Multidrug Metabolic Approach to Improve Exercise and Skeletal Muscle Oxidative Capacity in HFpEF

改善 HFpEF 运动和骨骼肌氧化能力的多药物代谢方法

• 批准号: 10182472
• 负责人: Payman Zamani
• 金额: $ 70.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10182472
• 关键词: Acetyl Coenzyme A; Activities of Daily Living; Adipose tissue; Animal Model; Attention; Basal metabolic rate; Bioenergetics; Biogenesis; Biological Availability; Biopsy; Blood; Blood Vessels; Blood flow; Carbohydrates; Carbon Dioxide; Cardiac Output; Cardiovascular Diseases; Cell Respiration; Clinical Trials; Consumption; Cross-Over Trials; Data; Disease; Double-Blind Method; EFRAC; Epidemic; Ergometry; Essential Fatty Acids; Exercise; Exercise Test; Exercise Tolerance; Exertion; Failure; Fatty Acids; Glucose; Goals; Gold; Heart failure; Hemoglobin; Imaging Techniques; Impairment; In Vitro; Individual; Intervention; Intramuscular; Ketone Bodies; Ketones; Kinetics; Lead; Life; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Mitochondria; Muscle; Muscle Fibers; Muscle Mitochondria; Myocardium; Nitric Oxide; Nitric Oxide Donors; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Palmitates; Participant; Pathway interactions; Patients; Perfusion; Pharmacology; Pharmacotherapy; Phenotype; Plasma; Play; Population; Potassium Chloride; Production; Proteome; Quality of life; Randomized; Respiration; Signal Transduction; Site; Skeletal Muscle; Sodium; Source; Syndrome; Techniques; Testing; Time; Triglycerides; Venous; Walking; Work; active control; acylcarnitine; base; electric impedance; endurance exercise; exercise capacity; exhaustion; fatty acid oxidation; functional disability; improved; in vivo; in vivo imaging; inhibitor/antagonist; insight; metabolome; novel; oxidation; potassium nitrate; preservation; prevent; primary endpoint; protein expression; respiratory; restoration; skeletal muscle metabolism; targeted treatment; therapeutic target; uptake

SUMMARY: Heart Failure with Preserved Ejection Fraction (HFpEF) is on pace to become the dominant form of heart failure, yet we have no treatments to offer patients, leaving them limited in terms of exercise tolerance and quality of life. While much attention has been paid to the myocardium, data suggest that abnormalities in skeletal muscle (SkM) oxygen utilization also contribute to exertional intolerance in this condition. Moreover, decreased nitric oxide (NO) bioavailability has been demonstrated in HFpEF patients. NO augments SkM oxygen delivery and plays a key role in enhancing fatty acid oxidation (FAO), both of which are important for submaximal exercise endurance. Recently, sodium-glucose cotransporter-2 inhibitors such as empagliflozin (EMPA) have demonstrated remarkable benefits in other cardiovascular disease patients, though their use in HFpEF remains unclear. EMPA could be beneficial in HFpEF patients via multiple mechanisms, many of which target abnormalities identified specifically in HFpEF, including: (a) increasing mitochondrial biogenesis, (b) increasing FAO, (c) increasing plasma ketone bodies, providing an additional source of acetyl-CoA for energy production, and (d) increasing blood hemoglobin, augmenting oxygen delivery for any given blood flow. Moreover, because NO is essential for FAO and a key mediator of exercise SkM blood flow, we propose that combining EMPA with a NO-donor such as potassium nitrate (KNO3) will lead to improvements in exercise capacity in HFpEF patients, as compared to EMPA alone or active control. Our overarching hypothesis is that impaired SkM oxidative phosphorylation capacity (OxPhos) limits exercise tolerance in HFpEF. We focus on submaximal exercise endurance in this proposal as submaximal exercise better reflects the level of exertion reached by HFpEF patients during daily activities, is more dependent on FAO than maximal effort exercise, and is less likely to constrained by cardiac output limitations. We will test the impact of three interventions in 53 HFpEF participants in a randomized double-blind cross-over trial: (1) EMPA; (2) EMPA + KNO3; and (3) Potassium chloride (active control). In Aim 1: participants will undergo cycle ergometry exercise tests. The primary endpoint will be the change in submaximal exercise endurance. In Aim 2: We will test the impact of our 3 interventions on SkM OxPhos using MRI following plantar flexion exercise. Novel MRI sequences will also be employed that quantify intramuscular perfusion. In Aim 3: We will conduct SkM tissue biopsies to assess mitochondrial respiration, the SkM metabolome, and quantify the SkM proteome, providing in vitro assessments to support our exercise measurements. Our proposal will target SkM metabolism in HFpEF and comprehensively assess the relationship between SkM OxPhos and submaximal exercise endurance using complementary techniques. This proposal has the potential to identify SkM metabolism as an important therapeutic target in this disease for which we currently have no approved pharmacologic therapies.

摘要：保留的射血分数（HFPEF）的心力衰竭正在成为主导形式 心力衰竭，但我们没有提供治疗的治疗方法，使他们在运动耐受方面有限 和生活质量。虽然对心肌有很多关注，但数据表明异常 在这种情况下，骨骼肌（SKM）氧气的利用率也有助于劳累不耐症。而且， HFPEF患者已经证明了一氧化氮（NO）生物利用度的降低。没有增强SKM 氧气递送并在增强脂肪酸氧化（FAO）中起关键作用，这两者对于 次最大运动耐力。最近，钠 - 葡萄糖共转运蛋白-2抑制剂，例如empagliflozin （EMPA）在其他心血管疾病患者中表现出了显着的好处 HFPEF仍然不清楚。 EMPA可能通过多种机制对HFPEF患者有益，其中许多机制 在HFPEF中特别鉴定出的靶标异常，包括：（a）增加线粒体生物发生，（b） 增加粮农 产生和（d）增加血液氯蛋白，增加任何给定的血液流量的氧气递送。 此外，由于NO对于FAO和运动SKM血流的关键调解人至关重要，因此我们建议 将EMPA与硝酸钾（KNO3）等无含量结合起来会改善运动 与仅EMPA或主动对照相比，HFPEF患者的容量。 我们的总体假设是SKM氧化磷酸化能力（OXPHOS）限制受损 HFPEF的运动耐受性。我们专注于本提案中的次最大运动耐力 锻炼更好地反映了HFPEF患者在日常活动中达到的努力水平，更多 取决于粮农组织而不是最大努力练习，并且不太可能受到心输出限制的限制。 我们将测试53位HFPEF参与者的三种干预措施的影响 试验：（1）EMPA； （2）EMPA + KNO3; （3）氯化钾（主动对照）。在AIM 1：参与者将 经过循环测试运动测试。主要终点将是次最大练习的变化 耐力。在AIM 2中：我们将使用MRI的3个干预措施对SKM OXPHOS的影响进行测试 足底屈曲运动。还将采用新的MRI序列来量化肌肉内灌注。在 目标3：我们将进行SKM组织活检以评估线粒体呼吸，SKM代谢组和 量化SKM蛋白质组，提供体外评估以支持我们的运动测量。 我们的建议将针对HFPEF中的SKM代谢，并全面评估关系 在SKM OXPHOS和使用互补技术的次最大运动耐力之间。这个建议 有可能将SKM代谢鉴定为该疾病的重要治疗靶点 目前尚无批准的药理学疗法。