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。来自机械和/或代谢敏感的 III 组和 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，即使在健康人类中，我们对 III/IV 组传入神经在运动和疲劳发展过程中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。通过研究心力衰竭患者以及年龄和活动匹配的健康对照 (CTRL)，我们将评估心力衰竭对这些肌肉传入对 a) 循环/通气控制和 b) 运动过程中中枢和外周疲劳发展的相对贡献的影响。此外，拟议的研究将检查心力衰竭是否影响与肌肉传入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注射芬太尼 在运动过程中阻断 III/IV 组肌肉传入的中央投射（对前馈驱动没有伴随影响）。这种独特的、先前经过验证的方法将使我们能够评估大肌肉量和小肌肉量节律运动（自行车和单腿膝关节伸展）期间 III/IV 组肌肉传入对腿部血流、心率、血压和通气的影响，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 CTRL 中采集基线和运动后血液样本，以确定每个群体白细胞上 ASIC3、P2X 和 TRPV1 代谢受体的表达 (mRNA)。最后，为了确定这些代谢敏感分子受体对心力衰竭患者和 CTRL 患者中枢性疲劳发展的具体贡献，我们将向未疲劳的股四头肌肌肉注射“代谢物汤”。我们设计了专门激活 ASIC3、P2X 和 TRPV1 代谢受体的“汤”，并且之前已在已发表的动物和人类研究中验证了其特异性。根据最近的研究结果表明，与 CTRL 患者相比，心力衰竭患者的代谢感受器敏感性减弱，我们预计，在由于肌内汤输注而对代谢感受器进行特异性刺激后，与心力衰竭患者相比，CTRL 患者的中枢疲劳程度更高。该分析的结果将有助于更好地理解代谢感受器作为运动心力衰竭患者中枢疲劳和反射异常的潜在机制的作用。总而言之，这项研究将为心力衰竭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提供新的见解。此外，我们的实验将确定治疗干预的潜在分子靶点，总体目的是改善心力衰竭患者的生活质量。

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.