Targeting breathing limitations to improve functional outcomes in HFpEF

项目总结/摘要 运动时呼吸困难（DOE）和运动不耐受是心力衰竭的标志性症状， 射血分数（HFpEF）。这些症状的机制是未知的，没有治疗策略存在 来治疗这些虚弱的症状因此，NHLBI工作组建议优先考虑能够促进 了解HFpEF相关（病理）生理学和这些患者症状的主要原因， 可以开发新的治疗剂。DOE和运动不耐症也是肥胖症的常见症状。 肥胖已经达到流行病的水平，影响着十分之四的美国成年人。肥胖症的患病率上升到 在HFpEF人群中，十分之八的成年人肥胖在引发DOE症状和运动中的作用 迄今为止，HFpEF患者的不耐受性一直被忽视。人类研究表明，肥胖会影响 呼吸力学，由此肺容量细分和最大呼气流量减少， 增加了呼气流量限制、动态过度充气和呼吸模式改变的风险， 锻炼的所有这些与肥胖相关的机械限制最终1）增加了氧气（O2）的消耗， 2）在运动过程中对通气（V ~ E）施加机械上限，这可能引起DOE， 降低运动能力。因此，我们假设肥胖可能是DOE和运动的重要贡献者 HFpEF患者的不耐受。到目前为止，呼吸的O2成本和肥胖相关机械的影响， 在HFpEF患者中，DOE和运动不耐受的解释性限制仍未得到验证。因此 本K99/R 00提案的总体目标是：1）调查呼吸的O2成本，并研究其如何影响 HFpEF患者的DOE和峰值运动能力，以及2）减少肥胖相关的机械消耗 限制可能减少DOE并增加HFpEF患者的运动能力。完成这些 目的：1）研究HFpEF（肺功能的潜在变化）和肥胖的相互作用 （肥胖相关的肺功能变化）对正常二氧化碳自主呼吸过度期间呼吸O2消耗的影响， 及其与恒定负荷运动中DOE和峰值运动能力的关系，2）研究 呼吸低密度氦氧混合气体（HeO 2：21% O2和79% He），这可以减少肥胖相关的 机械限制（HeO 2增加最大呼气流量，减少呼吸功， 减少呼气流量限制和动态过度充气，并增加VT扩张），在DOE期间 恒定负荷运动和峰值运动能力。我们预计这些调查将1）进一步了解 肥胖在HFpEF患者中引起DOE和运动不耐受症状的作用，2）确定新的 DOE和运动不耐症的潜在症状机制，这可能会大大改变传统的 思考HFpEF患者这些症状的主要原因，以及3）提供新的靶点， 独立的研究，以便开发新的治疗策略，并使新的范例， HFpEF的个性化治疗。

PROJECT SUMMARY/ABSTRACT Dyspnea on exertion (DOE) and exercise intolerance are hallmark symptoms of heart failure with preserved ejection fraction (HFpEF). The mechanisms of these symptoms are unknown, and no therapeutic strategy exists for these debilitating symptoms. As such, NHLBI working groups recommend prioritizing studies that advance understanding of HFpEF-related (patho)physiology and the primary causes of symptoms in these patients so that novel therapeutics can be developed. DOE and exercise intolerance are also very common symptoms of obesity. Obesity has reached epidemic levels and affects four-in-ten American adults. The prevalence of obesity rises to eight-in-ten adults in the HFpEF population yet, the role of obesity in provoking symptoms of DOE and exercise intolerance in HFpEF patients has, thus far, been neglected. Human studies demonstrate that obesity affects breathing mechanics, whereby lung volume subdivisions and maximal expiratory flow are decreased, which increases the risk of expiratory flow limitation, dynamic hyperinflation, and an altered breathing pattern during exercise. All these obesity-related mechanical ventilatory constraints ultimately 1) increase the oxygen (O2) cost of breathing and 2) impose a mechanical ceiling on ventilation (V̇E) during exercise, which could provoke DOE and reduce exercise capacity. Thus, we hypothesize that obesity is likely a significant contributor to DOE and exercise intolerance in patients with HFpEF. To date, the O2 cost of breathing and the effect of obesity-related mechanical ventilatory constraints on DOE and exercise intolerance remains untested in patients with HFpEF. Therefore, the overall aim of this K99/R00 proposal is to 1) investigate the O2 cost of breathing and examine how this impacts DOE and peak exercise capacity in patients with HFpEF, and 2) reduce obesity-related mechanical ventilatory constraints to potentially reduce DOE and increase exercise capacity in patients with HFpEF. To accomplish these goals, we will 1) investigate the interaction of HFpEF (underlying changes in pulmonary function) and obesity (obesity-related changes in pulmonary function) on the O2 cost of breathing during eucapnic voluntary hyperpnea, and its association with DOE during constant load exercise and peak exercise capacity, and 2) investigate the effects of breathing a low density helium-oxygen gas mixture (HeO2: 21% O2 and 79% He), which reduces obesity-related mechanical ventilatory constraints (HeO2 increases maximal expiratory flow, reduces the work of breathing, decreases expiratory flow limitation & dynamic hyperinflation, and increases VT expansion), on DOE during constant load exercise and peak exercise capacity. We anticipate these investigations will 1) further understanding of the role of obesity in provoking symptoms of DOE and exercise intolerance in HFpEF patients, 2) identify new mechanisms underlying symptoms of DOE and exercise intolerance, which could dramatically alter conventional thinking about the primary causes of these symptoms in patients with HFpEF, and 3) provide new targets for independent investigation so that novel therapeutic strategies can be developed and enable new paradigms for personalized therapy in HFpEF.