Neuromodulation of inflammation and endothelial function to treat elderly patients with systolic heart failure.

射血分数降低的心力衰竭（HFrEF）是心脏病患者发病和死亡的主要原因。 美国的衰老和HFrEF的独特之处在于它们具有共同的病理学，例如 自主神经失衡（交感神经张力增加，副交感神经张力降低），炎症 （称为“炎症”）和内皮功能障碍。衰老是不良反应的主要风险因素 与HFrEF相关的结果。尽管接受了治疗，但大多数HFrEF患者仍继续 运动能力降低，生活质量（QoL）差。最近的研究 表明与年龄相关的自主神经失衡、炎症和内皮功能障碍 可能在HFrEF的进展中发挥核心作用，支持减弱这些 异常可能有助于改善HFrEF的临床结局。之前我们已经证实 低水平经皮耳屏刺激（LLTS）改善了自主神经失衡， 抑制房颤和舒张功能障碍患者的炎症， HFrEF患者的内皮功能障碍。本建议的总体目标是 检查LLTS对HFrEF患者运动能力和QoL的影响， 同时确定其对核心年龄相关的病理轴，自主神经， 失衡、炎症和内皮功能障碍。我们的具体目标包括：1.审查 间歇性（每天1小时，持续3个月）LLTS对运动能力的中期影响， 相对于假刺激，HFrEF患者的生活质量为2。为了确定介质的影响- 晚期LLTS对自主神经失衡（通过心率变异性评估）和炎症的影响， HFrEF患者和3.确定中期LLTS对内皮功能的影响 在HFrEF患者中。拟议的概念验证人类可行性研究将提供 在较大的HFrEF人群中使用LLTS的基础。本提案旨在：a）阐明 LLTS对年龄相关异常（自主神经失调、炎症和 内皮功能障碍）和HFrEF结局进展（运动能力和QoL），以及B） 开发和进一步完善新的疗法，如LLTS，以改善潜在的年龄- 相关的紊乱和临床结果。随着越来越多的老年人 尽管接受了治疗，但仍继续出现HFrEF症状的患者， 在这种资助机制中，另一种新的方法，如LLTS， 改善HFrEF健康结局的潜力。预计这些调查将 有助于更广泛地了解与年龄相关的自主神经失衡，炎症和 HFrEF中的内皮功能障碍以及其抑制如何可用于提供治疗效果。

Heart failure with reduced ejection fraction (HFrEF) is a major cause of morbidity and mortality in United States. Aging and HFrEF are unique in that they share common pathologies, such as autonomic imbalance (increased sympathetic and reduced parasympathetic tone), inflammation (termed “inflammaging”) and endothelial dysfunction. Aging is a major risk factor for adverse outcomes associated with HFrEF. Despite treatment, majority of HFrEF patients continue to experience reduced exercise capacity and poor quality of life (QoL). Recent studies have suggested that age-associated autonomic imbalance, inflammation and endothelial dysfunction may play a central role in the progression of HFrEF, supporting the notion that attenuating these abnormalities may help improve clinical outcomes in HFrEF. We have previously demonstrated that low level transcutaneous tragus stimulation (LLTS) improves autonomic imbalance and suppresses inflammation in patients with atrial fibrillation and diastolic dysfunction and improved endothelial dysfunction in patients with HFrEF. The overall objective of this proposal is to examine the effects of LLTS on exercise capacity and QoL in patients with HFrEF and simultaneously determine its impact on the core age-related pathologic axes, autonomic imbalance, inflammation and endothelial dysfunction. Our specific aims include: 1. To examine the medium-term effect of intermittent (1-hour daily for 3 months) LLTS on exercise capacity and QoL, relative to sham stimulation, in patients with HFrEF, 2. To determine the effects of medium- term LLTS on autonomic imbalance (assessed by heart rate variability) and inflammation in patients with HFrEF and 3. To determine the effects of medium-term LLTS on endothelial function in patients with HFrEF. The proposed proof-of-concept human feasibility study will provide the basis for using LLTS among larger HFrEF populations. This proposal intends to a) elucidate the effects of LLTS on age-related abnormalities (autonomic imbalance, inflammation and endothelial dysfunction) and progression of HFrEF outcomes (exercise capacity and QoL) and b) develop and further refine novel therapies, such as LLTS, to ameliorate the underlying age- associated derangements and clinical outcomes. In light of the increasing number of elderly patients who, despite treatment, continue to experience HFrEF symptoms, recognized is a key point of interest in this funding mechanism, an alternative novel approach such as LLTS has the potential to improve health outcomes in HFrEF. It is anticipated that these investigations will contribute to a broader understanding of age-associated autonomic imbalance, inflammation and endothelial dysfunction in HFrEF and how its inhibition can be used to provide therapeutic effects.