Targeting breathing limitations to improve functional outcomes in HFpEF

针对呼吸限制以改善 HFpEF 的功能结果

• 批准号: 10663768
• 负责人: Bryce Balmain
• 金额: $ 13.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663768
• 关键词: Adult; Affect; Air; American; Breathing; Cardiovascular system; Chest; Dyspnea; EFRAC; Epidemic; Exercise; Exercise Test; Exertion; Frequencies; Functional Residual Capacity; Gases; Goals; Heart failure; Helium; Human; Hyperpnea; Investigation; Measures; Mechanics; National Heart, Lung, and Blood Institute; Non obese; Obesity; Oxygen; Patients; Pattern; Phase; Physiology; Population; Prevalence; Recommendation; Respiratory Mechanics; Rest; Risk; Role; Symptoms; Testing; Therapeutic; Thinking; Tidal Volume; Vital capacity; Work of Breathing; common symptom; comorbidity; cost; density; disabling symptom; exercise capacity; exercise intolerance; functional improvement; lung volume; mechanical load; neglect; novel therapeutic intervention; novel therapeutics; personalized medicine; preservation; pulmonary function; ventilation; working group

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.

项目摘要/摘要 劳动呼吸困难（DOE）和锻炼肠道是心力衰竭的标志性症状 射血分数（HFPEF）。这些符号的机制未知，没有治疗策略 对于这些使人衰弱的症状。因此，NHLBI工作组建议优先考虑进步的研究 了解与HFPEF相关（PATHO）生理学和这些患者症状的主要原因，以便 可以开发新的疗法。母鹿和运动肠道也是肥胖的非常常见的症​​状。 肥胖已经达到流行水平，影响了四分之二的美国成年人。肥胖症的流行率上升到 HFPEF人口中的八分之十成年人，肥胖在引发母鹿症状和运动中的作用 迄今为止，HFPEF患者的肠胃ance被忽略了。人类研究表明肥胖会影响 呼吸力学，从而减少肺部体积细分和最大呼气流量，这 增加了到期流动限制，动态过度通货膨胀以及呼吸模式的风险 锻炼。所有这些与肥胖相关的机械通气约束最终1）增加氧气（O2）成本 呼吸和2）在运动过程中强加机械天花板（V e），这可能会激发母鹿和 降低运动能力。这，我们假设肥胖可能是母鹿和运动的重要贡献 HFPEF患者的肠道。迄今为止，O2呼吸成本和与肥胖相关机械的影响 HFPEF患者对DOE和运动摄入术的通气限制仍未受到测试。因此， 该K99/R00建议的总体目的是1）研究呼吸的O2成本并检查这如何影响 HFPEF患者的DOE和峰值运动能力，以及2）减少与肥胖相关的机械通气 限制有可能减少HFPEF患者的DOE并增加运动能力的限制。完成这些 目标，我们将1）研究HFPEF（肺功能的基本变化）和肥胖的相互作用 （肥胖相关的肺功能变化）在欧洲自愿性肿瘤期间的O2呼吸成本上， 及其在持续的负载运动和高峰锻炼能力中与DOE的关联，以及2）研究效果 呼吸低密度氦氧气混合物（HEO2：21％O2和79％HE），可降低与肥胖有关的 机械通气约束（HEO2增加了最大到期流，减少了呼吸的工作， 减少呼气流量限制和动态过度充电，并增加VT的扩张） 持续的载荷运动和高峰锻炼能力。我们预计这些投资将1）进一步理解 肥胖在HFPEF患者中的挑衅症状和运动摄取症状中的作用，2）确定新的 母鹿和运动症状的基础机制，可能会极大地改变常规 考虑HFPEF患者这些症状的主要原因，3）为 独立调查，以便可以制定新的治疗策略，并为新的范式提供新的范式 HFPEF的个性化疗法。