Muscle Afferent Feedback Effects in Patients with Heart Failure

描述（由申请人提供）：慢性心力衰竭（HF）患者的特点是残疾和运动不耐受，这损害了他们的生活质量，是该人群发病率的主要来源。这些特征的主要决定因素包括过度的运动压力反射、过早疲劳和运动性呼吸困难。来自机械和/或代谢敏感的III组和IV组肌肉传入事件的异常升高的神经反馈可能在这些异常中起关键作用。然而，即使在健康人群中，我们对III/IV组传入神经在运动和疲劳发展过程中对循环和通气控制的确切作用/相对贡献的理解也是不完整的。通过研究HF患者和年龄和活动匹配的健康对照（ctrl），我们将评估HF对这些肌肉传入神经的相对贡献的影响：a)循环/通气控制，b)运动期间中枢和外周疲劳的发展。此外，拟议的研究将检查HF是否影响肌肉传入神经中代谢敏感受体相关基因的表达，以及这些变化对中枢性疲劳的功能影响。具体来说，我们将使用腰椎鞘内芬太尼来

DESCRIPTION (provided by applicant): Patients with chronic heart failure (HF) are characterized by disability and exercise intolerance which impair their quality of life and depict major source of morbidity in this population. Cardinal determinants of these characteristics include excessive exercise pressor reflex, premature fatigue, and exertional dyspnea. Abnormally elevated neural feedback from mechano- and/or metabosensitive group III and IV muscle afferents might play a key role in these abnormalities. However, even in healthy humans, our understanding of the exact role/relative contribution of group III/IV afferents to the circulatory and ventilatory control during exercise and the development of fatigue is incomplete. By studying both HF patients and age- and activity-matched healthy controls (CTRLs), we will evaluate the impact of HF on the relative contribution of these muscle afferents to a) the circulatory/ventilatory control, and b) the development of central and peripheral fatigue during exercise. Additionally, the proposed research will examine whether HF affects the expression of genes linked to metabosensitive receptors on muscle afferents and the functional impact of these changes in terms of central fatigue. Specifically, we will use lumbar intrathecal fentanyl to block the central projection of group III/IV muscle afferents during exercise (no concomitant effect on feedforward drive). This unique, previously proven approach will enable us to evaluate the effects of group III/IV muscle afferents on leg blood flow, heart rate, blood pressure and ventilation during large and small muscle mass rhythmic exercise (bicycle and single leg knee-extension), and the development of central and peripheral fatigue (using magnetic femoral nerve stimulation techniques). Furthermore, we will take baseline and post-exercise blood samples from HF patients and CTRLs to determine the expression (mRNA) of ASIC3, P2X, and TRPV1 metaboreceptors on leukocytes in each population. Finally, to determine the specific contribution of these metabosensitive molecular receptors to the development of central fatigue in HF patients and CTRLs, we will perform an intramuscular infusion of a "metabolite soup" into the unfatigued quadriceps muscle. We have designed the "soup" to exclusively activate ASIC3, P2X, and TRPV1 metaboreceptors and have previously verified its specificity in published animal and human studies. Based on recent findings suggesting blunted metaboreceptor sensitivity in HF patients vs. CTRLs, we expect, following the specific stimulation of metaboreceptors due to the intramuscular soup infusion, greater central fatigue in CTRLs vs HF patients. The results from this analysis will contribute to a better understanding of the role of metaboreceptors as a potential mechanism underlying central fatigue and reflex abnormalities characterizing exercising HF patients. Combined, this research will provide new insight into the impact of HF on neural feedback and its role in the control of circulation and ventilation and the development of fatigue during physical activity. Furthermore, our experiments will identify potential molecular targets for therapeutic interventions with the overall purpose to improve the quality of life in patients with HF.