Muscle Afferent Feedback Effects In Patients With Heart Failure

描述（由申请人提供）：慢性心力衰竭（HF）患者的特征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运动加压反射、过早疲劳和劳力性呼吸困难。机械和/或代谢敏感的第III和IV组肌肉传入神经反馈异常升高可能在这些异常中发挥关键作用。然而，即使在健康的人，我们的确切作用/相对贡献的第III/IV组传入运动和疲劳的发展过程中的循环和排泄控制的理解是不完整的。通过研究HF患者和年龄和活动匹配的健康对照（CTR），我们将评估HF对这些肌肉传入对a）循环/排泄控制和B）运动期间中枢和外周疲劳发展的相对贡献的影响。此外，拟议的研究将检查HF是否影响与肌肉传入神经上的代谢敏感受体相关的基因表达，以及这些变化对中枢疲劳的功能影响。具体来说，我们将使用腰椎鞘内芬太尼， 在运动过程中阻断III/IV组肌肉传入神经的中枢投射（对前馈驱动无伴随作用）。这种独特的，以前证明的方法将使我们能够评估第III/IV组肌肉传入对腿部血流量，心率，血压和通气的影响，在大肌肉和小肌肉质量的节奏运动（自行车和单腿膝盖伸展），以及中枢和外周疲劳的发展（使用磁股神经刺激技术）。此外，我们将从HF患者和CTR中采集基线和运动后血液样本，以确定每个群体中白细胞上ASIC 3、P2 X和TRPV 1代谢受体的表达（mRNA）。最后，为了确定这些代谢敏感性分子受体对HF患者和CTRL中枢疲劳发展的具体贡献，我们将向未疲劳的四头肌肌肉内输注“代谢物汤”。我们已经设计了专门激活ASIC 3，P2 X和TRPV 1代谢受体的“汤”，并且之前已经在已发表的动物和人类研究中验证了其特异性。基于最近的研究结果表明HF患者与CTRL相比代谢受体敏感性减弱，我们预计，在由于肌内汤输注引起的代谢受体的特异性刺激后，CTRL与HF患者相比中枢疲劳更大。这项分析的结果将有助于更好地理解代谢受体作为运动HF患者特征性中枢疲劳和反射异常的潜在机制的作用。结合起来，这项研究将提供新的见解，HF对神经反馈的影响及其在控制循环和通气以及体力活动期间疲劳的发展中的作用。此外，我们的实验将确定治疗干预的潜在分子靶点，其总体目的是改善HF患者的生活质量。

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.