Cardiac Sympathetic Afferent Denervation and Remodeling in Heart Failure

 描述(申请人提供)：慢性心力衰竭状态(CHF)的特征是神经体液激活和心脏重构(纤维化、扩张和肥大)。交感神经兴奋是由几种机制介导的，这些机制是本实验室以前研究的重点。在CHF状态下，一种强大的心源性反射被称为“心交感传入反射”(CSAR)，它是由脑室表面或靠近脑室表面的交感传入活动增加而激活的。这种兴奋性反射部分地将交感传出神经活动驱动到心脏和外周。在最近的一项研究中，我们证明了在大鼠心肌梗死(MI)时，用超强的TRPV1受体激动剂Resiniferitoxn(RTX)选择性地去除这些传入，会导致MI后9-11周的心和肾交感神经活动减少和去甲肾上腺素的排泄。此外，这种干预通过减少细胞外基质蛋白(纤维连接蛋白、胶原、α平滑肌肌动蛋白)来减少重塑过程。RTX治疗的结果是，随着心脏对异丙肾上腺素(心脏储备)的反应增加，左室舒张末期压力降低，舒张期功能增加。目前的建议扩展了这些观察结果，并试图进一步了解心肌梗死后和心力衰竭时CSAR消融的有益影响的机制。为了确定颈总动脉消融的益处是否通过减少心脏传出交感神经流出而实现，1将比较雷公藤红素治疗与交感神经全麻(6-羟基多巴胺)或特异性α-1或β-1阻断对重构过程的影响。此外，这一目标将确定在大鼠心肌梗死模型中，在交感神经流出和重塑方面，取消肾素-血管紧张素系统与RTX治疗是否相比较。具体目标2将通过RTX引起抗炎作用来解决传入神经肽耗竭的问题，而抗炎作用反过来又减少重塑过程。心脏血管通透性(伊文思蓝)和阻断P物质受体将被用来解决这个问题。为了使这一新的范例应用于临床，我们必须确定RTX治疗逆转或减弱CHF状态下的自主神经和纤维化事件的最佳治疗窗口。因此，专门的目标3将在大鼠心肌梗死后不同时间点检测心外膜RTX治疗的反应，并将确定应用RTX的硬膜外神经节周围(T1-T4 DRGs，包含主要的CSAR传入体体)的自主神经和重构效应，这被认为是另一种CSAR去神经策略。这些研究的新颖性在于，第一次，在CHF或MI后状态下，经典的传入伤害性感受通路是改善心功能的目标。虽然这些传入被认为主要传递心痛，但我们的数据清楚地表明，它们是多模式的，应该被视为新的治疗靶点。

 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.