Muscle Afferent Feedback Effects In Patients With Heart Failure

描述(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，并描述了这一人群的主要发病率来源。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III和IV类肌肉传入的神经反馈异常升高可能在这些异常中起关键作用。然而，即使在健康人中，我们对III/IV类传入神经在运动和疲劳发生过程中对循环和通风控制的确切作用/相对贡献的了解也是不完整的。通过对心力衰竭患者和年龄与活动相匹配的健康对照组(CtrlS)的研究，我们将评估心力衰竭对这些肌肉传入在a)循环/呼吸控制以及b)运动中中枢和外周疲劳的发展的相对贡献的影响。此外，这项拟议的研究将检查HF是否影响肌肉传入上与代谢敏感受体相关的基因的表达，以及这些变化在中枢疲劳方面的功能影响。具体地说，我们将使用腰鞘内芬太尼来 运动时阻断III/IV组肌肉传入的中枢投射(对前馈驱动无伴随效应)。这一独特的、先前已证实的方法将使我们能够评估III/IV类肌肉传入在大小肌肉群节奏性运动(自行车和单腿伸膝)中对腿部血流量、心率、血压和通气量的影响，以及中枢性和外周疲劳的发展(使用股神经磁性刺激技术)。此外，我们将采集心力衰竭患者和CtrlS患者的基线和运动后血液样本，以确定每个人群中白细胞上ASIC3、P2X和TRPV1代谢物受体的表达(MRNA)。最后，为了确定这些代谢物敏感分子受体在心力衰竭患者和Ctrls中枢性疲劳的发生中的具体作用，我们将进行肌肉内注入未疲劳的股四头肌的“代谢物汤”。我们已经设计了这种“汤”来专门激活ASIC3、P2X和TRPV1代谢物受体，并在先前发表的动物和人类研究中验证了它的特异性。根据最近的研究结果表明，与CtrlS相比，心力衰竭患者的代谢物受体敏感性减弱，我们预计，在肌肉内灌流对代谢物受体的特异性刺激之后，CtrlS患者的中枢性疲劳比心力衰竭患者更严重。这一分析的结果将有助于更好地理解代谢物受体作为运动性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HF对神经反馈的影响以及它在控制循环和通风以及体力活动中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.