PRIME HRrEF: Novel Exercise for Older Patients with Heart Failure with Reduced Ejection Fraction

抽象的。 心力衰竭（HF）是≥65岁美国人住院的主要原因， 患者和每年约392亿美元。HF患者呼吸急促、疲劳和运动 不容忍改善VO 2峰值是HF的一个重要临床目标，因为它与降低死亡率相关 提高生活质量。运动康复被认为是对HF患者的IA级建议， 指南建议中等强度的有氧运动，通常与阻力相结合， 训练（AT+RT）。这些指南的一个关键限制是，它们主要来自涉及患者的数据 队列有时比HF诊断的中位年龄（77岁）年轻20岁（范围51-81岁）。 考虑到老年HF患者的合并症患病率较高， 能力，肌肉质量和力量减少，5年生存率为25%，目前还不清楚目前是否 运动指南可以被大多数真实世界的HF患者耐受并产生功能益处。 众所周知，外周组织的损伤包括：肌肉血流量减少， 肌肉质量和异常的肌肉代谢对运动能力的降低有重要作用 在HF患者中。事实上，许多患有HF的老年患者表现出肌肉减少症的后遗症，其独立地 预示着不祥的预兆因此，我们已经开发并试点测试了“外围重塑 间歇性肌肉锻炼（PRIME）。PRIME提供低质量、高重复性、局部化 刺激外周肌肉和组织，而不施加中枢心肺紧张。以探索性 在一项告知当前建议的研究中，19名HFrEF受试者（> 65岁，VO 2峰值=13.5ml/kg/min）增加 VO 2峰值、无氧阈值和最大力量，PRIME 4周，AT+ RT 4周。 “对照”组进行AT+RT，持续8周，仅增加最大力量。 我们建议扩大这一有希望的数据，以明确确定在意向治疗试验招募92 HFrEF患者随机分配至：（A）4周PRIME，随后8周AT+RT，或（B）12 AT+ RT周。基线和12周干预后的数据将用于确定;（目标1） 最大周期运动期间VO 2峰值的组变化（肌肉力量和 （Aim 2）组中枢和外周血流动力学和组织灌注的变化。 探索性目的将检查CHF严重程度的血液标志物、生活质量和骨骼健康的问卷调查。 VO 2峰值的肌肉介质（选择性活检）。我们将进行为期6个月的耐久性培训后评估 健康和功能的任何变化 这项研究是关闭临床运动研究中出现的年龄偏见的重要一步。如果PRIME 显示对HFrEF老年患者有益，它可以更好地为这些患者提供运动康复指南。 个体

Abstract. Heart failure (HF) is the leading cause of hospitalization among Americans ≥65 years old with 5.7 million sufferers and an annual of ~$39.2 billion. Patients with HF suffer from shortness of breath, fatigue and exercise intolerance. Improving VO2peak is an important clinical goal in HF as it is correlated with reduced mortality rate and increased quality of life. Exercise rehabilitation is considered class IA recommendation for people with HF, with guidelines recommending moderate-intensity aerobic modalities, often in conjunction with resistance training (AT+RT). A key limitation of these guidelines is that they arise largely from data involving a patient cohort sometimes two decades younger (range 51-81 yrs) than the median age of diagnosis for HF (77 yrs). Considering that older adults with HF experience a high prevalence of co-morbidities, impaired functional capacity, reduced muscle mass and strength, and a 5-year survival of 25%, it is unclear whether the current exercise guidelines can be tolerated by and generate functional benefits by a majority real-world HF patients. It is well accepted that impairments in peripheral tissues including; decreased muscle blood flow, decreased muscle mass, and abnormal muscle metabolism have a significant contribution to the reduced exercise capacity in patients with HF. In fact, many older patients with HF exhibit the sequelae of sarcopenia, which independently carries an ominous prognosis. Accordingly, we have developed and pilot tested the “Peripheral Remodelling via Intermitted Muscular Exercise” (PRIME) approach. PRIME offers a low mass, high repetition, localised stimulus to peripheral muscles and tissues, without imposing central cardiorespiratory strain. In an exploratory study which informed the current proposal, 19 subjects with HFrEF (>65yr, VO2peak=13.5ml/kg/min) increased VO2peak, anaerobic threshold and maximal strength with 4 weeks of PRIME followed by 4 weeks of AT+RT. The “control” group performed AT+RT for the whole 8 weeks and only increased maximal strength. We propose to expand on this promising data to definitively determine in an intent-to-treat trial enrolling 92 patients with HFrEF randomized to either: (A) 4 weeks of PRIME followed by 8 weeks of AT+RT, or: (B) 12 weeks of AT+RT. Data at baseline and following the 12-week interventions will be used to determine; (Aim1) group changes in VO2peak during maximal cycle exercise (secondary clinical outcomes of muscle strength and activities of daily living); (Aim2) group changes in central and peripheral hemodynamics and tissue perfusion. Exploratory aims will examine blood markers of CHF severity, questionnaires for quality of life and skeletal muscle mediators of VO2peak (opt-in biopsy). We will perform a 6-month post training assessment for durability of any changes in fitness and function. This study represents an important step in closing the age-bias seen in clinical exercise studies. If PRIME is shown to benefit elderly patients with HFrEF it may better inform exercise rehabilitation guidelines for these individuals.