Peripheral Mechanisms of Cardiopulmonary Control during Exercise

 描述（由申请人提供）：慢性心力衰竭（HF）已发展成为一个主要的公共卫生问题。最近的数据表明，目前约有600万美国人患有HF。每年约有700，000例新的HF诊断，占每年心脏病住院的30%以上。重要的是，大约一半的HF诊断是在射血分数正常（保留）的患者中。随着新诊断技术的出现、心肌梗死后存活率的提高以及人口年龄的增加，预计这一上升趋势将继续下去。总体而言，HF患者的日常生活活动受限，因此运动不耐受是HF的标志，与生活质量降低、发病率增加和预后不良密切相关。有趣的是，最初的研究未能将中枢血流动力学或心室功能与运动能力联系起来。无论病因如何，HF很快成为涉及多个生理系统的全身性疾病。在所涉及的生理系统中，肺和肌肉骨骼因其在症状发展中的作用而受到相当大的关注。事实上，限制HF患者的两个最普遍的症状是呼吸困难和疲劳。潜在的介质连接功能限制和多系统参与HF包括骨骼肌中的神经受体。这种联系催生了“肌肉假说”，将运动肌肉的传入神经交通与运动的兴奋性和血液动力学反应联系起来。恰当地，“肌肉假说”已经确定了一个领域，这是知之甚少，但有可能解决一个主要的临床问题。本申请的目的是使用新的方法来量化运动肌传入反馈对HF患者运动期间通气和心血管血流动力学变化的贡献。我们的中心假设是，运动肌肉的传入反馈增强导致运动期间交感神经流出增加，导致过度通气和全身血管阻力增加，从而促进运动不耐受。该建议的基本原理是，对HF中运动不耐受和症状发展的机制知之甚少，但已知与发病率和死亡率相关。因此，确定导致排尿和心血管控制变化的具体机制可能为患者治疗、康复和疾病管理提供新的途径。

 DESCRIPTION (provided by applicant): Chronic heart failure (HF) has developed into a major public health concern. Recent data suggests ~6 million Americans currently live with HF. Approximately 700,000 new diagnoses of HF are made each year which accounts for over 30% of cardiac admissions per year. Importantly, approximately half of all HF diagnoses are in patients with normal (preserved) ejection fraction. Through the emergence of new diagnostic technologies, improved survival after myocardial infarction, and the increasing age of the population, an upward trend is expected to continue. As a whole, patients with HF are limited in their activities of daily living and as such exercise intolerance is hallmark of HF and closely linked to reduced quality of life, increased morbidity and worse prognosis. Interestingly, initial studies failed to link measures of central hemodynamics or ventricular function to exercise capacity. Regardless of the etiology, HF quickly becomes a systemic disease involving multiple physiologic systems. Of the physiologic systems involved, the pulmonary and musculoskeletal have gained considerable attention for their role in symptom development. In fact, the two most pervasive symptoms limiting HF patients are dyspnea and fatigue. Potential mediators linking functional limitation and multisystem involvement in HF include neurologic receptors in skeletal muscle. This link has spawned the 'muscle hypothesis', relating afferent neural traffic from locomotor muscles to ventilatory and hemodynamic responses to exercise. Appropriately, the 'muscle hypothesis' has identified an area that is poorly understood but has the potential to address a major clinical problem. The objective of this application is to use novel methodologies to quantify the contribution of locomotor muscle afferent feedback on changes in ventilation and cardiovascular hemodynamics during exercise in HF patients. Our central hypothesis is that enhanced afferent feedback from locomotor muscles leads to increased sympathetic outflow during exercise, resulting in excessive ventilation and increased systemic vascular resistance which promotes exercise intolerance. The rationale for this proposal is that mechanisms of exercise intolerance and symptom development in HF are poorly understood but known to be related to morbidity and mortality. As such, identifying the specific mechanisms leading to changes in ventilatory and cardiovascular control may provide new avenues for patient treatment, rehabilitation, and disease management.