Congestive Heart Failure; Coronary; Coupled; Data; Denervation; Development; Diagnosis; Diastolic blood pressure; Disease; Disease Progression; Dopamine; Efferent Neurons; Evans blue stain; Event; Excision; Excretory function; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Fibrosis; Functional disorder; Ganglia; Healthcare; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertrophy; Industrialization; Inflammatory; Intervention; Isoproterenol; Kidney; Laboratories; Laboratory Study; Matrix Metalloproteinases; Mediating; Modeling; Myocardial Infarction; Myocardial dysfunction; Myocarditis; Nerve; Nerve Endings; Neuropeptides; Nociception; Norepinephrine; Organ; Pain; Pathway interactions; Peripheral; Physiological; Play; Process; Pulmonary Edema; Rattus; Reflex action; Reflex control; Renin; Renin-Angiotensin System; Reporting; Resiniferatoxin; Role; Route; Sensory; Signal Transduction; Site; Smooth Muscle Actin Staining Method; Substance P; Substance P Receptor; Surface; System; TRPV1 gene; Therapeutic; Time; Translating; Treatment Efficacy; United States; Vanilloid; Vascular Permeabilities; Work; afferent nerve; analog; base; clinical application; improved; neuronal cell body; new therapeutic target; novel; novel therapeutics; prevent; public health relevance; receptor; response; sensory system

 DESCRIPTION (provided by applicant): The chronic heart failure state (CHF) is characterized by neurohumoral activation and cardiac remodeling (fibrosis, dilation and hypertrophy). Sympatho-excitation is mediated by several mechanisms that have been the focus of previous studies from this laboratory. In the CHF state a potent cardiogenic reflex known as the "cardiac sympathetic afferent reflex" (CSAR) is activated by an increase in the activity of sympathetic afferents on or near the surface of the ventricles. This excitatory reflex, in part, drives sympathetic efferent nerve activity to the heart and the periphery. In a recent study we demonstrated that selective removal of these afferents using the ultrapotent TRPV1 receptor agonist Resiniferitoxn (RTX), at the time of myocardial infarction (MI) in rats, resulted in a decrease in cardiac and renal sympathetic nerve activity and norepinephrine excretion 9-11 weeks following the MI. In addition, this intervention decreased the remodeling process by reducing extracellular matrix proteins (fibronectin, collagen, α smooth muscle actin). The resultant effect of RTX treatment was a decrease in LV end diastolic pressure and an increase in diastolic function along with an increase in the cardiac response to isoproterenol (cardiac reserve). The current proposal extends these observations and seeks to further understand the mechanisms responsible for the beneficial effects of CSAR ablation post MI and in CHF. In order to determine if the beneficial effects of CSAR ablation are mediated by reducing cardiac efferent sympathetic outflow Specific Aim 1 will compare RTX treatment with both global sympathetic blockade (6 hydroxy dopamine) or specific α1 or β1 blockade on the remodeling process. In addition, this aim will determine if abrogation of the renin-angiotensin system compares to RTX treatment for both sympathetic outflow and remodeling in the rat MI model. Specific Aim 2 will address the issue of afferent neuropeptide depletion by RTX evoking anti-inflammatory effects which, in turn, reduces the remodeling process. Cardiac vascular permeability (Evans Blue) and blockade of Substance P receptors will be used to address this question. In order for this novel paradigm to be clinically applicable, we must determine the optimal therapeutic window where RTX treatment reverses or attenuates the autonomic and fibrotic events in the CHF state. Therefore, Specific Aim 3 will examine the responses to epicardial RTX treatment at various time points following MI in the rat model and will determine autonomic and remodeling effects of epidural peri- ganglion (T1-T4 DRGs containing the predominant CSAR afferent soma) application of RTX, which is considered as an alternative CSAR denervation strategy. The novelty of these studies is that, for the first time, a classical afferent nociceptive pathway is the target for improvement in cardiac function in the CHF or post MI states. While these afferents have been viewed as primarily transmitting cardiac pain, our data clearly show they are polymodal and should be considered as new targets for therapy.

 描述（由适用提供）：慢性心力衰竭状态（CHF）的特征是神经肿瘤激活和心脏重塑（纤维化，词典和肥大）。交感神经激发是由几种机制介导的，这些机制一直是该实验室先前研究的重点。在CHF状态下，潜在的心源反射称为“心脏交感传入反射”（CSAR），通过在心室表面上或附近的交感传入活性增加而激活。这种兴奋的反射部分将有效的有效神经活动引起了心脏和周围。在最近的一项研究中，我们表明，使用超能力的TRPV1受体激动剂树脂毒素（RTX），在大鼠心肌梗塞（MI）时，选择性去除这些传入，导致心脏和肾交感神经和肾脏交感神经活性和肾脏肾上腺素极端9-11周后，导致心脏和肾交感神经活动和肾交感神经活动的下降。此外，这种干预措施通过减少细胞外基质蛋白（纤连蛋白，胶原蛋白，α平滑肌肌动蛋白）来减少重塑过程。 RTX治疗的最终影响是LV末端舒张压降低，舒张压功能增加，以及对异丙肾上腺素（心脏储备）的心脏反应增加。当前的提案扩展了这些观察结果，并试图进一步了解CSAR消融后MI和CHF的有益作用的机制。为了确定CSAR消融的有益作用是否通过减少心脏有效交感神经出口特异性目标1来介导RTX治疗与重塑过程中的全球交感神经阻滞（6个羟基多巴胺）或特定的α1或β1阻断。此外，此目的将确定肾素 - 血管紧张素系统的杂种是否与大鼠MI模型中的交感神经和重塑的RTX处理相比。特定的目标2将通过RTX引起抗炎作用来解决传入神经肽部署的问题，从而减少了重塑过程。心脏血管通透性（Evans Blue）和对物质P受体的阻滞将用于解决此问题。为了使这种新型范式在临床上适用，我们必须确定RTX治疗逆转或减弱CHF状态下的自主和纤维化事件的最佳治疗窗口。因此，具体目标3将检查大鼠模型MI之后的各个时间点的心外膜RTX处理的​​反应，并将确定硬膜外神经节（T1-T4 DRG）（包含CSAR主要传入SOMA的T1-T4 DRG）的自主神经和重塑效应RTX的应用，这被视为替代性CSAR DEREDERATION策略。这些研究的新颖性是，第一次，经典的传入伤害感受途径是改善CHF或MI Post MI状态心脏功能的目标。尽管这些传入被视为主要传播心脏疼痛，但我们的数据清楚地表明它们是多峰，应被视为治疗的新靶标。