Muscle Afferent Feedback Effects In Patients With Heart Failure

心力衰竭患者的肌肉传入反馈效应

• 批准号: 9039133
• 负责人: MARKUS AMANN
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039133
• 关键词: Accounting; Acute; Address; Affect; Age; Animals; Attenuated; Bicycling; Blood Circulation; Blood Pressure; Blood flow; Blood specimen; Characteristics; Complex; Congestive Heart Failure; Development; Devices; Dyspnea; Environmental air flow; Exercise; Exercise Tolerance; Fatigue; Feedback; Fentanyl; Fiber; Figs - dietary; Gene Expression; Goals; Health; Heart Rate; Heart failure; Human; Infusion procedures; Intramuscular; Knee; Leg; Leukocytes; Limb structure; Link; Magnetism; Molecular; Morbidity - disease rate; Muscle; Nerve; Neuraxis; P2X-receptor; Patients; Peripheral; Pharmacologic Substance; Physical activity; Play; Population; Publishing; Quality of life; Reflex action; Regulation; Research; Rest; Role; Skeletal Muscle; Source; Specificity; Symptoms; TRPV1 gene; Techniques; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; United States; Vascular resistance; Work; base; design; disability; endurance exercise; excessive exercise; exercise intolerance; exhaustion; femoral nerve; improved; insight; mRNA Expression; molecular targeted therapies; mortality; muscle form; premature; quadriceps muscle; receptor; reduce symptoms; relating to nervous system; research study; response; targeted treatment; treatment strategy; vasoconstriction; willingness

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.

描述（由申请人提供）：患有慢性心力衰竭（HF）的患者的特征是残疾和运动不耐受，损害其生活质量，并描述了该人群中发病率的主要来源。这些特征的主要决定因素包括过度的运动式压力反射，过早疲劳和劳累呼吸困难。机械和/或代谢性III和IV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。但是，即使在健康的人类中，我们对运动过程中III/IV组传入的确切作用/相对贡献的理解也不完整，并且疲劳的发展和疲劳的发展是不完整的。通过研究HF患者以及年龄和活动匹配的健康对照（CTRL），我们将评估HF对这些肌肉传入对a）循环/通风控制的相对贡献的影响，b）运动过程中中央和周围疲劳的发展。此外，拟议的研究将检查HF是否会影响与肌肉传入的代谢敏感受体相关的基因的表达，以及这些变化在中心疲劳方面的功能影响。具体而言，我们将使用腰椎鞘内芬太尼 阻止运动过程中III/IV肌传入的中心投影（对前驱动驱动没有影响）。这种独特的，以前证明的方法将使我们能够评估III/IV肌肉传入对腿部血流，心率，血压，血压和通风期间的影响（自行车和单腿膝盖伸展），以及中央和外围疲劳的发展（使用磁性雌性型型型型肌肉刺激技术）。此外，我们将从HF患者和CTRL中采取基线和运动后的血液样本，以确定每个人群中白细胞上ASIC3，P2X和TRPV1元受体受体的表达（mRNA）。最后，为了确定这些代谢敏感的分子受体对HF患者和CTRL中心疲劳发展的特定贡献，我们将对未吸收的四头肌肌肉进行肌肉内输注。我们已经设计了“汤”来专门激活ASIC3，P2X和TRPV1替伯感受器，并以前验证了其在已出版的动物和人类研究中的特殊性。根据最近的发现，表明HF患者与CTRL的钝器受体敏感性钝化，我们希望，由于肌内汤输注引起的分泌物受体的特定刺激，CTRLS与HF患者的中枢疲劳更大。该分析的结果将有助于更好地理解分泌感受器作为中心疲劳和反射异常的潜在机制的作用，以表征锻炼HF患者。合并后，这项研究将为HF对神经反馈的影响提供新的见解，及其在控制循环和通气以及体育锻炼期间疲劳的作用中的作用。此外，我们的实验将确定用于治疗干预措施的潜在分子靶标，其总体目的是改善HF患者的生活质量。