Exercise Pressor Reflex Dysfunction in Heart Failure: Mechanisms and Treatment

项目摘要 目前，美国约有650万男性和女性患有心力衰竭。到2030年， 预计这一数字将攀升至850万以上，与心力衰竭相关的直接医疗保健费用预计将 531亿美元。心力衰竭患者通常表现出交感神经水平过高， 与健康受试者相比，休息时和运动时的系统活动。过度增长， 运动期间的交感神经系统活动（即，交感神经兴奋）是运动的直接贡献者 不耐受和缺乏功能独立性，这是心力衰竭患者就医的主要原因 在乎一种神经反射，由收缩的骨骼肌内的机械和代谢信号激活 在运动过程中，对交感神经系统活动的增加有重要贡献。在 在心力衰竭患者中，这种被称为运动加压反射的反射的激活被夸大， 是运动引起的交感神经兴奋的机制基础。目前，没有治疗方法， 专门设计用于减少心力衰竭患者运动加压反射的激活， 我们目前对导致其夸大的机制的有限理解。我们将使用男性和 雌性大鼠的心脏衰竭（心肌梗死后模型），以研究其机制 夸大运动升压反射的基础和可能的治疗靶点。在目标1中，我们将研究 内过氧化物（EP）4受体所起的作用，其由内产生的野牡丹素刺激。 骨骼肌，在心力衰竭中唤起运动升压反射。在目标2中，我们将研究 机械激活的piezo 2通道在心力衰竭时引起运动升压反射。在Aim中 3、研究外周δ-阿片受体激动是否能降低心脏运动升压反射 失败我们将使用整个动物和分子水平的互补混合来研究这些目标 方法，使我们的研究结果是综合和翻译。总的来说，我们的实验可能会发现三个 治疗的可能靶点（EP 4受体、压电2通道和δ-阿片受体），旨在：1）减轻 运动中发生的交感神经兴奋和2）增加运动耐力，功能性 心力衰竭患者的独立性和整体生活质量。

PROJECT SUMMARY There are currently ~6.5 million men and women in the United States with heart failure. By 2030, that number is predicted to climb to over 8.5 million and direct heart failure-related health care costs are predicted to command $53.1 billion. Heart failure patients commonly exhibit exaggerated levels of sympathetic nervous system activity at rest and during exercise compared to healthy subjects. An exaggerated increase in sympathetic nervous system activity during exercise (i.e., sympatho-excitation) is a direct contributor to exercise intolerance and lack of functional independence which is the main reason that heart failure patients seek medical care. A neural reflex that is activated by mechanical and metabolic signals within contracting skeletal muscles contributes importantly to the increase in sympathetic nervous system activity that occurs during exercise. In heart failure patients, the activation of this reflex, termed the exercise pressor reflex, is exaggerated which underlies mechanistically the exercise-induced sympatho-excitation. Currently, there are no therapies that are designed specifically to reduce the activation of the exercise pressor reflex in heart failure patients which reflects our current limited understanding of the mechanisms that contribute to its exaggeration. We will use male and female rats with surgically-induced heart failure (post-myocardial infarction model) to study the mechanistic bases and possible therapeutic targets of the exaggerated exercise pressor reflex. In Aim 1, we will investigate the role played by endoperoxide (EP) 4 receptors, which are stimulated by prostaglandins produced within skeletal muscles, in evoking the exercise pressor reflex in heart failure. In Aim 2, we will investigate the role played by mechanically activated piezo2 channels in evoking the exercise pressor reflex in heart failure. In Aim 3, we will investigate whether peripheral δ-opioid receptor stimulation reduces the exercise pressor reflex in heart failure. We will investigate these aims using a complementary blend of whole animal and molecular level approaches so that our findings are integrative and translational. Collectively, our experiments may identity three possible targets (EP4 receptors, piezo2 channels, and δ-opioid receptors) for therapies aimed at 1) mitigating the sympatho-excitation that occurs during exercise and 2) increasing exercise tolerance, functional independence, and overall quality of life in heart failure patients.